Nusinersen for Spinal Muscular Atrophy

(PIERRE-PK Trial)

Overseen By Global Biogen Clinical Trial Center

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Biogen

Must be taking: Nusinersen

Disqualifiers: Other trials, Nusinersen naive, Pregnant, others

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

Compensation: Varies

Number of Visits: 2

58 Participants Needed

Trial Summary

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

The trial does not specify if you need to stop taking your current medications, but you must be on a regular maintenance dose of nusinersen to participate.

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

Research shows that Nusinersen has significant benefits for infants and children with spinal muscular atrophy, improving motor function and survival rates. It has also been effective in adults with the condition, and studies have confirmed its safety and efficacy in various types of spinal muscular atrophy, including those with severe symptoms. ^{1 2 3 4 5}

Is Nusinersen safe for humans?

Research shows that Nusinersen is generally safe for treating spinal muscular atrophy (SMA) in both children and adults, with no new safety concerns reported in various studies. ^{2 6 7 8 9}

How is the drug Nusinersen unique for treating spinal muscular atrophy?

Nusinersen is unique because it is the first approved treatment for spinal muscular atrophy and works by altering the splicing of the SMN2 gene to increase the production of a protein that is deficient in patients with this condition. It is administered directly into the spinal fluid (intrathecally), which is different from many other treatments that are taken orally or through injections into the bloodstream. ^{2 10 11 12 13}

What is the purpose of this trial?

In this PIERRE-PK study, researchers will learn how the body processes nusinersen when it is given through the ThecaFlex DRx™ System, compared to when nusinersen is given by lumbar puncture (LP). The ThecaFlex DRx system is an investigational implantable medical device developed by Alcyone Therapeutics, Inc. It consists of a catheter, which is a flexible tube, connected to a port which is placed under the skin. Alcyone Therapeutics, Inc. has an ongoing study called PIERRE to test the ThecaFlex DRx system. Participants with spinal muscular atrophy (SMA) in the PIERRE study may be enrolled in the PIERRE-PK study. The main objective of the PIERRE-PK study is to learn how the body processes nusinersen when given by the ThecaFlex DRx system compared to a lumbar puncture. The main questions researchers want to answer are: * What is the highest amount of nusinersen found in the blood after dosing? * How much nusinersen is found in the blood over the first 24 hours after dosing? The PIERRE-PK study will be done as follows: * Participants will be screened to check if they can join the study. The screening period will be up to 30 days for this study and may overlap with the PIERRE study. * Participants will receive a dose of nusinersen by lumbar puncture. * The ThecaFlex DRx system will be implanted after the lumbar puncture, as part of the PIERRE study. * Participants will receive a dose of nusinersen by the ThecaFlex DRx system, as part of the PIERRE study. * Researchers will take blood samples before and after each dose. The last blood sample will be taken 24 hours after the dose. * The total study duration for each participant in the PIERRE-PK study will be approximately 5 months. This period will overlap with the participant's first 5 months in the PIERRE study.

Research Team

Medical Director

Principal Investigator

Biogen

Eligibility Criteria

This trial is for both adults and children with Spinal Muscular Atrophy who are already on a regular nusinersen treatment every 4 months. They must be part of the PIERRE study, which involves an implantable device called ThecaFlex DRx System.

Inclusion Criteria

Participants must be enrolled in the PIERRE study to be eligible for enrolment in the PIERRE PK study

I am on a stable 4-month nusinersen treatment schedule.

Exclusion Criteria

I am taking nusinersen, but not at a 12 mg dose.

Participant is pregnant, currently breastfeeding, or intending to become pregnant during the study

Ongoing participation or participation within 6 months or 5 half-lives of the agent (whichever is longer) of enrolment in other interventional clinical trials for the treatment of SMA (except for the PIERRE study)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment - Lumbar Puncture

Participants receive a dose of nusinersen by lumbar puncture

1 day

1 visit (in-person)

Treatment - ThecaFlex DRx System

The ThecaFlex DRx system is implanted, and participants receive a dose of nusinersen via the system

1 day

1 visit (in-person)

Follow-up

Participants are monitored for nusinersen levels in the blood, with samples taken before and after each dose, up to 24 hours after dosing

5 months

Treatment Details

Interventions

• Nusinersen

Trial Overview Researchers are testing how nusinersen is processed in the body when delivered through the ThecaFlex DRx System compared to traditional lumbar puncture. Participants will receive doses by both methods, with blood samples taken before and after dosing to measure levels.

Participant Groups

Group I: Nusinersen Via LP and ThecaFlex DRx System Experimental Treatment 2 Interventions

Participants will receive a maintenance dose of nusinersen, 12 milligrams (mg) via LP in the PIERRE-PK study, followed by implantation of the ThecaFlex DRx System and the subsequent nusinersen 12 mg maintenance dose via the system in the PIERRE study.

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

Alcyone Therapeutics, Inc

Industry Sponsor

Trials

3

Recruited

110+

Findings from Research

Nusinersen has strong evidence (Class I) for improving motor milestones and survival rates in infants with spinal muscular atrophy (SMA) when treatment starts before 7 months of age, showing it is effective in early intervention.

In children aged 2-12 years with later-onset SMA, nusinersen also demonstrates significant improvements in motor function compared to sham control, indicating its efficacy across different age groups and stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence in focus: Nusinersen use in spinal muscular atrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Michelson, D., Ciafaloni, E., Ashwal, S., et al.[2019]

Nusinersen has been found to be safe and effective for treating patients with spinal muscular atrophy (SMA) type I, including those with chronic respiratory failure on permanent ventilation, based on a study of seven patients followed for an average of 46.2 months.

The treatment led to significant improvements in neuromuscular function, with 100% of patients showing disease amelioration by the 58- and 74-month follow-ups, and no significant adverse effects were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen for Spinal Muscular Atrophy Type I with Chronic Respiratory Failure: A Retrospective Study in South Korea. Shin, HJ., Na, JH., Lee, H., et al.[2023]

Nusinersen has shown a favorable safety profile in treating 323 infants and children with symptomatic spinal muscular atrophy (SMA), with a lower incidence of serious adverse events (41%) compared to sham procedures (61%).

The most common adverse events associated with nusinersen were mild and included pyrexia and upper respiratory infections, indicating that while some side effects occurred, they were consistent with typical SMA symptoms and lumbar puncture procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. Darras, BT., Farrar, MA., Mercuri, E., et al.[2021]

In a study of 32 adult patients with spinal muscular atrophy (SMA) treated with nusinersen over a median follow-up of 17 months, 78% showed improvement in motor function as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE) or the 6-minute walk test (6MWT).

Patients with SMA type 3 experienced significant increases in HFMSE scores at each time point, while type 2 patients showed initial benefits but remained stable afterward, indicating that nusinersen can be effective in improving motor function in adults with SMA, particularly in those with type 3.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen for adults with spinal muscular atrophy. Arslan, D., Inan, B., Kilinc, M., et al.[2023]

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 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 79 adult patients with spinal muscular atrophy (SMA), those treated with nusinersen showed significant improvements in motor function, particularly a 2-point increase in the Revised Upper Limb Module (RULM) after 6 months, compared to untreated patients.

After an average follow-up of 16 months, nusinersen was associated with meaningful improvements in various functional scales, with 64.1% of treated patients reporting improvement, although most patients experienced at least one mild adverse event.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen in adult patients with 5q spinal muscular atrophy: A multicenter observational cohorts' study. Vázquez-Costa, JF., Povedano, M., Nascimiento-Osorio, AE., et al.[2022]

In a study of 52 spinal muscular atrophy (SMA) patients treated with nusinersen, significant improvements in motor function were observed in pediatric patients with SMA types 1 and 2 after receiving the drug, particularly after four doses.

Nusinersen was found to be safe, with no new safety concerns reported during the administration of 437 doses; however, adult patients with SMA type 3 who started treatment after age 18 did not show significant improvements in motor performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Nusinersen in Type 1, 2 and 3 Spinal Muscular Atrophy: Croatian Real-World Data. Belančić, A., Strbad, T., Kučan Štiglić, M., et al.[2023]

In a study of 116 adult patients with spinal muscular atrophy (SMA), nusinersen treatment showed significant improvements in motor function for those with SMA3, with notable increases in the Hammersmith Functional Rating Scale Expanded (HFMSE) scores over time.

While patients with SMA2 did not show significant changes in motor function, there was a trend towards improvement in those with some baseline function, indicating that nusinersen may be more effective in earlier stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3. Maggi, L., Bello, L., Bonanno, S., et al.[2021]

Nusinersen treatment in adults with 5q spinal muscular atrophy showed significant improvements in motor function, with mean Hammersmith Functional Motor Scale Expanded (HFMSE) scores increasing at 6, 10, and 14 months compared to baseline, indicating its efficacy in this population.

The treatment was generally safe, with common side effects including headache and back pain, but no serious adverse events were reported, suggesting that nusinersen can be a viable option for adults with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study. Hagenacker, T., Wurster, CD., Günther, R., et al.[2020]

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 intrathecal antisense oligonucleotide, significantly improved motor functions in a 45-year-old female patient with spinal muscular atrophy type 3 (SMA3) after 11 months of treatment, despite her long disease duration of 40 years.

After discontinuation of Nusinersen due to worsening anxiety, the patient experienced disease progression, indicating that while the treatment is effective, stopping it may lead to a return to the natural course of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Discontinuation of Nusinersen Treatment in Long-Standing SMA3. Hiebeler, M., Abicht, A., Reilich, P., et al.[2021]

Nusinersen, an antisense drug designed to increase functional SMN protein levels, demonstrated acceptable safety and tolerability in a phase 2 study involving 20 infants with spinal muscular atrophy, with all participants experiencing adverse events deemed unrelated to the drug.

The 12 mg dose of nusinersen led to significant improvements in motor function and milestones, as well as increased SMN protein levels in the spinal cord, suggesting its efficacy in treating infantile-onset spinal muscular atrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Finkel, RS., Chiriboga, CA., Vajsar, J., et al.[2022]

References

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

Evidence in focus: Nusinersen use in spinal muscular atrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. [2019]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Nusinersen for Spinal Muscular Atrophy Type I with Chronic Respiratory Failure: A Retrospective Study in South Korea. [2023]

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

An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. [2021]

4. Italy pubmed.ncbi.nlm.nih.gov

Nusinersen for adults with spinal muscular atrophy. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

6. 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]

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

Nusinersen in adult patients with 5q spinal muscular atrophy: A multicenter observational cohorts' study. [2022]

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

Effectiveness of Nusinersen in Type 1, 2 and 3 Spinal Muscular Atrophy: Croatian Real-World Data. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3. [2021]

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

Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study. [2020]

11. Turkey pubmed.ncbi.nlm.nih.gov

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

12. Netherlands pubmed.ncbi.nlm.nih.gov

Effect of Discontinuation of Nusinersen Treatment in Long-Standing SMA3. [2021]

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

Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. [2022]