Phase 3 Trial Shows Low-Dose Carbetocin Effective for Hyperphagia in Prader-Willi Syndrome
Key Insights
Levo Therapeutics (search)' Phase 3 CARE-PWS trial found that the lower 3.2mg dose of intranasal carbetocin (LV-101) significantly reduced hyperphagia (search) and anxiety symptoms in patients with Prader-Willi syndrome (search), while the higher 9.6mg dose did not meet primary endpoints.
The oxytocin-receptor agonist was generally well-tolerated, with mild to moderate side effects including headache, flushing, and diarrhea at the effective dose, offering potential relief for a condition with no currently approved treatments for its most challenging symptoms.
Over 98% of trial participants elected to continue receiving the treatment in the long-term follow-up phase, with maintained benefits or further improvements observed, demonstrating sustained clinical value for this rare neurodevelopmental disorder affecting approximately 1 in 16,000 births.
Levo Therapeutics (search) has announced top-line results from its Phase 3 CARE-PWS clinical study evaluating LV-101 (intranasal carbetocin) for the treatment of Prader-Willi syndrome (search) (PWS), revealing that the lower 3.2mg dose showed statistically significant improvements in hyperphagia (search) while the higher 9.6mg dose failed to meet primary endpoints.
The study, which enrolled 119 evaluable patients aged 7-18 years, demonstrated that the 3.2mg dose of LV-101 significantly reduced hyperphagia (search) scores as measured by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) compared to placebo (p=0.016). Additionally, this lower dose showed consistent benefits across key secondary endpoints, including clinical global impression of change (CGI-C; p=0.027) and anxiety and distress behaviors (p=0.027).
Understanding Prader-Willi Syndrome and Carbetocin's Mechanism
PWS is a complex neurodevelopmental disorder occurring in approximately 1 in 16,000 births. It is characterized by a false state of starvation and associated hyperphagia (search) (unrelenting hunger), to which a deficiency in oxytocin is believed to contribute. The condition also presents with anxiety, obsessive-compulsive behaviors, and intellectual disability.
Carbetocin is an analog of oxytocin, a naturally occurring hormone released from the hypothalamus that plays roles in maternal care, bonding, social cognition, and appetite control. As a selective oxytocin-receptor agonist, carbetocin specifically targets only the oxytocin receptor (search), potentially limiting unwanted side effects that might occur through vasopressin signaling.
"This is a long-awaited step towards addressing the substantial needs of individuals living with PWS," said Sara Cotter, CEO of Levo Therapeutics (search). "We are excited by these important results that were achieved after decades of interest in addressing the oxytocin deficiency in PWS."
Trial Design and Key Findings
The CARE-PWS study was designed as a multi-center, randomized, double-blind, 8-week placebo-controlled study with participants evenly randomized (1:1:1) to receive either 9.6mg dose, 3.2mg dose, or placebo. The trial was originally intended to enroll 175 participants but was reduced to 119 due to the COVID-19 pandemic.
While the study did not meet its primary outcome measurements with the 9.6mg dose, the 3.2mg dose showed significant improvements in hyperphagia (search). Neither dose demonstrated a statistically significant effect on obsessive-compulsive behaviors as measured by the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS).
"With no approved therapies to address their most challenging symptoms, patients with PWS continue to suffer from insatiable hunger and anxiety, which are debilitating and can be life-threatening if left untreated," said Jennifer L. Miller, M.D., Pediatric Endocrinologist at the University of Florida. "These positive results strengthen the belief that intranasal carbetocin appears to be an effective treatment for patients living with PWS."
Safety Profile and Patient Response
LV-101 was generally well-tolerated across the study. Treatment emergent adverse events occurring in 5% or more of participants at the 3.2mg dose included headache (16.3% vs. 7.0% for placebo), flushing (14.0% vs. 0.0% for placebo), diarrhea (9.3% vs. 2.3% for placebo), nasal discomfort (7.0% vs. 2.3% for placebo), pyrexia (7.0% vs. 0.0% for placebo), and upper respiratory tract infection (7.0% vs. 4.7% for placebo). All adverse events were considered mild or moderate in severity.
Notably, more than 98% of patients enrolled in CARE-PWS elected to enter the long-term follow-up period after the initial 8-week placebo-controlled phase. Further improvements in scores were observed and subsequently maintained after week 8 in both dose arms, suggesting sustained benefits with continued treatment.
"The impact that PWS has on parents and caregivers is incredibly burdensome, beginning with diagnosis in infancy and continuing as individual symptoms worsen over time," said Elizabeth Roof, M.A., from Vanderbilt University. "As clinical researchers, we are thrilled to see the results from CARE-PWS and that treatment with LV-101 showed meaningful improvements in hyperphagia (search) and anxiety in patients with PWS."
Path Forward for LV-101
Based on these results, all patients actively participating in CARE-PWS will be transitioned to receive the 3.2mg dose of LV-101 for the remainder of their long-term follow-up and extension periods. Of the patients who have completed the 56-week long-term follow-up period, 100% have elected to participate in the extension program, highlighting the perceived benefit of the treatment.
"The results from the CARE-PWS study have brought hope to the PWS community as together we pursue effective therapies for these patients in need," said Theresa V. Strong, Ph.D., founding member of the Foundation for Prader-Willi Research. "We look forward to continuing to partner with Levo Therapeutics (search) to help bring LV-101 expeditiously to the PWS community."
Levo Therapeutics (search) has indicated they plan to work closely with regulatory authorities in the United States and abroad to bring this promising therapeutic to patients as quickly as possible. LV-101 has been granted orphan drug and Fast Track designations from the U.S. Food and Drug Administration (FDA), potentially expediting its review process.
Historical Context and Development
The development of carbetocin for PWS builds on earlier research showing oxytocin deficiency in the condition. After significant improvements in hyperphagia (search) and compulsive behaviors were observed during a Phase 2 trial sponsored by Ferring Pharmaceuticals, the rights to develop carbetocin were purchased by Levo Therapeutics (search), a company with a personal connection to PWS.
Through Levo's licensor, Ferring Pharmaceuticals, carbetocin is already approved in over 90 countries outside the United States for the prevention of uterine atony and excessive bleeding during cesarean section delivery, with an estimated cumulative exposure of over 10 million patients. This established safety profile in other indications may support its development for PWS.
The CARE-PWS results represent a significant milestone in addressing the unmet needs of PWS patients, particularly for hyperphagia (search) and anxiety symptoms that significantly impact quality of life.