No Substantial Evidence of LV-101 Nasal Spray’s Efficacy, FDA Committee Votes

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by Marta Figueiredo PhD |

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There is no substantial evidence supporting the efficacy of LV-101 (intranasal carbetocin), a nasal spray designed to reduce the insatiable hunger, called hyperphagia, that’s a hallmark of Prader-Willi syndrome (PWS), according to a 12-1 vote by a U.S. Food and Drug Administration (FDA) advisory committee.

The overwhelmingly negative vote followed a six-hour virtual public meeting, held Nov. 4, in which the FDA committee reviewed clinical trial data and then heard the opinions and experiences — this, positive — of patients and their family members regarding the use of LV-101.

An FDA advisory committee’s opinion typically is followed by the federal regulatory agency when making decisions on applications for the approval of new treatments.

A final decision on whether to approve LV-101’s commercial use for the treatment of hyperphagia and distress behaviors in people with PWS is expected by year’s end. The regulatory application had been granted priority review in July, which shortened the standard 10-month review period to six months.

“Obviously, this is a setback for our community,” Theresa Strong, PhD, founding member and director of research programs at the Foundation for Prader-Willi Research (FPWR), said in a press release.

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Strong vowed that the FPWR would continue to fight for the nasal spray’s approval, saying “we have learned nothing from PWS if not how to persevere through rough times. Our loved ones deserve a chance for a brighter future, and we’ll continue to work to see that become a reality.”

Pointing out that there currently are no approved therapies for PWS, the foundation noted that more than 100 comments had been submitted to the advisory committee asking them to support LV-101’s approval for the treatment of hyperphagia.

“We are so disappointed to see the hard work and efforts of the PWS community fall short in the eyes of the advisory committee,” said Elizabeth Roof, a senior research specialist at Vanderbilt University who was involved in LV-101 trials.

“We feel that the study evidence was overwhelming and coupled with the heartbreaking stories of the intense, life-threatening hunger in PWS that currently has NO FDA approved treatments, we were surprised and saddened that the advisory committee did not vote in favor of this safe and effective drug,” Roof said.

Indeed, the committee voted 12 “No” to one “Yes” on the question “Has the applicant provided substantial evidence of effectiveness for carbetocin nasal spray (LV-101) in the treatment of hyperphagia [insatiable hunger] associated with Prader-Willi syndrome?”

LV-101 is a nasal inhalation form of carbetocin, a lab-made compound designed to mimic oxytocin, a hormone involved in several behaviors and feelings — including empathy, trust, and satisfaction from food. The production of oxytocin is deficient in PWS patients.

By increasing these levels, the therapy, taken three times a day before meals, is expected to ease social and emotional difficulties and insatiable hunger in this patient population. The therapy is being developed by Levo Therapeutics.

“We are disappointed by the outcome of today’s vote,” said Sara Cotter, Levo Therapeutics’ CEO. But she said the company “will work with the FDA” as the agency completes its review.

“We continue to believe that [LV-101] can provide a much-needed option for patients based on the favorable benefit/risk profile demonstrated in the clinical development program,” Cotter said.

Many PWS community members had shared their personal thoughts and experiences live at the meeting or through written comments. The testimonies emphasized PWS’ profound impact on patients and their families, and highlighted the considerable risks people with the disease are willing to take in exchange for even moderate reductions in excessive hunger.

According to the advocates, hyperphagia itself is linked to life-threatening risks and behaviors, as well as to severe limitations on quality of life.

The improvements experienced with LV-101 were considered meaningful by both patients and their families, these advocates said, further strengthening their support of efforts toward LV-101’s approval.

A recording of the Psychopharmacologic Drugs Advisory Committee meeting on Nov. 4 is available here.

The regulatory application submitted for LV-101 was based on positive data from the proof-of-concept Phase 2 Study 114 (NCT01968187) and the larger, confirmatory Phase 3 CARE-PWS clinical trial (NCT03649477).

However, according to the informational report delivered by the FDA to its advisory committee, the agency had “a number of concerns” regarding the efficacy findings of both trials.

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Lowest Dose of LV-101 Fares Well in Phase 3 Trial of PWS Children

In Study 114, involving 38 PWS pediatric patients, ages 10 to 18, two weeks of treatment with 9.6 mg of LV-101 was found to work better than a placebo at promoting significant reductions in hyperphagia and obsessive-compulsive behaviors.

While Levo reported that the findings were statistically significant, the FDA said “the results of Study 114 were of unclear clinical significance and the study was too short to support a chronic indication” as would be needed for treating PWS. The agency had discussed with Levo the appropriate design of a future confirmatory trial.

Meant to confirm early findings in a larger number of patients, and with a longer treatment duration — as well as to explore other doses — CARE-PWS enrolled 130 children and adolescents with PWS. These participants, ages 7 to 18, were randomly assigned to receive either one of two LV-101 intranasal doses (9.6 mg and 3.2 mg) or a placebo for eight weeks, or about two months.

In contrast with previous Phase 2 results, CARE-PWS’s top-line data showed that LV-101’s 9.6 mg dose did not significantly lessen patients’ hyperphagia or obsessive-compulsive behaviors, relative to the placebo. In fact, the trial failed to meet both of its main goals.

However, significant reductions in hyperphagia, anxiety, and distress were observed with the lower dose, meeting the study’s secondary goals. Notably, the lower dose had no effect on obsessive-compulsive behaviors, when compared with the placebo.

At a November 2020 pre-new drug application (NDA) meeting, the FDA informed Levo that the results from both CARE-PWS and Study 114 were insufficient to support the filing of an NDA seeking LV-101’s approval.

The agency noted that the lack of efficacy of the 9.6 mg dose in the Phase 3 trial “questions the biological plausibility of the nominally significant result observed for … 3.2 mg.”

Given the perceived lack of substantial evidence of effectiveness, the FDA recommended that Levo appropriately test the 3.2 mg dose in a separate trial.

Still, the subsequent NDA was accepted for filing, “with questions regarding the study designs and the statistical and clinical meaningfulness of the findings to be addressed in a comprehensive review of the Applicant’s data,” the agency stated in the report.

The FDA also noted that the application was then granted priority review as per the previous fast track designation it had received and its intention to address an unmet medical need.

“To approve a drug, substantial evidence of effectiveness must be provided by the Applicant,” the FDA had concluded in its report to the advisory committee, setting forth the mission for the public meeting.

In commenting on their votes following the more than six-hour hearing, several committee members noted that they were moved by the patient testimony, but that the study findings did not meet the standards of “substantial” effectiveness as set forth by the FDA.