A Phase 3 Randomized, Double-blind, Placebo-controlled Study Evaluating the Efficacy and Safety of Ribitol (BBP-418) in Limb Girdle Muscular Dystrophy 2I/R9

Trial ID: 2023-503379-33-01
Protocol: MLB-01-005
Sponsor: ML Bio Solutions Inc.

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Diseases & Conditions

Muscular dystrophy

Objectives

The primary objective of this Phase 3 randomized, placebo-controlled, double-blind study is to evaluate the **clinical efficacy** and safety of BBP-418 (ribitol) in patients diagnosed with Limb Girdle Muscular Dystrophy 2I (LGMD2I/R9). This objective is clinically relevant as it aims to determine the therapeutic potential and safety profile of BBP-418, which could offer a new treatment option for individuals affected by this progressive muscular disorder.

Secondary objectives include:

Assessing the clinical efficacy of BBP-418 in patients with LGMD2I/R9.
Evaluating biomarkers for clinical efficacy of BBP-418 in these patients.

Participants

The clinical trial involves a total of **67 participants** diagnosed with **Limb Girdle Muscular Dystrophy 2I/R9**. The study population comprises both male and female subjects, aged between 18 to 60 years, who are clinically affected by the condition. Participants were selected based on a genetically confirmed diagnosis and demonstrated clinical weakness in a limb-girdle pattern or distal extremity. All participants have a body weight greater than 30 kg and are required to understand and consent to the study procedures. The trial includes individuals who are willing to adhere to study protocols, including the use of effective contraception methods for those of reproductive potential. The study population is characterized by a diverse range of lifestyle considerations, although specific details on diet, physical activity, or habits are not provided. The trial does not exclude vulnerable populations, indicating a broad inclusion of participants who meet the specified criteria.

Plans and Procedures

The clinical trial is a **Phase 3**, randomized, placebo-controlled, double-blind study designed to evaluate the efficacy and safety of **BBP-418 (ribitol)** in patients with **Limb Girdle Muscular Dystrophy 2I (LGMD2I)**. The trial aims to assess the clinical efficacy and safety of BBP-418 over a period of 36 months. Participants will be randomly assigned to receive either the investigational product, BBP-418, or a placebo, both administered as granules for oral solution. The trial will include several key phases, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as a genetically confirmed diagnosis of LGMD2I, age between 18 and 60 years, and a body weight greater than 30 kg. Participants must also agree to use effective contraception and be willing to complete all study procedures.

The study will consist of multiple visits, including follow-up visits at regular intervals to monitor the participants' health and response to the treatment. These visits will involve assessments such as physical examinations, laboratory tests, and electrocardiograms (ECGs) to evaluate primary endpoints like changes in the North Star Ambulatory Assessment for Dysferlinopathy (NSAD) and the frequency and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints will include changes in the 10-meter walk test (10MWT) velocity, pulmonary function, and glycosylated α-dystroglycan expression. The end-of-study visit will conclude the trial, summarizing the overall findings and ensuring the safety of the participants.

Participant involvement is expected to last for the entire 36-month duration of the trial, unless early termination is warranted due to conditions such as significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is not categorized as low intervention, and it is crucial for participants to adhere to the study protocol to ensure the integrity and validity of the trial results. The estimated recruitment start date is February 2, 2024, with an anticipated end date of September 7, 2027.

Treatment

The clinical trial involves the administration of **Ribitol**, a synthetic small molecule, as the experimental medication. Ribitol is provided in the form of **granules for oral solution**. The active substance, ribitol, is of chemical origin. The medication is administered orally, with a maximum daily dose of 24 grams. The total maximum dose over the treatment period is 26,280 grams. The treatment duration is set for a maximum of 36 months. The granules are to be dissolved in a suitable liquid before oral administration. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** designed to match BBP-418, which serves as the comparator treatment. The placebo is used to maintain the double-blind nature of the trial. It is administered in a manner identical to the experimental medication, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo does not contain any active pharmaceutical ingredients and is intended to mimic the appearance and administration route of the Ribitol granules. Participant compliance with the placebo administration will be similarly monitored to maintain the integrity of the study results.

Efficacy

The efficacy of BBP-418 (ribitol) in patients with **Limb Girdle Muscular Dystrophy 2I (LGMD2I)** will be assessed through a series of primary and secondary endpoints over a 36-month period. The primary endpoints include the change from baseline in the North Star Ambulatory Assessment for Dysferlinopathy (NSAD) at 36 months, the frequency and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), results from physical examinations including vital signs, chemistry and hematology laboratory analyses, and 12-lead ECGs with QTc intervals. Secondary endpoints will evaluate changes from baseline in the 10-meter walk test (10MWT) velocity, pulmonary function as measured by forced vital capacity (FVC) in a sitting position, the Performance of the Upper Limb (PUL) 2.0, total glycosylated α-dystroglycan (αDG) expression, the glycosylated αDG/total αDG ratio, and pre-functional assessment serum creatine kinase (CK) levels.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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 18 to 60 years of age (inclusive).
Have a body weight >30 kg.
The participant who signs the informed consent form (ICF) understands the study procedures and the participant agrees to participate in the study by giving informed consent.
Women of childbearing potential (WOCBP) 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.

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Exclusion Criteria

Evidence of clinically significant concomitant disease, including: Any significant concomitant medical condition, including cardiac, renal, pulmonary, hepatic, or endocrine disease other than that associated with LGMD2I/ R9; Moderate to severe renal impairment (eGFR < 60 mL/min/1.73 m2 based on cystatin C[CysC], as calculated by 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.
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, was on an experimental therapy or device within 90 days prior to the Screening Visit, or was on BBP-418 at any time
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.
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 enrol 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.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Not Recruiting	02 Feb 2024	15
Germany	Not Recruiting	02 Feb 2024	4
Italy	Not Recruiting	02 Feb 2024	4
The Netherlands	Not Recruiting	02 Feb 2024	—
Norway	Not Recruiting	02 Feb 2024	5
Netherlands	—	—	7