GLM101 for Congenital Disorders of Glycosylation

Recruiting at 4 trial locations

Overseen By Study Director Chief Medical Officer, Glycomine, Inc.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Glycomine, Inc.

Must not be taking: Antibiotics, Antivirals, Antifungals, Steroids

Disqualifiers: Other CDG, Active infection, COVID-19, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

44 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 2, randomized, open-label, 24-week treatment study to evaluate the potential pharmacodynamic (PD) activity, safety, tolerability, and pharmacokinetics (PK) of GLM101 in adult, adolescent, and pediatric, patients with a confirmed diagnosis of PMM2-CDG. The planned doses of GLM101 to be investigated are 10, 20, and 30 mg/kg. The study will consist of a Screening Period, a 24-week (6-month) Treatment Period, and a 30-day (1-month) Follow-Up Period.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. However, if you are taking medications for an active infection or systemic steroids, you may need to stop them at least 7 days before screening.

What data supports the effectiveness of the drug GLM101 for treating Congenital Disorders of Glycosylation?

Research shows that certain compounds similar to GLM101 can correct abnormal glycosylation in cells from patients with Congenital Disorders of Glycosylation by replenishing important molecules needed for proper protein function. This suggests that GLM101 might also help improve glycosylation in these patients. ^{1 2 3 4 5}

Is GLM101 (Mannose-1-phosphate replacement therapy) safe for humans?

Research on mannose supplementation, a related treatment, shows it can correct some symptoms in certain congenital disorders of glycosylation, but it may cause issues like embryonic lethality and eye defects in mice. Caution is advised, especially during pregnancy, as its safety in human fetuses is unknown. ^{2 4 5 6 7}

How is the drug GLM101 different from other treatments for congenital disorders of glycosylation?

GLM101 is unique because it is a mannose-1-phosphate replacement therapy that directly replenishes the deficient mannose-1-phosphate in cells, which is crucial for proper glycosylation. Unlike other treatments, it uses a membrane-permeable form of mannose-1-phosphate to improve glycosylation in patients with congenital disorders of glycosylation. ^{2 3 4 7 8}

Research Team

Horacio Plotkin, MD

Principal Investigator

Glycomine, Inc.

Eligibility Criteria

Adults aged 18-65 with PMM2-CDG, a genetic disorder affecting glycosylation. Participants must have low antithrombin III levels and agree to use contraception. Exclusions include severe allergies to GLM101 components, poor venous access, recent major surgery or substance abuse, active infections requiring strong medications, and other significant health issues as determined by the study leads.

Inclusion Criteria

Your antithrombin III (ATIII) levels are below 80%.

I have been diagnosed with PMM2-CDG through genetic testing.

I agree not to donate sperm during and for 30 days after the study.

Exclusion Criteria

I have not had major surgery in the last 30 days.

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 Principal Investigator's and Medical Monitor's discretion

I am not in another drug study and haven't been in one for the last 30 days or 5 half-lives, except for acetazolamide.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive GLM101 intravenously at doses of 10, 20, or 30 mg/kg weekly for 24 weeks to assess pharmacodynamics, safety, tolerability, and pharmacokinetics

24 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• GLM101

Trial Overview The trial is testing GLM101 at doses of 10 and 20 mg/kg for its effects on adults with PMM2-CDG over a period of six months. It aims to assess how the body processes the drug (pharmacokinetics), its safety, tolerability, and potential effectiveness (pharmacodynamics).

Participant Groups

Group I: 30 mg/kg GLM101 Experimental Treatment 1 Intervention

GLM101 IV infusions, given weekly

Group II: 20 mg/kg GLM101 Experimental Treatment 1 Intervention

GLM101 IV infusions, given weekly

Group III: 10 mg/kg GLM101 Experimental Treatment 1 Intervention

GLM101 IV infusions, given weekly

GLM101 is already approved in United States, European Union for the following indications:

Approved in United States as GLM101 for:

• PMM2-CDG (Phosphomannomutase 2-congenital disorder of glycosylation)

Approved in European Union as GLM101 for:

• PMM2-CDG (Phosphomannomutase 2-congenital disorder of glycosylation)

Who Is Running the Clinical Trial?

Glycomine, Inc.

Lead Sponsor

Trials

4

Recruited

250+

Findings from Research

In a study of 22 Danish patients with carbohydrate-deficient glycoprotein syndrome type 1A, specific PMM2 mutations were identified, with none being homozygous for the R141H mutation, suggesting that this genotype may be incompatible with life due to its severe impact on enzyme activity.

Functional analysis revealed that while some mutations like F119L retained 25% of normal PMM2 activity, others like R141H, G117R, and T237R showed no activity, indicating that at least one mutation must allow for residual enzyme function for patient survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carbohydrate-deficient glycoprotein syndrome type 1A: expression and characterisation of wild type and mutant PMM2 in E. coli. Kjaergaard, S., Skovby, F., Schwartz, M.[2010]

Phosphomannomutase (PMM2) deficiency is a common glycosylation disorder with no current therapy, affecting the N-glycosylation pathway in hundreds of patients.

Potential therapeutic strategies include using small molecules to boost Mannose-1-P levels and enhancing or replacing phosphomannomutase, with further research needed in cell and animal models to evaluate their effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards a therapy for phosphomannomutase 2 deficiency, the defect in CDG-Ia patients. Freeze, HH.[2021]

Inhibiting the enzyme phosphomannose isomerase (MPI) with the compound MLS0315771 can increase the availability of mannose 6-phosphate (Man-6-P) for glycosylation, which may benefit patients with CDG-Ia, a genetic disorder caused by PMM2 deficiency.

Daily mannose supplementation is effective for CDG-Ib patients but not for CDG-Ia patients, highlighting the potential of MPI inhibitors like MLS0315771 to improve glycosylation in CDG-Ia by redirecting Man-6-P metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phosphomannose isomerase inhibitors improve N-glycosylation in selected phosphomannomutase-deficient fibroblasts. Sharma, V., Ichikawa, M., He, P., et al.[2021]

Two synthesized compounds, C-I and C-II, were able to normalize the size of lipid-linked oligosaccharides (LLO) and improve glycosylation in fibroblasts from patients with Type I congenital disorders of glycosylation (CDG-Ia), with C-II being about twice as effective as C-I.

C-II not only replenished the GDP-Man pool in CDG-Ia cells but also restored glycosylation levels of a specific protein (DNaseI) to normal levels, demonstrating its potential as a therapeutic option for CDG-I patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydrophobic Man-1-P derivatives correct abnormal glycosylation in Type I congenital disorder of glycosylation fibroblasts. Eklund, EA., Merbouh, N., Ichikawa, M., et al.[2010]

The authors argue that dietary mannose supplementation should not be dismissed as a treatment for PMM2-CDG, a genetic disorder affecting glycosylation, and that further investigation is necessary.

They emphasize the importance of conducting controlled prospective clinical trials to evaluate the efficacy of mannose alongside other treatment options for PMM2-CDG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mannose supplementation in PMM2-CDG. Taday, R., Park, JH., Grüneberg, M., et al.[2021]

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) is linked to a deficiency that leads to serious health issues like hyperinsulinaemic hypoglycaemia and gastrointestinal problems.

A case study of an adult female who stopped mannose supplementation in her adolescence highlights the potential long-term complications of the disorder, including chronic anemia and joint issues, emphasizing the importance of ongoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes in an adult patient with mannose phosphate isomerase-congenital disorder of glycosylation who discontinued mannose therapy. Noman, K., Hendriksz, CJ., Radcliffe, G., et al.[2020]

Mannose supplementation, while intended to correct glycosylation issues in mice with a congenital disorder of glycosylation (CDG), led to significant adverse effects, including reduced litter size and increased embryonic lethality when given to pregnant mice.

The study found that mannose caused specific eye defects in surviving offspring, indicating that altering mannose metabolism during embryonic development can lead to unexpected health issues, suggesting caution for pregnant women considering mannose supplements for potential benefits in fetuses with CDG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice. Sharma, V., Nayak, J., DeRossi, C., et al.[2021]

Exogenous mannose supplementation did not increase intracellular levels of mannose-6-phosphate (Man-6-P) in human fibroblasts, including those from patients with Congenital Disorders of Glycosylation (CDG), suggesting it may not negatively affect glycosylation in these patients.

In mouse fibroblasts lacking the enzyme phosphomannose isomerase, increased Man-6-P levels from mannose did lead to a decrease in lipid-linked oligosaccharide (LLO) precursors, but this did not result in reduced overall protein N-glycosylation, indicating that mannose supplementation is unlikely to impair glycosylation in CDG patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exogenous mannose does not raise steady state mannose-6-phosphate pools of normal or N-glycosylation-deficient human fibroblasts. Higashidani, A., Bode, L., Nishikawa, A., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Carbohydrate-deficient glycoprotein syndrome type 1A: expression and characterisation of wild type and mutant PMM2 in E. coli. [2010]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Towards a therapy for phosphomannomutase 2 deficiency, the defect in CDG-Ia patients. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Phosphomannose isomerase inhibitors improve N-glycosylation in selected phosphomannomutase-deficient fibroblasts. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Hydrophobic Man-1-P derivatives correct abnormal glycosylation in Type I congenital disorder of glycosylation fibroblasts. [2010]

5. England pubmed.ncbi.nlm.nih.gov

Mannose supplementation in PMM2-CDG. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Clinical outcomes in an adult patient with mannose phosphate isomerase-congenital disorder of glycosylation who discontinued mannose therapy. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Exogenous mannose does not raise steady state mannose-6-phosphate pools of normal or N-glycosylation-deficient human fibroblasts. [2021]