Long-term ZYN002 eases irritability in fragile X patients: Trial data
CBD gel seen leading to clinically meaningful effects on behavioral symptoms
Long-term, daily treatment with the investigational cannabidiol (CBD) gel ZYN002 — also known as Zygel — led to clinically meaningful reductions in irritability and other behavioral symptoms in people with fragile X syndrome.
That’s according to up to three years of data from an ongoing open-label extension (OLE) study (NCT03802799) that were shared by ZYN002’s developer Harmony Biosciences in an oral presentation at the American Academy of Neurology (AAN) annual meeting, held April 5-9 in San Diego and online.
The presentation was titled, “Long-term Safety and Effectiveness of ZYN002 Cannabidiol Transdermal Gel in the Treatment of Irritability-Related Behavioral Symptoms in Children and Adolescents with Fragile X Syndrome: Update to Open-Label Extension Study (ZYN2-CL-017).”
“The acceptance of our Fragile X syndrome OLE data as a podium presentation at AAN underlines the significant unmet need in FXS [fragile X syndrome], and the potential for ZYN002 to become the first-and-only approved treatment for this condition,” Kumar Budur, MD, Harmony’s chief medical and scientific officer, said in a company press release.
Budur said the findings are “encouraging” as the company prepares for a top-line data readout of the confirmatory Phase 3 RECONNECT trial (NCT04977986) later this year, which if positive, could support regulatory applications for ZYN002’s approval. That study is testing the experimental therapy’s safety and efficacy against a placebo in up to 250 fragile X patients, ages 3-29.
‘Profound’ need for Fragile X treatment
“Approximately 80,000 individuals are living with this rare neurological disease in the U.S. alone and Harmony is deeply committed to addressing the profound unmet medical needs of this community both in the U.S. and globally,” Budur said.
Fragile X is caused by mutations in the FMR1 gene that’s responsible for producing a protein, FMRP, that’s critical for nerve cell function. Disease-causing mutations lead to a chemical modification called methylation that effectively suppresses the gene’s activity, leading to little or no FMRP being produced.
A lack of FMRP leads to a range of neurological Fragile X symptoms including intellectual disability, behavioral problems, and autism spectrum disorder.
The active ingredient in ZYN002 is a lab-made version of CBD, one of the main compounds found in the cannabis plant. Unlike the plant’s other main constituent, THC, CBD does not have psychoactive or intoxicating effects.
CBD modulates a natural system in the body that’s important for brain function called the endocannabinoid system, the dysfunction of which has been implicated in driving some of the behavioral issues seen in fragile X. ZYN002 is intended to restore more normal endocannabinoid signaling, thereby easing these disruptive symptoms.
The treatment comes as a topical gel that’s absorbed into the bloodstream when administered onto the skin, called transdermal delivery. It was originally developed by Zynerba Pharmaceuticals, which was acquired by Harmony in 2023.
The OLE study is evaluating ZYN002’s long-term safety and efficacy in people with fragile X, ages 3-17, who participated in the placebo-controlled Phase 2/3 CONNECT-FX trial (NCT03614663) or an open-label Phase 1/2 study called FAB-C or ZYN2-CL-009 (ACTRN12617000150347).
Before entering the OLE study, CONNECT-FX participants had received either the therapy or a placebo for about three months, and ZYN2-CL-009 participants had been treated with ZYN002 for 116 weeks (about two years).
All OLE study participants are receiving ZYN002 at a weight-based daily dose of 250 mg, 500 mg, or 750 mg.
Previous interim analyses showed that long-term ZYN002 treatment was safe and led to reductions in social avoidance behaviors, which are common in fragile X patients. Benefits were particularly seen in patients with complete FMR1 methylation, where the disease is generally more severe because essentially no FMRP is made.
Benefits for patients who switched from placebo to ZYN002 in OLE
The newly presented data, spanning the period from September 2018 through January 2024, concerned 240 OLE study participants, with a mean age of 9.7 at study’s start.
Results showed that long-term ZYN002 led to reductions in irritability, another common fragile X behavioral symptom, as assessed by the irritability subscale of the Aberrant Behavior Checklist – Community FXS (ABC-C FXS), a caregiver-reported assessment of fragile X behavioral problems.
Among those who had participated in CONNECT-FX, benefits were observed both in patients who had received ZYN002 from the start and in those who switched over from the placebo.
More than 60% of patients in both groups achieved a clinically meaningful reduction in irritability, defined as at least a 9-point drop on the ABC-C FXS irritability subscale for at least two consecutive visits.
Moreover, 40.6% of participants who had received ZYN002 in CONNECT-FX were rated by their caregivers as having demonstrated a clinically meaningful behavioral improvement, compared with 29.8% of those originally on the placebo. After three years in the OLE, such improvements were reported for nearly three-quarters of participants in either group.
As in previous analyses, ZYN002 was generally well tolerated. No treatment-related side effects were considered serious, with the most common being pain at the application site (6.7%).
In the ongoing Phase 3 RECONNECT trial, participants are receiving ZYN002 or a placebo gel for 18 weeks, or a little over four months. The trial’s main goal is to evaluate changes in ABC-C FXS scores among participants with complete FMR1 methylation.
Top-line findings were initially expected in 2023, but were delayed due to slow recruitment associated with high rates of respiratory illnesses including COVID-19. They’re now due by September.
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