Roche's Evrysdi Demonstrates Sustained Motor Function Improvement or Stabilization Over Two Years in Patients with Type 2 or Type 3 Spinal Muscular Atrophy

March 16, 2021 News /BioValleyBIOON/ -- Roche recently announced new exploratory 2-year long-term data from Part 2 of the SUNFISH study. SUNFISH is a global, placebo-controlled study evaluating the oral medication Evrysdi (risdiplam) for the treatment of patients aged 2 to 25 years with Type 2 or non-ambulatory Type 3 spinal muscular atrophy (SMA). The study showed thatIn both primary and secondary endpoint assessments, the improvements in motor function observed with Evrysdi treatment at 12 months were either sustained or further improved at 24 months.According to the natural history of the disease, motor function in patients with type 2 and type 3 SMA declines over time in the absence of treatment. These data were presented at the 2021 Muscular Dystrophy Association (MDA) Virtual Clinical & Scientific Conference, held March 15–18.Meetingpublished above.

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 infant, pediatric, adolescent, and adult patients with all types (Type 1, Type 2, Type 3) of spinal muscular atrophy (SMA). In August 2020, Evrysdi was first approved in the United States. To date, the drug has been approved in seven countries (the United States, Chile, Brazil, Ukraine, South Korea, Georgia, and Russia), and marketing applications have been submitted in more than 30 additional countries, including China.

It is worth mentioning that,Evrysdi is the first oral therapy for the treatment of 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 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.

InClinical TrialsIn the study, 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 affected in the natural course of SMA. Furthermore, compared with the natural history of the disease, Evrysdi also improved survival without permanent ventilation.

Eugenio Mercuri, MD, Principal Investigator of the SUNFISH study and from the Department of Pediatric Neurology at the Catholic University of Rome in Italy, stated, “These results build upon the one-year findings from the SUNFISH trial and importantly demonstrate the durability of improved or stabilized motor function after two years of treatment. Furthermore, as no new safety signals were identified, these second-year results may support the favorable benefit-risk profile of Evrysdi over a longer period.”

SMA Boy (Image from: drpgx.com)

In Part 2 of the SUNFISH study, patients aged 2 to 25 years received either Evrysdi (n=120) or placebo followed by Evrysdi (n=60; patients in the placebo group received placebo for 12 months, followed by Evrysdi for 12 months). This study evaluated several exploratory endpoints at 24 months, providing important insights into motor function and its impact on daily living activities.

Investigation results indicate that Evrysdi: (1) maintained improvements in motor function over the 12- to 24-month period, as measured by the Motor Function Measure-32 (MFM-32); (2) demonstrated increased motor function over the 12- to 24-month period, as measured by the Revised Upper Limb Module (RULM) and the Hammersmith Functional Motor Scale Expanded (HFMSE); (3) showed stabilized motor function in patients who initiated Evrysdi treatment after receiving placebo for 12 months, as assessed by MFM-32, RULM, and HFMSE; and (4) exhibited an increase in total scores from baseline in the caregiver-reported SMA Impact Scale (SMAIS) Upper Limb Module, while patient-reported SMAIS scores remained stable over the 12- to 24-month period.

Compared with the first year, both treatment groups exhibited reductions in serious adverse events, high-grade adverse events, and treatment-related adverse events during the second year. During the 12–24-month period, the most commonly observed adverse events in the Evrysdi group and the placebo + Evrysdi group were upper respiratory tract infection (15.8% and 10%, respectively), nasopharyngitis (21.7% and 16.7%, respectively), pyrexia (13.3% and 10%, respectively), headache (10% and 16.7%, respectively), diarrhea (7.5% and 10%, respectively), vomiting (11.7% and 13.3%, respectively), and cough (10% and 8.3%, respectively). The most common serious adverse events were pneumonia (6.7% and 0%, respectively) and influenza (0.8% and 0%, respectively).

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 its collaboration with the SMA Foundation and PTC Therapeutics, Genentech led the clinical development of Evrysdi. As part of a large-scale, comprehensive, 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 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 designed 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 2 years of age.HeredityDisease Killer: This condition is a relatively common “rare disease,” with an incidence 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 treating 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: New 2-Year Data Show Genentech’s Evrysdi (risdiplam) Continues to Demonstrate Improvement or Maintenance of Motor Function in People Aged 2-25 With Type 2 or Type 3 Spinal Muscular Atrophy (SMA)