Zynerba hopes to crack fragile X at last

The next few months will see data on the cannabinoid Zygel in fragile X syndrome, and a hit – or at least a near miss – will be necessary for more than just approval.


For a group in the late stages of developing a therapy for fragile X syndrome it must be somewhat daunting knowing that every prior phase III trial in the disorder met with failure. On the other hand, this at least means that there will be no competition for Zynerba if its cannabinoid project, Zygel, does succeed. 

It also means that regulators might take a lenient stance. While Zynerba’s chief executive, Armando Anido, is confident that Zygel’s pivotal trial will hit, he believes that approval might be granted even if it does not. 

“If you barely missed the primary endpoint and you hit the secondary endpoints you may still have a very substantial opportunity in fragile X, and the FDA – because there isn’t anything currently available – I think they would be open to conversations about a pathway for fragile X,” he tells Vantage

Easy as ABC

The trial in question is Connect-FX, which last month hit its enrolment target, signing up 210 children aged between three and 17. It aims to show an improvement on the social avoidance subscale of the aberrant behaviour checklist (ABC). This is a standard measure for use in developmental disability clinical trials that relies on the patient’s or caregiver’s impressions of symptoms.

Topline results are expected mid-2020, and the company has definite ideas about the magnitude of benefit Zygel will need to show. 

“We are anticipating that placebo will show an improvement of 20%, and we have powered the study with over 200 patients to be able to show a 40% improvement in the active arm,” Mr Anido says. 

Provided the active arm is 20 percentage points clear of placebo, the company ought to be able to file on the data by the end of this year. There is no objective measure of improvement, such as a biomarker, in fragile X, but Mr Anido says the ABC is validated and well recognised, adding that Abilify and Risperdal used the ABC for their approvals for autism spectrum disorder.

Safety will bear watching, too. In September the Zynerba reported that 96% of patients in a phase II trial of Zygel in a different disorder, developmental and epileptic encephalopathies (DEE), had had a treatment-emergent adverse event. Serious adverse events were seen in 22% of patients, and two of these, lower respiratory tract infection and status epilepticus, were possibly related to treatment. Zynerba’s shares slid 22%. 

Mr Anido said this was due to a “misinterpretation”, primarily of the safety data, and points out that DEE patients are very sick. The company plans to speak with the FDA in the coming months about starting pivotal DEE trials. 


Mechanistically, Zygel differs from earlier, failed fragile X projects such as Novartis’s AFQ056 and Seaside Therapeutics’ STX209. The rationale for using a cannabinoid comes from studies in knockout mice, which have reduced levels of endocannabinoids such as 2-arachidonoylglycerol and anandamide, which affect signalling and neuronal plasticity, Mr Anido says. 

“All the others that have been tried before have been either gaba-ergic compounds or mGluR compounds that work primarily by affecting the Gaba system. We feel pretty good that being different probably makes a makes a difference here,” Mr Anido says. 

The downside is that cannabinoids are readily metabolised, and can have gastrointestinal side-effects, when dosed orally. This is why Zygel is administered transdermally, with a small amount of the gel being applied to the patient’s upper arm twice a day.

If Connect-FX breaks with fragile X tradition by succeeding, the company intends to price Zygel at around $30,000 per year. With more than 70,000 patients in the US alone, 50% penetration here would make the drug a blockbuster. The FDA’s clearance of the first genetic test for fragile X could expand this further, enabling earlier diagnosis than currently possible, and limiting the propensity for the disorder to be misdiagnosed as a form of autism. 

EvaluatePharma’s consensus of sellside forecasts sees Zygel worldwide revenues reaching $354m by 2024.

Zynerba will launch the drug alone in its home market, but it is seeking a partner outside the US – another element that hinges on the forthcoming readout.

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