An Endocrine News roundup of the week’s pharmaceutical news, breakthroughs, and general information. *
Corcept’s Phase 3 Long-Term Extension Study of Relacorilant Demonstrated Durable Cardiometabolic Improvements in Patients with Hypercortisolism
Corcept Therapeutics Incorporated, a commercial-stage company engaged in the discovery and development of medications to treat severe endocrinologic, oncologic, metabolic, and neurologic disorders by modulating the effects of the hormone cortisol, presented results from its Phase 3 long-term, open-label extension study of relacorilant to treat patients with endogenous hypercortisolism (Cushing’s syndrome) at the WCIRDC. The results from this study demonstrated that patients treated with relacorilant experienced clinically meaningful and durable cardiometabolic improvements and relacorilant was well-tolerated, with a treatment duration of up to six years.
“The positive results from the long-term extension study of relacorilant are consistent with findings from our GRACE, GRADIENT and Phase 2 studies. These data will support relacorilant’s new drug application (NDA), which we plan to submit this month”
The Phase 3 long-term extension study enrolled 116 patients who had previously completed either Corcept’s Phase 3 GRACE or GRADIENT studies or its Phase 2 study in hypercortisolism. Patients experienced further improvement in blood pressure while maintaining response in other cardiometabolic measures, such as glycemic control and body weight. Consistent with its known safety profile, relacorilant was well-tolerated with a treatment duration of up to six years.
At month 24 of the study, patients exhibited clinically meaningful and statistically significant reductions in mean systolic blood pressure (10.0 mm Hg; p-value: 0.012) and mean diastolic blood pressure (7.3 mm Hg; p-value: 0.016), compared to their measurement at entry into the long-term extension study. Patients who resumed receiving relacorilant in the extension study, after being switched to placebo in the randomized-withdrawal phase of the GRACE study, experienced both a reversal of the deterioration they exhibited while receiving placebo and additional improvement beyond their blood pressure measurement at entry into the randomized portion of the study. To ensure accuracy, blood pressure was measured by 24-hour ambulatory blood pressure monitoring.
Richard Auchus, MD, PhD, professor of Internal Medicine in the Division of Metabolism, Endocrinology & Diabetes at the University of Michigan and Chief of the Endocrinology & Metabolism Section at the Ann Arbor VA Medical Center, presented the long-term extension results at WCIRDC.
“People living with hypercortisolism are at risk of serious cardiometabolic comorbidities, including hypertension and hyperglycemia,” Auchus says. “These long-term data demonstrate significant improvements across a broad set of signs and symptoms of hypercortisolism without the toxicities observed with current treatment options. It is especially encouraging to see data from patients treated for up to six years that show progressive reductions in blood pressure, maintenance of cardiometabolic improvements, and long-term drug tolerability.”
“The positive results from the long-term extension study of relacorilant are consistent with findings from our GRACE, GRADIENT and Phase 2 studies. These data will support relacorilant’s new drug application (NDA), which we plan to submit this month,” says Bill Guyer, PharmD, Corcept’s chief development officer. “Relacorilant’s strong efficacy and safety profile positions the medication to become a new standard of care in treating patients with hypercortisolism.”
The presentation at WCIRDC is available here.
Palatin Announces Positive Phase IIb BREAKOUT Study Results in Patients with Type 2 Diabetic Nephropathy
Palatin Technologies, Inc. on December 19 announced topline data for the BREAKOUT study. The BREAKOUT study is a Phase IIb, Multicenter, Open-Label, Prospective Study of BREmelanotide in DiAbetic Kidney Disease to Assess the Efficacy in Reducing Urinary PrOtein and Maintaining Podocyte Density and FUncTion.
The BREAKOUT Study (BMT-701) enrolled 16 patients with confirmed Type 2 diabetic nephropathy and >1000 mg/gm UP/Cr ratio, with 8 patients completing the six-month treatment regimen, at multiple sites in the United States. Patients were administered bremelanotide subcutaneously twice daily, in addition to their maximum tolerated dose of renin-angiotensin-aldosterone system (RAAS) inhibition therapy and monitored through a follow-up period.
The study showed that bremelanotide therapy for six months, in patients with established Type II diabetic nephropathy, resulted in positive and beneficial results for the majority of patients related to worsening kidney function and disease progression. Clinically meaningful endpoints included; 71% of patients achieved a >30% reduction in the urine protein to creatinine ratio (UP/Cr), 71% of patients achieved improved or stabilized estimated glomerular filtration rate (eGFR), increased urinary vascular endothelial growth factor (VEGF) levels in 37.5% of patients and reduced urinary synaptopodin losses in 36% of patients.
“The data from this trial is encouraging and validates that modulating the melanocortin system could potentially be a new therapeutic strategy and possibly disease-modifying treatment option for people living with this progressive kidney disease,” says Carl Spana, PhD, president and CEO of Palatin. “Targeting the melanocortin system in autoimmune and inflammation conditions reduces cellular stress, resolves inflammation and promotes tissue repair. Our melanocortin pipeline has demonstrated preclinical efficacy in over 10 disease models, including positive clinical results in this Phase IIb Diabetic Nephropathy study and our MELODY-1 Phase 3 dry eye disease trial earlier this year. Lastly, patient enrollment in our Phase 2 ulcerative colitis trial is complete, with topline data targeted for release in the first quarter of calendar year 2025.”
“The findings from this study are consistent with previous studies that the activation of melanocortin receptors can result in positive effects on kidney function by positively effecting synaptopodin and podocyte function,” says James A. Tumlin MD, CEO and founder of NephroNet Clinical Trials Consortium. “With diabetic nephropathy being one of the leading causes of end-stage renal disease across the world, this positive data supports the further development of a melanocortin agonist like bremelanotide, without melanocortin-2 receptor agonism, as a potential treatment option for diabetic nephropathy patients.”
TRYNGOLZA™ (Olezarsen) Approved in U.S. as First-Ever Treatment for Adults Living with Familial Chylomicronemia Syndrome as an Adjunct to Diet
O December 20, Ionis Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) has approved TRYNGOLZA™ (olezarsen) as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS), a rare, genetic form of severe hypertriglyceridemia (sHTG) that can lead to potentially life-threatening acute pancreatitis (AP). TRYNGOLZA is the first-ever FDA-approved treatment that significantly and substantially reduces triglyceride levels in adults with FCS and provides clinically meaningful reduction in AP events when used with an appropriate diet (≤20 grams of fat per day). TRYNGOLZA is self-administered via an auto-injector once monthly.
“Today’s FDA approval of TRYNGOLZA heralds the arrival of the first-ever FCS treatment in the U.S. – a transformational moment for patients and their families. For the first time, adults with FCS can now access a treatment that substantially reduces triglycerides and the risk of debilitating and potentially life-threatening acute pancreatitis,” says Brett P. Monia, PhD, chief executive officer, Ionis. “We are proud of our long-standing partnership with the FCS community and are grateful to the patients, families and investigators who participated in our clinical studies, enabling Ionis to make this new treatment a reality. The FDA approval of TRYNGOLZA is also a pivotal moment for Ionis, representing our evolution into a fully integrated commercial-stage biotechnology company – a goal we set out to achieve five years ago. With our rich pipeline of potentially life-changing medicines, we expect TRYNGOLZA to be the first in a steady cadence of innovative medicines we will deliver independently to people living with serious diseases.”
The FDA approval was based on positive data from the global, multicenter, randomized, placebo-controlled, double-blind Phase 3 Balance clinical trial in adult patients with genetically identified FCS and fasting triglyceride levels ≥880 mg/dL. In the Balance study, TRYNGOLZA 80 mg demonstrated a statistically significant placebo-adjusted mean reduction in triglyceride levels of 42.5% from baseline to six months (p=0.0084). Reductions from baseline to 12 months were further improved, with TRYNGOLZA achieving a placebo-adjusted 57% mean reduction in triglycerides. TRYNGOLZA also demonstrated a substantial, clinically meaningful reduction in AP events over 12 months; one patient (5%) experienced one episode of AP in the TRYNGOLZA group compared with seven patients (30%) who experienced 11 total episodes of AP in the placebo group.
TRYNGOLZA demonstrated a favorable safety profile. The most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and at a >3% higher frequency than placebo) were injection site reactions (19% and 9%, respectively), decreased platelet count (12% and 4%, respectively) and arthralgia (9% and 0%, respectively).
Results from the Phase 3 Balance study were previously published in The New England Journal of Medicine (NEJM).
“With no treatment options previously available, we were limited to relying only on extremely strict diet and lifestyle changes as the sole preventative treatment option,” says Alan Brown, M.D., FNLA, FACC, FAHA, clinical professor of medicine, Rosalind Franklin University of Medicine and Science; Balance trial investigator. “The FDA approval of TRYNGOLZA is an important moment for people living with FCS, their families and physicians who now, for the first time, have a treatment that significantly lowers triglycerides and decreases the risk of potentially life-threatening acute pancreatitis events, as an adjunct to a low-fat diet. I am excited to have a medicine I can prescribe to my patients that has been shown to change the course of their disease.”
FCS is a rare, genetic, potentially life-threatening form of sHTG that prevents the body from breaking down fats and severely impairs the body’s ability to remove triglycerides from the bloodstream due to an impaired function of the enzyme lipoprotein lipase (LPL). While healthy levels for adults are below 150 mg/dL, people with FCS often have triglyceride levels of more than 880 mg/dL and often have a history of pancreatitis. Those living with FCS have a high risk of potentially fatal AP, which is a painful inflammation of the pancreas, and chronic health issues such as fatigue and severe, recurrent abdominal pain. People living with FCS can also experience psychological and financial stress, which can significantly impact their quality of life. In the U.S., FCS is estimated to impact up to approximately 3,000 people, the vast majority of whom remain undiagnosed.
“As a rare and difficult to diagnose disease, FCS has a profound impact on the lives of patients and families. Many people living with FCS have experienced severe pain their whole lives – sometimes so intense they require lengthy hospitalization stays – and struggle through life with daily fatigue, nausea, brain fog, and stomach pain,” says Lindsey Sutton Bryan, co-founder and co-president, FCS Foundation. “Until now, our treatment options have been limited, relying on diet alone to try to manage triglyceride levels and keep acute pancreatitis attacks at bay. For the first time, adults with FCS have seen their hope for a treatment become a reality.”
TRYNGOLZA will be available in the U.S. before year end.
TRYNGOLZA was reviewed by the FDA under Priority Review and had previously been granted Fast Track designation for the treatment of FCS, Orphan Drug designation and Breakthrough Therapy designation. Olezarsen is undergoing review in the European Union and regulatory filings in other countries are planned. Olezarsen is currently being evaluated in three Phase 3 clinical trials – CORE, CORE2 and ESSENCE – for the treatment of sHTG. Olezarsen has not been reviewed or approved for the treatment of sHTG by regulatory authorities.
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