A Levo Therapeutics drug designed to curb the insatiable hunger experienced by patients with Prader-Willi syndrome has fallen short at the FDA, as the regulator turned down the biotech’s drug application and asked for another clinical trial.
The rejection follows a vote by an FDA advisory committee last November to recommend against approval of the drug, LV-101, citing a lack of evidence supporting the drug’s efficacy. Chicago-based Levo said Tuesday that it is discussing with the FDA the design of a new clinical study that can confirm the drug’s efficacy. Meanwhile, the privately held company is continuing to provide the drug to existing clinical trial participants.
Prader-Willi is a rare metabolic disorder caused by a genetic mutation. Patients who have the disease lose the ability to feel full from food, leading to a compulsion to continue eating. Obesity resulting from Prader-Willi raises the risk of heart and breathing problems that can be life threatening.
There are currently no FDA-approved therapies for Prader-Willi. Levo’s approach to the disorder is hormonal. Human behaviors, including social bonding and appetite, are regulated by a hormone called oxytocin. According to Levo, people who have Prader-Willi have fewer oxytocin producing neurons in the hypothalamus gland. Levo aims to increase oxytocin levels to reduce the feelings of hunger. Clinical studies have been conducted that evaluated oxytocin to treat the disorder. Levo’s LV-101 is carbetocin, which is an analog of naturally occurring oxytocin. The Levo drug is designed to be highly selective for binding to the oxytocin receptor.
Oxytocin also has a role in addressing postpartum hemorrhage. The hormone is given to mothers to help the uterus contract, preventing excessive bleeding. Carbetocin is already used as a treatment for preventing post-partum hemorrhage. The drug has approvals throughout the word for this application, but it is not currently approved by the FDA for any indication. Ferring Pharmaceuticals, which markets carbetocin for preventing postpartum hemorrhaging, advanced an intranasal version of the drug to Phase 2 testing in Prader-Willi. In 2016, Levo licensed global rights to the Phase 3-ready drug for the treatment of Prader-Willi.
Levo tested LV-101 in a placebo-controlled, double blind study enrolling 175 Prader-Willi patients. Patients were randomly assigned to receive either a 3.2 mg dose of the study drug, a 9.6 mg dose, or a placebo over the course of eight weeks. The two main goals were to show a change in score according to a scale used to rate feelings of extreme hunger and a scale used to measure obsessive and compulsive symptoms.
In 2020, Levo reported data showing that the high dose did not achieve statistical significance on the hunger or obsessive and compulsive measures measures. In the low dose group, Levo reported statistical significance based only on the hunger measure. LV-101’s new drug application was based on that result. The Levo drug was found to be safe and well tolerated by patients in the clinical trial.
FDA complete response letters are not public, but according to Levo, the agency said the data for the proposed 3.2 mg dose of the drug were insufficient to support approval. According to FDA briefing documents prepared for the advisory committee meeting, the agency told the company that the results of the pivotal study were unclear. The FDA also said that because Prader-Willi will likely require chronic treatment, Levo would need to conduct a longer study.
Prader-Willi has proven to be a challenge for drug developers. Zafgen’s efforts to develop a Prader-Willi drug were marked by problems in clinical trials, including patient deaths and clinical holds. Millendo Therapeutics reported in 2020 that its Prader-Willi drug failed in mid-stage testing. Both Zafgen and Millendo wound down those programs and the companies lived on only by serving as vehicles to take other biotechs public.
In a prepared statement, Levo CEO Sara Cotter said that her company is disappointed by the FDA’s review of LV-101’s drug application and the continued lack of treatments for the most significant symptoms of Prader-Willi.
“We are hopeful that our discussions with FDA regarding the next study will be productive and that we can initiate enrollment of a confirmatory study later this year,” Cotter added.
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