A Phase 1/2, adaptive, open-label, single ascending dose to multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of mRNA-3745 in participants with glycogen storage disease type 1a (GSD1a), followed by an open-label extension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Moderna Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Metabolism [G03]

Trial duration

20 Jun 2024 → 6 Oct 2025

Decision date (initial)

2024-05-28

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ModernaTX, Inc. United States

External identifiers

EU CT number

2022-502963-39-00

ClinicalTrials.gov

NCT05095727

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Safety, Pharmacokinetic

Evaluate the safety and tolerability of mRNA encoding human G6Pase-α S298C encapsulated in SM-716, OL-56, Cholesterol, and DSPC (mRNA-3745) via IV administration in participants with GSD1a.

Secondary objectives 3

1. 1. Characterize the PD response following single and multiple IV administration of mRNA-3745 assessed by evaluation of blood glucose and lactate levels during fasting challenges.
2. 2. Characterize the PK of mRNA encoding human G6PC-α (hG6PC-α) mRNA and of lipids SM-716 and OL-56, following single and multiple IV administration of mRNA-3745.
3. 3. Characterize the PD response to single and multiple doses of mRNA-3745 as assessed by other GSD1a metabolic biomarkers.

Conditions and MedDRA coding

Glycogen storage disease type 1a (GSD1a)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. ≥18 years of age at the time of informed consent. In the case of enrollment in the 12- to 17-year-old SAD or MAD Stage or the 6- to 11-year-old SAD or MAD Stage, participant and/or legally authorized representative will need to be willing and able to provide informed consent and/or assent as mandated by local regulations.
2. GSD1a is clinically stable as evidenced by absence of hospitalization for hypoglycemia in the 4 weeks prior to Screening.
3. Participant (and/or legally authorized representative for participants under the legal age of consent) is willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
4. Diagnosis of GSD1a with confirmation by G6PC gene sequencing. Note: Genetic confirmation of GSD1a is needed by the time of study drug administration. However, all Screening procedures and other assessments may proceed based on clinical diagnosis alone.
5. Aspartate aminotransferase and alanine aminotransferase values are <2.5 times the upper limit of normal (may be repeated up to 3 times during Screening at the discretion of the Investigator).
6. Absolute neutrophil count ≥1500/mm3, a platelet count ≥150,000/mm3, and hemoglobin ≥10 g/dL.
7. If female, must meet the following criteria: a. Not of childbearing potential (an FSH level may be measured at the discretion of the Investigator to confirm postmenopausal status), or b. If of childbearing potential, must be either not sexually active or using at least one method of highly effective contraception (failure rate <1% per year when used consistently and correctly) see Section 11.4) throughout the treatment with mRNA-3745 starting at least 28 days before the first administration of mRNA-3745 and through 52 weeks following the last administration of mRNA-3745.
8. If female of childbearing potential, must have a negative serum pregnancy test (beta human chorionic gonadotropin [β-hCG]) at Screening and a negative urine pregnancy test on Day -1.
9. If male and sexually active with a female partner of childbearing potential, must agree to use a condom from Day 1 throughout the treatment with mRNA-3745 and for 52 weeks following the last dose of mRNA-3745; additionally, their female partner of childbearing potential must use at least one method of highly effective contraception (failure rate <1% per year when used consistently and correctly) throughout the male participant’s treatment with mRNA-3745 and for 52 weeks following the last dose of mRNA-3745.

Exclusion criteria 22

1. 1. Genetically confirmed diagnosis of another inborn error of metabolism in addition to GSD1a.
2. 18. Positive SARS-CoV-2 RT-PCR or antigen test at Screening. A positive test result does not preclude future enrollment in the study provided that the participant subsequently tests negative for SARS-CoV-2 RT-PCR or antigen. There is no limit to the number of SARS-CoV-2 RT tests that can be performed to meet eligibility.
3. 19. History of anaphylaxis or severe hypersensitivity reactions to mRNA-based vaccines/products, requiring medical evaluation and management.
4. 2. Previously received gene therapy for GSD1a.
5. 20. Has any other clinically significant medical condition that in the Investigator’s opinion could interfere with the interpretation of study results, pose additional risk in administering study drug, or limit the participant’s participation in the study.
6. 21.Presence of an active skin condition that precludes CGM sensor placement.
7. 3. History of solid organ transplant (including liver transplantation).
8. 4. History of or current diagnosis of hepatocellular carcinoma.
9. 5. At least 1 hepatic adenoma >5 cm in size.
10. 6. Diagnosis of type 1 or type 2 diabetes mellitus.
11. 10. History of active tuberculosis requiring treatment in the past 3 years.
12. 7. At least 1 hepatic adenoma with an increase in size of >2 cm OR a finding of >5 newly diagnosed hepatic adenomas, when compared with the last imaging (obtained with a consistent technique) performed in the preceding 2 years.
13. 8. Positive serology for HIV (HIV 1, HIV 2), hepatitis B surface antigen, and/or hepatitis C (positive nucleic acid test for hepatitis C virus RNA) at Screening. Participants with a past or resolved hepatitis B virus infection (defined as the presence of total antibody to hepatitis B core antigen and absence of hepatitis B surface antigen) are eligible. A reactive or positive antibody test for hepatitis C virus with negative nucleic acid test for hepatitis C virus RNA is not exclusionary.
14. 9. Long-term immunosuppression due to comorbidities and/or required pharmacological treatment, which may increase the risk of secondary opportunistic infections (eg, participants with history of autoimmune disorder[s]).
15. 22. History of hypersensitivity to acetaminophen/paracetamol and/or ibuprofen or H1/H2-receptor blockers and changes to the premedication regimen are not possible.
16. 11. Hematologic disorders or complement abnormalities or those on medications known to affect platelet function or coagulation pathways including newer oral anticoagulants
17. 12. Serum triglyceride levels >1500 mg/dL at Screening (may be repeated up to 3 times during Screening at the discretion of the Investigator).
18. 13. GFR <60 mL/min/1.73 m2 as calculated by the 2021 Chronic Kidney DiseaseEpidemiology Collaboration (CKD-EPI) creatinine equation for participants ≥18 years of age (Inker et al 2021) or by the creatinine-based Schwartz formula for participants <18 years of age (Schwartz et al 2009).
19. 14. Clinically relevant abnormal 12-lead ECG at Screening or Day ˗1 confirmed by repeat (including prolonged Fridericia corrected QT interval [defined as >450 ms for adult males and >470 ms for adult females, or >480 ms using Bazett’s correction for participants.
20. 15. Inability to adhere to alcohol prohibition throughout the study.
21. 16. Exclusion Criterion #16 was deleted during Protocol Amendment 6. In order to preserve subsequent numbering, this criterion number is kept in the list.
22. 17. History of substance abuse that in the Investigator’s assessment would impair the participant’s ability to comply with the protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. • Incidence and severity of TEAEs, SAEs, and TEAEs leading to treatment discontinuation. • Changes in vital signs, ECG results, and laboratory findings (including hematology, serum chemistry, urinalysis, and coagulation parameters).

Secondary endpoints 2

1. • Absence of hypoglycemiaa for up to 12 hours during fasting challenges. • Change from baseline of area under the AUEC of blood glucose and lactate during fasting challenges. • Change from baseline in time to hypoglycemia during fasting challenges. Change in other PD parameters including Emax and TEmax, during fasting challenges.
2. • PK parameters determined during the SAD portion of the study including, but not limited to Cmax, Tmax, AUC0-t, AUC0-inf, t1/2, CL, and Vz. • Additional PK parameters determined during the MAD portion of the study including, but not limited to Cmax,ss, AUC0-t,ss, Vss, and Rac determined by the ratio of AUC0-t,ss and AUC0-t. • Change from baseline in metabolic biomarkers such as blood levels of uric acid, triglycerides, LDL, and HDL.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Moderna Therapeutics Inc.

Sponsor organisation

Moderna Therapeutics Inc.

Address

200 Technology Square

City

Cambridge

Postcode

02139-3578

Country

United States

Scientific contact point

Organisation

Moderna Therapeutics Inc.

Contact name

Moderna WeCare Team

Public contact point

Organisation

Moderna Therapeutics Inc.

Contact name

Moderna WeCare Team

Third parties 12

Locations

4 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 201 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications