Study to Evaluate the Efficacy and Safety of BBP-418 (Ribitol) in Patients With Limb Girdle Muscular Dystrophy 2I (LGMD2I)

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the safety and efficacy of long-term administration of BBP-418 in patients with LGMD2I/R9. The study will include patients ages 12 to 60, consistent with the existing preclinical toxicology profile. This will encompass the significant majority of existing diagnosed patients based upon the established epidemiology of the disease.

Official Title
-----------------
A Phase 3 Randomized, Placebo-controlled, Double-blind Study to Evaluate the Efficacy and Safety of BBP-418 (Ribitol) in Patients With Limb Girdle Muscular Dystrophy 2I (LGMD2I)

Conditions
-----------------
Limb-Girdle Muscular Dystrophy Type 2I (LGMD2I)

Intervention / Treatment
-----------------
* Drug: BBP-418 (ribitol)
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Participants must meet all the following criteria to be enrolled: Have a genetically confirmed diagnosis of LGMD2I/R9 (including review of records of previous molecular genetic testing) and be clinically affected (defined as demonstrating clinical weakness on bedside evaluation in either a limb-girdle pattern, or in a distal extremity). Male or female participants 12 to 60 years of age (inclusive). Have a body weight >30 kg. The participant (or parent/guardian) who signs the ICF understands the study procedures and the participant agrees to participate in the study by giving informed consent (and assent, if <18 years of age). Female participants of childbearing potential and male participants of reproductive potential must be willing to use a highly effective method of contraception from time of consent through 12 weeks after last dose. Willing and able to complete all study procedures, including biopsies, according to the Schedule of Assessments (see Appendix 1). Participants must not meet any of the following criteria to be enrolled: Evidence of clinically significant concomitant disease, including: Any significant concomitant medical condition, including mental, cardiac, renal, pulmonary, hepatic, or endocrine disease other than that associated with LGMD2I/R9. Moderate to severe renal impairment (estimated glomerular filtration rate [eGFR] of < 60 mL/min/1.73 m2 based on cystatin C [CysC]), as calculated by the central laboratory. Any other laboratory, vital sign, ECG abnormality, clinical history, or finding that, in the Investigator's opinion, is likely to unfavorably alter the risk-benefit of study participation, confound study results, or interfere with study conduct or compliance. Surgery for scoliosis or other indication that will significantly impact the participant's ability to execute clinical assessments planned or expected to be required to manage curvature within 12 months following the Screening Visit. A participant with a score of zero on any one or more of the primary or key secondary endpoints at the time of screening. (Participants who previously completed participation in Study MLB-01-001 and would be excluded due to this criterion may enroll in this study provided all inclusion and no other exclusion criteria are met.) If pregnant and/or breastfeeding or planning to conceive children within the projected duration of the study through 12 weeks after the last dose of study treatment. Use of ribose or other sugar alcohol-containing supplement within 90 days of the Screening Visit. Use of a systemic corticosteroid for the treatment of muscular dystrophy within 90 days of the Screening Visit. (An inhaled corticosteroid or bronchodilator for reactive airway disease is allowed if the participant is on a stable dose for 30 days prior to study entry.) Previously received gene therapy to treat LGMD2I/R9. Participants with active suicidal ideation as measured by Columbia-Suicide Severity Rating Scale during screening with most severe suicide ideation score of 4 (Active Suicidal Ideation with Some Intent to Act, without Specific Plan) or 5 (Active Suicidal Ideation with Specific Plan and Intent). Presence of a platelet disorder, bleeding disorder, or other contraindication to muscle biopsy. Actively on an experimental therapy or device or was on an experimental therapy or device within 90 days of the Screening Visit. In the judgment of the Investigator or Medical Monitor, has any clinically important ongoing medical condition or laboratory abnormality or condition that might jeopardize the participant's safety, increase their risk from participation, or interfere with the study. For COVID-19 infections, Investigator should refer to local guidance.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization will be stratified by mutation status (L276I homozygous or other), age (<12 years [to allow for possible addition of this age group in a future protocol amendment], 12 to <18 years, and 18 to 60 years of age), and qualification status for the Primary Efficacy Analysis Population (qualifies or does not qualify).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: BBP-418<br>BBP-418 Granules for Oral Solution will be supplied as granules in tri-ply PET/Aluminum/PE sachets for unit dose. The number of sachets to reconstitute will depend on the applicable dose to be delivered, 9 g BID or 12 g BID, as determined by the weight of the participant. The granules will be reconstituted in water for oral administration. | Drug: BBP-418 (ribitol)<br>* The BBP-418 drug product is provided as Granules for Oral solution consisting of BBP-418 drug substance and silicon dioxide in a multilaminate sachet with a foil barrier. Silicon dioxide is generally regarded as safe and listed in the FDA IIAD. Silicon dioxide is a compendial excipient and is commonly used in pharmaceutical dosage forms. The BBP-418 Granules for Oral Solution are provided in sachets to provide 3 g BBP-418 per sachet. The BBP-418 Granules for Oral Solution are reconstituted in water for oral administration.<br>Other: Placebo<br>* A placebo matched for similar taste and appearance was compounded at the clinical pharmacy with sucralose as a 0.35 mg/mL oral solution in purified water (USP) in a glass container. Sucralose is similar in taste to the compounded drug product.<br>|
| Placebo Comparator: Placebo to Match BBP-418<br>The placebo will be identical to the BBP-418 Granules for Oral Solution in appearance, packaging, labeling, and storage conditions. | Drug: BBP-418 (ribitol)<br>* The BBP-418 drug product is provided as Granules for Oral solution consisting of BBP-418 drug substance and silicon dioxide in a multilaminate sachet with a foil barrier. Silicon dioxide is generally regarded as safe and listed in the FDA IIAD. Silicon dioxide is a compendial excipient and is commonly used in pharmaceutical dosage forms. The BBP-418 Granules for Oral Solution are provided in sachets to provide 3 g BBP-418 per sachet. The BBP-418 Granules for Oral Solution are reconstituted in water for oral administration.<br>Other: Placebo<br>* A placebo matched for similar taste and appearance was compounded at the clinical pharmacy with sucralose as a 0.35 mg/mL oral solution in purified water (USP) in a glass container. Sucralose is similar in taste to the compounded drug product.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in North Star Assessment for Limb Girdle Muscular Dystrophy following 36 months of treatment to assess efficacy of BBP-418 or placebo |  | 36 months | 
| Frequency and severity of treatment-emergent adverse events following 36 months of treatment to assess safety of BBP-418 or placebo |  | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in 10 meter walk test velocity to assess the clinical efficacy of BBP-418 in patients with LGMD2I/R9 |  | 36 months | 
| Change from baseline in pulmonary function as measured by FVC (percent predicted, performed in a sitting position) to assess the clinical efficacy of BBP-418 in patients with LGMD2I/R9 |  | 36 months | 
| Change from baseline in the Performance of Upper Limb scale 2.0 to assess the clinical efficacy of BBP-418 in patients with LGMD2I/R9 |  | 36 months |