Roche's Evrysdi Becomes First Oral Therapy for Spinal Muscular Atrophy Filed in Japan, Under Regulatory Review in China

October 16, 2020 News /BioValleyBIOON/ -- Chugai Pharmaceutical, a Japanese pharmaceutical company controlled by Roche, recently announced that it has submitted a New Drug Application (NDA) for risdiplam to the Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment of spinal muscular atrophy (SMA). In Japan, the MHLW granted orphan drug designation to risdiplam for the treatment of SMA in March 2019, and the NDA for this drug will be subject to priority review.

This August, risdiplam (brand name: Evrysdi) received U.S.FDAApproved for the treatment of patients with spinal muscular atrophy (SMA) aged 2 months and older, including adults. Evrysdi is a liquid formulation that can be administered orally or via feeding tube at home once daily. It is indicated for the treatment of infants, children, adolescents, and adults with all types of SMA (Type 1, Type 2, and Type 3).

It is worth mentioning that,Evrysdi is the first oral therapy for SMA and the first SMA therapy that can be administered at home.Evrysdi is a survival motor neuron 2 (SMN2) mRNA splicing modifier that treats spinal muscular atrophy (SMA) by increasing the production of survival motor neuron (SMN) protein. SMN protein is distributed throughout the body and is essential for maintaining healthy motor neurons and motor function.

In 2 itemsClinical TrialIn China, Evrysdi demonstrated clinically meaningful improvements in motor function across SMA patients of varying ages and disease severities (including Types 1, 2, and 3). Infants treated with Evrysdi were able to sit independently for at least 5 seconds, a key motor milestone commonly compromised in the natural course of SMA. Furthermore, compared with natural history data, Evrysdi improved survival rates without permanent ventilation at 12 and 23 months.

At the time of Evrysdi's approval,FDARoche’s Genentech was also awarded a Priority Review Voucher (PRV) for rare pediatric diseases. As part of its ongoing commitment to patients with spinal muscular atrophy (SMA), Genentech has also submitted marketing authorization applications in Brazil, Chile, Indonesia, Russia, South Korea, and China (Mainland and Taiwan).

Dr. Osamu Okuda, President and Chief Operating Officer of Chugai Pharmaceutical, stated, “As the first oral medication for the treatment of SMA, risdiplam demonstrated clinically meaningful therapeutic effects in infant and adult patients across two clinical studies involving Type 1, Type 2, and Type 3 SMA. I am confident that risdiplam will make a significant contribution to SMA treatment, given its proven efficacy. We are committed to securing regulatory approval for risdiplam so that this new oral therapy can be made available to SMA patients in Japan as soon as possible.””

SMA Boy (Image source: drpgx.com)

Risdiplam Receives U.S.FDAThe approvals and the New Drug Application (NDA) submitted in Japan are both based on data from two clinical studies, which represent a broad real-world population of patients with spinal muscular atrophy (SMA): the FIREFISH study conducted in symptomatic infants aged 2 to 7 months, and the SUNFISH study conducted in children and adults aged 2 to 25 years. Notably, the SUNFISH study is the first and only placebo-controlled study to include adult patients with Type 2 and Type 3 SMA.

——In the FIREFISH study:(1) As measured by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), 41% (7/17) of infants receiving the therapeutic dose were able to sit independently for at least 5 seconds. (2) At 12 months of treatment, 90% (19/21) of infants survived without permanent ventilation and reached an age of 15 months or older. (3) After at least 23 months of treatment, 81% (17/21) of infants survived without permanent ventilation and reached an age of 28 months or older (median 32 months; range 28–45 months). In contrast, in the natural history of untreated infantile SMA, infants are unable to sit independently, and only 25% are expected to survive beyond 14 months of age without permanent ventilation.

——In the SUNFISH study:(1) As measured by the total score of the Motor Function Measure 32 (MFM-32), children and adults treated with Evrysdi demonstrated clinically meaningful and statistically significant improvements in motor function at 12 months compared to the placebo group (1.36 points [95% CI: 0.61, 2.11] vs. -0.19 points [95% CI: -1.22, 0.84]; mean difference: 1.55 points, p=0.0156). (2) As measured by the Revised Upper Limb Module (RULM), upper limb motor function improved compared to baseline (difference: 1.59 points, p=0.0028); this was a secondary independent motor function endpoint in the study.

In two studies, Evrysdi demonstrated favorable efficacy and safety. The most commonAdverse ReactionsFever, diarrhea, and rash. In infantile-onset SMA, the most common adverse events were similar, with the addition of upper respiratory tract infections, pneumonia, constipation, and vomiting. Neither study identified any treatment-related safety findings that led to study discontinuation.

Chemical Structure of Risdiplam (Image Source: medchemexpress.cn)

Evrysdi is an oral liquid formulation whose active pharmaceutical ingredient, risdiplam, is a splicing modifier of the survival motor neuron 2 (SMN2) gene, designed to continuously increase and maintain SMN protein levels in the central nervous system and peripheral tissues. Growing clinical evidence demonstrates that spinal muscular atrophy (SMA) is a multisystem disease, and the loss of SMN protein may affect many tissues and cells beyond the central nervous system. Following oral administration, risdiplam exhibits systemic distribution, sustainably increasing SMN protein levels in both the central nervous system and peripheral tissues, and has been shown to improve motor function in patients with Type 1, Type 2, and Type 3 SMA.

As part of the collaboration with the SMA Foundation and PTC Therapeutics, Genentech led the clinical development of Evrysdi. As part of a large-scale, extensive, and robust clinical trial program in the field of SMA, Evrysdi is being studied in more than 450 individuals. The program includes participants ranging from infants aged 2 months to adults aged 60 years, with varying symptoms and motor function impairments, such as scoliosis or joint contractures, and also includes patients who have previously received other SMA therapies. The drug’sClinical TrialThe population is intended to represent a broad, real-world SMA disease population, with the aim of ensuring that all eligible patients have access to treatment.

Currently, Roche is conducting four global, multicenter clinical trials (SUNFISH [NCT02908685], FIREFISH [NCT02913482], JEWELFISH [NCT03032172], and RAINBOWFISH [NCT03779334]) to evaluate the efficacy and safety of Evrysdi in treating all types (Type 1, Type 2, and Type 3) of spinal muscular atrophy (SMA), as well as presymptomatic SMA in neonates.

Spinal Muscular Atrophy (SMA) is a motor neuron disease that causes muscle weakness and atrophy. It is an autosomal recessive genetic disorder caused by gene defects, affecting muscles throughout the patient's body. Patients primarily present with generalized muscle atrophy and weakness, progressively losing various motor functions, including breathing and swallowing. SMA is the leading cause of death in infants under the age of two.HereditySMA Killer: This disease is a relatively common "rare disease," with an incidence rate of 1:6,000 to 1:10,000 in newborns. According to relevant reports, there are currently approximately 30,000 to 50,000 SMA patients in China.

In December 2016, Spinraza (nusinersen), a drug developed by Biogen and its partner Ionis, was approved, becoming the first therapy worldwide for spinal muscular atrophy (SMA). This medication is an antisense oligonucleotide (ASO) administered via intrathecal injection, delivering the drug directly into the cerebrospinal fluid (CSF) surrounding the spinal cord. It modulates the splicing of SMN2 pre-messenger RNA (pre-mRNA), thereby increasing the production of full-length functional SMN protein. In patients with SMA, insufficient levels of SMN protein lead to the degeneration of motor neuron function in the spinal cord. Clinical studies have demonstrated that treatment with Spinraza significantly improves motor function in patients with SMA.

May 2019, fromNovartisThe gene therapy Zolgensma (onasemnogene abeparvovec) was approved, becoming the world’s first gene therapy for the treatment of spinal muscular atrophy (SMA). Administered as a single, one-time intravenous infusion, the drug enables sustained expression of the SMN protein to halt disease progression, addresses the root cause of SMA, and holds promise for long-term improvement in patients’ quality of life.

In the Chinese market, Spinraza was approved in late February 2019 for the treatment of patients with 5q spinal muscular atrophy (5q-SMA). This approval made Spinraza the first drug available in China for the treatment of SMA. 5q-SMA is the most common form of SMA, accounting for approximately 95% of all SMA cases. It is caused by mutations in the SMN1 (survival motor neuron 1) gene on chromosome 5, hence the name 5q-SMA. (Bioon.com)

Original Source: Chugai Files a New Drugapplication for Risdiplam as the First Oral Drug for Spinal Muscular Atrophy in Japan