Heart Failure with Preserved Ejection Fraction (HFpEF)
Individuals with (HFpEF) have clinical symptoms of heart failure, but the ventricular ejection fraction is normal or near normal (left ventricular ejection fraction ≥45 %). It is the most common form, and comprises more than 50% of all patients with heart failure. There is currently no FDA-approved treatment for HFpEF.
Table 1. Negative Studies of Drugs for Heart Failure with Preserved Ejection Failure
| Drugs Tested | Endpoints Evaluated | Mechanism of Action |
|---|---|---|
| Alagebrium chloride | All-cause mortality | ARB inhibitors |
| Candesartan | 60-90-day mortalit | β-blockers |
| Carvedilol | CV death | Digitalis glycoside |
| Digoxin | HF mortality | Diuretic |
| Empagliflozin | Aborted cardiac arrest | Inorganic nitrates |
| Enalapril | CV hospitalization | MRA |
| Entresto | HF admission | Nitrates |
| Eplerenone | HF hospitalization | PDE5 inhibitor |
| Irbesartan | Rehospitalization rate | sGC stimulator |
| Isosorbide mononitrate | Peak VO2 | |
| Nebulized sodium nitrate | 6-minute walk distance | |
| Nebivolol | Daily activity level | |
| Perindopril | Change in E/é | |
| Riociguat | Change in mean pulmonary | |
| Sildenafil | ||
| Spironolactone |
Clinical Results
Phase 1 trial (AMS-1282):
We determined the safety and pharmacokinetics of our new medicine AMS-1282. Using stable isotope tracer methodology we determined that, in part, low physical function was related to altered muscle protein metabolism, and that AMS-1282 stimulated muscle protein synthesis in heart failure patients to a greater extent than a leading supplement specifically designed to support heart failure (Figure 1). There are currently no approved pharmlogical treatments for HFpEF.
Reduced physical function in HFpEF is also related to deficient regulation of blood flow due to limitation in the ability of the body to produce nitric oxide (NO). We therefore designed AMS-1282 to increase the production of NO in the body. We quantified the response of NO production in heart failure patients with stable isotope tracer methodology.
Phase 2 trial (AMS-1282):
Having determined that muscle protein synthesis and NO production were key metabolic reactions to target to improve physical function in heart failure, we performed a 12-week randomized clinical trial in which AMS-1282 was shown to improve physical function, as reflected by the distance walked in 6 minutes, as well as muscle strength. In addition, circulating levels of low-density lipoprotein and triglycerides were also reduced. These beneficial responses occurred in the absence of any organized exercise program.
Phase 3
FDA-approved Phase 3 clinical trial set to begin in July.
| Protocol Summary | |
|---|---|
| Study Type: | Interventional (Clinical Trial) |
| Allocation: | Randomized |
| Actual Enrollment: | 130 participants |
| Interventional Model: | Parallel assignment |
| Masking: | Double (participant, investigator) |
| Official Title: | A phase 3 randomized, double blind trial to evaluate functional capacity and other symptoms of heart failure with preserved ejection fraction. |
| Interventions: | Experimental: AMS-1282 Active comparator: Placebo |
| Primary Outcome Measures: | Distance walked in 6 minutes under controlled supervised conditions before, 12 and 24 weeks after start of investigation. |
| Secondary EndPoints: Before intervention, at 12 weeks and 24 weeks after start of intervention) | – Grip strength – Total body fat, % body fat – Plasma concentrations of N-terminal B-natriutic peptide, LDL and triglcerides – Filling pressure of the heart, systolic artery pressure. |
Hepatic seatosis (fatty liver)
Hepatic steatosis causes an inflammatory state in the liver and is a precursor of liver fibrosis and ultimately liver cirrhosis. Additionally, hepatic steatosis increases the risk for type 2 diabetes and cardiovascular disease. It has long been recognized that chronic excessive alcohol consumption causes metabolic alterations in the liver that lead to excess deposition of fat. More recently, it has become recognized that fatty liver can also occur in the absence of excessive alcohol consumption (Nonalcoholic steatohepatitis (NASH)).
Our treatment candidates act on multiple aspects of the fatty acid/ VLDL-TG cycling that affect liver fat and circulating triglyceride levels. The composition decreases the availability of fatty acids in the liver, increases the secretion of fat from the liver in the form of VLDL-TG, and increases the clearance of triglycerides from the blood by adipose tissue via lipoprotein lipase.
Clinical Results
Phase 2 trial (AMS-2392):
Alcoholic Fatty Liver Disease
Status: Completed
Four weeks of treatment with our composition significantly reduced liver fat, as determined by magnetic resonance spectroscopy, in individuals who were actively consuming large quantities of alcohol daily.
We are currently working with the FDA to design a randomized, double-blind clinical trial in which AMS-2392 will be tested against a placebo in a Phase 3 trial for potential NDA consideration.
Phase 2 Trial (AMS-2572):
Polycystic ovary syndrome
Status: ongoing
Polycystic ovary syndrome (PCOS) is a hormonal disorder common among young women. Severe liver inflammation due to excessive liver fat (NAFLD) is a relatively common complication of PCOS that can lead to diabetes and other pathologies.
We are currently performing a Phase 2 study in young women with PCOS to determine the effectiveness of AMS-2572 on decreasing liver fat. We anticipate that NAFLD is associated with increased hepatic lipogenesis, which will be suppressed by AMS-2572. We also anticipate treatment with AMS-2572 will decrease triglycerides and VLDL- TG levels in plasma. Trial is expected to complete in Ocotber 2021.
| Protocol Summary | |
|---|---|
| Study Type: | Interventional (Clinical Trial) |
| Allocation: | Randomized |
| Planned Enrollment: | 20 participants |
| Interventional Model: | Parallel assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Official Title: | Oral Amino Acid Nutrition to Improve Glucose Excursions in PCOS |
| Interventions: | Experimental: AMS-2572 Placebo |
| Primary Outcome Measures: | - Change in Hepatic Fat Fraction |
| Secondary EndPoints: (Measured before intervention and at 6 months after start of intervention) | - Liver fat mass (kg) - Visceral fat mass (kg) - Subcutaneous fat mass (kg) - Whole body fat mass (kg) - Weight (kg) - Resting energy expenditure (kg) - Resting energy expenditure (kg) - Diet induced thermogenesis (% kcal expended to digest 1 kcal of protein) - Glucose (Blood plasma glucose in mg/dL) - Insulin (Blood serum insulin in μL/ml) - Essential amino acids (blood plasma essential amino acids in mcmol/L) - Dietary intake (Objective) (Dietary record of intake in kcal/day for 3 days - Physical activity (Objective) (Physical activity by accelerometer kcal/day for 7 days) - Percent muscle fat (Muscle fat in kg%) - Muscle protein synthetic rate (kg/day) |
Obesity
Traditional weight loss programs and surgeries result in a loss of both body fat and muscle. The loss of muscle reduces metabolic rate, which in turn limits the rate at which fat is lost.
Our goal with all potential treatment candidates is to exclusively target fat loss while fully maintaining muscle mass, resulting in faster, more permanent weight loss and tangible gains in overall health and quality of life.
Clinical Results
Phase 2 trial (AMS-3830):
Fat loss in caloric restriction weight loss
AMS-3830 is a meal replacement that enables loss of body fat andmaintenance of muscle mass without major behavioral changes. Caloric expenditure is increased by a greater stimulation of muscle protein synthesis via activation of mTORC1 and acceleration of muscle mRNA translation.
Our recently completed Phase 2 trial looked at the changes in body composition after 4 weeks of substituting 1 dose of our treatment as compared to a leading meal replacement. Our treatment resulted in significantly (p<.05) more fat mass lost while maintaining muscle mass. The effect was strongest in women.
Phase 2 Trial (AMS-3469):
Accelerated fat loss following bariatric surgery
Status: ongoing
AMS-3469 stimulates muscle protein synthesis more than the most potent standard-of-care treatments currently available. This has the effect of decreasing the rate of muscle loss in hypocaloric circumstances, such as after bariatric surgery. AMS-3469 maintains energy expenditure, as reflected by greater diet-induced thermogenesis (DIT) in response to nutrient intake. The energy for muscle protein synthesis comes from the oxidation of fatty acids released from adipose tissue. Thus, accelerated fat loss is induced by stimulation of the translation of muscle protein mRNA.
We are currently performing a Phase 2 clinical trial in which the rate of fat loss after bariatric surgery in individuals given AMS-3469 is being compared with the rate of fat loss when subjects are given the current best standard of care.
| Protocol Summary | |
|---|---|
| Study Type: | Interventional (Clinical Trial) |
| Allocation: | Randomized |
| Planned Enrollment: | 40 participants |
| Interventional Model: | Parallel assignment |
| Masking: | Double (participant, investigator) |
| Official Title: | Nutritional Stimulation of Muscle Protein Synthesis and Metabolic Rate After Bariatric Surgery |
| Interventions: | Experimental: AMS-3469 Active comparator: Beneprotein® |
| Primary Outcome Measures: | - Lean body mass (kg) - Total energy expenditure (kcal per day) - Muscle mass (kg) |
| Secondary EndPoints: (Measured before intervention and at 6 months after start of intervention) | - Liver fat mass (kg) - Visceral fat mass (kg) - Subcutaneous fat mass (kg) - Whole body fat mass (kg) - Weight (kg) - Resting energy expenditure (kg) - Resting energy expenditure (kg) - Diet induced thermogenesis (% kcal expended to digest 1 kcal of protein) - Glucose (Blood plasma glucose in mg/dL) - Insulin (Blood serum insulin in μL/ml) - Essential amino acids (blood plasma essential amino acids in mcmol/L) - Dietary intake (Objective) (Dietary record of intake in kcal/day for 3 days - Physical activity (Objective) (Physical activity by accelerometer kcal/day for 7 days) - Percent muscle fat (Muscle fat in kg%) - Muscle protein synthetic rate (kg/day) |
Failure to Thrive
Children are diagnosed with failure to thrive when their weight or rate of weight gain is significantly below that of other children of similar age and sex. Physically, these children will be dramatically smaller or shorter than other children the same age.
Childhood short stature is one of the most common causes for referral to pediatric endocrinologists in the United States. Short stature is especially prevalent among those with failure to thrive (whose weight is significantly below the average weight of his/her peers). Growth hormone therapy is not an effective medical treatment of short stature when the cause of short stature is not growth hormone deficiency.
Clinical Results
Phase 2 trial (AMS-6731):
Accelerating growth in children
Status: Ongoing
AMS - 6731 promotes protein synthesis and chondrocyte proliferation by modulating the phosphorylation state of rapamycin complex C1 (mTORC1) and promoting mRNA translation. In addition, it has become recognized that the master growth pathway is strongly influenced by mTORC1 as well.
Our current clinical trial is investigating the effects of giving AMS-6731 daily for 6 months, with the goal of triggering growth of short stature children who have not yet reached puberty and are confirmed to have normal growth hormone levels.
| Protocol Summary | |
|---|---|
| Study Type: | Interventional (Clinical Trial) |
| Allocation: | Randomized |
| Planned Enrollment: | 60 participants |
| Interventional Model: | Parallel assignment |
| Masking: | Triple (Participant, Care Provider, Investigator) |
| Official Title: | Stimulation of Growth in Children With Short Stature Without Growth Hormone Deficiency |
| Interventions: | Experimental: AMS-6731 Placebo |
| Primary Outcome Measures: | - Linear Growth (cm/year) |
| Secondary Endpoints: | - Lean body mass - Body fat mass - Visceral fat mass - Serum growth factor concentrations [Insulin-Like Growth-Factor (IGF-I)] - Serum growth factor concentrations [Insulin-Like Growth-Factor Binding-Protein (IGF BP)-III] - Serum amino acid concentrations |
Cachexia
Cachexia is a condition of weakness and wasting of the body due to severe chronic illnesses such as cancer, AIDS, kidney disease and heart failure. Our initial treatment focus is cachexia caused by cancer, which often progresses to the point that the cachexia ultimately impairs the patient’s ability to withstand the rigors of prescribed cancer treatments.
Cancer leads to an altered metabolic state called “anabolic resistance,” which not only accelerates the rate of muscle protein breakdown, but renders traditional nutrition ineffective. We have determined the underlying metabolic basis for anabolic resistance in cancer patients and have designed a treatment to treat the progression of cachexia in cancer patients. We our currently designing our first clinical trial to treat cancer cachexia.
