Fenfluramine Demonstrates Efficacy in Lennox-Gastaut Syndrome in Phase 3 Results

Kelly Knupp, MD

Full results from the phase 3 Study 1601 (NCT03355209) of the investigational agent fenfluramine (Fintepla; Zogenix) showed that the trial met its primary end point, with the treatment demonstrating significant improvement in monthly drop in seizure frequency (MDSF) in patients with Lennox-Gastaut syndrome (LGS).¹

The study data on fenfluramine, which is previously known as ZX008, were presented virtually by Kelly Knupp, MD, pediatric neurologist and epilepsy specialist, Children’s Hospital Colorado, at the American Epilepsy Society (AES) Annual Meeting, December 4–8, 2020.

Knupp and colleagues found that treatment with fenfluramine 0.7 mg/kg/day achieved –19.9% estimated median difference from placebo (ESM; Hodges-Lehmann estimate) in MDSF from baseline (P = .001). The data were comparable to the magnitude demonstrated in all other recently completed LGS randomized controlled trials (range, –14.8% to –21.6%).

"We are honored to collaborate with leading international epilepsy experts to broaden our understanding of how FINTEPLA, a drug recently approved by the FDA to treat seizures associated with Dravet syndrome, may improve the lives of epilepsy patients and their families,” Bradley S. Galer, MD, chief medical officer, Zogenix, said in a statement.²

A total of 263 patients were randomized to placebo (n = 87), fenfluramine 0.2 mg/kg/day (n = 89), or fenfluramine 0.7 mg/kg/day (n = 87) for a 4-week baseline to establish MDSF, followed by 2 weeks of titration and then a 12-week treatment period.

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The ESM in MDSF from baseline for those in the fenfluramine 0.2 mg/kg/day group did not reach statistical significance (–10.5%; P = .09). However, more investigators and caregivers rated patients “much improved” or “very much improved” on clinical global impression of improvement (CGI-I) for both doses compared with placebo.

In total, 43% of patients within the study experienced generalized tonic-clonic seizures (GTCs; median baseline, 11.5–18.3; range, 1–198). Treatment with fenfluramine 0.7 and 0.2 mg/kg/day resulted in a 45.7% (P = .0007) and 58.2% (P <.0001) reduction of GTC frequency within those groups, respectively.

Knupp and colleagues noted, “Given that GTCs are a primary risk factor for sudden unexpected death in epilepsy, these results suggest FFA (fenfluramine) may be an advantageous choice for LGS patients experiencing this seizure type.”

Zogenix originally published topline data from the study back in February 2020. The data showed that the 0.7 mg/kg/day dose of fenfluramine demonstrated statistically significant improvements compared to placebo in a number of secondary efficacy measurements, including the proportion of patients with a clinically meaningful reduction, defined as ≥50%, in drop seizure frequency, which occurred in 25.3% of patients on that dose of active treatment compared to 10.3% on placebo (P = .0165).³

Overall, the therapy was deemed well tolerated, with a similar adverse event (AE) profile to what has been previously observed in its Dravet Syndrome (DS) development. The incidence of patients experiencing an AE was 89.7% in the 0.7 mg/kg/day group, 76.4% in the 0.2 mg/kg/day group, and 79.3% in the placebo group.

The most common AEs, occurring at a rate greater than 10% were decreased appetite, somnolence, fatigue, vomiting, diarrhea, irritability, seizure, and pyrexia. Serious AEs occurred at a rate of 11.5%, 4.5%, and 4.6% in the high-dose, low-dose, and placebo groups, respectively, with 6 patients in the high-dose and 4 in the low-dose discontinuing treatment, compared to 1 on placebo. There were no cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) observed.¹

Fenfluramine may be the next drug approved for patients with LGS after It was recently approved by the FDA for the treatment of DS as an oral solution for patients age 2 and older.⁴

"With new long-term data in Dravet syndrome, full results from our Lennox-Gastaut syndrome phase 3 trial, and data from investigator-initiated studies, we are eager to continue advancing Fintepla as a potential new treatment option for additional rare epilepsies,” Galer added in a statement.²

For more coverage of AES 2020, click here.

REFERENCES

1. Knupp K, Sullivan J, Nickels K, et al. Efficacy and safety of fintepla (fenfluramine) for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized, double-blind, placebo-controlled clinical trial. Presented at AES 2020 Annual Meeting; December 4–8, 2020. Abstract 852.

2. Zogenix and leading experts to present new rare epilepsy data at AES 2020. News release. Zogenix. December 1, 2020. Accessed December 1, 2020. https://www.morningstar.com/news/globe-newswire/8094468/zogenix-and-leading-experts-to-present-new-rare-epilepsy-data-at-aes-2020

3. Zogenix Announces Positive Top-line Results from Global Pivotal Phase 3 Trial of FINTEPLA® for the Treatment of Lennox-Gastaut Syndrome. News release. Zogenix. February 6, 2020. Accessed December 1, 2020. zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-announces-positive-top-line-results-global-pivotal-phase..

4. FDA approves Fintepla (fenfluramine) for the Treatment of Seizures Associated with Dravet Syndrome. News release. Zogenix. June 25, 2020. Accessed December 1, 2020. https://www.globenewswire.com/news-release/2020/06/26/2053803/0/en/FDA-Approves-FINTEPLA-fenfluramine-for-the-Treatment-of-Seizures-Associated-with-Dravet-Syndrome.html