In an interview with PharmaShots, Bradley Galer, M.D., Chief Medical Officer at Zogenix shed light on data supporting the regulatory application and what the EU approval of Fintepla will mean in terms of reducing the high physical, emotional, and financial burden associated with the disease.

Shots:

• Fintepla was approved by the EC in Dec'2020 as a new add-on therapy to other anti-epileptic medicines for patients with Dravet syndrome aged =2yrs. The approval is based on three P-III clinical studies and a 3-year OLE study
• Fintepla when added to the existing treatment regimens provided a highly statistically significant and clinically meaningful reduction in convulsive seizure frequency
• The company plan to follow the launch in Germany with launches in other major European countries as we receive national reimbursement approvals during 2021 and beyond

Tuba: Can you tell us more about Dravet Syndrome and the impact it has on patients and caregivers?

Bradley: Dravet syndrome is a rare, devastating, childhood-onset, and life-long form of epilepsy that generally begins during the first year of life and is marked by severe treatment-resistant seizures, frequent medical emergencies, and hospitalizations. In addition to refractory seizures of many different types, Dravet syndrome patients also suffer significant developmental, motor, and behavioral impairments, require around-the-clock care and face an increased risk of sudden unexpected death in epilepsy (known as SUDEP).

Dravet syndrome is highly resistant to anticonvulsant medications. Despite treatment with one or more of the currently available medications, most patients seizures are not adequately controlled. Furthermore, some of the most commonly used antiseizure medications (such as phenytoin and carbamazepine) are contraindicated, as they can in fact make the seizures worse.

The impact extends to caregivers and families, who play a huge role in the health and well-being of patients with Dravet syndrome. Due to the need for around-the-clock care, the need to keep the affected family member primarily at home to avoid seizure triggers, and constant anxiety about seizures and SUDEP, the quality of life for caregivers and families is severely impacted. This can include physical, psychosocial, emotional, and financial burdens.

Tuba: What treatment options are available to patients in Europe with Dravet syndrome?

Bradley: In Europe, existing medications for the treatment of seizures associated with Dravet syndrome included stiripentol approved in conjunction with clobazam and valproate and cannabidiol approved in conjunction with clobazam. Despite polypharmacy with these therapies, seizures often remain poorly controlled in most patients with Dravet syndrome, driving the need for effective new treatment options.

FINTEPLA was approved by the European Commission in December 2020 as a new add-on therapy to other anti-epileptic medicines for patients with Dravet syndrome aged two years and older. Across three Phase 3 clinical studies and a 3-year open-label extension study, this important novel treatment option has been shown to provide significant, clinically meaningful, and lasting convulsive seizure reduction. In addition, FINTEPLA has been demonstrated to be safe and generally well tolerated. We hope that FINTEPLA will improve the quality of life for more Dravet patients by significantly reducing seizures and, potentially, improving their associated comorbidities  and also for families by providing some respite and a better sense of connection and 'normalcy' in their day-to-day lives.

Tuba: Can we discuss the mechanism of action for FINTEPLA/fenfluramine and how it works in Dravet syndrome? 

Bradley: While the exact mechanism of action is not fully understood in Dravet syndrome, fenfluramine has a different mechanism of action to any other anti-epileptic drugs. It is a selective serotonin (5-HT)-releasing agent and thereby stimulates multiple 5-HT receptor subtypes through the release of serotonin. In addition, the medication has been shown to interact with the Sigma-1 receptor, which also has been shown to be involved in the generation of seizures. It may also act to reduce seizures through other mechanisms not yet identified.

Tuba: What Phase III clinical studies led to the approval of FINTEPLA in Europe?

Bradley: As with the US FDA approval, the European Commission's approval of FINTEPLA was based on positive safety and efficacy results from two randomized, international, multi-center, placebo-controlled Phase 3 trials (Study 1 and Study 2), as well as data from an interim analysis of a long-term, open-label extension study in 330 Dravet syndrome patients treated up to 3 years. The studies included patients taking one or more antiepileptic medications, including stiripentol, for whom those medications were not providing adequate seizure control. FINTEPLA added to their existing treatment regimens provided a highly statistically significant and clinically meaningful reduction in convulsive seizure frequency.

Zogenix also recently announced positive results from a third Phase 3 study, which corroborated the highly statistically significant and clinically meaningful convulsive seizure reductions seen in the first two multinational Phase 3 studies that were used as the basis for the European Commission's approval.

Tuba: When can we expect FINTEPLA to be launched in Europe and which patients will be eligible for the treatment?

Bradley: The approval by the European Commission authorizes Zogenix to market FINTEPLA as an add-on therapy for Dravet syndrome patients aged two and older in EU member countries as well as in the UK, Norway, Iceland, and Lichtenstein. Our first market launch is planned for Germany in Q1 2021, with other European countries to follow based on price and reimbursement being agreed according to each country's national regulations. Generally, each country takes about 10-14 months to review the dossier that Zogenix submits, and so we look forward to sharing our progress on country-level access in Europe through 2021 and the coming years.

In addition, as we gain country reimbursements, we will begin transitioning Dravet syndrome patients in Europe currently being treated with FINTEPLA under our clinical trials and expanded access programs to commercial product.

Tuba: Where next do you plan to launch FINTEPLA in Europe following the launch in Germany?

Bradley: We plan to follow the launch in Germany with launches in other major European countries as we receive national reimbursement approvals during 2021 and beyond.

Tuba: Are you planning to explore approval of FINTEPLA in other geographies?

Bradley: We have already received approval in the EU and US, and plan to file for approval in Japan. In addition, as we consider possible additional country-level regulatory submissions, we are working on a managed access program to address the urgent needs faced by Dravet syndrome patients in other countries.

Tuba: What types of materials will Zogenix provide to support treatment with FINTEPLA in Europe?

Bradley: Zogenix is committed to supporting patients or caregivers of patients who have been prescribed FINTEPLA with ongoing education and guidance from initiation of treatment through long-term therapy. A range of materials will be available to enhance understanding of Dravet syndrome and its treatment, including a dedicated European website (www.fintepla.eu), patient leaflets, and information for family members.
During COVID-19, Zogenix has adapted many of our normal physical activities and will be providing digital FINTEPLA brochures and planned webinars as we launch in specific countries, engaging in scientific exchanges at virtual medical meetings, holding one-on-one Zoom reviews of clinical study data with physicians through our Medical Affairs team, and sponsoring online medical education programs. Information specifically for physicians will also be featured on the European website for FINTEPLA (www.fintepla.eu), including patient safety guidance, which is our first and foremost top priority. In Europe, FINTEPLA will be made available under a controlled access program created to prevent off-label use for weight management. It will also confirm that prescribing physicians have been informed of the need for periodic cardiac monitoring in patients taking FINTEPLA.

Tuba: Is Zogenix planning to assess FINTEPLA in other indications beyond Dravet syndrome?

Bradley: Yes, Zogenix has investigated FINTEPLA for the treatment of seizures associated with another rare and severe childhood onset epilepsy called Lennox-Gastaut syndrome (LGS) and plans to initiate studies in other rare epilepsies in the year ahead, if COVID-19 restrictions allow.

In February 2020 we announced positive top-line results from the global Phase 3 clinical trial (Study 1601) in LGS, and in December shared a full data analysis at the American Epilepsy Society meeting (AES 2020), which can be viewed here. As with our studies in Dravet syndrome, this study showed that FINTEPLA was safe and generally well-tolerated  there were no cases of valvular heart disease or pulmonary arterial hypertension. The efficacy analysis of the Phase 3 study in LGS confirmed that FINTEPLA at the dose of 0.7 mg/kg/day demonstrated a statistically significant and clinically meaningful improvement in the frequency of seizures associated with a drop. It also showed that FINTEPLA was highly effective in reducing generalized tonic-clonic (or convulsive) seizures by 46% and 58% in the 0.7 and 0.2 mg/kg/day dose groups, respectively, compared to worsening of 3.7% in the placebo group. These seizures are a primary risk factor for SUDEP, being associated with a 10-fold increased risk, and are also a major cause of injuries and hospitalizations.

About Author:

Bradley S. Galer has served as Executive Vice President and CMO for Zogenix since Dec'2013. Dr. Galer received his medical doctorate and a neurology residency from Albert Einstein in New York, along with two Pain Fellowships at Memorial Sloane-Kettering in New York and University of California San Francisco.

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