Spinal Muscular Atrophy (SMA)
Central nervous system
Approved in the US
Evrysdi™ (risdiplam) is the first and only oral medication indicated for the treatment of spinal muscular atrophy (SMA) in patients of two months of age and older.
The drug was developed by Genentech, a member of the Roche Group, in partnership with SMA Foundation and PTC Therapeutics.
Evrysdi (risdiplam) is available as an oral solution with a maximum dose of 5mg administered once daily, directly distributed to patients’ homes in the US by Accredo Health Group, a speciality pharmacy.
The new drug application (NDA) for Evrysdi (risdiplam) was submitted to the US Food and Drug Administration (FDA) in September 2019 and accepted for priority review in November 2019.
The FDA approved Evrysdi (risdiplam) for the treatment of SMA in adults and children aged two months and older in August 2020. Evrysdi was given orphan drug designation in January 2017, while fast track designation was granted by the FDA in April 2017.
European Medicines Agency (EMA) granted PRIME (PRIority MEdicines) and orphan drug designations to risdiplam in December 2018 and February 2019, respectively.
Spinal Muscular Atrophy (SMA) causes and symptoms
Spinal Muscular Atrophy (SMA) is a serious, progressively fatal neuromuscular disorder affecting around one in every 10,000 infants, the main genetic cause of child mortality.
SMA is caused by a survival motor neuron 1 (SMN1) gene mutation, which results in SMN protein deficiency.
The protein is present in the body and is significant to the nerve system, which regulates muscles and movement. Nerve cells can’t function properly without the protein, leading to muscle fatigue.
SMA is classified into four main types 1, 2, 3, and 4 based on the disease’s intensity and the age when symptoms start. The physical strength of patients and their ability to walk, eat, or breathe may be greatly diminished or destroyed, depending on the type of SMA.
Severity of the disease is also associated with the number of copies of the SMN2 gene in each individual.
Risdiplam mechanism of action
Risdiplam is a splicing modifier of motor neuron 2 (SMN2) designed to treat patients with spinal muscular atrophy caused by chromosome 5q mutations leading to SMN protein deficiencies.
The drug demonstrated a significant increase in exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and the production of full-length SMN protein in the brain during in-vitro assays and studies in transgenic animal models of SMA.
In-vitro and in-vivo results suggest that risdiplam can induce alternate splicing of additional genes, including FOXM1 and MADD.
FOXM1 and MADD are believed to be active in the control of cell cycles and apoptosis, respectively, identified as potential contributors to adverse reactions seen in animals.
The safety and effectiveness of risdiplam in children under two months of age are currently unknown.
Clinical trials on Evrysdi
The FDA’s approval of Evrysdi was based on the results from two clinical studies FIREFISH with infantile-onset SMA and SUNFISH with later-onset SMA.
FIREFISH (study one) was an open-label, multi-centre, pivotal, and two-part clinical study that included 21 patients in the first stage and 41 patients in part two. The dose for part two was determined in part one.
SUNFISH (study two) was also a two-part, multicentre trial that enrolled 51 patients in part one and 180 patients in part two. Part one was an exploratory dose-finding study, while part two was a randomised, double-blind, and placebo-controlled pivotal study.
Study one enrolled infants (aged between two and seven months) with type 1 SMA while study two included patients (aged from 2 to 25 years) with SMA types 2 and 3.
In FIREFISH part one study, the efficacy was based on the survival without permanent ventilation and sitting without support for at least five seconds at 12 months of treatment measured by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III).
Patients were administered with the recommended Evrysdi dose of 0.2 mg/kg a day. Approximately 41% of the patients were able to sit comfortably for roughly five seconds (BSID-III, gross motor scale) after 12 months of treatment.
After 12 months of Evrysdi treatment, 90% of the patients were alive without permanent ventilation and reached the age of 15 months or older.
After a minimum of 23 months of Evrysdi treatment, 81% of all patients (median age of 32 months) were alive without permanent ventilation.
The primary endpoint in SUNFISH part two study was the mean change from baseline in the motor function measure (MFM-32) total score after 12 months of treatment with Evrysdi when compared to placebo.
Patients treated with Evrysdi reported a significantly greater change in motor function (n=115) from baseline to placebo (n=60), as assessed by MFM-32.
At month 12, patients on Evrysdi saw an average 1.36 increase in their MFM-32 score, compared to a 0.19 decrease in placebo patients (inactive treatment).
The percentage of patients treated with Evrysdi who had a total score change of three or more in baseline MFM-32 was 38.3%, compared to 23.7% for placebo.
Evrysdi treatment also improved upper limb motor function in children and adults compared to the baseline, as measured by the Revised Upper Limb Module (RULM), a secondary endpoint of the study.
Common adverse reactions observed during the studies were diarrhoea, fever, and rash in later-onset SMA (SUNFISH) and pneumonia, upper respiratory tract infection, vomiting, and constipation in FIREFISH (infantile-onset SMA).