Patent Application
20240207230
This application claims priority to United Kingdom Patent Application No. 2219591.1, filed Dec. 22, 2022, the entire contents of which are incorporated herein by reference.
The term interstitial lung disease (ILD) refers to a large and heterogeneous group of parenchymal lung disorders characterized by damage to the lung tissue caused by various degrees of fibrosis and/or inflammation. The term used and recognised by patients with ILDs that have progressed to the fibrotic stage, is pulmonary fibrosis (PF). Each of the fibrosing ILDs is characterised by a chronic, often progressive, irreversible, and devastating scarring of the interstitial tissue in the lung and for the great majority of these diseases there is no existing cure.
There are more than 300 ILDs with similar symptoms of breathlessness, usually caused by reduced oxygen exchange in the alveoli. Approximately 65% of patients are affected by an ILD of unknown cause, which include idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonias (IIP), ILDs associated with connective tissue disorders such as rheumatoid arthritis (RA), systemic sclerosis (SSc); and sarcoidosis.
Known causes for ILDs include pneumoconiosis (asbestosis, silicosis), hypersensitivity pneumonitis and post-infectious ILD (ERS Whitebook). The distribution of ILDs shows large variation geographically, but studies in North America have generally shown ILD related to connective tissue disorder to be the most common ILD subtypes (Ley, B., Collard, H. R., & King, T. E., Jr. (2011), “Clinical course and prediction of survival in idiopathic pulmonary fibrosis”, Am J Respir Crit Care Med, 183(4), 431-440. https://doi.org/10.1164/rccm.201006-0894CI). IPF is practically always associated with progressive pulmonary fibrosis, but patients diagnosed with other ILDs are also at risk of developing progressive pulmonary fibrosis, often with a phenotype not dissimilar to IPF. Although the underlying disease may in some cases be managed by medication, the development of progressive pulmonary fibrosis implies a non-remitting course of disease, associated with an increasing risk of morbidity and mortality.
IPF is characterised by a progressive deposition of extracellular matrix proteins and fibrous tissue in the lungs, resulting in destruction of lung architecture and reduced lung capacity. Symptoms of IPF, as with other types of PF, include shortness of breath, fatigue, and a dry intractable cough. IPF is lethal, and death is most commonly caused by acute or subacute respiratory failure due to progression of lung fibrosis. The prognosis of IPF is poor, with an estimated life expectancy of 3-5 years after diagnosis which is shorter than many malignancies. The prognosis for the other diseases leading to PF varies.
There are presently no curative treatment options except, in rare cases, lung transplantation. IPF resuls in a chronic, irreversible, progressive deterioration in lung function and then, in most cases, death within 3-5 years. While the overall prognosis is poor in IPF, it is difficult to predict the rate of progression in individual patients. Risk factors for IPF include age, male gender, genetic predisposition and history of cigarette smoking. The annual incidence is between 5-16 per 100,000 individuals, with a prevalence of 13-20 cases per 100,000 people, increasing dramatically with age (King et al., Lancet (2011) 378, 1949-1961; Noble et al., J. Clin. Invest. (2012) 122, 2756-2762). IPF s recalcitrant to therapies that target the immune system which distinguishes it from pulmonary fibrosis (PF) associated with other, purely systemic diseases.
The age- and sex-adjusted prevalence of fibrosing ILD per 100,000 in the US population has been estimated at approximately 118, of which about 70 were assessed to have chronic fibrosing ILD with a progressive phenotype (Olson A L, Patnaik P, Hartmann N, Bohn R L, Garry E M, Wallace L, “Prevalence and Incidence of Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype in the United States Estimated in a Large Claims Database Analysis”, Adv Ther, 2021 July; 38(7): 4100-4114, doi: 10.1007/s12325-021-01786-8. Epub 2021 Jun. 17. PMID: 34156606; PMCID: PMC8279991).
Specifically looking at IPF, there are approximately 3 million people worldwide living with the disease. Debilitating symptoms typically appear between the ages of 50 and 70 years and, while the disease is most common in men, the number of cases in women is increasing. With PF related to connective tissue disorder or sarcoidosis, onset usually starts much earlier in life (30-50) and affects women as well as men.
At present there are no medicines that cure or even improve the pulmonary fibrosis associated with ILDs. There are two antifibrotic drugs, nintedanib and pirfenidone, which are approved for treatment of IPF. Nintedanib is additionally approved for treatment of chronic fibrosing ILDs with a progressive phenotype and for slowing the rate of decline in pulmonary function in patients with systemic sclerosis-associated ILD (SSc-ILD). Both nintedanib and pirfenidone merely slow disease progression (annual rate of decline of FVC) and are not a long-term cure, while having significant, primarily gastrointestinal, side effects.
The knowledge of being diagnosed with an ILD, such as IPF, comes as a shock to many patients as there is often no identified cause and patients may feel that they lose control of living the way they want. They fear that they will no longer be able to fulfil their role in life, whether that be as a parent, spouse, or grandparent. In the case of IPF, this is often at a time in life when patients are approaching retirement. People with an ILD learn that daily activities may have to change; normal routines like taking walks or travel must be adjusted around the debilitating respiratory symptoms of the disease, as well as the use of oxygen tanks and tubes, safety measures for protection against infections like COVID-19, and commonly a persistent and embarrassing cough. This can have a negative impact on mental health, particularly in patients experiencing a noticeable deterioration in physical symptoms. Several studies have reported that symptoms of depression and anxiety are common in patients with IPF. The prevalence of depression ranges from 24.3-49.2% while the proportion of patients with anxiety may be as high as 60% in IPF (Akhtar, A. A., Ali, M. A., & Smith, R. P. (2013), “Depression in patients with idiopathic pulmonary fibrosis”, Chron Respir Dis, 10(3), 127-133, https://doi.org/10.1177/1479972313493098; Glaspole, I. N., Watson, A. L., Allan, H., Chapman, S., Cooper, W. A., Corte, T. J., Ellis, S., Grainge, C., Goh, N., Hopkins, P., Keir, G., Macansh, S., Mahar, A., Moodley, Y., Reynolds, P. N., Ryerson, C. J., Walters, E. H., Zappala, C. J., & Holland, A. E. (2017), “Determinants and outcomes of prolonged anxiety and depression in idiopathic pulmonary fibrosis”, Eur Respir J, 50(2), https://doi.org/10.1183/13993003.00168-2017; Ryerson, C. J., Berkeley, J., Carrieri-Kohlman, V. L., Pantilat, S. Z., Landefeld, C. S., & Collard, H. R. (2011), “Depression and functional status are strongly associated with dyspnea in interstitial lung disease”, Chest, 139(3), 609-616, https://doi.org/10.1378/chest.10-0608). Studies have also shown that IPF reduces quality of life (Lee, Y. J., Choi, S. M., Lee, Y. J., Cho, Y. J., Yoon, H. I., Lee, J. H., Lee, C. T., & Park, J. S. (2017), “Clinical impact of depression and anxiety in patients with idiopathic pulmonary fibrosis”, PloS One, 12(9), e0184300, https://doi.org/10.1371/journal.pone.0184300). Several studies indicate that the problem with anxiety is applicable to ILDs in general, and not limited to IPF (Abebaw Mengistu Yohannes, “Depression and anxiety in patients with interstitial lung disease”, Expert Review of Respiratory Medicine, 14(9) 859-862, https://doi.org/10.1080/17476348.2020.1776118).
Cognitive behavioural therapy (CBT) is a recommended first-line treatment for anxiety disorders (Powers, M. B., E.; Gorman, J.; Kissen, D.; Smits, J; (2015), “Anxiety and Depression Association of America—Clinical practice review for GAD”, https://adaa.org/resources-professionals/practice-guidelines-gad). However, the usual standard of care for IPF in the US does not include referral to a psychologist, despite the potential benefits of treatment (Raghu, G., Rochwerg, B., Zhang, Y., Garcia, C. A., Azuma, A., Behr, J., Brozek, J. L., Collard, H. R., Cunningham, W., Homma, S., Johkoh, T., Martinez, F. J., Myers, J., Protzko, S. L., Richeldi, L., Rind, D., Selman, M., Theodore, A., Wells, (2015) “An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline”, Am J Respir Crit Care Med, 192(2), e3-19, https://doi.org/10.1164/rccm.201506-1063ST).
Patients with an ILD face barriers in accessing traditional CBT as it can be very expensive, and the costs are typically not reimbursed or only minimally reimbursed. However, even if cost were not an issue, there are not enough specialists to serve the need. In addition, there are difficulties/risks associated with travelling to a psychologist's office, whether due to risk of infections like COVID-19 or distance. Studies have shown that patients with chronic lung diseases including IPF have poor clinical outcomes with COVID-19 disease (Gerayeli, F. V., Milne, S., Cheung, C., Li, X., Yang, C. W. T., Tam, A., Choi, L. H., Bae, A., & Sin, D. D. (2021), COPD and the risk of poor outcomes in COVID-19: A systematic review and meta-analysis, EclinicalMedicine, 33, 100789, https://doi.org/10.1016/j.eclinm.2021.100789; Naqvi, S. F., Lakhani, D. A., Sohail, A. H., Maurer, J., Sofka, S., Sarwari, A., & Hadi, Y. B. (2021), Patients with idiopathic pulmonary fibrosis have poor clinical outcomes with COVID-19 disease: a propensity matched multicentre research network analysis, BMJ Open Respir Res, 8(1). https://doi.org/10.1136/bmiresp-2021-000969). In fact, any airway infection can cause exacerbations of chronic lung diseases. As a result, it is therefore likely that patients with IPF and other ILDs are less willing to have face-to-face counselling.
Aspects of the present disclosure are directed to methods of treating an interstitial lung disease (ILD) in a patient, comprising administering a pharmaceutical treatment that is useful in the therapy of an ILD; and, in conjunction with the administration of the pharmaceutical treatment, engaging in a digital therapeutic program that delivers cognitive behavioural therapy for the treatment of the ILD.
Suitable pharmaceutical treatments include those that are useful in the therapy of an ILD, including pharmaceutical treatments that are in some way (IL) disease-modifying and/or capable of altering the course or the pathology of the ILD or at least slowing its progression, such as such as an antifibrotic agent, an immunomodulatory imide drug (IMID) or an angiotensin II type 2 receptor agonist (ATRAG), such as C21 (defined below). Suitable pharmaceutical treatments also include concomitant treatments for diseases that are associated with ILDs, including those that treat a comorbidity of an ILD, or are capable of treating sequelae of ILDs, including mental and/or psychosomatic effects or exacerbations.
In some embodiments, the pharmaceutical treatment may be selected from anti-inflammatory, an anti-tussive, an immunomodulatory, a cytotoxic, an anti-oxidant, an anti-coagulant, an anti-chemokine, or an anti-angiogenic drug.
In some embodiments, the pharmaceutical treatment may be a RAS-blocker, an endothelin antagonist or sildenafil.
In some embodiments, the pharmaceutical treatment may be selected from one or more antifibrotic agents, such as nintedanib, pirfenidone, immunomodulatory imide drugs (IMIDs) or an angiotensin II type 2 receptor agonist (ATRAG).
In some embodiments, the pharmaceutical treatments include anti-tussive drugs (e.g. dextromethorphan, codeine, benzonate and nalbuphine), glucocorticoids (e.g., beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone); the c-Jun N-terminal kinase inhibitor CC-90001 (Celgene/Bristol Myers Squibb); the HSP47 RNAi therapeutic ND-L02-s0201/BMS-986263 (Nitto Denko/Bristol Meyers Squibb), the Hedgehog cell-signalling pathway inhibitor ENV-101/taladegib (Endeavor Biomedicines), the dual inhibitor of αVβ1/αVβ6 PLN-74809 (Pliant Therapeutics), the dual of NADPH and inhibitor oxidase isoforms NOX4 NOX1 setanaxib/GKT137831/GKT831 (Calliditas Therapeutics/Genkyotex), HEC585 (Sunshine Lake Pharma Co), the Galectin-3 inhibitor GB0139/TD139 (Galecto Biotech), Src tyrosine kinase inhibitor saracatinib (AstraZeneca), the humanised anti-FXIIa monoclonal antibody garadacimab/CSL312 (CSL Behring). The LPA1 receptor antagonist BMS-986278 (Bristol Myers Squibb), the LPA1 receptor antagonist HZN-825 (Horizon Therapeutics), the deuterium-substituted analogue of pirfenidone deupirfenidone/LYT100 (PureTech), the autotaxin inhibitor cudetaxestat/BLD-0409 (Blade Therapeutics), the prolyl-tRNA synthetase inhibitor DWN12088 (Daewoong Pharmaceutical Co), the monoclonal antibody AMB-05X targeting colony stimulating factor 1 receptor (AmMax Bio), the IL-11 receptor-blocking antibody LASN01 (Lassen Therapeutics), the MMP7-lowering RNAi treatment ARO-MMP7 (Arrowhead Pharmaceuticals), the autotaxin inhibitor BBT-877 (Bridge Biotherapeutics), the smad ubiquitin regulatory factor 1 inhibitor LTP001 (Novartis), AP-01/inhaled pirfenidone (Avalyn Pharma), tipelukast/MN-001 (MediciNova/Kyorin), Ifenprodil/NP-120 (Algernon Pharmaceuticals), the connective tissue growth factor inhibitor pamrevlumab (Fibrogen), RG-6354/PRM-151/recombinant human pentraxin-2 (Roche/Promedior), the prostacyclin analogue treprostinil (United Therapeutics), the phosphodiesterase 4 inhibitor BI1015550 (Boehringer Ingelheim); xylocaine; inhaled nitric oxide; other immunosuppressants, such as azathioprine and mycophenolate mofetil; vitamins (e.g. vitamin B, C and D); mucolytics (e.g. acetylcysteine and ambroxol); inflammation suppressants, such as cyclophosphamide; other immunosuppressants, such as azathioprine and mycophenolate mofetil; and antioxidants, such as N-acetylcysteine.
Preferred pharmaceutical treatments include, antifibrotics (e.g. nintedanib and pirfenidone); IMIDs (e.g. lenalidomide, pomalidomide and, particularly, thalidomide) and, most preferably, ATRAGs, such as any of those described generically and specifically in international patent applications with publications WO 2021/053344, WO 2021/186185, WO 2021/186180, WO 2021/186180, WO 2022/200787, WO 2022/200786 and WO 2022/200785, unpublished international patent application PCT/GB2022/051760 and, especially, N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (Compound 21 or ‘C21’).
In a preferred embodiment, the pharmaceutical treatment is N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (Compound 21 or ‘C21’).
In some embodiments, the pharmaceutical treatment may be an anxiolytic drug. Suitable anxiolytic drugs include selective serotonin reuptake inhibitors including, but not limited to, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and dapoxetine; serotonin-norepinephrine reuptake inhibitors including, but not limited to, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramado and venlafaxine; benzodiazepines including, but not limited to, clorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam, flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam, triazolam, climazolam, loprazolam, midazolam and clobazam; antipsychotic drugs including, but not limited to, trifluoperazine, quetiapine, aripiprazole, olanzapine and risperidone; beta-adrenoceptor antagonists including, but not limited to, acebutolol, bisoprolol, carvedilol, propranolol, atenolol and metoprolol; and other anxiolytic drugs such as buspirone, carbamazepine, pregabalin, gabapentin, lamictal, tegretol.
Such pharmaceutical treatments may be administered alone or in combination with each other and/or may be administered prior to and during the course of the digital therapeutic.
Pharmaceutically-acceptable doses, of pharmaceutical treatments such as those mentioned above include those that are known in the art and described for the drugs in question to in the medical literature, such as Martindale—The Complete Drug Reference, 38th Edition, Pharmaceutical Press, London (2014) and the documents referred to therein, the relevant disclosures of which documents are hereby incorporated by reference.
When the pharmaceutical treatment comprises C21, suitable lower daily doses in adult patients (average weight e.g., 70 kg), may be about 10 mg, such as about 20 mg, for example about 25 mg, per day. Suitable upper limits of daily dose ranges of C21 may be about up to about 900 mg, such as 600 mg, including about 400 mg. In particular, daily doses may be about 300 mg, such as about 250 mg, including about 200 mg, such as about 175 mg or about 150 mg, including about 100 mg, and including about 75 mg, about 60 mg or about 50 mg.
All of the above doses are calculated as free C21. Doses may be split into multiple individual doses per day. Doses may be given between once and six, such as four times daily, preferably three times daily and more preferably twice daily.
In some embodiments, the method of treating an ILD in a patient comprises administering a pharmaceutical treatment for use in an ILD and, in conjunction with the administration of the pharmaceutical treatment, engaging in a digital therapeutic program that delivers cognitive behavioural therapy for the treatment of a psychological symptom of the ILD.
In some embodiments, the method of treating the ILD in a patient comprises: administering a pharmaceutical treatment for an ILD; and, in conjunction with the administration of the pharmaceutical treatment, engaging in a digital therapeutic program that delivers cognitive behavioural therapy, thereby achieving improved suppression and/or alleviation of symptoms of the relevant ILD compared with a patient receiving only pharmaceutical treatment (such as pirfenidone, nintedanib, buspirone, clonazepam, desvenlafaxine, fluoxetine, gabapentin, lorazepamomeprazole, pantoprazole and/or rabeprazole).
In some embodiments, the suppression or alleviation of the symptoms of the relevant ILD is statistically significant compared with a patient receiving only pharmaceutical treatment
In some embodiments, the method of treating the relevant ILD in a patient comprises:
administering a pharmaceutical treatment for ILD; and, in conjunction with the administration of the pharmaceutical treatment, engaging in a digital therapeutic program that delivers cognitive behavioural therapy for the treatment of the ILD thereby providing a more effective treatment.
Aspects of the present disclosure relate to a digital therapeutic for the treatment of symptoms of anxiety in a patient diagnosed with an interstitial lung disease (ILD) such as idiopathic pulmonary fibrosis (IPF) or any ILD causing pulmonary fibrosis (PF).
There is presently no product on the market specifically addressing the psychological aspects of living with an ILD, such as IPF. The digital therapeutic described herein was developed specifically to address this unmet need—providing an accessible, digital CBT therapy to specifically deal with the doubts, fears, and anxieties that ILD patients face.
Accordingly, in some embodiments there is provided a digital therapeutic intended for the treatment of symptoms of anxiety and improvement of health-related quality of life in patients with ILDs by providing neurobehavioral interventions from CBT and related disciplines. The digital therapeutic disclosed and described herein may be used adjunctively to other treatment modalities for ILDs, including IPF. The digital therapeutic is intended to treat and improve the symptoms and anxiety caused by an ILD but is not intended to directly treat an ILD or the physical manifestations of ILDs.
In some embodiments, there is provided a digital therapeutic for the treatment of a patient diagnosed with ILD, the digital therapeutic comprising computer executable instructions for: conducting a personalised functional analysis with the patient to determine a first personal pulmonary fibrosis (PF) signature, the first personal PF signature including one or more anxiety triggers which the patient identifies as exacerbating the symptoms of anxiety and thereby causing behavioural restrictions; storing the first personal PF signature; identifying one or more digital cognitive behavioural therapy (dCBT) tools for modifying the first personal PF signature; determining a first personalised dCBT treatment plan which incorporates the use of the identified dCBT tools; administering the first personalised dCBT treatment plan; and, determining changes in relation to the behavioural restrictions associated with the first personal PF signature of the patient.
In some embodiments, the digital therapeutic may further comprise computer executable instructions for determining the anxiety level of the patient in relation to the one or more identified anxiety triggers before administering the first personalised dCBT treatment plan.
In some embodiments, the digital therapeutic may further comprise computer executable instructions for determining the anxiety level of the patient in relation to the one or more anxiety triggers after administering the first dCBT treatment plan.
In some embodiments, the digital therapeutic may further comprise computer executable instructions for comparing the determined anxiety levels to assess changes in the personal PF signature of the patient.
In some embodiments, the dCBT tools for modifying the personal PF signature may be contained within one or more modules. The modules may be classified as information modules or therapy modules, and patient access to the therapy modules may be restricted.
In some embodiments, administering the first personal dCBT treatment plan comprises steps of: providing the patient with an exercise introduction incorporating one or more questions for the patient to answer, wherein the exercise introduction is related to an exercise that is part of an identified dCBT tool for modifying the first personal PF signature; in response to the answers provided by the patient, modifying the exercise; and providing the patient with the modified exercise.
In some embodiments, at least one of the identified dCBT tools comprises an exercise, and wherein after completion of the exercise the associated dCBT tool is unlocked for future use by the patient.
In some embodiments, determining changes in relation to the behavioural restrictions associated with the first personal PF signature of the patient further comprises a step of determining changes in the perceived quality of life of the patient.
In some embodiments, the digital therapeutic further comprises computer executable instructions for: determining a second personal PF signature, by modifying the first personal PF signature to incorporate the determined changes in relation to the behavioural restrictions associated with the first personal PF signature of the patient; and storing the second personal PF signature.
In some embodiments, the digital therapeutic further comprises computer executable instructions for: identifying one or more digital cognitive behavioural therapy (dCBT) tools for modifying the second personal PF signature; determining a second personalised dCBT treatment plan which incorporates the use of the identified dCBT tools; administering the second personalised dCBT treatment plan; and determining changes in relation to the behavioural restrictions associated with the second personal PF signature of the patient.
The digital therapeutic disclosed and described herein may be used to treat anxiety caused by any disease or condition with dyspnea/difficulty breathing as a symptom, including asthma, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension such as pulmonary arterial hypertension, respiratory infections such as bronchitis and pneumonia, airway-blocking cancers including lung cancer, cardiac diseases such as heart failure and myocardial ischemia, neuromuscular disorders affecting the respiratory muscles, pregnancy, obesity and/or psychogenic breathing disorders.
An example of the present disclosure will now be described in detail with reference to the accompanying drawings, in which:
Patients with IPF usually seek medical assistance due to chronic and progressive exertional dyspnea and cough. Imaging of the lung classically reveals traction bronchiectasis, thickened interlobar septae, with (typical Usual Interstitial Pneumonia (UIP)) or without (possible UIP) subpleural honeycombing. When all three manifestations are present and there is no evidence of a systemic connective tissue disease or environmental exposure, a diagnosis of IPF is very likely. A definite diagnosis is usually made by high-resolution computed tomography (HRCT) and/or lung biopsy and requires a multidisciplinary team of expertise including pulmonologists, radiologists and pathologists experienced in ILDs.
IPF demonstrates different stages with different prognosis, defined as mild, moderate and severe. Mild cases follow a stable progressive path with patients sometimes taking several years to seek medical advice. Acute exacerbations of IPF are defined as a rapid worsening of the disease, and patients often deteriorate from mild to moderate or moderate to severe with very poor outcomes with a high mortality rate in the short run.
The cause of IPF is unknown but it appears to be a disorder likely arising from an interplay of environmental and genetic factors resulting in fibroblast driven unrelenting tissue remodeling rather than normal repair; a pathogenesis primarily driven by fibrosis rather than inflammation. A growing body of evidence suggests that the disease is initiated through alveolar epithelial cell microinjuries and apoptosis, activating a scarring process The fibroblastic foci secrete exaggerated amounts of extracellular matrix that destroys the lung parenchyma and ultimately leads to loss of lung function.
As a restrictive lung disease, IPF is typically diagnosed using static spirometry. Here, the only consideration is the volume of air that is exhaled, as opposed to dynamic spirometry, which measures the time taken to exhale a certain volume of air, and is typically used to diagnose obstructive lung diseases, like COPD and asthma.
The most usual and useful static spirometric test to diagnose IPF and/or monitor its progression is the forced vital capacity (FVC) test, in which a subject is urged to breathe in as far as he or she can, and then out as far as he or she can. This test is classified as static because it does not involve an element of time.
The mean annual rate of decline in lung function (FVC) in IPF is within a range of 0.13-0.4 litres. Symptoms precede diagnosis by 1-2 years and radiographic signs may precede symptoms (Ley et al., Am. J. Respir. Crit. Care Med. (2011) 183, 431-440).
Numerous IPF treatment approaches have been tested in pre-clinical models and clinical trials such as anti-inflammatory, immune-modulatory, cytotoxic, general anti-fibrotic, anti-oxidant, anti-coagulant, anti-chemokine, anti-angiogenic drugs as well as RAS-blockers, endothelin antagonists, and sildenafil, all of which have basically been shown to provide limited or no benefits (Rafii R et al., J. Thorac. Dis. (2013) 5, 48-73).
Current clinical treatment of IPF includes oxygen supplementation. Medications that are used include pirfenidone or nintedanib, but with only limited success in slowing the progression of the disease.
For example, the review article by Maher and Strek (Respiratory Research, 20, 205 (2019)) states that, clinical trials have demonstrated that nintedanib and pirfenidone reduce the decline in lung function in patients with IPF, more specifically reducing the rate of decline (according to FVC measurements) by approximately 50% over the period of a year.
Thus, although nintedanib and pirfenidone are believed to reduce the risk of acute deteriorations in lung function and to improve life expectancy by reducing the rate at which IPF progresses, and also (as reported by Isshiki et al, Respiratory Medicine, 187, 106551 (2021)) that they may help protect against acute exacerbation of IPF (AE-IPF; acute respiratory worsening in the absence of other known causes, which has a very poor median survival rate), both of these drugs are only capable of slowing down the progression of the disease. Furthermore, these drugs commonly cause (predominantly gastrointestinal) side-effects, which can sometimes curtail treatment (see e.g., Maher and Strek supra).
Currently, a lung transplant is the only intervention that substantially improves survival in IPF patients. However, complications such as infections and transplant rejection are not uncommon.
The Renin-Angiotensin System (RAS) is a key regulator of blood pressure homeostasis. Renin, a protease, cleaves its only known substrate (angiotensinogen) to form angiotensin I (Ang I), which in turn serves as substrate to angiotensin converting enzyme (ACE) to form Ang II. The endogenous hormone Ang II is a linear octapeptide (Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8) and is an active component of the renin angiotensin system (RAS).
The angiotensin II type 1 (AT1) receptor is expressed in most organs and is believed to be responsible for the majority of the pathological effects of Ang II. The safety and efficacy of losartan (an AT1-receptor inhibitor) has recently been investigated in a small uncontrolled open-label pilot trial on IPF (www.clinicaltrials.gov identifier NCT00879879).
Several studies in adult individuals appear to demonstrate that, in the modulation of the response following Ang II stimulation, activation of the angiotensin II type 1 (AT2) receptor has opposing effects to those mediated by the AT1 receptor.
AT2 receptor agonists (ATRAGs) have been shown to be of potential utility in the treatment and/or prophylaxis of disorders of the alimentary tract, such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see international patent application WO 99/43339).
N-Butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (Compound 21 or, as used hereinafter, ‘C21’) is a selective ATRAG. Promising findings in preclinical models of IPF (see e.g., Bruce et al, Br. J. Pharmacol., 172, 2219 (2015) and Rathinasabapathy et al, Front. Physiol., 9, 180 (2018)), led to C21 being in clinical development for use in IPF treatment (see also international patent application WO 2016/139475).
In an ongoing Phase II clinical trial in IPF patients, although the targeted efficacy endpoint at the outset of this study was a reduction in the deterioration in lung function, as measured by FVC, over time compared to current standard of care in IPF (nintedanib and pirfenidone), it was found, remarkably, that C21 is not only capable of arresting the progression of deterioration in lung function in IPF patients in a clinical setting, but actually at least partially restoring it, potentially representing an extremely important development in the treatment of this debilitating and ultimately fatal disease.
In addition to, and, to some extent, as a consequence of, the physical symptoms of IPF, anxiety and its associated mental health problems, such as depression, is a very common and serious comorbidity in people with idiopathic pulmonary fibrosis (IPF), which drastically affect quality of life.
To make matters worse, the anxiety associated with the anticipation of exhibiting IPF symptoms, including shortness of breath or a coughing fit, can often bring about the precise physiological response that results in such symptoms, which in turn can make the anxiety worse.
In this respect, there is a real clinical need, not only for safer and/or more effective treatments of ILDs, such as IPF, that deal not only with the physical symptoms mentioned above, but also more holistic and personalized treatments that deal with a patient's mental well-being. The development of new treatment strategies is very important, and a fundamental challenge for the future is to develop appropriate therapeutic approaches that will not only slow down or stop the progression of the disease, but also improve quality of life for those suffering from the condition.
The user device 101 may be implemented using any conventional computer system such as, for example, a laptop, cellular telephone, desktop computer or tablet computer. Having readily available access to digital CBT provided via the digital therapeutic system 100 enables improved patient outcomes by helping patients to manage the symptoms and anxiety relating to an ILD, such as IPF, and may improve their overall health and wellbeing, among other benefits.
The digital therapeutic may be accessed via a therapy application using the user device 101. For example, the digital therapeutic 104 may be rendered using a browser (for example in a web-based implementation of the therapy application) or a bespoke software application (for example a smartphone app). In particular, the program may be incorporated into an app accessible from a mobile phone or wearable device, which may also be used to drive further content for, and patient interaction with, the program. Alternatively, the therapy application may be stored and run remotely from the user device 101, within the network 102 or at the server 103. Similarly, data accessed by the therapy application may be stored locally at the user device 101, within the network 102 or at the server 103.
In some embodiments, the therapy application and its data to be stored locally at the user device 101. Data concerning the patient may be encrypted while stored locally and decrypted by the therapy application during use. The benefits of local storage specific to this application include: improve speed of data access, improve security by removing the need for network communication during use and so avoiding the transmission of sensitive data on potentially insecure networks, avoiding a single point of storage of sensitive data within the network that may be a target for malicious access, avoiding user concerns for privacy due to the knowledge that their interactions with the application are not provided to a healthcare provider or other entity. In examples in which the therapy application and data are stored locally at the user device 101, the user device 101 does not necessarily need to be connected to the network 102 during use of the digital therapy. Such an implementation may also be advantageous for users without ready access to a network.
Alternatively, to reduce the data footprint on the user device 101, the digital therapeutic system may be configured to provide the digital therapy 104 via a web-based interface during use. According to one example, the digital therapeutic is provided via an interactive online-based program, which can be accessed via the user device using an up-to-date browser (Google Chrome, Mozilla Firefox, Microsoft Edge, or Safari). In such embodiments, the content rendered to the patient may be generated at the server 103 and provided to the user device 101 via the network 102 in real time. Data transmitted over the network 102 between the user device 101 and the server 103 may be encrypted or otherwise sent using secure communication methods. Similarly, patient data stored at the server may be encrypted while stored at the server 103 and decrypted by the therapy application at the user device 101.
The network 102 may be provided by a wired and/or wireless network. The network 102 may be provided by the internet, another wide area network or a local area network. The therapy application may be distributed to the user device 101 by providing a download from the server 103 via the network 102. The server 103 may be operated by an HCP or wholly independently from the HCP. The server 104 of the digital therapeutic system 100 may be configured to allow the HCP to interact with the patient and/or the therapy application. For example, the server may be configured to allow the HCP to view a status or information associated with the patient (e.g., information related to whether or when the patient has completed one or more modules associated with the therapy application), communicate with the patient, and so on. In such examples, data from the program may only be shared with the HCP if the patient chooses to show the HCP the completed modules using, for example, a patient dashboard.
It will be appreciated that, in some examples, the various hardware units may be integrated with one another. For example, where the user device 110 is provided by a tablet computer or cellular telephone, a display of the device 110 may provide both the display of the output device 118 and a touch sensor providing the input device 116.
The digital therapeutic is configured to deliver tailored digital cognitive behavioural therapy (dCBT) for the treatment and management of symptoms and anxiety relating to an ILD, such as IPF, in which future dialogue presented to the user may depend upon the user response to earlier dialogue. The digital therapeutic data 126 comprises content separated into a number of modules. The content within the modules defines what is presented to the user. The content may be formulated to use motivational interviewing techniques in an effort to effectively engage the user by addressing ambivalence through custom-tailored individualization and personalization via the delivery of the simulated therapeutic dialogue. The content may also incorporate principles and techniques from acceptance and commitment therapy, or other evidence-based behaviour change techniques drawn from cognitive behavioural therapy or mindfulness.
In a first step (201), a personalised functional analysis is conducted with the to determine a personal PF signature. The personal pulmonary fibrosis signature includes one or more anxiety triggers, which the patient identifies as exacerbating the mental suffering of living with an ILD, such as IPF, and thereby causing behavioural restrictions. Behavioural restrictions are any restriction on the behaviour of the patient as a result of an ILD. A patient concerned about an anxiety trigger is likely to avoid situations where such an anxiety trigger may be encountered, thereby restricting the patient's behaviour.
For example, a patient wanting to perform physical exercise may be anxious that performing physical exercise could exacerbate PF symptoms or even accelerate the progression of the underlying disease. This anxiety could limit or even entirely prevent the patient from performing the desired physical exercise. Such a patient would therefore have a behavioural restriction relating to physical exercise, caused by anxiety relating to an ILD. In this case, the anxiety is in relation to the possible effects of performing physical exercise on the patient's health.
Further anxiety triggers could include, but are not limited to, going outside, having to carry and/or use equipment to assist breathing such as an oxygen tank, taking medication, entering social environments, meeting with people, coughing, shortness of breath, safety of activities, perceived risk of catching an infection while doing an activity.
In the first step (201), the level of anxiety in the patient is determined in relation to one or more of the identified anxiety triggers. A questionnaire may be used to assess the anxiety level of a patient, such as the Generalized Anxiety Disorder 7 item scale (GAD-7).
In a second step (202), the determined PF signature is stored. The stored PF signature includes at least one anxiety trigger which the patient identifies as exacerbating the symptoms of an ILD, thereby causing behavioural restrictions. The stored PF signature may also include additional patient information, such as age, gender, diagnosis (for example IPF), disease progression, interests, fears, and anxiety level.
In a third step (203), one or more digital cognitive behavioural therapy (dCBT) tools are identified for modifying the personal pulmonary fibrosis signature. The identified dCBT tools may be, for example, one or more of: strategies for behaviour change, coping skills to help the patient handle difficult thoughts and feelings, guided sound meditation, a logging flow to gain a better understanding of one's feelings, a step-by-step guide to practice a psychological tool or a text summary of a psychological tool.
In a fourth step (204), a personalised dCBT treatment plan is developed. The dCBT treatment plan includes the one or more dCBT tools that are identified in the third step (203). The determined treatment plan may be configured to be undertaken by the patient over a pre-determined period of time, for example over a period of 8-weeks. The determined dCBT treatment plan may be configured with predetermined daily usage targets, for example with an intended daily use of 10 minutes.
In a fifth step (205), the personalised dCBT treatment plan determined in the fourth step (204) is administered to the patient. Administering the personalised dCBT treatment plan involves the patient making use of the one or more dCBT tools identified in the third step (203). The dCBT treatment plan determined in the fourth step (204) may be delivered in a sequence of modules of neurobehavioral interventions, patient education, and skill-building. The modules may comprise, for example, sound exercises, video exercises, and interactive exercises, among many others, as part of the dCBT tools identified in the third step (203).
In a sixth step (206), subsequent to at least part of the personalised dCBT plan having been administered, changes in relation to the behavioural restrictions associated with the personal PF signature of the patient are determined. Changes may be indicated by comparing the level of anxiety in the patient in relation to the same anxiety triggers identified in the first step (201), the anxiety level of the patient being determined using the same method as was used in the first step (201).
In an example, the personal PF signature of a patient determined in the first step (201) and stored in the second step (202) contains a determined anxiety level in relation to an anxiety trigger that causes behavioural restrictions. The determined anxiety level may be, for example, a value determined using the GAD-7 scale. Alternatively, or additionally, the anxiety level may be self-determined by the patient or may be determined through answers to questions presented to the patient by the digital therapeutic. In the sixth step (206), the anxiety of the patient in relation to the same anxiety trigger action is determined. The anxiety level may be determined by any suitable means or may be self-determined by the patient. The anxiety level determined in the sixth step (206) is compared to the anxiety level that was determined in the first step (201) and is stored in the personal PF signature, thereby to determine whether a reduction in the level of anxiety in relation to the anxiety trigger has been achieved. A reduction in the level of anxiety in relation to the anxiety trigger should indicate a reduction in the associated behavioural restrictions. Any change in the anxiety level of the patient in relation to the one or more anxiety triggers is used to update the personal PF signature of the patient.
Following the assessment performed in the sixth step (206), any or all of the earlier steps (201-205) may be repeated by the patient. As discussed previously, the sixth step (206) may result in a modification to the personal PF signature. For example, any changes in the anxiety level of the patient in relation to one or more anxiety triggers is recorded and will result in a change to the personal PF signature of the patient. When repeating the earlier steps, this modified PF signature may result in different dCBT tools being identified in the third step (203), to further modify the personal PF signature. This would, in turn, result in a different dCBT treatment plan being determined in the fourth step (204) and administered in the fifth step (205). A patient may repeat the entire process (201-206) multiple times to modify different aspects of the PF signature of the patient, thereby.
In some examples, an additional electronic device may be used to measure and record patient health data during the digital therapeutic treatment. For example, a smart watch may be used to measure and record information such as the heart rate of the patient during treatment. Such health data can be used by the digital therapeutic to estimate the anxiety level of the patient during treatment. This additional estimate of the patient anxiety level may be used in combination with the information provided by the patient via anxiety assessments performed during treatment (for example, through use of the GAD-7 scale) to estimate the anxiety level of the patient more frequently. In some examples, this may identify further anxiety triggers, or to highlight known anxiety triggers that are particularly strong. In some examples, the additional electronic device may measure and record further information such as respiration rate, heart rate variability (HRV), steps per day, oxygenation.
The personalised dCBT treatment plan illustrated in
The patient is then introduced (306) to one or more exercises, which may be presented in the form of modules (as discussed in more detail below). The exercise introductions (306) may include questions to help modify the exercise to match the needs of the patient more closely. An example of how such an introduction may be presented is illustrated in the first screen (501) of
Following the exercise introduction (306), the patient is presented with an exercise to perform (307). The exercise (307) may be a standard exercise, or it may be an exercise that has been modified in order to match the personalised requirements of the patient more closely. After completion of the exercise (307), a “tool” may be unlocked and added to the patient “toolbox” (310). An example of this process is illustrated in the second screen (502) of
After completion of the exercise (307), the patient is then presented (308) with a summary of the exercise in order to reflect on the exercise and the progress that may have been made while performing the exercise. The patient is then given “homework” (309) which involves practising the exercise in order for the exercise to provide further benefits to the patient. The patient may be instructed to repeat the skill practise a number of times (the number being pre-set or may be determined by reference to the personal PF signature of the patient). An example of this process is illustrated in the third screen (503) of
After completion of the administered personalised dCBT treatment plan (302), the personal PF signature of the patient may be updated (303).
The first screen (301) of
The first screen (601) of
Following diagnosis, the digital therapeutic disclosed herein may be made available to the patient. In a preferred example, the digital therapeutic is arranged into several modules (210). In a preferred example, the modules (210) are separated into two groups: “information modules” (211), and “therapy modules” (212). The modules are provided to the patient via an electronic device, for example through an app running on a smartphone.
The information modules (211) are non-interventional PF-specific information and activities modules. The information modules (211) may include general wellness modules, and may provide relevant information about ILDs such as IPF, tips on nutrition specific to ILDs and intestinal issues that occur with some treatments, PF-specific breathing exercises for coping with shortness-of-breath, suggestions on better sleep habits and ways to incorporate an acceptable level physical activity. The information modules (211) may help to support patients in creating a sustainable and healthy lifestyle with an ILD and helping to facilitate engagement with the therapy modules (212).
Examples of possible information modules (211) are:
The therapy modules (212) are interventional CBT modules. In some examples, each therapy module (212) is designed to take the patient approximately 8-weeks to work through, if used as intended.
Examples of possible therapy modules (212) include:
As discussed previously, the first step (201) in using the digital therapeutic involves conducting a personalised functional analysis with the patient to determine a personal PF signature. In some examples, this step may involve assessing the patient anxiety levels, for example by using a GAD-7 scale. Patient anxiety levels can also be determined by answering questions presented by the digital therapeutic. Additionally, or alternatively, the patient anxiety level can simply be self-determined by the patient, for example by choosing an anxiety level on a pre-determined scale provided by the digital therapeutic.
In a preferred example, an anxiety level screening (202) is performed before therapy modules (212) are made available to the patient. This anxiety level screening may be separate to the assessment of anxiety performed in the first step (101) discussed above. The anxiety level screening may be, for example, in relation to generalised feelings instead of in relation to a particular anxiety trigger. Alternatively, the anxiety level screening (202) may be in relation to the one or more anxiety triggers causing behavioural limitations identified by the patient in the first step (101).
The anxiety level screening (202) may be performed using the GAD-7 scale. Patients can determine their need for psychological support by answering the GAD-7 questions within the digital therapeutic app. This assessment is not considered to be a diagnosis, but instead is a way for the patient themselves to gain an understanding of the relative status of their mental health. If the score is above a certain level on the GAD-7 (5 or higher on a scale of 0-21), patients may be referred to consult with an HCP (for example an ILD specialist or a primary care physician).
Self-assessments may also be provided mid-way through the determined treatment program as well as after completing treatment. The self-assessments may be in relation to general anxiety. The self-assessments may alternatively, or additionally, be in relation to the one or more anxiety triggers identified in the first step (101) and stored in the personal PF signature of the patient. The self-assessments are designed to be a way for the patient themselves to get an understanding of their progress. In some examples, the self-assessment results may not be shared with healthcare providers automatically, although patients may choose to share their results verbally or by sharing a summary (for example a final PDF form) provided by the digital therapeutic.
In a preferred example, if the anxiety level screening (202) determines that the anxiety level of the patient is below a threshold value (204), the patient is only given access to the information modules (211). In examples where the GAD-7 score is used, a patient may be determined to be below the threshold anxiety level (204) if they receive a score equal to or less than 4 on the GAD-7 scale.
If the anxiety level screening (202) indicates that the patient has an anxiety level above a threshold level (203), the patient may be provided access to the therapy modules (212). In examples where the GAD-7 score is used, a patient may be determined to be above the threshold anxiety level (203) if they receive a score equal to or greater than 5 on the GAD-7 scale.
In some examples, if the patient is determined to have an anxiety level above the threshold level (203), the patient may be referred to an HCP before access is given to the therapy modules (212). In these examples, the HCP may determine which of the therapy modules (212) may be appropriate for the patient to use. In some examples, access to the therapy modules (212) is only given to the patient if the therapy module (212) is prescribed to the patient by the HCP. In such examples, each therapy module (212) may be unlockable by means of a code which is provided to the patient following prescription of the module by the HCP.
In a preferred example, the modules (211, 212) may comprise “Sessions”, “Tools” or “Tool Practice”.
“Sessions” are the primary scheduled interaction between the patient and the treatment, focusing on psychoeducation through text, video and audio, all of which introduce psychological concepts and strategies from CBT and ACT. The Sessions may also include stories from other ILD patients and interactive exercises where the patient is encouraged to reflect upon their own situation by answering questions. Sessions may be built to resemble face-to-face therapy sessions with a psychologist in structure and content, although they are entirely software-based and no actual psychologist is involved.
Strategies for behaviour change, as well as coping skills to handle difficult thoughts and feelings, are referred to as “Tools” in the modules and in the digital therapeutic. As the patient progresses through Sessions, new Tools are unlocked and added to the patient's Toolbox. Tools may be, for example, a guided sound meditation, a logging flow to allow the patient to gain a better understanding of their feelings, a step-by-step guide to practice a psychological tool or a text summary of a psychological tool. The Tools are designed to resemble the tools that a patient would be introduced to in face-to-face therapy with a psychologist.
“Tool Practice” is the skill building activity of using and practicing the Tools in everyday life. The patients may be tasked to use a Tool for a set number of times during a set number of days. Once the task is completed, the patient may be asked to reflect upon what they have done before proceeding to the next task. Tool Practice resembles “homework” that is an established practice in face-to-face CBT. In traditional CBT, patients would receive homework to complete during the week in-between therapy sessions. A further advantage of the digital therapeutic disclosed herein is that this practise work may be scheduled at the patient's own pace.
A digital therapeutic app designed according to the present disclosure has been tested in a pilot study involving 10 patients. For admittance to the pilot study, the following inclusion criteria were imposed on potential trial patients:
The following exclusion criteria were used:
The results of the pilot study are illustrated below in Table 1. The GAD-7 scores were self-reported by patients, with a score taken at the start and at the end of the study on a 0-21 point scale. On a GAD-7 scoring chart, the determined anxiety of the patient is as follows: 0-5 mild, 6-10 moderate, 11-15 moderately severe, 15-21 severe anxiety.
As noted above, the patient had to register a score of at least 5 to be admitted to the pilot study. Between the start and end scores, the patient used the digital therapeutic app to provide dCBT in accordance with the present disclosure.
As illustrated in Table 1, all patients who used the digital therapeutic observed a reduction in their GAD-7 scores, with an average reduction of 4.2 points or 49% of their GAD-7 score. It was noted after the trial that patients 9 and 10 did not use the digital therapeutic app for the full amount of time required during the trial. These results are therefore marked with an asterisk and should not be considered to be entirely representative of the effectiveness of the digital therapeutic app, when used as intended. However, even with incomplete usage, patients 9 and 10 did still observed a small reduction in their anxiety levels following use of the digital therapeutic treatment.
The remaining patients, numbered 1 to 8 in Table 1, observed an average reduction of 5 points in their GAD-7 score following treatment using the digital therapeutic. This represents an average reduction of 59% in the measured anxiety levels following treatment using the digital therapeutic.
Of the ten patients recruited to the study, six were concomitantly treated with antifibrotic drugs (pirfenidone or nintedanib), four were treated with drugs for anxiety (buspirone, clonazepam, desvenlafaxine, fluoxetine, gabapentin and/or lorazepam) and five were treated with proton pump inhibitors (omeprazole, pantoprazole or rabeprazole). Considering that DTx reduced the GAD-7 score in all 10 patients, it can be concluded that the dCBT resulted in reduced anxiety beyond any anxiolytic or other therapeutic effects of these drugs.
Although the description above is with reference to ILDs such as IPF, the digital therapeutic described herein may in addition be used to treat anxiety caused by any disease or condition with dyspnea/difficulty breathing as a symptom, including asthma, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension such as pulmonary arterial hypertension, respiratory infections such as bronchitis and pneumonia, airway-blocking cancers including lung cancer, cardiac diseases such as heart failure and myocardial ischemia, neuromuscular disorders affecting the respiratory muscles, pregnancy, obesity and/or psychogenic breathing disorders.
The drugs listed below are used in one or more of these other common chronic conditions that can cause anxiety due to dyspnea/difficulties breathing.
Short-acting bronchodilators such as albuterol, ipratropium, metaproterenol, levalbuterol, salbutamol, terbutaline.
Long-acting bronchodilators such as aclidinium, arformoterol, formoterol, indacaterol, tiotropium, salmeterol, umeclidinium, vilanterol, umeclidinium, glycopyrrolate, aclidinium.
Inhaled corticosteroids such as fluticasone, flunisolide, budesonide, mometasone, beclomethasone, ciclesonide, triamcinolone acetonide.
Inhaled drug combinations such as fluticasone+vilanterol, fluticasone+umeclidinium +vilanterol, formoterol+budesonide, salmeterol+fluticasone, aclidinium+formoterol, albuterol+ipratropium, formoterol+glycopyrrolate, glycopyrrolate+indacaterol, mometasone+formoterol, olodaterol+tiotropium, umeclidinium+vilanterol.
Phosphodiesterase-4 inhibitors such as cilomilast, ibudilast, roflumilast.
Leukotriene modifying drugs such as montelukast, zafirlukast, zileuton.
Biologic drugs such as omalizumab, benralizumab, dupilumab, mepolizumab, reslizumab.
Angiotensin-converting enzyme inhibitors such as alacepril, captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril.
Angiotensin II receptor blockers such as eprosartan, valsartan, losartan, azilsartan, olmesartan, telmisartan, fimasartan, irbesartan.
Beta receptor blocking agents such as atenolol, bisoprolol, carvedilol, labetalol, metoprolol, propranolol, sotalol.
Diuretics such as chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, eplerenone, spironolactone, triamterene.
Positive inotropes such as dopamine, dobutamine, levosimendan, milrinone, digoxin, amrinone, enoximone.
Sodium-glucose co-transporter 2 inhibitors such as canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin etabonate, sergliflozin etabonate, sotagliflozin, tofogliflozin
Other relevant pharmaceutical treatments tadalafil, ambrisentan, bosentan, opsumit, epoprostenol, epoprostenol, treprostinil, iloprost, selexipag, riociguat, ivabradine, hydralazine, isosorbide dinitrate, vericiguat, theophylline, angiotensin-(1-7), omeprazole, esomeprazole, ilaprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2219591.1 | Dec 2022 | GB | national |
