The vice president of Clinical Research at Eisai provides updates on the MOMENTUM trials which will examine lorcaserin as a potential treatment for patients with Dravet syndrome.
After consulting with the FDA, Eisai recently announced that it has initiated the phase 3 MOMENTUM1 clinical study (Study 304; NCT04572243), which will evaluate lorcaserin in patients with Dravet syndrome (DS).1 Lorcaserin, a selective serotonin 5-HT2C receptor agonist, will be used as an adjunctive treatment in both the phase 3 trial as well as an open-label extension.
The drug was originally FDA-approved under the name Belviq, a weight-loss medication which was voluntarily withdrawn from the market in February 2020 after data from a cardiovascular safety study, CAMELLIA-TIMI 61, showed an increased occurrence of cancer in patients taking the drug.2 Despite not being indicated for DS, the drug was being used off-label treatment in this patient population at the time.
As part of our NeuroVoices series, we sat down with Michael Irazarry, PhD, vice president, Clinical Research, Eisai, to discuss details of the recently initiated MOMENTUM trials and why lorcaserin’s selectivity makes it a good match for the pathology seen in patients with DS.
Michael Irazarry, PhD: The MOMENTUM trial is designed similarly to a standard epilepsy trial. Patients with Dravet syndrome have a range of types of epileptic seizures, but we’re going to focus on the convulsive seizures. Those are the tonic-clonic or clonic seizures that have the greatest impact on the increased risk of sudden death in epilepsy. The primary end point of these studies is the percent reduction in convulsive seizures, while the 50% responder rate acts as a secondary end point. It is a randomized, double-blind, controlled trial that includes patients with a diagnosis of Dravet syndrome greater than or equal to 2 years of age. To help improve the detectability of treatment effect, they have to have greater than or equal to 4 seizures per month or 4 seizures in the screening period. Based on that, they are randomized to either placebo or lorcaserin. The lorcaserin dose is weight-based, so the greater the weight, the greater the dose. There are 3 dosing categories in the trial and there’s an opportunity for investigators to do 1 dose increase within the weight category as well. [Patients are] followed for 14 weeks and will use seizure diaries as a way to assess the whole range of seizures that are experienced, with convulsive seizures serving as the primary outcome. After the completion of the study, they have the opportunity to enroll into an expanded access program which allows them to get continuous dosing of lorcaserin. Following the FDA withdrawal, we set up this program for these patients who were on the drug and would have lost access to it.
One reason we selected Dravet syndrome was because of the understanding of the network dysfunction and the potential role of targeting the 5-HT2C receptor. In Dravet syndrome, over 80% of cases are caused by a sodium channel mutation. That sodium channel particularly impacts GABA inhibitory interneurons. Those neurons can suppress firing and it is thought that when that inhibition is released, it increases the susceptibility to seizures. Well, those GABA interneurons are ergic in their dendritic portion, and contain 5-HT2 receptors, in a nutshell. By stimulating those, we can increase the inhabitation, or the release of disinhibition, and suppress seizures. The main mechanism is increasing the activity of those GABAergic inner neurons that have these specific receptors. Because its specific to 5-HT2C, it won’t have some of the safety liabilities that other drugs who target the serotonergic system that have valvular safety issues, have. Notably, fenfluramine also activates the 5-HT2C receptor, but also activates the 5-HT2B receptor. We do hope that our selectivity can help differentiate either in terms of clinical effect or in safety.
We hadn’t originally been developing lorcaserin for Dravet. It had been approved for a managed weight loss medication. As part of the approval, there was a post-marketing commitment that required a large cardiovascular safety study. In that study, which featured 12,000 people over 4 years, there was no cardiovascular liability. However, that study showed a numerical imbalance in malignancies, which was around 7.1% in placebo and 7.7% in lorcaserin.
Even though the regulators didn’t find evidence of causality for that, they thought that the benefit:risk for weight loss wasn’t justified, and thus recommended to stop the marketing. Soon after we did that, Eisai and the FDA received numerous requests from patients and physicians in advocacy groups. At the time, lorcaserin was being used to treat Dravet syndrome and other refractory epilepsies. As I mentioned, we set up the expanded access program and then looked into more detail in terms of the evidence around that mechanism. There was some basic scientific evidence describing the role of 5HT2C receptors on GABAergic interneurons.
Additionally, there was a zebrafish model of Dravet syndrome that tested multiple antiepileptic drugs. This was a couple of years ago, but lorcaserin came out as one of the most effective. There were then 2 publications of lorcaserin use in the clinic for both Dravet and refractory epilepsy. It was an open-label trial, but the investigators felt as though there was enough efficacy of lorcaserin. That nonclinical evidence about the networks, nonclinical model of zebrafish, and the case histories from physicians treating patients with epilepsy all impressed us and the FDA as well. In consultation with the FDA, we designed the expanded access program and the clinical trial.
Our intention would be to seek approval after this study. The way we’ve designed it, we’re looking for a large treatment effect. Our expectation is to see the study demonstrate efficacy. In terms of safety, we have a large safety database from the weight loss programs, as well as from a pediatric weight loss study that was ongoing before we withdrew the treatment. We believe the safety is well understood, and the key question will be the efficacy that’s demonstrated.
Transcript edited for clarity.