Full Dataset Shows Fenfluramine’s Significant Treatment Effect in Lennox-Gastaut Syndrome


Both fenfluramine dose groups showed significant decreases in generalized tonic-clonic seizures, whereas those on placebo showed worsening of their condition.

Kelly Knupp, MD, MSCS, FAES, associate professor, Children’s Hospital Colorado

Kelly Knupp, MD, MSCS, FAES

Just more than a month after the FDA approved fenfluramine (Fintepla; UCB Pharma) for the treatment of seizures in patients with Lennox-Gastaut syndrome (LGS), the full findings from Study 1601 (NCT03355209)—the trial which supported its approval—have been published in JAMA Neurology.1,2

All told, the primary end point was met, with a 19.9% estimated mean difference (95% CI, –31.0 to –8.7) in monthly drop seizure frequency reduction (MDSF) between the fenfluramine 0.7-mg/kg/day group and placebo (P = .001), while the 0.2-mg/kg/day group reported an estimated mean difference of 10.5% (95% CI, –25.0 to 4.0) in MDSF reduction compared with placebo (P = .09). Additionally, a subgroup analysis showed that fenfluramine was highly effective in reducing the frequency of generalized tonic-clonic seizures (GTCs) in nearly 50% of patients.

"Our trial data and the clinical evidence demonstrates the safety and efficacy of Fintepla in LGS and especially for patients where generalized tonic-clonic seizures are the predominant seizure type, where there is a greater risk of mortality," principal investigator Kelly Knupp, MD, MSCS, FAES, associate professor, Children’s Hospital Colorado, said in a statement.1 “LGS is a highly treatment-resistant developmental and epileptic encephalopathy and we need differentiated treatment options, such as Fintepla, which has a unique mechanism of action different from and complementary to current antiseizure medications."

Study 1601 was a double-blind, placebo-controlled, parallel-group trial that included 263 patients aged 2 to 35 years with LGS who were randomly assigned to either fenfluramine 0.7 mg/kg/day (n = 87), fenfluramine 0.2 mg/kg/day (n = 89), or placebo (n = 87). After a 2-week titration period, patients were maintained on their randomized dose for 12 additional weeks. At baseline, 89% of patients were using 2 to 4 concomitant antiseizure medications, the most common being valproate (56%).

Also approved for the treatment of Dravet syndrome (DS), in this study of LGS, fenfluramine 0.7 mg/kg/day resulted in a median reduction of 26.5% in MDSF compared with 14.2% reduction in the 0.2-mg/kg/day group and 7.6% reduction in the placebo group. In total, 25% of patients in the fenfluramine 0.7-mg/kg/day group achieved at least a 50% response compared with 10% of those on placebo (P = .02). Similar results were observed for achieved reductions of 75% or more in seizure frequency (both fenfluramine groups: 14%; placebo: 3%).

READ MORE: Steven Wolf, MD, on the State of Lennox-Gastaut Syndrome and the Improving the Diagnostic Process

Clinically meaningful improvements, whether much improved or very much improved, on Clinical Global Impression of Improvement (CGI-I) scale were observed in 26% (P = .001) and 20% (P = .01) of patients in the fenfluramine 0.7- and 0.2-mg/kg/day groups, respectively, compared with 6% of those on placebo. Similarly, caregivers gave a clinically meaningful improvement rating to more patients in the fenfluramine groups (0.7 mg/kg/day: 34% [P <.001]; 0.2 mg/kg/day: 27% [P <.001]) than in the placebo group (5%).

In total, 46% of patients (n = 120) had GTC seizures occur at baseline. The percentage reduction in GTC frequency during the titration and maintenance period was 45.7% in the fenfluramine 0.7-mg/kg/day group (P <.001) and 58.2% in the 0.2-mg/kg/day group (P <.001) compared with an increase of 3.7% in the placebo group. In the fenfluramine 0.7- and 0.2-mg/kg/day groups, the estimated median difference in GTC seizure frequency was –50.3% (95% CI, –76.7 to –23.8; P = .001) and –60.4% (95% CI, –84.9 to –36.0; P <.001), respectively, compared with placebo.

During the titration and maintenance period combined, the 0.7-mg/kg/day group demonstrated a 46.7% reduction in tonic or atonic seizures compared with 6.8% in the placebo group (P = .046). Furthermore, the estimated median difference from placebo in tonic or atonic seizure frequency was –31.5% (95% CI, –61.1 to –2.0; P = .046) in the 0.7-mg/kg/day group compared with –35.1% (95% CI, –67.1 to –3.1; P = .04) in the maintenance only period.

"This study further validates the importance of Fintepla as a new treatment option for seizures associated with LGS, including generalized tonic-clonic seizures,” Mike Davis, Global Head of Epilepsy, UCB, said in a statement.1 "Through our close connection with the LGS community, we know the challenges they face go beyond treatment resistant seizures to include difficulty with behavior and cognition, and we hope that Fintepla can help people living with LGS."

As for safety, fenfluramine was well-tolerated, with treatment-emergent adverse events (TEAEs) that were consistent with what had been previously observed. The most common TEAEs included decreased appetite (22%), somnolence (13%), and fatigue (13%), with more patients in the fenfluramine treatment groups experiencing decreased appetite than those on placebo. Additionally, weight loss of 7% or more from baseline was reported in 8% and 2% of those in the fenfluramine 0.7 and 0.2 mg/kg/day groups, respectively, compared with 2% of those on placebo.

Throughout the study, there were no observed cases of valvular heart disease or pulmonary arterial hypertension. One patient in the fenfluramine 0.7-mg/kg/day group had an end-of-study echocardiogram reading as mild aortic regurgitation without any changes in valve morphological structure and a subsequent diagnostic transesophageal echocardiogram revealed absent aortic regurgitation and a normal aortic valve.

At the 2022 American Academy of Neurology Annual Meeting, April 2-7, in Seattle, Washington, Knupp sat down with NeurologyLive® to speak further about the potential of fenfluramine in the LGS population. Specifically, she shared her perspective and experience with its long-term use as well as some highlights of its interim open-label data presented at the meeting.

"What I’ve learned in my experience with this medication is that sometimes it’s helpful to make an adjustment and then watch for 4 weeks before making the next adjustment. That’s how the open-label extension was designed, but a number of my patients saw ongoing improvement over that 4-week period without us making an adjustment in their medication. Perhaps we do need slower titration to see the full benefit of this medication," Knupp told NeurologyLive®. For more of her insight, check out the video below.

1. JAMA Neurology publishes phase 3 results on efficacy and safety of fintepla (fenfluramine) oral solution in Lennox-Gastaut syndrome (LGS). News release. UCB Pharma. May 2, 2022. Accessed May 8, 2022. https://www.ucb-usa.com/stories-media/UCB-U-S-News/detail/article/jama-neurology-publishes-phase-3-study-results-on-the-efficacy-and-safety-of-fintepla-fenfluramine-oral-solution-in-lennox-gastaut-syndrome-lgs
2. Knupp KG, Scheffer IE, Ceulemans B, et al. Efficacy and safety of fenfluramine for the treatmet of seizures associated with Lennox-Gastaut syndrome: a randomized clinical trial. JAMA Neurol. Published online May 2, 2022. doi:10.1001/jamaneurol.2022.0829
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