Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy

Overview of SMA

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. The most common form is caused by a homozygous deletion or mutation of the survival of motor neuron 1 (SMN1) gene on chromosome 5q, which encodes SMN,^{1, 2} an essential protein for normal development and functional homeostasis.³ Most individuals carry a second gene, SMN2, that produces small amounts of functional SMN protein.⁴ SMA is characterized by the progressive loss of spinal motor neurons leading to muscle weakness.² Without therapeutic intervention, it is the leading genetic cause of mortality in infants and young children, with an incidence of 1 in 10,000 live births.⁵

SMA manifests in various degrees of severity defined by age of onset and highest motor milestone achieved;² there are three main subtypes: Type 1 (patients never sit independently), Type 2 (patients can sit but not walk), and Type 3 (patients achieve independent walking).⁶ All subtypes have common clinical signs, including hypotonia, muscle weakness and atrophy, and impaired mobility.⁷

The first two therapies that received Health Authority (HA) approval for the treatment of SMA were as follows: the intrathecally administered SMN2-targeting antisense oligonucleotide nusinersen (SPINRAZA®)⁸ and onasemnogene abeparvovec-xioi (ZOLGENSMA®), a gene-transfer therapy that uses a nonreplicating adeno-associated virus to deliver a functional copy of an SMN1 gene by a single intravenous infusion in patients aged < 2 years.⁹ Despite these available treatment options, an unmet medical need remains for this broad patient population. For some patients treated with nusinersen, repeated intrathecal administration is either not feasible due to severe scoliosis or too burdensome for both patients and healthcare systems.¹⁰ Onasemnogene abeparvovec administration requires preparation and administration in a protected environment, systemic glucocorticoid treatments, and close monitoring of liver function and cardiac parameters.⁹ In addition, there is a lack of data in older patients or those with different disease types.

Overview of risdiplam

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral SMN2 pre-mRNA splicing modifier,¹¹ which has recently been approved by the FDA for the treatment of patients with SMA aged 2 months and older in the United States¹² and is currently under HA review in the EU. Risdiplam directly targets the underlying SMA pathophysiology by promoting the inclusion of exon 7 into SMN2 pre-mRNA, to generate full-length SMN2 mRNA. This molecule increases the production of functional SMN protein in the central nervous system and throughout the body.¹³ Risdiplam has a favorable safety profile and positive efficacy results in infants, children, and adults, supporting its use in SMA.^14-16

Preclinical retinal toxicity

In a study of risdiplam administered at three dose levels in cynomolgus monkeys with 39 weeks of daily treatment, retinal toxicity was observed consisting of peripheral photoreceptor degeneration and microcystoid macular degeneration (MMD) in the central retina after 5 − 6 months of treatment.¹¹

Photoreceptor degeneration (most pronounced in the periphery) was observed only at the mid and high doses of risdiplam (with the mid-dose corresponding to exposures >2-fold of the mean exposures achieved at the proposed therapeutic dose for risdiplam). While some improvement was noted in the layer integrity/organization of the far periphery, the areas with pronounced degeneration of cells (only seen in animals previously treated with the high dose) did not reverse within the 22-week post-treatment phase.

MMD, characterized by microcystoid spaces in the inner nuclear layer (INL), was noted in monkeys treated with the high dose only (approximately four times the exposures achieved at the pivotal approved dose in patients with SMA). MMD was reversible during the recovery phase, as observed with spectral domain optical coherence tomography (SD-OCT), electroretinography, and histopathology.

Experimental evidence suggested that risdiplam has high melanin-binding capacity, causing its retention in pigmented retinal cells.¹¹ The high concentration of risdiplam in these cells may have led to an impairment of lysosomal/autophagosomal function, thus, affecting recycling of photoreceptors.¹¹ However, this finding appears to be monkey specific, as pigmented rats showed similar melanin-binding potential but no retinal toxicity at even higher doses. Possible long-term consequences associated with such structural changes in the peripheral retina would be impaired night vision or loss of peripheral vision. MMD-related impairment of vision was not noted in any of the monkeys – not even in animals with pronounced photoreceptor degeneration or MDD.

Figure 1 depicts an SD-OCT image from a cynomolgus monkey that demonstrates photoreceptor degeneration, cystic changes in the INL, thinning of the retinal pigment epithelium, and disappearance of the normal ellipsoid and myoid zones of the photoreceptors.

Based on preclinical data, full therapeutic effect was expected to be achieved with a two-fold increase in SMN protein.¹¹ This increase was reached at exposures corresponding to the no-observed-adverse-effect level (NOAEL) for retinal toxicity in monkeys. Risdiplam, therefore, proceeded into clinical development with a dose that corresponds, in terms of systemic exposure in blood, to the exposure at the NOAEL for retinal toxicity in monkeys; in addition, a comprehensive panel of ophthalmologic assessments was included for all studies.

Overview of clinical development studies

Risdiplam is currently under clinical evaluation in four clinical studies (Fig. 2): a study in infants with symptomatic Type 1 SMA (FIREFISH NCT02913482),¹⁷ a study in symptomatic, treatment-naïve patients with Type 2 and 3 SMA (SUNFISH NCT02908685),¹⁸ a study in symptomatic, non-naïve patients, (JEWELFISH NCT03032172),¹⁹ and a study in presymptomatic patients with SMA (RAINBOWFISH NCT03779334).²⁰ These studies were designed to assess safety, tolerability, and efficacy of risdiplam.

FIREFISH is a two-part, multicenter, open-label study to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of risdiplam in infants (aged 1 to 7 months at enrollment) with Type 1 SMA.¹⁷ The study consists of a dose-finding Part 1 and a confirmatory Part 2 at the dose selected in Part 1. In total, 21 patients were enrolled in Part 1.¹⁴ Part 2 of FIREFISH has completed recruitment (41 infants) and is ongoing. Following selection of the Part 2 dose, patients in Part 1 entered an extension phase to continue treatment with the Part 2 dose.

SUNFISH is a two-part, multicenter, randomized, placebo-controlled, double-blind study to investigate safety, tolerability, PK/PD, and efficacy of risdiplam in patients with Type 2 and 3 SMA (aged 2–25 years).¹⁸ The study consists of a dose-finding Part 1 and a confirmatory Part 2 at the dose selected in Part 1. In total, 51 patients were enrolled in Part 1.¹⁵ Patients receiving placebo were switched to active treatment at the dose tested in their respective cohort after a minimum 12-week, placebo-controlled treatment period. After selection of the dose for Part 2, all Part 1 patients received the pivotal dose during an open-label extension phase. Part 2 has completed recruitment (180 patients), is ongoing, and was still blinded at the clinical cut-off date (CCOD) – 06 September 2019.

JEWELFISH is an open-label, noncomparative study of risdiplam in patients with SMA who were previously enrolled in Roche Study BP29420 (MOONFISH) with the splicing modifier RG7800 (RO6885247) (development discontinued) or previously treated with nusinersen, onasemnogene abeparvovec, or olesoxime (previous Roche acquired development compound, since discontinued).¹⁹ Forty-five patients of the planned target of 180 had been enrolled up to the CCOD of 28 June 2019; these 45 patients (43 patients with Type 2 or 3 SMA and two with Type 1 SMA) had previously received nusinersen (n = 24), olesoxime (n = 12), or RG7800 (n = 9). JEWELFISH has completed recruitment (174 patients) and is ongoing.

Risdiplam is approved for treatment of SMA in the United States and is under HA review in EU. The new drug application submitted to the FDA/EMA included extensive safety data, including ophthalmologic safety data in patients with SMA participating in the FIREFISH, SUNFISH, and JEWELFISH studies.

Study oversight

The FIREFISH, SUNFISH, and JEWELFISH trials were approved by an ethics committee at each study site and were conducted in accordance with Good Clinical Practice guidelines and with the World Medical Association Declaration of Helsinki. Written informed consent was provided by patients or the caregivers of patients.

Analysis population

In total, 338 patients were included in the analysis (Table 1):

Eligibility criteria

Eligibility criteria for the respective studies are listed in the supplementary appendices. Patients with a history of ophthalmologic disease within the last year that may have potentially confounding ophthalmologic baseline findings or patients unable to perform the ophthalmologic assessments were ineligible to participate. Patients with any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin, or thioridazine, or use of other medications known to or suspected of causing retinal toxicity within 1 year prior to randomization were also ineligible.

Ophthalmologic monitoring

Ophthalmologic assessments included:

As studies progressed in the absence of any signals emerging from this monitoring, and in consideration of the extreme burden imposed upon this severely disabled patient population, Sloan LCVA and FAF were no longer performed and the frequency of some assessments was reduced over subsequent protocol amendments. However, the main assessment, SD-OCT, remained for all patients, at a bi-monthly schedule in SUNFISH and FIREFISH and changed from bi-monthly (initially) to every 3 months in JEWELFISH with repeats being systematically requested in case of insufficient quality of images. Table 2 includes details on the ophthalmologic assessments.

A dedicated independent central reader, Annesley Eye Brain Center (AEBC; formerly the Optic Nerve Research Center), Thomas Jefferson University (Philadelphia, PA, USA), provided training for the site ophthalmologists and technicians and performed stringent quality reviews of all images. To increase exploration of the peripheral retina, the central reader developed an innovative SD-OCT protocol that combined posterior pole and cross-hair scans captured following nasal, temporal, superior, and inferior fixation (Fig. 3).

Changes from baseline that occurred through the assessments, but were no longer observed at the last available assessment, were considered related to test/retest variability or transient findings that disappeared despite ongoing risdiplam treatment. These findings were, therefore, not considered to be risdiplam-induced effects and are not presented. Only findings present at the patient’s last available assessment are summarized.

Predefined criteria (Table 3) were used to reduce assessment variability and specify which findings should be considered abnormal or potentially clinically significant changes from baseline (thereafter referred to as “findings”). Findings were reviewed by a central reader who provided recommendations for additional assessments in consultation with the site ophthalmologist, if required. For the purpose of data presentation, findings in both eyes at the same assessment or the same finding observed in different ophthalmologic assessments are counted separately.

The duration of ophthalmologic monitoring was estimated based on the key assessment SD-OCT, which was among the most frequently performed assessments (once every 8 or 12 weeks depending on the study). Patient numbers were estimated after discounting exposure in patients on placebo based on 2:1 randomization in SUNFISH Part 2.

Adverse events (AEs)

AEs were reported from the first dose of study treatment and continuously throughout the observation period. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0. All AEs coding to the primary System Organ Class (SOC) “Eye Disorders” as well as ophthalmologic events coding to other SOCs are presented.

Patient population

A total of 338 patients (64 with Type 1 SMA; 274 with Type 2/3 SMA) received at least one dose of the assigned treatment; 278 patients received risdiplam and 60 patients received placebo.

In the “all open-label/unblinded risdiplam” pool, approximately 80% of the exposure time to risdiplam was at the therapeutic dose and 20% at subtherapeutic doses. In the “blinded Part 2 SUNFISH” pool, all patients who were treated with risdiplam received the therapeutic dose.

Overall, 13 patients withdrew from the study prior to the CCOD 28 June 2019 (seven patients with Type 1 died due to SMA-related respiratory complications and six with Types 2/3 SMA withdrew for nonsafety-related reasons).

Demographic characteristics

Demographic characteristics (Table 1) are reflective of the inclusion criteria and geographical distribution of study sites. Patients were aged 2.2 months–60.9 years. While the majority were Caucasian, approximately 15% of patients were Asian. The percentage of male and female patients was balanced.

Duration of ophthalmologic follow-up

The longest duration of follow-up was 30.2 months; 91.7% of patients (310 of 338) reached at least the first assessment time point postbaseline and successfully performed the first postbaseline SD-OCT (Table 4). At the CCOD (28 June 2019), 28 patients had not reached the first assessment time point postbaseline: one patient in FIREFISH Part 1 (who died prior to reaching the first assessment time point), three patients in FIREFISH Part 2, and 24 patients in JEWELFISH. Overall, 85% of all patients successfully completed their SD-OCT assessments as scheduled.

In total, 245 patients treated with risdiplam had successful postbaseline SD-OCT monitoring for at least 2 months. Fifteen patients had SD-OCT assessments for 2.5 years, 52 patients for 2 years, 143 patients for 1 year, and 233 patients for 6 months.

Ophthalmologic safety findings

Overall, 207 patients had 477 ophthalmologic safety findings at the last ophthalmology visit. Most findings were either changes in retinal layer thickness due to angulation variability during SD-OCT assessment, measurement variability in IOP, BCVA, SLOAN LCVA, or threshold perimetry, which were not clinically significant. Findings that were deemed clinically significant and reported as AEs are described below.

Ophthalmologic AEs

Overall, in the “all open-label/unblinded risdiplam” pool (n = 158), nine patients (5.7%) had an ophthalmologic AE coding to SOC Eye Disorders (Table 5). No ophthalmologic events were reported in other SOCs. Events were mild to moderate in intensity, were reported as unrelated to risdiplam, resolved despite ongoing treatment, and were not suggestive of risdiplam-induced effects. All ophthalmologic AEs were mono-ocular (no events involved both eyes).

Three of these events were reported by the study ophthalmologist as a result of the scheduled ophthalmologic assessment and resolved despite ongoing treatment with risdiplam:

In the “blinded Part 2 SUNFISH” pool (treatment arm unknown), 13 (7.2%) patients had ophthalmologic AEs coding to SOC Eye Disorders (Table 6), which were mild to moderate in intensity and resolved with the exception of two incidences of subcapsular cataract and one of mild visual impairment. The latter occurred in a 5-year-old patient, who had an event of visual impairment without corresponding findings at ophthalmologic assessments, which had been observed in the context of headache; however, this finding could not be verified or validated by two certified board ophthalmologists at the reading center. The two events of subcapsular cataract were observed during ophthalmologic examination in a 13-year-old Asian female who had a subcapsular cataract (left eye) and posterior capsule opacification (right eye); however, these findings also could not be verified or validated by a certified board of ophthalmologists and they were not confirmed by red reflex images acquired after the CCOD. In addition, one patient had a small conjunctival nevus at slit lamp examination (right eye) at Week 17 that was stable through to Week 43 and, therefore, may have been missed at screening. This finding was reported as an AE of mild, unrelated, and unresolved eye nevus.