High-Dose Nusinersen for Spinal Muscular Atrophy

(ASCEND Trial)

Not currently recruiting at 63 trial locations

Overseen By Han Phan

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Biogen

Must be taking: Risdiplam

Must not be taking: Gene therapy

Disqualifiers: Major illness, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 21

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a higher dose of nusinersen, a medication for spinal muscular atrophy (SMA), to assess its effects on muscle and movement abilities in teens and adults who cannot walk independently. Researchers aim to determine if this higher dose can improve specific arm and hand movements. Participants should have SMA with symptoms that began after 6 months of age and must have been treated with another SMA drug, risdiplam. Interested individuals should be willing to discontinue risdiplam and begin the new treatment. The study will also monitor the safety of the higher nusinersen dose. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

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.

Is there any evidence suggesting that high-dose nusinersen is likely to be safe for humans?

Research has shown that higher doses of nusinersen have been tested for safety and effectiveness. In earlier studies, patients received two initial doses of 50 mg each, followed by regular doses of 28 mg. These studies found that participants generally tolerated nusinersen well, even at higher doses.

The studies did not reveal any unexpected safety issues. Instead, they confirmed that side effects were similar to those seen with standard doses of nusinersen, which is already approved for treating spinal muscular atrophy (SMA) in many countries. This suggests that nusinersen remains safe, even at higher doses.

Nusinersen is administered through a lumbar puncture, which involves injecting the drug into the lower back. This procedure is common for this type of treatment and carries known, manageable risks. Overall, the findings from these studies provide reassuring evidence about the safety of high-dose nusinersen for those considering joining clinical trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for SMA?

Unlike the standard treatments for spinal muscular atrophy (SMA), which typically involve lower doses of nusinersen, this new approach uses a higher dose regimen. Researchers are excited because this could potentially offer more significant improvements in muscle strength and motor function. The therapy starts with two loading doses of 50 mg each, followed by maintenance doses of 28 mg every four months, which is a different dosing strategy that may enhance long-term efficacy. This higher dosing method could change the game for those living with SMA by offering an option that might deliver better and faster results.

What evidence suggests that high-dose nusinersen might be an effective treatment for spinal muscular atrophy?

Research has shown that nusinersen effectively treats spinal muscular atrophy (SMA) across various ages and types. Studies highlight its ability to improve movement abilities in patients with SMA over extended periods, with some benefiting for up to 10 years. In this trial, all participants will receive a higher dose of nusinersen. Early results from trials on higher doses suggest they might enhance these benefits. This treatment is administered through a lumbar puncture, injecting it into the lower back to directly reach the spinal cord and improve muscle and movement abilities. Overall, nusinersen is considered safe, supporting its use for SMA. ^{2 6 7 8 9}

Who Is on the Research Team?

Medical Director

Principal Investigator

Biogen

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

Interventions

• Nusinersen

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.

How Is the Trial Designed?

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.

Nusinersen is already approved in United States, European Union for the following indications:

Approved in United States as Spinraza for:

• Spinal muscular atrophy in pediatric and adult patients

Approved in European Union as Spinraza for:

• Spinal muscular atrophy

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

Published Research Related to This Trial

In a phase 1 study involving 28 children aged 2 to 14 with spinal muscular atrophy, 73 lumbar punctures were performed with a complication rate of 32%, primarily involving headaches and back pain.

The study found that adverse events were more common in older children and those with type 3 spinal muscular atrophy, suggesting that the size of the needle used also influenced the frequency of complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Haché, M., Swoboda, KJ., Sethna, N., et al.[2018]

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]

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]

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4782111/

Results from a phase 1 study of nusinersen (ISIS-SMNRx) in ... This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns. Spinal muscular ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05067790

NCT05067790 | A Study to Learn About the Effect of Higher ... In this study, researchers will learn more about the use of a higher dose of nusinersen (BIIB058) in participants with spinal muscular atrophy (SMA).

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37393513/

DEVOTE Study Exploring Higher Dose of Nusinersen in ... A 3-part clinical study evaluating safety, tolerability, and efficacy of higher dose of nusinersen, and results from the initial Part A.

4. investors.biogen.com investors.biogen.com/news-releases/news-release-details/new-data-nusinersen-underscore-biogens-commitment-advancing

New Data for Nusinersen Underscore Biogen's ... SPINRAZA has shown sustained efficacy across ages and SMA types with a well-established safety profile based on data in patients treated up to 10 years.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02386553

NCT02386553 | A Study of Multiple Doses of Nusinersen ... The primary objective of the study is to examine the efficacy of multiple doses of Nusinersen administered intrathecally in preventing or delaying the need ...

6. investors.biogen.com investors.biogen.com/news-releases/news-release-details/new-higher-dose-nusinersen-efficacy-and-safety-data-presented

New Higher Dose Nusinersen Efficacy and Safety Data ... The investigational, higher dose regimen of nusinersen comprises a more rapid loading regimen, two 50 mg doses 14 days apart, and higher maintenance regimen, ...

7. investors.biogen.com investors.biogen.com/news-releases/news-release-details/biogen-provides-regulatory-update-high-dose-regimen-nusinersen

Biogen Provides Regulatory Update on High Dose ... SPINRAZA (nusinersen) 12mg/5 mL injection is approved in more than 71 countries to treat infants, children and adults with spinal muscular ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04089566

Study of Nusinersen (BIIB058) in Participants With Spinal ... The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal ...

9. curesma.org curesma.org/new-higher-dose-nusinersen-shows-benefit-in-sma/

New Higher Dose Nusinersen Efficacy and Safety Data ... Findings from Part B and Part C of the DEVOTE study support the clinical benefits of a higher dose regimen of nusinersen (50/28 mg) in both ...