Fintepla (ZX008), an investigational therapy from Zogenix, significantly lowered the frequency of drop seizures and was well tolerated in children and adults with Lennox‑Gastaut syndrome, according to topline results from a Phase 3 study.
“We are pleased with the topline efficacy and safety results from Study 1601, which highlight FINTEPLA’s potential to be an important new treatment option for one of the most difficult to treat rare epilepsies,” Stephen J. Farr, PhD, president and CEO of Zogenix, said in a press release. “We look forward to working with regulatory agencies to potentially bring FINTEPLA to the LGS patient community,”
Fintepla, a low-dose, oral solution of fenfluramine hydrochloride, is being developed as a potential add-on treatment for seizures in patients with LGS and Dravet syndrome, a type of severe childhood epilepsy.
The Phase 3 Study 1601 (NCT03355209) was designed to evaluate the safety and effectiveness of two doses of Fintepla (0.2 or 0.7 mg/kg) to reduce seizures in LGS patients, compared with a placebo.
The study enrolled 263 LGS patients between 2 and 35 years old who had seizures that could not be controlled by one or more current anti-epileptic therapies. On average, patients tested seven other anti-epileptic therapies.
Participants’ seizure frequency was first determined over four weeks, during which they received Fintepla or a placebo as an add-on therapy to their current anti-epileptic regimen. After this period, they were randomly assigned to receive one of the two doses of Fintepla (to a maximum of 26 mg a day) or a placebo during a two-week period of dose titration (in which doses are sequentially increased up to the maximum proposed dosage). They then received maintenance treatment at a fixed dose for 12 weeks.
Those who completed maintenance treatment were eligible to enter Part 2 of the trial, an ongoing, one-year, open-label extension study to assess the long-term safety, tolerability, and effectiveness of Fintepla. So far, 247 (93.9%) patients have entered the second part of the trial.
The trial’s primary goal was to assess changes in the frequency of drop seizures between the beginning of the study and after 14 weeks of Fintepla treatment at the 0.7mg/kg daily dose, compared with a placebo.
Secondary goals included a similar assessment for the 0.2mg/kg daily dose of Fintepla and the proportion of patients showing a 50% decrease in drop seizures, considered a clinically meaningful reduction.
The trial met is primary endpoint, as patients who received the 0.7 mg/kg daily dose of Fintepla showed a significant median monthly reduction — 26.5% — in drop seizures from the beginning of the trial, compared with a median reduction of 7.8% in patients taking placebo.
Patients treated with Fintepla also showed a 26.5% greater decrease in mean monthly drop seizure frequency than patients receiving the placebo.
Although the 0.2 mg/kg daily dose of Fintepla decreased the median percent change in monthly drop seizures by 13.2%, this was not statistically significant when compared with the placebo.
The 0.7 mg/kg dose also translated into significant improvements in other, secondary endpoints. Treatment with that dose resulted in a significant increase in the proportion of patients with a clinically meaningful reduction in drop seizure frequency compared with placebo (25.3%, compared with 10.3%).
The proportion of patients who improved on the higher dose of Fintepla was 48.8%, compared with 33.8% in the placebo group. The proportion of patients assessed as “much improved” or “very much improved” on the higher dose was 26.3%, compared with 6.3% on placebo.
The improvements were assessed using the Clinical Global Impression of Improvement rating (CGI-I), a seven-point scale that measures lessening of symptoms, with a score of 1 representing very much improved and a score of 7 indicating very much worse.
Fintepla was generally well tolerated, with side effects consistent with those previously observed in two Phase 3 studies assessing the therapy in Dravet syndrome patients. A total of 89.7% of patients in the Fintepla 0.7 mg/kg group showed at least one side effect, compared with 76.4% of patients in the Fintepla 0.2 mg/kg group and 79.3% of patients in the placebo group.
The most common adverse events in the Fintepla-treated patients were decreased appetite, somnolence, fatigue, vomiting, diarrhea, and fever.
Serious side effects occurred in 11.5% of the higher-dose group, in 4.5% of the lower-dose group, and in 4.6% of the placebo group. Six patients in the 0.7 mg/kg group had a side effect that led to them to discontinue the trial, compared withfour patients in the 0.2 mg/kg group, and one patient in the placebo group. Most of these side effects were thought to be related to the treatment.
No cases of valvular heart disease or pulmonary hypertension were seen in the trial. There was one death, in the higher-dose group, which was attributed to sudden unexpected death in epilepsy and deemed unrelated to treatment.
After completing the second part of the trial, participants considered to be candidates for continued treatment with Fintepla may enter an open-label Phase 3 study (NCT03936777) evaluating the long-term safety and effectiveness of Fintepla treatment for up to three years.
“The results observed in this placebo-controlled study are indicative of the potential of fenfluramine to treat patients with refractory LGS,” said associate professor Kelly Knupp, MD, an associate professor at Children’s Hospital Colorado and the trial’s principal investigator. “If approved, FINTEPLA could represent an important new treatment option for these patients and their families in need.”
The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granted orphan drug designation to Fintepla for the treatment of Lennox-Gastaut syndrome in 2017.