Roche's Evrysdi Approved in EU as First Oral Therapy for Spinal Muscular Atrophy; Under Regulatory Review in China

March 30, 2021 News /BioValleyBIOON/ -- Roche recently announced that the European Commission (EC) has approved Evrysdi (risdiplam), an oral liquid formulation for the treatment of patients aged ≥2 months with clinicalDiagnosisFor patients with type 1/2/3 SMA or 5q spinal muscular atrophy (SMA) carrying 1–4 SMN2 copies.

SMA is the leading cause of death in infants and young childrenGeneticsAmong the factors, 5q-SMA is the most common type. This disease can lead to muscle weakness and progressive loss of motor function, representing a significant unmet medical need, particularly among adult patients. Roche is collaborating with EU health authorities to enable broad and rapid access to treatment for SMA patients. To date, inClinical Trial, compassionate use, and in the real world, more than 3,000 patients have received treatment with Evrysdi.

In August 2020, Evrysdi received approval from the U.S. FDA for the treatment of spinal muscular atrophy (SMA) in pediatric patients aged 2 months and older, as well as in adult patients. Upon approving Evrysdi,FDARoche was also awarded a Priority Review Voucher (PRV) for rare pediatric diseases.

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 liquid formulation that can be administered orally or via feeding tube at home, once daily. This medication is indicated for the treatment of infants, children, adolescents, and adult patients with all types (Type 1, Type 2, Type 3) of spinal muscular atrophy (SMA). To date, Evrysdi has been approved in 38 countries and marketing applications have been submitted in an additional 33 countries, including China.

Evrysdi is a splicing modifier of survival motor neuron 2 (SMN2) mRNA that treats 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 movement. From two pivotalClinical TrialsData confirm that Evrysdi is effective in infants aged 2 months and older, as well as in pediatric and adult patients, achieving clinically meaningful improvements in motor function across different ages and disease severities (including types 1, 2, and 3) of spinal muscular atrophy (SMA). Infants treated with Evrysdi were able to sit unsupported for at least 5 seconds, a key motor milestone unattainable in the natural course of SMA. Furthermore, compared with the natural history of the disease, Evrysdi also improved survival without permanent ventilation.

SMA Boy (Image source: drpgx.com)

In the European Union, the approval of Evrysdi was based on data from two clinical studies that represent a broad real-world SMA population: the FIREFISH study, conducted in symptomatic infants with Type 1 SMA aged 2 to 7 months, and the SUNFISH study, conducted in symptomatic pediatric and adult patients with Type 2 and Type 3 SMA 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, the median age at enrollment for infants was 5.3 months: (1) As measured by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), 29% (12/41) of infants treated with Evrysdi for 12 months were able to sit independently for at least 5 seconds, a key motor milestone never achieved in the natural history of type 1 SMA. (2) 93% of infants survived, and 85% remained event-free (survival without permanent ventilation). (3) According to the Hammersmith Infant Neurological Examination (HINE), 5% (2/41) of infants were able to stand with support, and 83% were able to feed orally. The CHOP-INTEND score increased by at least 4 points in 90% (37/41) of infants, with 56% (23/41) achieving a score above 40, and the median increase was 20 points.

— In the SUNFISH study, the median age of enrolled patients was 9 years: (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 with 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), children and adults treated with Evrysdi also experienced significant improvements in upper limb function (a key secondary endpoint) at 12 months of treatment compared with the placebo group (1.61 points [95% CI: 1.00, 2.22] vs. 0.02 points [95% CI: -0.83, 0.87]; mean difference: 1.59 points, p=0.0469).

In the two studies, Evrysdi demonstrated favorable efficacy and safety. The most commonAdverse ReactionsThe adverse events included upper respiratory tract infection, pneumonia, nasopharyngitis, fever, constipation, rhinitis, diarrhea, headache, cough, and vomiting. Neither of the two studies identified any treatment-related safety findings leading to study withdrawal.

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

Evrysdi is an oral liquid 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 patients ranging from infants aged 2 months to adults aged 60 years, with varying symptoms and motor functions, such as scoliosis or joint contractures, and also includes patients who have previously received other SMA therapies. The drug’sClinical TrialsThe 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 a prevalence of 1 in 6,000 to 1 in 10,000 among 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.

In 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 for the treatment of SMA in the Chinese market. 5q-SMA is the most common type of SMA, accounting for approximately 95% of all SMA cases. This type of SMA is caused by mutations in the SMN1 (survival motor neuron 1) gene on chromosome 5, hence the name 5q-SMA. (Bioon.com)

Original Source: Roche’s Evrysdiapproved by European Commission as first and only at home treatment for spinal muscular atrophy