BIIB115 for Spinal Muscular Atrophy
Palo Alto (17 mi)Age: < 65
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Biogen
Trial Summary
What is the purpose of this trial?In this study, researchers will learn about a study drug called 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 BIIB115 and how participants respond to different doses of BIIB115. 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 BIIB115. They will do this by measuring the levels of BIIB115 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 BIIB115 or a placebo. A placebo looks like the study drug but contains no real medicine.
* Participants will receive a single dose of either BIIB115 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 BIIB115 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 BIIB115. Both researchers and participants will know they are receiving BIIB115.
* Participants will receive 2 total doses of BIIB115 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.
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 ION306.110121314
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.45678
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.238911
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.
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.Treatment Details
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).
7Treatment groups
Experimental Treatment
Placebo Group
Group I: Part B: Cohort 6: BIIB115 Dose 4Experimental Treatment1 Intervention
Pediatric SMA participants previously treated with onasemnogene abeparvovec will receive two doses of BIIB115, Dose 4, via IT bolus injectionat two separate time points.
Group II: Part B: Cohort 5: BIIB115 Dose 3Experimental Treatment1 Intervention
Pediatric SMA participants previously treated with onasemnogene abeparvovec will receive two doses of BIIB115, Dose 3, via IT bolus injection at two separate time points.
Group III: Part A: Cohort 4: BIIB115 Dose 4Experimental Treatment1 Intervention
Participants will receive a single dose of BIIB115, Dose 4, via IT bolus injection, on Day 1.
Group IV: Part A: Cohort 3: BIIB115 Dose 3Experimental Treatment1 Intervention
Participants will receive a single dose of BIIB115, Dose 3, via IT bolus injection, on Day 1.
Group V: Part A: Cohort 2: BIIB115 Dose 2Experimental Treatment1 Intervention
Participants will receive a single dose of BIIB115, Dose 2, via IT bolus injection, on Day 1.
Group VI: Part A: Cohort 1: BIIB115 Dose 1Experimental Treatment1 Intervention
Participants will receive a single dose of BIIB115, Dose 1, via IT bolus injection, on Day 1.
Group VII: Part A: Cohorts 1-4: BIIB115-Matching PlaceboPlacebo Group1 Intervention
Participants will receive a single dose of BIIB115-matching placebo, via IT bolus injection, on Day 1.
Find a clinic near you
Research locations nearbySelect from list below to view details:
Children's Hospital of Eastern OntarioOntario, Canada
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Who is running the clinical trial?
BiogenLead Sponsor
References
Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. [2022]Spinal muscular atrophy (SMA) is caused by insufficient levels of survival motor neuron (SMN) protein. Recently, we found that sodium 4-phenylbutyrate (PB), a well-tolerated FDA approved drug, enhances SMN gene expression in vitro. We provide here the first evidence that oral administration of PB (triButyrate significantly increases SMN expression in leukocytes of SMA patients. This finding provides a strong rationale to further investigate the effects of PB as also supported by preliminary clinical data.
Clinical outcome measures in spinal muscular atrophy. [2009]Spinal muscular atrophy is one of the most devastating neurological diseases of childhood. Affected infants and children suffer from often severe muscle weakness caused by degeneration of lower motor neurons in the spinal cord and brainstem. Identification of the causative genetic mutation in most cases has resulted in development of potential treatment strategies. To test these new drugs, clinically feasible outcomes are needed. Several different assessments, validated in spinal muscular atrophy or similar disorders, are being used by national and international research groups; however, their sensitivity to detect change is unknown. Acceptance of a few standardized, easily administered, and functionally meaningful outcomes, applicable to the phenotypic spectrum of spinal muscular atrophy, is needed. Consensus is imperative to facilitate collaboration and explore the ability of these measures to identify the therapeutic effect of disease-modifying agents. Following is an evidence-based review of available clinical outcome measures in spinal muscular atrophy.
Spinal muscular atrophy: diagnosis, treatment and future prospects. [2020]To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support.
Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance. [2021]The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by deleterious SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogeneous and largely remain to be elucidated. In a Bulgarian family affected by autosomal-dominant proximal SMA, we performed genome-wide linkage analysis and whole-exome sequencing and found a heterozygous de novo c.320C>T (p.Ser107Leu) mutation in bicaudal D homolog 2 (Drosophila) (BICD2). Further analysis of BICD2 in a cohort of 119 individuals with non-5q SMA identified a second de novo BICD2 mutation, c.2321A>G (p.Glu774Gly), in a simplex case. Detailed clinical and electrophysiological investigations revealed that both families are affected by a very similar disease course, characterized by early childhood onset, predominant involvement of lower extremities, and very slow disease progression. The amino acid substitutions are located in two interaction domains of BICD2, an adaptor protein linking the dynein molecular motor with its cargo. Our immunoprecipitation and localization experiments in HeLa and SH-SY5Y cells and affected individuals' lymphoblasts demonstrated that p.Ser107Leu causes increased dynein binding and thus leads to accumulation of BICD2 at the microtubule-organizing complex and Golgi fragmentation. In addition, the altered protein had a reduced colocalization with RAB6A, a regulator of vesicle trafficking between the Golgi and the endoplasmic reticulum. The interaction between p.Glu744Gly altered BICD2 and RAB6A was impaired, which also led to their reduced colocalization. Our study identifies BICD2 mutations as a cause of non-5q linked SMA and highlights the importance of dynein-mediated motility in motor neuron function in humans.
Spinal muscular atrophy: from gene discovery to clinical trials. [2014]Spinal muscular atrophy (SMA) is a common neuromuscular disorder with autosomal recessive inheritance, resulting in the degeneration of motor neurons. The incidence of the disease has been estimated at 1 in 6000-10,000 newborns with a carrier frequency of 1 in 40-60. SMA is caused by mutations of the SMN1 gene, located on chromosome 5q13. The gene product, survival motor neuron (SMN) plays critical roles in a variety of cellular activities. SMN2, a homologue of SMN1, is retained in all SMA patients and generates low levels of SMN, but does not compensate for the mutated SMN1. Genetic analysis demonstrates the presence of homozygous deletion of SMN1 in most patients, and allows screening of heterozygous carriers in affected families. Considering high incidence of carrier frequency in SMA, population-wide newborn and carrier screening has been proposed. Although no effective treatment is currently available, some treatment strategies have already been developed based on the molecular pathophysiology of this disease. Current treatment strategies can be classified into three major groups: SMN2-targeting, SMN1-introduction, and non-SMN targeting. Here, we provide a comprehensive and up-to-date review integrating advances in molecular pathophysiology and diagnostic testing with therapeutic developments for this disease including promising candidates from recent clinical trials.
Decay in survival motor neuron and plastin 3 levels during differentiation of iPSC-derived human motor neurons. [2018]Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in Survival Motor Neuron 1 (SMN1), leading to degeneration of alpha motor neurons (MNs) but also affecting other cell types. Induced pluripotent stem cell (iPSC)-derived human MN models from severe SMA patients have shown relevant phenotypes. We have produced and fully characterized iPSCs from members of a discordant consanguineous family with chronic SMA. We differentiated the iPSC clones into ISL-1+/ChAT+ MNs and performed a comparative study during the differentiation process, observing significant differences in neurite length and number between family members. Analyses of samples from wild-type, severe SMA type I and the type IIIa/IV family showed a progressive decay in SMN protein levels during iPSC-MN differentiation, recapitulating previous observations in developmental studies. PLS3 underwent parallel reductions at both the transcriptional and translational levels. The underlying, progressive developmental decay in SMN and PLS3 levels may lead to the increased vulnerability of MNs in SMA disease. Measurements of SMN and PLS3 transcript and protein levels in iPSC-derived MNs show limited value as SMA biomarkers.
Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial. [2021]Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy.
Motor neuron biology and disease: A current perspective on infantile-onset spinal muscular atrophy. [2020]Infantile-onset spinal muscular atrophy (SMA) is a prototypical disease in which to investigate selective neurodegenerative phenotypes. Caused by low levels of the ubiquitously expressed Survival Motor Neuron (SMN) protein, the disease mainly targets the spinal motor neurons. This selective phenotype remains largely unexplained, but has not hindered the development of SMN repletion as a means to a treatment. Here we chronicle recent advances in the area of SMA biology. We provide a brief background to the disease, highlight major advances that have shaped our current understanding of SMA, trace efforts to treat the condition, discuss the outcome of two promising new therapies and conclude by considering contemporary as well as new challenges stemming from recent successes within the field.
Advances in Treatment of Spinal Muscular Atrophy - New Phenotypes, New Challenges, New Implications for Care. [2020]Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a mild, adult-onset type with slow rate of progression. Over the past decade, new treatment options such as splicing modulation of SMN2 and SMN1 gene replacement by gene therapy have been developed. First drugs have been approved for treatment of patients with SMA and if initiated early they can significantly modify the natural course of the disease. As a consequence, newborn screening for SMA is explored and implemented in an increasing number of countries. However, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage. In this review we provide an overview of available and emerging therapies for spinal muscular atrophy and we discuss new phenotypes and associated challenges in clinical care. Collection of real-world data with standardized outcome measures will be essential to improve both the understanding of treatment effects in patients of all SMA subtypes and the basis for clinical decision-making in SMA.
Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. [2021]Nusinersen showed a favourable benefit-risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of nusinersen over 3 years.
Biomarkers of disease progression in adolescents and adults with 5q spinal muscular atrophy: a systematic review and meta-analysis. [2022]Since the introduction of disease modifying treatments there is an unmet need to identify biomarkers of spinal muscular atrophy (SMA) natural history. We performed a systematic review and meta-analysis to summarize available evidence. We searched MEDLINE, Embase, Cochrane Library and gray literature until February 2021. The primary outcome was biomarkers longitudinal course in adolescents and adults. The secondary outcome was the discrimination of patients from controls. We included 42 records examining 606 patients from 19 population cohorts over a maximum follow-up of 17-years. Lung function and serum biomarkers could not depict disease progression. We identified potential biomarkers of disease activity [SMA functional rating scale, MoviPlate, pinch strength, compound muscle action potential (CMAP), motor unit number estimation (MUNE)] that require further investigation. Data regarding Hammersmith functional motor scale expanded, Revised upper limb module, 6-minute walk test were contradictory impeding any pooled estimate. The pooled analysis regarding our secondary outcome revealed that upper limb CMAP amplitudes and MUNE mean values differed significantly between SMA patients and controls [mean difference -3.63(-6.2, -1.06), -119.74(-153.93, -85.56) respectively]. Given the lack of natural history data on this population, our qualitative synthesis and meta-analysis could provide valuable evidence and identify promising predictive biomarkers requiring further longitudinal examination. PROSPERO Registration: CRD42021235605.
Longer-term follow-up of nusinersen efficacy and safety in adult patients with spinal muscular atrophy types 2 and 3. [2022]The effectiveness of nusinersen treatment in patients with spinal muscular atrophy (SMA) was established in clinical trials only for pediatric patients. Few cohort studies confirmed its benefit in adults up to 22 months of treatment. We report a longer-term observation of nusinersen treatment effects and safety in a large cohort of adult patients. Patients with SMA type 2 and 3 treated with nusinersen at Tel-Aviv Medical Center between March 2018 and September 2020 were prospectively recruited. Neurological impairment, motor, respiratory function, and side effects were recorded. We compared baseline measurements with those after 6, 14, and 26 months of treatment and calculated the annual rates of change. Overall, 37 patients were treated (21-64 years old). 16 completed 26 months, and 8 completed 30 months of treatment. The median score on the Medical Research Council strength scale increased from baseline to visits at 6 and 14 months (p ≤ 0.03), but not afterwards, with a median increase of 1.85 points per year. Revised Hammersmith Scale median score increased only from baseline to 6 months (p = 0.02), with a calculated annual rate of change of 0 points. No significant change was noticed in the respiratory function. The only side effect was post lumbar puncture headache. In conclusion, our study further supports the efficacy and safety of nusinersen treatment in adult patients with SMA2 and SMA3, with modest improvement in muscle strength, and stabilization of motor function over a relatively long period of observation.
Adverse events in the treatment of spinal muscular atrophy in children and adolescents with nusinersen: A systematic review and meta-analysis. [2023]To systematically analyze adverse events (AEs) in treatment of spinal muscular atrophy (SMA) with Nusinersen in children and adolescents.
Nusinersen Treatment of Children with Later-Onset Spinal Muscular Atrophy and Scoliosis Is Associated with Improvements or Stabilization of Motor Function. [2023]Nusinersen has been shown to improve or stabilize motor function in individuals with spinal muscular atrophy (SMA). We evaluated baseline scoliosis severity and motor function in nusinersen-treated non-ambulatory children with later-onset SMA. Post hoc analyses were conducted on 95 children initiating nusinersen treatment in the CHERISH study or SHINE long-term extension trial. Participants were categorized by baseline Cobb angle (first nusinersen dose): ≤10°, >10° to ≤20°, and >20° to <40° (no/mild/moderate scoliosis, respectively). Outcome measures included the Hammersmith Functional Motor Score-Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Regression analysis determined the relationships between baseline scoliosis severity and later motor function. For children with no, mild, and moderate scoliosis, the mean increase in HFMSE from baseline to Day 930 was 6.0, 3.9, and 0.7 points, and in RULM was 6.1, 4.6, and 2.3 points. In the linear model, a 10° increase in baseline Cobb angle was significantly associated with a -1.4 (95% CI -2.6, -0.2) point decrease in HFMSE (p = 0.02) and a -1.2 (95% CI -2.1, -0.4) point decrease in RULM (p = 0.006) at Day 930. Treatment with nusinersen was associated with improvements/stabilization in motor function in all groups, with greater response in those with no/mild scoliosis at baseline.