BIIB115 for Spinal Muscular Atrophy

Recruiting at 18 trial locations

Overseen By Global Biogen Clinical Trial Center

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Biogen

Must be taking: Onasemnogene abeparvovec

Must not be taking: Nusinersen, Risdiplam

Disqualifiers: Liver injury, Thrombotic microangiopathy, others

Compensation: Varies

Number of Visits: 23

62 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, if you are in Part B and have been treated with nusinersen, you must wait at least 12 months from your last dose before starting BIIB115. Also, ongoing steroid treatment following onasemnogene abeparvovec is not allowed at the time of screening.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking certain medications like nusinersen, you must have stopped at least 12 months before the first dose of BIIB115. It's best to discuss your specific medications with the trial team.

What data supports the idea that BIIB115 for Spinal Muscular Atrophy is an effective treatment?

The available research shows that new treatments for Spinal Muscular Atrophy, like BIIB115, have been developed to address the genetic causes of the disease. These treatments, if started early, can significantly change the course of the disease, leading to better outcomes for patients. Although specific data on BIIB115 is not detailed, the general success of similar treatments in modifying the disease suggests that BIIB115 could be effective. Compared to older treatments, these new options offer hope for improved quality of life for those affected by the condition. ^{1 2 3 4 5}

What data supports the effectiveness of the drug BIIB115 for treating spinal muscular atrophy?

The research highlights that new treatments for spinal muscular atrophy, like gene therapy and splicing modulation, have been developed and can significantly change the disease's natural course if started early. However, evidence for these treatments is often limited to a small group of patients, indicating a need for more data to fully understand their effects. ^{1 2 3 4 5}

What safety data exists for BIIB115/ION306 in treating spinal muscular atrophy?

The provided research does not contain specific safety data for BIIB115 or ION306. The studies focus on the safety and efficacy of nusinersen and phenylbutyrate in treating spinal muscular atrophy, but do not mention BIIB115 or ION306. ^{6 7 8 9 10}

Is the drug BIIB115 a promising treatment for Spinal Muscular Atrophy?

BIIB115 is considered a promising treatment for Spinal Muscular Atrophy because it is part of new therapies being developed to address the genetic causes of the disease. These therapies aim to improve the function of motor neurons, which are affected in SMA, and offer hope for better management of the condition. ^{4 11 12 13 14}

What is the purpose of this trial?

In this study, researchers will learn about a study drug called salanersen (BIIB115) in healthy male volunteers and in participants with spinal muscular atrophy (SMA). This study will focus on children with SMA. The main objective of the study is to learn more about the safety of salanersen and how participants respond to different doses of salanersen. The main question researchers want to answer is: How many participants have adverse events and serious adverse events during the study? Adverse events are unwanted health problems that may or may not be caused by the study drug. Researchers will also learn more about how the body processes salanersen. They will do this by measuring the levels of salanersen in both the blood and the cerebrospinal fluid, also known as the CSF. This is the fluid around the brain and spinal cord. The study will be split into 2 parts - Part A and Part B. During Part A: * After screening, healthy volunteers will be randomly placed into 1 of 4 groups to receive either salanersen or a placebo. A placebo looks like the study drug but contains no real medicine. * Participants will receive a single dose of either salanersen or the placebo as an injection directly into the spinal canal on Day 1. * Neither the researchers nor the participants will know if the participants will receive salanersen or the placebo. * The treatment and follow up period will last for 13 months. * Participants will have up to 6 clinic visits and 4 telephone calls. During Part B: * In Part B, children with SMA will receive salanersen. Both researchers and participants will know they are receiving salanersen. * Participants will receive 2 total doses of salanersen given at 2 different times. * The treatment and follow up period will last for 25 months. * Participants will have up to 14 clinic visits and 6 telephone calls. In both parts, participants will stay in the clinic for 24 hours after each dose for so that researchers can check on their health and any medical problems they might have.

Research Team

Medical Director

Principal Investigator

Biogen

Eligibility Criteria

This trial is for healthy males aged 18-55 and children aged 0.5 to 12 with Spinal Muscular Atrophy (SMA) who've been treated with onasemnogene abeparvovec. Adults must have a BMI of 18-30 kg/m^2 and be in good health, while children need to weigh at least 7 kg and may benefit from treatment due to SMA.

Inclusion Criteria

Part A: Must be in good health as determined by the investigator, based on medical history and screening evaluations

Part A: Have a body mass index of 18 to 30 kg/m^2, inclusive

I weigh at least 7 kg.

Exclusion Criteria

I have a history of blood clotting disorders.

Part A: History of any clinically significant cardiac, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, or renal disease, or other major disease, as determined by the Investigator

Part A: Current enrollment or a plan to enroll in any interventional clinical study of a drug, biologic, or device, in which an investigational treatment or approved therapy for investigational use is administered within 3 months (or 5 half-lives of the agent, whichever is longer) prior to randomization

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment (Part A)

Healthy volunteers receive a single dose of BIIB115 or placebo via IT bolus injection

1 day

1 clinic visit, 24-hour stay

Follow-up (Part A)

Participants are monitored for safety and effectiveness after treatment

13 months

Up to 6 clinic visits, 4 telephone calls

Treatment (Part B)

Pediatric SMA participants receive two doses of BIIB115 at two different times

2 days

2 clinic visits, 24-hour stay after each dose

Follow-up (Part B)

Participants are monitored for safety and effectiveness after treatment

25 months

Up to 14 clinic visits, 6 telephone calls

Treatment Details

Interventions

• BIIB115

Trial Overview The study tests the safety and tolerability of BIIB115, given through spinal injection, comparing it with a placebo. It's conducted in two parts: one-time dosing for healthy adults (Part A), and multiple doses for pediatric SMA patients previously treated with gene therapy (Part B).

Participant Groups

Group I: Part B: Cohort 6: Salanersen Dose 4 Experimental Treatment 1 Intervention

Pediatric SMA participants previously treated with onasemnogene abeparvovec will receive two doses of salanersen, Dose 4, via IT bolus injectionat two separate time points.

Group II: Part B: Cohort 5: Salanersen Dose 3 Experimental Treatment 1 Intervention

Pediatric SMA participants previously treated with onasemnogene abeparvovec will receive two doses of salanersen, Dose 3, via IT bolus injection at two separate time points.

Group III: Part A: Cohort 4: Salanersen Dose 4 Experimental Treatment 1 Intervention

Participants will receive a single dose of salanersen, Dose 4, via IT bolus injection, on Day 1.

Group IV: Part A: Cohort 3: Salanersen Dose 3 Experimental Treatment 1 Intervention

Participants will receive a single dose of salanersen, Dose 3, via IT bolus injection, on Day 1.

Group V: Part A: Cohort 2: Salanersen Dose 2 Experimental Treatment 1 Intervention

Participants will receive a single dose of salanersen, Dose 2, via IT bolus injection, on Day 1.

Group VI: Part A: Cohort 1: Salanersen Dose 1 Experimental Treatment 1 Intervention

Participants will receive a single dose of salanersen, Dose 1, via IT bolus injection, on Day 1.

Group VII: Part A: Cohorts 1-4: Salanersen-Matching Placebo Placebo Group 1 Intervention

Participants will receive a single dose of salanersen-matching placebo, via IT bolus injection, on Day 1.

Who Is Running the Clinical Trial?

Biogen

Lead Sponsor

Trials

655

Recruited

468,000+

Daniel Quirk

Biogen

Chief Medical Officer

MD

Christopher A. Viehbacher

Biogen

Chief Executive Officer since 2022

Graduated from Queen's University, Kingston, Ontario, Canada

Findings from Research

New treatments for Spinal Muscular Atrophy (SMA), including gene therapy and splicing modulation, can significantly alter the disease's progression if started early, highlighting the importance of newborn screening for early detection.

Current evidence for these therapies is limited to a narrow range of patients, emphasizing the need for real-world data collection to better understand treatment effects across all SMA subtypes and improve clinical decision-making.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Treatment of Spinal Muscular Atrophy - New Phenotypes, New Challenges, New Implications for Care. Schorling, DC., Pechmann, A., Kirschner, J.[2020]

A systematic review and meta-analysis of 42 studies involving 606 patients with spinal muscular atrophy (SMA) found that traditional biomarkers like lung function and serum levels do not effectively track disease progression over time.

However, potential biomarkers such as the SMA functional rating scale, compound muscle action potential (CMAP), and motor unit number estimation (MUNE) showed significant differences between SMA patients and controls, indicating they may be useful for further research into disease activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers of disease progression in adolescents and adults with 5q spinal muscular atrophy: a systematic review and meta-analysis. Gavriilaki, M., Moschou, M., Papaliagkas, V., et al.[2022]

Spinal muscular atrophy (SMA) is caused by a deletion of the SMN1 gene, leading to reduced SMN protein levels and resulting in muscle weakness and paralysis; early diagnosis and supportive care are crucial for improving patient outcomes.

Current treatments can help delay disease progression and improve quality of life, but they cannot reverse the damage already done to motor neurons or muscle cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spinal muscular atrophy: diagnosis, treatment and future prospects. Baioni, MT., Ambiel, CR.[2020]

Infantile-onset spinal muscular atrophy (SMA) is primarily caused by low levels of the Survival Motor Neuron (SMN) protein, which leads to the selective degeneration of spinal motor neurons, although the exact reasons for this selectivity are still unclear.

Recent advances in SMA research have led to the development of promising new therapies that focus on increasing SMN protein levels, marking significant progress in treatment options for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Motor neuron biology and disease: A current perspective on infantile-onset spinal muscular atrophy. Jha, NN., Kim, JK., Monani, UR.[2020]

Spinal muscular atrophy (SMA) is a severe childhood neurological disease caused by the degeneration of lower motor neurons, leading to significant muscle weakness.

There is a need for standardized and sensitive clinical outcome measures to effectively assess the impact of new treatments for SMA, as current assessments vary and their ability to detect changes is not well established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcome measures in spinal muscular atrophy. Montes, J., Gordon, AM., Pandya, S., et al.[2009]

In a phase 2 study involving 20 infants with infantile-onset spinal muscular atrophy, nusinersen treatment led to significant improvements in motor milestones, with 63% of participants showing incremental gains over 3 years.

The study also reported a favorable safety profile, with 75% of participants alive at the end of the study, although serious adverse events were common, primarily related to disease progression rather than the treatment itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. Finkel, RS., Chiriboga, CA., Vajsar, J., et al.[2021]

Oral administration of sodium 4-phenylbutyrate (PB) significantly increases survival motor neuron (SMN) protein expression in leukocytes of patients with spinal muscular atrophy (SMA), suggesting a potential therapeutic benefit.

This study provides the first evidence of PB's effect in SMA patients and supports further investigation into its efficacy, backed by preliminary clinical data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. Brahe, C., Vitali, T., Tiziano, FD., et al.[2022]

In a review of 15 studies involving 967 children, Nusinersen was found to have a low rate of definite adverse events (0.57%) and a higher rate of probable adverse events (7.76%), indicating it is generally safe for treating spinal muscular atrophy.

Nusinersen significantly reduced the incidence of serious and fatal adverse events compared to placebo, suggesting it not only has a favorable safety profile but also contributes to better overall health outcomes in children and adolescents with spinal muscular atrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in the treatment of spinal muscular atrophy in children and adolescents with nusinersen: A systematic review and meta-analysis. Zhong, ZJ., Zheng, PM., Dou, HH., et al.[2023]

In a study of 95 non-ambulatory children with later-onset spinal muscular atrophy (SMA) treated with nusinersen, improvements in motor function were observed, particularly in those with no or mild scoliosis, as measured by the Hammersmith Functional Motor Score-Expanded (HFMSE) and the Revised Upper Limb Module (RULM).

A significant relationship was found between baseline scoliosis severity and motor function outcomes, with greater scoliosis (measured by Cobb angle) correlating with lower improvements in motor function, indicating that scoliosis severity may impact the efficacy of nusinersen treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen Treatment of Children with Later-Onset Spinal Muscular Atrophy and Scoliosis Is Associated with Improvements or Stabilization of Motor Function. Dunaway Young, S., Montes, J., Glanzman, AM., et al.[2023]

Nusinersen treatment in adults with spinal muscular atrophy (SMA) type 2 and 3 showed modest improvements in muscle strength over 26 months, with significant increases in strength observed at 6 and 14 months, but not thereafter.

The treatment was found to be safe, with the only reported side effect being post-lumbar puncture headache, and it stabilized motor function without significant changes in respiratory function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longer-term follow-up of nusinersen efficacy and safety in adult patients with spinal muscular atrophy types 2 and 3. Fainmesser, Y., Drory, VE., Ben-Shushan, S., et al.[2022]

This study identified mutations in the BICD2 gene as a cause of non-5q spinal muscular atrophy (SMA) in a Bulgarian family, highlighting the genetic diversity of SMA beyond the common SMN1 mutations.

The identified BICD2 mutations lead to altered protein interactions that disrupt dynein-mediated transport, which is crucial for motor neuron function, suggesting a potential mechanism for the disease's progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance. Peeters, K., Litvinenko, I., Asselbergh, B., et al.[2021]

In a 12-week trial involving 27 patients with spinal and bulbar muscular atrophy, the IGF-1 mimetic BVS857 was found to be generally safe, with no serious adverse events reported, although a high incidence of immunogenicity was observed in 72% of participants.

BVS857 treatment helped maintain thigh muscle volume (TMV) compared to a decrease in the placebo group, indicating potential efficacy in stabilizing muscle mass, but did not lead to improvements in muscle strength or function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial. Grunseich, C., Miller, R., Swan, T., et al.[2021]

Induced pluripotent stem cells (iPSCs) derived from a family with chronic spinal muscular atrophy (SMA) were differentiated into motor neurons, revealing significant differences in neurite length and number among family members, which highlights the variability in disease manifestation.

The study found that levels of SMN protein and PLS3 decreased progressively during the differentiation of iPSC-derived motor neurons, suggesting that this decline may contribute to the increased vulnerability of motor neurons in SMA, although these levels have limited value as biomarkers for the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decay in survival motor neuron and plastin 3 levels during differentiation of iPSC-derived human motor neurons. Boza-Morán, MG., Martínez-Hernández, R., Bernal, S., et al.[2018]

Spinal muscular atrophy (SMA) is a genetic disorder caused by mutations in the SMN1 gene, affecting approximately 1 in 6000-10,000 newborns, with a carrier frequency of 1 in 40-60, highlighting the importance of genetic screening for early detection.

While there is currently no effective treatment for SMA, several promising strategies are being developed, including targeting the SMN2 gene, introducing functional SMN1, and exploring non-SMN targeting approaches, based on the disease's molecular mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spinal muscular atrophy: from gene discovery to clinical trials. Nurputra, DK., Lai, PS., Harahap, NI., et al.[2014]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Advances in Treatment of Spinal Muscular Atrophy - New Phenotypes, New Challenges, New Implications for Care. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Biomarkers of disease progression in adolescents and adults with 5q spinal muscular atrophy: a systematic review and meta-analysis. [2022]

3. Brazil pubmed.ncbi.nlm.nih.gov

Spinal muscular atrophy: diagnosis, treatment and future prospects. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Motor neuron biology and disease: A current perspective on infantile-onset spinal muscular atrophy. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Clinical outcome measures in spinal muscular atrophy. [2009]

6. England pubmed.ncbi.nlm.nih.gov

Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse events in the treatment of spinal muscular atrophy in children and adolescents with nusinersen: A systematic review and meta-analysis. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Nusinersen Treatment of Children with Later-Onset Spinal Muscular Atrophy and Scoliosis Is Associated with Improvements or Stabilization of Motor Function. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Longer-term follow-up of nusinersen efficacy and safety in adult patients with spinal muscular atrophy types 2 and 3. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Decay in survival motor neuron and plastin 3 levels during differentiation of iPSC-derived human motor neurons. [2018]

14. England pubmed.ncbi.nlm.nih.gov

Spinal muscular atrophy: from gene discovery to clinical trials. [2014]