Effective Date

Date of Origin   

04-01-2025           

Evrysdi®

(risdiplam)

Powder for oral solution

Treatment of spinal muscular atrophy (SMA) in pediatric and adult patients

1

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is the second most common autosomal recessive neurodegenerative disorder, caused by deletion or loss of function mutation of the survival motor neuron 1 (SMN1) gene.(2,11) SMA is characterized by dysfunction and then loss of the alpha motor neurons in the spinal cord that causes progressive muscle atrophy and weakness.(10) There are two forms of survival motor neuron (SMN), SMN1 and SMN2, which are located on chromosome 5q13.2.(5) SMN1 is the primary gene responsible for functional production of SMN protein.(3) SMN1 can be absent because of deletion or SMN1-to-SMN2 conversion.(5) SMN2 preferentially excludes exon 7 during splicing and, as a result, produces only a small fraction of functional SMN protein as compared with SMN1. Because SMN2 produces a reduced number of SMN proteins, it can only partially compensate for the loss of SMN1 gene. SMA has an incidence of approximately 1 in 10,000 live births and a carrier frequency of approximately 1 in 54. It is one of the leading causes of infant mortality.(3)

Molecular genetic testing of SMN1/SMN2 is highly reliable and is the standard tool for the diagnosis of SMA.(2,4,10) Genetic testing for homozygous deletion will confirm the disease in 95% of patients. Essentially all other patients with SMN-related SMA will be compound heterozygotes with a single SMN1 deletion and a mutation in the other SMN1 copy.(4) With newborn screening (NBS) becoming more widespread, infants can be diagnosed and receive early disease-modifying treatment, even before they become symptomatic. SMA newborns identified by NBS and before treatment initiation should be characterized by SMN2 copy number (probable Type), current motor function, age at symptom onset, and severity of symptoms. Early diagnosis and treatment will give infants with SMA the best outcomes and a healthier life.(10,12)  

SMA was historically classified into Types 0-4 based on age of onset of symptoms and motor milestone achievement. Applied retroactively, it was most applicable to older children and adults.(2,13) Type 0 is very rare with symptoms beginning prior to birth and survival being only a few months. Type 1 is the most common and severe form and usually diagnosed during the first six months of life. Type 2 is usually diagnosed after six months of age but before 2 years of age. Type 3, known as juvenile SMA, is typically diagnosed after 18 months of age and before 3 years of age. However, some SMA Type 3 patients can be diagnosed as late as the teenage years. Type 4 is very rare, less than 1% of cases, and usually symptoms appear as early as 18 years of age but most commonly after 35 years of age.(13)

SMN2 copy number is predictive of phenotype severity. The more copies of SMN2, the milder phenotypic presentation.(10) For example, in a large German study, 80% of SMN Type 1 patients had two or less copies of SMN2, 82% with SMN Type 2 patients had three copies, and 96% of SMN Type 3 patients had 3 or 4 copies. The most severe is Type 0 with a single copy of SMN2. Infants with two or three SMN2 copies are likely to develop SMA Type 1 or 2. Type 4 usually has 4 or more SMN2 copies.(4,10) Therefore, determination of SMN2 copy number is a powerful predictor of disease and appropriate treatments.(10) With the approval of SMN-enhancing treatments and the addition of newborn screening (NBS), a dramatic changed in the natural history of SMA across all ages and has led to a shift in disease management.(13) According to the updated treatment algorithm from the SMA NBS Multidisciplinary Working Group, infants diagnosed through NBS with up to four SMN2 gene copies require immediate treatment. Patients with five (or more) SMN2 gene copies should be observed and screened for symptoms.(7,10,13)

Guidelines recommend the use of age-appropriate function assessments to advise initiation and follow-up of drug therapy in SMA patients. They acknowledge that the tests vary in availability, physician expertise and preference, and the patient’s ability, based on age, to participate. The function assessments that were considered for use in SMA patients were CHOP-INTEND, Hammersmith Infant Neurological Examination (HINE-2), Hammersmith Functional Motor Scale-Expanded (HFMSE), six-minute walk test (6MWT), Revised Upper Limb Module (RULM) test, and Bayley Scales of Infant and Toddler Development (BSID). Risdiplam efficacy trials utilized Bayley Scales of Infant and Toddler development, Third Edition (BSID-III), and Motor Function Measurement score (MFM32).(10)

Efficacy

The efficacy of Evrysdi for the treatment of patients with infantile-onset, later-onset, and presymptomatic SMA was evaluated in three clinical trials, Study 1 (FIREFISH NCT02913482), Study 2 (SUNFISH NCT02908685), and Study 3 (RAINBOWFISH NCT03779334), respectively.(1)

FIREFISH

This was an open-label, 2-part study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of Evrysdi in patients with Type 1 SMA with symptom onset between 28 days and 3 months of age. Patients had genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene, and two SMN2 gene copies. There were two segments of the study: a 12-week exploratory dose-finding segment and a 24-month confirmatory segment. The primary endpoint was the proportion of patients with the ability to sit without support for at least 5 seconds Bayley Scales of Infant and Toddler Development - Third Edition [BSID-III] gross motor scale, Item 22) after 12-months of treatment; 29% of patients (n=12/41) achieved this milestone. At Month 24, 40% (23/58) of patients who received the recommended dose achieved sitting without support for 30 seconds (BSID-III, Item 26). At month 24, patients continued to achieve additional motor milestones; 28% (16/58) of patients achieved a standing measure, as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2) which assesses motor milestones. The proportion of patients alive without permanent ventilation (event-free survival) was 84% for all patients at Month 24. These results indicated a clinically meaningful deviation from the natural history of untreated infantile-onset SMA.(1,8)

SUNFISH

This was a 2-part, multicenter, randomized, double-blind, placebo-controlled trial to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of Evrysdi in patients with SMA Type 2 or Type 3. The inclusion criteria for segment 2 were patients with Type 2 or 3 SMA (with a confirmed diagnosis of 5q-autosomal recessive SMA) that were non-ambulatory and a negative blood pregnancy test. Exclusion criteria included concomitant or previous administration of a SMN2-targeting antisense oligonucleotide, SMN2 splicing modifier, or gene therapy, patients that were hospitalized for a pulmonary event within the last two months, unstable GI, renal, hepatic, endocrine, or cardiovascular disease considered to be clinically significant by the investigator, or requirement of invasive ventilation or tracheostomy. There were two segments of the study: a 12-week exploratory dose-finding segment and a 24-month confirmatory segment. The primary endpoint was the change from baseline to Month 12 in the Motor Function Measure 32 (MFM32) score. The primary analysis on the change from baseline in MFM32 total score at Month 12 showed a clinically meaningful and statistically significant difference between patients treated with Evrysdi and placebo.(1,9)

RAINBOWFISH

This was an open-label, single-arm, multicenter clinical study to assess safety, pharmacokinetic, pharmacodynamics, and efficacy of Evrysdi in infants up to 6 weeks of age (at first dose) who had been genetically diagnosed with SMA (5q-autosomal recessive SMA, including confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene) but had not shown symptoms yet. Exclusion criteria included concomitant or previous administration of a SMN2-targeting antisense oligonucleotide, SMN2 splicing modifier, gene therapy, or requirement of invasive ventilation or tracheostomy. The primary efficacy population (N=5) included patients with 2 SMN2 copies and a baseline CMAP amplitude greater than or equal to 1.5 mV. The primary efficacy endpoint was the proportion of patients with the ability to sit without support for at least 5 seconds (BSID-III, Item 22) at Month 12. This milestone was achieved by 80% (4/5) of patients in the primary efficacy population. This milestone was also achieved by 87.5% (7/8) of all patients with 2 copies of SMN2 and 96.2% (25/26) of patients in the full treated population. At Month 12, 80.8% (21/26) of patients in the full treated population achieved sitting without support for 30 seconds (BSID-III, Item 26). Of the 26 patients treated with Evrysdi, 25 patients had motor milestones measured by the HINE-2 at Month 12. Of these, 24 (96%) achieved sitting (23 patients could pivot/rotate and 1 achieved stable sit); 21 (84%) could stand (13 patients could stand unaided and 8 could stand with support); and 12 (48%) could walk independently. All 26 patients were alive at 12 months without permanent ventilation.(1,6)

Safety

Risdiplam has no FDA labeled contraindications for use.(1)

1

Evrysdi prescribing information. Genentech, Inc. September 2024.

2

Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscular Disorders. 2017;28(2):103-115. doi:10.1016/j.nmd.2017.11.005

3

Mendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med 2017;377:1713-22. 

4

Arnold WA, Kassar D, Kissel JT. Spinal Muscular Atrophy: Diagnosis and Management in a New Therapeutic Era. Muscle Nerve 2015 Feb;51(2):157-167. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293319/.

5

Fang P, Li L, Zeng J, et al. Molecular Characterization and Copy Number of SMN1, SMN2 and NAIP in Chinese Patients with Spinal Muscular Atrophy and Unrelated Healthy Controls. BMC Musculoskelet Disord. 2015;16(1):11.

6

A Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy (Rainbowfish). https://clinicaltrials.gov/study/NCT03779334.

7

Glascock J, Sampson J, Connolly AM, et al. Revised Recommendations for the Treatment of Infants Diagnosed with Spinal Muscular Atrophy Via Newborn Screening Who Have 4 Copies of SMN2. Journal of Neuromuscular Diseases. 2020;7(2):97-100. doi:10.3233/jnd-190468

8

Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type 1 Spinal Muscular Atrophy (FIREFISH). https://clinicaltrials.gov/ct2/show/NCT02913482.

9

A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy (SMA) Participants (SUNFISH). https://clinicaltrials.gov/ct2/show/NCT02908685.

10

Glascock J, Sampson J, Haidet-Phillips A, et al. Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening. J Neuromuscul Dis. 2018;5(2):145-158. 

11

Keinath MC, Prior DE, Prior TW. (2021). Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance. The application of clinical genetics, 14, 11-25. https://doi.org/10.2147/TACG.S239603

12

Schroth M, Deans J, Arya K, et al. Spinal Muscular Atrophy Update in Best Practices Recommendations for Diagnosis Considerations.; 2024. doi:10.1212/CPJ.00200310

13

Spinal Muscular Atrophy - Symptoms, Causes, Treatment. National Organization for Rare Disorders. Updated April 2024. https://rarediseases.org/rare-diseases/spinal-muscular-atrophy/.

Evrysdi

risdiplam for soln

0.75 MG/ML

M ; N ; O ; Y

N

Evrysdi

risdiplam for soln

0.75 MG/ML

240

mLs

30

DAYS

Evrysdi

risdiplam for soln

0.75 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Evrysdi

risdiplam for soln

0.75 MG/ML

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

PA

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has a diagnosis of spinal muscular atrophy (SMA) AND
2. The patient has a deletion or mutation at the survival motor neuron 1 (SMN1) gene on chromosome 5q confirmed by genetic testing (medical records required) AND
3. The patient has a diagnosis of probable SMA Type 1, 2, or 3, AND ONE of the following:
   1. If symptomatic, symptom onset was evident prior to 18 years of age OR
   2. If asymptomatic, the patient has no more than 4 copies of SMN2 (medical records required) AND
4. The patient retains meaningful voluntary motor function (e.g., manipulate objects using upper extremities, ambulate, etc.) (medical records required) AND
5. The patient has had at least ONE of the following baseline (prior to starting therapy with the requested agent) functional assessments (medical records required):
   1. Motor function/milestones, including but not limited to, at least ONE of the following validated scales:
      1. Hammersmith Infant Neurological Examination (HINE)
      2. Hammersmith Functional Motor Scale Expanded (HFMSE)
      3. Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND)
      4. Bayley Scales of Infant and Toddler Development Third Edition (BSID-III)
      5. Six-minute walk test (6MWT)
      6. Upper Limb Module (ULM)
      7. Motor Function Measurement score (MFM32)
      8. Revised Upper Limb Module (RULM) OR
   2. Respiratory function tests [e.g., forced vital capacity (FVC), etc] OR
   3. Exacerbations necessitating hospitalizing and/or antibiotic therapy for respiratory infection in the preceding year/timeframe OR
   4. Patient weight (for patients without a gastrostomy tube) AND
6. The patient does NOT have advanced disease (e.g., complete limb paralysis, permanent ventilation support, etc.) AND
7. The patient has NOT received gene therapy for the requested indication (e.g., Zolgensma [onasemnogene abeparvovec-xioi]) (medical records required) AND
8. If the patient has used Spinraza (nusinersen) in the last four months, they will complete a four-month washout period between the last Spinraza (nusinersen) dose and the initiation of therapy with the requested agent AND
9. The patient will NOT be using the requested agent in combination with Spinraza (nusinersen) for the requested indication (medical records required) AND
10. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist, geneticist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
11. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria. 

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has responded to therapy compared to baseline (prior to starting therapy with the requested agent) with the requested agent as indicated by at least ONE of the following:
   1. Stability or improvement in net motor function/milestones, including but not limited to, at least ONE of the following validated scales:
      1. Hammersmith Infant Neurological Examination (HINE)
      2. Hammersmith Functional Motor Scale Expanded (HFMSE)
      3. Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND)
      4. Bayley Scales of Infant and Toddler Development Third Edition (BSID-III)
      5. Six-minute walk test (6MWT)
      6. Upper Limb Module (ULM)
      7. Motor Function Measurement score (MFM32)
      8. Revised Upper Limb Module (RULM) OR
   2. Stability or improvement in respiratory function tests [e.g., forced vital capacity (FVC), etc.] OR
   3. Reduction in exacerbations necessitating hospitalizing and/or antibiotic therapy for respiratory infection in the preceding year/timeframe OR
   4. Stable or increased patient weight (for patients without a gastrostomy tube) OR
   5. Slowed rate of decline in the aforementioned measures AND
3. The patient has NOT received gene therapy for the requested indication (e.g., Zolgensma [onasemnogene abeparvovec-xioi]) AND
4. The patient will NOT be using the requested agent in combination with Spinraza (nusinersen) for the requested indication AND
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist, geneticist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
6. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Quantity Limit for the Target Agent(s) will be approved when ONE of the following is met:

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit 

Length of Approval: up to 12 months