According to the U.S. Epilepsy Foundation, one in 26 people in the country will develop epilepsy at some point in their lives and the condition is the fourth most common neurological disease that affects people of all ages. That is why the current anti-epilepsy drug therapy market is large and estimated to be worth more than $8.5 billion currently, rising to in excess of $9.5 billion in five years. While there are many drugs available for a physician to use in order to reduce the incidence of seizures associated with the disease, a significant number of patients don't respond to their prescribed drugs, creating a critical need for the development of new and innovative treatments.
Fortunately, new drugs are reaching the market, the latest of which is Brussels-based UCB SA's Nayzilam (midazolam) nasal spray, a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern in those with epilepsy, 12 and older. In May, the FDA gave the green light to Nayzilam, the first new medication approved to treat seizure clusters in more than 20 years in the U.S.
Last year, the FDA approved GW Pharma plc's liquid Epidiolex, the first pharmaceutical formulation of purified, plant-based cannabidiol (CBD) to reach the market, in Dravet syndrome (DS), one of the most severe epileptic encephalopathies, and Lennox-Gastaut syndrome (LGS). (See BioWorld, June 26, 2018.)
That drug has rapidly taken off, with the company reporting more than 12,000 patients receiving Epidiolex prescriptions since its launch and generating $68.4 million in revenues during its second full quarter on the market, a total that surpassed Wall Street consensus. According to a Cowen and Co. report, "Initial demand and prescribing trends suggest Epidiolex will increasingly penetrate the refractory epilepsy population in the months ahead, albeit probably at a slower rate than during H1."
New approvals could also be on the horizon. Emeryville, Calif.-based Zogenix Inc. said last week it has resubmitted its new drug application to the FDA for Fintepla (ZX-008, fenfluramine hydrochloride) for the treatment of seizures associated with DS.
The application is based on data from two pivotal phase III trials in DS and an interim analysis from an ongoing open-label extension study, which included 232 patients treated for up to 24 months. The company is also investigating the compound in LGS, another rare childhood-onset epilepsy, for which a phase III trial is ongoing and top-line data are anticipated in the first quarter of next year.
The company's NDA follows a refusal to file (RTF) letter in April from the agency in response to its first submission. Critically, the resubmission need not include new chronic toxicity studies requested in the RTF, leading analysts to project that a 2020 launch of Fintepla could be possible.
"We continue to believe that Fintepla has best-in-class efficacy in Dravet syndrome, and that it could potentially have strong efficacy in the Lennox-Gastaut syndrome phase III study, which is on track for a readout in 1Q20," noted SVB Leerink analysts.
SK Life Science Inc.'s cenobamate is another epilepsy treatment of partial or focal seizures that could receive FDA approval later this year. It has a Nov. 21 PDUFA date and, if approved, would be initially marketed as an adjunctive therapy. Cenobamate's mechanism of action is not fully understood, but it is believed to work through two separate mechanisms: enhancing inhibitory currents through positive modulation of GABA A receptors and decreasing excitatory currents by inhibiting the persistent sodium current. (See BioWorld, Feb. 13, 2019.)
In February, Arvelle Therapeutics GmbH entered an exclusive licensing agreement with SK Life Sciences to develop and commercialize cenobamate in Europe in return for an up-front payment of $100 million and $430 million more for downstream regulatory and commercial milestones. The company, which was formed out of Axovant Sciences Ltd., raised €159 million (US$180 million) in a series A round to help support the funding of its tie-up with SK Life Sciences.
Last Thursday, Radnor, Pa.-based Marinus Pharmaceuticals Inc. announced that its drug candidate, ganaxolone, a GABA A receptor agonist, met the primary endpoint in a phase II study evaluating intravenous (I.V.) administration in patients with refractory status epilepticus (RSE), a rare epileptic seizure of prolonged duration, lasting more than five minutes for convulsive seizures or 30 minutes for non-convulsive. The condition is believed to affect approximately 75,000 patients in the U.S. each year. None of the 17 patients in the study progressed to I.V. anesthetics within 24 hours of treatment initiation, the primary endpoint. Ganaxolone had an acceptable safety and tolerability profile for the RSE patient population in all dose groups. The company's shares (NASDAQ:MRNS) jumped 23% on the news to close at $1.69.
H.C. Wainwright & Co. analyst Douglas Tsao noted that "Marinus reported impressive phase II results in RSE, which we believe should provide a much-needed boost to investor sentiment regarding ganaxolone's clinical utility."
The company said it is preparing for an end-of-phase II meeting with the FDA to discuss the next steps toward a potential phase III pivotal study and, in parallel, is evaluating a new ready-to-use dose formulation that does not require compounding, mixing or diluting.
In its second-quarter financials, the company reported that enrollment is progressing in the phase III studies evaluating oral ganaxolone in children with CDKL5 deficiency disorder and PCDH19-related epilepsy, two debilitating conditions with no currently approved treatments.
Also, this month several companies have reported on their ongoing clinical studies. Devon, Pa-based Zynerba Pharmaceuticals Inc., which is developing pharmaceutically produced transdermal cannabinoid therapies for rare and near-rare neuropsychiatric disorders, reported positive top-line results from the open-label phase II BELIEVE 1 trial assessing the safety and efficacy of Zygel in developmental and epileptic encephalopathies, a heterogeneous group of rare pediatric epilepsy syndromes, including DS and LGS. Patients who experienced focal impaired-awareness and convulsive seizures achieved 44% to 58% monthly median reductions in seizures compared to baseline from month two to month six of treatment with Zygel.
Ovid Therapeutics Inc. reported positive initial data from the ENDYMION trial, a phase II open-label extension study of soticlestat (OV-935/TAK-935) in patients with rare developmental and epileptic encephalopathies. Soticlestat is a highly selective first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase being investigated as a novel approach to treating adults and children with rare epilepsies in collaboration with Takeda Pharmaceutical Co. Ltd.
At 12 weeks, safety and tolerability observations with soticlestat in the study were consistent with the completed phase Ib/IIa trial. Median seizure frequency reductions were 84% following 25 to 36 weeks (n=6) and 90% following 37 to 48 weeks (n=4) of treatment. In addition, the longest seizure-free durations experienced by two different patients were 264 consecutive days and 150 consecutive days, respectively.
Last week, Knopp Biosciences LLC, of Pittsburgh, said it received a grant award for year four from the NIH's Blueprint Neurotherapeutics Network (BPN) to advance its lead Kv7 potassium channel activator, KB-3061, in rare neonatal epilepsy. Following the achievement of a milestone, the company was awarded an additional $679,492 in direct support. The grant has a total potential direct award value of $2.4 million over four years. Beyond the direct award, the NIH BPN may use BPN-sponsored contract research organizations to underwrite the cost of toxicology and safety pharmacology studies and drug manufacturing required to submit an investigational new drug application to the FDA for KB-3061. It is advancing the development of KB-3061 (BPN-25203) as a potential precision medicine treatment for KCNQ2 epileptic encephalopathy, a genetically defined disease associated with seizures beginning in the first days of life and with profound developmental delay. The disease is caused by dominant-negative mutations in the KCNQ2 gene, which produces a potassium channel, Kv7.2, critical to early brain development.