Epalrestat for PMM2-CDG

Overseen By Jess Ward, BS

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Eva Morava-Kozicz

Must not be taking: Aldose reductase inhibitors

Disqualifiers: Other CDG, Hepatic impairment, Renal impairment, Anemia, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 9 months

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether epalrestat, taken as a pill three times daily, can aid children with PMM2-CDG, a rare genetic condition affecting metabolism and causing various health issues. Researchers aim to determine if this treatment is safe and can improve symptoms and metabolic health compared to a placebo (a pill with no active medicine). Eligible participants include children diagnosed with PMM2-CDG through genetic testing who can adhere to the study schedule. As a Phase 3 trial, this study represents the final step before FDA approval, providing participants an opportunity to contribute to a potentially groundbreaking treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot participate if you have used an investigational drug in the past 28 days or plan to use unapproved therapeutics during the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that epalrestat has been tested for safety in various situations. Epalrestat is already approved for treating diabetic nerve damage, indicating it is generally safe to use. In past studies, patients responded well, with only a few mild side effects reported. While some side effects might occur, they are usually not serious. The current trial is in a later stage, providing some confidence in the safety of epalrestat for treating PMM2-CDG. However, as with any treatment, monitoring for unexpected reactions is important. Discuss with a doctor to understand what this might mean personally. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Epalrestat is unique because it targets a specific enzyme pathway that is not addressed by current treatments for PMM2-CDG. Most treatments for this condition focus on managing symptoms rather than addressing the underlying biochemical issues. Epalrestat works by inhibiting aldose reductase, potentially reducing toxic sugar alcohols that accumulate in cells. Researchers are excited because this mechanism could directly tackle the root cause of PMM2-CDG, offering a more effective approach than simply alleviating symptoms.

What evidence suggests that epalrestat might be an effective treatment for PMM2-CDG?

Research has shown that epalrestat, which participants in this trial may receive, might help treat PMM2-CDG, a rare genetic disorder, by boosting the activity of the PMM2 enzyme, crucial for normal body functions. Initially used for treating nerve damage in diabetes, epalrestat has improved enzyme activity, potentially benefiting PMM2-CDG patients. Specifically, a child with PMM2-CDG who took oral epalrestat for one year showed significant improvement in growth and coordination. These findings suggest that epalrestat could effectively manage PMM2-CDG symptoms. ^{1 2 3 5 6}

Who Is on the Research Team?

Eva Morava-Kozicz, MD, PhD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for children aged 2 to under 18 with PMM2-CDG, a rare genetic disorder. They must be able to follow the study plan and not be pregnant or at risk of pregnancy without proper contraception. Kids can't join if they're allergic to epalrestat, have anemia, kidney problems, low platelets, liver issues, other CDGs or are on certain other drugs.

Inclusion Criteria

For subjects of child-bearing potential-only, subject has been counseled on and agrees to the requirement either for double barrier contraceptive methods and/or for total abstinence from prior to randomization through 3-months after the cessation of treatment.

Be willing and able to adhere to the study assessments and schedule described in the protocol and consent/assent documents

I am between 2 and 17 years old.

Exclusion Criteria

I have had liver problems, like high enzyme levels or liver stiffness, in the last 6 months.

Any other medical condition, which, in the opinion of the investigator, will interfere with the patient's ability to comply with the protocol, compromises patient safety, or interferes with the interpretation of the study results.

I haven't used any experimental drugs or biologics recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral epalrestat or placebo, administered 3 times per day, to assess safety, tolerability, and clinical and metabolic improvement

9 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Epalrestat
• Placebo

Trial Overview The study tests oral Epalrestat against a placebo in kids with PMM2-CDG. It's designed to see if it's safe and tolerable and whether it improves their condition. Participants will randomly receive either the drug or placebo without knowing which one they get.

How Is the Trial Designed?

Group I: Epalrestat Experimental Treatment 1 Intervention

Epalrestat will be administered orally, 3 times per day (TID) spaced out as evenly as possible over 24 hours in a divided dose starting on Day 1 of the Study.

Group II: Placebo Placebo Group 1 Intervention

Placebo will be administered orally, 3 times per day (TID) spaced out as evenly as possible over 24 hours in a divided dose starting on Day 1 of the Study.

Who Is Running the Clinical Trial?

Eva Morava-Kozicz

Lead Sponsor

Trials

4

Recruited

80+

Maggie's Pearl, LLC

Lead Sponsor

Trials

1

Recruited

40+

Published Research Related to This Trial

In a study involving human prostate cancer models, the combination of estramustine and docetaxel significantly prolonged tumor growth delay (TGD) in docetaxel-resistant tumors, achieving a TGD of 50 days compared to 18 days with estramustine alone.

Despite the efficacy of the combination treatment, its use may be limited in elderly patients or those with comorbidities due to the risk of serious side effects, such as venous thrombosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A preclinical therapeutic schedule optimizing docetaxel plus estramustine administration in prostate cancer. Dahmani, A., de Plater, L., Guyader, C., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04925960

Oral Epalrestat Therapy in Pediatric Subjects With PMM2- ... Study outcomes include evaluating the metabolic improvement of pediatric subjects treated with oral epalrestat therapy compared to placebo, evaluating safety, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9618201/

Patient reported outcomes for phosphomannomutase 2 ... Patient reported outcomes for phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG): listening to what matters for the patients and health ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6899038/

Repurposing the aldose reductase inhibitor and diabetic ... We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy.

4. maggiespearl.com maggiespearl.com/maggies-pearl-phase-3-pmm2-cdg-trial

Maggie's Pearl Phase III trial Phase III epalrestat clinical trial to evaluate safety, tolerability, and clinical and metabolic improvement of pediatric subjects with PMM2-CDG.

5. cdghub.com cdghub.com/cdg/pmm2-cdg-cdg-ia/

PMM2-CDG (CDG-Ia) | CDG Hub Recently, promising results were seen in a child PMM2-CDG patient given oral epalrestat for one year, with significant improvement in growth and coordination ...

6. gimjournal.org gimjournal.org/article/S1098-3600(23)01043-2/fulltext

Neurological manifestations in PMM2-congenital disorders ... Affected individuals can manifest with either an isolated neurological phenotype or with a combination of neurological and visceral phenotypes.