High-Dose Nusinersen for Spinal Muscular Atrophy

(ASCEND Trial)

Recruiting at 43 trial locations

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Biogen

Must be taking: Risdiplam

Must not be taking: Gene therapy

Disqualifiers: Major illness, Active infection, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

In this study, researchers will learn more about the use of a higher dose of nusinersen (BIIB058) in participants with spinal muscular atrophy (SMA). This study will focus on teenagers and adults who are unable to walk on their own and who have previously taken another drug for SMA called risdiplam. The main goal of this study is to learn about the effect of high dose (HD) nusinersen on muscle and movement ability (motor function) in SMA. The main question that researchers want to answer is: - How do the scores of a movement test called the Revised Upper Limb Module change from the start of treatment? The Revised Upper Limb Module is a test used to measure a participant's ability to do specific tasks that involve their shoulders, arms, wrist, elbows, and hands. It measures the changes in their abilities over time. Researchers will also learn more about the safety of HD nusinersen. They will check participants for adverse events and changes in vital signs, heart tests, and laboratory tests including blood and urine tests. The study will be done as follows: * Participants will be screened to check if they can join the study. * After screening, participants will enter the Core Treatment period. * At the start of the Core Treatment period, they will receive 2 "loading" doses of nusinersen. These are 50 mg doses of nusinersen given 2 weeks apart. * Afterwards, they will continue to receive "maintenance" doses of nusinersen once every 4 months. These doses will be 28 mg. * The Core Treatment period will last about 2 years, with a follow-up visit 4 months after the last dose. * Participants who complete the Core Treatment period will have the option to continue receiving 28 mg of nusinersen in the Long-Term Extension (LTE) period for about 2 years. There will also be a follow-up visit 4 months after the last dose. * Nusinersen will be given through a lumbar puncture, which involves injecting the drug into the fluid around the spinal cord in the lower back. * In total, participants will have up to 18 study visits. They will also be called by researchers after each dose of nusinersen. * Participants will stay in the study for about 4.5 years if they complete both the Core Treatment and LTE periods.

Will I have to stop taking my current medications?

The trial requires participants to stop taking risdiplam before starting the study. The protocol does not specify about other medications, so it's best to discuss your current medications with the study team.

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

Research shows that Nusinersen, a drug for spinal muscular atrophy, has been effective in improving motor function in patients with types II and III of the condition. Studies in both children and adults have demonstrated its safety and effectiveness, with ongoing surveillance in Japan confirming these findings in real-world settings. ^{1 2 3 4 5}

What safety data exists for high-dose Nusinersen in humans?

Nusinersen, also known as Spinraza, has been studied for safety in treating spinal muscular atrophy (SMA). In clinical trials and real-world settings, common side effects included headache, back pain, and fever, with serious side effects occurring in about 11.5% of cases. Overall, no new safety concerns have been identified, and the treatment is considered to have a favorable safety profile. ^{1 2 3 6 7}

How is the drug nusinersen unique in treating spinal muscular atrophy?

Nusinersen is unique because it is an antisense oligonucleotide drug that is administered directly into the spinal fluid (intrathecally) to increase the production of a crucial protein called SMN, which is often lacking in patients with spinal muscular atrophy. This approach specifically targets the genetic cause of the disease, making it different from other treatments that may not address the underlying genetic issue. ^{1 2 3 4 8}

Research Team

Medical Director

Principal Investigator

Biogen

Eligibility Criteria

This trial is for individuals aged 15-50 with a confirmed genetic diagnosis of spinal muscular atrophy (SMA), weighing over 20 kg, and able to perform certain functional assessments. Participants must have been previously treated with risdiplam but are willing to stop it and start high-dose nusinersen treatment. They should not be able to walk independently for 15 feet, not have severe illnesses or conditions that could affect the study, nor be pregnant or breastfeeding.

Inclusion Criteria

My upper limb mobility score is 3 or higher.

I can do the physical tests required for my age in the study.

My RULM score is between 5 and 30.

Exclusion Criteria

I need a breathing machine during the day for reasons other than spinal muscular atrophy management.

Ongoing medical condition that according to the Investigator would interfere with the conduct and assessments of the study. An example is a medical disability (e.g., wasting or cachexia, severe anemia, and respiratory parameters) that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures

I haven't had a major illness in the month before my screening or in the week leading up to my first dose.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Core Treatment

Participants receive 2 loading doses of 50 mg nusinersen 2 weeks apart, followed by maintenance doses of 28 mg every 4 months

2 years

Up to 18 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the Core Treatment period

4 months

1 visit (in-person)

Long-Term Extension (optional)

Participants may continue receiving 28 mg nusinersen every 4 months for about 2 years

2 years

Regular calls after each dose

Follow-up after LTE

Participants are monitored for safety and effectiveness after the Long-Term Extension period

4 months

1 visit (in-person)

Treatment Details

Interventions

• Nusinersen (Antisense Oligonucleotide)

Trial Overview The trial is testing whether a higher dose of nusinersen can improve motor function in patients who have SMA and were previously treated with risdiplam. It will also assess the safety and tolerability of this increased dosage regimen.

Participant Groups

Group I: Higher Dose Nusinersen Experimental Treatment 1 Intervention

All participants in the core study period, previously treated with risdiplam (nusinersen-naive participants and nusinersen-experienced participants), will receive HD nusinersen, administered as 2 loading doses of 50 milligrams (mg) each, approximately 2 weeks apart, followed by maintenance doses of 28 mg approximately every 4 months. Following the core study period, participants may be given the opportunity to receive maintenance doses of 28 mg nusinersen administered approximately every 4 months up to 2 years during the optional long-term extension (LTE) period.

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

Nusinersen (Spinraza) is the first approved drug for spinal muscular atrophy (SMA) and has shown significant improvements in motor function across all types of SMA in clinical trials.

The treatment is generally safe and well-tolerated, with common side effects including respiratory infections and headaches, but its administration via intrathecal delivery and high cost present challenges in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen: A Treatment for Spinal Muscular Atrophy. Claborn, MK., Stevens, DL., Walker, CK., et al.[2020]

Nusinersen, an antisense oligonucleotide, significantly improved motor function in 72% to 88% of patients with spinal muscular atrophy (SMA) types II and III over a treatment period of up to 26 months, as measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE).

The treatment was found to be safe, with no significant side effects reported, making it a viable option for SMA patients, including those with severe scoliosis or requiring respiratory support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen for spinal muscular atrophy types II and III: a retrospective single-center study in South Korea. Shin, HJ., Na, JH., Lee, H., et al.[2023]

In a study of 52 spinal muscular atrophy (SMA) patients receiving a total of 265 nusinersen injections, the complication rate was very low, with only 2.2% experiencing post-lumbar puncture headaches requiring treatment, indicating that the procedure is generally safe.

Different injection techniques, including CT-guided and fluoroscopy-guided methods, were successfully used, demonstrating that image-guided procedures can be effective and safe alternatives to surgical approaches for administering nusinersen in SMA patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen injections in adults and children with spinal muscular atrophy: a single-center experience. Özütemiz, C., Karachunski, P., Nascene, DR.[2021]

In a post-marketing surveillance study of 524 patients treated with nusinersen for spinal muscular atrophy (SMA), the treatment showed significant safety and effectiveness, with 35.9% of patients experiencing adverse events, mostly mild to moderate.

Nusinersen significantly improved motor function in patients with both infantile-onset and later-onset SMA, with 98.5-100% of patients reporting improvement or no change in their condition after nearly 3 years of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 524 patients: results from an interim analysis of post-marketing surveillance in Japan. Tachibana, Y., Sato, R., Makioka, H., et al.[2023]

In a study of 401 patients with spinal muscular atrophy (SMA) receiving nusinersen, the treatment showed a favorable safety profile with no new safety concerns identified, and adverse events were consistent with expectations, occurring in 31.7% of patients.

Nusinersen demonstrated significant effectiveness in improving motor function, with 99.7-100% of patients assessed as 'effective' based on clinical improvement measures, indicating a strong benefit-risk balance for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 401 Japanese patients: results from an interim analysis of post-marketing surveillance. Tachibana, Y., Takasaki, S., Hoshino, M., 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]

Nusinersen (SPINRAZA™) is an innovative treatment for spinal muscular atrophy (SMA) that works by modifying the splicing of SMN2 mRNA to increase the production of the essential SMN protein, which is crucial for motor neuron health.

The drug has been approved for intrathecal use in both pediatric and adult patients in the USA, marking a significant milestone in the treatment of SMA, with regulatory assessments ongoing in the EU and other countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen: First Global Approval. Hoy, SM.[2018]

References

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

Nusinersen: A Treatment for Spinal Muscular Atrophy. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Nusinersen for spinal muscular atrophy types II and III: a retrospective single-center study in South Korea. [2023]

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

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. [2018]

4. Turkey pubmed.ncbi.nlm.nih.gov

Nusinersen injections in adults and children with spinal muscular atrophy: a single-center experience. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 524 patients: results from an interim analysis of post-marketing surveillance in Japan. [2023]

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

Real-world safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 401 Japanese patients: results from an interim analysis of post-marketing surveillance. [2022]

7. 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]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Nusinersen: First Global Approval. [2018]