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FIREFISH

Risdiplam in Type 1 Spinal Muscular Atrophy

Year of Publication: 2021

Authors: Baranello G, Darras BT, Day JW, ..., Rose K

Journal: New England Journal of Medicine

Citation: Part 1: N Engl J Med. 2021;384(10):915-923. Part 2: Darras BT et al. N Engl J Med. 2021;385(5):427-435. PMID: 34320287. NCT02913482

Link: https://pubmed.ncbi.nlm.nih.gov/33626251/

Clinical Question

What is the safety, PK/PD profile, and preliminary efficacy of oral risdiplam in infants with SMA Type 1?

Bottom Line

Oral risdiplam at 0.2 mg/kg/day increased SMN protein 1.9x and enabled 41% of SMA Type 1 infants to achieve sitting. Four deaths from respiratory complications occurred. High dose selected for confirmatory Part 2.

        Major Points
        First oral SMN2 splicing modifier tested in infants with SMA Type 1 -- addressing need for non-invasive alternative to intrathecal nusinersen
High-dose risdiplam (0.2 mg/kg/day) increased blood SMN protein from median 2.54 to 5.66 ng/mL (1.9x baseline)
7/17 (41%) high-dose infants achieved sitting without support for >=5 seconds at 12 months vs 0/4 low-dose
4 infants died of respiratory complications (consistent with natural history of untreated SMA Type 1)
High dose (0.2 mg/kg/day) selected for confirmatory Part 2 based on PK/PD modeling and clinical responses
Oral liquid formulation administered once daily -- significant practical advantage over intrathecal or IV routes
Led to FDA approval of risdiplam (Evrysdi) in August 2020 for SMA patients >=2 months old

      

Design

Study Type: Phase 2-3, open-label, two-part, dose-finding study (Part 1 reported)

Randomization:

Blinding: Open-label

Enrollment Period: 2016-2018

Follow-up Duration: 12 months for Part 1

Centers: 31

Countries: United Kingdom, Belgium, Switzerland, Italy, United States, France, Brazil, China, Croatia, Japan, Poland, Russia, Turkey

Sample Size: 62

Analysis: Descriptive statistics; PK/PD modeling for dose selection; no formal hypothesis testing

Inclusion Criteria

Clinical SMA Type 1 onset between 28 days and 3 months of age
Gestational age 37-42 weeks at birth
Confirmed 5q-autosomal recessive SMA (genetically confirmed)
Two SMN2 gene copies (centrally confirmed)
Body weight >=3rd percentile for age
Adequate nutrition and hydration (with or without gastrostomy)
Recovered from any acute illness at time of enrollment

Exclusion Criteria

Prior investigational drug or device within 90 days (or 5 half-lives)
Previous SMN2-targeting antisense oligonucleotide, SMN2 splicing modifier, or gene therapy
History of cell therapy
Pulmonary hospitalization within 2 months of screening
Clinically relevant ECG abnormalities
Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular disease
Requirement for invasive ventilation or tracheostomy
Awake non-invasive ventilation requirement or hypoxemia (O2 saturation <95%)
Unrecovered respiratory failure or severe pneumonia history
Multiple or fixed contractures at birth; hip subluxation or dislocation at birth
Non-SMA concurrent syndromes or diseases
Major illness within 1 month or febrile illness within 1 week of screening
Use of CYP3A4/OCT-2/MATE inhibitors within 2 weeks or CYP3A4 inducers within 4 weeks
Prior or anticipated use of quinolones, thioridazine, vigabatrin, retigabine, or retinal-toxic drugs
Ophthalmic disease history (<6 months) interfering with study assessments
Prior therapeutic use (>=8 weeks) of riluzole, valproic acid, hydroxyurea, phenylbutyrate, creatine, carnitine, growth hormone, HDAC inhibitors, or phototoxic medications

Arms

Field	Low-dose risdiplam	High-dose risdiplam
Intervention	Oral risdiplam 0.08 mg/kg/day administered as liquid formulation once daily	Oral risdiplam 0.2 mg/kg/day administered as liquid formulation once daily
Duration	12 months	12 months

Outcomes

Outcome	Type	Control	Intervention	P-value
Safety, pharmacokinetics, pharmacodynamics (blood SMN protein concentration), and dose selection for confirmatory Part 2	Primary	Low-dose: baseline 1.31 ng/mL, month 12: 3.05 ng/mL (3.0x increase)	High-dose: baseline 2.54 ng/mL, month 12: 5.66 ng/mL (1.9x increase)
Part 1: Sitting without support >=5 seconds at 12 months	Secondary	Low-dose: 0/4 (0%)	High-dose: 7/17 (41%)
Part 2: Sitting without support >=5 seconds at 12 months	Secondary	5% historical (SMA Type 1 natural history)	12/41 (29.3%, 90% CI 17.84-43.07)	<0.0001
Part 2: Sitting without support >=5 seconds at 24 months	Secondary		25/41 (61.0%)	<0.0001
Part 2: Sitting without support >=30 seconds at 24 months	Secondary		18/41 (43.9%)	<0.0001
Part 2: CHOP INTEND >=40 at 12 months	Secondary		23/41 (56.1%)	<0.0001
Part 2: CHOP INTEND >=4 point increase from baseline	Secondary		37/41 (90.2%)	<0.0001
Part 2: Motor milestone responders (HINE-2) at 12 months	Secondary		32/41 (78.0%)	<0.0001
Part 2: Alive at 12 months	Secondary		38/41 (92.68%)	0.0005
Part 2: Alive without permanent ventilation at 12 months	Secondary		35/41 (85.37%)	<0.0001
Part 2: Standing or walking at 24 months	Secondary		0/41 (0%)
Deaths - Part 1	Adverse		4 infants died of respiratory complications (consistent with SMA Type 1 natural history)
Deaths - Part 2	Adverse		3/41 died (all attributed to SMA disease progression)
Pneumonia	Adverse		Common serious AE across Parts 1 and 2
Respiratory tract infection	Adverse		Common serious AE
Acute respiratory failure	Adverse		Serious AE in multiple infants
Pyrexia	Adverse		Common AE

Subgroup Analysis

Part 1: Higher blood SMN protein levels at steady state correlated with better motor milestone outcomes; PK modeling supported 0.2 mg/kg/day for Part 2. Part 2: Continued improvement between 12 and 24 months (sitting increased from 29.3% to 61.0%), but no infant achieved standing or walking, suggesting ceiling effect of oral SMN2 splicing modification in Type 1.

Criticisms

Small sample size (n=21 total; high-dose n=17) limits statistical power
Open-label design without concurrent control group -- cannot differentiate treatment effect from natural history variability
Part 1 dose-finding study; confirmatory efficacy data required from Part 2
4 deaths from respiratory complications, though consistent with SMA Type 1 natural history
Limited baseline characteristic reporting makes comparison with other SMA trials difficult
No formal statistical hypothesis testing -- descriptive statistics only
Low-dose cohort too small (n=4) for meaningful efficacy comparison

Funding

F. Hoffmann-La Roche

Based on: FIREFISH (New England Journal of Medicine, 2021)

Authors: Baranello G, Darras BT, Day JW, ..., Rose K

Citation: Part 1: N Engl J Med. 2021;384(10):915-923. Part 2: Darras BT et al. N Engl J Med. 2021;385(5):427-435. PMID: 34320287. NCT02913482

Content summarized and formatted by NeuroTrials.ai.

FIREFISH

(2021)

Objective

To evaluate the safety, pharmacokinetics, and efficacy of oral risdiplam in infants with SMA Type 1

Study Summary

• High-dose risdiplam (0.2 mg/kg/day) increased blood SMN protein from 2.54 to 5.66 ng/mL (1.9x baseline); 7/17 (41%) high-dose infants achieved sitting without support vs 0/4 low-dose
• 4 infants died of respiratory complications (consistent with natural history of SMA Type 1); high dose selected for confirmatory Part 2; SAEs included pneumonia, respiratory tract infection, acute respiratory failure

Intervention

Oral risdiplam: low dose 0.08 mg/kg/day or high dose 0.2 mg/kg/day

Inclusion Criteria

Infants 1-7 months of age with SMA Type 1 (inability to sit without support)

Study Design

Arms: Low-dose cohort (0.08 mg/kg/day) and High-dose cohort (0.2 mg/kg/day)

Patients per Arm: Low-dose: 4, High-dose: 17

Outcome

• Blood SMN protein: High-dose 2.54 to 5.66 ng/mL (1.9x); Low-dose 1.31 to 3.05 ng/mL (3.0x)
• Sitting without support >=5 sec at 12 months: 7/17 (41%) high-dose vs 0/4 (0%) low-dose
• 4 deaths from respiratory complications; serious AEs: pneumonia, respiratory failure; high dose selected for Part 2

Bottom Line

Major Points

First oral SMN2 splicing modifier tested in infants with SMA Type 1 -- addressing need for non-invasive alternative to intrathecal nusinersen
High-dose risdiplam (0.2 mg/kg/day) increased blood SMN protein from median 2.54 to 5.66 ng/mL (1.9x baseline)
7/17 (41%) high-dose infants achieved sitting without support for >=5 seconds at 12 months vs 0/4 low-dose
4 infants died of respiratory complications (consistent with natural history of untreated SMA Type 1)
High dose (0.2 mg/kg/day) selected for confirmatory Part 2 based on PK/PD modeling and clinical responses
Oral liquid formulation administered once daily -- significant practical advantage over intrathecal or IV routes
Led to FDA approval of risdiplam (Evrysdi) in August 2020 for SMA patients >=2 months old

Study Design

Study Type: Phase 2-3, open-label, two-part, dose-finding study (Part 1 reported)
Randomization: No
Blinding: Open-label
Sample Size: 62
Follow-up: 12 months for Part 1
Centers: 31
Countries: United Kingdom, Belgium, Switzerland, Italy, United States, France, Brazil, China, Croatia, Japan, Poland, Russia, Turkey

Primary Outcome

Definition: Safety, pharmacokinetics, pharmacodynamics (blood SMN protein concentration), and dose selection for confirmatory Part 2

Control	Intervention	HR/OR	P-value
Low-dose: baseline 1.31 ng/mL, month 12: 3.05 ng/mL (3.0x increase)	High-dose: baseline 2.54 ng/mL, month 12: 5.66 ng/mL (1.9x increase)	-

Limitations & Criticisms

Small sample size (n=21 total; high-dose n=17) limits statistical power
Open-label design without concurrent control group -- cannot differentiate treatment effect from natural history variability
Part 1 dose-finding study; confirmatory efficacy data required from Part 2
4 deaths from respiratory complications, though consistent with SMA Type 1 natural history
Limited baseline characteristic reporting makes comparison with other SMA trials difficult
No formal statistical hypothesis testing -- descriptive statistics only
Low-dose cohort too small (n=4) for meaningful efficacy comparison

Citation

Part 1: N Engl J Med. 2021;384(10):915-923. Part 2: Darras BT et al. N Engl J Med. 2021;385(5):427-435. PMID: 34320287. NCT02913482

View Original Publication →

FIREFISH

Risdiplam in Type 1 Spinal Muscular Atrophy

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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