Results from Zynerba Pharmaceuticals Inc.'s phase II Believe 1 trial created a Rodney Dangerfield moment Wednesday when the generally positive data were met with the back of the market's hand as the stock dropped 21.8% on the day.

"We scratched our heads a little about the market reaction today and, after talking all morning, we realized there was confusion around the safety profile, and that's something we've clarified," Armando Anido, Zynerba's CEO, told BioWorld. "The profile is pretty daggone good and Zygel was well-tolerated."

Despite yesterday's downward drift – shares (NASDAQ;ZYNE) closed the day at $8.84 – the stock has swelled 203% since Jan. 2.

The Believe 1 trial assessed the safety and efficacy of Zygel, a CBD gel and the company's lead candidate, in developmental and epileptic encephalopathies (DEE), a heterogeneous group of rare pediatric epilepsy syndromes, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), in children and adolescents. Top-line data showed patients who experienced those seizure types achieved 44% to 58% monthly median reductions in seizures compared to baseline from month two to month six of treatment. However, through six months of therapy, 96% of patients experienced a treatment-emergent adverse event (TEAE) and 60% of patients experienced a treatment-related adverse event, most of which were mild to moderate.

The patient group is difficult to treat, Anido said, where many are wheelchair-bound and susceptible to myriad problems. Those adverse events could have included the flu, sniffles or diarrhea, and they don't necessarily mean they're related to the drug, he said, adding, "Even if the physician doesn't believe it's related to the drug, it still goes into the record."

The majority of the events were not serious and were similar to those GW Pharma plc found in its studies for Epidiolex, Anido added. The FDA approved Epidiolex for treating DS and LGS in patients 2 or older last year. LGS and DS, which bring high rates of early mortality, are tough-to-treat childhood epilepsies that often require multiple seizure medications, and the majority of patients are resistant to approved therapies. (See BioWorld, June 26, 2018.)

Believe 1's most common treatment-related adverse events (in >5% of patients) are application-site dryness (8.3%), application-site pain (8.3%) and somnolence (8.3%). Ten patients reported a serious adverse event (SAE); most were infection-related. Two SAEs (lower respiratory tract infection and status epilepticus) were determined to be possibly related to treatment. There were no patient deaths during the study.

Qualitative assessments by caregivers in the study demonstrate that Zygel also had a positive effect on behavioral and cognitive symptoms, Anido said.

"We saw 58% of patients that had increased alertness and awareness," he said. "We also saw improved cognition in half of the patients."

The data showed 58% of patients reporting improved vitality, 51% reporting improvement in seizures, 47% reporting improved concentration, 44% reporting improved socially avoidant behaviors, 28% of parents reporting their child attended school on time and more often, and 26% reporting difficulty in applying the gel to their child.

Of the 46 patients in the modified intent-to-treat population (mITT) population, 72% had focal impaired-awareness seizures (FIAS; previously known as complex partial seizures) and/or convulsive seizures (focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures) at baseline. Those patients experienced a mean baseline seizure count of 64 FIAS and/or convulsive seizures, and a median baseline seizure count of 8.2 FIAS and/or convulsive seizures. Compared to baseline seizure frequency, those patients experienced a ≥44% median reduction in seizures from month two onward using monthly seizure frequency normalized to 28 days.

Anido said the trial gives Zynerba plenty of positive data to take to the FDA early next year when they discuss a two-part phase III. He expects the program will have two well-controlled four-month studies, including a double-blind comparison to placebo.

A Jefferies analyst in a Wednesday note agreed that a placebo-controlled study is warranted and noted the differences between Epidiolex and Zygel, saying a 30% to 50% reduction in seizures would be comparable and that a 50% reduction would be competitive. Epidiolex at 20 mg/kg reduced seizures by 40% to 45% vs. 15% to 25% for placebo in 14-week studies, the reported noted.

Eight patients discontinued the Believe 1 study; one discontinued as a result of an application-site reaction, and seven discontinued as a result of withdrawal of consent or perceived lack of efficacy.

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