Fenfluramine Continues to Show Meaningful Seizure Reduction in Lennox-Gastaut Syndrome

Kelly Knupp, MD

Interim analysis from an ongoing, 12-month, open-label extension (OLE) of the phase 3 Study 1601 (NCT03355209) revealed that treatment with fenfluramine (Fintepla; Zogenix) oral solution resulted in a clinically meaningful and sustained reduction in drop seizures in patients with Lennox-Gastaut syndrome (LGS) on other antiseizure medications (ASMs).¹

The data, presented at the Child Neurology Society 2021 Annual Meeting, September 29-October 2, included 247 patients with LGS who entered the OLE after completion of the randomized, controlled portion of Study 1601. Results showed a 39.4% reduction in seizure frequency at month 3 (n = 227; P <.0001) and 51.8% decline for patients assessed between months 10-12 (n = 170; P <.0001) on treatment with fenfluramine. Prior to study treatment, the median baseline seizure frequency declined by 75 per month (range, 4-2943).

"We are excited to report this study analysis on the long-term treatment effect of Fintepla for LGS patients in need of relief from the significant burden associated with life-long, treatment-resistant seizures," Kelly Knupp, MD, MSCS, FAES, associate professor, Children’s Hospital Colorado, and principal investigator of the study, said in a statement.¹ "These results highlight the potential of Fintepla to reduce the frequency of seizures experienced by LGS patients to meaningfully improve the outcomes associated with the disease long-term."

The data readout comes days after Zogenix announced that it submitted a supplemental new drug application for fenfluramine to treat seizures associated with LGS.² The therapy previously received FDA greenlight to treat seizures associated with Dravet syndrome, another rare form of epilepsy, in June 2020.³

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Among the 170 patients assessed during the 10- to 12-month period in Study 1601, 51.2% of them responded with a clinically meaningful (≥50%) reduction in drop seizures, while 25.3% of patients demonstrated a profound (≥75%) reduction. Additionally, using Clinical Global Impression of Improvement (CGI-I) scale, 49.2% of investigators and 48.8% of caregivers rated their patients as being “much improved,” or “very much improved.”

In safety analysis, the drug was shown to be well-tolerated, with no observed valvular heart disease or pulmonary hypertension. Decreased appetite (n = 40; 16.2%), fatigue (n = 33; 13.4%), nasopharyngitis (n = 31; 12.6%), and seizures (n = 27; 10.9%) were the most reported treatment-emergent adverse events. There was 1 death in the study caused by aspiration pneumonia, but it was deemed unrelated to the study drug.

"We are very pleased with the compelling results of this study analysis demonstrating the potential long-term impact and clinical benefit of Fintepla for LGS patients, who face challenges in finding effective seizure control," Gail Farfel, PhD, executive vice president and chief development officer, Zogenix, said in a statement.¹ "We are also excited to have recently submitted a supplemental New Drug Application seeking approval of the use of Fintepla for the treatment of seizures associated with LGS."

At the 2020 American Epilepsy Society Annual Meeting, results from Study 1601 showed that fenfluramine 0.7 mg/kg/day (n = 87) achieved a –19.9% estimated median difference (ESM) from placebo (n = 87) 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%).⁴

The ESM in MDSF from baseline for those in the fenfluramine 0.2 mg/kg/day group (n = 89) did not reach statistical significance (–10.5%; P = .09); however, more investigators and caregivers rated patients “much improved” or “very much improved” on CGI-I for both doses compared with placebo. Tonic-clonic seizures, which were documented in 43% of the patient population, were reduced by 45.7% (P = .007) and 58.2% (P <.0001) with treatment of fenfluramine 0.7 mg/kg and 0.2 mg/kg per day, respectively.

Additional data from Study 1601 were presented at the 2021 American Academy of Neurology Annual Meeting, April 17-22, which demonstrated fenfluramine’s positive impact on everyday function. Using the Behavior Rating Inventory of Executive Function (BRIEF) scale, patients with LGS between 6 to 18 years old showed improvements in each of the 4 BRIEF 2 indexes compared to those on placebo. More specifically, there was a 24% improvement in Behavior (placebo, 13%; P = .118), 19% improvement in Emotions (placebo, 16%; P = .665), 27% improvement in Cognition (placebo, 13%; P = .665), and 25% improvement in Global Executive Composite overarching summary score (placebo, 11%; P = .034).⁵

REFERENCES

1. New Fintepla (fenfluramine) data show long-term seizure frequency reductions in patients with Lennox-Gastaut syndrome. News release. September 30, 2021. Accessed September 30, 2021. https://finance.yahoo.com/news/fintepla-fenfluramine-data-show-long-120000643.html

2. Zogenix submits supplemental new drug application for fintepla (fenfluramine) for the treatment of seizures associated with Lennox-Gastaut syndrome. News release. Zogenix. September 28, 2021. Accessed September 30, 2021. https://finance.yahoo.com/news/zogenix-submits-supplemental-drug-application-120000336.html

3. FDA approves Fintepla (fenfluramine) for the Treatment of Seizures Associated with Dravet Syndrome. News release. Zogenix. June 25, 2020. Accessed September 30, 2021. 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

4. 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.

5. Zogenix presents new data at Virtual AAN 2021 showing improved executive function in Lennox-Gastaut syndrome (LGS) patients treated with Fintepla (fenfluramine) oral solution. News release. Xogenix. April 22, 2021. Accessed September 30, 2021. https://www.globenewswire.com/news-release/2021/04/22/2215020/0/en/Zogenix-Presents-New-Data-at-Virtual-AAN-2021-Showing-Improved-Executive-Function-in-Lennox-Gastaut-Syndrome-LGS-Patients-Treated-with-FINTEPLA-Fenfluramine-Oral-Solution.html