Zogenix’s Fintepla (fenfluramine) as an adjunctive therapy for Dravet syndrome faces rocky uptake prospects despite expert anticipation of a straightforward FDA approval.

GW Pharmaceutical’s Epidiolex (cannabidiol), the first approved drug for Dravet syndrome in June 2018, has established its place firmly in the treatment paradigm with its first-mover advantage, experts said. Even Biocodex’sDiacomit (stiripentol), which was subsequently approved in August 2018, has experienced relatively slow uptake compared to Epidiolex, and similar inertia could be expected for fenfluramine, they noted.

Additionally, the increasing use of medical marijuana and cannabidiol (CBD) products competes in the space, some experts said. Some parents of patients with Dravet syndrome might prefer to use medical marijuana or CBD before considering pharmaceutical options as former options are considered to be more natural due to being plant-derived, they explained.

Fenfluramine’s differentiated MOA provides an exciting edge for patients whose seizures are inadequately controlled with typical antiepileptic drugs (AEDs), experts said, adding it is uncertain whether it can be best-in-class, as two analyst reports suggest. Epidiolex’s draw as an adjunctive therapy was also its differentiated MOA, and the lack of head-to-head data between fenfluramine and Epidiolex makes it hard to claim a superiority advantage for either, some experts said.

Four other analyst reports concurred on the straightforward approval prospects. Two of the reports projected peak sales in Dravet syndrome reaching about $500m and $800m in the US and EU respectively. Zogenix has a market cap of $2.4bn.

Fenfluramine’s Prescription Drug User Fee Act (PDUFA) date is 25 March, according to a November 2019 press release. The drug’s New Drug Approval (NDA) was resubmitted on 29 September 2019 following a 13 May 2019 Refusal to File letter from the FDA, which was due to insufficient nonclinical animal data and an incorrectly submitted dataset.

Zogenix did not respond to a request for comment.

Uphill climb against established players

Epidiolex has firmly established itself in the Dravet syndrome and Lennox-Gastaut syndrome (LGS) space, which it is also approved for. While there is still a space for new entries in these spaces, they would have to face Epidiolex’s first-mover advantage, said Dr Robert Flamini, pediatric neurologist, PANDA Neurology & Atlanta Headache Specialists, Georgia. Since Epidiolex’s approval, the demand from parents of Davet syndrome and LGS patients has remained strong, and payer access had not been particularly problematic, said Dr Daniel Tarquinio, pediatric neurologist, Center for Rare Neurological Diseases, Norcross, Georgia.

Part of Epidiolex’s strong reception had to do with strong patient advocacy even during its clinical development period, Flamini said. Parents had heard about the CBD-derived drug, and their demand to enrol their children into the trial was overwhelming, he said. Because current AEDs have modest efficacy at best, and many patients need to take as many as four concurrent AEDs and contend with their host of side effects, the prospect of an apparently nature-derived drug is appealing to parents, said Dr Elizabeth Thiele, professor of neurology, Harvard University, Boston, Massachusetts.

Even Diacomit’s entry into the Dravet space seems lukewarm compared to Epidiolex’s entry, as Diacomit’s patient awareness was not as strong, said a pediatric neurologist. When fenfluramine is ready to enter the market, it will be facing competition from both Epidiolex and Diacomit, he noted. Epidiolex’s 2019 sales were projected to be $296m, according to GW’s 12 January preliminary sales report. Diacomit sales figures were unavailable.

Additionally, more US states are loosening up their laws on medical marijuana and CBD oils by increasing their access, making them more attractive for parents of Dravet patients, even though there have not been definitive clinical data supporting marijuana and CBD oil efficacy, all experts agreed. It is fair to expect fenfluramine will also face competition from medical marijuana and CBD products, the pediatric neurologist said.

Despite MOA edge, market positioning still uncertain

However, whether fenfluramine could be first-in-class as an adjunctive treatment remains to be seen, Flamini said. Fenfluramine is certainly welcomed as an adjunctive treatment, as it works along the serotonergic pathway rather than the typical gamma-aminobutyric acid (GABA) pathway of other AEDs, all experts agreed.

Epidiolex’s MOA is also differentiated, as it is targeting cannabinoid receptors rather than GABA, and there is no data suggesting targeting serotonin works better for treating refractory epilepsy than cannabinoid receptors, the pediatric neurologist said.

While fenfluramine’s Phase III data in seizure reduction is impressive compared to Epidiolex, it is still unfair to just compare the datasets in the absence of a head-to-head study, Thiele and the pediatric neurologist said. The 87-patient dataset of fenfluramine’s Phase III trial (NCT02926898) showed treated patients saw a 63.1% median reduction from baseline in convulsive seizures compared to 1.1% in placebo patients (p<0.001, Nabbout, et al, Abst. 3.461, AES 2018 Annual Meeting Abstract Database).

Epidiolex has been out for slightly longer than one year, but excitement surrounding it should eventually wane, opening up the space for competitors such as Diacomit and fenfluramine, said the pediatric neurologist. Some physicians are finding Epidiolex’s efficacy and tolerability modest at best, he added. In Epidiolex’s 171-patient Phase III (NCT02224690) dataset, treated patients’ seizures improved by a median of 43.9% compared to 21.8% on placebo (p=0.0096) during the four-week treatment period (Thiele, et al, Lancet. 2018 Mar 17;391(10125):1085–1096). Experts said anywhere from 5–20% of their patients might discontinue Epidiolex either due to insufficient efficacy or finding it intolerable. Fenfluramine could enter this space to address patients who are refractory to current AEDs and adjunctive treatments such as Epidiolex, Tarquino said. After a few years, when physicians have gained more familiarity with the product they could possibly reach for it even before Epidiolex, he added.

Still, all experts agreed straightforward approval is expected for fenfluramine due to its strong, positive Phase III data and the high unmet need in Dravet syndrome. Fenfluramine has met its primary endpoint, as the treated arm achieved 54% superiority versus placebo in mean monthly convulsive seizure frequency (p<0.001). A total of 54.5% and 34.9% of treated patients achieved a 50% (p<0.001) and 75% reduction (p=0.003) respectively, which is unprecedented in the refractory space, strengthening its approval prospects, Thiele and Tarquino noted.

By Shaun Sim in New York, US.

Shuan Sim is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.