In this 36-minute Return of Results session, David Ryman of Levo Therapeutics provides insights into the Phase 3 clinical trial of carbetocin, including next steps for making the drug available to treat hyperphagia and anxiety behaviors in PWS. This session includes a brief question-and-answer session with the attendees at the 2020 FPWR Virtual Conference.
Click below to watch the video. If you're short on time, scroll down for timestamps to find the portions you're most interested in.
Presentation Summary With Timestamps
0:13 David Ryman, Levo Therapeutics, presenting
- Study results of intranasal carbetocin study, also known as the CARE-PWS Study or Carbetocin Safety and Efficacy Study in PWS patients.
1:09 Overview of oxytocin in PWS
- A hormone produced in the bran, oxytocin has multiple functions including control of appetite, satiety, trust and social-emotional behaviors, and anxiety.
- Oxytocin works in the brain in PWS patients in a different way: individuals with PWS have a significantly decreased number of oxytocin-producing brain cells.
- Trials of oxytocin in PWS patients have had mixed results, possibly due to it not being able to bind to receptors.
5:25 Carbetocin overview
- Carbetocin is an oxytocin analog, whose molecule structure is designed to be very similar to oxytocin and to behave in a very similar way oxytocin does.
- Two main differences are improved half-life so that it can be taken three times a day; and improved selectivity, so that it binds specifically to oxytocin receptors.
- Currently approved in over 90 countries outside of the US for a different use, intravenously.
- A previously completed two-week-long Phase 2 study of intranasal carbetocin in PWS patients demonstrated significant improvements in hyperphagia and obsessive-compulsive symptoms.
8:35 CARE-PWS study summary
- CARE-PWS is a Phase 3 randomized, placebo-controlled, double-blind study for a total of 175 participants with PWS.
- The study evaluates efficacy, safety and tolerability of intranasal carbetocin at two different dose levels compared with placebo.
- There are 24 study sites that enrolled patients in the study in the US, Canada and Australia.
10:32 CARE-PWS study design
- There is an initial 8-week placebo-controlled phase, followed by a 56-week period of long-term follow-up. All participants receive a dose of intranasal carbetocin after the initial 8-week period, either 3.2 mg or 9.6 mg.
- Participants who complete long-term follow-up may enter an optional extension period to continue receiving carbetocin.
11:20 Impact of COVID-19 on the study
- Because of the potential impact of the pandemic on reduced study visits, the study closed for enrollment earlier than anticipated, and only 130 out of the 175 targeted patients were enrolled.
- The primary efficacy analysis was based on all the efficacy data collected through March 1, 2020.
12:36 Patient disposition and baseline demographics
- Participants were randomly assigned to the three initial groups in equal proportions (3.2 mg of carbetocin, 9.6 mg of carbetocin, or placebo)
- The participants in each group had similar characteristics when entering the study.
14:00 Efficacy measures
- For each dose group, the study evaluated hyperphagia symptoms and behaviors (HQ-CT) and obsessive-compulsive symptoms and behaviors (CY-BOCS), and the changes that occurred in those scores from Baseline to Week 8
- The 9.6 mg dose was tested as the primary endpoint, and the 3.2 mg dose was tested as the first secondary endpoint.
- Additional secondary endpoints were included, such as PWS Anxiety and Distress Questionnaire (PADQ) and Clinical Global Impression of Change (CGI-C) scores.
16:30 Top line results showing improvements
- There was a decrease in score of up to 5.37 in the lower dose, and an overall score decrease of 4.40 in all of the carbetocin-treated patients.
- In the summary of results of improvements compared to placebo (baseline to week 8), most scores showed improvement.
- Results show that hyperphagia improvements continue with time, up to week 16.
- Line chart shows the overall improvement on HQ-CT, CY-BOCS and PADQ scores over time at all doses, from baseline to week 64
22:36 Efficacy summary
- The CARE-PWS study supports that intranasal carbetocin reduces hyperphagia and anxiety behaviors in PWS, with maintenance of improvements over a longer period of time in the follow-up phase, up to 64 weeks.
- There is an internally consistent effect observed with the 3.2 mg dose across multiple measures, including PADQ for PWS Anxiety and Distress behaviors, as well as CGI-C and CGI-S, for the Clinical Global Impressions of PWS symptoms.
23:50 Safety results
- The adverse effects reported during the placebo-controlled period occur in 5% or more of participants in any group.
- Some of the most common adverse effects reported were flushing during the initial period, diarrhea, epistaxis, gynecomastia, headache, nasopharyngitis and pyrexia.
27:40 Additional safety data
- A panel of standard clinical laboratory assessments were performed to monitor additional safety data.
- Review of the additional safety data have identified no notable trends or apparent safety signals.
28:18 Overall conclusions
- The Phase 2 and Phase 3 placebo-controlled studies indicate that intranasal carbetocin effectively reduces symptoms of PWS.
- Data supports that intranasal carbetocin is generally safe and well tolerated.
- It is agreed that the overall data supports continued advancement of the 3.2 mg dose as the lowest effective dose studied.
30:22 Q&A with David Ryman