ALMS1

A multinational research collaboration has developed a new peptide dubbed “PATAS”, which appears to fix the metabolic abnormalities leading to type 2 diabetes (T2D). The research was coordinated by Vincent Marion, Ph.D., with France-based Inserm in collaboration with the University of Birmingham (UK), Monash University (Australia) and with Dr. Alexander Fleming, M.D., former senior endocrinologist at the U.S. Food and Drug Administration, and was published Wednesday in the journal Diabetes. Type 2 diabetes is marked by high glucose levels in the blood. Unlike type 1 diabetes, which is an autoimmune disease caused by the patient’s immune system attacking and destroying the pancreas cells that produce insulin, type 2 diabetes is the result of insulin resistance in cells in the body. The incidence of T2D has been increasing for decades because of the obesity epidemic and an aging population. Inserm notes that there “have been no disruptive therapeutic innovations to reach market in over a decade.” Obesity is connected to hypertrophic adipocytes (oversized fat cells), which leads to impaired glucose absorption. Adipocytes are key regulators of whole-body metabolic fitness because of how they control insulin sensitivity. The new research, conducted on animal models, demonstrated that PATAS (peptide derived from PKC alpha Targeting AlmS) restored glucose uptake in the fat cells (adipocytes), which treated insulin resistance while benefiting the entire body. Earlier research suggested that adipose tissue abnormalities caused by a dysfunctional protein, ALMS1, led to severe insulin resistance in people with Alstrom syndrome who had early-onset T2D. In animal models, fixing this protein within the adipocytes restored blood glucose balance. Alstrom syndrome is a rare disease that affects many systems throughout the body. It includes obesity, T2D, short stature, heart disease and a progressive loss of vision and hearing. It is caused by mutations in the ALMS1 gene. The researchers then turned their focus on ALMS1 and how it relates to other adipocyte proteins. They found that in the absence of insulin, ALMS1 binds to a protein dubbed PKC alpha. Insulin activation caused ALMS1 and PKC alpha to separate, allowing glucose to enter cells. But in people with T2D insulin resistance, the connection between the two proteins is maintained. “Thanks to PATAS, the adipocytes that could no longer access glucose were once again able to absorb it and then metabolize it in order to synthesize and secrete lipids which are beneficial to the entire body. These positive effects are visible in our animal models, with a marked improvement in insulin resistance. Other parameters and comorbidities are also improved, including better blood glucose control and decreased liver fibrosis and steatosis,” Marion stated. The next step is a clinical trial to evaluate PATAS in humans. The researchers say this class of antidiabetic drugs may be able to treat not only T2D but also other cardio-metabolic diseases where dysfunctional adipocytes and insulin resistance are a problem. The authors wrote, “In vivo, PATAS reduced whole-body insulin resistance, and improved glucose intolerance, fasting glucose, liver steatosis and fibrosis in rodents. Thus, PATAS represents a novel first-in-class peptide that targets the adipocyte to ameliorate insulin resistance and its associated comorbidities.” Currently, the most common treatments for T2D aside from weight loss and diet are glucagon-like peptide-1 (GLP-1) agonists, such as Eli Lilly’s Trulicity (dulaglutide), Novo Nordisk’s Victoza (liraglutide) and Ozempic (semaglutide).

Sarah Silbiger/Getty Images The U.S. Food and Drug Administration has approved Boston-based Rhythm Pharmaceutical’s Imcivree (setmelanotide) for patients with Bardet-Biedl syndrome (BBS), a rare genetic disease with a wide range of symptoms, including severe obesity. Imcivree is already approved by the European Commission (EC) and Great Britain’s Medicines & Healthcare Products Regulatory Agency (MHRA) for obesity and control of hunger linked with genetically confirmed loss-of-function biallelic proopiomelanocortin (POMC), including PCSK1, deficiency or biallelic LEPR deficiency in adults and children six years of age and older. The drug is a melanocortin-4 receptor (MC4R) agonist. MC4R plays a key role in the biological pathway that regulates hunger, caloric intake and energy expenditure. “This FDA approval represents a significant milestone for Rhythm, validating our strategy of developing Imcivree for people with hyperphagia and severe obesity caused by rare MC4R-pathway diseases and allowing us to provide our precision therapy to an established community of patients living with BBS and their families who are eagerly awaiting a new treatment option,” Dr. David Meeker, M.D., chair, president and chief executive officer of Rhythm, said in a statement. “Leveraging the robust infrastructure we put in place following the initial approval of Imcivree for obesity due to biallelic POMC, PCSK1 or LEPR deficiency and our new high-touch patient support services to assist patients throughout the journey from diagnosis to ongoing treatment, we are able to make Imcivree available for BBS immediately," he added. On Monday, the company presented data from its long-term extension study of the drug in BBS syndrome, or POMC or LEPR deficiency obesity receiving the therapy between 18 months and three years. The presentation took place at the Endocrine Society Annual Meeting & Expo (ENDO) held in Atlanta. Forty-two patients with BBS treated with setmelanotide in Phase II or Phase III continued into the long-term extension. As of the data cutoff, 30 and 19 patients received at least 18 and 24 months of the drug, respectively. The mean percent change in body mass index (BMI) across all patients was -9.5% and -14.3% at 18 and 24 months, respectively. BBS affects about 1,500 to 2,500 people in the U.S. They may experience insatiable hunger (hyperphagia), with severe obesity starting early in life. Other symptoms include retinal degeneration, decreased kidney function, extra fingers or toes (polydactyly), hypogonadism and learning disabilities. The approval was based on data from the company’s pivotal Phase III trial. The drug demonstrated early, significant and sustained weight reduction, hitting its primary endpoint and all key secondary endpoints. The mean percentage change in BMI was -7.9% without diet and exercise. There was a statistically significant mean change in hunger score of -2.1 at 52 weeks in patients 12 years of age and older who could self-report their hunger. Dropped toward the end of the announcement, the company indicated the FDA had issued a complete response letter (CRL) for the sNDA for setmelanotide in Alström syndrome. Alström syndrome is also a rare disease affecting a broad range of body systems. It is marked by a progressive loss of vision and hearing, a type of heart disease that enlarges and weakens the heart muscle called dilated cardiomyopathy, obesity, type 2 diabetes and short stature. It ranges greatly in severity. It is caused by mutations in the ALMS1 gene. Meeker said, “We appreciate the FDA’s careful review of our sNDA for Imcivree for the treatment of Alström syndrome but are disappointed in this outcome. We are tremendously grateful to the Alström syndrome patients, caregivers and physicians who participated in our clinical development efforts and look forward to providing an update regarding our path forward.” The company also announced it had entered into a Revenue Interest Financing Agreement with HealthCare Royalty Partners for an investment of up to $100 million. Rhythm plans to use the proceeds and its cash on hand to support worldwide commercialization activities for Imcivree and ongoing clinical programs. Under the deal, it will receive an initial investment of $37.5 million due to Thursday’s approval.