Efficacy and Safety Evaluation of Intravenous GLM101 in PMM2-CDG: A Phase 2b, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study

The primary objective of this study is to **characterize** the change from baseline in **ataxia** at 24 weeks, comparing GLM101 to placebo in participants with PMM2-CDG, as assessed by the International Cooperative Ataxia Rating Scale (ICARS). This is clinically relevant as it aims to determine the efficacy of GLM101 in improving ataxia symptoms, which are a significant manifestation of PMM2-CDG, a rare genetic disorder.

Secondary objectives include:

• Characterizing the change from baseline in ataxia at 24 weeks using the Scale for the Assessment and Rating of Ataxia (SARA).
• Characterizing the change from baseline in gross motor function at 24 weeks, as assessed by the Gross Motor Function Measure (GRO).
• Evaluating the participant, caregiver, and physician global impression of improvement/change and severity at 24 weeks.
• Assessing the safety and tolerability of multiple doses of GLM101 at 24 weeks compared with placebo.
• Evaluating the effect of GLM101 on changes in ICARS, GRO, and SARA scores to the end of the study.
• Evaluating the participant, caregiver, and physician global impression of improvement/change and severity up to 48 weeks of dosing with GLM101.
• Assessing the safety and tolerability of multiple doses of GLM101 from baseline through 48 weeks of dosing.
• Assessing the pharmacokinetics (PK) of GLM101 in participants with PMM2-CDG up to the end of the study.

The clinical trial involves a total of **5 participants** diagnosed with **PMM2-CDG**, a rare genetic disorder. The study population includes both male and female subjects, aged **4 years and older**, who have a molecular diagnosis of PMM2-CDG. Participants were selected based on specific inclusion criteria, including the ability to complete the ICARS assessment and having a screening total ICARS score between 20 and 80. The trial population is characterized by a vulnerable group, requiring the presence of a caregiver to assist with questionnaires and consent. Participants are required to have appropriate measures in place to prevent pregnancy, and male participants must agree to refrain from donating sperm during the study and for 50 days after the last infusion. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is a **Phase 2b**, multicenter, double-blind, randomized, placebo-controlled study designed to assess the efficacy and safety of weekly doses of GLM101 administered intravenously to participants with **PMM2-CDG**. The primary objective is to evaluate the change from baseline in ataxia at 24 weeks, as assessed by the International Cooperative Ataxia Rating Scale (ICARS), comparing GLM101 to placebo. The trial is expected to commence recruitment on April 1, 2025, and conclude by August 31, 2026, with a total duration of 48 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, molecular diagnosis of PMM2-CDG, and the ability to complete the ICARS. Following randomization, participants will receive either GLM101 or a placebo via **intravenous administration**. The study includes regular follow-up visits to monitor efficacy and safety parameters, including adverse events, clinical safety laboratory tests, and vital signs. The end-of-study visit will occur at the 48-week mark, where final assessments will be conducted.

Participant involvement is expected to last for the entire 48-week period unless early termination is warranted. Conditions for early termination include significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial will also evaluate secondary endpoints, such as changes in the Scale for the Assessment and Rating of Ataxia (SARA) and global impressions of change and severity, to provide a comprehensive assessment of GLM101's impact on PMM2-CDG symptoms.

The clinical trial involves the administration of **GLM101**, an investigational medicinal product, to evaluate its efficacy and safety in participants with PMM2-CDG. **GLM101** is formulated as an **injection/infusion** and contains the active substance **alfa-d-mannopyranosyl phosphate dipotassium**. The pharmaceutical form is designed for **intravenous administration**. The dosing regimen involves a maximum daily dose of 30 mg/kg, with a total maximum dose of 1440 mg/kg over a treatment period of 48 weeks. The administration is conducted on a weekly basis. The product is developed by Glycomine Inc and is classified as an orphan drug, indicating its use in rare conditions.

The study also includes a **placebo** control, which is a **0.9% Sodium Chloride Intravenous Infusion Solution**. This solution is used as a comparator to assess the efficacy of GLM101. The placebo is also administered via **intravenous infusion** and follows the same dosing schedule as the experimental treatment, with a maximum daily dose of 30 mg/kg and a total maximum dose of 1440 mg/kg over 48 weeks. The placebo is manufactured by Laboratoire Aguettant and serves as a standard-of-care therapy in the trial to ensure the validity of the study results.

The efficacy of GLM101 in participants with PMM2-CDG will be assessed primarily through the **International Cooperative Ataxia Rating Scale (ICARS)**. The primary endpoint is the change from baseline in ICARS at 24 weeks, comparing GLM101 to placebo. Secondary endpoints include changes from baseline in the Global Rating of Change (GRO) and the Scale for the Assessment and Rating of Ataxia (SARA) at 24 weeks. Additionally, changes in participants' and caregivers' global impressions of change and severity, as well as clinicians' global impressions of improvement, will be evaluated at 24 weeks. Safety parameters, including adverse events (AEs), adverse events of special interest (AESIs), serious adverse events (SAEs), deaths, and discontinuations due to AEs, will be monitored throughout the study.

Assessments will be conducted at specified intervals, with visit-wise changes from baseline in ICARS, GRO, and SARA being tracked up to 48 weeks of GLM101 treatment. The study will also evaluate the change from baseline to week 24 compared to the change from week 24 to week 48 for participants who switch from placebo to GLM101 treatment. Pharmacokinetic parameters, including concentrations of total M1P, will be estimated to further understand the drug's efficacy. The study is designed to provide a comprehensive evaluation of GLM101's impact on ataxia and related symptoms in PMM2-CDG patients over a 48-week period.