Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG

A Prospective, Randomized, Double-Blind, Placebo-Controlled, Single-Center Study of Oral Epalrestat Therapy in Pediatric Subjects With Phosphomannomutase 2-congenital Disorder of Glycosylation (PMM2-CDG)

This is a prospective, single-center, randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and clinical and metabolic improvement of pediatric subjects with PMM2-CDG on oral epalrestat therapy vs. placebo.

Study Overview

• Status: Active, not recruiting
• Conditions: Pmm2-CDG; Phosphomannomutase 2 Deficiency; Phosphomannomutase 2 Congenital Disorder of Glycosylation; Phosphomannomutase II Congenital Disorder of Glycosylation; Phosphomannomutase II Deficiency
• Intervention / Treatment: Drug: Epalrestat; Drug: Placebo

Detailed Description

This is a prospective, single-center, randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and clinical and metabolic improvement of pediatric subjects with PMM2-CDG on oral epalrestat therapy vs. placebo. The primary study objective is to evaluate the safety and probable benefit of oral epalrestat therapy in pediatric subjects with PMM2-CDG. Study outcomes include evaluating the metabolic improvement of pediatric subjects treated with oral epalrestat therapy compared to placebo, evaluating safety, clinical improvement, and pharmocokinetics (PK) of oral epalrestat therapy in pediatric subjects compared to placebo, and evaluating urine polyols, adverse events, laboratory data, other safety measures, PK, and Quality of Life surveys to measure clinical improvement.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jess Ward, BS; Phone Number: 507-266-9619; Email: ward.jessica1@mayo.edu

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 2 and < 18 years
2. Diagnosis of PMM2-CDG, based on molecularly confirmed biallelic PMM2 pathogenic variants (can be historical diagnosis with lab report on file)
3. Informed consent (and assent, as applicable) document personally signed by the legally authorized representative of the patient, indicating that the patient's parent/guardian has been informed and agreed to all aspects of the study
4. Be willing and able to adhere to the study assessments and schedule described in the protocol and consent/assent documents
5. Negative urine pregnancy test (only for female subjects of child-bearing potential)
6. 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.

Exclusion Criteria:

1. Known or suspected other known CDG
2. Known allergy to aldose reductase inhibitors
3. Hypersensitivity to epalrestat

4. Hepatic impairment defined as any one of the following:

   1. AST/ALT >5x ULN in the 6 months prior to screening
   2. Bilirubin >2X ULN in the last 6 months prior to screening
   3. Synthetic liver dysfunction (albumin deficiency < 2.8 mmol/L) at screening, or
   4. Diagnosis of liver fibrosis (Fibroscan > 7 kPa) confirmed by liver elastogram at screening
5. Renal impairment defined as serum creatinine: > 0.5 mg/dL (≤ 6 years); > 0.7 mg/dL (7-10 years); > 1.24 mg/dL (≥ 11 years)
6. Low platelet count (< 125x109 /L)
7. Any other clinically significant lab abnormality which, in the opinion of the investigator, should be exclusionary
8. Anemia (Hgb < 10 g/dL)
9. Use of an investigational drug, including acetazolamide, in the past 28 days; use of an investigational biologic in the past 12 months
10. Concurrent or planned participation in interventional protocol or use of any other unapproved therapeutics, and,
11. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Epalrestat; 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.	Drug: Epalrestat; Epalrestat is a noncompetitive and reversible aldose reductase inhibitor (ARI) used for the treatment of diabetic neuropathy in Japan. The drug's ability to safely improve symptoms of neuropathy alone by reducing oxidative stress, increasing glutathione levels, and reducing intracellular sorbitol accumulation make it a desirable medication for PMM2-CDG patients who commonly suffer with various neuropathies. However, work recently conducted by Perlara, a public benefit company with the mandate to screen existing commercially available drugs for possible application in rare diseases, has demonstrated that Epalrestat can also elevate the level PMM2 produced endogenously. This may reduce the severity of the morbidities associated with PMM2-CDG.
Placebo Comparator: Placebo; 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.	Drug: Placebo; The placebo capsule with be identical in appearance to the Epalrestat capsule. It will contain microcrystalline cellulose filler in a gelatin capsule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in sorbitol (mmol/mol creatinine)	Change in sorbitol from baseline between study arms	9 months
Change in ICARS	Change in ICARS from baseline between study arms	9 months
Change in Antithrombin III (ATIII)	Change in ATIII from baseline between study arms	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Body Max Index (BMI) percentile	Change of BMI percentile from baseline between study arms	9 months
Change of factor XI activity percentage	Change of factor XI activity from baseline between study arms	9 months
Change of liver transaminases (U/L)	Change of liver transaminases from baseline between study arms	9 months
Change of transferrin glycosylation (ratio)	Change of transferrin glycosylationfrom baseline between study arms	9 months
Change in Nijmegen Pediatric CDG Rating Scale (NPCRS) score	Change in NPCRS from baseline between study arms	9 months
Change of normalized mannitol (mmol/mol creatinine)	Change of normalized mannitol from baseline between study arms	9 months

Collaborators and Investigators

• Sponsor: Maggie's Pearl, LLC
• Investigators: Principal Investigator: Eva Morava-Kozicz, MD, PhD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Actual): November 10, 2022
• Primary Completion (Estimated): February 28, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: June 8, 2021
• First Submitted That Met QC Criteria: June 8, 2021
• First Posted (Actual): June 14, 2021

Study Record Updates

• Last Update Posted (Actual): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Congenital Disorders of Glycosylation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Epalrestat
• Other Study ID Numbers: 21-000492

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No