EVRYSDI (Page 4 of 6)

13.2 Animal Toxicology and/or Pharmacology

Retinal toxicity

Risdiplam-induced functional and structural retinal abnormalities were seen in animal studies. In a 39-week toxicity study in monkeys, oral administration of risdiplam (0, 1.5, 3, or 7.5/5 mg/kg/day; high dose lowered after 4 weeks) produced functional abnormalities on the electroretinogram (ERG) in all mid- and high-dose animals at the earliest examination time (Week 20). These findings were associated with retinal degeneration, detected by optical coherence tomography (OCT), on Week 22, the first examination time. The retinal degeneration, with peripheral photoreceptor loss, was irreversible. A no-effect dose for the retinal findings (1.5 mg/kg/day) was associated with plasma exposures (AUC) similar to that in humans at the maximum recommended human dose (MRHD) of 5 mg.

Effect on Epithelial Tissues

Oral administration of risdiplam to rats and monkeys resulted in histopathological changes in epithelium of the gastrointestinal (GI) tract (apoptosis/single cell necrosis), lamina propria (vacuolation), the exocrine pancreas (single cell necrosis), the skin, tongue, and larynx (parakeratosis/hyperplasia/degeneration) with associated inflammation. The skin and GI epithelial effects were reversible. The no-effect doses for effects on epithelial tissues in rats and monkeys were associated with plasma exposures (AUC) similar to that in humans at the MRHD.

14 CLINICAL STUDIES

The efficacy of EVRYSDI for the treatment of patients with infantile-onset, later-onset, and pre-symptomatic SMA was evaluated in three clinical studies, Study 1 (NCT02913482) and Study 2 (NCT02908685), and Study 3 (NCT03779334), respectively.

The overall findings of these studies support the effectiveness of EVRYSDI in SMA pediatric and adult patients and appear to support the early initiation of treatment with EVRYSDI.

14.1 Infantile-Onset SMA

Study 1 was an open-label, 2-part study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of EVRYSDI in patients with Type 1 SMA (symptom onset between 28 days and 3 months of age). All patients had genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene, and two SMN2 gene copies.

Part 1 of Study 1 was designed as a dose-finding study. Part 2 of Study 1 assessed the safety and efficacy of EVRYSDI at 0.20 mg/kg, the recommended dose determined in Part 1 [see Dosage and Administration (2.4)]. Patients from Part 1 did not take part in Part 2.

A total of 62 patients with symptomatic Type 1 SMA were enrolled in FIREFISH Part 1 (n=21) and Part 2 (n=41), of which 58 patients received the recommended dose. The median age of onset of clinical signs and symptoms was 1.5 months (range: 0.9 to 3.0 months). The median age at enrollment was 5.6 months (range: 2.2 to 6.9 months), and the median time between onset of symptoms and the first dose was 3.7 months (range 1.0 to 6.0 months). Of these patients, 60% were female, 57% were Caucasian, and 29% were Asian. The demographics and baseline disease characteristics were comparable between Part 1 and Part 2 of the study.

Effectiveness was established based on the ability to sit without support for at least 5 seconds (as measured by Item 22 of the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III) gross motor scale) and on the basis of survival without permanent ventilation. Permanent ventilation was defined as requiring a tracheostomy or more than 21 consecutive days of either non-invasive ventilation (≥ 16 hours per day) or intubation, in the absence of an acute reversible event.

The primary endpoint was the proportion of patients with the ability to sit without support for at least 5 seconds (BSID-III gross motor scale, Item 22) after 12 months of treatment in Part 2; 29% of patients (n=12/41) achieved this milestone.

Other efficacy endpoints of EVRYSDI-treated patients in Study 1 (pooled Part 1 and Part 2) are shown in Table 3.

Table 3 Key Efficacy Results at Month 12 and Month 24 (Study 1, Parts 1 and Part 2)

Efficacy Endpoints	Proportion of Patients Parts 1 & 2 at Month 12	Proportion of Patients Parts 1 & 2 at Month 24
* Results were pooled from all patients who received the recommended dose of risdiplam (all patients in Part 2 and those in the high-dose cohort of Part 1; n=58). † Results were pooled from all patients who received any dose of risdiplam in Part 1 and Part 2 (n=62).
Motor Function and Development Milestones	N = 58 *
BSID-III, Item 22: sitting without support for at least 5 seconds	32.8%	60.3%
Survival and Event-Free Survival	N= 62 †
Alive without Permanent Ventilation	87.1%	83.8%

At Month 24, 40% (23/58) of patients who received the recommended dose achieved sitting without support for 30 seconds (BSID-III, Item 26). In addition at Month 24, patients continued to achieve additional motor milestones; 28% (16/58) of patients achieved a standing measure (16% [9/58] supporting weight and 12% [7/58] standing with support), as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2) which assesses motor milestones.

The proportion of patients alive without permanent ventilation (event-free survival) was 84% for all patients at Month 24 (Table 3). Out of 62 patients, 6 infants died (4 within the first 3 months following study enrollment) and one additional patient withdrew from treatment and died 3.5 months later. Four patients required permanent ventilation by Month 24. These results indicate a clinically meaningful deviation from the natural history of untreated infantile-onset SMA. As described in the natural history of untreated infantile-onset SMA, patients would not be expected to attain the ability to sit independently, and no more than 25% of these patients would be expected to survive without permanent ventilation beyond 14 months of age.

14.2 Later-Onset SMA

Study 2 was a 2-part, multicenter trial to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of EVRYSDI in patients diagnosed with SMA Type 2 or Type 3. Part 1 of Study 2 was dose-finding and exploratory in 51 patients (14% ambulatory). Part 2 was randomized, double-blind, placebo-controlled, and is described below.

The primary endpoint in Study 2 Part 2 was the change from baseline to Month 12 in the Motor Function Measure 32 (MFM32) score. A key secondary endpoint was the proportion of patients with a 3-point or greater change from baseline to Month 12 in the MFM32 total score. The MFM32 measures motor function abilities that relate to daily functions. The total MFM32 score is expressed as a percentage (range: 0 to 100) of the maximum possible score, with higher scores indicating greater motor function. Another key secondary endpoint was the Revised Upper Limb Module (RULM). The RULM is a tool used to assess motor performance of the upper limb in SMA patients. It tests proximal and distal motor functions of the arm. The total score ranges from 0 (all the items cannot be performed) to 37 (all the activities are achieved fully without any compensatory maneuvers).

Study 2 Part 2 enrolled 180 non-ambulatory patients with Type 2 (71%) or Type 3 (29%) SMA. Patients were randomized 2:1 to receive EVRYSDI at the recommended dosage [see Dosage and Administration (2.2)] or placebo. Randomization was stratified by age group (2 to 5, 6 to 11, 12 to 17, or 18 to 25 years of age).

The median age of patients at the start of treatment was 9.0 years (range 2 to 25), and the median time between onset of initial SMA symptoms and first treatment was 102.6 months (range 1 to 275). Of the 180 patients included in the trial, 51% were female, 67% were Caucasian, and 19% were Asian. At baseline, 67% of patients had scoliosis (32% of them with severe scoliosis). Patients had a mean baseline MFM32 score of 46.1, and RULM score of 20.1. Overall baseline demographic characteristics were reasonably balanced between the treatment groups (EVRYSDI and placebo), with the exception of scoliosis (63% in the EVRYSDI arm vs. 73% in the placebo group).

The primary analysis on the change from baseline in MFM32 total score at Month 12 showed a clinically meaningful and statistically significant difference between patients treated with EVRYSDI and placebo. The results of the primary analysis and key secondary endpoints are shown in Table 4 and Figure 1.

Table 4 Summary of Efficacy in Patients with Later-Onset SMA at Month 12 of Treatment (Study 2 Part 2)

Endpoint	EVRYSDI(N = 120)	Placebo(N = 60)
* The Mixed Model Repeated Measure (MMRM) analysis included the change from baseline total score as the dependent variable and as independent variables the baseline total score, treatment group, time, treatment-by-time interaction, and the randomization stratification variable of age group (2 to 5, 6 to 11, 12 to 17, 18 to 25). † The MFM total score was calculated according to the user manual, expressed as a percentage of the maximum score possible for the scale (i.e., sum of the 32 item scores divided by 96 and multiplied by 100). ‡ Based on the missing data rule for MFM32, 6 patients were excluded from the analysis (EVRYSDI n = 115; placebo control n = 59). § The adjusted p-value was obtained for the endpoints included in the hierarchical testing and was derived based on all the p-values from endpoints in order of the hierarchy up to the current endpoint. ¶ The logistic regression analysis included the baseline total score, treatment and age group as independent variables. # Based on the missing data rule for RULM, 3 patients were excluded from the analysis (EVRYSDI n = 119; placebo control n = 58).
Primary Endpoint:
Change from baseline in total MFM32 score at Month 12, LS means (95% CI) *, †, ‡	1.36 (0.61, 2.11)	-0.19 (-1.22, 0.84)
Difference from Placebo, Estimate (95% CI)* p-value	1.55 (0.30, 2.81)0.0156
Secondary Endpoints:
Proportion of patients with a change from baseline MFM32 total score of 3 or more at Month 12 (95% CI)†, ‡	38.3% (28.9, 47.6)	23.7% (12.0, 35.4)
Odds ratio for overall response (95% CI)adjusted § (unadjusted) p-value ¶	2.35 (1.01, 5.44)0.0469 (0.0469)
Change from baseline in total score of RULM at Month 12, LS means (95% CI)*, #	1.61 (1.00, 2.22)	0.02 (-0.83, 0.87)
Difference from Placebo, Estimate (95% CI)adjusted § (unadjusted) p-value *	1.59 (0.55, 2.62)0.0469 (0.0028)

* Error bars denote the 95% confidence interval. † The MFM total score was calculated according to the user manual, expressed as a percentage of the maximum score possible for the scale (i.e., sum of the 32 item scores divided by 96 and multiplied by 100).

Figure 1 Mean Change from Baseline in Total MFM32 Score Over 12 Months (Study 2 Part 2)*, †

(click image for full-size original)