Positive Fenfluramine Data in LGS Suggest an FDA Approval Is on the Horizon

Kelly Knupp, MD

Full results from the phase 3 Study 1601 (NCT03355209) of fenfluramine (Fintepla; Zogenix) presented at the American Epilepsy Society (AES) Virtual Meeting, December 4–8, 2020, revealed that the trial met its primary end point in patients with Lennox-Gastaut syndrome (LGS). The investigational agent was able to demonstrate a significant improvement in monthly drop in seizure frequency and the data was comparable to other recently completed LGS randomized controlled trials.

Lead author Kelly Knupp, MD, pediatric neurologist and epilepsy specialist, Children’s Hospital Colorado, and colleagues found that treatment with fenfluramine 0.7 mg/kg/day and 0.2 mg/kg/day resulted in a 45.7% (P = .0007) and 58.2% (P <.0001) reduction of generalized tonic-clonic seizure frequency within those groups, respectively. Fenfluramine may be the next drug approved for patients with LGS after it was recently approved by the FDA for the treatment of Dravet syndrome (DS) as an oral solution for patients age 2 and older.

Knupp sat down with NeurologyLive to provide further context on her study, discuss whether the drug is ready for FDA approval, and how it might fit into the treatment landscape if approved.

NeurologyLive: Can you provide some background on your study and what you observed?

Kelly Knupp, MD: This was a randomized, double-blind study, very similar to your standard clinical trial to determine the efficacy in children with Lennox-Gastaut syndrome. We identified children with Lennox-Gastaut syndrome who were having a fair amount of seizures. The seizure measure was a little bit different in this study than in others for Dravet [syndrome], due to the difference in the disease. One of the outcome measures that has worked well in this population is seizure associated with a drop. Kids with Dravet have a lot of different types of seizures, but kids with Lennox-Gastaut syndrome have more smaller seizures that can sometimes be hard to count. This is a good way for families to count seizures reliably during both the treatment and maintenance period. Any seizure that is associated with a fall or drop is 1 that gets counted in the study. That would include generalized tonic-clonic seizure, atonic seizure, or seizures that may make you fall. All of these kinds of things get encompassed within that.

The children enrolled had their seizures measured at baseline and then started study drug. There was a titration period, and then a maintenance period, and each patient had their seizure frequency compared from those time periods back to baseline. We saw a large number of patients on both the low and high dose that had a significant reduction of at least 25% in seizures. We also saw a large number of patients who experienced a ≥50% reduction. When we looked at the ≥75% reduction numbers, they weren’t significant enough. Overall, the thought that both the low and high doses demonstrated a reduction in seizures was super exciting.

Topline results that showed the study met its primary end point were released in February, but were there any shocking data in the full analysis?

This is what we had hoped for. In the primary end point, the low dose was not statistically significant, but when you look at our secondary end points, we do see a benefit in the low dose group as well. I don’t think it’s surprising that it’s not as robust as what we saw with Dravet because the population is very homogeneous, whereas Lennox-Gastaut syndrome the population is more heterogeneous. Despite the results not being as robust, it was clear that it demonstrated efficacy in this population and will definitely be a treatment tool.

What does the treatment landscape currently look like for patients with LGS? How might fenfluramine fit into that landscape?

Lennox-Gastaut syndrome has a number of treatments that have demonstrated benefit. One of the more unfortunate parts about Lennox-Gastaut syndrome is that we rarely ever see seizure freedom. Even in this study, when we look at the 75% reduction in seizures, there’s no statistically significant data. As a clinician, whenever I have a patient with Lennox-Gastaut syndrome, I need lots of tools to treat them. I’m thankful we have a number of medicines that have been approved. This is just 1 more additional treatment we can use for these kids because clearly, they still need a lot of help if we’re not reaching that seizure freedom point.

What I particularly like about fenfluramine is that it has a different mechanism of action than any of our other seizure medications right now. I think that’s particularly helpful. When you look at some of the other medicines, including clobazam, felbamate, rufinamide, this is yet 1 more medicine that has a very different mechanism from the rest. That makes me hopeful that we’ll see some of our patients take benefit from this medication. In general, it was pretty well-tolerated. Oftentimes in the clinical setting when we’re choosing a medication among the many options, we start to look at the side effects. To that point, a number of our medicines have led to increased weight. The fact that this has an appetite suppressant may be an added benefit to some of our patients. It’s definitely a side effect that we have to watch for, especially because it may not be of benefit to some, but for the others who may need that, it can be of benefit.

What are the next steps? Do you feel fenfluramine is ready to be sent to the FDA for a possible approval?

I don’t work for the company, so I don’t know what they plan on doing. As a pediatric neurologist, I’ve seen this be approved for Dravet and would love to see it be approved for Lennox-Gastaut syndrome so that we can expand the patient populations that we can use it in. It clearly has demonstrated some benefit. We have to keep in mind there are lots of children who don’t have Dravet or Lennox-Gastaut syndrome but may still have a form of refractory epilepsy. That’s important for all pharmaceutical partners to take a look at when observing this patient population and determine a way that we can study them in an effective manner.

Is there anything else you’d like to mention?

One of the really important things for people to know is that there have been no cardiac side effects reported in any of the patients within the studies to date. There’s a lot of fear, understandably so, both in the patient populations and providers. This was a medication that was pulled off the market in the past because of concerns over cardiac side effects. We have yet to see that, which is reassuring. In the Dravet population there’s a very robust REMS (Risk Evaluation and Mitigation Strategy) program that’s in place which will continue to surveil that and make sure we’re not missing anything. I would be less concerned about using this medication from a cardiac standpoint, and all the data has assured of that.

Transcript edited for clarity.

REFERENCE

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.