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Risdiplam: Spinal Muscular Atrophy (SMA) Treatment

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Spinal muscular atrophy (SMA) is a rare recessively inherited neuromuscular disorder caused by a lack of functional survival motor neuron 1 (SMN1) gene.

The rapid and irreversible loss of motor neurons results in progressive muscle weakness and loss of muscle function, which includes breathing, swallowing and basic movements. The disease spectrum ranges by the level of weakness, according to the ‘best achievable motor function’ in their lifetime. There are five primary types of SMA categorised by age of onset and disease severity, from Type 0 (prenatal onset) to Type 4 (adult onset). Approximately 60% of all SMA cases are Type 1, characterised by early onset with diagnosis usually in an infant’s first 6 months. Type 1 SMA leads to death or the need for permanent ventilation and feeding support by age 2 in more than 90% of cases, if untreated. Aside from the debilitating clinical burden, chronic disease also places significant caregiver strain on the families affected.

In the absence of a local registry, the prevalence of autosomal recessive disease in Singapore is poorly characterised. In Caucasian populations, the prevalence is 1 in 6,000 and 1 in 10,000 live births. 

Current treatment landscape

There is no cure for SMA and the standard of care is focused on providing supportive therapy to treat or prevent complications of muscle weakness. In the last decade, however, the advent of novel disease-modifying therapies has provided patients and caregivers options for proactive management of the debilitating disorder. To date, three innovative drugs have received FDA approval for SMA treatment – nusinersen (Spinraza), onasemnogene abeparvovec (Zolgensma) and risdiplam (Evrysdi). 

Rsidiplam Drug Molecule

In Singapore, risdiplam is the only disease-modifying therapy granted local market authorisation by the Health Sciences Authority (HSA). Approval was granted in October 2021, for the ‘treatment of SMA in patients 2 months of age and older based on results from two pivotal studies, SUNFISH and FIREFISH, conducted in treatment-naïve patients with later onset and infantile-onset SMA, respectively. The drug is administered once daily at a dose titrated to age and weight. Its novel oral administration is considered beneficial for facilitating convenient at-home treatment, minimising the costs and caregiver burden associated with drugs that require in-hospital administration or healthcare professional supervision.

  • The other 2 FDA-approved therapies, nusinersen and onasemnogene, are presently not locally registered but can be imported via the HSA’s special access route (SAR). Nusinersen is an antisense oligonucleotide administered by intrathecal injection with maintenance dosing every 4 months after an initial 4 loading doses, and onasemnogene abeparvovec is a one-time intravenously infused gene therapy. 
  • The efficacy of onasemnogene abeparvovec for children 2 years of age and older is unknown. For older children (age ≥2 years) and adults with moderate symptoms of SMA, treatment with nusinersen or risdiplam is thus recommended.
  • Trials for all 3 therapies have demonstrated modes efficacy for a disease that, if left untreated, leads to profound disability and death. However, in the absence of direct comparisons between these drugs, guidelines recommend individualizing treatment decisions based on availability, cost, patient preference, administrative burden and adverse effect profile. 
  • As of July 2020, no SMA disease-modifying therapies have been approved for reimbursement in Singapore and remain extraordinarily expensive. Despite regulatory approval, treatment access is thus likely severely limited in the absence of public funding mechanisms.

Risdiplam – A summary of its efficacy and safety data

Risdiplam is a small molecule SMN2 splicing modifier that binds two sites in SMN2 pre-messenger RNA and corrects the splicing deficit of SMN2. This leads to increased levels of functional full-length SMN protein. 

The risdiplam development program is ongoing and has evaluated over 450 patients spanning naïve and pre-treated Types 1, 2 and 3 SMA patients to date. The drug has demonstrated durable increases in SMN protein through the central nervous system and in peripheral tissues. The key efficacy and safety outcomes of the key trials that led to risdiplam’s regulatory approval are described in the table below. 

Trial Population  Intervention/ Comparator Efficacy Outcomes Safety Outcomes
SUNFISH Part 2

N=180

Patients with SMA Type 2 (71%) and non-ambulant SMA Type 3 (29%) aged 2 to 25 years

50.6% female

Median age at screening 9 years (range 2-25) 

Mean age of symptoms onset 15.5 months (SD 14.1)

Mean MFM-32 score 46.11 (SD 11.46)

Randomized 2:1 to oral daily risdiplam or matched placebo
  • At 12 months, risdiplam treatment led to clinically meaningful improvements in the primary endpoint: average increase in MFM-32 score from baseline of 1.36 (risdiplam) vs. 0.19 (placebo); treatment difference 1.55, 95% CI 0.30-2.81
  • Preliminary 24-month data demonstrate that the increase in MFM-32 score has been maintained between months 12 and 24 in the risdiplam treatment arm
  • Revised Upper Limb Module (RULM) scores showed risdiplam significantly improved motor function after 12 months vs. placebo 
  • Caregivers reported improvements in independence after treatment with risdiplam (p=0.0022), measured by the SMA independence scale (SMAIS) 
Incidence of AEs and serious AEs were similar between treatment groups

The most common AEs were upper respiratory tract infection (31.7%), nasopharyngitis (25.8%), pyrexia (20.8%), headache (20%), diarrhoea (16.7%), vomiting (14.2%), cough (14.2%)

The most common serious AEs were pneumonia (7.5%), gastroenteritis (1.7%), bacteraemia (1.7%), influenza (1.7%), pyrexia (1.7%)

FIREFISH Part 2 

N=41

Infants with Type 1 SMA and two SMN2 gene copies aged 1-7 months at enrolment who received risdiplam for 12 months at the dose selected in Part 1 of FIREFISH 

54% female

The median age of symptom onset 1.5 months (range 1.0-3.0)

Single-arm – oral daily risdiplam  At data cut-off on 14 Nov 2019: 

  • 29% (12 of 41) of risdiplam-treated infants met the primary endpoint (P<0.0001) – the proportion of infants sitting without support for 5 seconds at Month 12 as assessed by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development (BSID-III)
  • 85% (35 of 41) of infants were event-free* at Month 12. In natural history, the median age (IQR) for reaching death or permanent ventilation for infants with two SMN2 copies was 10.5 (8.1-13.6) months 
  • 78% of infants responded to treatment with significant gains in motor milestones after 12 months as measured by the HINE-2 scale 
The most common AEs (occurring in ≥4 patients) were upper respiratory tract infection (46%), pneumonia (39%), pyrexia (39%), constipation (20%), nasopharyngitis (12%) and rhinitis (12%)

The most common serious AEs (occurring in ≥2 patients) were pneumonia (32%), bronchiolitis (5%), respiratory failure (5%) and hypotonia (5%) 

*Endpoint-free survival was defined as alive and not requiring at least 16 hours/day of non-invasive ventilation support for at least 2 weeks

In addition, the JEWELFISH and RAINBOWFISH trials are ongoing and evaluate pre-treated SMA patients aged 6 months to 60 years old and pre-symptomatic SMA patients from birth to 6 weeks old, respectively. Data from these studies provide hope for addressing a large prevalent and underserved population that currently lacks treatment options with robust supporting evidence.

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