After a few bumps along the way, on June 25, the U.S. Food and Drug Administration (FDA) granted approval to Fintepla for the prevention of seizures in patients ages 2 and older who have Dravet syndrome.
In an interview with Dravet Syndrome News, Farr said he is “thrilled” and “delighted” by the FDA decision: “I think it’s obviously vindicated a business decision several years ago to embark on this journey.
“The fact that we’ve now gotten over the finish line, at least in the United States with an approval, fills us with a lot of pride, that we’ve been able to translate what was promising data in a very small number of patients in Belgium into now, an approved drug product that all Dravet patients in the United States could potentially benefit from.”
Path to approval
Originally developed as an appetite suppressant, Fintepla is an oral, low-dose fenfluramine solution. Fenfluramine had shown early promise in treating the seizures that characterize Dravet syndrome, although the exact mechanism by which the medication works is still not entirely clear.
Researchers had found evidence that fenfluramine reduced seizures by preventing nerve cells from reusing the neurotransmitter, or chemical messenger, serotonin. However, more recent research suggests it may act on sigma receptors — a type of cell membrane receptor common in nerve cells. In both cases, the end result is restoration of healthy communication between nerves.
Farr describes research into fenfluramine’s use for Dravet syndrome as “bedside to bench,” rather than the more traditional “bench-to-bedside” path, in which potential therapies are first developed in a lab (upon the lab bench) and later tested on patients in clinical trials.
“When we first started our work on fenfluramine in Dravet syndrome, all we really had was the clinical data, which is so unusual in drug development,” he said.
It was the results of a Belgian study that originally encouraged Zogenix to investigate fenfluramine as a commercial therapy. In 2012, researchers Berten Ceulemans, MD, PhD; Lieven Lagae, MD, PhD; and their colleagues demonstrated that individuals with Dravet syndrome experienced marked reductions in seizures in response to fenfluramine, including seizure-free periods while actively on that medication.
“It was really that data,” Farr says, “which sort of piqued our interest, but it didn’t really come into full focus for us until about a year or so later, when we decided that this is something we needed to pursue, and I actually went across to Belgium with a few of my colleagues to meet Berten and Lieven and had the pleasure to sit with them and talk with them about their results.”
Despite promising data from these early experiments and from later clinical trials, fenfluramine experienced some delays on the road to approval. The FDA initially denied the new drug application for Fintepla, citing a failure to include non-clinical studies and an issue with one of the clinical data sets submitted in the application.
Zogenix discussed these issues with the FDA and resubmitted the application in late 2019. The FDA then extended its review period for the medication early this year. Despite these setbacks, Farr says he remained confident that Fintepla would eventually win approval.
“When we were able to read out our first Phase 3 result, which was in the 2017 timeframe, [it] really showed and supported the dramatic efficacy of now Fintepla in patients with Dravet syndrome. I think that, for us, was a defining moment, that we had something that should be able to get approved in the United States.”
Fintepla’s average cost is estimated at $96,000 per year, according to Farr, who says that the price is “really based upon the fact that this has shown absolutely profound efficacy in Dravet syndrome.”
In addition to weighing the clinical profile and benefit to patients in regards to cost, he also points out that Zogenix has worked with payers to find a price they will support.
“We are putting in place systems and support services that will ensure that the price to patients is very small, if not a zero copay, so that the price … is to the payers and not to the patient.”
The ultimate price per individual treatment will vary somewhat, as the medication is dosed according to patient weight.
Patient assistance programs
Fintepla, which is classified as a Schedule 4 controlled substance, does carry the risk of developing valvular heart disease and pulmonary arterial hypertension, which prompted Zogenix to establish something called the Risk Evaluation and Mitigation Strategy, or REMS, Program. This program is meant to ensure that only specially certified providers can prescribe and distribute it, and that patients receive proper cardiac monitoring.
Despite this risk, Farr stresses that there have been no instances of such complications during testing.
“The most important element to ensure safe use is the continuation to conduct [echocardiograms]. We conducted a very comprehensive cardiac safety monitoring program within all our Phase 3 trials. We’ve conducted upwards of 6,000 echocardiograms on children, so we have probably the largest database on echoes in children anywhere in the world.”
While Farr says there has been no evidence of heart disease in the Phase 3 trial, the association between these conditions and serotonergic medications like Fintepla makes it important to adequately monitor patient echocardiograms via the REMS program once the product is commercially available.
All REMS requirements, such as scheduling echocardiograms, will be coordinated through a program called Zogenix Central, which will serve as a logistical hub, through which patient care and information will be managed.
“It will ensure that the patients and the caregivers are … educated about the safe use of Fintepla. And that same hub will also take care of the reimbursement discussions that will be required for each and every patient, in terms of whether or not their insurance is through commercial payers, or it’s through Medicaid, so all that will be taken care of,” he said.
Through Zogenix Central, certified specialty pharmacies will fill prescriptions and ship the medication directly to a caregiver’s house. This program is designed, Farr says, to make any hurdles related to obtaining Fintepla invisible to patients and caregivers.
Use with other medications
Fintepla can be prescribed alongside other medications with few restrictions, according to Farr, but dose adjustments may be needed if it is taken in combination with other therapies. For example, if Fintepla is prescribed with Diacomit (stiripentol), the latter’s dose may need to be reduced.
“Conversely,” Farr says, “there is no dose reduction if a prescriber or physician would like to try cannabidiol, or CBD, in combination with Fintepla.”
Fintepla’s potential use alongside CBD could be an important consideration, in light of the 2018 FDA approval of Epidiolex, a CBD solution developed by GW Pharmaceuticals for the treatment of seizures in Dravet syndrome. To this end, a Phase 1/2 clinical trial (NCT03467113) is currently evaluating the medication’s safety in combination with a cannabis-based therapy for patients with Dravet or Lennox-Gastaut syndromes.
Furthermore, “fenfluramine doesn’t impact the blood levels of any of the other antiepileptic drugs,” Farr said, which is important to note since Dravet patients tend to be treated with multiple therapies.
As far as any obstacles in making Fintepla available given the current COVID-19 situation, Farr says supply lines for the therapy are not affected, but they are monitoring the situation with hospitals and clinics, and taking steps to make sure that patients and caregivers can gain access to Fintepla.
“We are ensuring that we can make this drug available and physicians know about it, caregivers know about it, through a variety of virtual tools that we put in place, so we are taking advantage of telemedicine and ensuring that physicians … will be able to prescribe this product without there being an in-person visit with the patient,” he said.
Farr added that they have also worked to put into a place a system whereby echocardiograms can be done at local centers closer to where patients live rather than at major hospitals.
“We’ve had a few months to think this through while waiting for the FDA to conclude their review, and we feel that we put in place a number of systems that will enable us to offer this product despite the COVID-19 situation right now,” he said.
Fintepla is also currently under review for approval in the European Union, with a decision anticipated by the end of the year, according to Farr.
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