Harmony Biosciences reported that the Phase 3 RECONNECT trial of ZYN002 did not meet its primary endpoint. To support families, FRAXA hosted a Q&A with Elizabeth M. Berry-Kravis, MD, PhD that explained what is known, what is still unknown, and what may come next in research. The discussion addressed placebo effects, outcome measures, and how these findings relate to the broader Fragile X landscape.
Families shared concerns and questions. The conversation acknowledged the disappointment while outlining ongoing research and reasons for hope.
What Happened in RECONNECT
- ZYN002 is a transdermal cannabidiol gel studied in Fragile X syndrome.
- The Phase 3 study focused on individuals with fully methylated FMR1.
- Topline results reported that the primary endpoint was not met.
- A large placebo effect made it difficult to detect a treatment benefit.
Key Takeaways from the Webinar
Placebo Effects in Fragile X Studies
Questions focused on why placebo responses are strong in Fragile X. Dr. Berry-Kravis explained that increased clinical attention, frequent visits, and high expectations can lead to measurable improvements even without active treatment.
Outcome Measures and Trial Design
Existing tools may not be sensitive enough to detect meaningful change. Work is underway with regulators to develop Fragile X-specific measures for use in future trials.
Subgroups and Methylation
The trial assessed only participants with ≥90% methylation of the FMR1 gene. Families asked about age differences, such as outcomes in children versus young adults. Detailed subgroup analyses have not yet been released.
Hope in the Research Pipeline
Although ZYN002 did not succeed, other studies continue to advance. Dr. Berry-Kravis highlighted Shionogi’s large Phase 3 zatolmilast (PDE4D inhibitor) trial, expected to report results later in 2025, along with progress in biomarker research and genetic strategies.
If ZYN002 Seemed Helpful
Many families reported meaningful gains during the study, and those experiences matter. Even when a trial does not meet regulatory criteria, individual benefits can be real and deserve thoughtful consideration.
Any changes to treatment should be planned with a healthcare provider. Options exist, but suitability, access, and cost vary by person and situation. A clinician can help weigh potential benefits and risks, review coverage, and identify realistic next steps.
Options to Discuss With Your Care Team
- Epidiolex (Prescription CBD)
- What it is: FDA-approved cannabidiol for certain epilepsy syndromes like Dravet syndrome and Lennox-Gastaut.
- Fragile X use: Off-label only. Prescribers must document an approved indication (usually seizures).
- Pros: Pharmaceutical grade. Consistent dosing. Physician monitoring.
- Cons: No formal approval for Fragile X.
- Cost: Often expensive out of pocket. Estimates range from about $1,200 to $2,500 per month depending on dose and weight. Coverage may be possible for qualifying epilepsy diagnoses.
- Over-the-Counter CBD Products
- What they are: Oils, capsules, gummies, and similar products.
- Considerations: Quality and dosing vary as there is no FDA oversight. Some products are mislabeled. Look for a third-party certificate of analysis.
- Evidence: Not studied specifically for Fragile X.
- Cost: Often $50–$150 per month, but quality differs widely.
- Action: Review any product choice with the treating clinician. choose a product with a certificate of analysis (COA) from a third-party lab.
- Behavioral and Medical Alternatives
While no single treatment replaces what ZYN002 offered, there are several therapies and clinical trials addressing similar symptoms.- Anxiety and irritability: Options may include SSRIs (like sertraline), stimulants, guanfacine, or clonidine.
- Sleep: Melatonin and behavioral interventions.
- Aggression or severe behaviors: Risperidone or aripiprazole are FDA-approved for irritability in autism and are sometimes considered.
- Speech and cognition: Ongoing trials exploring targeted treatments, see below.
What’s Next in Research
While the outcome of this trial is disappointing, FRAXA is funding multiple promising approaches. These include targeted treatments aimed at underlying synaptic dysfunction, as well as curative strategies such as FMR1 reactivation and gene therapy. Studies are also moving toward more personalized designs and greater use of in-home participation.
To keep up with research news including upcoming clinical trials please subscribe to FRAXA email updates.
