Patent Application
20230255946
Pirfenidone (Deskar®), CAS# 53179-13-8, Pirespa, AMR-69, Pirfenidona, Pirfenidonum, Esbriet, Pirfenex, 5-methyl-1-phenyl-1H-pyridin-2-one, 5-Methyl-1-phenyl-2-(1H)-pyridone, 5-methyl-1-phenylpyridin-2(1H)-one, is an orally administered antifibrotic agent. Pirfenidone is currently approved in the United States and elsewhere for idiopathic pulmonary fibrosis (IPF).
Pirfenidone is a small molecule that has anti-fibrotic and anti-inflammatory effects. And it is one of two approved therapies for the treatment of idiopathic pulmonary fibrosis (IPF). However, pirfenidone has a very short half-life in humans and consequently relatively frequent dosing is required. The recommended daily maintenance dose of pirfenidone is 801 mg three times per day (2403 mg·day-1) (a total of nine (9) pills per day at full dose) with a 14-day titration period upon treatment initiation.
In order for patients with IPF to obtain the maximum benefits of pirfenidone treatment, however, the adverse events (AEs) associated with pirfenidone need to be managed. The most common AEs are gastrointestinal (GI) and skin-related adverse events, for example, nausea, rash, diarrhea, fatigue, dyspepsia, anorexia, dizziness, gastroesophegeal reflux disease, decreased appetite, decreased weight, photosensitivity, and cough. In addition, several treatment-emergent adverse events have been reported, including upper respiratory infection and bronchitis. A recent study in patients treated with pirfenidone under a compassionate use program demonstrated that 44% of the patients had an adverse event with pirfenidone, with only half of them continuing on pirfenidone after a dose-reduction. Raghu & Thickett. Thorax; 68: 605-608 (2013). Adverse events common with pirfenidone at 2403 mg/day include nausea, rash, fatigue, diarrhea, vomiting, dyspepsia, photosensitivity, and anorexia. Noble et al. Lancet; 377: 1760-69 (2011).
The results of several expanded clinical trials are summarized in Lancaster et al., Eur Resp Rev 2017:26:170057 which reports treatment-emergent adverse events (TEAEs) as rates per 100 PEY (equivalent to the frequency at which a physician might expect these TEAEs to occur if 100 patients with IPF were followed for 1 year). Herein, it is noted that the most common reported AEs leading to discontinuation are nausea, fatigue, diarrhea, and/or rash with frequencies as high as 62.1 per 100 PEY (nausea), 27.6 per 100PEY (diarrhea), 52.4 per 100PEY (fatigue). In a single-center, retrospective, observational study of 351 patients who were receiving pirfenidone, 75% of reported AEs were GI-related, with loss of appetite (17%) and nausea/vomiting (15%) being most frequent, similar to what was observed in the phase III trials. The highest number of treatment discontinuations occurred with appetite loss and nausea/vomiting. The incidence of AEs and discontinuation increases with age. The proportion of patients with ADRs leading to dose modification/interruption or discontinuation increased with increasing age: an ADR leading to dose modification/interruption occurred in 32.7% of patients aged at least 80 years and in 18.0% of patients aged less than 65 years, while an ADR leading to discontinuation occurred in 20.9% of patients aged at least 80 years and in 7.5% of patients aged <65 years. In addition, modification of eating habits of the patient is required when adjusting the pirfenidone dose. Taking pirfenidone with a substantial amount of food, specifically the full dose at the end of a substantial meal or spreading out the three capsules during the meal, may reduce the rate of pirfenidone absorption and mitigate the onset of GI-related AEs.
Although slower titration and dose modification may assist in addressing patient AEs, employing such measures has significant therapeutic impact, notably patients who received pirfenidone 1197 mg/day were reported to experience greater lung function decline than patients who were receiving the full dose of 2403 mg/day.
Pirfenidone treatment also has potential adverse effects on liver function, as may be indicated by elevated aminotransferase levels. Therefore, monitoring liver function is also important during pirfenidone treatment. Elevations of aspartate transaminase (AST) and alanine transaminase (ALT) levels to >3× the upper limit of normal (ULN) occurred in the phase III trials (3.2%), which were managed by dose modifications or discontinuation. If AST and ALT elevations (>3× to ≤5× ULN) occur without symptoms or hyperbilirubinaemia, the dose may be reduced or interrupted until values return to normal. However, in cases in which the AST and ALT elevations (>3× to ≤5× ULN) are accompanied by hyperbilirubinaemia or if patients exhibit >5× ULN, pirfenidone must be permanently discontinued.
Therefore, pirfenidone treatment requires various AE management strategies, including a slower dose titration for initiating treatment, taking pirfenidone with substantial meals, spacing capsules throughout the meal, diet modification, weight-based dosing regimens and dose reductions and interruptions, as well as continual liver function monitoring.
There exists a need for a therapy that can slow the progression and preserve lung function in patients with interstitial lung diseases (ILDs), while having a superior tolerability profile compared to current antifibrotics
There further exists a need to address the limitations of pirfenidone that include: a short half-life of only about 2.5 hours; a high pill burden (of 9 capsules per day (TID dosing); poor tolerability including nausea, diarrhea and photosensitivity; a high dose required for efficacy that induces side effects; and significant interpatient variability.
It has been discovered that the deuterium-enriched pirfenidone LYT-100 has an unexpectedly high tolerability, allowing for higher dosing for greater effectiveness without the adverse effects seen at equivalent doses for pirfenidone. It also allows for dosing without titration to immediately and more effectively treat patients. It also allows for a lower pill burden, less often, e.g., two pills twice a day, with equivalent or significantly enhanced efficacy. LYT-100 has the following structure:
In one aspect the invention provides a method of treating a life-threatening fibrotic disorder, comprising administering to a subject in need thereof a total daily dose of up to 2500 mg, of deuterium-enriched pirfenidone having the structure:
wherein the life-threatening fibrotic disorder is treated in the subject.
In some embodiments, the total daily dose is 2000 mg.
In some embodiments, administering comprises titrating up to the total daily dose from an initial total daily dose which is below the total daily dose.
In some embodiments, the deuterium-enriched pirfenidone is administered without dose escalation.
In some embodiments, the deuterium-enriched pirfenidone is administered in two daily doses of 1000 mg each without dose escalation
In some embodiments, the deuterium-enriched pirfenidone is administered without regard to food. In some embodiments, the LYT-100 is administered without food.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 100 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in three daily doses of 100 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 200 mg each. In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in three daily doses of 200 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 500 mg each. In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in three daily doses of 500 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 750 mg each. In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in three daily doses of 750 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 1000 mg each. In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 1000 mg each without dose escalation.
In some embodiments, the life-threatening fibrotic disorder is selected from the group consisting of Idiopathic Pulmonary Fibrosis (IPF), silicosis, systemic sclerosis, pneumoconiosis, chalicosis, asbestosis, anthracosis, diffuse parenchymal lung disease, fibrotic sarcoidosis, and Hermansky-Pudlak syndrome.
In some embodiments, the life-threatening fibrotic disorder is Idiopathic Pulmonary Fibrosis (IPF).
In some embodiments, the deuterium-enriched pirfenidone is administered with food. In some embodiments, the deuterium-enriched pirfenidone is administered without food. In some embodiments, the deuterium-enriched pirfenidone is administered without regard to food.
In another aspect is provided a method of treating a functionally impairing fibrotic-mediated disorder or a collagen-mediated disorder, comprising administering to a subject in need thereof an interventional total daily dose of up to 2500 mg of deuterium-enriched pirfenidone having the structure:
In some embodiments, the method further comprises administering a maintenance dose for a maintenance period after the interventional dose is administered for an intervention period.
In some embodiments, the deuterium-enriched pirfenidone is administered without regard to food. In some embodiments, the deuterium-enriched pirfenidone is administered without food.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 100 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in three daily doses of 100 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 200 mg each. In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in three daily doses of 200 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 500 mg each. In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in three daily doses of 500 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 750 mg each. In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in three daily doses of 750 mg each.
In some embodiments, the deuterium-enriched pirfenidone is administered orally without food in two daily doses of 1000 mg each.
In some embodiments, the functional impairment is arrested.
In some embodiments, the functionally impairing fibrotic-mediated disorder or a collagen-mediated disorder is a respiratory disease stemming from a viral respiratory infection.
In some embodiments, the functionally impairing fibrotic-mediated disorder or a collagen-mediated disorder is pulmonary fibrosis caused by a COVID-19 infection.
In some embodiments, the functionally impairing fibrotic-mediated disorder or a collagen-mediated disorder is a hepatitis C virus (HCV) infection, diabetic nephropathy, diabetic kidney disease (including Kimmelstiel-Wilson disease), diabetic nephritis, ANCA vasculitis, myocardial fibrosis, neurofibromatosis, renal fibrosis, spleen fibrosis caused by sickle-cell anemia, secondary fibrosis caused by cancer (including glioma, glioblastoma, breast cancer, colon cancer, melanoma and pancreatic cancer), and endotoxin-induced fibrosis after partial hepatectomy or hepatic ischemia.
In some embodiments, the deuterium-enriched pirfenidone is administered with food. In some embodiments, the deuterium-enriched pirfenidone is administered without food. In some embodiments, the deuterium-enriched pirfenidone is administered without regard to food.
In a further aspect is provided a method of treating a chronic fibrotic-mediated disorder or a collagen-mediated disorder, the method comprising administering to a subject in need thereof a 1000 mg or 1500 mg total daily dose of deuterium-enriched pirfenidone from induction.
In some embodiments, the chronic disease is edema. In some embodiments, the edema is secondary lymphedema.
In some embodiments, the chronic disease or disorder is primary lymphedema, rheumatoid arthritis, tuberculosis, multiple sclerosis, uterine fibroids, juvenile systemic sclerosis (J-SSC), keloid scarring, lupus nephritis, chronic kidney disease, polycystic kidney disease, membranous nephropathy, minimal change disease, dermatopolymyositis, medical device or implant rejection (such as breast capsular contracture), a fatty liver disease such as non-alcoholic steatohepatitis (NASH), alcoholic liver disease (including hepatic steatosis, hepatic fibrosis and hepatic cirrhosis), hepatitis-C fibrosis, a dermatopolymyositis (PM/DM) (including polymyositis and dermatomyositis, juvenile dermatomyositis polymyositis, and inclusion body myositis), systemic sclerosis, CREST syndrome, mixed connective tissue disease, intercapillary or intracapillary glomerulosclerosis, neurofibromatosis, hypertrophic cardiomyopathy (HCM), scleroderma, mediastinal fibrosis, and neutropenia-associated fibrosis.
In a still further aspect is provided a method of treating a fibrotic-or collagen-mediated disorder, comprising administering to a subject in need thereof a total daily dose of up to 2500 mg of deuterium-enriched pirfenidone having the structure:
wherein the fibrotic-or collagen-mediated disorder is treated in the subject.
In some embodiments, the total daily dose is from about 250 to about 2000 mg. In some embodiments, the total daily dose is about 500, about 750, about 1000, about 1500, or about 2000 mg. In some embodiments, the total daily dose is 2000 mg.
In some embodiments, the total daily dose is administered in two equal administrations. In some embodiments, the LYT-100 is administered in two equal doses of 1000 mg.
In some embodiments, the LYT-100 is administered without regard to food. In some embodiments, the LYT-100 is administered without food.
In some embodiments, the LYT-100 is administered orally without food in two daily doses of 100 mg each.
In some embodiments, the LYT-100 is administered orally without food in three daily doses of 100 mg each.
In some embodiments, the LYT-100 is administered orally without food in two daily doses of 200 mg each. In some embodiments, the LYT-100 is administered orally without food in three daily doses of 200 mg each.
In some embodiments, the LYT-100 is administered orally without food in two daily doses of 500 mg each. In some embodiments, the LYT-100 is administered orally without food in three daily doses of 500 mg each.
In some embodiments, the LYT-100 is administered orally without food in two daily doses of 750 mg each. In some embodiments, the LYT-100 is administered orally without food in three daily doses of 750 mg each.
In some embodiments, the LYT-100 is administered orally without food in two daily doses of 1000 mg each.
In some embodiments, administering comprises titrating up to the total daily dose from an initial total daily dose which is below the total daily dose. In some embodiments, the LYT-100 is administered without dose escalation.
In some embodiments, a ratio of an average concentration of a 5-carboxy-1-phenylpyridin-2(1H)-one metabolite to an average concentration of the LYT-100, as determined by AUC, of about 0.45 or less is achieved
In some embodiments, a difference in one or more of a Cmax, an AUC, and a Tmax of the LYT-100 in the treated subject, when administered to the subject in a fed and a fasted state, is less than about 25%.
In some embodiments, a Cmax, an AUC, or both, of a 5-carboxy-1-phenylpyridin-2(1H)-one metabolite in the treated subject is reduced relative to a Cmax, an AUC, or both, corresponding to administration of the same dose of non-deuterium enriched pirfenidone (5-methyl-1-phenyl-1H-pyridin-2-one) in the treated subject.
In some embodiments, a difference in one or more of a Cmax, an AUC, and a Tmax of the LYT-100 in the treated subject is less than about 25% when the administration of the LYT-100 is performed in the subject in a fed state and in a fasted state.
In some embodiments, a difference in a Cmax, a difference in an AUC, or both of a 5-carboxy-1-phenylpyridin-2(1H)-one metabolite in the treated subject is about 5% or less when the administration of the LYT-100 is performed in the subject in a fed state and in a fasted state
In some embodiments, the fibrotic- or collagen-mediated disorder is a life-threatening disorder. In some embodiments, the life-threatening disorder is selected from the group consisting of Idiopathic Pulmonary Fibrosis (IPF), silicosis, systemic sclerosis, pneumoconiosis, chalicosis, asbestosis, anthracosis, diffuse parenchymal lung disease, fibrotic sarcoidosis, and Hermansky-Pudlak syndrome. In some embodiments, the life-threatening disorder is Idiopathic Pulmonary Fibrosis (IPF).
In some embodiments, the LYT-100 is administered in two daily doses of 1000 mg each (1000 mg BID) for an interventional period, followed by a maintenance period, wherein the LYT-100 is administered in two daily doses of 250 mg, 500 mg, or 750 mg each
In some embodiments, the fibrotic- or collagen-mediated disorder is a functionally impairing disorder.
In some embodiments, the LYT-100 is administered in two daily doses of 1000 mg each (1000 mg BID) for an interventional period. In some embodiments, the method further comprises administering a maintenance dose for a maintenance period after the interventional dose is administered for the interventional period. In some embodiments, the maintenance dose is 250 mg, 500 mg, or 750 mg BID.
In some embodiments, the functional impairing disorder is alleviated, progression of the functionally impairing disorder is arrested, or both.
In some embodiments, the functionally impairing disorder is a respiratory disease stemming from a viral respiratory infection. In some embodiments, the functionally impairing disorder is pulmonary fibrosis resulting from the corona virus disease COVID-19.
In some embodiments, the functionally impairing disorder is a hepatitis C virus (HCV) infection, diabetic nephropathy, diabetic kidney disease (including Kimmelstiel-Wilson disease), diabetic nephritis, ANCA vasculitis, myocardial fibrosis, neurofibromatosis, renal fibrosis, spleen fibrosis caused by sickle-cell anemia, secondary fibrosis caused by cancer (including glioma, glioblastoma, breast cancer, colon cancer, melanoma and pancreatic cancer), or endotoxin-induced fibrosis after partial hepatectomy or hepatic ischemia.
In some embodiments, the fibrotic- or collagen-mediated disorder is a chronic disease or disorder.
In some embodiments, the method comprises administering to the subject in need thereof a total daily dose of 1000 mg or 1500 mg of the LYT-100, administered in two equal daily doses.
In some embodiments, the chronic disorder is edema. In some embodiments, the edema is secondary lymphedema.
In some embodiments, the chronic disease or disorder is primary lymphedema, rheumatoid arthritis, tuberculosis, multiple sclerosis, uterine fibroids, juvenile systemic sclerosis (J-SSC), keloid scarring, lupus nephritis, chronic kidney disease, polycystic kidney disease, membranous nephropathy, minimal change disease, dermatopolymyositis, medical device or implant rejection (such as breast capsular contracture), a fatty liver disease such as non-alcoholic steatohepatitis (NASH), alcoholic liver disease (including hepatic steatosis, hepatic fibrosis and hepatic cirrhosis), hepatitis-C fibrosis, a dermatopolymyositis (PM/DM) (including polymyositis and dermatomyositis, juvenile dermatomyositis polymyositis, and inclusion body myositis), systemic sclerosis, CREST syndrome, mixed connective tissue disease, intercapillary or intracapillary glomerulosclerosis, neurofibromatosis, hypertrophic cardiomyopathy (HCM), scleroderma, mediastinal fibrosis, or neutropenia-associated fibrosis.
LYT-100, a new chemical entity, is a deuterated, oral small molecule designed to overcome the challenges associated with pirfenidone, an approved and marketed anti-inflammatory and anti-fibrotic drug. Pirfenidone is currently approved for the treatment of idiopathic pulmonary fibrosis (IPF), but it is associated with significant tolerability issues and dose-limiting toxicities. A long-term observational safety study found that adverse drug reactions led to permanent treatment discontinuation in 28.7% of patients taking pirfenidone. Cottin, V., Koschel, D., Günther, et al. (2018). Long-term safety of pirfenidone: Results of the prospective, observational PASSPORT study. ERJ Open Research, 4(4), 00084-2018. doi: 10.1183/23120541.00084-2018.
LYT-100 retains the pharmacology of pirfenidone but has a differentiated PK profile, which is designed to enable improved tolerability, less frequent dosing and potentially increased efficacy. The results of a multiple ascending dose and food effect study for LYT-100 (deupirfenidone) demonstrated favourable proof-of-concept for LYT-100′s tolerability, including at high doses, and pharmacokinetic (PK) profile and which enables twice-a-day (BID) dosing of LYT-100 for the treatment of conditions involving inflammation and fibrosis, disorders of lymphatic flow, as well as serious respiratory complications that persist following the resolution of COVID-19 infection. The results of this study showed that LYT-100 was well-tolerated at all doses tested, including a cohort of 1000 mg twice-a-day. Surprisingly, tolerability was achieved throughout the multiple ascending dose study, even at the highest (1000 mg) single dose—and this was achieved in the absence of any dose escalation. In contrast, pirfenidone is required to be titrated (i.e., escalated) over two weeks up to the recommended 801 mg daily maintenance dose due to a lack of tolerability. Temporary dosage reductions, interruptions, and even discontinuations may also be required due to adverse reactions with pirfenidone. In short, the demonstrated tolerability of LYT-100 at all doses suggests that LYT-100 may be further differentiated from pirfenidone with respect to the potential to avoid dose titration, or at least reduce the duration of any dose titration.
Previous studies have shown that a single dose of 801 mg of LYT-100 yielded greater exposure than a single dose of 801 mg (FDA-approved dose) of pirfenidone. The results from this study show that LYT-100 has the potential to offer a tolerability and bioavailability profile that could be highly differentiated at the same exposure levels of pirfenidone, which indicates suitability for use in treating indications where pirfenidone is shown to have benefit but where tolerability concerns limit its use.
The study showed that all adverse events (AEs) at all doses were mild and transient and there were no discontinuations. The most common AEs across all cohorts were headache (23.3% with LYT-100 vs. 20% with placebo), abdominal distension (10% with LYT-100 vs. 0% with placebo), nausea (10% with LYT-100 vs. 0% with placebo) and abdominal discomfort (6.7% with LYT-100 vs. 10% with placebo). No dose-limiting toxicities were observed in the study, and there was no dose response in AEs. No maximum tolerated dose was reached, and the only AEs observed in the highest dose cohort (1000 mg BID) were two headaches.
The food effect portion of the study evaluated two common PK measures that are used to determine the dose of a product candidate - area under the curve (AUC), which represents exposure, and Cmax, which reflects the maximum concentration following drug administration. The LYT-100 AUC and Cmax were both observed to decrease with food as compared to fasting conditions. Under fed conditions, the AUC reduction observed with LYT-100 (19%) was comparable to the AUC reduction stated in the ESBRIET® (pirfenidone) US Prescribing Information (16%). The Cmax reduction observed with LYT-100 was 23%, while the Cmax reduction stated in the ESBRIET® (pirfenidone) US Prescribing Information is 49%. Based on the food effect findings, PureTech intends to explore the use of LYT-100 in future studies without regard to when food is consumed.
The therapeutic dose of pirfenidone approved by the US Food and Drug Administration (FDA) for the treatment of IPF is 801 mg three times a day, and LYT-100 is designed to potentially improve upon this dosing. In a previously conducted, single-dose crossover study, an 801 mg dose of LYT-100 resulted in greater drug exposure than an 801 mg of pirfenidone. In the recently completed Phase 1 study, LYT-100 was well-tolerated at a dose above 801 mg. These data, together with PureTech’s PK modelling of LYT-100 and pirfenidone exposures, indicate the potential for twice-a-day dosing with LYT-100.
Fibrosis and inflammation are a common mechanism across several lung diseases, and there is increasing data that respiratory complications of COVID-19, including shortness of breath, begin during the acute phase of illness and may persist as lung fibrosis. According to a research letter published in the Journal of the American Medical Association (JAMA), more than 40% of COVID-19 survivors assessed in an Italian study still reported shortness of breath an average of 60 days following symptom onset. Carlì, A., Bernabei, R., & Landi, F. (2020). Persistent Symptoms in Patients After Acute COVID-19. Jama, 324(6), 603. doi:10.1001/jama.2020.12603. These data suggest that a significant percentage of COVID-19 survivors may be at risk for long-term sequelae, a condition that is now referred to as “Long COVID.” Similar complications caused by the Severe Acute Respiratory Syndrome (SARS) epidemic lasted for years, leading to impaired lung function in many survivors. The anti-fibrotic and anti-inflammatory properties of LYT-100 may be beneficial in treating a range of respiratory conditions, including those associated with COVID-19 - both in the early phases of the disease and as part of the often-long recovery.
During the multiple ascending dose study in healthy subjects preceding a lymphedema efficacy study, a discovery was made that not only provides dosing for increased efficacy and safety in treating chronic indications, such as lymphedema, but provides dosing with far greater efficacy for the treatment of life-threatening diseases than previously considered practicable due to surprising tolerability for LYT-100. Furthermore, this discovery provides dosing for greater efficacy in interventional dosing to arrest and prevent functional impairment. Finally, the surprising tolerability of LYT-100 can provide dosing that does not require titration for life-threatening diseases, interventional therapy, as well as chronic dosing.
Based on the results of comparison with pirfenidone in Example 1, for example, it was believed that the 750 mg dosing of LYT-100 would be the maximum tolerated dosing (750 mg BID; 1500 mg total daily dose) for LYT-100. Specifically, since the Cmax of a 750 mg dose of LYT-100 was expected to be at or to exceed that of the Cmax of an 801 mg dose of pirfenidone (see e.g.,
An advantage of deuterated pirfenidone is that it can be administered on a twice-a-day dosing schedule, in contrast to pirfenidone, which requires a three-times-a-day dosing schedule. Thus, at least because of a simplified dosing schedule, LYT-100 can engender increased patient compliance and reduced pill burden relative to pirfenidone and can ultimately be a more effective therapeutic agent. Accordingly, disclosed herein is a method of treating a fibrotic-mediated or collagen-mediated disorder, comprising administering to a subject in need thereof deuterated pirfenidone, e.g., LYT-100, twice a day.
Accordingly, in one aspect, a method of treating subjects with a life-threatening disease, e.g., Idiopathic Pulmonary Fibrosis (IPF), is provided. The method includes administering 1000 mg BID (2000 mg total daily dose) of LYT-100 daily. This new method will provide significantly increased efficacy in these subjects, as compared to pirfenidone, since a 750 mg LYT-100 dose is expected to be as efficacious as a 1250 mg dose of pirfenidone would be- if pirfenidone was as well tolerated as LYT-100.
In another aspect, a method of providing interventional treatment for functional impairment in a subject in need thereof, e.g. arresting and treating functional lung impairment in the aftermath of a COVID-19 or other respiratory infection, is provided. The method includes administering up to 1000 mg BID (2000 mg total daily dose) of LYT-100 for an interventional period, followed by a maintenance dose, e.g., 750 mg BID, 500 mg BID or 250 mg BID, for a maintenance period.
While the terms used herein are believed to be well understood by one of ordinary skill in the art, definitions are set forth herein to facilitate explanation of the presently-disclosed subject matter.
The term “Adverse Event” refers to any event, side-effect, or other untoward medical occurrence that occurs in conjunction with the use of a medicinal product in humans, whether or not considered to have a causal relationship to this treatment. An AE can, therefore, be any unfavourable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Events meeting the definition of an AE include: Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition; New conditions detected or diagnosed after study drug administration that occur during the reporting periods, even though it may have been present prior to the start of the study; Signs, symptoms, or the clinical sequelae of a suspected interaction; Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or concomitant medications (overdose per se will not be reported as an AE/SAE). AE’s may have a causal relationship with the treatment, may be possibly related, or may be unrelated. Severity of AEs may be graded as one of:
The term “life-threatening” refers to a critical impairment of a vital life function such that the risk of mortality is high or mortality is assured. IPF is an example of a life-threatening disease.
The terms “functional impairment” or “functionally impairing” refer to compromise or impairment of vital organs, such as the lungs, which while not life-threatening, impairs the function of a vital organ. For example, impairment of lung function may include a diminished capacity for oxygen exchange, a decline in tolerability in the multiple ascending dose capacity (FVC), or both, which may affect quality of life in a patient. By “forced vital capacity (FVC)” is meant the total amount of air exhaled during the forced expiratory volume (FEV) test, which measures how much air a person can exhale during a forced breath. The amount of air exhaled may be measured during the first (FEV1), second (FEV2), and/or third seconds (FEV3) of the forced breath.
The term “chronic” refers to a persisting or recurring disease or disorder. Often it is long-lasting and difficult to eradicate.
As used herein, the term “clinically effective amount,” “clinically proven effective amount,” and the like, refer to an effective amount of an API as shown through a clinical trial, e.g., a U.S. Food and Drug Administration (FDA) clinical trial.
The term “pharmaceutical composition” refers to a preparation that is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components that are unacceptably toxic to a subject to which the composition would be administered. Pharmaceutical compositions can be in numerous dosage forms, for example, tablet, capsule, liquid, solution, soft gel, suspension, emulsion, syrup, elixir, tincture, film, powder, hydrogel, ointment, paste, cream, lotion, gel, mousse, foam, lacquer, spray, aerosol, inhaler, nebulizer, ophthalmic drops, patch, suppository, and/or enema. Pharmaceutical compositions typically comprise a pharmaceutically acceptable carrier, and can comprise one or more of a buffer (e.g. acetate, phosphate or citrate buffer), a surfactant (e.g. polysorbate), a stabilizing agent (e.g. human albumin), a preservative (e.g. benzyl alcohol), a penetration enhancer, an absorption promoter to enhance bioavailability and/or other conventional solubilizing or dispersing agents. Choice of dosage form and excipients depends upon the active agent to be delivered and the disease or disorder to be treated or prevented, and is routine to one of ordinary skill in the art.
The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The deuterium enrichment can be determined using conventional analytical methods, such as mass spectrometry and nuclear magnetic resonance spectroscopy.
The term “is/are deuterium,” when used to describe a given variable position in a molecule or formula, or the symbol “D,” when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium. In some embodiments, deuterium enrichment is of no less than about 1%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 98%, or in some embodiments no less than about 99% of deuterium at the specified position. In some embodiments, the deuterium enrichment is above 90% at each specified position. In some embodiments, the deuterium enrichment is above 95% at each specified position. In some embodiments, the deuterium enrichment is about 99% at each specified position.
The term “isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope of an element at a given position in a molecule in the place of the more prevalent isotope of the element.
The term “non-isotopically enriched” refers to a molecule in which the percentages of the various isotopes are substantially the same as the naturally occurring percentages.
The term “fibrosis” refers to the development of excessive fibrous connective tissue within an organ or tissue.
The term “collagen-mediated disorder” refers to a disorder that is characterized by abnormal or undesired collagenic infiltration, that when collagen infiltration activity is modified, leads to the desired responses depending on the route of administration and desired end result. A collagen-mediated disorder may be completely or partially mediated through the modulation of collagen infiltration. In particular, a collagen-mediated disorder is one in which modulation of collagen infiltration activity results in some effect on the underlying disorder, e.g., administering a collagen-infiltration modulator results in some improvement in at least some of the patients being treated.
The term “fibrotic-mediated disorder” refers to a disorder that is characterized by abnormal or undesired fibrotic activity, that when fibrosis activity is modified, leads to the desired responses depending on the route of administration and desired end result. A fibrosis-mediated disorder may be completely or partially mediated through the modulation of fibrosis. In particular, a fibrosis-mediated disorder is one in which modulation of fibrosis activity results in some effect on the underlying disorder, e.g., administering a fibrosis modulator results in some improvement in at least some of the patients being treated.
The terms “fibrosis modulator” or “modulating fibrosis” are meant to be interchangeable and refer to the ability of a compound disclosed herein to alter the occurrence and/or amount of fibrosis. A fibrosis modulator may increase the occurrence or level of fibrosis, may increase or decrease the occurrence and/or amount of fibrosis depending on the concentration of the compound exposed to the adrenergic receptor, or may decrease the occurrence and/or amount of fibrosis. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and/or may be manifest only in particular cell types.
The term “collagen infiltration” refers to the entry of the connective tissue collagen into cells or into the extracellular matrix around cells. This occurs in organs and tissues naturally and under normal circumstances but can occur excessively and accompany or cause disease.
The terms “collagen-infiltration modulator” or “modulating collagen infiltration” are meant to be interchangeable and refer to the ability of a compound disclosed herein to alter the occurrence and/or amount of collagen infiltration. A collagen infiltration modulator may increase the occurrence or level of collagen infiltration, may increase or decrease the occurrence and/or amount of collagen infiltration depending on the concentration of the compound exposed to the adrenergic receptor, or may decrease the occurrence and/or amount of collagen infiltration. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and/or may be manifest only in particular cell types.
Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to therapeutic measures that cure, slow down, ameliorate or lessen one or more symptoms of, halt progression of, and/or ameliorate or lessen a diagnosed pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. In some embodiments, a subject is successfully “treated” for a disease or disorder according to the methods provided herein if the patient shows, e.g., total, partial, or transient alleviation or elimination of symptoms associated with the disease or disorder. For example, “treating edema” can include, but is not limited to, decreasing swelling, decreasing inflammation, decreasing fibrosis, decreasing pain, increasing range of motion, decreasing heaviness, decreasing tightness, decreasing skin thickening, and/or improving lymphatic function.
“Prevent” or “prevention” refers to prophylactic or preventative measures that obstruct, delay and/or slow the development of a targeted pathologic condition or disorder or one or more symptoms of a targeted pathologic condition or disorder. Thus, those in need of prevention include those at risk of or susceptible to developing the disorder. Subjects that are at risk of or susceptible to developing lymphedema include, but are not limited to, cancer patients undergoing radiation therapy, chemotherapy, and/or surgical lymph node dissection. In some embodiments, a disease or disorder is successfully prevented according to the methods provided herein if the patient develops, transiently or permanently, e.g., fewer or less severe symptoms associated with the disease or disorder, or a later onset of symptoms associated with the disease or disorder, than a patient who has not been subject to the methods of the invention.
The terms “subject” and “patient” refers to a mammalian subject, including a human subject. In some embodiments, the patient is human subject.
In some embodiments, the deuterium-enriched pirfenidone administered is a compound, including LYT-100, or a metabolite thereof, described in WO 2008/157786, WO 2009/035598, WO 2012/122165, or WO 2015/112701, the entireties of which are hereby incorporated by reference.
The compounds may be prepared or isolated in general by synthetic and/or semisynthetic methods known to those skilled in the art for analogous compounds and by methods described in detail herein. Synthesis of the N-aryl pyridinones of the present invention, including pirfenidone and deuterium-enriched pirfenidone compounds, are described in WO 2008/157786, WO 2009/035598, WO 2012/122165, and WO 2015/112701, the entireties of which are hereby incorporated by reference.
In some embodiments, the present invention includes administering a deuterium-enriched compound shown in Table 1.
The compounds as disclosed herein can be prepared by methods known to one of skill in the art and routine modifications thereof, and/or procedures found in Esaki et al., Tetrahedron 2006, 62, 10954-10961, Smith et al., Organic Syntheses 2002, 78, 51-56, U.S. Pat. No. 3,974,281, U.S. Pat. No. 8,680,123, WO2003/014087, WO 2008/157786, WO 2009/035598, WO 2012/122165, or WO 2015/112701; the entirety of each of which is hereby incorporated by reference; and references cited therein and routine modifications thereof.
Both LYT and pirfenidone share a common major metabolite. As demonstrated in the examples below, following administration of LYT-100 and pirfenidone, the most abundant measured circulating metabolite was 5-carboxy-pirfenidone (LYT-105; SD-789).
Referring to Example 1, the pharmacokinetics of the active LYT-100 (deupirfenidone) and metabolite nondeuterated 5-carboxy-pirfenidone (LYT-105) were evaluated. Administration in the fed state of a single 801 mg dose of LYT-100 resulted in overall greater exposure (AUC, Cmax) than observed with administration of an 801 mg dose of pirfenidone. No appreciable difference in the apparent elimination t½ or time to Cmax was observed for the 2 compounds. Administration of the 801 mg dose of LYT-100 resulted in greater drug exposure than with the same pirfenidone dose, but surprisingly, the incidence of gastrointestinal and nervous system adverse events was not increased with LYT-100 administration as compared to pirfenidone.
Disclosed herein are methods of reducing the level of 5-carboxypirfenidone in a subject, comprising administering a pirfenidone derivative, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the level of 5-carboxypirfenidone is relative to that in a subject treated with pirfenidone. A pirfenidone “derivative” as used herein generally refers to a pirfenidone molecule that has been functionalized or chemically altered. In some embodiments, the functionalization or chemical alteration includes deuteration, fluorination, or bioisosteric replacement of one or more functional groups. In some embodiments, the functionalization or chemical alteration can include replacement of one or more hydrogen atoms of the 5-methyl group of pirfenidone with deuterium. In some embodiments, the functionalization or chemical alteration can include replacement of one or more hydrogen atoms of the 5-methyl group of pirfenidone with an alkyl group. In some embodiments, the functionalization or chemical alteration can include replacement of one or more hydrogen atoms of the 5-methyl group of pirfenidone with an electron-withdrawing functional group. Electron-withdrawing groups include, but are not limited to, halogen (e.g., fluorine, chlorine, bromine), haloalkyl (e.g., —CF3, —CF2H), and —C(O)OR, wherein R is an alkyl or aryl group. Exemplary pirfenidone derivatives include, without limitation, a halogenated derivative of pirfenidone, a deuterium-enriched derivative of pirfenidone, a pirfenidone further substituted on one or more rings, and the like.
Further disclosed herein is a method of reducing adverse events arising from pirfenidone treatment, comprising administering a pirfenidone derivative, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the adverse events are reduced by reducing the level of 5-carboxypirfenidone in a subject. In some embodiments, the functionalization or chemical alteration includes deuteration, fluorination, or bioisosteric replacement of one or more functional groups. In some embodiments, the functionalization or chemical alteration can include replacement of one or more hydrogen atoms of the 5-methyl group of pirfenidone with deuterium. In some embodiments, the functionalization or chemical alteration can include replacement of one or more hydrogen atoms of the 5-methyl group of pirfenidone with an alkyl group. In some embodiments, the functionalization or chemical alteration can include replacement of one or more hydrogen atoms of the 5-methyl group of pirfenidone with an electron-withdrawing functional group.
Disclosed herein is a pharmaceutical composition comprising a (a) means for reducing the levels of 5-carboxyperfenidone in a subject relative to those found in a subject treated with pirfenidone, and (b) a pharmaceutically acceptable carrier.
Also disclosed herein is a pharmaceutical composition comprising a (a) means for reducing the adverse effects associated with pirfenidone treatment, and (b) a pharmaceutically acceptable carrier.
The higher peak and overall exposure of LYT-100 was associated with a lower systemic exposure of the 5-carboxy-pirfenidone (25% Cmax reduction; 15% AUC reduction), suggesting the kinetic isotope effect at least partially protects against pre-systemic conversion of pirfenidone into 5-carboxy-pirfenidone. Accordingly, in some embodiments, administration of a deuterated pirfenidone, e.g., LYT-100, reduces the exposure to the 5-carboxy-pirfenidone metabolite. In some embodiments, exposure is reduced relative to pirfenidone by approximately 15% for AUC, 25% for Cmax, or both. In some embodiments, the deuterated pirfenidone, e.g., LYT-100, at least partially protects against pre-systemic conversion of pirfenidone into 5-carboxy-pirfenidone.
Referering to Table 2, e.g., on average, after administration of LYT-100, the 5-carboxypirfenidone metabolite (LYT-105) represents 43.3% of the parent in comparison to 68.1% of the parent after administration of pirfenidone (Cmax). On average, after administration of LYT-100, the 5-carboxypirfenidone metabolite (LYT-105) represented 43.8% of the parent in comparison to 65.9% of the parent after administration of pirfenidone (AUC). This difference in exposure was not associated with a change in half-life, suggesting formation, and not clearance, of this non-deuterated metabolite is affected by the deuterium substitution in the parent molecule.
Referring to Example 2, the multiple ascending dose study in human subjects, similar results were observed across all dose Cohorts. The major metabolite was 5-carboxypirfenidone at all doses, and the average ratio of metabolite to the parent (M/P) by AUC was 0.45. The dose dependence of AUC was evaluated for LYT-100 and 5-carboxypirfenidone across all dose Cohorts using the AUC96-108 data points. Linear dose proportionality for both parent and major metabolite was observed. Surprisingly, however, the linear trend of each had different slopes; the parent exposure increased with dose more rapidly than metabolite exposure (
Data across the Cohorts was compared against data from Huang et al. (“Pharmacokinetics, Safety and Tolerability of Pirfenidone and its Major Metabolite after Single and Multiple Oral Doses in Healthy Chinese Subjects under Fed Conditions.” Drug Res (Stuttg) 63, 388-395; 2013; 200 mg BID pirfenidone), extrapolated to 100, 250, 500, 750, 1000 mg, assuming dose proportionality and comparing to AUC0-12 and Cmax, LYT-100 and 5-carboxy metabolite only (Table 3). With the exception of the 500 mg dose, there was an increase for LYT-100 AUC over that of pirfenidone and a decrease for the Cmax of the 5-carboxy metabolite over that of same metabolite from pirfenidone.
Also surprising is that LYT-100 demonstrated minimal food effect. Referrring to Table 4, in the fed state, the AUC of LYT-100 was decreased 19% relative to that achieved when subjects were dosed in the fasted state, and in the fed state, the Cmax of LYT-100 was decreased 23% relative to that achieved when subjects were dosed in the fasted state. There was a small increase for Tmax.
In the fed state, the AUC of pirfenidone was decreased 15% relative to that achieved when subjects were dosed in the fasted state (similar to LYT-100), the Cmax was decreased 49% relative to that achieved when subjects were dosed in the fasted state. There was a large increase of 500% in Tmax.
With respect to the metabolite food effect, surprisingly, there was no food effect on Cmax or AUC of the major metabolite 5-carboxypirfenidone (<5% change in Cmax, AUC; Table 5). There was only a small increase in Tmax.
In some embodiments, the deuterated pirfenidone, e.g., LYT-100, has at least one of the following properties: a) decreased inter-individual variation in plasma levels of the compound or a metabolite thereof as compared to pirfenidone; b) increased average plasma levels of the compound per dosage unit thereof as compared to pirfenidone; c) decreased average plasma levels of at least one metabolite of the compound per dosage unit thereof as compared to pirfenidone; d) increased average plasma levels of at least one metabolite of the compound per dosage unit thereof as compared to pirfenidone; and e) an improved clinical effect during the treatment in the subject per dosage unit thereof as compared to pirfenidone. Thus, disclosed herein are methods for treating a subject, including a human, having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder (e.g., any of the disorders disclosed herein) or for preventing such disorder in a subject prone to the disorder; comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound, e.g., LYT-100; so as to effect one or more of a) - e) above during the treatment of the disorder as compared to pirfenidone. In some embodiments, the deuterium-enriched pirfenidone compound has at least two of the properties a) through e) above. In some embodiments, the deuterium-enriched pirfenidone compound has three or more of the properties a) through e) above. In one embodiment, administration of LYT-100 has the properties of increased AUC and Cmax compared to pirfenidone; and decreased average plasma levels of 5-carboxy-pirfenidone a compared to pirfenidone. Additionally, in some embodiments, administration of LYT-100 has minimal or no adverse events, or significantly reduced adverse events relative to pirfendione. Additionally, in some embodiments, LYT-100 has an improved clinical effect during the treatment in the subject as compared to pirfenidone.
In certain embodiments, the average plasma levels of a metabolite of the compound as disclosed herein are decreased by greater than about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 40%, or by greater than about 50% (including any numerical increment between the listed percentages) as compared to the corresponding non-isotopically enriched compounds. Accordingly, in one embodiment, administering LYT-100 results in about a 35% increase in AUC compared to pirfenidone. In one embodiment, administering LYT-100 results in about a 25% increase in Cmax compared to pirfenidone. Accordingly, in some embodiments, administration of a deuterated pirfenidone, e.g., LYT-100, reduces the exposure to the 5-carboxy-pirfenidone metabolite. In some embodiments, exposure is reduced relative to pirfenidone by approximately 15% for AUC, 25% for Cmax, or both. In some embodiments, the deuterated pirfenidone, e.g., LYT-100, at least partially protects against pre-systemic conversion of pirfenidone into 5-carboxy-pirfenidone. In one embodiment, administring LYT-100 results in about a 25% increase in Cmax compared to pirfenidone
In one embodiment, administration of LYT-100 results in a half life of greater than 2.5 hours, e.g., between about 2.5 to about 3 hours, or about 3 hours. Additionally, in some embodiments, there is a decreased pill burden including BID dosing as compared to TID with pirfenidone. In addition, LYT-100 has the property of increased patient tolerability, e.g., minimal or no adverse events. In addition, LYT-100 has the property of increased Cmax and systemic exposure as compared to pirfenidone.
In one embodiment, the half-life of LYT-100 is increased by greater than about 10%, between 10% and 15%, or about 15% as compared to pirfenidone. In certain embodiments, the pill burden of the compounds as disclosed herein, is decreased by greater than about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 40%, or by greater than about 50% (including any numerical increment between the listed percentages) as compared to the corresponding non-isotopically enriched compound. In some embodiments, the pill burden is reduced by greater than about 30% (e.g.., 6 pills a day), greater than about 40% (e.g., 4 pills a day), or by greater than about 50% (e.g., 2 pills a day).
In certain embodiments, the patient tolerability of the compounds as disclosed herein, or metabolites thereof, is increased by greater than about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 40%, by greater than about 50%, by greater than about 60%, by greater than about 70%, by greater than about 80%, by greater than about 90%, or by greater than about 100% (including any numerical increment between the listed percentages) as compared to the corresponding non-isotopically enriched compound. In certain embodiments, the patient tolerability of the compounds as disclosed herein, or metabolites thereof, is increased by about 1.5-fold, increased by about 2-fold, greater than about 2-fold, greater than about 3-fold, greater than about 4-fold, greater than about greater than about 5-fold, greater than about 10-fold or more (including any numerical increment between the listed percentages) as compared to the corresponding non-isotopically enriched compound. In certain embodiments, the patient tolerability of LYT-100 is increased by greater than about 90%, or by about 100% as compared to pirfenidone. In certain embodiments, there are no significant adverse events. In certain embodiments, there are no adverse events.
Disclosed herein are methods for treating a fibrotic-mediated disorder and/or a collagen-mediated disorder, that include administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., LYT-100, at doses up to a 2500 mg total daily dose, wherein the disorder is treated. In some embodiments, there are no adverse events associated with the total daily dose of LYT-100.
Disclosed herein are methods for treating an inflammatory disorder, that include administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., LYT-100, at doses up to a 2500 mg total daily dose, wherein the disorder is treated. In some embodiments, there are no adverse events associated with the total daily dose of LYT-100.
A fibrotic-mediated disorder and/or a collagen-mediated disorder include, but are not limited to, idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial fibrilation, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, spleen fibrosis caused by sickle-cell anemia, rheumatoid arthritis, edema, lymphedema, and/or any disorder ameliorated by modulating fibrosis and/or collagen infiltration into tissues.
Provided herein are methods of treating a life-threatening fibrotic-mediated disorder or a collagen-mediated disorder that include administering a high dose, e.g., a total daily dose of up to 2500 mg of LYT-100, wherein the life-threatening fibrotic-mediated disorder or collagen-mediated disorder is treated. The method can further include administering a lower maintenance dose, or titrating down to a lower dose of, e.g., 2000 mg daily, 1500 mg daily, or 1000 mg daily. In some embodiments, the total daily dose is from about 250 to about 2000 mg. In some embodiments, the total daily dose is about 500, about 750, about 1000, about 1500, or about 2000 mg. In some embodiments, the total daily dose is 2000 mg.
In some embodiments, the total daily dose is administered in two equal administrations. In some embodiments, the LYT-100 is administered in two equal doses of 1000 mg. In some embodiments, the LYT-100 is administered in two equal doses of 1000 mg without any dose escalation (titration).
In some embodiments, the LYT-100 is administered without regard to food. In some embodiments, the LYT-100 is administered without food.
In some embodiments, the LYT-100 is administered in two daily doses of 1000 mg each (1000 mg BID) for an interventional period. In some embodiments, the method further comprises administering a maintenance dose for a maintenance period after the interventional dose is administered for the interventional period. In some embodiments, the maintenance dose is 250 mg, 500 mg, or 750 mg BID.
In some embodiments, the LYT-100 is administered in two daily doses of 1000 mg each (1000 mg BID) for an interventional period, followed by a maintenance period, wherein the LYT-100 is administered in two daily doses of 250 mg, 500 mg, or 750 mg each.
In some embodiments, the method treats an interstitial lung disease (ILD). ILDs encompasses a large and heterogeneous group of parenchymal lung disorders which overlap in their clinical presentations and patterns of lung injury. ILDs include several diseases of unknown cause, as well as ILDs known to be related to other diseases or to environmental exposures. Non-limiting examples of ILDs include non-idiopathic pulmonary fibrosis, idiopathic non-specific interstitial pneumonia (iNSIP), autoimmune or connective tissue disease (CTD)-ILDs, unclassifiable ILDs (uILD), chronic hypersensitivity pneumonitis (HP), interstitial pneumonia with autoimmune features (IPAF), genetic and/or familial idiopathic pulmonary fibrosis (g/f IPF), chronic sarcoidosis, exposure-related ILDs, and drug-induced ILDs.
In some embodiments, the ILD is iNSIP or interstitial pneumonia with autoimmune features (IPAF). In some embodiments, the ILD is chronic HP. Chronic HP is a complex syndrome caused by sensitization to an inhaled antigen that leads to an aberrant immune response in the small airways and lung parenchyma. Susceptibility is believed to be affected by genetics, antigen concentration and frequency of exposure, and immune tolerance In some embodiments, the ILD is autoimmune or CTD-ILD. Autoimmune diseases are commonly associated with pulmonary complications including ILD. Patients across the spectrum of CTDs are at risk of developing ILD. In some embodiments, the autoimmune or CTD-ILD is systemic sclerosis ILD (SSc-ILD). In some embodiments, the ILD is rheumatoid arthritis ILD (RA-ILD). In some embodiments, the ILD is lupus-induced pulmonary fibrosis. In some embodiments, the ILD is scleroderma interstitial lung disease. In some embodiments, the ILD is mixed CTD-associated ILD.
In some embodiments, the ILD is a childhood interstitial lung disease (chILD), which is a broad term for a group of rare lung diseases that can affect babies, children, and teens. These diseases have some similar symptoms, such as chronic cough, rapid breathing, and shortness of breath. These diseases also harm the lungs in similar ways. For example, they damage the tissues that surround the lungs’ alveoli and bronchial tubes, and sometimes directly damage the air sacs and airways. The various types of chILD can decrease lung function, reduce blood oxygen levels, and disturb the breathing process. In some embodiments, the chILD is selected from a surfactant dysfunction mutation, a childhood lung developmental disorder such as alveolar capillary dysplasia, a lung growth abnormality, neuroendocrine cell hyperplasia of infancy (NEHI), pulmonary interstitial glycogenosis (PIG), idiopathic interstitial pneumonia (such as nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia), an alveolar hemorrhage syndrome, an aspiration syndrome, a hypersensitivity pneumonitis, an infectious or post infectious disease (bronchiolitis obliterans), eosinophilic pneumonia, pulmonary alveolar proteinosis, pulmonary infiltrates with eosinophilia, pulmonary lymphatic disorders (lymphangiomatosis, lymphangiectasis), pulmonary vascular disorders (haemangiomatosis), an interstitial lung disease associated with systemic disease process (such as connective tissue diseases, histiocytosis, malignancy-related lung disease, sarcoidosis, storage diseases), or a disorder of the compromised immune system (such as opportunistic infection, disorders related to therapeutic intervention, lung and bone marrow transplant-associated lung diseases, diffuse alveolar damage of unknown cause).
In some embodiments, the ILD is chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis. Sarcoidosis is an inflammatory disease characterized by the formation of granulomas in one or more organs of the body. When left unchecked, this chronic inflammation can lead to fibrosis. Sarcoidosis affects the lungs in approximately 90% of cases, but can affect almost any organ in the body.
In some embodiments, the ILD is pulmonary fibrosis caused by infection. In some embodiments, the ILD is an exposure-related ILD, or a drug-induced ILD. In some embodiments, the exposure-related ILD is pneumoconiosis. Pneumoconiosis is one of a group of ILDs caused by breathing in certain kinds of dust particles, such as asbestos, coal, or silica. In some embodiments, the exposure-related ILD is asbestos-induced pulmonary fibrosis, silica-induced pulmonary fibrosis, coal-induced pulmonary fibrosis, other environmentally induced pulmonary fibroses, or radiation-induced pulmonary fibrosis.
In some embodiments, the ILD is acute interstitial pneumonia (AIP, also known as Hamman-Rich syndrome). AIP is an acute, rapidly progressive idiopathic pulmonary disease that often leads to fulminant respiratory failure and acute respiratory distress syndrome (ARDS). In some embodiments, the ILD is alveolitis, including, chronic fibrosing alveolitis and fibrosing alveolitis.
In some embodiments, the ILD is an unclassifiable ILD (uILD). The term “unclassifiable interstitial lung disease” was introduced in the American Thoracic Society/European Respiratory Society Consensus Classification of the Idiopathic Interstitial Pneumonias (IIP) in 2002 to encompass a subset of ILDs that cannot be classified within the confines of the current diagnostic framework. The paradoxical classification as “unclassifiable” results from either 1) inadequate or 2) discordant clinical, radiologic, and pathologic data, such that a specific ILD diagnosis is not possible.
Many ILDs are characterized by inflammation and chronic fibrosis. Patients with certain types of chronic fibrosing ILD are at risk of developing a progressive phenotype. These include, but are not limited to, iNSIP), uILD, autoimmune ILDs, chronic sarcoidosis, HP, g/f IPF, and exposure-related diseases, such as asbestosis and silicosis. The term “progressive fibrosing ILDs” is generally used to describe ILDs in patients who, independent of the classification of the ILD, at some point in time exhibit a progressive fibrosing phenotype.
One of the most common types of ILD is idiopathic pulmonary fibrosis (IPF). IPF is, by definition, a progressive fibrosing ILD of unknown cause, characterized by a decline in lung function and early mortality. A progressive phenotype is characterized histologically by self-sustaining fibrosis, a process common to a variety of conditions, and which leads to worsening quality of life, decline in lung function and, eventually, early mortality. Because these various conditions share similarities regarding pathogenesis and clinical behavior, they are increasingly described under the umbrella terminology of “progressive fibrosing ILDs” (PF-ILDs) or “fibrosing ILD with a progressive phenotype.” The term “progressive phenotype” implies that progression of disease has occurred despite state-of-the-art management, including, for example, the use of corticosteroids and/or immunosuppressive therapy. Estimates based on a survey and insurance claims in the USA indicate that 18-32% of patients diagnosed with non-IPF ILDs would develop progressive fibrosis (Wijsenbeek et al. “Progressive fibrosing interstitial lung diseases: current practice in diagnosis and management” Curr Med Res Opin 2019: 1-10). In the same study, time from symptom onset to death was estimated to be 61-80 months, a poor survival rate, yet better than that for IPF. The incidence and prevalence of PF-ILDs are not well defined, partly due to the heterogeneous nature of this group. Currently, no drugs are approved for the treatment of progressive fibrotic ILDs other than nintedanib and pirfenidone for the treatment of IPF. Accordingly, LYT-100, having the potential for higher dosing than pirfenidone by virtue of its enhanced tolerability, may be particularly advantageous in treating PF-ILDs.
In some embodiments, the ILD is a PF-ILD. In some embodiments, the PF-ILD is not IPF. In some embodiments, the PF-ILD is iNSIP, a CTD-ILD, a uILD, chronic fibrotic HP, a g/f IPF, sarcoidosis, an exposure-related ILD, or a drug-induced ILD. In some embodiments, the PF-ILD is IPF.
In some embodiments, the method treats focal segmental glomerulosclerosis (FSGS). In some embodiments, renal function decline is slowed or abated. It has been demonstrated that pirfenidone may have a beneficial effect on slowing the loss of GFR in patients with advanced FSGS. See, for example, Cho et al., Clin J Am Soc Nephrol 2: 906-913 (2007).
Provided herein are methods of treating a functionally impairing fibrotic-mediated disorder or a collagen-mediated disorder that include administering an interventional total daily dose of, e.g., 2000 mg of LYT-100. The method can further include administering a lower maintenance dose after an initial interventional period.
Provided herein are methods of treating a chronic fibrotic-mediated disorder or a chronic collagen-mediated disorder that include administering a total daily dose of, e.g., 1500 mg or 2000 mg of LYT-100.
In some embodiments, the method treats radiation-induced fibrosis. In some embodiments, the method provides an increased range of motion. Simone et al., Radiat Oncol 2, 19 (2007) provides evidence that oral pirfenidone increased range of motion in patients with chronic fibrosis resulting from radiotherapy: a pilot study.
In some embodiments, the method treats patients with lymphatic filariasis lymphedema. In some embodiments, the patients experience a reduction in lymphedema.
In some embodiments, the chronic disease is rheumatoid arthritis, uterine fibroids, tuberculosis, or multiple sclerosis.
In some embodiments, the methods disclosed herein comprise escalating a dose, titrating down a dose, or combinations thereof.
In some embodiments, methods described herein include escalation of doses of deuterium-enriched pirfenidone over a certain period until the full maintenance dose is reached. In some embodiments, the escalation period is 7 days. In some embodiments, the escalation period is 14 days. In some embodiments, the escalation period is 21 days. In some embodiments, the methods described herein include reducing a dose. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, a subject can be administered a starting dose of 200 mg/day, 250 mg/day, 500 mg/day, 750 mg/day, 1000 mg/day or 1500 mg/day, followed by adjustment of the total daily dose up or down to any of these dosages, or additional dosages. For example, in some embodiments, a subject can start at 500 mg/day, the dose level can be titrated down to 250 mg/day, e.g., where an AE or drug interaction is experienced. In some embodiments, the dose level can later be titrated back up to a dose level where no AE is experienced, e.g., 500 mg/day, 1000 mg/day or 1500 mg/day. In some embodiments, the dosage is administered once a day (QID). In some embodiments, the dosage is administered twice a day (BID). In some embodiments, the dosage is administered three times a day (TID).
In one embodiment, the deuterium-enriched pirfenidone is administered at a total daily dose of 250 mg (250 mg, once a day) for one week, followed by a maintenance dose of total daily dose of 500 mg (250 mg, twice a day).
In another embodiment, the deuterium-enriched pirfenidone is administered at a total daily dose of 250 mg (250 mg, once a day) for one week, followed by a total daily dose of 500 mg (250 mg, twice a day) for one week, and thereafter at a maintenance dose of total daily dose of 1000 mg (500 mg, twice a day).
In some embodiments, males receive a different initiation or starting dose than females. In some embodiments, the subject is a female subject and the starting dosage is 200 mg/day, 250 mg/day, or 500 mg/day. In some embodiments, the subject is a male subject and the starting dosage is 200 mg/day, 250 mg/day, or 500 mg/day.
In some embodiments, the deuterium-enriched pirfenidone is administered at a total daily dose of 250 mg for an initial time period of, e.g., 5 days, 10 days, one week, or two weeks. In some embodiments, the deuterium-enriched pirfenidone is thereafter administered orally at a total daily dose of 500 mg, 1000 mg or 1500 mg, either for a second period of, e.g, 5 days, 10 days, one week, or two weeks, or as a maintenance dose.
In some embodiments, the deuterium-enriched pirfenidone is administered orally at a total daily dose of 500 mg for an initial time period of, e.g., 5 days, 10 days, one week, or two weeks. In some embodiments, the deuterium-enriched pirfenidone is thereafter administered orally at a total daily dose of 200 mg, 250 mg, 1000 mg or 1500 mg for a second period of, e.g., 5 days, 10 days, one week, or two weeks, or as a maintenance dose.
In some embodiments, the deuterium-enriched pirfenidone is administered orally at a total daily dose of 1000 mg for an initial time period of, e.g., 5 days, 10 days, one week, or two weeks. In some embodiments, the deuterium-enriched pirfenidone is thereafter administered orally at a total daily dose of 200 mg, 500 mg or 1500 mg either for a second period of, e.g., 5 days, 10 days, one week, or two weeks, or as a maintenance dose.
In some embodiments, the deuterium-enriched pirfenidone is administered at a first total daily dose selected from the group consisting of: 200 mg, 250 mg, 500 mg, 1000 mg or 1500 mg for an initial time period, followed by a second period wherein the deuterium-enriched pirfenidone is administered at a second total daily dose selected from the group consisting of: 200 mg, 250 mg, 500 mg, 1000 mg or 1500 mg for a second time period. In some embodiments, the first time period is 5 days, 10 days, one week, or two weeks. In some embodiments, the second time period is a maintenance period or 5 days, 10 days, one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, 8 months, one year, or two years. In some embodiments, the method further comprises administering the deuterium-enriched pirfenidone at a third total daily dose selected from the group consisting of: 200 mg, 250 mg, 500 mg, 1000 mg or 1500 mg. In some embodiments, the third time period is a maintenance dose or a period of 5 days, 10 days, one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, 8 months, one year, two years.
In any of the embodiments provided in the present disclosure, the therapeutic methods and uses described herein include escalation of doses of pirfenidone or deuterium-enriched pirfenidone over a certain period until the full maintenance dose is reached. In some embodiments, the escalation period is 5 days. In some embodiments, the escalation period is 7 days. In some embodiments, the escalation period is 10 days. In some embodiments, the escalation period is 14 days. In some embodiments, the escalation period is 15 days. In some embodiments, the escalation period is 21 days. In some embodiments, the methods described herein include reducing a dose. In some embodiments, the methods described herein include reducing a dose to achieve the therapeutic dose, reducing a dose for a period of time (e.g., temporary reduced dose), and/or reducing a dose and subsequently increasing a dose to achieve the therapeutic dose. In some embodiments, the therapeutic dose is the maximum tolerated dose. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, the daily dose is escalated from 100 mg to 250 mg. In some embodiments, the daily dose is escalated from 100 mg to 500 mg, wherein a 250 mg step (dose) is optionally included. In some embodiments, the daily dose is escalated from 100 mg to 1000 mg, wherein a 250 mg step, a 500 mg step, and/or a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 500 mg. In some embodiments, the daily dose is escalated from 250 mg to 750 mg, wherein a 500 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 1000 mg, wherein a 500 mg step and/or a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 1500 mg, wherein a 500 mg step and/or a 750 mg step and/or a 1000 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 750 mg. In some embodiments, the daily dose is escalated from 500 mg to 1000 mg, wherein a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 1500 mg, wherein a 750 mg step and/or 1000 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 2000 mg, wherein a 750 mg step, a 1000 mg step, and/or a 1500 mg step is optionally included. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, the daily dose is escalated from 100 mg to 250 mg over a period of 5 days. In some embodiments, the daily dose is escalated from 100 mg to 500 mg over a period of 5 days, wherein a 250 mg step (dose) is optionally included. In some embodiments, the daily dose is escalated from 100 mg to 1000 mg over a period of five days, wherein a 250 mg step, a 500 mg step, and/or a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 500 mg over a period of 5 days. In some embodiments, the daily dose is escalated from 250 mg to 750 mg over a period of 5 days, wherein a 500 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 1000 mg over a period of 5 days, wherein a 500 mg step and/or a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 1500 mg over a period of 5 days, wherein a 500 mg step and/or a 750 mg step and/or a 1000 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 750 mg over a period of 5 days. In some embodiments, the daily dose is escalated from 500 mg to 1000 mg over a period of 5 days, wherein a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 1500 mg over a period of 5 days, wherein a 750 mg step and/or 1000 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 2000 mg over a period of 5 days, wherein a 750 mg step, a 1000 mg step, and/or a 1500 mg step is optionally included. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, the daily dose is reduced from 250 mg to 100 mg. In some embodiments, the daily dose is reduced from 250 mg to 100 mg over a period of 5 days. In some embodiments, the daily dose is reduced from 500 mg to 100 mg, wherein a 250 mg step (dose) is optionally included. In some embodiments, the daily dose is reduced from 500 mg to 100 mg over a period of 5 days, wherein a 250 mg step (dose) is optionally included. In some embodiments, the daily dose is reduced from 1000 mg to 100 mg over a period of five days, wherein a 750 mg step, a 500 mg step, and/or a 250 mg step is optionally included. In some embodiments, the daily dose is reduced from 1000 mg to 100 mg, wherein a 750 mg step, a 500 mg step, and/or a 250 mg step is optionally included. In some embodiments, the daily dose is reduced from 500 mg to 250 mg. In some embodiments, the daily dose is reduced from 500 mg to 250 mg over a period of 5 days. In some embodiments, the daily dose is reduced from 750 mg to 250 mg, wherein a 500 mg step is optionally included. In some embodiments, the daily dose is reduced from 750 mg to 250 mg over a period of 5 days, wherein a 500 mg step is optionally included. In some embodiments, the daily dose is reduced from 1000 mg to 250 mg, wherein a 750 mg step and/or a 500 mg step is optionally included. In some embodiments, the daily dose is reduced from 1000 mg to 250 mg over a period of 5 days, wherein a 750 mg step and/or a 500 mg step is optionally included. In some embodiments, the daily dose is reduced from 1500 mg to 250, wherein a 1000 mg step and/or a 750 mg step and/or a 500 mg step is optionally included. In some embodiments, the daily dose is reduced from 1500 mg to 250 over a period of 5 days wherein a 1000 mg step and/or a 750 mg step and/or a 500 mg step is optionally included. In some embodiments, the daily dose is reduced from 750 mg to 500 mg. In some embodiments, the daily dose is reduced from 750 mg to 500 mg over a period of 5 days. In some embodiments, the daily dose is reduced from 1000 mg to 500 mg, wherein 750 mg step is optionally included. In some embodiments, the daily dose is reduced from 1000 mg to 500 mg over a period of 5 days, wherein 750 mg step is optionally included. In some embodiments, the daily dose is reduced from 1500 mg to 500 mg, wherein a 100 mg step and/or a 750 mg step is optionally included. In some embodiments, the daily dose is reduced from 1500 mg to 500 mg over a period of 5 days, wherein a 100 mg step and/or a 750 mg step is optionally included. In some embodiments, the daily dose is reduced from 2000 mg to 500 mg, wherein a 1500 mg step, a 1000 mg step, and/or a 750 mg step is optionally included. In some embodiments, the daily dose is reduced from 2000 mg to 500 mg over a period of 5 days, wherein a 1500 mg step, a 1000 mg step, and/or a 750 mg step is optionally included. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, the daily dose is escalated from 100 mg to 250 mg over a period of 14 days. In some embodiments, the daily dose is escalated from 100 mg to 500 mg over a period of 14 days, wherein a 250 mg step (dose) is optionally included. In some embodiments, the daily dose is escalated from 100 mg to 1000 mg over a period of 14 days, wherein a 250 mg step, a 500 mg step, and/or a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 500 mg over a period of 14 days. In some embodiments, the daily dose is escalated from 250 mg to 750 mg over a period of 14 days, wherein a 500 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 1000 mg over a period of 14 days, wherein a 500 mg step and/or a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 1500 mg over a period of 14 days, wherein a 500 mg step and/or a 750 mg step and/or a 100 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 750 mg over a period of 14 days. In some embodiments, the daily dose is escalated from 500 mg to 1000 mg over a period of 14 days, wherein a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 1500 mg over a period of 14 days, wherein a 750 mg step and/or 100 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 2000 mg over a period of 14 days, wherein a 750 mg step, a 1000 mg step, and/or a 1500 mg step is optionally included. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, the daily dose is escalated from 100 mg to 250 mg from day 1 to day 7 and then escalated from 250 mg to 500 mg from day 7 to day 14. In some embodiments, the daily dose is escalated from 250 mg to 500 mg from day 1 to day 7 and then escalated from 500 mg to 1000 mg from day 7 to day 14. In some embodiments, the escalation from 500 mg to 1000 mg includes a 750 mg step. In some embodiments, the daily dose is escalated from 500 mg to 750 mg from day 1 to day 7 and then escalated from 750 mg to 1000 mg from day 7 to day 14. In some embodiments, the daily dose is escalated from 750 mg to 1000 mg from day 1 to day 7 and then escalated from 1000 mg to 1500 mg from day 7 to day 15. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, the daily dose is escalated from 100 mg to 250 mg over a period of 21 days. In some embodiments, the daily dose is escalated from 100 mg to 500 mg over a period of 21 days, wherein a 250 mg step (dose) is optionally included. In some embodiments, the daily dose is escalated from 100 mg to 1000 mg over a period of 21 days, wherein a 250 mg step, a 500 mg step, and/or a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 500 mg over a period of 21 days. In some embodiments, the daily dose is escalated from 250 mg to 750 mg over a period of 21 days, wherein a 500 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 1000 mg over a period of 21 days, wherein a 500 mg step and/or a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 250 mg to 1500 mg over a period of 21 days, wherein a 500 mg step and/or a 750 mg step and/or a 100 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 750 mg over a period of 21 days. In some embodiments, the daily dose is escalated from 500 mg to 1000 mg over a period of 21 days, wherein a 750 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 1500 mg over a period of 21 days, wherein a 750 mg step and/or 100 mg step is optionally included. In some embodiments, the daily dose is escalated from 500 mg to 2000 mg over a period of 21 days, wherein a 750 mg step, a 1000 mg step, and/or a 1500 mg step is optionally included. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, the daily dose is escalated from 100 mg to 250 mg from day 1 to day 7, then escalated from 250 mg to 500 mg from day 7 to day 14, and then escalated from 500 mg to 750 mg from day 14 to day 21. In some embodiments, the daily dose is escalated from 250 mg to 500 mg from day 1 to day 7, then escalated from 500 mg to 750 mg from day 7 to day 14, and then escalated from 750 mg to 1000 mg from day 14 to day 21. In some embodiments, the daily dose is escalated from 500 mg to 750 mg from day 1 to day 7, then escalated from 750 mg to 1000 mg from day 7 to day 14, then escalated from 1000 mg to 1500 mg from day 14 to day 21. In some embodiments, the daily dose is escalated from 750 mg to 1000 mg from day 1 to day 7, then escalated from 1000 mg to 1500 mg from day 7 to day 14, and then escalated from 1500 mg to 2000 mg from day 14 to day 21. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, the daily dose is escalated from 100 mg to 250 mg from day 1 to day 7, then escalated from 250 mg to 500 mg from day 7 to day 14, and then escalated from 500 mg to 750 mg from day 14 to day 21. In some embodiments, the daily dose is escalated from 250 mg to 500 mg from day 1 to day 7, then escalated from 500 mg to 750 mg from day 7 to day 14, and then escalated from 750 mg to 1000 mg from day 14 to day 21. In some embodiments, the daily dose is escalated from 500 mg to 750 mg from day 1 to day 7, then escalated from 750 mg to 1000 mg from day 7 to day 14, then escalated from 1000 mg to 1500 mg from day 14 to day 21. In some embodiments, the daily dose is escalated from 750 mg to 1000 mg from day 1 to day 7, then escalated from 1000 mg to 1500 mg from day 7 to day 14, and then escalated from 1500 mg to 2000 mg from day 14 to day 21. In any of these embodiments, the daily dose is administered in one dose, or split into two or three doses, i.e., administration is once, twice or three times daily.
In some embodiments, the dosing regimen comprises administering pirfenidone or a deuterium-enriched pirfenidone, e.g., LYT-100, as follows: daily dose is 100 mg BID for 5-7 days, daily dose is 250 mg BID for 5-7 days, daily dose is 500 mg BID, which is the therapeutic dose (500 mg BID/day). In some embodiments, the dosing regimen comprises administering pirfenidone or a deuterium-enriched pirfenidone, e.g., LYT-100, as follows: daily dose is 100 mg BID for 5 days, daily dose is 250 mg BID for 5 days, daily dose is 500 mg BID, which is the therapeutic dose. In some embodiments, following a daily dose of 500 mg BID for a period of time (e.g., 5-7 days or longer), the therapeutic dose is increased, e.g., to 750 mg BID/day or 1000 mg BID/day or other maximum tolerated daily dose. In some embodiments, following a daily dose of 500 mg BID for a period of time (e.g., 5-7 days or longer), the therapeutic dose is decreased, e.g., to 250 mg BID/day or 100 mg BID/day or other tolerated daily dose.
In some embodiments, the dosing regimen comprises administering pirfenidone or a deuterium-enriched pirfenidone, e.g., LYT-100, as follows: daily dose is 100 mg BID for 5-7 days, daily dose is 250 mg BID for 5-7 days, daily dose is 500 mg BID for 5-7 days, daily dose is 750 mg BID, which is the therapeutic dose (750 mg BID/day). In some embodiments, the dosing regimen comprises administering pirfenidone or a deuterium-enriched pirfenidone, e.g., LYT-100, as follows: daily dose is 100 mg BID for 5 days, daily dose is 250 mg BID for 5 days, daily dose is 500 mg BID, daily dose is 750 mg BID, which is the therapeutic dose. In some embodiments, following a daily dose of 750 mg BID for a period of time (e.g., 5-7 days or longer), the therapeutic dose is increased, e.g., to 1000 mg BID/day or other maximum tolerated daily dose. In some embodiments, following a daily dose of 750 mg BID for a period of time (e.g., 5-7 days or longer), the therapeutic dose is decreased, e.g., to 500 mg BID/day or 250 mg BID/day or 100 mg BID/day or other tolerated daily dose.
In some embodiments, the dosing regimen comprises administering pirfenidone or a deuterium-enriched pirfenidone, e.g., LYT-100, as follows: daily dose is 250 mg QD for 5-7 days, daily dose is 250 mg BID for 5-7 days, daily dose is 500 mg BID, which is the therapeutic dose (500 mg BID/day). In some embodiments, the dosing regimen comprises administering pirfenidone or a deuterium-enriched pirfenidone, e.g., LYT-100, as follows: daily dose is 250 mg QD for 7 days, daily dose is 250 mg BID for 7 days, daily dose is 500 mg BID, which is the therapeutic dose. In some embodiments, following a daily dose of 500 mg BID for a period of time (e.g., 5-7 days or longer), the therapeutic dose is increased, e.g., to 750 mg BID/day or 1000 mg BID/day or other maximum tolerated daily dose. In some embodiments, following a daily dose of 500 mg BID for a period of time (e.g., 5-7 days or longer), the therapeutic dose is decreased, e.g., to 250 mg BID/day or 100 mg BID/day or other tolerated daily dose.
In some embodiments, the dosing regimen comprises administering pirfenidone or a deuterium-enriched pirfenidone, e.g., LYT-100, as follows: daily dose is 250 mg QD for 5-7 days, daily dose is 250 mg BID for 5-7 days, daily dose is 500 mg BID for 5-7 days, daily dose is 750 mg BID, which is the therapeutic dose (750 mg BID/day). In some embodiments, the dosing regimen comprises administering pirfenidone or a deuterium-enriched pirfenidone, e.g., LYT-100, as follows: daily dose is 250 mg QD for 7 days, daily dose is 250 mg BID for 7 days, daily dose is 500 mg BID for 7 days, daily dose is 750 mg BID, which is the therapeutic dose. In some embodiments, following a daily dose of 750 mg BID for a period of time (e.g., 5-7 days or longer), the therapeutic dose is increased, e.g., to 1000 mg BID/day or other maximum tolerated daily dose. In some embodiments, following a daily dose of 750 mg BID for a period of time (e.g., 5-7 days or longer), the therapeutic dose is decreased, e.g., to 500 mg BID/day or 250 mg BID/day or 100 mg BID/day or other tolerated daily dose.
In a prophylactic context, the pharmaceutical composition of the invention can be administered at any time before or after an event, for example, radiation therapy, chemotherapy, or surgical lymph node dissection, which places a subject at risk of or susceptible to lymphatic injury and/or developing edema. In some embodiments, the pharmaceutical composition is administered prophylactically up to about one week before the event, such as 1, 2, 3, 4, 5, 6, or 7 days before the event. In some instances, the pharmaceutical composition is administered prophylactically on the same day as the event. In some embodiments, the pharmaceutical composition is administered prophylactically within six weeks of the event, for example, within about 1, 2, 3, 4, 5, or 6 days, or within about 1, 2, 3, 4, 5 or 6 weeks of the event. In some embodiments, the pharmaceutical composition is administered prophylactically for about 2-4 weeks or for about 1, 2, 3, 4, 5, or 6 weeks.
In another aspect, pharmaceutical compositions are provided for administration in the methods described herein. Pharmaceutical compositions include the active compound, e.g., LYT-100, and one or more pharmaceutically acceptable excipients or carriers. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
Embodiments of the present disclosure can be further defined by reference to the following non-limiting examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure.
Example 1 illustrates the unexpected pharmacokinetic profile of deuterated pirfenidone which provides a significantly reduced pill burden and efficacy at a significantly lower dose, with a significant potential for reducing dose-related side effects and for reduced interpatient variability as compared to pirfenidone. Example 2 provides a dosing and food effect study for deuterated pirfenidone as well as its efficacy in lymphedema. Examples 3, 4, 5, and 6 illustrate the anti-fibrotic and anti-inflammatory efficacy of deuterated pirfenidone. Example 7 provides pharmaco- and toxicokinetic data for LYT-100 in the rat.
LYT-100 was studied in a single dose, double-blinded, cross-over clinical trial of 24 healthy volunteers to assess safety and pharmacokinetics (PK). Following screening, eligible healthy volunteer subjects were admitted to a single clinical study site and were randomized to 1 of 2 treatment sequences. Subjects received a single 801 mg oral dose of either LYT-001 or pirfenidone in Period 1 and, following washout, crossed over to receive the other treatment in period 2. In each period, a standardized breakfast was provided to subjects prior to administration of study drug (to compare the PK profiles in the clinically relevant fed state) and plasma samples were collected over a 48-hour period after dosing for evaluation of PK. Dosing between the 2 periods was separated by a minimum of 7 days. Subjects completed the study upon completion of the 48-hour post-dose assessments following dosing period 2.
To avoid confounding the analysis of results with any influence of formulations, both study drugs (LYT-100 and pirfenidone) were synthesized using the same manufacturing process and were provided as unformulated powder in capsules: LYT-100 801 mg (267 mg capsules x 3); and pirfenidone 801 mg (267 mg capsules x 3).
All capsules were identical in size, shape, and external color. Both the LYT-100 and the pirfenidone used in this trial were provided in hard-shell gelatin capsules containing 267 mg of either LYT-100 or pirfenidone powder with no excipients. The order of the two treatments was assigned via a randomization schema in a 1:1 ratio such that half of the subjects received LYT-100 first and the other half received pirfenidone first.
The plasma concentrations of LYT-100, pirfenidone, and their respective associated metabolites (e.g., 5-carboxy-pirfenidone, 5-hydroxymethyl-pirfenidone, and 4′-hydroxy-pirfenidone) and sample collection times were used for calculation of the following pharmacokinetic parameters for each subject and treatment:
It was observed that the systemic exposure of LYT-100 was about 35% greater than for pirfenidone, and about 25% greater for Cmax, with no appreciable difference in the apparent elimination half-life.
The increased systemic exposure to LYT-100 was accompanied by changes in the relative abundance of downstream metabolites. Following LYT-100 and pirfenidone, the most abundant measured circulating metabolite was 5-carboxy-pirfenidone (LYT-105). 5-carboxy-pirfenidone was reduced after LYT-100 relative to pirfenidone by approximately 15% and 25% for AUC and Cmax, respectively. As a percent of the parent analyte AUC0-∞, 5-carboxy-pirfenidone represented 43.8% for LYT-100 as compared to 65.9% for pirfenidone (Table 9). The remaining measured metabolites, 5-hydroxymethyl-pirfenidone (LYT-111) and 4′-hydroxy-pirfenidone (LYT-104), were far less abundant, representing less than 2% of parent in terms of AUC. The formation of the metabolite 5-hydroxymethyl-pirfenidone was approximately 50% greater in terms of overall systemic exposure (AUC) after administration of LYT-100. Similarly, 4′-hydroxy-pirfenidone was detectable more frequently after LYT-100 than after pirfenidone. Given the low plasma concentrations of these metabolites, however, these changes contributed little to the overall pharmacokinetic profile of LYT-100 relative to pirfenidone.
a The analytes were pirfenidone (LYT-101), nondeuterated 5-hydroxymethyl-pirfenidone (LYT-111), nondeuterated 5-carboxy-pirfenidone (LYT-105), nondeuterated 4′-hydroxy-pirfenidone (LYT-104), LYT-100 (deupirfenidone), deuterated 5-hydroxymethyl-pirfenidone (LYT-110), and deuterated 4′-hydroxy-pirfenidone (LYT-103).
On average, after administration of LYT-100, the 5-carboxypirfenidone metabolite (LYT-105) represented 43.8% of the parent in comparison to 65.9% of the parent after administration of pirfenidone. This difference in exposure was not associated with a change in half-life, suggesting formation, and not clearance of this non-deuterated metabolite is affected by the deuterium substitution in the parent molecule.
Administration in the fed state of a single 801 mg dose of LYT-100 resulted in overall greater exposure (AUC, Cmax) than observed with administration of an 801 mg dose of pirfenidone. No appreciable difference in the apparent elimination t½ or time to Cmax was observed for the 2 compounds. The higher peak and overall exposure of LYT-100 was associated with a lower systemic exposure of the 5-carboxy-pirfenidone, suggesting the kinetic isotope effect at least partially protects against pre-systemic conversion of pirfenidone into 5-carboxy-pirfenidone.
The deuterium kinetic isotope effect appears independent of phenotype when comparing exposure between deuterated and non-deuterated pirfenidone. CYP1A2 has been reported as the main metabolizing enzyme for pirfenidone and higher enzyme activity in the hyperinduced CYP1A2 phenotype is associated with lower exposure of both deuterated and non-deuterated forms of pirfenidone relative to normal expression levels.
Overall, single doses of LYT-100 and pirfenidone were well tolerated and have a comparable safety profile. No clinically significant differences were observed between the 2 treatments in terms of type, severity, or frequency of treatment emergent adverse events. The most common adverse event following either treatment was headache. Of interest, although administration of the 801 mg dose of LYT-100 resulted in greater drug exposure than with the same pirfenidone dose, the incidence of gastrointestinal and nervous system adverse events was not increased with LYT-100 administration as compared to pirfenidone. No significant changes in laboratory parameters, vital signs, or ECGs were observed following either treatment.
This study is a Phase 1 Multiple Ascending Dose and Food Effect Study in healthy volunteers to determine the pharmacokinetics and maximally tolerated dose of deupirfenidone (LYT-100) followed by a randomized double-blind placebo-controlled phase 1B in patients with breast cancer-related upper limb secondary lymphoedema.
The Multiple Ascending Dose (MAD) and Food Effect (Parts 1 and 2) will be performed at a single Study Centre in Australia. Part 3 will take place at up to 5 study centres in Australia.
This study has 3 Parts, with each Part having specific objectives. Part 1 will assess safety and tolerability in a multiple dose-escalation design, Part 2 is a food effect assessment, and Part 3 is a placebo-controlled assessment of safety and efficacy signals in the target population.
Part 1: To evaluate safety and tolerability of multiple twice-daily (BID) doses of LYT-100 administered over 5 days.
Part 1: To determine time to steady state (up to Day 5) and to characterise the steady-state PK profile of LYT-100.
Part 1: To determine the maximum tolerated dose (MTD) for multiple BID doses of LYT-100 administered over 5 days.
Part 1: To assess the pharmacokinetic (PK) profiles of multiple BID doses of LYT-100 administered over 5 days for dose proportionality.
Part 2: To descriptively compare the PK profile and compare the relative bioavailability of a single dose of LYT 100 administered at a dose below the MTD without food, to the equivalent dose with food.
Part 3 will be performed in breast carcinoma patients with secondary mild to moderate lymphoedema following axillary node dissection and/or sentinel lymph node biopsy, with or without radiation, dosed with LYT-100 (dose to be determined from Part 1 outcomes) BID (without regard to food) for 6 months. Part 3 is a 26-week randomized, double-blind, placebo-controlled assessment of LYT-100 at multiple study centres in patients with secondary lymphoedema following axillary node dissection and/or sentinel lymph node biopsy treatment for breast carcinoma. Informed consent will be obtained prior to each study part. Screening will be performed up to 21 days prior to administration of the first dose of LYT-100 for all study parts. Only participants who meet all of the applicable inclusion and none of the applicable exclusion criteria per study part will be enrolled.
To assess safety and tolerability.
To explore efficacy signals of LYT-100 on: lymphatic obstruction and subsequent oedema, infection (as characterised by cellulitis and/or lymphangitis), and quality of life
This is a randomised, double-blind, placebo-controlled, multiple ascending dose design to assess the safety, tolerability and PK profile of multiple doses of LYT-100 administered under fed conditions at steady state in healthy participants. Up to 5 dosing cohorts are planned in Part 1. Planned dose levels are as follows in Table 10.
All Part 1 cohorts will be dosed every 12 hours with food for 5 days. Additional cohorts and intermediate doses may be selected in lieu of predefined doses as noted and in accordance with safety and tolerability responses, but doses will not exceed 1000 mg BID or a total daily dose of 2000 mg.
In cohort 6, three sentinel subjects (2 active and 1 placebo) will enrol and dose ≥48 hours in advance of the remaining 5 subjects (4 active and 1 placebo). If clinically significant safety signals assessed as > Mild/Grade 1 are observed in the 3 sentinel subjects in advance of dosing the remaining 5 subjects, the Safety Review Committee may meet to review safety data before the remaining 5 subjects are enrolled.
Up to 40 participants will be enrolled in Part 1 (n=6 LYT-100 and n=2 placebo in each cohort) unless additional intermediate cohorts are needed. Participants will be admitted to the Clinical Research Unit (CRU) on Day -1 and will be discharged on Day 7 in the absence of clinically significant safety signals, following completion of all Day 7 assessments and at the Investigator’s discretion.
During the treatment period (Day 1 through Day 5), participants will be administered their assigned study medication BID, every 12 h ± 0.25 h (with approximately 240 mL of non-carbonated water), 30 minutes after the start of consumption of their standardised breakfast or dinner (12 h apart). A standardised lunch will be served ≥ 4 h post breakfast and ≥ 4 h prior to dinner. An evening snack will be served ≥ 3 h following evening study medication administration. No additional fluids will be allowed during the 1 h pre- and post-doses. On Day 6, subjects will replicate mealtimes as scheduled on Day 1-5. To ensure study drug dosing every 12 hours, here is an example of meal and dosing schedule in Part 1:
Breakfast: meal to be served 30 mins prior to AM dosing. Breakfast must be completed within 30 mins of start time.
Lunch: meal to be served at least 4 h post-AM study drug dose.
Dinner: meal to be served at least 11.5 h post-AM dose and served 30 minutes prior to PM study drug dose.
Evening snack: Snack to be served at least 15 h post-AM dose (at least 3 h post-PM dose).
Participants will return to the study centre for a follow-up visit 7 days after their final dose of study drug. For all cohorts in Part 1, the decision to escalate or modify the dose prior to dosing of the next Cohort will be determined by a Safety Review Committee (SRC). Part 2: Treatment Period
Eight (8) subjects completing Part 1 will participate in Part 2 (n=6 LYT-100 and n=2 placebo). An unblinded statistician will ensure that subjects receiving active treatment or placebo in Part 1 will maintain the same treatment allocation in Part 2, though the dose of active study treatment and number of matching placebo capsules may differ.
A single dose of 500 mg of LYT-100 or placebo will be administered on two days, separated by a minimum 7-day washout period. Four (4) subjects (3 active and 1 placebo) will be randomized to receive their single dose of Part 2 study treatment under fed conditions, while 4 subjects (3 active and 1 placebo) will be randomized to receive their single dose of Part 2 study treatment under fasted conditions.
Participants will return in Part 2 to the CRU following a minimum 7-day washout period to receive a single dose of 500 mg LYT-100 or placebo after crossing-over to the alternate fasted or fed single dose study treatment administration condition. Participants will be administered a single dose of their assigned treatment under fasting conditions (Cohort 5) in order to permit a comparison of the rate and extent of absorption of LYT-100 when given the equivalent dose under fed conditions (Cohort 5). The comparison will be based on Day 1, Day 2 and Day 3 PK plasma samples after the first dose of study drug on Day 1 under fast and fed conditions of Part 2.
Rescreening of participants in Part 2 prior to the first dose of study drug will be conducted according to the Schedule of Events for Part 2 to ensure that the participant continues to meet study eligibility criteria. A total of eight (8) participants will participate in Part 2 (n=6 LYT-100 and n=2 placebo).
Participants in Part 2 will receive the same treatment allocation of active or placebo while they were participating in Part 1, though the dose of active study treatment and number of matching placebo capsules may differ. Subjects will be randomized to one of two meal sequences as follows:
Subjects will be admitted to the CRU on Day -1 and will fast overnight for at least 10 h. On Day 1, a single dose of study drug, i.e., 500 mg LYT-100 or placebo will be administered with approximately 240 mL of non-carbonated water while either fasted or fed per randomization sequence.
On Fasted Days, meals will be provided as follows:
On Day 1, breakfast will be provided ≥ 4 h post-study drug administration. A standardised lunch will be served ≥ 4 h following breakfast, and dinner will be served ≥ 4 h following lunch. An evening snack will be served≥ 3 h following dinner. No additional fluids will be allowed during the 1 h pre- and post-dose. On Day 2, subjects will replicate mealtimes as scheduled on Day 1.
Mealtimes on Day 1 in relation to dosing in Part 2 are as follows:
On Fed Days, meals will be provided as follows:
On Day 1, a standardised breakfast will be provided 30 minutes prior to study drug administration. A standardised lunch will be served ≥ 4 h post breakfast and ≥ 4 h prior to dinner. An evening snack will be served ≥ 15 h following morning study medication administration. Fluids are restricted only during the 1 h pre- and post- morning dose. On Day 2, subjects will replicate mealtimes as scheduled on Day 1.
Mealtimes on Day 1 in relation to dosing in Part 2 are as follows:
Participants will remain in the CRU until completion of the 48 h post-dose assessments following the single dose administration with fed or fasted as outlined in the Schedule of Events and in the absence of clinically significant safety signals, following completion of all Day 3 assessments and at the Investigator’s discretion. Subjects will return after a ≥ 7-day washout period to participate in the alternate randomized meal sequence. They will return on Day 10 for their final study day visit.
All participants in Part 1 and Part 2 will be monitored for safety (including assessment of chemistry, haematology and urinalysis parameters, electrocardiograms [ECGs], vital signs and adverse events [AEs]) and samples will be collected for assessment of PK at predefined time points pre and post-dose as delineated in the Schedule of Events.
All participants in Part 1 will be followed for at least 30 days and Part 2 will be followed for at least 10 days after the last administered dose of study drug.
In Part 1, participants will attend the CRU on an outpatient basis 7 days (± 1 day) following the last administered dose for safety assessments and a final safety follow up teleconference between site staff and the study participant will occur 30 days (± 3 days) after the last administered dose, at the discretion of the Investigator. If required, following the teleconference, an onsite visit to the CRU will be scheduled, at the Investigator’s discretion.
In the case of premature discontinuation from the study, participants will return to the CRU and complete an early termination visit with assessments as delineated in the Schedule of Events. Following the early termination visit, participants will be contacted by telephone by site staff 30 days (± 3 days) in Part 1 and 10 days (± 3 days) in Part 2, post the last administered dose of study drug for a final safety review, at the Investigator’s discretion.
Part 3 is a double-blind, parallel, placebo-controlled study being conducted to evaluate the safety and efficacy of LYT-100 compared to placebo. Part 3 will be conducted across multiple centres, with up to 50 patients randomized to receive LYT-100 or placebo, in a ratio of 1:1.
Dosing is determined from outcomes in Part 1 and Part 2. LYT-100 dosing is to be titrated starting at 500 mg BID during the first 3 days of dosing, followed by 750 mg BID thereafter, or matching placebo. Participants will take double blind-study medication orally without regard to food BID (approximately 10 to 12 hours between the two daily doses) on an outpatient basis for 26 weeks. Patients will be followed for an additional 22 weeks post-treatment to assess for longer-term outcomes.
1LYT-100 500 mg BID2 or matching Placebo x 3 days
1LYT-100 750 mg BID2 or matching Placebo x 179 days
1Participants will be administered LYT-100 study medication, or placebo, orally without regard to food with approximately 10 to 12 hours between the two daily doses.
2Doses may be adjusted according to safety and tolerability to avoid toxicity by adjusting to lower doses in response to patient safety and tolerability issues. If dosing titration is not well tolerated, adjustments to dosing may be made as follows: reductions to 250 mg, BID X 2 days (may be longer if needed), 500 mg BID X 2 days (may be longer if needed), 750 mg BID thereafter vs. matching placebo. In addition, if tolerability issues persist, the patient may be instructed to take study medication with food.
Patients with breast cancer related lymphoedema will be assessed for safety, tolerability, clinical endpoints, PK, and biomarkers while receiving LYT-100 or placebo over a 6-month dosing period. If a patient is using a standard of care compression sleeve, compression pump therapy, and/or manual lymphatic drainage within 4 weeks prior to screening, they must be agreeable to continuing the same routine care throughout the 6-month study treatment period and throughout 2 weeks post-study drug discontinuation. Qualified patients currently using a compression sleeve at least 4 weeks prior to screening should be properly fitted for a new compression sleeve and begin wearing this at least 1 week prior to their baseline visit/assessments. If a patient is not using a standard compression sleeve, compression pump therapy, and/or manual lymphatic drainage ≥ 4 weeks prior to screening and are not planning to be using these prior to the study, they must be agreeable to not using the lymphoedema therapy(s) throughout treatment and 2-weeks post-study drug discontinuation. Patients will be stratified at enrolment into the standard compression sleeve, compression pump therapy, and/or manual lymphatic drainage stratum vs. non-compression/non-lymphatic drainage stratum. In addition, patients will be stratified by higher risk of lymphoedema progression (axillary lymph node dissection) vs. lower risk of lymphoedema progression (sentinel node biopsy).
Following confirmation of study eligibility, patients will be seen in the clinic for their final baseline assessments (Day -1). Patients will begin their BID dosing of study medication on the following morning (Study Day 1) and will continue for 26 weeks, with clinic visits at Weeks 1, 2, 4, 8, 12, 16, 20 and 26. The site will contact the patient by phone at Week 23 to check in and assess for compliance to study drug, assess for new concomitant medications and adverse events and remind the patient to complete their Patient Diary one week prior to the Week 26 study visit.
All patients in Part 3 will be monitored for safety (including assessment of chemistry, haematology and urinalysis parameters, ECGs, vital signs and AEs). Participants will complete the Efficacy assessments which will include clinical and quality of life measures at time points as delineated in the Schedule of Events. Sparse PK samples will be obtained for population PK analysis to determine the variability of LYT 100 drug concentration data in individual patients across multiple clinical sites. Fibrotic and inflammatory biomarkers will be assessed for changes from baseline. With patients using compression sleeves, pumps and/or lymphatic drainage as a treatment modality(s) at least 4 weeks prior to and at Screening, they will remain on compression treatments during the treatment period as noted. Compression sleeves will be removed upon arrival at each study visit and until after the bioimpedance assessment is collected which should be scheduled toward the end of the study visit and just prior to blood pressure and blood collection. Time of sleeve removal will be noted at each study visit. In addition to routine practices such as diet, exercise, or skin care, use or non-use of compression sleeves, compression pumps and/or lymphatic drainage will be recorded in the Patient Diary one week prior to each study visit with lymphoedema assessments, including frequency of use and the number of hours used on each occasion. Medication compliance will also be recorded on the Patient Diary.
Following the completion of treatment with study medication, a post-treatment follow-up period will commence. The first post-treatment visit at Week 28 will occur 2 weeks after the last dose of LYT-100 or placebo is administered at Week 26. If patients have been using compression sleeves during the trial, they should receive a new and properly fitted compression sleeve to use for the next 22 weeks. As before in the 26-week treatment period, use or non-use of compression sleeves, compression pumps, and/or lymphatic drainage will continue as per the patient’s routine during the follow-up period. Compression sleeves, if used, will be removed upon arrival at the study visit and until the bioimpedance assessment is collected toward the end of the Week 28 visit. Additional post-treatment follow-up visits will occur at Week 36 and Week 48 to evaluate long-term lymphoedema progression status.
As with the prior treatment period, routine practices (e.g., diet, exercise, or skin care, use or the non-use of compression sleeves, compression pumps and/or lymphatic drainage) will be recorded in the Patient Diary one week prior to each study visit with lymphoedema visits, including frequency of use and the number of hours used on each occasion and any disruptions in taking study medication as instructed.
The study will be subject to oversight by a SRC comprised of the Principal Investigator (PI), medical monitor (MM), and Sponsor representative, at a minimum. Details of the roles and functioning of the SRC will be available in the SRC Charter.
The SRC will provide recommendations on the dose of LYT-100 for the next Cohort. The raw data will remain blinded. In the event that unblinding of an individual participant is required, every effort will be made to not compromise the overall blinded status of the study.
If an intolerable dose of LYT-100 is identified, the dose will not be further escalated and the previously tolerated dose will be considered the MTD or alternatively, an intermediate dose, lower than the intolerable dose, may be explored.
Escalation from one dose level to the next will occur after review of raw clinical safety data and approval by the SRC up to and including the onsite follow-up visit on Day 12 (7 days post last administration of study drug) for the last participant in the preceding cohort; cumulative data for earlier cohorts may also be reviewed.
As noted previously, in Cohort 6, three sentinel subjects (2 active and 1 placebo) will enrol and dose ≥48 hours in advance of the remaining 5 subjects (4 active and 1 placebo). If clinically significant safety signals assessed as > Mild/Grade 1 are observed in the 3 sentinel subjects in advance of dosing the remaining 5 subjects, the Safety Review Committee may meet to review safety data before the remaining 5 subjects are enrolled.
A single dose of 500 mg of LYT-100 or placebo will be administered on two days, separated by a minimum 7-day washout period.
Stopping Rules for Part 1 and Part 2:
At any phase of the study, administration of study drug will be paused and participants will not receive further study drug until data review, recommendations, and approval have been provided by the SRC.
Dose-limiting toxicity will be defined as 2 or more clinically significant AEs or abnormal laboratory values assessed as unrelated to intercurrent illness, or concomitant medications, which are determined by the Investigator to be related to the study drug and meet any of the following criteria:
With observation of apparent dose-limiting toxicity, review by the SRC will take place as soon as possible to evaluate the events and determine next steps.
This is a phase 1b, multi-centre, double-blind, parallel arm, placebo-controlled study of LYT-100 in patients with breast cancer-related lymphoedema. The study will be performed in up to 5 clinical sites in Australia.
The SRC will convene after 20% of the patients enrolled in Part 3 have completed Week 8 of the Treatment Phase and the double-blind data is available for review. If safety or tolerability issues are identified by the medical monitor for patients while receiving LYT-100 vs. placebo at any time in Part 3, the SRC may meet again to review safety and available population PK data and provide recommendations. Options for changes to dosing or protocol assessments may be recommended by the SRC. Ultimate decisions regarding those recommendations remain with the Sponsor. Adverse events of special interest including elevated liver enzymes (e.g., ALT, AST, total bilirubin elevations), photosensitivity and rash, and gastrointestinal symptoms (e.g., nausea, vomiting diarrhea, dyspepsia, gastroesophageal reflux and abdominal pain) will be reviewed by the medical monitor periodically for changes in IP tolerability throughout the trial and if warranted, may trigger additional ad hoc SRC meeting(s).
Parts 1 and 2: Up to 40 healthy female and male adult participants (3:1 ratio), unless additional intermediate cohorts are needed.
Part 3: Up to 50 patients with breast cancer-related upper-limb unilateral secondary lymphoedema (1:1 ratio).
1. Male or female between 18 and 75 years old (inclusive) at the time of screening.
2. In good general health at screening, free from clinically significant unstable medical, surgical or psychiatric illness, at the discretion of the Investigator.
3. Participants have a body mass index (BMI) between ≥ 18.0 and ≤ 35.0 kg/m2 at screening.
4. Vital signs (measured in supine position after 5 minutes’ rest) at screening:
5. Systolic blood pressure ≥90 and ≤140 mmHg;
6. Diastolic blood pressure ≥40 and ≤ 90 mmHg;
7. Heart rate ≥40 and ≤100 bpm;
8. Temperature ≥35.5° C. and ≤ 37.5° C.;
9. Vital signs may be repeated once, within a minimum of 10 minutes of the completion of the last set of vital signs (while maintaining supine position until the repeated set of vital signs are collected), if it is suspected that falsely high or low levels have been obtained.
10. No relevant dietary restrictions, and willing to consume standard meals provided and willing to avoid soy products while participating in the trial.
11. Willing to comply with all study procedures and requirements, including not driving or operating machinery for 12 h following study drug administration.
12. Willing to abstain from direct sun exposure from 2 days prior to dosing and until final study procedures have been conducted.
1. History or presence of malignancy at screening or baseline, with the exception of adequately treated localised skin cancer (basal cell or squamous cell carcinoma) or carcinoma in-situ of the cervix.
2. Clinically significant infection within 28 days of the start of dosing, or infections requiring parenteral antibiotics within the 6 months prior to screening.
3. Clinically significant surgical procedure within 3 months of screening, at the discretion of the Investigator.
4. Currently suffering from clinically significant systemic allergic disease at screening or baseline or has a history of significant drug allergies including a history of anaphylactic reaction (particularly reactions to general anaesthetic agents); allergic reaction due to any drug which led to significant morbidity; prior allergic reaction to pirfenidone.
5. Chronic administration (defined as more than 14 consecutive days) of immunosuppressants or other immune-modifying drugs within 3 months prior to study drug administration. Corticosteroids are permitted at the discretion of the Investigator.
6. History or presence at screening or baseline of a condition associated with significant immunosuppression.
7. Positive test for hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg), or human immunodeficiency virus (HIV) antibody at screening.
8. Symptoms of dysphagia at screening or baseline or known difficulty in swallowing capsules.
9. Any condition at screening or baseline (e.g., chronic diarrhoea, inflammatory bowel disease or prior surgery of the gastrointestinal tract) that would interfere with drug absorption or any disease or condition that is likely to affect drug metabolism or excretion, at the discretion of the Investigator.
10. History or presence at screening or baseline of cardiac arrhythmia or congenital long QT syndrome.
11. QT interval corrected using Fridericia’s formula (QTcF) > 450 msec. ECG may be repeated30 to 60 minutes apart from the first one collected at screening. If repeat ECG is ≤450 msec, the second ECG may be used to determine patient eligibility. However, if repeat ECG confirms QTcF remains >450 msec, the subject is not eligible.
12. Use of tobacco or nicotine containing products in the previous 3 months prior to dosing or a positive urine cotinine test at Screening or Baseline.
13. Lack of willingness to abstain from the consumption of tobacco or nicotine-containing products throughout the duration of the study and until completion of the final Follow-up visit.
14. Regular alcohol consumption defined as > 21 alcohol units per week (where 1 unit = 284 mL of beer, 25 mL of 40% spirit or a 125 mL glass of wine) or the Participant is unwilling to abstain from alcohol for 48 h prior to admission and 48 h prior to study visits.
15. Use of any prescription drugs (other than permitted contraception), over-the-counter (OTC) medication, nonsteroidal anti-inflammatory agents (NSAIDs), herbal remedies, supplements or vitamins within the 2 weeks prior to dosing or throughout the duration of the study, without prior approval of the Investigator and written approval of the Medical Monitor.
16. Paracetamol may be utilised, provided that the dose of Paracetamol does not exceed 2 g in any 24 h period.
17. Use of any of the following drugs within 28 days or 10 half-lives of that drug, whichever is longer, prior to study drug administration:
18. Vaccination with a live vaccine within the 4 weeks prior to screening or that is planned within 4 weeks of dosing.
19. Exposure to any significantly immune suppressing drug within the 3 months prior to screening or 5 half-lives, whichever is longer.
20. Use of any investigational drug or device within 3 months prior to screening.
21. Consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange juice, or any foods containing these ingredients, within 7 days prior to dosing or unwilling to abstain from these throughout the duration of the study.
1. Female or male between ≥ 18 and ≤ 80 years old (inclusive) at the time of informed consent.
2. At least 6 months since any type of breast cancer surgery (excluding fine needle aspiration biopsy [FNA]), at the time of study screening. No intention to have breast reconstructive surgery, nipple reconstruction and/or tattooing during the course of the study.
3. At least 3 months since completion of all types of treatment for breast cancer, including but not limited to, neoadjuvant therapy, investigational adjuvant therapy, radiotherapy, adjuvant chemotherapy intravenous and/or oral, biologic therapy (e.g., trastuzumab and pertuzumab) at the time of study screening.
4. At least 3 months of stable adjuvant treatment with hormonal or anti-HER2 therapy at the time of screening, with no planned changes to this therapy throughout the duration of the study.
5. Diagnosis of primary breast cancer, and without evidence of local, locoregional and/or distant recurrence, and/or metastasis of breast cancer for at least 6 months since breast cancer surgery, as determined at screening and baseline.
6. Documented evidence of Stage 1 or 2 lymphedema. Such evidence may include pitting oedema in one arm for at least 3 months and also at screening and at least one of the following:
7. Receiving standard of care compression or agreeable to using care compression, i.e. sleeves and/or pumps and/or manual lymphatic drainage, or no compression care and/or no manual lymphatic drainage ≥ 4 weeks prior to screening and throughout the study.
8. In good general health at screening and baseline apart from a history of breast cancer and secondary lymphoedema, i.e., free from clinically significant unstable medical, surgical or psychiatric illness (at the discretion of the Investigator); no acute conditions requiring invasive care or hospitalisation; and no conditions or elective procedures requiring invasive intervention within the next 6 months.
9. Vital signs (measured in supine position after 10-minutes rest) at screening:
10. Body Mass Index ≥18 and ≤35 kg/m2 at screening.
11. Willing and able to abstain from direct whole body sun exposure from 2 days prior to dosing and until final study procedures have been conducted. Participants should be instructed to avoid or minimise exposure to sunlight (including sunlamps), use an SPF 50 sun block, or higher, wear clothing that protects against sun exposure and avoid concomitant medications known to cause photosensitivity.
1. Bilateral lymphoedema or history of bilateral axillary lymph node removal (i.e., sentinel lymph node biopsy or axillary lymph node dissection), or primary lymphoedema or lymphatic or vascular malformation, determined at screening.
2. Chronic administration (defined as more than 14 consecutive days) of immunosuppressants or other immune-modifying drugs within 3 months prior to study drug administration; corticosteroids are permitted at the discretion of the PI.
3. Recent history (in the 8 weeks prior to screening) of cellulitis, lymphangitis, dermatitis, necrotising fasciitis, or current open wounds or sores in the affected extremity.
4. Fibrotic stranding on affected arm not related to BCRL; history of breast or arm procedures unrelated to axillary node dissection such as non-cancer related reconstructive or cosmetic breast surgery, Botox for hyperhidrosis, chronic intravenous use, port, pic-line, etc., for medical or recreational reasons, tattoos (excluding pink ribbon tattoo designated to inform health caretaker not to take blood pressure in affected arm), or other extreme body modifications, determined at screening.
5. Stage III lymphedema, or history of clinically diagnosed secondary lymphoedema greater than 2 years, determined at screening.
6. Initiated use of compression or manual lymphatic drainage or other lymphoedema therapies at the start of the study within 4 weeks of the screening visit. Rescreening is allowed following a course of stable compression regimen of > 4 weeks.
7. Presence of malignancy, with the exception of adequately treated localised skin cancer (basal cell or squamous cell carcinoma), carcinoma in-situ of the cervix, or unilateral breast cancer history with completed treatment and with no active cancer at the time of screening or in the preceding 6 months.
8. Evidence of clinically relevant medical history/illness at screening, as determined by the Investigator including stroke, uncontrolled hypertension, and other cardiac disease, vascular disease, pulmonary disease, gastrointestinal disease, hepatic disease, renal failure and other kidney disease, rheumatologic disease, coagulopathy or other haematological disease, uncontrolled diabetes and other endocrine disorders, any progressive neurologic disorder, psychiatric disease, dermatological disorder, or surgical history except for orthopaedic and reconstructive breast cancer surgery.
9. Clinically significant infection within 28 days of the start of dosing, as determined by the Investigator.
10. Clinically significant surgical procedure/s, including but not limited to breast cancer reconstruction surgery, within 3 months of screening, or further breast cancer reconstruction surgery planned during the Study.
11. For baseline liver function tests (LFT) 2.5 x upper normal limit (UNL) or severe hepatic impairment
12. Currently suffering from clinically significant systemic allergic disease at screening or baseline or has a history of significant drug allergies including a history of anaphylactic reaction (particularly reactions to general anaesthetic agents); allergic reaction due to any drug which led to significant morbidity; prior allergic reaction to pirfenidone.
13. Symptoms of dysphagia or known difficulty in swallowing capsules, determined at screening.
14. History or presence of cardiac arrhythmia or congenital long QT syndrome determined at screening.
15. QTcF > 450 msec demonstrated by two ECGs between 30 and 60 minutes apart at screening.
16. Use of tobacco or nicotine containing products in the previous 3 months prior to dosing or a positive urine cotinine test at Screening or Baseline.
17. Regular alcohol consumption defined as >21 alcohol units per week (where 1 unit = 284 mL of beer, 25 mL of 40% spirit or a 125 mL glass of wine), determined at screening.
18. Use of any over-the-counter medication, herbal supplements, or diet aids within 48 h prior to dosing.
19. Treated with immunosuppressive or antifibrotic drugs, anti-tumour necrosis factor, immunotherapy, or investigational drugs at screening or within the preceding 30 days.
20. Use of any of the following drugs within 28 days or 10 half-lives of that drug, whichever is the longer, prior to study drug administration:
21. Use of any investigational drug or device within 28 days or 10 half-lives of the drug, whichever is the longer, prior to start of dosing.
22. Any condition (e.g., chronic diarrhoea, inflammatory bowel disease or prior surgery of the gastrointestinal tract) that would interfere with drug absorption or any disease or condition that is likely to affect drug metabolism, or excretion, determined at screening.
23. History of anaphylactic reaction (particularly reactions to general anesthetic agents); allergic reaction due to any drug which led to significant morbidity; prior allergic reaction to pirfenidone.
All participants in Parts 1 or 2 will be randomised 3:1 to receive either LYT-100 (deupirfenidone) formulated as powder in capsules, or placebo (a matching, inactive capsule containing methyl cellulose). All patients in Part 3 will be randomized to receive LYT-100 or placebo in a 1:1 ratio. The dosing regimen per study part and cohort is presented below:
A All participants from prior cohorts from Part 1 will be invited to return following a minimum 7-day washout to participate in the Part 2 Fed/Fasted cohort (Cohort 5), where a single dose of 500 mg LYT-100 or Placebo will be administered under fed or fasted conditions. The alternate fast/fed meal sequence for the second single dose received will occur ≥ 7 days later.
† Cohort 5 will consist of any participants who participated previously in another of the cohorts in Part 1. A washout period of at least 7 days will apply between single dosing under fed conditions and fasted.
Safety and tolerability will be assessed throughout Part 1, Part 2 and Part 3 of the study by monitoring AEs, physical examination, vital signs, 12-lead ECGs, clinical laboratory values (haematology panel, multiphasic chemistry panel and urinalysis), and review of concomitant treatments/medication use.
For Part 3 only, the following parameters will be measured at each study visit except the screening visit:
For Part 3 only, the following will be assessed at Day -1, Weeks 1, 12 and 26 (or early termination), and during follow-up post end of treatment (Weeks 28, 36 and 48):
For Part 3 only, the following will be assessed along with Adverse Events:
Participants will provide blood samples at Baseline (Day -1) for the determination of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 genotype to support exploratory PK analyses. Participants are required to provide consent for genotyping.
In Part 1, blood samples (4 mL each) for PK will be collected for Cohorts 1, 2, 3, 4, and 6 at specified times (hours) at each as follows:
Data will be used to assess the PK profiles of multiple BID doses of LYT-100 administered with food over 5 days for dose proportionality.
In Part 2, blood samples (4 mL each) for PK will be collected for Cohort 5 fed and fasted at specified times as follows:
Data will be used to descriptively compare the PK profile and compare the relative bioavailability of a single dose of LYT-100 administered at a dose below the MTD with food, to the equivalent dose without food. Comparison of the PK parameters in the fed and fasted states will be performed, and analysis of PK by gender may be performed if the data allow.
Plasma concentration time data for LYT-100, and its metabolite(s) will be analysed using non-compartmental methods. Pharmacokinetics for Day 1 to 3 in Part 2 (fed state) will be compared to PK for Day 1 to Day 3 in Part 2 (fasted state). Plasma PK parameters (non-compartmental or compartmental analysis as appropriate) will include, but are not limited to:
Blood samples (4 mL each) for population pharmacokinetics will be collected for Cohort 7 at specified times at any visit from Week 1 to Week 26 of the study. Each participant will provide up to a minimum of 1 sample at each timepoint in reference to dosing: Pre-dose, 1 to <2 h, 2 to <4 h, 4 to <8 h, 8 to 12 h.
Sparse PK sampling will be employed for population PK analysis (as a secondary endpoint) to determine the variability of LYT-100 drug concentration data from individual patients across multiple clinical sites.
The conclusion from Part 2 demonstrated that the food effect on the PK Cmax of LYT-100 appears to be less than the reported food effect PK Cmax of pirfenidone, which is thought to be related to the acute adverse events of pirfenidone. There were no clear correlations between the adverse events seen and the fed and fasted states. The overall safety and tolerability profile with and without food, taken together with the reduced food effect on Cmax in Part 2 of this study suggests that there is no clear rationale for patients to take LYT-100 with regard to food. If safety and tolerability issues are reported during the study, the patient may be instructed to take study medication with food during Part 3.
The following parameters will be measured in Part 3 only at all study visits except the screening visit:
Comparisons between LYT-100 and placebo will be based on clinical interpretation of effect, magnitudes of effect, and a preponderance of evidence. Estimates of changes over time from these data may be used to power future clinical studies. The number of occurrences of cellulitis and lymphangitis within the treatment period will be tabulated. Visual-analogue scales (VAS) for pain, swelling, discomfort, and function, and QoL assessments using the LSIDS-A and LYMQOL questionnaires will be provided at baseline and treatment period timepoints.
In Part 1 and Part 2, eight participants per cohort were chosen to adequately characterise the rate and extent of absorption as measured by select PK parameters, and to allow comparison of PK in a fed versus fasted state.
Part 3 will randomize 50 patients with secondary lymphoedema, in a 1:1 ratio to LYT-100 or placebo, as part of this early development and exploratory study of LYT-100. Formal sample size calculations will not be performed; rather, the sample size selected should be adequate for preliminary evaluation of safety, tolerability, efficacy signalling, PK and fibrotic and inflammatory biomarker parameters in the targeted patient population.
The analysis will be consistent with the study design, with assessment of each Part performed separately. The baseline for all variables will be the last measurement obtained prior to the participant receiving the first dose of study treatment.
Participant disposition (including the number and percent of participants/patients who are enrolled, who receive treatment, who prematurely discontinue and reasons for discontinuation, and who complete the study) will be tabulated by treatment group. Summary statistics for days of exposure and concentration of exposure will be provided by treatment group.
Adverse events, concomitant medications, clinical laboratory findings, physical examinations, ECGs and vital signs for each participant will be tabulated or summarised descriptively, where appropriate.
Demographic information will be presented for each participant and summarised. Treatment-emergent adverse events and laboratory, vital signs, and ECG parameters will be summarised. In addition, change from baseline will be summarised for laboratory and vital sign parameters. Shift tables will also be provided for clinical laboratory results. ECG results will be classified as normal and abnormal and summarised. ECG results for QTcF will also be classified as <450 msec, 450-500 msec or >500 msec. Changes in physical exams will be described.
Analysis populations will be defined for each Part separately. In general:
Analyses will be performed for each cohort separately. Determination of steady state for LYT-100 will be performed using Helmert Contrasts using trough concentrations at Days 2, 3, 4, 5, and 6. Pharmacokinetic parameter values will be listed and summarised by dose. Dose-linearity across the LYT-100 doses will be assessed. Comparison of the PK parameters in the fed and fasted states will be performed, and analysis of PK by gender may be performed if the data allow.
Analysis of clinical assessments and potential progression or disease will be explored. Comparisons between LYT-100 and placebo will be based on clinical interpretation of effect, magnitudes of effect, and a preponderance of evidence. Estimates of changes over time from these data may be used to power future clinical studies.
The primary endpoints are safety (clinical laboratory parameters, vital signs, ECGs and spontaneously reported AEs) and tolerability. Secondary endpoints include efficacy (lymphoedema assessments, infection and health related QOL), population PK and fibrotic and Inflammatory biomarkers: Change from Baseline to each post-Baseline visit (through Week 26; on-treatment effect), as well as the change from Baseline to Week 28, 36 and Week 48 on the following endpoints will be calculated for the following endpoints: fibrotic and inflammatory biomarkers (G-CSF, MIG, FGF-2, IL-4, IL-10, lymphotoxin α/TNF-β, leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, MCP-1), limb water content (BIS), limb volume (truncated cone tape measure and/or perometry), tissue dielectric constant (MoistureMeterD), tissue firmness (tonometry/SkinFibroMeter), visual-analogue scales (pain, swelling, discomfort, and function), and QoL (LSIDS-A, LYMQOL). For select efficacy outcomes, use of a mixed model for repeated measures (MMRM) will be used to provide model-based estimates of changes over time in each of these outcomes. Descriptive statistics will also be provided at each time point. Details for the model (including covariates to be included) will be provided in the SAP. Data for all endpoints will be tabulated, displayed graphically or summarised descriptively, as appropriate. No formal hypothesis testing will be performed.
All cohorts (n=6 each) were dosed every 12 hours with food for 5 days at either 100, 250, 500, or 750 mg BID. Blood samples were obtained according to the schedule described herein above, and LYT-100 (d3-pirfenidone), 5-carboxy-pirfenidone, d2-5-hydroxymethyl-pirfenidone, and d3-4′-hydroxy-pirfenidone, and their corresponding internal standards (pirfenidone, d5-5-carboxy-pirfenidone, d5-5-hydroxymethyl-pirfenidone, and 4′-hydroxy-pirfenidone) extracted from the human plasma using a protein precipitation plate procedure. Following processing, the samples were analyzed by HPLC on a Phenomenex Luna PFP(2), 3 µm, 50 x 2.0 mm column, and the eluates were monitored by an API4000 MS/MS detector in positive MRM mode. The data were acquired and processed by the data acquisition system Analyst® (Sciex). The method range was from 5.00 to 5,000 ng/mL for LYT-100 and 5-carboxy-pirfenidone, and 0.500 to 500 ng/mL for the secondary metabolites, using a 50 µL aliquot of human plasma and has a run time of approximately 6 minutes per sample.
Pharmacokinetic data for Cohort 4 (Tmax, Cmax, AUC0-12, AUC12-24, AUC96-108, and AUC accumulation ratio (AUC96-108/AUC0-12)) for the active and each metabolite is provided in
Pharmacokinetic data for LYT-100 and each metabolite (SD-789, SD-790, and SD-1051) are provided for each dosing Cohort (100 mg, 250 mg, 500 mg, and 750 mg BID) in
The dose dependent AUC was evaluated for LYT-100 and SD-789 across all four dose Cohorts using the AUC96-108 data points. The data (
Pharmacokinetic data for LYT-100 and each metabolite (SD-789, SD-790, and SD-1051) are provided for Cohort 6 (1000 mg BID) in
Pharmacokinetic data for LYT-100 and each metabolite (SD-789, SD-790, and SD-1051) are provided for each dosing Cohort (100 mg, 250 mg, 500 mg, 750 mg, and 1000 mg BID) in
Pharmacokinetic data for LYT-100 and each metabolite (SD-789, SD-790, and SD-1051) are provided for each of the six subjects of Cohort 6 (1000 mg BID) in
Pharmacokinetic data for Cohort 6 (Tmax, Cmax, AUC0-12, AUC12-24, AUC96-108, and AUC accumulation ratio (AUC96-108/AUC0-12)) for the active and each metabolite is provided in
Pharmacokinetic data for LYT-100 and each metabolite (SD-789, SD-790, and SD-1051) are provided for each dosing Cohort (100 mg, 250 mg, 500 mg, 750 mg, and 1000 mg BID) in
The dose dependent AUC was evaluated for LYT-100 and SD-789 across all dose Cohorts using the AUC96-108 data points. The data (
Data across the Cohorts was compared against data from Huang et al. (“Pharmacokinetics, Safety and Tolerability of Pirfenidone and its Major Metabolite after Single and Multiple Oral Doses in Healthy Chinese Subjects under Fed Conditions.” Drug Res (Stuttg) 63, 388-395; 2013) at 200 mg BID pirfenidone, extrapolated to 100, 250, 500, 750, 1000 mg assuming dose proportionality, and comparing to AUC0-12 and Cmax, LYT-100 and SD-789 only. With the exception of the 500 mg dose, there was an increase for LYT-100 AUC over that of SD-559 and a decrease for SD-789 Cmax over that of SD-559 (
Pharmacokinetic data for LYT-100 and each metabolite (SD-789, SD-790, and SD-1051) are provided for dosing Cohort 5 (500 mg single dose; fasted and fed states) in
Pharmacokinetic data for Cohort 5 (Tmax, Cmax, AUC0-inf) for the active and each metabolite in fasted and fed subjects following a single 500 mg dose is provided in
A comparsion of data from the 750 mg MAD dose, pirfenidone at 750 mg, and the SAD dose of LYT-100 extrapolated to 750 mg (
A total of 28 of 40 (70.0%) participants randomized to LYT-100 or placebo had at least one treatment-emergent adverse event (TEAE) in the MAD study. Fifteen of 30 (50.0%) participants treated with LYT-100 experienced TEAEs that were considered at least possibly treatment-related, with no apparent trend of increasing frequency with increasing dose, while 3 of 10 (30.0%) participants treated with placebo experienced at least possibly treatment-related TEAEs. Based on the blinded data obtained in the MAD study, all adverse events were mild and transient, and none lead to study discontinuation. The most commen events were headache, abdominal distension, and nausea (Table 14). Overall, LYT-100 was found to be well-tolerated in the dose range from 100 mg up through 1000 mg BID over 5 days of treatment. During Part 2 (assessment of food effect), there was no evidence of any tolerability concerns for a single dose of 500 mg given either with or without food.
In contrast to pirfenidone (Phase I study, PIPF-005), LYT-100 did not demonstrate a dose-related increase in adverse events based on the MAD blinded study data. For example, the low 250 mg BID dose had the most AEs, while the high dose (1000 mg) had the lowest (two incidences of headache; Table 14).
There were no clinically significant (CS) hematology and coagulation, chemistry, or urinalysis results reported for participants in the LYT-100 treated or placebo groups. There were no observed trends of increasing or decreasing parameters with ascending dose level, repeat dosing, or differences between placebo and LYT-100 groups, and no clinically significant vital signs, weight, ECG or physical examination findings were observed on the study. There were no dose limiting toxicities observed, and no maximally tolerated dose was reached.
Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation, hepatocyte ballooning and degeneration progressing to liver fibrosis. LYT-100 was orally administered at 0 mL/kg (Vehicle only: 0.5% CMC) or 10 mL/kg twice daily from 6-9 weeks of age in 18 male mice in which NASH mice was induced by a single subcutaneous injection of 200 µg streptozotocin solution 2 days after birth and feet with a high fat diet after 4 weeks of age. LYT-100 was administered at an oral dose of 30 mg/kg twice daily (60 mg/kg/day). In addition, nine non-NASH mice were fed with a normal diet and monitored.
Liver sections from the Vehicle group exhibited severe micro- and macro vesicular fat deposition, hepatocellular ballooning and inflammatory cell infiltration. While LYT-100 hepatocyte ballooning was similar to Vehicle, scores were lower for lobular inflammation and steatosis. (Table 16).
As evidenced above, LYT-100 significantly reduced the area of fibrosis, reduced inflammation, and reduced accumulation of fat (steatosis), as compared to the untreated NASH mice.
LYT-100 was evaluated for an ability to reduce the TGF-β-induced proliferation of, and collagen levels in, Primary Mouse Lung Fibroblasts (PMLF).
Inhibition of p38 members by LYT-100 is important as p38 members are activated by TGF-β signaling pathway. TGF-β activation, in turn plays a significant role in transcriptional induction of the collagen type IA2. The collagen type IA2 makes up the majority of extracellular matrix, which accumulates during progression of, e.g., IPF. Deposition of collagen is one of the most important components of fibrotic lung tissue, a process primarily induced by TGF-β. Since accumulation of insoluble collagen encroaches on the alveolar space, it plays pivotal role in distortion of lung architecture and progression of IPF. Therefore, inhibition of TGF-β -induced collagen synthesis is an important target for IPF. In addition to insoluble (structural) collagen, fibrotic lungs of IPF patients also show high levels of non-structural (soluble) collagen.
Although this type of collagen may eventually become insoluble collagen, until then, soluble collagen can serve as a ligand for integrin receptors of lung fibroblasts and epithelial cells. Binding of soluble collagen to these receptors induces proliferation and migration of these cells. Fibronectin is another important component of fibrotic lungs as it is induced by TGF-β and functions both as a structural component of extra cellular matrix (ECM), as well as a ligand for integrin receptors. Just like soluble collagen, binding of fibronectin to integrin receptors induces the proliferation of fibroblast and epithelial cells of the lungs and plays significant role in progression of IPF.
Primary Mouse lung fibroblast were prepared as follows. One lung was removed from 2 months old male BalbC Mouse, perfused with sterile PBS, minced and incubated in 2 ml of serum free Dulbecco’s Modified Eagle’s Medium (DMEM) containing 100 µg/ml of collagenase I for one hour at 37° C. Each sample was centrifuged at 1500 r.p.m (revolution per minute) for 5 minutes, washed three times with PBS and the final cellular pellet was resuspended in DMEM supplemented with 10% serum and Pen/Strep, and incubated in 150 mm plates at 37 ∘C with 80% humidity and %% CO2. The growth medium was removed and fresh medium was added every day for 10 days.
LYT-100 was evaluated for an ability to alter TGF-β-induced proliferation of PMLF. At the end of 10-day incubation period above, lung fibroblasts were confluent. Before testing the effect of LYT-100 on survival of these cells, fibroblasts were tripsinized and five thousand cells were plated into 96 well plate in 200 µL complete DMEM, and incubated until cells reached to 95-100% confluency, then the medium was removed and complete DMEM containing Prolin (10 µM) and Ascorbic acid (20 µg/ml) was added. LYT-100, dissolved in pure ethanol, was added to the plates at a final concentration of 500 µM 1 h prior to addition of TGF-β (5 ng/ml), and cells were further incubated for 72 hrs. One hundred µL of the growth medium was removed and 20 µL of MTT stock solution (prepared in PBS at 5.5 mg/ml concentration) was added and cells were incubated for 4 hours, then 100 µl of DMSO was added, and absorbance of developed color was monitored at 540-690 nm.
As shown in
The effect of LYT-100 on inhibition of TGF-β-induced collagen synthesis was evaluated in PMLF in a 6-well format. One hundred thousand Primary Mouse Lung Fibroblasts were plated in 6-well plates and incubated in complete DMEM until they reached confluency. The incubation medium was removed and complete DMEM containing Prolin (10 µM) and Ascorbic acid (20 µg/ml) was added. LYT-100 was added to the plates at a final concentration of 500 µM 1 h prior addition of TGF-β (5 ng/ml), and cells were further incubated for 72 hrs.
Supernatant was removed, cells were washed with cold PBS, 1 ml Sircol reagent was added. The Sircol reagent contains the collagen binding dye Sirius red. The cells were scraped off with Sircol reagent and samples were shaken for 5 h at room temperature (RT), centrifuged at 10,000 rpm for 5 min, supernatant was removed, the pellet was washed in 0.5 M acetic acid to remove unbound dye, and recentrifuged at 10,000 rpm for 5 min, supernatant was removed and the final pellet was dissolved in 1 ml 0.5 M NaOH and shaken at RT for 5 h. A sample of 100 µl of resultant solution was placed in 96-well. The color reaction was assessed by optical density at a wavelength of 600 nm.
As shown in
The effect of LYT-100 on TGF-β-induced collagen was confirmed in a high throughput collagen assay using 96-well plate format. Approximately 5,000 primary mouse fibroblasts were plated in complete DMEM in 96 well plates and incubated for 3 days at which time the cultures achieved confluency. After cells reached confluency, the medium was removed and fresh DMEM supplemented with ascorbic acid (20 µg /ml) and prolin (10 µMol) was added. LYT-100 was then added to the appropriate cultures at a final incubation concentration of 500 µM. One hour later, TGF-β was added to the appropriate cultures at a final concentration of 5 ng/ml. After 72 hours, the media was replaced with a 0.5% glutaraldehyde solution. After 30 minutes, the adherent cells were washed and subsequently incubated with acetic acid at a final concentration of 0.5 M. After a 30 min room temperature incubation, and subsequent washing steps, the wells were incubated with Sircol reagent. After 5 hours, the unbound dye was removed and the plates were washed and allowed to dry. To extract collagen-bound Sircol, 100 µL of alkaline solution (0.5 M NaOH) was added and plates were shaken for 1 h on rotary shaker at room temperature. Absorbance at 600 nm was determined to detect bound collagen.
As shown in
LYT-100 was evaluated for its ability to modify TGF-β-induced soluble fibronectin and soluble collagen synthesis using a selective ELISA. Approximately 5,000 primary mouse lung fibroblasts were plated in complete DMEM in 96 well plates and incubated for 3 days at which time the cultures achieved confluency. After cells reached to confluency, medium was removed and fresh DMEM supplemented with ascorbic acid (20 µg /ml) and prolin (10 µM) was added. LYT-100 was then added to the appropriate cultures at a final incubation concentration of 500 µM. One hour later, TGF-β (5 ng/ml) was added to the appropriate cultures at a final concentration. After 72 hours, 200 µl samples of the supernatant were placed onto an ELISA plate and incubated overnight. After blocking with %1 BSA for 2 h, plates were incubated with either an anti-collagen type I antibody or an anti-fibronectin antibody.
The plates were washed after 1 hour and incubated with secondary horseradish peroxidase-conjugated antibodies (anti-goat for the collagen antibody, anti-rabbit for the fibronectin antibody). After a series of washing steps the color reagent TMB (3,3′,5,5′-Tetramethylbenzidine) was added and 15 minutes later the reactions were terminated with equal volumes of 2 N H2SO4. The levels of soluble collagen and fibronectin were determined by evaluating absorbance at 450 nm.
Referring to
As shown in
In summary, LYT-100 was found to: (i) reduce TGF-β-induced cell proliferation, (ii) reduce both background and TGF-β-induced levels of insoluble (structural) collagen; (iii) reduce both background and TGF-β-induced levels of soluble collagen; and (iv) reduce both background and TGF-β-induced levels of soluble fibronectin.
During the progression of IPF, an accumulation of extra cellular matrix components such as collagen and an increase in the fibroblast population is observed. Persistent proliferation of fibroblasts is considered an important contributor to the lung architecture in IPF, including the diminished interstitial spaces of the alveoli. Thus, reducing TGF-β-induced proliferation of fibroblasts and structural collagen with LYT-100 has the potential to prolong lung function in IPF. In addition to inhibiting TGF-β-induced insoluble collagen level, LYT-100 also inhibits TGF-β-induced secreted collagen and fibronectin β. Secreted collagen and fibronectin not only increase the rate of formation of fibrotic foci in the lung, these proteins can also act as ligands for integrin receptors. When integrin receptors are activated they induce not only the proliferation of epithelial cells and fibroblasts of the lungs, but they also, along with TGF-β, induce epithelial mesenchymal transition (EMT) of the epithelial cells of the lungs. EMT causes these cells to migrate to different regions of the lungs. This migration is considered to be a very important contributor for the generation of new fibrotic foci in the lungs and progression of IPF.
LYT-100 has the ability to inhibit TGF-β-induced pro-fibrotic processes and to reduce basal factors, which have the potential to exacerbate ongoing fibrosis.
The effect of LYT-100 on survival of L929 cells was determined. Five thousand L929 cells were plated in completed DMEN and incubated until confluency for 3 days. Medium was removed and complete DMEM containg Prolin (20 µg/ml) and ascorbic acid (10 uM) was added. LYT-100 was given at 500 µM 1 h prior addition of TGFb (5 ng/ml), and cells were further incubated for 72 hrs. 100 µL of medium was removed, 20 µL MTT solution was added for 4 hrs, then 100 µl of DMSO was added, and absorbance of developed dark pink color was determined at 54-690 nM.
The effect of LYT-100 on TGF-induced collagen synthesis in 6-wells was determined. 100,000 L929 cells were plated in complete DMEN and incubated until confluency for 3 days. Medium was removed and complete DMEM containg Prolin (20 µg/ml) and ascorbic acid (10 µM) was added. LYT-100 was given at 500 µM 1 hour prior addition of TGF-β (5 ng/ml). Cells were further incubated for 72 hrs. Supernatant was removed, cells were washed with cold PBS, 1 ml SIRCOL reagent was added onto the cells and cells were scraped off, samples were shaken for 5 h.at RT, centrifuged at 10.000 rpm for 5 min, supernatant was removed, pellet was dissolved in 0.5 M acetic acid to remove unbound dye, and re-centrifuged at 10.000 rpm for 5 min, supernatant was removed and final pelet was dissolved in 1 ml 0.5 M NaOH, shaken at RT for 5 h, 100 µl of resulted solution was placed in 96-well and O.D was determined at 600. The results are summarized in
Next, the effect of LYT-100 onTGF-induced collagen synthesis was confimed using 96-well plate format. Five thousand L929 cells were plated in complete DMEN and incubated until confluency for 3 days. Medium was removed and complete DMEM containg Prolin (20 µg/ml) and ascorbic acid (10 µM) was added. LYT-100 was given at 500 µM 1 h prior addition of TGF-β (5 ng/ml). Cells were further incubated for 72 hrs. Supernatant was removed, 0.5% gluteraldehyde was added for 30 min at RT, removed, washed 3X with ddwater, 0.5 M acetic acid was added for 30 min at RT, removed, washed with water, air dried and 100 µl SIRCOL dye was added for 5 h at RT. Dye was removed, plate was washed extensively under running water, air dried and 200 µl of 0.5 M NaOH was added, plates were shaken at RT for 1 h, and OD was determined at 600 nm. The results summarized in
The effect of LYT-100 on TGF-induced Soluble Collagen Synthesis was determined using a 96-well plate format. Five thousand L929 cells were plated in complete DMEN and incubated until confluency for 3 days. Medium was removed and complete DMEM containing Prolin (20 µg/ml) and ascorbic acid (10 µM) was added. LYT-100 was given at 500 µM 1 h prior addition of TGF-β (5 ng/ml). Cells were further incubated for 72 hrs. 200 µl supernatant of 96-well SIRCOL plate was placed onto ELISA plate and incubated O/N. Next day, supernatant was removed and 100 ul of 1%BSA in PBST was added and incubated for 2 h at RT, BSA was removed, plate was washed 3x with 200 µl of PBST, and anti-collagen type I a.b was added at 1:2000 dilution (prepared in %1 BSA in PBST), incubated at RT for 1 h, primary a.b was removed, plate was washed 3x with 200 µl PBST, and secondary anti-goat HRP was added at 1:2000 dilution, incubate at RT for 1 h, removed, plate was washed 3x with 200 µl PBST and 100 µl of TMB solution was added for color development for 15 min, then 100 µl of 2 N H2SO4 was added to stop the reaction and O.D of developed yellow color was determined at 450 nm.
As illustrated in
Fibronectin is another important component of fibrotic lungs as it is induced by TGF-β and functions both as a structural component of extra cellular matrix as well as well as a ligand for integrin receptors. Just like soluble collagen, binding of fibronectin to integrin receptors induces the proliferation of fibroblast and epithelial cells of the lungs. The effect of LYT-100 of TGF-induced soluble fibronectin synthesis was determined using a process similar to that described in the above paragraph for soluble collagen synthesis except that a fibronectin ELISA was used. As illustrated in
This experiment tested the effect of LYT-100 in a mouse tail model of lymphedema. LYT-100 or control (carboxymethylcellose) was delivered once daily by oral gavage, in mice with ablated tail lymphatics via circumferential excision and ablation of collecting lymphatic trunks. Tail volume was measured weekly for all animals, starting pre-surgery and continuing until the occurrence of COVID19 required termination of the study at 6 weeks. At sacrifice, tails were harvested for histology and immunofluorescent imaging to characterize tissue changes with surgery and LYT-100 or control treatment. Tail volume and markers of lymphatics, fibrosis, and inflammation were compared between LYT-100 and the control group.
Animals: 14 adult (10-14 week old) C57BL/6 J mice. 7 animals per group.
Surgery: The superficial and deep collecting lymphatics of the mid portion of the tail were excised using a 2-mm full-thickness skin and subcutaneous excision performed at a distance of 15 mm from the base of the tail. Lymphatic trunks (collecting lymphatics) adjacent to the lateral veins were identified and ablated through controlled, limited cautery application under a surgical microscope.
The dosing amounts, route and schedule are provided in Table 17.
Measurements are provided in Table 18.
Study procedure and timing are provided in Table 19.
LYT-100 and pirfenidone were administered orally once daily for 91 consecutive days to Sprague Dawley rats to evaluate the potential reversibility of any findings following a 4-week recovery period. The profile of LYT-100, pirfenidone, and their metabolites were compared in order to understand the relationship between systemic exposure and their toxicity.
Male and female Sprague Dawley rats were separated in 6 different groups based on the 250, 500 and 750 mg/kg dose levels of LYT-100 and 750, and 875/1000 mg/kg (1000 mg/kg to male rats only on Day 1 only) dose levels of pirfenidone (Table 20).
a Individual dose volume was calculated based on the most recent body weight.
b The first preparation of Group 6 dose formulations (prepared at 100 mg/kg) was administered at 8.75 mL/kg. The subsequent dose formulations were prepared at 87.5 mg/mL to allow for consistent dose volumes of 10 mL/kg to be administered to all study animals.
C A subset of Group 6 male TK animals was administered Test Article by oral gavage once to obtain Day 1 TK profile for male animals at an adjusted dose level of 875 mg/kg.
LYT-100 (deupirfenidone, SD-560) and SD-559 (pirfenidone) were administered via an oral gavage to fed male and female Sprague Dawley rats. Dose levels were administered once daily for 91 consecutive days with 250, 500, and 750 mg/kg (LYT-100) in Groups 2, 3, and 4, respectively and 750 and 875 mg/kg (SD-559) in Groups 5 and 6, respectively. The dose level of SD-559 for Group 6 was lowered from 1000 mg/kg to 875 mg/kg on Day 1 (Tox and TK females; Tox males) and Day 2 (TK males) due to test article-related clinical signs. The original male TK animals received 1000 mg/kg of SD-559 on Day 1 and continued on study. The protocol was amended to add additional TK male animals in Group 6 for Day 1 collection of TK samples at 875 mg/kg.
Blood samples were collected from 3 subsets of 3 animals/sex on Day 1 and Day 28 at predose, 0.25, 0.5, 1, 2, 4, 8 and 24 hours (hr) post-dose for groups 2 to 6 and from one subset of 3 animals/sex at 0.25 hr post-dose for the vehicle group (group 1). Plasma was analyzed for LYT-100 and its metabolites d2-5-hydroxymethyl-pirfenidone (SD-790; active metabolite), d3-4′-hydroxy-pirfenidone (SD-1051) and 5-carboxy-pirfenidone (SD-789; inactive metabolite) (Groups 2 to 4) and for SD-559 and its metabolites 5-hydroxymethyl-pirfenidone (SD-788; active metabolite), 4′-hydroxy-pirfenidone (SD-1050) and 5-carboxy-pirfenidone (SD-789; inactive metabolite) (Groups 5 and 6) using validated LC-MS/MS bioanalytical methods. Analysis of samples from Group 1 for all analytes confirmed showed no exposure to any compound. Non-compartmental analysis (NCA) of plasma concentration data was conducted using Phoenix® WinNonlin®, version 8.0. A summary of the toxicokinetic (TK) parameters is presented in
The increased exposure for LYT-100 relative to pirfenidone supports a less frequent dosing and/or lower dose than pirfenidone. Exemplary
In animals dosed with deupirfenidone (SD-560), females generally had higher Cmax and AUC0-24 values than males for analytes SD-560 and SD-1051 with differences being > 2-fold in some of the dose groups. No marked gender difference (≤ 2.0-fold) was observed for analytes SD-790 and SD-789 on all collection days, except Group 3 AUC0-24 on Day 1 for SD-789 and AUC0-24 in Group 4 on Day 91 for SD-790. Similarly, in animals dosed with pirfenidone (SD-559), females generally had higher Cmax and AUC0-24 values than males for analytes SD-559 and SD-1050 with differences being > 2-fold in some of the dose groups on all collection days except for the 750 and 875 mg/kg dose levels on Days 28 and 91due to the absence of TK parameters for males (BLQ values were observed over the complete sampling interval for all animals). No marked gender difference was observed for analytes SD-788 and SD-789 at the two dose levels on all collection days, except for SD-789 Cmax in Group 5 on Day 91.
In animals dosed with pirfenidone (SD-559), females generally had higher Cmax and AUC0-24 values than males for analytes SD-559 and SD-1050 with differences being > 2-fold in some of the dose groups on all collection days except for the 750 and 875 mg/kg dose levels on Days 28 and 91 due to the absence of TK parameters for males. No marked gender difference was observed for analytes SD-788 and SD-789 at the two dose levels on all collection days, except for SD-789 Cmax in Group 5 on Day 91.
Exposure of SD-560 in Groups 2 to 4, as assessed with Cmax and AUC0-24, increased with dose where the increases were approximately less than dose proportional for Cmax and dose proportional for AUC0-24 over the entire dose range of 250 to 750 mg/kg. Exposure of SD-790 increased with dose where the increases were, in general, dose proportional for Cmax and AUC0-24 over the entire dose range of 250 to 750 mg/kg with the exception of Cmax in females and males on Day 28 (lower than dose proportional increase) and AUC0-24 in males on Day 91 (higher than dose proportional increase). Exposure of SD-1051 in Groups 2 through 4, as assessed with Cmax, increased approximately in a less than dose proportional manner for Cmax over the entire dose range, except for males on Day 1. Exposure of SD-1051, as assessed with AUC0-24, increased dose proportionally on Day 1 over the entire dose range. However, on Days 28 and 91, the increase in AUC0-24 was less than dose proportional in females and greater than dose proportional in males. Exposure of SD-789 in Groups 2 through 4, as assessed with Cmax and AUC0-24, increased with dose where the increases were generally approximately dose proportional for Cmax (with some variability) and were dose proportional for AUC0-24 over the entire dose range.
Exposure of SD-559, and metabolites SD-788, SD-789 and SD-1050 in Groups 5 and 6, as assessed with Cmax and AUC0-24 values, generally did not increase with increasing dose from 750 to 875 mg/kg and similar exposure for SD-559 and the different metabolites was observed between the two groups. The difference between dose levels is 14%, which may be masked by inter-individual variability of plasma concentrations. However, Cmax was lower for the 875 mg/kg dose level when compared to 750 mg/kg in females on Day 91 for SD-789 and in males on Day 1 for SD-1050.
No accumulation was observed for SD-560, SD-559 or the different metabolites at the different dose levels after multiple dosing for 28 Days. Exposure to parent SD-560 or SD-559 was lower on Day 28 compared to Day 1 with accumulation ratios between 0.68 and 0.21. Lower accumulation was observed for the high dose of SD-560 and the lowest was for SD-559. Following 91 days of dosing, exposure to parent SD-560 and SD-560 was higher than on Day 28 and lower or equal to exposure on Day 1 with the lowest accumulation ratio for SD-559 (0.58-0.71). After 91 days of dosing, little to moderate accumulation was observed for SD-790 and SD-788 based AUC0-24, for SD-789 based on AUC0-24 following SD-560 administration and for SD-789 based on Cmax following SD-559 administration, and SD-1050 based on AUC0-24.
It is interesting to note that, while on Day 1 exposure to LYT-100 (Cmax or AUC0-24) was slightly lower (0.77 and 0.83 fold for females and males, respectively) than exposure of SD-559 at the same nominal dose (750 mg/kg); on Day 28 this is reversed (1.19 and 1.20 fold for females and males, respectively). This may be attributed to a slowing down of the metabolism of LYT-100 versus SD-559 because of deuterium incorporation. The stabilization imparted by deuterium substitution would manifest in a slower metabolism and therefore a higher exposure to the parent compound.
Assessment of similarity in exposure (AUC0-24) and Cmax between SD-560 at 750 mg/kg and SD-559 at 750 mg/kg, suggested that SD-560 showed comparable Cmax and exposure to SD-559 on Days 1, 28 and 91 in both sexes with the exception of AUC0-24,on day 91 for the 750 mg/kg dose. Metabolite SD-790 generated from SD-560 at 750 mg/kg showed almost twice the exposure and Cmax on all days and in both genders vs. the non-deuterated corresponding metabolite (SD-788) generated from SD-559 at 750 mg/kg. Metabolite SD-1051, deuterated analog of SD-1050, showed significantly higher levels and exposure than metabolite SD-1050 on all days and in both genders at 750 mg/kg of SD-560 versus 750 mg/kg of SD-559. However, SD-560 sequential metabolite, SD-789, formed from SD-790 showed approximately 50% lower Cmax and exposure than SD-789, sequential metabolite of SD-559. Increased exposure to the 5-hydroxy metabolite, SD-790 (deuterated) or SD-788 (non-deuterated), and decreased exposure to the 5-carboxy metabolite, SD-789, in animals dosed with deupirfenidone versus pirfenidone can be ascribed to deuterium stabilization against metabolism of deupirfenidone vs. pirfenidone. By slowing down the conversion of d2-5-hydroxymethyl pirfenidone (SD-790) to 5-carboxy pirfenidone (SD-789), deuterium in deupirfenidone would decrease Cmax and exposure to 5-carboxy pirfenidone while leading to accumulation of d2-5-hydroxy pirfenidone. Deuterium however does not appear to significantly slow down metabolism of deupirfenidone to d2-5-hydroxy pirfenidone in rat as exposure to deupirfenidone is similar to that of pirfenidone at the same dose level.
Similar trends in exposure and Cmax of SD-560 across all dose levels (250, 500 and 750 mg/kg), after adjusting for the different doses, were observed, when compared to SD-559 at 875 mg/kg or 1000 mg/kg (male rats on Day 1).
This data also provides relevant information to human dosing. Day 1 TK data, compared to the single dose human PK data, show that the highest human exposure to parent and metabolites is covered in the present toxicity study. Exposure to LYT-100 in the TK study, as assessed by AUC, is about 5-fold larger at 750 mg/kg, on Day 1 and in male rats, than its exposure in human at the high dose of 801 mg. Exposure to deuterated 5-hydroxymethyl pirfenidone (SD-790; active metabolite) is about 1250-fold higher in the rat and exposure to 5-carboxy-pirfenidone (SD-789; inactive metabolite) in the rat is about 8-fold higher than in human, using the TK data on Day 1 in male rats for the comparison since there is a gender effect and because the exposure in male is lower than in female. Finally, the deuterated 4′-hydroxy pirfenidone metabolite (SD-1051) was not quantifiable in human. A similar conclusion can be reached when comparing Day 1 Cmax between male rat and human, where Cmax of LYT-100, deuterated 5-hydroxymethyl-pirfenidone (SD-790; active metabolite), and 5-carboxy-pirfenidone (SD-789; inactive metabolite) are about 15-, 1825-and 9-fold, respectively, larger in rat than in human. When using data collected in male rat after 28 days of daily dosing, the conclusion is still applicable as exposures to LYT-100, deuterated 5-hydroxymethyl-pirfenidone (SD-790; active metabolite), and 5-carboxy-pirfenidone (SD-789; inactive metabolite) are about 5-, 1600-, and 7-fold, respectively, larger in rats than in humans.
The rodent bleomycin-induced fibrosis model (BLM) is commonly utilized in the preclinical setting as it appears to have clinical relevance as an animal model of human fibrosis (e.g., idiopathic pulmonary fibrosis) based on the observed pulmonary pathophysiology following the bleomycin challenge in rats. See, e.g., Corboz et al., Pumonary Pharm. & Ther. 49 (2018), 95-103).
Bleomycin is a metabolite of the bacterium Streptomyces verticillus first identified in 1962. Specifically, bleomycin is a non-ribosomal hybrid peptide-polyketide natural product having the structure:
While bleomycin possesses antibacterial activity, its toxicity precludes use as an antibiotic. Bleomycin is used as a chemotherapeutic agent in the treatment of various cancers, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, testicular cancer, ovarian cancer, and cervical cancer among others. Bleomycin acts by induction of DNA strand breaks, and may also inhibit incorporation of thymidine into DNA strands. DNA cleavage by bleomycin depends on oxygen and metal ions, at least in vitro, though the exact mechanism of DNA strand scission is unresolved.
Common side effects associated with bleomycin chemotherapy include fever, weight loss, vomiting, rash, and a severe type of anaphylaxis. The most serious complication of bleomycin therapy, occurring with increasing dosage, is pulmonary fibrosis and impaired lung function. In high concentrations, bleomycin induces DNA strand rupture, generates free radicals, and causes oxidative stress tresulting in cell necrosis and/or apoptosis. Recent studies support the role of the proinflammatory cytokines IL-18 and IL-1beta in the mechanism of bleomycin-induced lung injury. Bleomycin is normally metabolized by the enzyme bleomycin hydrolase, but the lung is particularly susceptible to bleomycin toxicity by virtue of the scarcity of this enzyme in the lung. Lung inflammation, fibrosis, reductions in lung compliance, and impaired gas exchange are the consequences of a bleomycin challenge.
The effect of LYT-100 in alleviating fibrosis is assessed in the BLM animal model. Specifically, the effects of early (e.g., Day 1) start and late (e.g., Day 10-14) start of LYT-100 is investigated in the BLM using therapeutic dosing.
In assessing anti-fibrotic potential of compounds of interest, evaluation is generally performed in the phase of established fibrosis, i.e., 10-15 days after the initiation, rather than in the early period of bleomycin-induced inflammation. Conversion of proline into hydroxyproline and incorporation into lung collagen occurs as early as 4 days after bleomycin addition. The switch between inflammation and fibrosis occurs in rats around day 9 after bleomycin administration. Accordingly, evaluation 10 days after the bleomycin challenge is generally used to minimize any potential effects on the early inflammatory phase. However, in the present disclosure, it is desirable to evaluate activity of LYT-100 during both the inflammatory and fibrotic stages of the model. An exemplary study design is provided in Table 22 below:
The present invention relates to dosing of deupirfenidone. This application is a continuation of International Application No. PCT/US2021/040551, filed Jul. 6, 2021, which claims priority to U.S. Provisional Application No. 63/048,564 filed on Jul. 6, 2020, U.S. Provisional Application No. 63/087,116 filed on Oct. 2, 2020, U.S. Provisional Application No. 63/116,520 filed Nov. 20, 2020, U.S. Provisional Application No. 63/121,168 filed Dec. 3, 2020, U.S. Provisional Application No. 63/123,989 filed Dec. 10, 2020, U.S. Provisional Application No. 63/135,374 filed Jan. 8, 2021 and U.S. Provisional Application No. 63/175,063 filed Apr. 15, 2021, the contents of each are incorporated herein by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63175063 | Apr 2021 | US | |
| 63135374 | Jan 2021 | US | |
| 63123989 | Dec 2020 | US | |
| 63121168 | Dec 2020 | US | |
| 63116520 | Nov 2020 | US | |
| 63087116 | Oct 2020 | US | |
| 63048564 | Jul 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2021/040551 | Jul 2021 | WO |
| Child | 18150055 | US |
