Risdiplam (Evrysdi®): A Comprehensive Monograph on the First Oral SMN2 Splicing Modifier for Spinal Muscular Atrophy

Executive Summary

Risdiplam, marketed under the brand name Evrysdi®, represents a paradigm shift in the management of spinal muscular atrophy (SMA), a devastating, progressive neuromuscular disorder. As the first small-molecule, orally administered, and systemically distributed disease-modifying therapy for SMA, Risdiplam addresses critical unmet needs left by earlier therapeutic modalities. Its development was a direct response to the significant treatment burdens associated with invasive, facility-based administrations, offering patients a therapy that can be taken at home. The mechanism of action is highly specific: Risdiplam is a Survival of Motor Neuron 2 (SMN2) pre-mRNA splicing modifier that selectively promotes the inclusion of exon 7, thereby correcting the primary molecular defect of the SMN2 gene and enabling the production of full-length, functional Survival of Motor Neuron (SMN) protein. This action is not confined to the central nervous system; as an orally bioavailable small molecule, Risdiplam increases SMN protein levels systemically, addressing the growing understanding of SMA as a multi-system disorder.

A comprehensive clinical development program, encompassing four pivotal trials—FIREFISH, SUNFISH, RAINBOWFISH, and JEWELFISH—has established the efficacy and safety of Risdiplam across an unprecedentedly broad spectrum of the SMA population. Evidence demonstrates clinically meaningful benefits in patients of all ages, from presymptomatic newborns to adults, and across SMA Types 1, 2, and 3. In infants with the most severe form of the disease, Risdiplam has been shown to improve survival and motor milestones, such as sitting without support, that are never achieved in the natural course of the disease. In children and adults with later-onset SMA, it has been shown to improve or stabilize motor function, a crucial outcome for preserving independence in a progressive condition. Most profoundly, when administered to presymptomatic infants identified through newborn screening, Risdiplam has enabled the achievement of motor milestones like sitting, standing, and walking within the normal developmental windows for healthy children, heralding a new era of preventative therapy for SMA. The drug maintains a consistent and manageable safety profile, with the most common adverse events being fever, diarrhea, and rash. This monograph provides an exhaustive review of Risdiplam, detailing its chemical properties, sophisticated pharmacological mechanism, the extensive clinical evidence supporting its use, its regulatory journey, and its pivotal role in transforming the therapeutic landscape for individuals living with spinal muscular atrophy.

Section 1: Introduction to Spinal Muscular Atrophy and the Therapeutic Landscape

1.1 The Genetic and Molecular Basis of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease that stands as the leading genetic cause of infant mortality.[1] The disease arises from a deficiency of the ubiquitously expressed Survival of Motor Neuron (SMN) protein, which is critical for the maintenance and function of motor neurons.[2] The genetic underpinning of SMA is located on chromosome 5q, where the vast majority of cases (approximately 92%) are caused by a homozygous deletion or mutation of the

Survival of Motor Neuron 1 (SMN1) gene.[3] This gene is responsible for producing the majority of full-length, functional SMN protein. A deficiency of this protein leads to the progressive degeneration of alpha motor neurons in the anterior horn of the spinal cord, which in turn results in debilitating muscle atrophy, profound weakness, and, in its most severe forms, premature death.[1]

Fortunately, humans possess a nearly identical paralogous gene, Survival of Motor Neuron 2 (SMN2), which serves as the primary therapeutic target for Risdiplam and other SMN-enhancing therapies.[6] The

SMN2 gene differs from SMN1 by a single, translationally silent C-to-T nucleotide transition within exon 7.[3] While this change does not alter the amino acid sequence, it disrupts an exonic splicing enhancer and creates an exonic splicing silencer. This critical difference alters the pre-mRNA splicing process, causing the spliceosome to predominantly exclude exon 7 from the final mRNA transcript. The resulting protein, known as SMNΔ7, is truncated, unstable, and rapidly degraded, rendering it largely non-functional.[3] Consequently, the

SMN2 gene produces only a small fraction (approximately 10%) of the full-length, functional SMN protein that the SMN1 gene would normally provide.[3]

The number of SMN2 gene copies an individual possesses is variable and serves as the most important genetic modifier of disease severity. While the SMN2 gene cannot fully compensate for the loss of SMN1, a higher copy number generally correlates with increased baseline production of functional SMN protein and, therefore, a milder disease phenotype.[6] This correlation is a foundational concept in SMA pathology and prognostication, influencing the clinical classification of the disease.

1.2 Clinical Spectrum and Classification of SMA

The clinical presentation of SMA is remarkably heterogeneous, traditionally classified into types based on the age of symptom onset and the highest motor milestone achieved. This classification provides a framework for understanding the disease's natural history and for evaluating the impact of therapeutic interventions.

1.2.1 Type 1 (Werdnig-Hoffmann Disease)

SMA Type 1 is the most severe and common form, with symptom onset occurring between birth and 6 months of age.[5] Infants with Type 1 SMA present with profound, symmetric muscle weakness and hypotonia, often described as having a "frog-leg" posture.[5] They exhibit a weak cry, difficulty with feeding and swallowing, and significant respiratory distress due to weakness of the intercostal muscles, leading to a characteristic bell-shaped chest and paradoxical breathing pattern.[5] Tongue fasciculations are also a common finding. Cognition and facial muscle function are typically spared.[5] The natural history of untreated Type 1 SMA is grim; affected infants are never able to sit without support and, without permanent ventilatory support, rarely survive beyond two years of age.[8] This severe trajectory serves as a critical baseline against which the efficacy of modern therapies like Risdiplam is measured.

1.2.2 Type 2 (Intermediate Form)

In SMA Type 2, symptoms typically manifest between 6 and 18 months of age.[5] Children with this form of the disease are able to sit independently but are unable to stand or walk without support.[5] They experience progressive proximal muscle weakness, absent deep tendon reflexes, and fine tremors (minipolymyoclonus) in the distal limbs.[5] Complications such as progressive scoliosis and restrictive lung disease are common and contribute significantly to morbidity.[5] While the lifespan is variable, mortality often occurs in young adulthood without proactive respiratory care.[5]

1.2.3 Type 3 (Kugelberg-Welander Disease)

SMA Type 3 is a milder form with an age of onset after 18 months.[5] Individuals with Type 3 SMA achieve the ability to walk independently, although this milestone may be delayed. They typically present with difficulty climbing stairs or frequent falls due to proximal muscle weakness.[5] Over time, many individuals may lose ambulation and require a wheelchair.[5] Most patients with Type 3 SMA have a normal or near-normal life expectancy.[5]

1.2.4 Presymptomatic SMA

The advent of newborn screening programs has introduced a new and critical patient category: presymptomatic SMA. These are infants who have a confirmed genetic diagnosis of SMA (i.e., homozygous deletion of SMN1) but have not yet developed clinical symptoms.[12] This stage represents a crucial therapeutic window. Intervention before the onset of symptoms offers the potential to prevent or significantly mitigate the irreversible loss of motor neurons, thereby altering the natural history of the disease in a profound way, a concept robustly validated in the RAINBOWFISH clinical trial of Risdiplam.[13]

1.3 The Evolving Therapeutic Paradigm Prior to Risdiplam

Before the approval of the first disease-modifying therapies, the management of SMA was entirely supportive, focusing on respiratory, nutritional, and orthopedic care. The therapeutic landscape was revolutionized by the introduction of two groundbreaking treatments that, for the first time, targeted the underlying genetic cause of the disease.

The first approved therapy was Nusinersen, an antisense oligonucleotide (ASO) designed to modify the splicing of SMN2 pre-mRNA to promote the inclusion of exon 7.[8] While highly effective, its administration requires repeated intrathecal injections into the cerebrospinal fluid, a procedure that is invasive, requires hospital visits, and can become technically challenging in patients with severe scoliosis.[2]

The second major advance was Onasemnogene Abeparvovec, a gene replacement therapy that uses an adeno-associated virus vector to deliver a functional copy of the SMN1 gene to motor neurons.[2] It is administered as a one-time intravenous or intrathecal infusion.[2] While transformative, this approach also involves a significant, facility-based intervention.

These pioneering therapies established the principle that restoring SMN protein could dramatically alter the course of SMA. However, their invasive routes of administration and the associated logistical burdens created a clear and significant unmet need for a less invasive, more accessible treatment option. The development of Risdiplam was not merely an iterative improvement but a strategic and direct response to these fundamental limitations. The limitations of its predecessors paved the way for a new approach in drug design philosophy, one that prioritized not only efficacy but also patient quality of life, ease of administration, and the potential for systemic treatment. While all three therapies target the restoration of SMN protein, Risdiplam’s design as a small molecule for oral, at-home administration represents a pivotal shift. This modality has profound implications for both the patient experience, by moving treatment from the hospital to the home, and for the biological scope of the therapy. The growing recognition of SMA as a multi-system disorder, with SMN protein being expressed ubiquitously, suggests that a systemically distributed drug could offer a mechanistic advantage over therapies delivered primarily to the central nervous system.[1] Risdiplam was engineered to meet this need, offering the promise of a therapy that was not only effective but also convenient and biologically comprehensive.[2]

Section 2: Risdiplam: Chemical Profile and Synthesis

2.1 Nomenclature and Identifiers

Risdiplam is a synthetic organic small molecule that is precisely identified across scientific, chemical, and regulatory databases through a standardized set of names and codes. This ensures clarity and prevents ambiguity in research and clinical practice.

• International Union of Pure and Applied Chemistry (IUPAC) Name: The formal chemical name for Risdiplam is 7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one.[8]
• Synonyms and Development Codes: During its development, Risdiplam was known by several codes, including RG-7916, RG7916, RO-7034067, and RO7034067.[2] Its approved brand name is Evrysdi®.[8]
• Key Database Identifiers: To facilitate cross-referencing, Risdiplam is assigned unique identifiers in major databases:
• CAS Number: 1825352-65-5 [8]
• DrugBank ID: DB15305 [2]
• ChEMBL ID: CHEMBL4297528 [8]
• PubChem CID: 118513932 [8]
• UNII (Unique Ingredient Identifier): 76RS4S2ET1 [8]

2.2 Physicochemical Properties

The physicochemical properties of Risdiplam are fundamental to its function as an orally bioavailable drug that can distribute throughout the body. These characteristics were optimized during its discovery to ensure it possessed favorable "drug-like" qualities.

• Molecular Formula and Weight: The molecular formula of Risdiplam is C22​H23​N7​O.[8] This corresponds to a molecular weight of approximately 401.47 g/mol and a monoisotopic mass of 401.1964 Da.[8]
• Appearance and Purity: In its solid state, Risdiplam is a crystalline solid.[22] The powder for oral solution is described as having a color ranging from light yellow to light green.[26] Pharmaceutical-grade Risdiplam has a purity exceeding 98%.[22]
• Solubility: Risdiplam demonstrates solubility in chloroform (10 mg/mL) and is soluble in aqueous acidic solutions, such as 1 equivalent of HCl, where concentrations up to 100 mM can be achieved with gentle warming.[22] This solubility profile is consistent with its classification as a basic compound.[20]
• Computed Properties and "Drug-Likeness": Computational analysis of Risdiplam's structure reveals properties that are highly favorable for an oral drug, conforming to Lipinski's Rule of Five, a set of guidelines used to predict oral bioavailability. It has 1 hydrogen bond donor and 8 hydrogen bond acceptors (Lipinski criteria), a calculated logarithm of the octanol-water partition coefficient (AlogP) of 1.96, and a polar surface area of 79.83 Ų.[20] With zero violations of Lipinski's rules, its structure is well-suited for passive diffusion across biological membranes, including the intestinal wall and the blood-brain barrier.[20]

Table 1: Key Identifiers and Physicochemical Properties of Risdiplam

Property	Value	Source Snippet(s)
IUPAC Name	7-(4,7-diazaspiro[2.5]octan-7-yl)-2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyrido[1,2-a]pyrimidin-4-one	8
CAS Number	1825352-65-5	8
DrugBank ID	DB15305	2
Molecular Formula	C22​H23​N7​O	15
Molecular Weight	401.47 g/mol	8
Appearance	Crystalline Solid (Powder: Light yellow to light green)	22
Solubility	Soluble in 1eq. HCl and Chloroform	22
AlogP	1.96	20
H-Bond Donors	1	20
H-Bond Acceptors	8	20
Polar Surface Area	79.83 Ų	20
#RO5 Violations	0	20

2.3 Synthesis and Formulation

The chemical synthesis of Risdiplam has evolved from its initial discovery to optimized commercial-scale production, reflecting a continuous effort to improve efficiency and accessibility. The molecule itself is formulated to be stable and easy for patients or caregivers to administer at home.

• Synthetic Strategies: The synthesis of Risdiplam involves the construction of its complex heterocyclic core, the 4H-pyrido[1,2-a]pyrimidin-4-one scaffold, and its subsequent decoration with the imidazo[1,2-b]pyridazine and 4,7-diazaspiro[2.5]octane fragments.[30] Early synthetic routes, including the one used during its discovery, relied on methods such as Conrad–Limpach-type condensation and often involved challenging steps like palladium complex-catalyzed cross-coupling reactions.[30] These reactions, while effective, can be costly and require strict control of conditions. Recognizing these challenges, subsequent research has focused on developing more convenient and efficient synthetic pathways. Novel approaches have been developed that avoid the use of palladium catalysts altogether, utilizing alternative chemical strategies like copper(I)-catalyzed heterocyclization.[30] The evolution of Risdiplam's synthesis is a critical factor in its long-term viability as a therapeutic agent. Simplifying the manufacturing process can lead to lower production costs, a more robust and resilient supply chain, and a reduced environmental footprint. These factors are particularly important for a medication intended for lifelong administration to a global rare disease population, as they directly impact the drug's affordability and accessibility, helping to ensure long-term availability and support the resilience of healthcare systems.[15]
• Formulation: Risdiplam is available in two formulations to accommodate a wide range of patients. The primary formulation is a powder for oral solution, supplied in a bottle containing 60 mg of Risdiplam. This powder must be reconstituted by a pharmacist or other healthcare provider prior to dispensing, creating a solution with a final concentration of 0.75 mg/mL.[26] The reconstituted solution is stable for 64 days when stored under refrigeration.[32] More recently, a 5 mg tablet formulation was approved, offering a more convenient option for patients aged 2 years and older who weigh at least 20 kg.[26] The unconstituted powder is stable for at least 4 years.[24]

Section 3: Preclinical and Clinical Pharmacology

3.1 Mechanism of Action: A Novel Small Molecule Splicing Modifier

Risdiplam's therapeutic effect is derived from its highly specific and innovative mechanism of action as a small molecule modifier of SMN2 pre-mRNA splicing. It directly targets the underlying molecular pathology of SMA, correcting the genetic flaw at the RNA level to restore production of the essential SMN protein.

3.1.1 Targeting SMN2 Pre-mRNA

Risdiplam is classified as a selective SMN2 pre-mRNA splicing modifier.[15] Its primary function is to bind directly to the

SMN2 pre-mRNA and modulate the action of the spliceosome, the cellular machinery responsible for editing mRNA transcripts. By doing so, it effectively corrects the inherent splicing defect of the SMN2 gene, promoting the inclusion of the otherwise skipped exon 7 into the mature mRNA transcript.[2] This correction results in the production of full-length, stable, and fully functional SMN protein, thereby compensating for the deficiency caused by the non-functional

SMN1 gene.[3]

3.1.2 Dual-Binding Mechanism and Specificity

The remarkable specificity of Risdiplam for SMN2 pre-mRNA, which minimizes the potential for off-target splicing events, is attributed to a sophisticated dual-binding mechanism. Research has revealed that Risdiplam interacts with two distinct sites on the SMN2 pre-mRNA transcript.[6] The first binding site is at the 5' splice site (5'ss) of exon 7, the very location where the U1 small nuclear ribonucleoprotein (snRNP) complex must bind to initiate proper splicing. The natural C-to-T nucleotide variation in

SMN2 weakens this binding site. Risdiplam's interaction at this location stabilizes the binding of the U1 snRNP complex, effectively converting the weak splice site into a stronger, more recognizable one.[6]

A second binding site, known as the exonic splicing enhancer 2 (ESE2), was identified within exon 7.[6] The simultaneous binding of Risdiplam to both the 5'ss and the ESE2 element is believed to provide a high degree of selectivity for

SMN2 pre-mRNA. This dual interaction ensures that the splicing modification is precisely targeted, a crucial feature for any drug that modulates a fundamental cellular process like RNA splicing.[6]

3.1.3 Systemic Distribution and Effect

A defining characteristic of Risdiplam is its design as a small molecule capable of broad systemic distribution following oral administration. Preclinical studies in animal models, as well as clinical data, have confirmed that Risdiplam effectively crosses the blood-brain barrier to exert its effects on motor neurons within the central nervous system (CNS).[2] Crucially, it also distributes to peripheral tissues and organs throughout the body.[4] This systemic action is of growing importance as the understanding of SMA evolves. SMN protein is expressed ubiquitously, and evidence increasingly suggests that SMA is a multi-system disorder where SMN deficiency affects not only motor neurons but also other cells and tissues, potentially impacting cardiac, metabolic, and other functions.[1] A systemically distributed therapy like Risdiplam is therefore well-positioned to address both the central and peripheral manifestations of the disease.

3.2 Pharmacodynamics

The primary pharmacodynamic effect of Risdiplam is the direct and measurable increase in functional SMN protein levels in the body, a response that is both rapid and durable.

3.2.1 SMN Protein Induction

Across all clinical trials and in all SMA patient populations studied, from infants to adults, treatment with Risdiplam leads to a rapid and significant increase in SMN protein levels. Data consistently demonstrate a greater than 2-fold median increase from baseline SMN protein concentration within just 4 weeks of initiating therapy.[2] This swift biological response confirms that the drug effectively engages its target and initiates the intended molecular correction.

3.2.2 Sustained Response

The increase in SMN protein is not transient. Clinical trial data, with follow-up extending beyond 24 months, show that the elevated levels of SMN protein are sustained for the duration of treatment.[16] In the JEWELFISH study, this sustained 2-fold increase was observed for over two years.[38] This durable pharmacodynamic effect is critical for a neurodegenerative disease, as the continuous production of SMN protein is necessary to protect the remaining motor neurons from further degeneration, thereby stabilizing the disease and allowing for the potential improvement of motor function over the long term.

3.3 Pharmacokinetics (ADME)

The pharmacokinetic profile of Risdiplam has been well-characterized in both healthy adults and patients with SMA. Its properties of absorption, distribution, metabolism, and excretion (ADME) are consistent with its design as an effective, once-daily oral medication.

3.3.1 Absorption

Following oral administration, Risdiplam is readily absorbed, with peak plasma concentrations (Tmax) reached between 1 and 4 hours.[2] The pharmacokinetics are approximately linear across the range of studied doses.[2] While it can be administered with or without food, in the pivotal clinical trials, it was typically given with a morning meal or after breastfeeding.[2] After once-daily administration, Risdiplam reaches steady-state concentrations in the body within 7 to 14 days, with an observed accumulation of approximately 3-fold.[2]

3.3.2 Distribution

As intended by its design, Risdiplam distributes widely throughout the body, penetrating both the CNS and peripheral tissues.[2] The apparent volume of distribution at steady state is 6.3 L/kg, or approximately 190.4 L for a 31.3 kg patient, indicating extensive tissue distribution.[2] In the plasma, Risdiplam is highly protein-bound (approximately 89%), primarily to serum albumin, with a free fraction of 11% available to distribute to tissues.[2]

3.3.3 Metabolism

Risdiplam's metabolic pathway is a key feature that contributes to its favorable drug-drug interaction profile. Its metabolism is primarily mediated by flavin monooxygenases 1 and 3 (FMO1 and FMO3), enzymes that are less commonly involved in drug metabolism than the cytochrome P450 (CYP) system.[2] The CYP system is a frequent source of drug-drug interactions because many medications can inhibit or induce these enzymes, altering the metabolism of co-administered drugs. Because Risdiplam's metabolism is dominated by the FMO pathway, which is not readily induced or inhibited, it has an inherently lower potential for many common drug-drug interactions, simplifying its use in patients who may require concomitant medications.[41] Minor metabolic contributions are made by CYP enzymes 1A1, 2J2, 3A4, and 3A7.[2] The parent drug is the major component found in circulation, accounting for 83% of drug-related material.[2] A major circulating metabolite, designated M1, has been identified. While M1 is pharmacologically inactive with respect to SMN splicing, it importantly retains inhibitory activity against the MATE1 and MATE2-K drug transporters, similar to the parent drug.[2] This observation has significant clinical implications, as it suggests that the potential for drug interactions involving MATE transporters is influenced by the total exposure to both Risdiplam and its M1 metabolite. The inhibitory effect could therefore be more prolonged than if it were mediated by the parent drug alone, reinforcing the clinical guidance to avoid co-administration with MATE substrates.

3.3.4 Excretion

Risdiplam and its metabolites are eliminated from the body through both renal and fecal routes. Following an oral dose, approximately 53% is excreted in the feces (with 14% as unchanged Risdiplam) and 28% is excreted in the urine (with 8% as unchanged Risdiplam).[2] The terminal elimination half-life is approximately 50 hours in healthy adults, a long duration that supports the convenience of a once-daily dosing schedule.[2]

3.3.5 Pharmacokinetics in Special Populations

The pharmacokinetics of Risdiplam are most significantly influenced by age and body weight, and the approved dosing regimens are specifically designed to account for these factors to achieve consistent drug exposures across all patient populations.[27] For other patient-specific factors, no dose adjustments are recommended for patients with any degree of renal impairment or for those with mild to moderate hepatic impairment. However, as Risdiplam is predominantly metabolized in the liver, its use should be avoided in patients with severe hepatic impairment, as its pharmacokinetics have not been studied in this population and drug exposure could be significantly increased.[27]

Table 2: Summary of Pharmacokinetic Parameters of Risdiplam

Pharmacokinetic Parameter	Value	Source Snippet(s)
Time to Peak Concentration (Tmax)	1–4 hours	2
Plasma Protein Binding	~89% (primarily to albumin)	2
Apparent Volume of Distribution (Vd)	6.3 L/kg	2
Primary Metabolic Enzymes	Flavin Monooxygenase 1 and 3 (FMO1, FMO3)	2
Major Metabolite	M1 (pharmacologically inactive, MATE inhibitor)	2
Terminal Half-life (t½)	~50 hours (in healthy adults)	2
Route of Excretion	Feces (~53%), Urine (~28%)	2

Section 4: Clinical Development Program and Efficacy Analysis

4.1 Overview of the Risdiplam Clinical Trial Program

The clinical development of Risdiplam was distinguished by its comprehensive and strategic design, which intentionally enrolled a broad and diverse patient population to reflect the real-world spectrum of individuals living with SMA.[1] This approach was not limited to proving efficacy in isolated patient groups but was constructed to systematically build a robust evidence base for Risdiplam's utility across the entire continuum of the disease. The program was anchored by four pivotal, multicenter clinical trials, each designed to answer a specific and critical question about the drug's role in a different segment of the SMA population. This progression of trials—from treating symptomatic patients (FIREFISH and SUNFISH), to preventing symptoms in newborns (RAINBOWFISH), and finally to addressing the needs of complex, previously treated patients (JEWELFISH)—demonstrates a thorough, lifecycle approach to evidence generation that has established Risdiplam as a viable therapeutic option at every stage of the patient journey.

Table 3: Overview of Pivotal Clinical Trials for Risdiplam

Trial Name (NCT ID)	Patient Population	Age Range	Study Design	Primary Endpoint(s)
FIREFISH (NCT02913482)	Symptomatic Type 1 SMA	2–7 months	Open-label, two-part	Proportion of infants sitting without support for ≥5 seconds at 12 months (BSID-III)
SUNFISH (NCT02908685)	Symptomatic Type 2 or 3 SMA	2–25 years	Randomized, double-blind, placebo-controlled, two-part	Change from baseline in MFM-32 total score at 12 months
RAINBOWFISH (NCT03779334)	Presymptomatic SMA	Birth to 6 weeks	Open-label, single-arm	Proportion of infants sitting without support for ≥5 seconds at 12 months (BSID-III)
JEWELFISH (NCT03032172)	Previously treated SMA	6 months–60 years	Open-label, single-arm	Safety and pharmacodynamics (change in SMN protein levels)

4.2 Efficacy in Infantile-Onset SMA (FIREFISH Trial)

The FIREFISH trial was designed to evaluate the efficacy and safety of Risdiplam in infants with Type 1 SMA, the most severe form of the disease, where the natural history is one of rapid decline and early mortality.

4.2.1 Study Design

FIREFISH was a two-part, open-label study conducted in symptomatic infants aged 2 to 7 months at the time of enrollment.[9] Part 1 of the study was a dose-finding phase involving 21 infants to determine the optimal therapeutic dose for further investigation.[9] Part 2 was the pivotal, single-arm efficacy portion of the trial, which enrolled 41 infants with Type 1 SMA who were treated with the recommended dose.[9] Given the universally fatal progression of untreated Type 1 SMA, a placebo control was deemed unethical; thus, outcomes were compared against the well-documented natural history of the disease.

4.2.2 Primary and Key Endpoints

The primary efficacy endpoint for the FIREFISH trial was the proportion of infants who were able to sit without support for at least 5 seconds after 12 months of treatment, as assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III).[9] This milestone is of profound clinical significance because it is an ability that is never achieved by infants with untreated Type 1 SMA.[9] A key secondary endpoint was survival without the need for permanent ventilation.

4.2.3 Efficacy Outcomes

The results from the FIREFISH trial demonstrated a dramatic and clinically meaningful deviation from the natural history of Type 1 SMA. After 12 months of treatment, 41% (7 of 17) of infants in the therapeutic dose cohort achieved the primary endpoint of sitting without support for at least 5 seconds.[10] The positive effects continued with longer-term treatment, with data at 24 months showing continual improvements in motor function and the achievement of additional developmental milestones.[45]

The survival data were equally compelling. In the natural history of the disease, no more than 25% of infants are expected to survive without permanent ventilation beyond 14 months of age.[9] In stark contrast, after a minimum of 23 months of treatment with Risdiplam, 81% of patients were alive and free from permanent ventilation.[8] Long-term follow-up data at 5 years provided a more complete picture of outcomes, reporting that of 58 infants who received the recommended dose, 11 were not deemed "event-free"; of these, 6 had met the definition of permanent ventilation and 5 had died.[9] These results unequivocally established the efficacy of Risdiplam in altering the devastating course of infantile-onset SMA.

4.3 Efficacy in Later-Onset SMA (SUNFISH Trial)

The SUNFISH trial was a landmark study, being the first placebo-controlled trial of an SMA therapy to include a broad age range of patients, including adults, with later-onset (Type 2 or 3) SMA.

4.3.1 Study Design

SUNFISH was a two-part, randomized, double-blind, placebo-controlled pivotal study that enrolled 180 patients aged 2 to 25 years.[1] The study was intentionally designed to represent a real-world SMA population, including a significant number of patients with established disease complications such as scoliosis (63% in the Risdiplam arm) and joint contractures.[18] Part 1 of the study was an exploratory dose-finding portion with 51 patients.[47] Part 2 was the confirmatory efficacy portion, in which 180 patients were randomized in a 2:1 ratio to receive either Risdiplam or placebo for 12 months, after which all patients received open-label Risdiplam.[47]

4.3.2 Primary Endpoint

The primary endpoint of the SUNFISH trial was the change from baseline in the total score of the 32-item Motor Function Measure (MFM-32) scale after 12 months of treatment.[1] The MFM-32 is a validated scale used to evaluate a wide range of fine and gross motor functions in individuals with neuromuscular disorders, making it suitable for the heterogeneous population in this trial.[47]

4.3.3 Efficacy Outcomes

The SUNFISH trial successfully met its primary endpoint. After 12 months, patients treated with Risdiplam demonstrated a statistically significant and clinically meaningful improvement in motor function compared to those who received a placebo. The mean change from baseline in the MFM-32 total score was significantly greater in the Risdiplam group, with a mean difference of 1.55 points between the two arms (p=0.0156).[10]

Exploratory analyses of longer-term data provided further evidence of sustained benefit. After 24 months of treatment (including 12 months of open-label treatment for the initial placebo group), the gains in motor function were either maintained or improved upon. In the group that received Risdiplam for the full 24 months, 32% of patients showed a clinically meaningful improvement (a change of ≥3 points on the MFM-32 scale), and an additional 58% showed stabilization (a change of ≥0 points).[11] This finding of disease stabilization is of profound clinical importance. In a progressive neurodegenerative disease like SMA, simply halting the expected decline in function is a significant therapeutic victory. For an older patient with established disease, preserving their existing motor abilities—such as the ability to use a computer, feed themselves, or operate a wheelchair—is a primary treatment goal that directly translates to maintaining independence and quality of life. The SUNFISH trial thus reframed the definition of therapeutic success in later-onset SMA, demonstrating that Risdiplam could not only improve function in some but could also critically preserve function in others.[46] Subgroup analyses showed that the most robust improvements were seen in the youngest age group (2-5 years), while the stabilization effect was particularly evident and important in the older adolescent and adult population (18-25 years).[46]

4.4 Efficacy in Presymptomatic SMA (RAINBOWFISH Trial)

The RAINBOWFISH trial represents a paradigm shift in the management of SMA, moving from treatment of established symptoms to pre-emptive intervention aimed at preventing the disease from ever fully manifesting.

4.4.1 Study Design and Rationale

RAINBOWFISH is an ongoing, open-label, single-arm study evaluating Risdiplam in infants from birth to 6 weeks of age who have a confirmed genetic diagnosis of SMA but have not yet developed clinical symptoms.[1] The majority of these infants (77%) were identified through newborn screening programs.[52] The fundamental rationale for the trial is to initiate SMN protein restoration during the critical presymptomatic window, before the irreversible death of motor neurons occurs, with the goal of enabling a more normal developmental trajectory.

4.4.2 Efficacy Outcomes

The interim results from the RAINBOWFISH trial have been transformative. After 12 months of treatment, an overwhelming majority of infants achieved key motor milestones. Among the 26 infants in the intent-to-treat population, 96% (25 of 26) were able to sit without support for at least 5 seconds, and 81% (21 of 26) could sit without support for at least 30 seconds.[50] Furthermore, 81% (21 of 25) were able to stand (with or without support), and 48% (12 of 25) were able to walk independently.[50]

The outcomes at 24 months were even more remarkable. All 23 infants who completed 24 months of treatment were able to sit without support.[50] Of these, 96% (22 of 23) were able to stand, and 87% (20 of 23) were able to walk independently.[50] Critically, a majority of these infants achieved these milestones within the standard developmental windows defined by the World Health Organization for healthy, typically developing children.[52] In addition to motor milestones, all infants were alive without permanent ventilation at 24 months and maintained the ability to swallow and feed exclusively by mouth.[52] These data provide powerful evidence that early diagnosis through newborn screening, followed by prompt initiation of Risdiplam, can fundamentally alter the natural history of SMA, allowing for a developmental trajectory that closely resembles that of unaffected children.

4.5 Efficacy in Previously Treated Patients (JEWELFISH Trial)

The JEWELFISH trial was designed to address a complex and increasingly common clinical scenario: the management of patients who have previously been treated with other SMA-targeting therapies. It is the largest and most diverse study ever conducted in this specific patient population.

4.5.1 Study Design

JEWELFISH is an open-label, single-arm exploratory trial that enrolled 174 patients ranging in age from 6 months to 60 years.[1] All participants had previously received other SMA therapies, including the ASO nusinersen, the gene therapy onasemnogene abeparvovec, or the investigational compound olesoxime.[38] The trial population was notable for its severity, with 63% having a baseline HFMSE score below 10 and 83% having scoliosis.[39]

4.5.2 Primary Outcomes (Safety and Pharmacodynamics)

The primary objectives of the JEWELFISH trial were to assess the safety and pharmacodynamic profile of Risdiplam in this population. The safety profile was found to be consistent with that observed in treatment-naïve patients, with no new safety signals identified.[56] The pharmacodynamic results were clear and consistent: treatment with Risdiplam led to a rapid (within 4 weeks) and sustained median 2-fold increase in SMN protein levels from baseline. This increase was maintained for over two years of treatment and was observed irrespective of the patient's prior therapy.[38]

4.5.3 Exploratory Efficacy

While not the primary focus, exploratory efficacy endpoints were assessed. The data suggest that motor function, as measured by the MFM-32, Revised Upper Limb Module (RULM), and Hammersmith Functional Motor Scale Expanded (HFMSE) scales, was generally maintained or improved over the two-year treatment period.[39] In the context of a progressive disease, the stabilization of motor function in a heavily pre-treated and severely affected population is a clinically meaningful outcome. These findings provide clinicians with evidence that switching to or adding Risdiplam can be a safe and beneficial option for patients who may be experiencing tolerability issues, administration burdens, or a waning therapeutic effect from their previous SMA treatment.

Section 5: Safety and Tolerability Profile

The safety and tolerability of Risdiplam have been extensively evaluated across its comprehensive clinical development program, which included over 480 patients with a median exposure duration of nearly two years.[27] The overall safety profile is consistent across different SMA types and age groups and is generally considered manageable. A notable positive finding for a systemically distributed drug intended for chronic use is the absence of significant signals for severe, organ-specific toxicities, such as clinically apparent liver injury or hematological abnormalities.[15] The most serious adverse events reported in trials, such as pneumonia, are often reflective of the underlying respiratory complications inherent to SMA rather than direct drug toxicity, and the rate of such events has been observed to decrease over time with treatment, suggesting that by improving the underlying disease, the drug may reduce the incidence of its most severe complications.[39]

5.1 Adverse Reactions

The profile of adverse reactions (ARs) observed with Risdiplam varies slightly between the later-onset and infantile-onset SMA populations, primarily reflecting the different background rates of common illnesses in these age groups.

5.1.1 In Later-Onset SMA (SUNFISH Trial)

In the placebo-controlled portion of the SUNFISH trial involving children and adults with Type 2 or 3 SMA, the most common adverse reactions reported in at least 10% of patients treated with Risdiplam and at a higher incidence than in the placebo group were fever (22% vs. 17% in placebo), diarrhea (17% vs. 8%), and rash (17% vs. 2%).[8] Other adverse reactions that occurred in at least 5% of patients and with an incidence at least 5% greater than placebo included mouth and aphthous ulcers (7% vs. 0%), arthralgia (5% vs. 0%), and urinary tract infections (5% vs. 0%).[8]

5.1.2 In Infantile-Onset SMA (FIREFISH Trial)

In infants with Type 1 SMA, the adverse reaction profile was similar to that seen in the later-onset population. However, reflecting the higher incidence of common pediatric illnesses in this age group, additional adverse reactions were reported in at least 10% of patients. These included upper respiratory tract infections (such as nasopharyngitis and rhinitis), lower respiratory tract infections (such as pneumonia and bronchitis), constipation, vomiting, and cough.[8]

5.1.3 Long-Term Safety

Long-term follow-up data from the open-label extension phases of the clinical trials have shown that the safety profile of Risdiplam remains consistent over time, with treatment durations extending up to four years.[57] Encouragingly, the rate of adverse events was observed to decrease after the first year of treatment and then remain stable.[39] Across all pivotal trials, there were no treatment-related safety findings that led to patient withdrawal, underscoring the drug's overall good tolerability.[1]

Table 4: Summary of Common Adverse Reactions by Patient Population from Pivotal Trials

Adverse Reaction	Later-Onset SMA (Risdiplam %) (N=120)	Later-Onset SMA (Placebo %) (N=60)	Infantile-Onset SMA (Risdiplam %) (Incidence ≥10%)
Fever	22	17	≥10
Diarrhea	17	8	≥10
Rash	17	2	≥10
Upper Respiratory Tract Infection	-	-	≥10
Lower Respiratory Tract Infection	-	-	≥10
Constipation	-	-	≥10
Vomiting	-	-	≥10
Cough	-	-	≥10
Mouth and aphthous ulcers	7	0	-
Arthralgia	5	0	-
Urinary tract infection	5	0	-
Data for Later-Onset SMA from SUNFISH Part 2.27 Data for Infantile-Onset SMA from FIREFISH.27 Dashes indicate the event did not meet the specified reporting threshold for that column.

5.2 Warnings and Precautions

While Risdiplam is generally well-tolerated, there are important warnings and precautions that must be considered in specific patient populations.

• Pregnancy and Lactation: Based on findings from animal studies, Risdiplam may cause embryofetal harm. Therefore, pregnancy testing is recommended for females of reproductive potential before initiating therapy. These individuals should be counseled on the use of effective contraception during treatment and for at least one month after the final dose.[32] A pregnancy exposure registry has been established to monitor outcomes in women exposed to Risdiplam during pregnancy.[32] It is not known whether Risdiplam is present in human milk, so the potential risks and benefits must be carefully considered.[32]
• Male Fertility: Animal toxicology studies have suggested that Risdiplam may have adverse effects on male reproductive organs and could potentially compromise fertility. Male patients of reproductive potential should be counseled about this risk, and sperm preservation may be considered before starting treatment.[32]
• Hepatic Impairment: The safety and efficacy of Risdiplam have not been studied in patients with severe hepatic impairment. Since the liver is the primary site of Risdiplam metabolism, severe hepatic impairment could potentially lead to increased drug exposure. Therefore, the use of Risdiplam should be avoided in this patient population.[32]
• Handling Precautions: The Risdiplam powder for oral solution and the reconstituted solution should be handled with caution. Healthcare providers, pharmacists, and caregivers should avoid inhalation of the powder and direct contact with the powder or solution on skin or mucous membranes. If contact occurs, the area should be washed thoroughly with soap and water, and eyes should be rinsed with water. Disposable gloves should be worn during preparation and cleanup.[27]

5.3 Drug-Drug Interactions

Risdiplam has a relatively low potential for drug-drug interactions (DDIs), primarily because its metabolism is not heavily reliant on the cytochrome P450 enzyme system. However, one clinically significant interaction has been identified.

• Effect of Risdiplam on MATE Substrates: The most important DDI involves the Multidrug and Toxin Extrusion (MATE) protein transporters. In vitro studies have shown that both Risdiplam and its major metabolite, M1, are inhibitors of MATE1 and MATE2-K.[2] These transporters are involved in the renal secretion of various drugs. By inhibiting them, Risdiplam can increase the plasma concentrations of co-administered MATE substrates, such as the widely used diabetes medication metformin.[32] Due to this potential interaction, the co-administration of Risdiplam with MATE substrates should be avoided. If concurrent use is unavoidable, patients should be closely monitored for drug-related toxicities, and a dosage reduction of the MATE substrate should be considered in accordance with its labeling.[32]
• Other Interactions: Risdiplam is a weak inhibitor of CYP3A and may cause a slight, non-clinically relevant increase in the exposure of sensitive CYP3A substrates like midazolam.[28] It does not significantly inhibit or induce other major CYP enzymes.[64] Furthermore, strong inhibitors of CYP3A (e.g., itraconazole) do not have a clinically relevant effect on the pharmacokinetics of Risdiplam.[27] Risdiplam is also a weak substrate of the P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) transporters, and inhibitors of these transporters are not expected to cause clinically significant increases in Risdiplam concentrations.[27]

Section 6: Regulatory Journey and Market Access

The regulatory pathway for Risdiplam was characterized by speed and global coordination, reflecting the high unmet medical need in the SMA community and the strength of the clinical trial data. Regulatory agencies worldwide recognized the drug's potential and utilized multiple expedited pathways to bring it to patients as quickly as possible. This rapid succession of approvals and label expansions demonstrates a high degree of regulatory confidence in Risdiplam's favorable risk-benefit profile. The process began with strong early data, which earned the drug access to expedited review programs. This, in turn, facilitated the faster generation and submission of later-stage data for subsequent label expansions, creating a positive feedback loop that accelerated patient access globally.

6.1 Global Approval Timelines

Risdiplam has achieved widespread approval from major regulatory bodies around the world, making it a globally accessible treatment for SMA.

• U.S. Food and Drug Administration (FDA) Approval: The FDA granted the first approval for Risdiplam on August 7, 2020, for the treatment of SMA in patients aged 2 months and older.[8] In a significant label expansion based on the compelling interim data from the RAINBOWFISH trial, the FDA extended the indication on May 31, 2022, to include presymptomatic infants under 2 months of age.[13] To further enhance patient convenience, a new 5 mg tablet formulation was approved on February 12, 2025.[8]
• European Medicines Agency (EMA) Approval: The European Commission granted marketing authorization for Risdiplam on March 26, 2021. The approval covered the treatment of 5q SMA in patients 2 months of age and older with a clinical diagnosis of Type 1, 2, or 3 SMA, or with one to four SMN2 copies.[66] Following the FDA's lead, the EMA also expanded the label on August 29, 2023, to include the treatment of presymptomatic infants under two months old.[55]
• Other Regions: Risdiplam's global reach is extensive, with approvals in over 100 countries as of early 2025.[34] This includes approvals from regulatory bodies in numerous other countries, such as China, Brazil, Chile, Russia, and South Korea.[10]

6.2 Impact of Special Regulatory Designations

The development and review of Risdiplam were significantly accelerated through the strategic use of several special regulatory designations designed for therapies addressing rare and serious diseases.

• Orphan Drug Designation: Both the FDA (in 2017) and the EMA (in 2019) granted Risdiplam Orphan Drug Designation.[8] This status is reserved for medicines intended for rare diseases and provides various incentives to the developer, including market exclusivity and exemptions from certain regulatory requirements, such as the Pediatric Research Equity Act (PREA) assessments in the U.S..[71]
• Fast Track and Priority Review (FDA): The FDA granted Risdiplam both Fast Track designation, which facilitates development and expedites the review of drugs for serious conditions, and Priority Review, which shortens the review timeline from a standard 10 months to 6 months.[8] These designations underscored the agency's recognition of Risdiplam's potential to provide a significant improvement in the treatment of SMA.
• PRIME Designation and Accelerated Assessment (EMA): In 2018, the EMA granted Risdiplam access to its PRIority MEdicines (PRIME) scheme.[10] This program offers enhanced support and early dialogue to developers of promising medicines that target an unmet medical need. The subsequent review of the marketing authorization application was conducted under the EMA's accelerated assessment pathway, reducing the review time and reflecting the drug's potential for major public health and therapeutic innovation.[68]

6.3 Approved Indications

As a result of its comprehensive clinical development program, Risdiplam has received a broad indication for use across the full spectrum of the SMA patient population. The approved indication in the United States and other regions is for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.[12] This inclusive label, which covers patients from presymptomatic newborns to adults with later-onset disease, is a direct reflection of the robust evidence generated in the FIREFISH, SUNFISH, and RAINBOWFISH trials, solidifying Risdiplam's role as a foundational therapy for SMA.

Section 7: Prescribing Information and Patient Management

Effective and safe use of Risdiplam requires a clear understanding of its dosing, preparation, and administration procedures. The regimen is tailored to individual patients based on age and body weight to ensure consistent drug exposure and optimal outcomes.

7.1 Dosage and Administration

The dosing of Risdiplam is carefully calibrated to the patient's age and weight, reflecting the significant impact these factors have on its pharmacokinetics.

7.1.1 Dosing Regimen

Risdiplam is administered orally once daily. The specific dose is determined as follows:

• For infants less than 2 months of age: The recommended dose is 0.15 mg/kg.
• For patients 2 months to less than 2 years of age: The recommended dose is 0.2 mg/kg.
• For patients 2 years of age and older weighing less than 20 kg: The recommended dose is 0.25 mg/kg.
• For patients 2 years of age and older weighing 20 kg or more: A fixed dose of 5 mg is recommended.

This tiered dosing schedule is designed to achieve similar systemic drug exposures across the diverse patient population.[26]

Table 5: Risdiplam Dosing Regimen by Age and Body Weight

Age and Body Weight	Recommended Daily Dosage	Available Dosage Form(s)
Less than 2 months of age	0.15 mg/kg	Oral Solution
2 months to less than 2 years of age	0.2 mg/kg	Oral Solution
2 years of age and older weighing < 20 kg	0.25 mg/kg	Oral Solution
2 years of age and older weighing ≥ 20 kg	5 mg	Oral Solution or 5 mg Tablet
Source: 26

7.1.2 Formulations and Preparation

Risdiplam is available in two distinct formulations to meet the needs of different patients.

• Oral Solution: The primary formulation is a powder supplied in a bottle containing 60 mg of Risdiplam. This powder is not for direct use and must be reconstituted by a pharmacist or other qualified healthcare provider before it is dispensed to the patient.[26] Reconstitution involves carefully adding 79 mL of purified water to the bottle and shaking well to yield a final volume of 80 mL, with a concentration of 0.75 mg/mL.[27]
• Tablet: For patients who can take a fixed 5 mg dose, a 5 mg tablet is available. This tablet can be swallowed whole with water. For patients who have difficulty swallowing, the tablet can also be dispersed in a small amount of non-chlorinated drinking water (e.g., filtered water) before administration.[26]

7.1.3 Administration Guidelines

Proper administration is crucial for ensuring the patient receives the correct dose.

• General Instructions: Risdiplam should be taken once daily at approximately the same time each day. It can be taken with or without food.[26] After administration, the patient should drink water to ensure the full dose has been swallowed.[26]
• Oral Solution Administration: The prescribed volume of the oral solution must be measured and administered using the specific reusable oral syringe provided with the medication. Syringes are available in 1 mL, 6 mL, and 12 mL sizes to ensure accurate dosing.[28] The dose must be administered immediately after being drawn into the syringe; if it is not taken within 5 minutes, the dose must be discarded, and a new dose prepared.[26] The oral solution should not be mixed with milk or formula.[27] For patients with a nasogastric or gastrostomy tube, the oral solution can be administered via the tube, which should be flushed with water afterward.[26]
• Tablet Administration: The 5 mg tablet should be swallowed whole and not chewed, cut, or crushed.[26] If dispersed in water, the mixture should be administered immediately and the cup rinsed with additional water to ensure no residue is left behind. The dispersed tablet mixture cannot be administered via a feeding tube.[26]

7.2 Patient and Caregiver Considerations

Effective patient management involves clear communication and education for patients and their caregivers on several key aspects of Risdiplam therapy.

• Missed or Incomplete Doses: Caregivers should be instructed that if a dose is missed, it should be taken as soon as possible, but only if it is still within 6 hours of the regularly scheduled time. If more than 6 hours have passed, the missed dose should be skipped, and the regular dosing schedule should resume the following day. If a patient vomits or does not fully swallow a dose, a second dose should not be administered to make up for the lost dose.[28]
• Storage: The reconstituted oral solution is stable for 64 days and must be kept refrigerated between 36°F and 46°F (2°C to 8°C).[32] It should be kept in its original amber bottle to protect it from light. The tablets should be stored in their original bottle with the cap tightly closed to protect them from moisture.[63]
• Counseling Points: Clinicians should discuss several important topics with patients and caregivers. This includes reinforcing the proper handling procedures to avoid skin contact with the solution.[32] For females of reproductive potential, the need for effective contraception must be emphasized due to the potential for embryofetal harm.[32] For male patients, the potential effects on fertility should be discussed, and the option of sperm preservation may be presented.[32]

Section 8: Concluding Analysis and Future Perspectives

8.1 Synthesis of Evidence: A Favorable Risk-Benefit Profile

The totality of evidence from a robust and comprehensive clinical development program establishes a highly favorable risk-benefit profile for Risdiplam in the treatment of spinal muscular atrophy. The drug has demonstrated statistically significant and, more importantly, clinically meaningful efficacy across the entire spectrum of the disease. In infants with Type 1 SMA, where the natural history is one of inexorable decline and early death, Risdiplam improves survival and enables the achievement of motor milestones that would otherwise be impossible. In children and adults with later-onset SMA, it improves or critically stabilizes motor function, preserving independence and quality of life against the backdrop of a progressive disease. Most profoundly, in presymptomatic infants, early intervention with Risdiplam has been shown to permit a developmental trajectory that mirrors that of healthy children, fundamentally altering the prognosis of SMA.

These substantial benefits are achieved with a safety profile that is consistent, well-characterized, and generally manageable. The most common adverse reactions are typically non-severe, and the incidence of serious adverse events often reflects the underlying complications of SMA itself, with rates decreasing over time with sustained treatment. The absence of significant organ toxicity and the low rate of discontinuation due to adverse events in clinical trials further strengthen the conclusion that the benefits of SMN protein restoration with Risdiplam decisively outweigh the associated risks.

8.2 Risdiplam's Unique Position in the SMA Treatment Paradigm

Risdiplam occupies a unique and vital position within the therapeutic armamentarium for SMA, distinguished by several key advantages that have reshaped the treatment landscape.

• Oral, At-Home Administration: Its most transformative feature is its oral route of administration, which allows for at-home treatment.[4] This fundamentally changes the patient and caregiver experience, liberating them from the logistical, physical, and emotional burdens of the repeated, invasive, facility-based procedures required for other SMA therapies. This convenience improves quality of life and may enhance long-term treatment adherence.
• Systemic Distribution: As a small molecule designed for oral bioavailability, Risdiplam achieves systemic distribution, increasing SMN protein levels in both the central nervous system and peripheral tissues.[3] This offers a potential mechanistic advantage in addressing the multi-system nature of SMA, where SMN deficiency impacts various organs beyond the motor neurons.
• Breadth of Evidence: The clinical development program for Risdiplam is unparalleled in its breadth, providing high-quality evidence for its use in nearly every conceivable patient scenario: symptomatic infants, children, and adults; presymptomatic newborns; and patients previously treated with other therapies. This extensive evidence base provides clinicians with a high degree of confidence when considering Risdiplam for a diverse range of patients.

8.3 Future Directions and Unanswered Questions

While Risdiplam and other SMN-enhancing therapies have revolutionized SMA treatment, the field continues to evolve. The focus is now shifting from simply rescuing neurons to restoring maximum function and addressing the secondary consequences of the disease.

• Combination Therapies: The next frontier in SMA therapeutics is likely to involve combination therapies. This is exemplified by the ongoing MANATEE trial (NCT05115110), a Phase 2/3 study evaluating Risdiplam in combination with GYM329 (RG6237), an anti-myostatin molecule.[55] This trial signals a critical evolution in therapeutic strategy. The first generation of SMA therapies, including Risdiplam, successfully addressed the primary molecular defect by restoring SMN protein to halt or slow neurodegeneration. This new approach acknowledges that neuronal health is a necessary but not always sufficient condition for optimal function, especially in patients who have already experienced significant muscle atrophy. Myostatin is a natural protein that inhibits muscle growth; blocking its action is a strategy to promote muscle hypertrophy. The MANATEE trial is therefore testing a synergistic, dual-mechanism approach: Risdiplam provides the stable neuronal foundation by ensuring SMN protein is present, while the anti-myostatin agent aims to directly build back the muscle tissue that was lost. This represents a more holistic and ambitious therapeutic goal, moving beyond stabilization to active functional restoration.
• Long-Term Outcomes: The long-term data from the pivotal trials are highly encouraging, but continued follow-up into adulthood and later life will be essential to fully understand the effects of lifelong, systemic SMN protein restoration. Questions remain regarding the impact on non-motor aspects of SMA and whether early treatment can prevent all long-term complications of the disease.
• Evolving Landscape: The combination of newborn screening and the availability of highly effective therapies like Risdiplam is transforming SMA. What was once a uniformly fatal or severely disabling condition is becoming a chronic, manageable disease. This success creates new challenges and opportunities for the healthcare community, requiring a focus on long-term, multidisciplinary care to support individuals with SMA as they live longer, fuller lives. Risdiplam, with its convenient administration and robust evidence base, is poised to be a cornerstone of this new era of SMA management.

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