Emeryville, Calif.-based Zogenix Inc.’s positive top-line data from the phase III study with Fintepla (fenfluramine oral solution) in Lennox-Gastaut syndrome (LGS) failed to charm Wall Street, which by day’s end trimmed the shares (NASDAQ:ZGNX) by $20.50, or 39%, putting the final price at $32.12.
The trial called Study 1601 met its primary objective of demonstrating that Fintepla – known to have serotonergic effects while targeting the sigma-1 receptor – was, when given at a dose of 0.7 mg/kg/day, superior to placebo in reducing the frequency of drop seizures in LGS, based on the change between baseline and the titration and maintenance treatment period (p=0.0012). But investors apparently wanted even better efficacy.
SVB Leerink analyst Marc Goodman said his firm has not “changed our positive view that the product can grab material share in Dravet syndrome [DS], but we are clipping our LGS (and some off-label) sales forecasts, as we now believe the product will be used predominately in the refractive LGS setting and off-label use may be reduced.” He lowered U.S. peak sales from about $1.1 billion to about $700 million, and brought down Zogenix’s price target from $62 to $48. In DS, Fintepla’s NDA is under priority review with a PDUFA date of March 25, 2020, although the road has not proved entirely smooth. The FDA walloped the candidate with a refusal to file letter in April 2019. Zogenix resolved the matter by late June.
LGS took the spotlight most recently, though. It’s a severe form of epilepsy that typically becomes apparent during infancy or early childhood. Affected children experience several different types of seizures, classed as atonic, tonic and atypical. The condition strikes males slightly more often than females. The annual incidence in children is estimated to be two per 100,000 children, with onset usually between the ages of 2 and 7, with a peak onset between 3 and 5, according to the National Organization for Rare Disorders.
The multicenter, global Study 1601 has two parts: part one was a double-blind, placebo-controlled study to assess the safety, tolerability and efficacy of Fintepla when added to a patient’s current antiepileptic regimen. Included was a total of 263 patients between the ages of 2 and 35 whose seizures were currently uncontrolled while on one or more antiepileptic drugs (AEDs), randomized into three treatment groups: Fintepla 0.7 mg/kg/day (26 mg maximum daily dose; n=87); 0.2 mg/kg/day (n=89); and placebo (n=87). The median age of patients was 13, with 29% being 18 or older.
Patients entering the study were taking between one and four AEDs and had tried and discontinued an average of seven other such therapies. The median baseline drop seizure frequency across the study groups was 77 seizures per month. After establishing baseline seizure frequency for four weeks, randomized patients were titrated to their dose over a two-week period, followed by a 12-week fixed-dose maintenance stretch. Patients who completed part one were eligible to enter part two, an ongoing 12-month open-label extension study to test long-term safety, tolerability and effectiveness of the drug.
Trial participants taking Fintepla 0.7 mg/kg/day achieved a median drop seizure reduction of 26.5% compared to a median reduction of 7.8% in patients taking placebo (p=0.0012). Using a parametric analysis, patients taking 0.7 mg/kg/day of the drug turned up a 26.5% greater reduction in mean monthly drop seizure frequency compared to placebo (p=0.0034). For some Zogenix watchers, here’s the rub, or one of them: The median percent reduction in monthly drop seizures between baseline and the treatment period for the lower study dose of Fintepla (0.2 mg/kg/day), a secondary endpoint, was 13.2% and did not reach statistical significance compared to placebo (p=0.0915). In previous studies that tested the drug against DS, all Fintepla doses of 0.2-0.8 mg/kg/day achieved some level of statistically superior efficacy vs. placebo in seizure reductions, noted SVB Leerink’s Goodman. Also, the placebo-adjusted seizure reductions in the high-dose LGS arm are “substantially lower” than Fintepla’s data in DS, he said. “There are six patients in the high-dose arm that discontinued due to adverse events, and one patient had sudden unexpected death in epilepsy,” he pointed out further, though the death was deemed unrelated to Fintepla.
During a conference call hosted by Zogenix, the subject of GW Pharma plc’s Epidiolex came up. In June 2018, the FDA approved Cambridge, U.K.-based GW’s liquid therapy for DS and LGS, the first pharmaceutical formulation of purified, plant-based cannabidiol to reach the market. Analyst Paul Matteis, of Stifel, Nicolaus, wanted to “clarify if you had any theory surrounding the inevitable cross-draw comparison as it relates to your study [and] the Epidiolex LGS study. It looks like the absolute seizure reduction was lower, but also the placebo effect is a lot less substantial. I was wondering if you had any theories on that.”
Chief Development Officer Gail Farfel said Fintepla’s “placebo response rate was low, and our active response rate, which was statistically improved, was three times the placebo response rate. If I remember correctly, GW had a much higher placebo response rate, and I think their active rate was two times higher.” But with “different studies, run at different times, it’s always difficult to make direct comparisons,” she said.
Evercore ISI analyst Josh Schimmer said in a report that the Fintepla update “lifts a competitive overhang for GW shares,” but that, “given differences in price/positioning (Zogenix has indicated [it would pursue] orphan pricing), we hadn’t expected Fintepla to be a meaningful, direct threat to Epidiolex in LGS without dramatically superior data.” He said his firm “continue[s] to have a strong outlook for GW shares in 2020.”
GW’s stock (NASDAQ:GWPH) closed at $126.65, up $8.41.