Patent Application
20250134865
The present disclosure provides a method of reducing weight, body fat mass, and liver fat in a subject who has an abnormal HbAlc level, wherein the method comprises administering to the subject a therapeutically effective amount of 5-[(2,4-initrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof.
Obesity is a well-known risk factor for the development of many common diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Obesity is best viewed as any degree of excess adiposity that imparts a health risk. Glycosylated hemoglobin HbAlc is a biomarker that indicates a subject's blood glucose levels and is used along with other markers to diagnose diabetes. Obesity and overweight are among many factors that cause an elevated HbAlc. An elevated HbAlc level has been associated with a higher risk of developing complications, such as heart disease, liver disease, pancreas disease, kidney diseases, etc. Therefore, there is a great need for effective treatments for reducing weight in a subject with an elevated HbAlc.
The administration of chemical uncouplers of mitochondria as a means to decrease fat deposits has been a scientific goal for many years. While there are several small molecules which uncouple mitochondrial oxidative phosphorylation, the most well-known is 2,4-dinitrophenol (DNP). Though DNP is known to uncouple with robust effect, it unfortunately is associated with an unacceptable high rate of significant adverse effects (J. Med. Toxicol. 2011 September; 7 (3): 205-212). These adverse effects may include hyperthermia, tachycardia, diaphoresis and tachypnoea, eventually leading to death. Being a small, highly permeable, lipophilic acid, DNP is rapidly absorbed in the stomach. The high concentration rapidly distributes and uncouples immediately, producing high levels of heat in a short period of time. Thus, DNP has a small therapeutic index and is extremely dangerous in overdose. DNP was labelled as “extremely dangerous and not fit for human consumption” by the Federal Food, Drug and Cosmetic Act of 1938. Accordingly, there is a need for uncouplers that can safely treat mitochondria-related disorders or conditions.
5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole is a novel small molecule uncoupler (Compound 1). It works as a controlled metabolic accelerator (CMA). It is designed to effectively address the root cause of metabolic diseases, the accumulation of fat and sugars in the body. CMAs work to improve cellular metabolism and increase energy expenditure and calorie consumption, reducing the accumulation of fat. Using a new controlled and targeted approach, Compound 1 can increase mitochondrial proton leak, an ongoing process in the body that dissipates energy, and accounts for 20%-40% of daily calories. Compound 1 leverages a mitochondrial uncoupling mechanism to increase substrate utilization.
In one aspect, the present disclosure provides a method for weight loss in a subject who has an abnormal HbAlc level, wherein the method comprises administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the abnormal HbAlc level is the elevated HbAlc.
In another aspect, the present disclosure provides a method for reducing liver fat in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the method result in reduction of liver fat in the subject.
In certain embodiments, the method is to treat non-alcoholic fatty liver disease (NAFLD) in subjects with elevated liver fat.
In certain embodiments, the subject has a high body mass index (BMI).
In certain embodiments, the reduction of liver fat in the subject is at least 30% in the subject.
In certain embodiments, the reduction of liver fat is least 40% in the subject with the elevated HbAlc level.
In certain embodiments, the methods slow the progression of non-alcoholic fatty liver disease.
In certain embodiments, the subject suffers from obesity, excess body fat, diabetes, high blood pressure (hypertension), dyslipidemia, hypertriglyceridemia, acquired lipodystrophy, inherited lipodystrophy, partial lipodystrophy, or metabolic syndrome.
In certain embodiments, the subject is suffering from at least one of symptoms selected from reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, and ankle swelling.
In certain embodiments, the subject suffers from disorders selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
In certain embodiments, the therapeutically effective amount of Compound 1 is from about 30 mg to about 1400 mg per day, from about 50 mg to about 100 mg per day, from about 150 mg to about 600 mg per day, or from 200 mg to 550 mg orally once daily.
In certain embodiments, the subject experiences weight loss after administration of Compound 1, wherein weight loss is greater than 5%, 10%, 20%, or 30%.
In one embodiment, the subject experiences at least one of:
In another embodiment, the method slows the progression of obesity, hypertension, or diabetes.
While various embodiments and aspects of the present invention are shown and described herein, it will be obvious to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.
5-[(2,4-Dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole is a novel small molecule uncoupler. It has the following structure:
5-[(2,4-Dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole may be prepared by the procedures described in WO 2018/129258.
In this disclosure, Compound 1 and CM1 are interchangeable. They both refer to 5-[(2,4-Dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole.
The terms “a” or “an,” as used in herein means one or more.
The terms “comprise,” “include,” and “have,” and the derivatives thereof, are used herein interchangeably as comprehensive, open-ended terms. For example, use of “comprising,” “including,” or “having” means that whatever element is comprised, had, or included, is not the only element encompassed by the subject of the clause that contains the verb.
As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term “about” means within a standard deviation using measurements generally acceptable in the art. In some embodiments, “about” means a range extending to +/−10%, +/−5%, or +/−2% of the specified value. In some embodiments, “about” means the specified value.
As used herein, “treatment” or “treating” or “palliating” or “ameliorating” or “reducing” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit. By therapeutic benefit means eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. Treatment includes causing the clinical symptoms of the disease to slow in development by administration of a composition; suppressing the disease, that is, causing a reduction in the clinical symptoms of the disease; inhibiting the disease, that is, arresting the development of clinical symptoms by administration of a composition after the initial appearance of symptoms; and/or relieving the disease, that is, causing the regression of clinical symptoms by administration of a composition after their initial appearance.
“Patient” or “subject” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by using the methods provided herein. The term does not necessarily indicate that the subject has been diagnosed with a particular disease, but typically refers to an individual under medical supervision. Non-limiting examples include humans, other mammals.
As used herein, “administration” of a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, e.g., as described herein.
“Pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms and other materials that are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.
An “effective amount” is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, reduce one or more symptoms of a disease or condition, reduce viral replication in a cell). An example of an “effective amount” is an amount sufficient to contribute to the treatment, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). Efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
As used herein, the term “increase in body temperature” in a subject refers to a body temperature increase that is associated with deleterious effects on the subject, not limited to illness, physical discomfort or pain, coma and death. In one non-limiting embodiment, the significant increase in body temperature is an increase of about 0.5° C., about 1° C., about 1.5° C., about 2° C., about 2.5° C., about 3° C., about 3.5° C., about 4° C., about 4.5° C., about 5° C., about 5.5° C., about 6° C. or higher.
As used herein, “an elevated liver fat” generally refers to when more than 8% of the liver's weight is made up of fat. However, AASLD defined NAFLD elevated liver fat as 5%. Chalasani et al., Hepatology, 2018 67:328-357. Le et al. Diabetes, 2022; 71 (Supplement_1) 119-OR. Others have suggested that any elevation of liver fat at any level is unhealthy. Minhdale et al. Diabetes 2022; 71 (Supplement_1): 119-OR. Other researchers suggested that the presence of any liver fat may be abnormal [and a Liver Fat Content] cutoff of around 2% may be optimal for defining non-alcoholic fatty liver disease.”
In one aspect, provided here in is a method for weight loss in a subject who has an abnormal HbAlc level, comprising administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof.
For people without diabetes, the normal range for the hemoglobin HbAlc level is between 4% and 5.6%. Hemoglobin HbAlc levels between 5.7% and 6.4% can be characterized as prediabetes and a higher risk of developing diabetes. Levels of 6.5% or higher are considered as diabetic.
In certain embodiments, the abnormal HbAlc level is the elevated HbAlc.
In another embodiment, the subject has an elevated HbAlc level greater than 5.7.
In certain embodiments, the subject suffers from obesity, excess body fat, diabetes, high blood pressure (hypertension), dyslipidemia, hypertriglyceridemia, acquired lipodystrophy, inherited lipodystrophy, partial lipodystrophy, or metabolic syndrome.
In certain embodiments, the subject suffers from obesity or excess body fat.
In certain embodiments, the subject suffers from diabetes.
In certain embodiments, the diabetes is type 2 diabetes (T2DM).
In another embodiment, the subject suffers from disorders selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
In certain embodiments, the subject is suffering from at least one of symptoms selected from reduced exercise tolerance, fatigue, tiredness, increased time to recover after exercise, and ankle swelling.
In another aspect, provided herein is a method for reducing body fat mess in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof.
In another aspect, provided herein is a method for reducing liver fat in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject in need thereof has elevated liver fat.
In certain embodiments, the above method result in reduction of liver fat in the subject.
In certain embodiments, the method is to treat non-alcoholic fatty liver disease (NAFLD) in subjects with elevated liver fat.
In certain embodiments, the subject has a high body mass index (BMI).
In certain embodiments, the reduction of liver fat in the subject is at least 30% in the subject.
In certain embodiments, the reduction of liver fat is least 40% in the subject with the elevated HbAlc level.
In certain embodiments, the subject's BMI is greater than 28.0 kg/m2.
In certain embodiments, the subject's BMI is between 28.0-45.0 kg/m2.
In certain embodiment, the bodyweight reduction is attributed to fat reduction.
In certain embodiment, the bodyweight reduction is attributed to liver fat reduction.
In certain embodiments, the therapeutically effective amount is 150 mg and the reduction of liver fat is about 40% in the subject.
In certain embodiments, the therapeutically effective amount is 150 mg and the reduction of liver fat is about 43% of liver fat in the subject with the elevated HbAlc level.
In certain embodiments, the therapeutically effective amount is 300 mg and the reduction of liver fat is about 70% in the subject with the elevated HbAlc level.
In certain embodiments, the therapeutically effective amount is 300 mg and the reduction of liver fat is about 75% in the subject with the elevated HbAlc level.
In certain embodiments, the therapeutically effective amount is 450 mg and the reduction of liver fat is about 72% in the subject.
In certain embodiments, the therapeutically effective amount is 450 mg and the reduction of liver fat is about 86% in the subject with the elevated HbAlc level.
In certain embodiments, the methods slow the progression of non-alcoholic fatty liver disease.
In certain embodiments, the present disclosure provides a method for reducing the risk for a subject with NAFLD to advance to non-alcoholic steatohepatitis (NASH), wherein the subjects have elevated liver fat, comprising administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof.
In another aspect, the patient with NAFLD has elevated adiposity, or elevated HbAlc.
In certain embodiments, the subject suffers from obesity, excess body fat, diabetes, high blood pressure (hypertension), dyslipidemia, hypertriglyceridemia, acquired lipodystrophy, inherited lipodystrophy, partial lipodystrophy, or metabolic syndrome.
In certain embodiments, the method slows the progression of obesity, hypertension, or diabetes.
In another aspect, disclosed here in a method for treating fibrosis, progressive fibrosis, or progressive fibrotic liver diseases NASH in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1H-imidazole, or a pharmaceutically acceptable salt thereof.
In certain embodiments, the therapeutically effective amount is from about from about 30 mg to about 1400 mg per day, from about 50 mg to about 100 mg per day, from about 150 mg to about 600 mg per day, or from 200 mg to 550 mg per day.
In certain embodiments, the therapeutically effective amount is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or 600 mg per day.
In certain embodiments, the therapeutically effective amount is about 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, or 95 mg, per day.
In certain embodiments, therapeutically effective amount is about 150 mg, 300 mg, or 450 mg per day.
In certain embodiments, Compound 1 is administered orally once daily.
In certain embodiments, the subject experiences weight loss after administration of Compound 1, wherein the improvement comprising weight loss greater than 5%, 10%, >20%, or 30%.
In certain embodiments, the therapeutically effective amount of Compound 1 is about 150 mg and weight loss greater than 10%.
In certain embodiments, the therapeutically effective amount of Compound 1 is about 300 mg and weight loss greater than 20%.
In certain embodiments, the therapeutically effective amount of Compound 1 is about 450 mg and weight loss greater than 30%.
In certain embodiments, the subject experiences at least one of:
In certain embodiments, the subject experiences at least one of:
In certain embodiments, the subject experiences a reduction of HbAlc by at least 1.5%.
In certain embodiments, the method slows the progression of obesity, hypertension, or diabetes.
The present disclosure includes novel pharmaceutical dosage forms of Compound 1 or a pharmaceutically acceptable salt thereof. The dosage forms described herein are suitable for oral administration to a subject. The dosage form may be in any form suitable for oral administration, including, but not limited to, a capsule or a tablet. In some embodiments, the present disclosure provides a single unit dosage capsule or tablet form containing from about 30 mg to about 1400 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 600 mg, or from 200 mg to 550 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is administered in a hydroxypropyl methylcellulose capsule.
In some embodiments, the amount of Compound 1 in a unit dosage is about 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 170 mg, 200 mg, 250 mg, 300 mg, 340 mg, 350 mg, 400 mg, 450 mg, 500 mg, 510 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, or 1400 mg. In some embodiments, the single unit dosage form is a capsule. In some embodiments, the single unit dosage form is a tablet.
In some embodiments, the amount of Compound 1 in a unit dosage is about 30 mg, 100 mg, 200 mg, 500 mg, 600 mg, 1050 mg, or 1400 mg. In some embodiments, the amount of Compound 1 in a unit dosage is about 200 mg, 400 mg, or 550 mg. In some embodiments, the amount of Compound 1 in a unit dosage is about 170 mg, 340 mg, 510 mg. In some embodiments, the amount of Compound 1 in a unit dosage is about 150 mg, 300 mg, 450 mg.
In therapeutic use for controlling or preventing weight gain in a mammal, a compound of the present disclosure or its pharmaceutical compositions can be administered orally, or parenterally.
This was a 61-day randomized, double-blind trial placebo controlled trial to assess the safety and efficacy of 3 doses of orally administered Compound 1 compared to placebo in subjects with nonalcoholic fatty liver disease (NAFLD), elevated liver fat (>8%), and elevated body mass index (BMI) (28 to 45 kg/m2). Subjects were stratified by glycated hemoglobin (HbAlc≥5.7%). The primary endpoint was the relative change in liver fat content from baseline to Day 61 assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF); secondary endpoints included safety, change in body composition, weight, glycemic control, and inflammation markers.
Eighty subjects were enrolled (placebo n=20, Compound 1 150 mg n=20, 300 mg n=21, 450 mg n=19). At baseline, HbAlc was elevated in 40% of subjects. At Day 61, the absolute and relative reductions in liver fat in Compound 1 treated subjects and the HbAlc subset were highly significant (p<0.0001 vs. placebo). A responder analysis using 30% or greater reduction in liver fat by MRI-PDFF showed responses in 40%, 71%, and 72% for Compound 1 150 mg, 300 mg, and 450 mg doses, respectively, and 43%, 75%, and 86% in the HbAlc subset vs. 0-5% with placebo (p<0.05 for all comparisons). Compound 1 treatment was associated with significant reductions in whole body fat, body weight, inflammatory markers, and glycated albumin. Lean body mass was preserved. No serious adverse events occurred. Six subjects discontinued early, 3 with Compound 1 (150 mg n=2, 300 n=1) and 3 with placebo. Diarrhea and flushing, most often mild, occurred in 35% and 25% of Compound 1 subjects, respectively.
This was a Phase 2, single-center, randomized, parallel-group, double-blind, placebo-controlled, study to evaluate the safety and efficacy of Compound 1 in healthy subjects with high BMI and evidence of elevated liver fat. Subjects were screened over a 45-day period, and eligible subjects were randomized to receive once-daily oral doses of Compound 1 at 150 mg, 300 mg, or 450 mg or matching placebo under fasting conditions for 61 days. Randomization was stratified by glycated hemoglobin Alc (HbAlc) with normal baseline defined as HbAlc <5.7% and high baseline defined as HbAlc≥5.7%. A final follow-up visit occurred within 10 to 14 days after the last dose. See
The randomization will be blocked and stratified by HbAlc. Subjects will be stratified into tow HbAlc strata: one subgroup of subjects with normal baseline HbAlc defined as HbAlc <5.7% and the other subgroup of subjects with high baseline HbAlc defined as HbAlc between 5.7% and 9.0% inclusive.
The primary efficacy and safety objectives of this study are:
Subjects must meet all the following inclusion criteria to be eligible:
1. Adult male or females, 28 to 65 years of age (inclusive) at the time of informed consent with BMI between 28.0 and 45.0 kg/m2 (inclusive).
Subjects will be excluded from the study if any of the following criteria are met:
18. Serum triglyceride concentrations exceeding 500 mg/dL.
The phase 2a metabolic trial of Compound 1 was a 61-day randomized, double-blind, placebo-controlled trial designed to assess the safety and efficacy of three dose levels of Compound 1 (150 mg, 300 mg, and 450 mg) in obese participants (body mass index 28 to 45 kg/m2) with elevated liver fat (greater than 8%). Eighty (80) participants ranging in age between 28 and 65 years were randomly assigned to one of three Compound 1 treatment groups or the matched placebo group, stratified and blocked for HbAlc levels of 5.7% or greater, and dosed once daily (fasting). Participants were instructed to not change behavior with regard to diet or exercise. The Phase 2a trial met primary (liver fat reduction by MRI-PDFF) and secondary (body weight and fat reduction by abdominal MRI) endpoints. Key results and observations include:
At the dose of 300 mg and 450 mg doses, Compound 1 demonstrated significant positive effects on several endpoints, including InBody scale measurements of body weight, body fat mass, and percent body fat with no significant effect on skeletal muscle mass, lean body mass or dry lean mass. Compared with placebo, mean body weight decreased by 6 pounds in the 450 mg group at Day 61 and by 10 pounds in the subgroup of subjects with elevated HbAlc, while skeletal muscle mass (and lean body mass and dry lean mass) remained unchanged. Significant reductions in inflammatory and metabolic markers were observed with Compound 1. Glycated albumin was used in this study rather than HbAlc to assess metabolic control because a change in glycated albumin occurs earlier than with HbAlc (120 days) and was a better marker of glycemic control in this 61-day study. A 0.5% reduction in HbAlc was observed, in parallel with a greater reduction in glycated albumin that was statistically significant. The preferential loss of fat and improved glycemic control in the subjects with elevated HbAlc is intriguing and as longer-term therapy has the potential to improve metabolic and inflammatory health in people with type 2 diabetes and obesity.
(1) Treatment effect in change relative liver fat demonstrated across all doses in subjects with elevated HbAlc as shown in
(2) Analysis of covariance for MRI-proton density fat fraction (PDFF) is shown in Table 2. Mean change from baseline at Day 61 for subjects in HbAlc 5.7%-9.0%. Subgroup only (LSMean±95% CI).
(3) Treatment results in response (>30% liver fat reduction by MRI-PDFF) across all dose arms as shown in Table 3 below:
(4) Significant weight reduction (lbs) in subjects with elevated HbAlc as shown in
This MMRM analysis was performed with the model including the effects for treatment, visit, and treatment-by-visit interaction as fixed effects, and baseline HbAlc stratification as a factor with baseline value of the response variable as a covariate.
(5) Fat loss in subjects with elevated HbAlc population (Mean±SEM) is shown in
(6) Weight loss in overall population and in the elevated HbAlc group is shown in
(7) Body Fat Mass was reduced in the elevated HbAlc group as shown in table 5 and in the overall population as shown in Table 6. The reduction in Body Fat Mass was higher in the patient population with elevated HbAlc.
(8) Response rate, i.e. ≥30%, reduction in liver fat from the baseline to day 61 is shown in
(9) Absolute and relative percent (%) change in liver fat at 150 mg, 300 mg, and 450 mg of Compound 1 (from baseline to day 61) is in shown in
(10) Percent (%) change from baseline for liver stiffness parameters at 150 mg, 300 mg, and 450 mg of Compound 1 is shown in
(11) Reduction of glycated albumin (percent (%) change) from baseline to day 61 is shown in Table 7 and
(12) LS mean change in liver parameters at day 61 is show in Table 8 below:
This analysis was performed with the model including treatment as a fixed effect and baseline HbAlc stratification as a factor with baseline value of the response variable as a covariate. a p<0.05; b p<0.01; c p<0.001.
(13) Change in MRI-Proton Density Fat Fraction (%) from baseline to Day 61 in all subjects and the subgroup of subjects with elevated HbAlc is shown in Table 9.
(14) Change in liver volume and whole-body adiposity from baseline to Day 61 in all subjects and the subgroup of subjects with elevated HbAlc is shown in Table 10.
aNegative values indicate decreases in parameter value.
bThe LS means for the change from baseline and the associated 95% CIs, the difference in the LS means and the associated 95% CIs, and 2-sided p-values are from an ANCOVA model with treatment as the fixed effect, baseline HbA1c stratification as a factor, and baseline parameter value as the covariate.
In summary, Compound 1 at 150 mg, 300 mg, and 450 mg demonstrated significant dose-related positive effects on the primary efficacy endpoint of the change from baseline in liver fat content by MRI-PDFF across the overall population and among those with elevated HbAlc, and these changes occurred within 61 days of treatment. Approximately 60% of the subjects overall and 68% of subjects in the subgroup experienced at least a 30% decrease in liver fat based on MRI-PDFF, and placebo-corrected mean percent change from baseline ranged from −33% to −43% for subjects overall and from −42% to −50% for subjects in the subgroup. Decreases in liver fat content were accompanied by decreases in body weight, which was accounted for by body fat without a loss of lean body mass. Improvement in liver volume, SAT, and CAP score, occurred with Compound 1, in the overall group and in the subgroup with elevated HbAlc.
In addition, 300 mg and 450 mg doses of Compound 1 demonstrated significant positive effects on several secondary endpoints, including In Body scale measurements of body weight, body fat mass, and percent body fat with no effect on skeletal muscle mass, lean body mass or dry lean mass. Compared with placebo, mean body weight decreased by 6 pounds in the 450 mg group at Day 61 and by 10 pounds in the subgroup of subjects with elevated HbAlc, while skeletal muscle mass (and lean body mass and dry lean mass) remained unchanged. Significant reductions in inflammatory and metabolic markers were observed with Compound 1. Glycated albumin was used in this study rather than HbAlc to assess metabolic control because a change in glycated albumin occurs earlier than with HbAlc (120 days) and was a better marker of glycemic control in this 61-day study. A 0.5% reduction in HbAlc was observed, in parallel with a greater reduction in glycated albumin that was statistically significant. The preferential loss of fat and improved glycemic control in the subjects with elevated HbAlc is intriguing and as longer-term therapy has the potential to improve metabolic and inflammatory health in people with type 2 diabetes and obesity.
This International PCT Application claims priority to and the benefit of U.S. Provisional Application No. 63/307,470 filed on Feb. 7, 2022 and U.S. Provisional Application No. 63/382,426, filed on Nov. 4, 2022, the contents of which are herein incorporated by reference in their entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2023/062065 | 2/6/2023 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63307470 | Feb 2022 | US | |
| 63382426 | Nov 2022 | US |
