Roche's Evrysdi Demonstrates Sustained Improvement in Motor Function and Survival Over Two Years in Type 1 Spinal Muscular Atrophy Infants; Under Regulatory Review in China

April 15, 2021 /Bio ValleyBIOON/ -- Roche recently announced new two-year data from Part 2 of the global Phase 2/3 FIREFISH study evaluating the oral medication Evrysdi (risdiplam) for the treatment of spinal muscular atrophy (SMA). The study was conducted in symptomatic infants with Type 1 SMA aged 1 to 7 months at enrollment. The data showed that Evrysdi continued to improve motor function, including the ability to sit without support, between 12 and 24 months. The study also demonstrated that Evrysdi continued to enhance survival rates, improve oral feeding abilities, and reduce the need for permanent ventilation. Exploratory data indicated that, compared with the natural history of Type 1 SMA, Evrysdi continued to improve swallowing function and reduce hospitalization rates. The safety profile of Evrysdi was consistent with its established safety profile. These long-term data build upon the one-year key findings from Part 2 of the FIREFISH study and will be presented at the 73rd Annual Meeting of the American Academy of Neurology (AAN), held from April 17 to 22, 2021.

SMA is the leading cause of death in infants and young childrenHeredityAmong 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. Evrysdi was approved in the United States in August 2020.FDAApproved for the treatment of pediatric and adult patients with SMA aged ≥2 months. In March 2021, Evrysdi received EU approval for the treatment of patients aged ≥2 months with clinicalDiagnosisFor patients with Type 1, Type 2, or Type 3 SMA, or with 5q SMA carrying 1–4 copies of the SMN2 gene. To date, Evrysdi has been approved in 39 countries and marketing applications have been submitted in an additional 33 countries, including China.

Evrysdi is the first oral therapy for SMA and the first SMA therapy that can be administered at home.This medication is a liquid formulation that can be administered orally or via feeding tube at home, once daily. It 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).

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. Data from two pivotalClinical TrialData confirm that Evrysdi is effective in infants aged 2 months and older, as well as in children and adults, achieving clinically meaningful improvements in motor function across patients with spinal muscular atrophy (SMA) of varying ages and disease severities (including types 1, 2, and 3). 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.

Dr. Basil Darras, FIREFISH study investigator, Professor of Neurology at Harvard Medical School, and Director of the SMA Program at Boston Children’s Hospital, stated, “The natural history of type 1 SMA tells us that, tragically, without treatment, children are never able to sit independently and typically do not survive beyond two years of age. Encouragingly, infants continued to show improvement after 12 months of Evrysdi treatment, and among infants treated with Evrysdi for two years, twice as many were able to sit independently for at least five seconds. Infants treated with Evrysdi also demonstrated a range of improvements in motor function, a reduction in severe events typically caused by disease progression—such as the need for permanent ventilation or hospitalization—and improved survival rates.”

SMA Boy (Image source: drpgx.com)

The primary endpoint of the FIREFISH study was the percentage of infants able to sit independently for at least 5 seconds at 12 months. Data showed that after 12 months of treatment, infants treated with Evrysdi were able to sit independently for 5–30 seconds. Data at 24 months demonstrated continued improvement compared with month 12: as measured by the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Motor Scale, 61% (25/41) of infants could sit independently for at least 5 seconds at 24 months versus 29% (12/41) at 12 months, and 44% (18/41) could sit independently for at least 30 seconds at 24 months versus 17% (7/41) at 12 months. Importantly, infants treated with Evrysdi maintained the ability to feed orally at 24 months (92%; 35/38). Furthermore, exploratory data indicated similar preservation of swallowing function (95%; 36/38). In the natural course of the disease, infants with type 1 SMA older than 12 months typically require feeding support.

After 24 months of treatment, 93% of infants (38/41) survived. 83% of infants (34/41) survived and were free from permanent ventilation after 24 months, showing improvement compared to the natural course of the disease. No new deaths occurred between 12 and 24 months. In contrast, without treatment, the median age for death or permanent ventilation in infants was 13.5 months. Additionally, fewer hospitalizations were observed during the second year of Evrysdi treatment compared to the natural course of the disease, with 34% of infants (14/41) not requiring hospitalization during the 24-month treatment period. Other study results indicated that Evrysdi continued to improve outcomes based on the Hammersmith Infant Neurological Examination Scale-2 (HINE-2) at both 24 months and 12 months, including the ability to hold their head upright (63% vs. 44%), roll from supine to prone position (44% vs. 10%), stand with support (15% vs. 5%), and walk (4% vs. 2%). The total CHOP-INTEND score also showed continuous improvement, with a higher proportion of patients achieving a score above 40 by month 24 (76%; 31/41) compared to month 12 (56%; 23/41). In the natural course of the disease, children with type 1 SMA rarely achieve a total score of 40.

In the study, the observed adverse events and serious adverse events were consistent with those in previous studies. The most commonAdverse ReactionsUpper respiratory tract infection (54%), pneumonia (46%), fever (44%), constipation (29%), nasopharyngitis (17%), bronchitis (15%), diarrhea (15%), and rhinitis (12%). During the first and second 12-month periods of Part 2 of the FIREFISH study, the incidence of severe pneumonia decreased by approximately threefold. The most common serious adverse events were pneumonia (39%) and respiratory distress (7%). No drug-related adverse events led to withdrawal or discontinuation of treatment.

Dr. Levi Garraway, Chief Medical Officer and Global Head of Product Development at Roche, stated, “These data highlight the real-world impact of this revolutionary medicine on infants with the most severe form of SMA. For example, after 24 months of treatment, all surviving infants were able to swallow, enabling them to feed orally rather than via a feeding tube. These findings enhance our understanding of how this first-in-class therapy extends the lives of infants with Type 1 SMA, offering much-needed hope to their families.”

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

Evrysdi is an oral liquid formulation whose active pharmaceutical ingredient, risdiplam, is a survival motor neuron 2 (SMN2) splicing modifier 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 disorder, and the loss of SMN protein may affect numerous 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, Roche led the clinical development of Evrysdi. Currently, inClinical TrialIn compassionate use and real-world settings, more than 3,000 patients have received Evrysdi treatment.

As part of a large-scale, broad, and robust clinical trial program in the field of SMA, Evrysdi is being studied in more than 450 individuals. The program includes infants as young as 2 months old to adults up to 60 years of age, 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 patient 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 genetic defects, affecting muscles throughout the patient's body. The primary manifestations include generalized muscle wasting and weakness, progressive loss of various motor functions, and even impairment of breathing and swallowing. SMA is the leading cause of death in infants under the age of two.GeneticsSMA Killer: This disease is a relatively common "rare disease," with a prevalence 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 in partnership with 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 SMA patients.

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: Roche’s Evrysdi Continues to Improve Motor Function and Survival in Babies with Type 1 Spinal Muscular Atrophy (SMA)