The first in-human trials of risdiplam, which were conducted in healthy volunteers (i.e. a Phase 1 clinical trial), were initiated in late 2015, with the first volunteers enrolled in early 2016 (clinicaltrials.gov trial identifier: NCT02633709). SMA patients were first enrolled in clinical trials of risdiplam in late 2016: the FIREFISH trial involving infants with Type 1 SMA and the SUNFISH trial involving participants with SMA Type 2 and 3 (see below). JEWELFISH and RAINBOWFISH trials followed later.

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Treatment with risdiplam was associated with an increase in SMN protein that was maintained over at least a 12-month treatment period in FIREFISH, SUNFISH and JEWELFISH trials. Data is not yet available for RAINBOWFISH.

FIREFISH

Patients enrolled via Part 1 of the trial

Patients involved in Part 1 continued to receive treatment at the dose selected from the 12-week dose-finding study.

Outcomes for infants with SMA Type 1 following 12 months of risdiplam treatment were:

• 7 out of 17 (41%) able to sit without support for at least five seconds, compared to 0% of untreated infants (natural history data).
• 11 (65%) able to sit (with or without support),
• 9 (53%) achieved upright head control (assessed by HINE-2)
• 1 (6%) achieved the milestone of standing (supporting own weight).
• 10 out of 17 (59%) achieved a CHOP-INTEND total score of 40 points or more.
  • Median change from baseline to month 12 in CHOP-INTEND was 17.5 points.
  • The maximum CHOP-INTEND score was 57 points after 12 months treatment, increasing from a maximum of 49 points after 8 months.
  • After 16 months of treatment, 82% (14/17) of high-dose patients had a CHOP-INTEND score ≥40.
• After 16 months of treatment, no infant required tracheostomy or reached permanent ventilation
• 86% (18/21) of all infants were event-free after receiving risdiplam for 16 months. An event is defined as the time when ventilation support for breathing is required for at least 16 hours a day for 14 consecutive days, or sadly when a patient dies.

Patients enrolled via Part 2 of the trial

Outcomes for infants with SMA Type 1 receiving 12 months of risdiplam treatment:

• 29% of infants (12/41; p<0.0001) able to sit without support for at least five seconds, compared to 0% of untreated infants (natural history data).
• 18 (43.9%) able to hold their head upright.
• 13 (31.7%) able to roll to the side.
• 2 (4.9%) able to stand with support (measured with HINE-2).
• 90% (37/41) had a CHOP-INTEND score increase of at least 4 points.
• 56% (23/41) achieved a score above 40; the median increase was 20 points.
• 85% (35/41) were event-free

SUNFISH

Outcomes for those with SMA Type 2 or 3 aged 2 – 25 years

Patients enrolled via Part 1 of the trial

Patients involved in Part 1 continued to receive treatment at the dose selected from the 12-week dose-finding study.

• risdiplam significantly improved motor function after 24 months of risdiplam treatment:
  • MFM-32 (Motor function measure which assesses 32 items) total change from baseline was greater in patients receiving risdiplam – 3.99 point difference (95% CI: 2.34, 5.65) p< 0.0001) compared with natural history data.

Patients enrolled via Part 2 of the trial

• risdiplam significantly improved motor function after 12 months of treatment:
  • MFM-32 total change from baseline was greater in patients receiving risdiplam, compared to placebo (1.55 point mean difference; p=0.0156).
  • the RULM (Revised Upper Limb Module which assesses the functioning of the arm) also showed an improvement (1.59 point difference; p=0.0028).

JEWELFISH

An interim analysis of the trial, published in February 2023, indicates that after a year of treatment, risdiplam is safe and causes a sustained, two-fold increase in SMN protein in the blood. Participants will continue to be assessed until they have received treatment for at least two years.

RAINBOWFISH

Interim data, presented virtually at the 2022 MDA Clinical and Scientific Conference (13th-16th March), demonstrated the safety and efficacy of Evrysdi for newborns. The majority of babies treated with Evrysdi for at least 12 months were able to stand and walk within timeframes typical of healthy babies.

To date, there have been no drug-related safety findings leading to withdrawal of patients from FIREFISH, SUNFISH, JEWELFISH or RAINBOWFISH.

All trials and testing to date indicate that risdiplam has a tolerable safety profile.

Overall, reported adverse events were designated as “not risdiplam-related”, because they are issues commonly observed in untreated SMA patients. Detailed reports were as follows:

FIREFISH

Patients enrolled via Part 1 of the trial

• Most common adverse events were fever (pyrexia; 52%), upper respiratory tract infections (43%), diarrhoea (29%), vomiting (24%), cough (24%) pneumonia (19%) and constipation (19%).
• Most common serious adverse event was pneumonia (10/21).
• Three infants experienced fatal complications of their disease after approximately 1, 8, and 13 months of treatment.

Patients enrolled via Part 2 of the trial

• Most common adverse events were upper respiratory tract infection (46%), pneumonia (39%), pyrexia (39%), constipation (20%) nasopharyngitis (12%), rhinitis (12%) and diarrhoea (10%).
• Most common serious adverse events were pneumonia (32%), bronchiolitis (5%), respiratory failure (5%) and hypotonia (5%).
• At 12 months, 93% (38/41) of infants were alive.

SUNFISH

Patients enrolled via Part 1 of the trial

• Most common adverse events fever (pyrexia; 55%), cough (35%), vomiting (33%), upper respiratory tract infections (31%), cold (nasopharyngitis; 24%) and sore throat (oropharyngeal pain; 22%).
• Most common serious adverse event was pneumonia (3/51).

Patients enrolled via Part 2 of the trial

• Most common adverse events were upper respiratory tract infection (32%), nasopharyngitis (26%), pyrexia (21%), headache (20%), diarrhoea (17%), vomiting (14%) and cough (14%).
• While the rate of lower respiratory tract infections overall was similar between risdiplam (19%) and placebo (20%), serious lower respiratory tract infections occurred in more patients in the risdiplam group (10% versus placebo 2%).

JEWELFISH

• Most common adverse events were upper respiratory tract infections (17%), fever (17%), headache (16%), nausea (12%), diarrhoea (11%), nasopharyngitis (10%) and vomiting (8%).
• A total of six patients have had at least one serious adverse event that led to dose modification or interruption; however, none were considered to be due to risdiplam.

RAINBOWFISH

• Thus far, no adverse events leading to withdrawal or study discontinuation have occurred.
• The most common adverse events thus far were nasal congestion (33%), cough (25%), teething (25%), vomiting (25%), eczema (17%), abdominal pain (17%), diarrhoea (17%), gastroenteritis (17%), papule (rash; 17%) and pyrexia (fever; 17%).