Risdiplam as an orphan drug treatment of spinal muscular atrophy in adults and children (2 months or older)

ABSTRACT

Introduction

Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 (survival motor neuron1) and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a milder, slower progressing adult-onset type. The field of SMA treatment has changed significantly over the last years from being a nearly untreatable condition to the marketing of 3 new therapeutic options and the possibility to diagnose the disease very early through newborn screening.

Areas covered

This article covers and summarizes the published articles of preclinical and clinical data on risdiplam, a new oral centrally and peripherally distributed SMN2 pre-mRNA splicing modifier, together with reviews of abstract of important scientific meetings that have been organized over the past 4 years.

Expert opinion

The favorable efficacy/safety profile allows risdiplam to address remaining still unmet needs in the recent era of new SMA therapies. In particular, the possibility to administer risdiplam orally at home will make of it an attractive treatment option across all SMA phenotypes. Long-term efficacy and safety are still under evaluation.

KEYWORDS:

• SMA
• SMN2
• SMN
• splicing
• modificator

1. Background

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder with an incidence of 1 in 11000 live births characterized by the progressive loss of spinal motor neurons leading to muscle weakness [1].

SMA manifests with a broad spectrum of disease severity, where the SMA phenotypes are categorized into five subtypes based on age of symptom onset and highest motor milestone achieved (ranging from type 0 to 4, corresponding from most to least severe clinical type respectively) [2].

In type 1 SMA, onset of symptoms occurs before 6 months of age and affected infants typically fail to achieve motor milestones. Instead they experience progressive motor muscle function decline, including a decline in respiratory and swallowing functions. By 12 months of age, affected infants typically require nutritional support (nasogastric or gastrostomy tube) and/or combined ventilatory support and feeding [3]. Most untreated SMA type 1 infants do not survive beyond the age of 2.

Individuals with type 2 SMA typically show symptom onset between the age of 6 and 18 months. They acquire an autonomous sitting position, and some may stand with support but never walk independently. Individuals with type 3 SMA present after 18 months and achieve independent ambulation, but many lose this ability over time [4].

SMA is caused by a homozygous deletion or mutation of the survival of the motor neuron 1 (SMN1) gene on chromosome 5q (locus 5q13) which encodes the survival motor neuron protein (SMN), an essential protein for normal development and functional homeostasis in all species, in both neuronal and non-neuronal cells [5].

SMN2, a nearly identical gene, also produces SMN protein; however, most of the SMN2 pre-mRNA transcript undergoes alternative splicing to exclude exon 7, resulting in an abundance of nonfunctional SMN protein levels and only a small portion of functional SMN protein, insufficient to compensate the loss of the SMN1 gene [5] (Figure 1).

Figure 1. Diagram of SMN1 and SMN2 genes on chromosome 5 demonstrating that a C-to-T transition at position 6 of SMN2 creates an exonic splicing suppressor (ESS), which then leads to skipping of exon 7 during transcription, resulting in the production of truncated nonfunctional SMN protein. AA: amino acids. Reprinted with permission from [6] .

SMA severity depends, to a large extent, on the on the number of copies of the SMN2 gene (more copies are predictive of a less severe form of the disease) present in the patient genome [7]. The main neuropathological feature of SMA is the progressive degeneration of the α-motor neurons in the brainstem and spinal cord leading to muscle atrophy and disease-related complications such as swallowing and respiratory difficulties (particularly in SMA type 1 and 2, the most severe forms) that can impact survival. However, accumulated data suggest that SMA is not only a disease of motor neurons. SMA is increasingly described as a whole body disease affecting tissues (especially in muscles) and cell types beyond the motor neurons, this probably in relation with the ubiquitous expression of SMN1 in many tissues [8].

In recent years, three treatments were approved for SMA. Onasemnogene abeparvovec (ZOLGENSMA®⁾ is an intravenously administered adenovirus associated viral gene therapy indicated for the treatment of patients younger than 2 years (US) or for patients with type 1 SMA or who have three or fewer SMN2 copies (EU) [9,10]. Onasemnogene abeparvovec delivers the missing SMN1 gene in patients resulting in the production of SMN functional protein [11]. Nusinersen (SPINRAZA®) is an intrathecally administered SMN2-targeting antisense oligonucleotide indicated in adult and pediatric patients [12]. It binds to a sequence within and modifies the splicing of SMN2 pre-mRNA, thereby promoting expression of full-length SMN protein [13]. Risdiplam (EVRYSDI®) is an orally administered small molecule, indicated for the treatment of patients aged 2 months and older (US, FDA) [14,15] or aged 2 months and older with type 1, 2, or 3 SMA or one to four copies of the SMN2 gene (EU, EMA) [16]. Risdiplam promotes alternative splicing and the inclusion of exon 7 in SMN2 mRNA, increasing functional SMN protein in the CNS and peripheral organs [17].

The introduction of new drug therapies for SMA led to the observation of new disease trajectories (phenotypes) that differ significantly from the known natural history of the disease, blurring the boundaries of the traditional subtypes of SMA. For example, a patient with onset before six months of age (typical for SMA type 1) might achieve independent sitting (SMA type 2 by definition) if treatment is initiated early. It is now more appropriate to define the clinical phenotype by the highest motor milestone achieved in a patient (non-sitter, sitter, walker) and rely on a combination of age of onset, age at start of drug treatment, and number of SMN2copies rather than the traditional subtypes to anticipate a clinical trajectory of SMA [18].

In this paper, after having shortly addressed some important and particular preclinical information, we will summarize and comment on the recent results of the extensive clinical development program currently available for risdiplam.

Table

Drug summary box.

• Drug name (generic): risdiplam • Phase (for indication under discussion): Four https://clinicaltrials.gov/ct2/show/NCT05232929?term=risdiplam& draw=2&rank=1) • Indication (specific to discussion): Treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older • Date and location of ODD: orphan drug designation 4 January 2017; marketing approval 7 August 2020 USA • Pharmacology description/mechanism of action: Risdiplam is a centrally and peripherally distributed oral survival of motor neuron 2 (SMN2) pre-mRNAsplicing modifier that increases the levels of functional SMN protein • Route of administration: Oral daily administration • Pivotal trials o FIREFISH (NCT02913482): Clinicaltrials.gov/ NCT02913482 - Risdiplam in type1 spinal muscular atrophy. Baranello G et al on behalf of the FIREFISH working group. N Engl J Med. 11 March 2021; 384(10): 915–923. - Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. Darras BT et al on behalf of the FIREFISH working group. N EnglJ Med. 29 July 2021; 385(5): 427–435. oSUNFISH (NCT02908685): Clinicaltrials.gov/ NCT02908685 - Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind,randomized, placebo-controlled trial. Mercuri E et al on behalf of the SUNFISH working group. Lancet Neurol. 21 January 2022; 21(1):42–52.

2. Rationale and preclinical data

In 2014, Naryshkin reported the identification of highly selective SMN2 splicing modifiers that improved motor function and longevity in mice with spinal muscular atrophy [19]. These molecules could be orally delivered and demonstrated SMN protein increases in both the central nervous system (CNS) and peripheral organs and tissues [17].

By combining RNA splicing, transcription, and protein chemistry techniques, evidence was provided that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA [17], thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes.

Two lead compounds entered human clinical trials in SMA. The first compound (RG7800, RO6885247) was studied in humans in the context of a single‑ascending dose, placebo-controlled, double-blind study in healthy volunteers conducted in 2016, and afterward in SMA patients to assess it safety and pharmacodynamics effects. The compound was safe and well tolerated showing a dose and exposure dependent effect on SMN2 exon 7 splicing in whole blood. However, the clinical study was put on hold as a precautionary measure due to safety findings in cynomolgus monkeys (nonreversible histological findings in the retina) in the long-term chronic toxicity study (39 weeks) performed in parallel to the clinical trial [20].

[21] The second compound, risdiplam (RG7916 RO7034067, which also belongs to the pyridopyrimidinone series) was profiled to increase the therapeutic window versus non target related potential side effect (e.g. hERG channel interaction, phospholipidosis, phototoxicity) and at the same time to improve its potency so as to reduce the required efficacious dose/exposure [19].

Particular attention was focused on compound interactions with the splicing machinery but affecting targets other than SMN2 (secondary targets), in particular in genes relevant for their functional roles in cell cycle regulation, or cell death signaling, such as FOXM1 and MADD [19]. Risdiplam was shown to act quite selectively toward the SMN2 target, with most of the secondary splice target effects seen with very weak or even undetectable levels at the concentrations with full pharmacodynamics effects on the SMN2 target [12,[19].

Importantly, the in vitro and animal toxicity studies with risdiplam did not show any observed adverse effect levels such as micronucleation induction, histopathological changes in the gastrointestinal tract, parakeratosis/hyperplasia/degeneration of the skin, or degeneration of germ cells in the testis of cynomolgus monkeys and rats [19].

Finally but importantly, repeated daily oral treatment with risdiplam at elevated doses in animals led to the observation of histological findings in the retina of cynomolgus monkeys, and this after 5 to 6 months of exposure. Findings included multifocal peripheral retina degeneration in the photoreceptor layer and microcystic spaces in the inner retinal layers that were detected using optical coherence tomography. Similar effects had been observed with RG7800. Although a full therapeutic effect was expected at exposures in patients not exceeding the no adverse effect level, retinal toxicity was selected as a potential side effect of interest with as a consequence the development of an in-depth OCT evaluation in all SMA patients included in clinical trials [19].

3. Clinical studies overview

Based on the preclinical data, a large clinical trial program for the investigation of risdiplam was launched in humans including studies in healthy subjects (n = 5) in subjects with mild/moderate hepatic impairment (n = 1) and 4 ongoing studies in SMA patients (see Table 1).

Table 1. Overview of risdiplam clinical studies in SMA patients.

Protocol	Objectives	Design	Treatment/dose	Formulation	N total per study
BP39055	Part 1: Safety, tolerability, PK and PD, dose selection for Part 2 Part 2: Efficacy, safety and tolerability, PK and PD	Seamless, multi-center, two-part study as follows: Part 1: A double-blind, placebo-controlled, randomized, exploratory dose-finding study in patients with Type 2 and Type 3 SMA (ambulant and non-ambulant) to select the dose for Part 2. Part 2: A double-blind, randomized, placebo-controlled, parallel design study to investigate the efficacy, safety, and tolerability of risdiplam in patients with Type 2 and non-ambulant Type 3 SMA.	OD administration Part 1 Initial doses Age 12–25 years: PBO, 3 mg or 5 mg Age 2–11 years: PBO, 0.02, 0.05, 0.15 or 0.25 mg/kg. Minimum of 12-week placebo-controlled treatment, after which patients on PBO switched to risdiplam at the dose tested in their cohort. After the dose selection for Part 2, all patients switched to the pivotal dose. Part 2 Pivotal dose 0.25 mg/kg (BW <20 kg; 5 mg (BW ≥20 kg); PBO. 24-month treatment period; patients on PBO switched in a blinded manner to active treatment after 12 months of treatment. OLE: pivotal dose.	Oral solution	Part 1: 51 patients in 2 age groups, 2 − 11 years of age (n = 31) and 12 − 25 years of age (n = 20) Part 2: 180 patients aged 2 − 25 years
BP39056	Part 1: Safety, tolerability, PK and PD, dose selection for Part 2 Part 2: Efficacy, safety and tolerability, PK and PD	Seamless, multi-center, two-part study in SMA Type 1 infants aged 1 to 7 months at the time of enrollment: Part 1: Open-label dose-escalation study to select the dose for Part 2 Part 2: Open-label study to assess the efficacy, safety, and tolerability of risdiplam	OD administration Part 1: Starting dose for first infant: 0.00106 mg/kg single dose. 0.0106, 0.04, 0.08, 0.2, 0.25 mg/kg once daily. The final selected dose was 0.08, 0.2, and 0.25 mg/kg Part 2: Starting dose at enrollment: Infants >1−<3 months: 0.04 mg/kg Infants 3−<5 months: 0.08 mg/kg Infants ≥ 5 months: 0.2 mg/kg. The dose for all infants <2 years has been adjusted to 0.2 mg/kg. Infants ≥2 years: 0.25 mg/kg. OLE phase in Parts 1 and 2 (after 24 months of treatment): pivotal dose - 0.2 mg/kg for infants < 2 years and 0.25 mg/kg for infants ≥2 years.	Oral solution	Part 1: 21 infants Part 2: 41 infants
BP39054	Safety, tolerability, PK, PD	Multi-center, open-label, singlearm study in SMA patients previously enrolled in Study BP29420 (MOONFISH) with the splicing modifier RO6885247 or previously treated with nusinersen, AVXS-101, or olesoxime	OD administration Initial dose was 3 mg (patients 12 − 60 years). Dosing was amended in line with the pivotal dose selection in Studies BP39055 (SUNFISH) and BP39056 (FIREFISH). Age 2 − 60 years: 5 mg (patients with BW ≥ 20 kg); 0.25 mg/kg (patients with BW < 20 kg). Age 6 months to < 2 years: 0.2 mg/kg. 24-month treatment period after which patients can enter an open-label extension phase.	Oral solution	180 patients planned; 174 patients enrolled at CCOD 31 July 2020 (aged 6 months to 60 years)
BN40703	Efficacy, safety, PK, PD	Open-label, single-arm, multicenter study in pre-symptomatic patients with SMA	OD administration Starting dose between 0.04 and 0.2 mg/kg 24-month treatment period after which patients can enter an open-label extension phase.	Oral solution	25 patients planned (from birth to 6 weeks of age); 12 patients enrolled at CCOD 21 January 2021

3.1. Pharmacokinetics

After single administration in healthy male subjects, at doses ranging from 0.6 to 18 mg (phase I study BP29840), risdiplam was shown to be rapidly absorbed with a median tmax between 2 and 3 hours under fasting conditions. Peak plasma concentration (Cmax) and total plasma exposure (AUC) increase in a dose-proportional manner.²¹ The elimination half-life id was approximately 40–69 hours [22]. The major pathway of elimination was fecal excretion (mass-balance study, BP39122), followed by urinary excretion.

Food, race (study NP39625), and moderate hepatic impairment (study BP40995) had no relevant effect on the PK of risdiplam.

Based on additional PK studies performed during the two pivotal studies in SMA patients (NCT02913482 FIREFISH and NCT02908685 SUNFISH), the estimated exposure varied between 2000 ng•h/mL(SMA type 1) and 2070 ng•h/mL [23] (SMA type 2–3; for details see Table 1). The maximum concentration varied between 120 ng/mL (NCT02908685 SUNFISH Part 2), and 194 ng/mL (BP39056). An increase in dose was correlated with increase in risdiplam plasma concentrations and there was no indication of nonlinear PK versus dose nor a change in PK with time after multiple-dose administration. Steady-state was attained after 7 to 14 days (once daily administration).

Four studies in patients with SMA are ongoing: the ongoing open-label extension phases of the two pivotal two-part phase II/III studies, one in infants with type 1 SMA (NCT02913482 FIREFISH) and another in children and young adults with type 2 and 3 SMA (NCT02908685 SUNFISH), open-label study (NCT03032172, JEWELFISH) in patients with type 1, 2, and 3 SMA previously enrolled in study NCT02240355 (MOONFISH) with the splicing modifier RO6885247 or previously treated with nusinersen, onasemnogene abeparvovec (AVXS-101), or olesoxime, and a phase II study (NCT03779334 RAINBOW FISH) to assess the efficacy, safety, and tolerability, and pharmacokinetic/ pharmacodynamics (PK/ PD) of risdiplam in pre-symptomatic infants genetically diagnosed with SMA (Table 1).

3.2. Clinical efficacy in SMA

FIREFISH (NCT02913482) is an open-label study of risdiplam in infants with type 1 SMA and is divided into 2 parts. Part 1 comprising 21 SMA type 1 patients was designed to assess the safety and tolerability, as well as the pharmacokinetics and pharmacodynamics of risdiplam and to select the dose for Part 2. Part 2 comprising 41 patients was designed as the confirmatory part of the study, using the dose selected from Part 1. Both parts consisted of a treatment period of 24 months followed by an open-label extension (OLE) phase for an additional 3 years that is currently ongoing [23].

Both parts recruited symptomatic patients aged 1–7 months; the main efficacy endpoint (specifically defined for part 2) after 12 months of treatment was met: 7/21 and 12/41 of patients respectively included in part 1 and part 2 were able to sit without support for 5 seconds, a motor milestone (Item 22 of the BSID-III gross motor scale) not attained by untreated infants with type 1 SMA. These results show a clear difference when compared to the natural developments in untreated patients. Moreover in Part 2 all secondary endpoints were met: the percentages of infants with a CHOP-INTEND score of 40 or higher, with a HINE-2 motor-milestone response, and finally a survival without permanent ventilation were always higher in the treated group compared with the upper boundary of confidence intervals from historical (untreated) controls (P < 0.001 for all comparisons), demonstrating a clinical meaningful effect of risdiplam [24,[25–27] .

At the most recent clinical cutoff date of 12 November 2020, from the 58 patients that were enrolled in the high-dose cohort (from Part 1 and all of Part 2) 52 patients were alive after 24 months of risdiplam treatment.

Results showed that prolonged risdiplam treatment was associated with clinically meaningful improvements in survival, motor function, and developmental motor milestones in patients with type 1 SMA. The effects observed at 12 months of treatment were maintained, and further motor improvements in a greater number of patients were observed at month 24 [28].

SUNFISH (NCT02908685) is a phase II, two-part, seamless, multi-center, randomized,

placebo-controlled, double-blind study to investigate the safety, tolerability,

pharmacokinetics, pharmacodynamics and efficacy of risdiplam in a broad base of pediatric and adult patients (2–25 years) with type 2 and 3 SMA [29].

Part 1 (n = 51) was designed to assesses the safety, tolerability, and pharmacokinetics/pharmacodynamics of different risdiplam dose levels in types 2 and 3 SMA (ambulant and non-ambulant).

Part 2 (n = 180) assesses the efficacy and safety of the Part 1-selected dose of risdiplam versus placebo in type 2 and non-ambulant type 3 SMA. In Part 2 (confirmatory part), risdiplam was administered orally at a dose of 5 mg once daily for patients with body weight (BW) > 20 kg and 0.25 mg/kg once daily for patients with BW <20 kg. Importantly, included patients had varied baseline comorbidities including severe scoliosis. Additionally, patients with contractures were not excluded from the study.

Both parts consisted of a treatment period of 24 months followed by an open-label extension phase. All efficacy endpoints in Part 1 were considered exploratory and the key efficacy endpoints and assessments were identical for both Part 1 and Part 2 [30,[31].

In part 1, after 12 months of treatment clinically meaningful improvements in motor function with risdiplam treatment were observed which were maintained or improved at month 24. This was assessed by two different motor function, the MFM32 [32] and the RULM (a scale evaluating upper limb function) [33]. Furthermore, consistent with the MFM data, results from the Hammersmith Functional Motor Scale Expanded (HFMSE) [34], a general motor scale, indicated improvements in motor function and substantially diverged from what is typically observed in natural history studies of patients with type 2 or 3 SMA [35].

In part 2, results at 12 months met the primary endpoint, showing an improvement in the change from baseline in the MFM32 total compared to the placebo group. Additionally, a statistically significantly greater proportion of patients in the risdiplam group (38.3%) than in the placebo group (23.7%) showed an improvement in the MFM32 total score, and the improved change from baseline in the RULM total score with risdiplam compared to the placebo was both clinically meaningful and statistically significant [36].

SUNFISH brought level 1 evidence to demonstrate efficacy of a treatment for SMA across a broad age group (2–25 years), that included children, teenagers and adults with a wide-ranging spectrum of functional ability and comorbidities such as scoliosis and contractures. Subgroup analysis showed that the greatest treatment difference was in the younger population (2–5 years of age) and that there was evidence of efficacy favoring risdiplam with improved MFM32 or RULM scores across all age groups[36.

Finally and more recently longer-term exploratory risdiplam efficacy of the SUNFISH program showed continued clinically relevant gains in motor function over 2 years: improvements (32% of patients) and stabilization (58% of patients) in MFM32 total score at month 24, progressive improvements on RULM as well as caregiver-reported SMAIS were demonstrated [37].

3.3. Safety

A comprehensive assessment of the safety profile of risdiplam was evaluated and pooled from data from FIREFISH Parts 1 and 2, SUNFISH Part 1, SUNFISH Part 2, and JEWELFISH available at the CCODs (12 November 2020, 15 January 2020, 30 September 2020 and 29 January 2021, respectively). Safety assessments included AEs (non-serious and serious), laboratory assessments, vital signs, ECGs, and ophthalmologic monitoring [38].

For the total of 465 SMA patients who received risdiplam the overall exposure to risdiplam was 856.9 Patient Years (PY).

At the CCODs, there were no treatment-related safety findings leading to treatment withdrawal in any of the three risdiplam trials included in the pooled safety analysis. The vast majority of reported AEs and SAEs were associated with underlying disease or disease progression. Over the time a reduction in AE rates was observed which may be indicative of the therapeutic benefit of risdiplam treatment, as this is not typically observed during the natural course of disease progression.

The differences in the AE profile between type 1 and types 2/3 SMA populations appeared to be driven by illnesses and conditions that are common in the respective age groups. The rate of SAEs was overall more than 3.3-fold higher in patients with type 1 SMA compared with patients with types 2/3 SMA. This difference appears mainly driven by the more severe SMA phenotype of Type 1 SMA. Seven deaths were reported overall; all in patients with type 1 SMA who died of SMA-related respiratory complications.

Preclinical safety findings were not observed in any patient. Extensive ophthalmologic monitoring for up to 46 months confirms the absence of retinal findings (only observed at high doses) observed in a preclinical study in monkeys [39]. Hematologic parameters have remained stable over time and no drug-induced skin SAE findings have been observed. Data across all studies suggest risdiplam has a favorable safety profile.

4. Conclusion

In August 2020 and in March 2021 risdiplam was approved by FDA in patients suffering from Spinal Muscular Atrophy (SMA) aged ≥2 months and by EMA for patients aged ≥2 months with a clinical diagnosis of SMA type 1, 2 or 3 or SMA patients with 1–4 copies of SMN2. The favorable efficacy/safety profile allows risdiplam to address remaining still unmet needs in this recent era of new SMA therapies. In particular, the possibility to administer risdiplam orally at home will make of it an attractive treatment option across all SMA phenotypes. Long-term efficacy and safety are still under evaluation.

More generally, as newborn screening is starting to get integrated in more countries, and patients are being followed up in worldwide disease registries, the availability of well-tolerated and safe compounds to treat SMA will change the course of the disease and the lives of many patients in the near future.

5. Expert opinion

From this ongoing clinical trial program one can already draw some reflections/conclusions:

Both FIREFISH in type 1 SMA and SUNFISH in type 2–3 non-ambulant patients demonstrated a statistically and clinically significant improvement across the broad spectrum of SMA phenotypic presentation. The improvement over a 1 year period of time, and when treatment was initiated in symptomatic patients, was of a similar order of magnitude to the one observed in patients treated with nusinersen (across the extended SMA spectrum) or onasemnogene abeparvovec (in SMA type 1), although precise head-to-head comparison data are not yet available. As for nusinersen, clear improvement was observed mainly in younger individuals whereas stabilization was observed in older individuals with SMA type 2. For the SUNFISH trial, these results were achieved in a population with a broad age range (although limited to patients younger than 25 years) and functional status, including individuals with advanced disease progression and comorbidities, that would not have been included in the other clinical trials.

Moreover, risdiplam treatment was not associated with any drug-related safety findings leading to withdrawal. Intensive ophthalmological monitoring, now over more than 4 years for many patients, did not reveal any safety findings and is still ongoing [38].

This up to now favorable efficacy/safety profile allows risdiplam to fulfill unmet needs in this recent era of new SMA therapies. Risdiplam is orally administered and has been shown (there is at least real evidence from animals) to cross the blood brain barrier where it most probably acts on motor neurons [14]. Administration does not require hospitalization, nor invasive procedures or invasive intrathecal administration and the concomitant use of other medicines as it is the case for nusinersen, which has been shown to be a limiting factor for some patients, with for example occurrences of headache and anxiety in some children and teenagers or technical infusion difficulties in patients that have undergone spine fusion in the past [40]. The benefit of home dosing, not requiring the last, cannot be underestimated especially in the current era of a pandemic. This makes risdiplam a strong candidate to improve the quality of life of up until now untreated patients or treated patients who experience side effects of their current treatment.

Moreover, it has been investigated in a broader range of patients than Zolgensma of which the indication is limited to patients under the age of 2 (US) or patients with SMA type 1 with 3 or less SMN2 copies [9,[10] and of which the use is limited by the weight of infants.

Although longer-term data from pivotal studies are now progressively available, the sustainability of efficacy, the favorable safety profile of risdiplam as well as direct comparison with nusinersen will still need to be followed with a particular focus. Data at 3 years will soon be available for the SUNFISH trial.

Recently communicated data from the RAINBOW FISH trial are very encouraging in patients including very young infants identified after newborn screening [41]. These results can help to inform the dosing for patients under the age of 2 months.

Regarding the pharmacodynamic effect of risdiplam, available data from FIREFISH and SUNFISH demonstrated that oral administration of risdiplam increases SMN protein levels in blood. Moreover a parallel dose‐dependent increase in SMN protein levels was seen in CNS and peripheral tissues (muscle) in two SMA mouse models dosed with risdiplam [42]. Although these results may suggest the potential benefit of risdiplam on peripheral tissues (this in comparison to nusinersen), this ‘peripheral’ effect remains insufficiently demonstrated.

The ex-post assessment of preclinical and clinical development of risdiplam were remarkable for several reasons. At a preclinical level, risdiplam was developed as an enhanced version of RG7800, with an improved PK/PD and safety profile [20], and minimalized off target effects.

Clinical development was from the start directed toward a broad age range and groups of patients that had not been targeted by other approaches. The design of pivotal trials comprised two parts, both in FIREFISH and SUNFISH, with part 1 aiming to validate the dose for part 2. This approach allowed the trials to run in a more streamlined manner, resulting in shorter timeframes and simpler logistical and regulatory approaches for the centers conducting the trials.

Finally, how will risdiplam market authorization impact treatment strategy of SMA?

The availability of 3 drugs with different mechanisms of action, pharmacokinetics, and routes of delivery makes in theory possible for the patient to combine or switch from one to another or eventually to combine treatments, a possibility that is being more and more requested by patients and their caregivers. However, one has to keep in mind that this concept is based on the unproven hypothesis that a synergistic effect could be achieved that would optimize function of the surviving motor neuron pool. It is challenging to demonstrate that a patient with SMA treated with one SMN-enhancing drug has the capacity to respond further upon the addition of a second drug. On a medical point of view, the possibility of combining therapies raises the question of additive efficacy vs long-term safety. There is still indeed a discussion regarding the required dosage of SMN along life and development. For example it is well known that the demand of SMN-protein shows a natural decrease after the second year of life [42]. This strategy will be of course highly dependent on the reimbursement schemes and switch authorization possibilities from the regulators. Indeed, the very high price of these new drugs will most probably exacerbate inequalities in access between countries with publicly and privately funded health care but also for patients without any health care coverage.

Nevertheless, having an option to choose the most effective and most tolerated drug on an individual basis is a big step forward in the treatment of SMA both for patients and for treating physicians.

Declaration of interest

N Deconinck has participated in advisory boards/been the Principal Investigator in clinical studies for Nusinersen, Onasomnogene abeparvovec, and Risdiplam. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors of this article are a member of ERN Euro-NMD (European Reference Network).

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received honoraria for lectures and the participation in Advisory Boards from Roche, Novartis Gene therapies, Biogen, PTC, and Pfizer. No other peer reviewers on this manuscript have relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.