RECONNECT (ZYN002) Topline Results — September 24, 2025
Harmony Biosciences has announced that the Phase 3 RECONNECT trial of ZYN002 in Fragile X syndrome did not meet its primary endpoint of improving social avoidance in participants, citing a higher-than-expected placebo response. While the results are disappointing, the study adds important knowledge that will inform future clinical research in Fragile X syndrome.
We want to recognize positives that came from RECONNECT:
- It was the first Fragile X trial to successfully implement an at-home/virtual participation option, reducing barriers and expanding access for families who otherwise could not take part. This paves the way for at-home participation in future trials.
- It was a truly global Fragile X trial, with sites across the United States, Australia, Ireland, and the United Kingdom.
Families affected by Fragile X still have no approved treatment. These results — while not what we hoped — move the field forward by teaching us more about trial design, placebo effects, and how best to measure meaningful change in Fragile X.
Continuing the Search for Fragile X Treatments
While ZYN002 did not meet its primary goal, the field continues to advance. Shionogi's large Phase 3 trial of zatolmilast is expected to report results later this year. FRAXA is committed to funding and supporting diverse research strategies, and we will keep the community updated as these and other studies move forward.
Harmony Biosciences: Community Statement and Press Release
Q&A: RECONNECT Trial Results
The trial missed its primary endpoint: improvement in the ABC-C FXS Social Avoidance score in participants with fully methylated FMR1 (≥90%). Harmony has not reported positive signals on the secondary endpoints yet, but a full dataset analysis is still underway.
Yes. RECONNECT was:
- The first Fragile X trial to successfully use at-home and virtual visits, making participation possible for many more families.
- A global study spanning the U.S., Australia, Ireland, and the U.K.
- Another step in learning how to design Fragile X trials that can better detect meaningful changes in behavior.
So far, Harmony has not reported new safety concerns in the topline readout. ZYN002 was generally well tolerated in earlier studies. Full safety data are expected in upcoming conference presentations or publications.
Families in RECONNECT should follow guidance from their study site about next steps. Some programs include an open-label extension, but it is not yet clear how Harmony will proceed given the topline results.
It underscores that Fragile X remains an area of unmet medical need. Other promising clinical trials are ongoing — including a late-stage trial from Shionogi expected to report later in 2025. FRAXA will continue to support and fund research, including rigorous preclinical validation of potential therapeutic strategies.
