Latest Japan Approvals Include Evrysdi For SMA
Plus Global First For Imeglimin
Executive Summary
Japan's latest batch of product approvals includes the country's second therapy for SMA and the first nod globally for a novel antidiabetic.
Chugai Pharmaceutical Co., Ltd.’s Evrysdi (risdiplam) is among the latest batch of new drug approvals in Japan, providing another option for spinal muscular atrophy (SMA) patients in the country. The survival motor neuron 2 (SMN2)-directed splicing modifier was granted orphan designation in March 2019 and filed for approval last October.
Attention is now turning to how the therapy will be priced under the national health insurance system, which will enable national launch, given the precedent set by the only other SMA drug approved in Japan, Novartis AG’s intravenously administered gene therapy Zolgensma (onasemnogene abeparvovec).
This was launched in May 2020 for use in infants under two years of age with an NHI price of JPY167m ($1.5m) for its one-time administration, becoming the most expensive therapy ever to be granted reimbursement in Japan.
Evrysdi is similarly designed to increase and sustain the production of the SMN protein, a deficiency of which characterizes the genetic neuromuscular disease. SMA causes muscle atrophy and weakness due to motor neuron degeneration, caused by mutations in chromosome 5q of the SMN2 gene and SMN1 dysfunction that lead to the deficiency of SMN.
Unlike Zolgensma, Evrysdi is indicated in use for all SMA patients from infants to adults and the once-daily 60mg oral dry syrup formulation allows at-home dosing. SMS is designated an “intractable disease” in Japan, where it affects around 850 people in total, and the pediatric population aged 0-9 years comprises around 30 people.
At the time of launch, Zolgensma was expected to be administered to only 15-20 patients annually, given its age range restrictions.
Evrysdi was approved in the US in August 2020 (marketed by Genentech, Inc.) and in Europe in March 2021 for the treatment of patients aged two months and older. Chugai said the Japanese approval was based on results from two pivotal studies, FIREFISH in infants with symptomatic SMA Type 1 and SUNFISH in children and young adults with SMA Type 2 or 3.
Assuming a successful reimbursement process, the first commercial sales in Japan will trigger a $10m milestone payment from Chugai’s parent Roche Holding AG to original co-developer PTC Therapeutics, Inc.
Aimovig and Ajovy For Migraine
Also approved by the Ministry of Health, Labour and Welfare were two new drugs for migraine.
Amgen, Inc.’s Aimovig (erenumab) was cleared for the suppression of onset of migraine attacks in adults. It becomes the first calcitonin gene-related peptide receptor (CGRP-R) blocker to be approved in the country and also marks the first independent submission and approval for Amgen’s own wholly owned affiliate in Japan, formed in April 2020.
The nod was based on two placebo-controlled Japanese studies: a Phase II trial in adults with episodic migraine and a 261-patient Phase III study with a 70mg dose every four weeks in adults with both episodic and chronic migraine. In both, Aimovig significantly reduced monthly migraine days from baseline over months 4, 5 and 6 of the double-blind treatment period.
Amgen said that approximately 8.4 million people in Japan suffer from migraine, with more than 70% having never visited a hospital for the condition and about 50% trying to use over-the-counter medicines. In Japan, the indication is for subcutaneous dosing in a clinical setting every four weeks, consistently from first dose to continuous administration, and likewise after resuming from interruption.
Aimovig is already approved in 71 countries or territories, including the US and EU.
Meanwhile, Teva Pharmaceutical Industries Ltd.’s long-acting anti-CGRP drug Ajovy (fremanezumab) has been approved for the preventive treatment of migraine in adults through local licensee Otsuka Pharmaceutical Co. Ltd. under a deal signed in May 2017.
The regulatory decision was again supported by two local pivotal studies in patients with episodic and chronic migraine, both of which reached clinical and statistical significance versus placebo.
Teva cited data showing the annual prevalence of migraine in Japan is 8.4% of adults and highlighted the flexible dosing options for Ajovy, which is subcutaneously injected in either quarterly (3 x 225mg) or monthly (1 x 225mg) prefilled syringe or autoinjector dosing options (no starting dose required). These can be given in-office by a healthcare professional or at home by a patient or caregiver.
Older prescription options for migraine in Japan include GSK’s 5-HT agonist Imigran (sumatriptan).
Global-First Approval For Twymeeg
Sumitomo Dainippon Pharma Co., Ltd.’s (SDP) Twymeeg (imeglimin; licensed from Poxel SA) has been given marketing authorization for type 2 diabetes, marking the first approval anywhere in the world for the first-in-class tetrahydrotriazine-containing, oxidative phosphorylation blocking molecule. (Also see "Poxel/Sumitomo's Novel Diabetes Therapy Imeglimin Nears Japan Market" - Scrip, 25 Mar, 2021.)
The Japanese firm said it sees potential for use both as a monotherapy and in combination with other existing therapies; SDP already markets several diabetes drugs including the DPP-4 inhibitor Equa (vildagliptin; with Novartis) and the GLP-1 agonist Trulicity (dulaglutide; with Eli Lilly and Company).
Imeglimin has both a pancreatic action, which promotes glucose concentration-dependent insulin secretion, and an extra-pancreatic action that improves glucose metabolism in the liver and skeletal muscle through mitochondrial action. This has the potential to prevent endothelial and diastolic dysfunction, which may provide micro- and macrovascular protection, and also for protective effects on beta-cell survival and function.
The Japanese approval was supported by multiple studies including the three-trial Phase III TIMES program in over 1,100 patients conducted by both companies in Japan. This investigated both monotherapy and combination therapy including with a DPP-4 inhibitor, SGLT2 inhibitor, metformin, sulphonylurea, glinide, alpha-glucosidase inhibitor, thiazolidinedione, GLP1 receptor agonist and insulin.
Under Poxel and SDP’s October 2017 partnership for imeglimin, SDP has development and commercialization rights in Japan, China, South Korea, Taiwan and nine other Southeast Asian countries. The new approval triggers a JPY1.75bn ($15.9m) milestone payment to French firm Poxel, which is also entitled to escalating double-digit sales royalties and sales-based payments of up to JPY26.5bn.
In 2018, imeglimin has been licensed to Roivant Sciences for $35m upfront, plus up to $600m in other payments, for the US, Europe and other Asia markets. But in November last year, Roivant’s Metavant subsidiary said it had decided not to move forward with the deal. This January, Poxel then confirmed that the partnership would be terminated, with Metavant to return all rights.
Like Evrysdi, the other newly approved drugs are now awaiting the granting of a reimbursement price before they can be launched under the NHI system.