Phase 2 Study on Pharmacodynamics, Safety, and Pharmacokinetics of GLM101 in PMM2-CDG Patients
- Trial ID
- 2024-513119-29-00
- Protocol
- GLM101-002
- Sponsor
- Glycomine Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to **characterize** the changes from baseline in **ataxia** after 12 and 24 weeks of dosing with GLM101 in participants with PMM2-CDG. This is clinically relevant as PMM2-CDG, a congenital disorder of glycosylation, often presents with ataxia, and understanding the impact of GLM101 on this symptom could inform treatment strategies and improve patient outcomes.
Secondary objectives include:
- Assessing the 12- and 24-week safety and **tolerability** of multiple doses of GLM101 in cohorts of participants with PMM2-CDG.
- Evaluating the **pharmacokinetics** (PK) of GLM101 in participants with PMM2-CDG over 24 weeks of dosing.
Participants
The clinical trial involves a total of **25 participants** diagnosed with **PMM2-CDG**, a rare genetic disorder. The study population includes both male and female subjects, with age ranges spanning from 2 to 65 years. Participants are divided into cohorts based on age: 18 to 65 years, 12 to 17 years, and 2 to 11 years. All participants have a molecularly confirmed diagnosis of PMM2-CDG, characterized by biallelic pathogenic variants or variants of uncertain pathogenicity with corresponding enzyme activity. The trial does not include a vulnerable population. Participants were selected based on their ability to provide informed consent or assent, either directly or through a legally authorized representative. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The trial does not focus on any specific lifestyle modifications or restrictions beyond the use of medically accepted contraception methods for participants of childbearing potential and sexually active males. The sponsor has not provided additional information regarding the general health status of the participants.
Plans and Procedures
The clinical trial is a **Phase 2**, randomized, open-label study designed to evaluate the pharmacodynamics, safety, tolerability, and pharmacokinetics of multiple doses of GLM101 administered intravenously to participants with **PMM2-CDG**. The trial is set to last for 24 weeks, with the primary objective being to characterize changes in ataxia from baseline after 12 and 24 weeks of dosing. The study will include adult, adolescent, and pediatric participants, with specific age cohorts ranging from 2 to 65 years. The trial will assess the primary endpoint of change in ICARS, alongside secondary endpoints that include safety evaluations through adverse events and pharmacokinetic parameters.
Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on molecular diagnosis and other criteria. Following the screening, participants will receive GLM101 via **intravenous use** at specified intervals throughout the 24-week period. Follow-up visits will be conducted to monitor safety, collect pharmacokinetic data, and assess changes in clinical parameters. The end-of-study visit will conclude the trial, where final assessments will be made to evaluate the overall impact of the treatment.
The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Participants are required to adhere to contraceptive guidelines if applicable, and males must refrain from donating sperm during the study and for 60 days post-treatment. The trial is not classified as low intervention and is conducted under the sponsorship of Glycomine Inc, with GLM101 being an orphan drug designated for this rare metabolic disorder.
Treatment
The clinical trial involves the administration of **GLM101**, an experimental medication developed by Glycomine Inc. The active substance in GLM101 is **alfa-d-mannopyranosyl phosphate dipotassium**, a chemical compound. The pharmaceutical form of GLM101 is an **injection/infusion**, and it is administered via the **intravenous route**. The dosing regimen for GLM101 involves a maximum daily dose of 30 mg/kg, with a total maximum dose of 30 mg/kg over the treatment period. The treatment duration is set for a maximum of 24 weeks. The study aims to evaluate the pharmacodynamics, safety, tolerability, and pharmacokinetics of multiple doses of GLM101 in participants with PMM2-CDG.
In addition to the experimental treatment, the study includes the use of **liposomal mannose-1-phosphate** as a non-experimental medicinal product. This substance serves as a comparator treatment within the trial. The administration details, including dosage and frequency, for liposomal mannose-1-phosphate are not specified in the provided data. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the change in the International Cooperative Ataxia Rating Scale (ICARS) scores. This endpoint will evaluate the impact of GLM101 on **ataxia** in participants with PMM2-CDG over a 24-week period. The ICARS is a validated scale used to measure the severity of ataxia symptoms, providing a quantitative assessment of motor function and coordination. Measurements will be taken at baseline, 12 weeks, and 24 weeks to determine the changes in ataxia symptoms over time.
Secondary endpoints include the evaluation of safety parameters, such as adverse events (AEs), adverse events of special interest (AESIs), serious adverse events (SAEs), deaths, and discontinuations due to AEs. Additionally, clinical laboratory tests, electrocardiograms (ECGs), vital signs, and physical examination findings will be collected to further assess safety. Pharmacokinetic parameters will also be evaluated by measuring concentrations of total mannose-1-phosphate (M1P) to estimate parameters such as Cmax, Clast, tmax, tlast, t1/2, AUC0-last, AUC0-∞, AUC0-tau, %AUCex, CL, Vz, Vss, and λz. These assessments will provide a comprehensive understanding of the drug's efficacy and safety profile in the target population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Is male or female, 18 to 65 years of age, inclusive, at Screening (Cohorts 1-3, 7), 12-17 years of age, inclusive, at Screening (Cohort 4) or 2-11 years of age, inclusive, at Screening (Cohorts 5 and 6)
- Molecularly confirmed diagnosis of PMM2-CDG. Diagnosis is defined as biallelic pathogenic and/or likely pathogenic variants, or, in the case of variants of uncertain pathogenicity, demonstration of bi-allelic variants AND phosphomannomutase-2 (PMM2) enzyme activity consistent with a diagnosis of PMM2-CDG. Historical diagnosis with lab report(s) on file is permitted
- If the participant is a female of childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile (permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy)) she must not be pregnant (confirmed by a negative serum pregnancy test), is using a medically accepted method of contraception (abstinence, a hormonal contraceptive associated twith inhibition of ovulation in conjunction with a barrier method, or use of an intrauterine device), and must agree to continue using this method for 50 days after the last infusion of GLM101
- If the participant is a female of non-childbearing potential, she must be pre-pubertal, surgically sterile, or must have an ovarian dysfunction confirmed by a follicle stimulating hormone (FSH) >40 IU/L and absence of menses for 12 months without an alternative medical cause
- If the participant is a sexually active male with female partners, the sexually mature, nonsterile male participant agrees to use a medically acceptable method of contraception (abstinence, the partner taking a hormonal contraceptive in conjunction with a male condom, or use by the partner of an intrauterine device with a male condom) and agrees to continue using this method for 50 days after the last infusion of GLM101. Males are considered surgically sterile if they have undergone bilateral orchiectomy or vasectomy at least 3 months prior to Screening
- If the participant is male, he must agree to refrain from donating sperm during the study and 60 days after the last infusion of GLM101
- Is willing and able to provide informed consent/assent, directly or through his/her legally authorized representative
Exclusion Criteria
- Diagnosis of congenital disorder of glycosylation (CDG) other than PMM2; Diagnosis is defined as biallelic pathogenic and/or likely pathogenic variants, or, in the case of variants of uncertain pathogenicity, demonstration of bi-allelic variants AND the defined CDG enzyme activity consistent with a diagnosis of the CDG other than PMM2 CDG.
- Has an active infection requiring parenteral antibiotics, antivirals, or antifungals or treatment with systemic steroids within 7 days prior to Screening
- Has confirmed active coronavirus disease-2019 (COVID-19) or tests positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at Screening or check in to the clinical site
- ALT or AST >3× ULN OR total bilirubin >2× ULN or INR >1.5
- Has a history of a severe allergic reaction to any drug or excipients of GLM101 (as listed in the GLM101 Investigator’s Brochure)
- Has a known history of poor venous access
- Has a history of liver transplant
- Has a history of drug or alcohol use disorder within 12 months prior to Screening
- Has had a major surgical procedure within 30 days prior to Screening
- Has Screening or eligibility confirmation laboratory value(s) outside the laboratory reference range considered clinically significant and not related to PMM2-CDG
- If female, has a positive serum pregnancy test during Screening
- If female, must not be breastfeeding
- Has serology positive for hepatitis B surface antigen or hepatitis C antibody during Screening;
- Has history or presence, upon clinical evaluation, of any illness that might impact the safety of GLM101 infusion or evaluability of drug effect based on the Investigator’s and Medical Monitor’s discretion
- Has a QTc ≥ 450 ms, or other clinically significant ECG abnormalities
- Has uncontrolled cardiovascular, hepatic, pulmonary, gastro-intestinal, endocrine, metabolic, ophthalmologic, immunologic, psychiatric or other significant disease
- Is currently participating in another interventional clinical study or has completed another clinical study with an investigational drug or device within 30 days or 5 half-lives before GLM101 infusion
- Weight exceeds 75 kg
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 02 Dec 2022 | 19 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
GLM101 | Test | INJECTION/INFUSION | INTRAVENOUS USE | 30 | 24 | PRD11189218 |