SAPPHIRE
Research type
Research Study
Full title
Phase 3, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Apitegromab (SRK-015) in Patients with Later-Onset Spinal Muscular Atrophy Receiving Background Nusinersen or Risdiplam Therapy
IRAS ID
1004906
Contact name
Stephanie Howard
Contact email
Sponsor organisation
Scholar Rock, Inc.
Eudract number
2021-005314-34
Clinicaltrials.gov Identifier
Research summary
Scholar Rock, Inc. is sponsoring a study of an investigational drug called apitegromab (SRK 015) as a possible treatment for later-onset spinal muscular atrophy (SMA).
Apitegromab is a protein that acts upon a muscle protein called myostatin. Myostatin is one of the factors that control the size and function of muscles.
The main goal of this study is to learn how well apitegromab (SRK-015) works and how safe apitegromab (SRK-015) is compared with placebo when added to treatments with nusinersen and risdiplam. A placebo is an inactive material that looks like the study drug but does not have any active drug, in this case apitegromab (SRK-015). Researchers use a placebo to see if apitegromab (SRK-015) works better or is safer than taking nothing.
This study will take place at about 55 to 60 study centres globally and will include about 204 patients with SMA (approximately 156 patients who are 2 to 12 years of age and 48 patients who are 13 to 21 years of age). The study is divided into 3 periods: a screening period (up to 4 weeks), a treatment period (52 weeks), and a follow-up period (20 weeks). Participants will be in this study for approximately 76 weeks (about 18 months), and participants will need to come to the study centre 18 times over this period. If the study drug helps the participants' condition, participants may be offered the option to enter an extension research study after they complete 52 weeks (12 months) of treatment.
Participants will have a 67% (2 in 3) chance of receiving apitegromab and a 33% (1 in 3) chance of receiving placebo. Neither participants nor the study doctor can choose which study drug participants receive. Participants, the Sponsor studying the drug, the study doctor, and almost all other people involved in the study will not know whether participants are receiving apitegromab or placebo.
A description of this clinical study is available on http://www.clinicaltrials.gov. ClinicalTrials.govSummary of results
Study SRK-015-003 titled “Phase 3, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Apitegromab (SRK-015) in Patients with Later-Onset Spinal Muscular Atrophy Receiving Background Nusinersen or Risdiplam Therapy (SAPPHIRE)” was conducted by Scholar Rock, Inc. in the US, EU, and UK. Study enrollment began in March 2022, and the study was completed in December 2024. In total, 188 participants were enrolled in this study.Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease of genetic origin characterized by both irreversible degeneration of motor neurons and progressive muscle atrophy. Together, both motor neuron degeneration and muscle atrophy drive the progression of SMA and lead to disabilities such as limited mobility, ventilatory insufficiency, and potentially life-threatening complications which can affect the patient's ability to perform activities of daily living (ADL) and significantly impact their quality of life (QoL) and independence. SMA patients often struggle to walk, sit, stand, write, and use forms of technology that would aid in performing ADL or that would enhance QoL. Due to head and neck muscle dysfunction, patients often have difficulty eating, chewing and swallowing, as well as the inability to talk, read, work, or use a mobile phone. These further decrease the ability to perform ADL and exacerbate loss of independence. All of this leads to significant emotional and psychosocial challenges for individuals with SMA, caregivers, and their families.
While currently approved, SMN-targeted treatments target motor neurons, but do not directly target the muscle to address the muscle atrophy-related functional impairment experienced over time by individuals with SMA (Hua et al. 2011; Finkel et al. 2024; Oskoui et al. 2023). Even with existing survival motor neuron (SMN)-targeted treatment, patients can still experience impairment and an eventual decline in motor function, ability to perform ADL, and independence (Day et al. 2022). Therefore, a significant unmet need remains to address the progressive motor function decline in SMA patients.
Early intervention with a muscle-targeted treatment that complements existing SMN-targeted treatments is needed to maintain and improve functionality, ability to perform ADL, and QoL in individuals with SMA (Day et al. 2022), and Study SRK-015-003 was conducted to evaluate apitegromab, a selective muscle-targeted treatment designed to improve motor function.
Study SRK-015-003 (NCT05156320) was a Phase 3 trial conducted in patients ≥2 years old at Screening, who were previously diagnosed with Type 2 and Type 3 SMA and were receiving an approved SMN-targeted treatment (i.e., either nusinersen or risdiplam), to confirm the efficacy and safety of apitegromab used with nusinersen and evaluate the efficacy and safety of apitegromab used with risdiplam. The primary endpoint was change from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) total score at 12 months (52 weeks) in subjects 2 through 12 years old. HFMSE is a well-established, clinically relevant motor function scale that has been validated in SMA and is routinely used to assess the physical abilities of patients with type 2 and type 3 SMA.
Study SRK-015-003 included 188 male and female patients with later-onset SMA:
• Main Efficacy Population (age 2-12 years old): 156 patients were randomized to receive apitegromab 10 mg/kg (n=53), apitegromab 20 mg/kg (n=53), or placebo (+SMN-targeted treatment alone) (n=50) at a ratio of 1:1:1.
• 13-21 Population (age 13-21 years old): 32 patients were randomized to receive apitegromab 20 mg/kg (n=22) or placebo (n=10) at a ratio of 2:1.In Study SRK-015-003, treatment with apitegromab was associated with clinically meaningful and statistically significant improvement in motor function at 12 months compared to placebo. Improvement of motor function occurred as early as 2 months after treatment. Apitegromab treatment was well tolerated and resulted in an acceptable safety profile. Serious adverse events were consistent with the known manifestation and common medical complications associated with SMA, (e.g. infection, respiratory and gastrointestinal events, or with common procedures for the subject-age group). No SAEs were related to apitegromab.
Taking into account that the natural trajectory of SMA patients treated with SMN-targeted treatment is that of progressive decline after initial improvement, the results from the SAPPHIRE study support apitegromab as an effective muscle-targeted treatment that complements SMN-targeted treatment in further improving clinical outcomes and motor function for patients with SMA
REC name
East Midlands - Derby Research Ethics Committee
REC reference
22/EM/0054
Date of REC Opinion
8 Apr 2022
REC opinion
Further Information Favourable Opinion