An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy

Phase 1

Completed

Conditions: Spinal Muscular Atrophy

Interventions: Drug: Nusinersen

Registration Number: NCT01703988

Lead Sponsor: Biogen

Brief Summary: This study will test the safety, tolerability, and pharmacokinetics of escalating doses of nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over the duration of the trial, in participants with spinal muscular atrophy (SMA).

Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort of approximately 8 participants, where all participants will receive active drug.

Detailed Description: This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc. In August 2016, sponsorship of the trial was transferred to Biogen.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 34

Inclusion Criteria

Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
Clinical signs attributable to SMA
Able to complete all study procedures, measurements, and visits and parent/patient has adequately supportive psychosocial circumstances, in the opinion of the Investigator
Estimated life expectancy > 2 years from Screening
Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure

Key

Exclusion Criteria

Respiratory insufficiency defined by the medical necessity for invasive or non-invasive ventilation during a 24-hour period
Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Investigator
Previous scoliosis surgery that would interfere with the lumbar puncture injection procedure
Hospitalization for surgery (e.g. scoliosis surgery) or pulmonary event within 2 months of screening or planned during the duration of the study
Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
History of brain or spinal cord disease that would interfere with lumbar puncture procedures or cerebrospinal fluid (CSF) circulation
Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system catheter
History of bacterial meningitis
Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4
Dosing with ISIS 396443 in clinical study ISIS 396443-CS10
Clinically significant abnormalities in hematology or clinical chemistry parameters or electrocardiogram (ECG) at the Screening visit, as assessed by the Site Investigator that would render the subject unsuitable for inclusion
Treatment with investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of screening. Any history of gene therapy or cell transplantation
Ongoing medical condition that would interfere with the conduct and assessments of the study. Examples are medical disability (e.g. wasting or cachexia, severe anemia) that would interfere with the assessment of safety or would compromise the ability of the patient to undergo study procedures.

NOTE: Other protocol defined inclusion/exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Nusinersen 6 mg	Nusinersen	6 mg nusinersen on Days 1, 29, 85, IT injection
Nusinersen 3 mg	Nusinersen	3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection
Nusinersen 12 mg	Nusinersen	12 mg nusinersen on Days 1, 29, 85, IT injection
Nusinersen 9 mg	Nusinersen	9 mg nusinersen on Days 1 and 85, IT injection

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs	Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days	An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.

Secondary Outcome Measures

Name	Time	Method
Plasma Pharmacokinetics: Time to Reach Cmax in Plasma	Day 1 and Day 85
Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)	Day 1 and Day 85
Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations	Day 1, Day 29, and Day 85
Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)	Day 1 and Day 85
Urine Pharmacokinetics: Renal Clearance, Cohort 4	Day 1 and Day 85	Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.

Trial Locations

Locations (4): University of Utah School of Medicine
🇺🇸
Salt Lake City, Utah, United States
Boston Children's Hospital
🇺🇸
Boston, Massachusetts, United States
UT Southwestern Medical Center - Children's Medical Center Dallas
🇺🇸
Dallas, Texas, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States