Zynerba Pharmaceuticals Inc. in late May popped the lid off top-line data from the open-label phase II study called Bright with ZYN-002 (Zygel, pharmaceutical-grade cannabidiol transdermal gel) in children and adolescents with autism spectrum disorder (ASD), and the findings drew adjectives from Wall Street such as “provocative” and “encouraging.”

The trial was designed to assess the safety, tolerability and efficacy in moderate to severe ASD as an add-on therapy to standard of care. Enrolled were 37 patients with ASD at a single clinical site, who were given weight-based doses of 250 mg or 500 mg daily of Zygel. Results showed that five subscales of the Aberrant Behavior Checklist – Community (ABC-C) as well as the Parent Rated Anxiety Scale – Autism Spectrum Disorder showed statistically significant and clinically meaningful improvements at 14 weeks of treatment from baseline. Other efficacy measures looked good, too, including the Clinical Global Impressions – Improvement scale, supporting the subscale results observed in the ABC-C, and Zygel was well-tolerated, with no serious or severe adverse events (AEs), Devon, Pa.-based Zynerba said.

Specifically, 14 weeks of treatment yielded improvements from baseline of 36% to 43%. “Caveats apply,” Wainwright analyst Oren Livnat said in a report, citing the small sample size and single site, “but preliminary data are encouraging. Management believes these magnitudes are clearly above expected placebo response rates.” Approved for irritability in autism are the antipsychotics Abilify (aripiprazole, Otsuka Pharmaceutical Co. Ltd.) and Risperdal (risperidone, Johnson & Johnson), and studies with those compounds were done mostly in treatment-naïve subjects. Those tested in the Zygel experiment were refractory, with 92% on concomitant medications, including 65% taking at least one psychotropic drug such as antidepressants and/or antipsychotics.

CEO Armando Anido said during a conference call with investors that Zynerba is “in the process of assessing some of the trials and some of the placebo responses that have been seen in other trials. What we do know is [that] some of the trials for risperidone and aripiprazole were done 10 and 20 years ago. The standards of how you actually control placebo response have actually been improved tremendously over the last few years,” he said. Chief Medical Officer Joseph Palumbo said that “these kids [enrolled in the Zygel trial] are a little bit sicker – they're a different population than was studied in the pivotal studies for risperidone and aripiprazole, for example,” so they were allowed to be on standard of care. Refractory patients were chosen deliberately, so that an efficacy signal would send a definite message. “We have some mild kids, but mostly these are severe kids, some moderate kids,” he said. “But they reflect the kids who would be going to a specialist, who are not responding. To me, as a clinician, these were thrilling results.”

The drug’s benign safety profile held in the latest study, too, with only 14% of treatment-emergent AEs, all of them application site-related. The approved antipsychotics threaten a list of unpleasant side effects. Included are somnolence, weight gain, gastrointestinal problems and movement disorders.

Jefferies analyst Andrew Tsai noted that although Abilify and Risperdal have shown a higher 44% to 57% absolute benefit on irritability in their pivotal studies, “we think a 39% reduction for Zygel (if replicated later in phase IIb/III) could be competitive, since antipsychotics do not help with anxiety.” A placebo-controlled study could have “a fairly good chance of success” if Zynerba enriches again for moderate to severe patients, he wrote in a report. Tsai also fretted some, however. Zygel’s efficacy still turned up lower on an absolute basis in the smallish experiment, so that the latest outcome “lacks a ‘wow’ factor,” and bigger phase IIb/III studies might not pan out.

In 2020, the CDC reported that about one in 54 children in the U.S. is diagnosed with ASD, according to 2016 data – one in 34 boys and one in 144 girls. Most children were still being diagnosed after age 4, though autism can be reliably diagnosed as early as age 2, according to the grassroots organization Autism Speaks. Thirty-one percent of children with ASD have an intellectual disability (intelligence quotient [IQ] <70), 25% are in the borderline range (IQ 71–85) and 44% have IQ scores in the average to above average range (i.e., IQ >85). Autism affects all ethnic and socioeconomic groups, though minority groups tend to be diagnosed later and less often.

Asked about primary endpoints in future work, Palumbo said that “a wonderful group of people [is] in place at FDA right now who are partnered in many ways and [are in] dialogue with academia. They're a good group, and when you present that good group interesting data with a different mechanism of action, they're alert and they're listening. I would be highly optimistic that we're going to have a good discussion with FDA. What will be the endpoint? I can't predict that, [but] they're going to see a different profile with this mechanism than they have with the atypical antipsychotics.”

In Livnat’s May 28 dispatch, he wrote that it was “premature to add ASD to our valuation, pending FDA clarity” on the next steps. “We remain focused on the all-important fragile X syndrome (FXS) phase III data by the end of June. Zynerba’s valuation reflects extreme skepticism heading into FXS data, in our view, but we remain optimistic.” Two hundred and twelve children and adolescents with genetically confirmed FXS have been randomized into Connect-FX, a pivotal, multinational, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of Zygel in treating common behavioral symptoms of FXS. Zynerba completed enrollment in February 2020.

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