The most inclusive clinical trial program in SMA2

The most inclusive clinical trial program in
SMA2

Participants reflective of real-world SMA population1,12*

Over 450 SMA patients ranging from 2 months to 60 years old

450+ patients with infantile-onset and later-onset SMA

With different levels of disease severity and functional ability

Both ambulatory and nonambulatory

With and without scoliosis (mild to severe)

With and without prior disease-modifying treatment§ (evaluated for safety)

Firefish, sunfish and jewelfish trial icons

EFFICACY DATA in patients aged 2 months to 25 years

SAFETY DATA in patients aged 2 months to 60 years

 

The first SMA trial program to include patients older than 18 years, some of whom have severe scoliosis2
The first SMA trial program to include patients older than 18 years, some of whom have severe scoliosis2

*Enrollment across 3 clinical trials.
Infantile-onset SMA defined as Type 1 SMA; later-onset SMA defined as Type 2 or Type 3 SMA.
7 ambulatory patients included in SUNFISH Part 1; no ambulatory patients included in Part 2. There are 16 patients included in JEWELFISH who are ambulatory.
§Approved and investigational therapies including an SMN2-splicing modifier or gene-replacement therapy.

4 ongoing clinical trials

Four ongoing trials, Firefish, Sunfish, Jewelfish and Rainbowfish

*Targeted enrollment.

SUNFISH is a 2-part, placebo-controlled trial in later-onset spinal muscular atrophy (SMA): the first placebo-controlled trial in adults and children older than 9 years with SMA (ages ranged from 2 to 25 years)1,2

 Sunfish study design
SUNFISH was purposefully designed to include older adults and children with complications, such as contractures and severe scoliosis1,2
  • Part 1 (N=51) was the exploratory, dose-finding portion
  • In Part 2:
    • Adults and children were randomized 2:1 to receive either the recommended dose of Evrysdi or placebo. After 12 months, adults and children receiving placebo were switched to Evrysdi
    • The primary endpoint is mean change from baseline in MFM-32 at 12 months

MFM-32=Motor Function Measure–32 Items.

Participants included a broad range of individuals designed to reflect the real-world SMA population1,2*

SUNFISH PART 2
  Evrysdi
(n=120)
Placebo
(n=60)
Patient characteristics
SMA Type, % (n)
Type 2
Type 3

70.0% (84)
30.0% (36)

73.3% (44)
26.7% (16)
Disease severity
Mean age at onset, months (SD) 14.1 (8.4) 18.5 (21.1)
Scoliosis, % (n)
Yes
>40° curvature

63.3% (76)
28.3% (34)

73.3% (44)
38.3% (23)
Surgery for scoliosis before screening, % (n)
Yes
No

24.2% (29)
52.5% (63)

28.3% (17)
55.0% (33)
Motor function assessment scores at baseline
MFM-32 total score, median (min-max)
n
46.9 (16.7-71.9)
115
47.9 (17.7-71.9)
59
RULM total score, median (min-max)
n
19.0 (3.0-36.0)
119
20.0 (9.0-38.0)
58
HFMSE total score, median (min-max)
n
14.0 (0.0-48.0)
120
13.0 (2.0-43.0)
60

*The overall baseline demographic characteristics were well balanced between Evrysdi and placebo groups, with the exception of an imbalance of patients with scoliosis (63% in the Evrysdi arm and 73% in the placebo arm).
HFMSE=Hammersmith Functional Motor Scale Expanded; MFM-32=Motor Function Measure-32 Items; RULM=Revised Upper Limb Module.

FIREFISH is a 2-part, open-label trial in infantile-onset spinal muscular atrophy (SMA) establishing the safety and efficacy of Evrysdi in infants 2 months and older1,14

 Firefish study design
Evrysdi continues to be studied in FIREFISH Part 1 and in FIREFISH Part 21,14
  • In Part 1, efficacy was established at 12 months based on ability to sit without support for ≥5 seconds, as measured by Item 22 of the BSID-III gross motor scale, and on survival without permanent ventilation
  • In Part 2, the primary endpoint was ability to sit without support for ≥5 seconds, as measured by Item 22 of the BSID-III gross motor scale

*The first 4 enrollees received a lower dose (titration to target dose of 0.08 mg/kg/day) for 12 months; all other enrollees (n=17) had their dose adjusted to the recommended dose (0.2 mg/kg/day) before 12 months. Efficacy and safety were assessed at 12 months, after which all participants received the recommended dose (0.2 mg/kg/day).

BSID-III=Bayley Scales of Infant and Toddler Development–Third Edition.

Infants reflected those seen in a real-world setting, including age, disease progression, baseline motor function and levels of disease severity.1,2,14

FIREFISH PART 1
FIREFISH Part 1 baseline demographics
All-patients cohort (N=21)
Patient characteristics  
Median age at onset, months (range) 2.0 (0.9-3.0)
Median age at enrollment, months (range) 6.7 (3.3-6.9)
Median weight, kg (range) 6.7 (5.2-8.9)
Motor function assessment scores  
CHOP INTEND, median (range) 24.0 (10.0-34.0)
HINE-2, median (range) 1.0 (0.0-3.0)

CHOP INTEND=Children’s Hospital of Philadelphia Infant Test of Neurological Disorders; HINE-2=Hammersmith Infant Neurological Examination Module 2.

JEWELFISH is an ongoing, open-label safety trial in adults, children, and infants aged 1 to 60 years with Type 1, 2, or 3 spinal muscular atrophy (SMA) taking Evrysdi who have received previous treatment with approved or investigational therapies12

 Jewelfish study design
  • This trial is investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of Evrysdi in both ambulatory and nonambulatory patients
    • Ambulatory and nonambulatory patients: 9% (n=16) walkers, 57% (n=99) sitters, and 34% (n=59) nonsitters
  • Participants have received previous treatment with approved or investigational therapies* including an SMN2-splicing modifier (≥90 days prior to screening) or gene-replacement therapy (≥12 months prior to screening)

*Investigational at the start of JEWELFISH.

A broad and heterogeneous population with a high degree of motor impairment at baseline12

PREVIOUS TREATMENT
    RG7800* (MOONFISH)
n=13
Nusinersen
n=76
Olesoxime*
n=71
Onasemnogene abeparvovec
n=14
All patients
N=174
Patient characteristics
Age at enrollment, years Median (range) ≥18 years, % (n) 30.0 (16-58)
85% (11)
12.0 (1-60)
28% (21)
16.0 (11-36)
44% (31)
2.0 (1-5)
0%
14.0 (1-60)
36% (63)
Gender, % (n) Male 69% (9) 53% (40) 49% (35) 79% (11) 55% (95)
SMA type, % (n) 1
2
3
0%
39% (5)
62% (8)
12% (9)
57% (43)
32% (24)
3% (2)
70% (50)
27% (19)
29% (4)
71% (10)
0%
9% (15)
62% (108)
29% (51)
SMN2 copy number, % (n) 1
2
3
4
Unknown
0%
0%
46% (6)
46% (6)
8% (1)
0%
12% (9)
74% (56)
15% (11)
0%
0%
0%
90% (64)
7% (5)
3% (2)
7% (1)
21% (3)
71% (10)
0%
0%
1% (1)
7% (12)
78% (136)
13% (22)
2% (3)
Disease severity
Scoliosis, % (n) Yes
>40° curvature
69% (9)
23% (3)
84% (61/73)§
37% (27/73)§
93% (66)
51% (36)
27% (3/11)§
0%
83% (139/168)§
39% (66/168)§
Hip subluxation or dislocation, % (n) Yes 15% (2) 34% (25/73)§ 28% (20) 36% (4/11)§ 30% (51/168)§
Motor function assessment scores at baseline
Motor function at baseline, % (n) Nonsitters
Sitters
Walkers
54% (7)
23% (3)
23% (3)
28% (21)||
55% (42)||
17% (13)
41% (29)
59% (42)
0%
14% (2)||
86% (12)||
0%
34% (59)||
57% (99)||
9% (16)
Baseline HFMSE total score <10, % (n) Yes 62% (8) 48% (35/73)§ 83% (59) 27% (3/11)§ 63% (105/168)§

*Investigational therapies; not approved by FDA for any use.
Three patients had also received olesoxime previously.
One patient received treatment with onasemnogene abeparvovec first, followed by nusinersen. Ten patients were enrolled in STRONG, three patients in STR1VE, and one patient in STR1VE EU prior to enrollment in JEWELFISH.
§Only reported for patients aged 2 to 60 years.
||For patients younger than 2 years, baseline motor milestones were evaluated by the HFMSE Module 2.

FDA=Food and Drug Administration; HFMSE=Hammersmith Functional Motor Scale Expanded; SMN=survival motor neuron.

Indication

Evrysdi is indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months of age and older.

Interactions with Substrates of MATE Transporters

  • Based on in vitro data, Evrysdi may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K, such as metformin
  • Avoid coadministration of Evrysdi with MATE (multidrug and toxin extrusion) substrates. If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug if needed

Pregnancy & Breastfeeding

  • Evrysdi may cause embryofetal harm when administered to a pregnant woman. In animal studies, administration of Evrysdi during pregnancy and/or lactation resulted in adverse effects on development. Advise pregnant women of the potential risk to the fetus
  • Pregnancy testing is recommended prior to initiating Evrysdi. Advise female patients to use contraception during treatment with Evrysdi and for at least 1 month after the last dose
  • The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Evrysdi and any potential adverse effects on the breastfed infant

Potential Effects on Male Fertility

  • Counsel male patients that fertility may be compromised by treatment with Evrysdi. Male patients may consider sperm preservation prior to treatment

Most Common Adverse Reactions

  • The most common adverse reactions in later-onset SMA (incidence in at least 10% of patients treated with Evrysdi and more frequent than control) were fever, diarrhea, and rash
  • The most common adverse reactions in infantile-onset SMA were similar to those observed in later-onset SMA patients. Additionally, adverse reactions with an incidence of at least 10% were upper respiratory tract infection, pneumonia, constipation, and vomiting

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see full Prescribing Information for additional Important Safety Information.

 

 

    • Evrysdi® (risdiplam) Prescribing Information. Genentech, Inc.

      Evrysdi® (risdiplam) Prescribing Information. Genentech, Inc.

    • Data on file. Genentech USA, Inc.

      Data on file. Genentech USA, Inc.

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