A study to investigate the safety and efficacy of mRNA-3927 in participants with genetically confirmed propionic acidemia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Moderna Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

Trial duration

11 Aug 2025 → ongoing

Decision date (initial)

2024-06-03

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ModernaTX, Inc. United States

External identifiers

EU CT number

2022-502910-10-00

ClinicalTrials.gov

NCT04159103

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Pharmacokinetic, Safety

Part 1: Evaluate the safety and tolerability of mRNA-3927 in participants with PA
Part 2: Demonstrate the efficacy of mRNA-3927 as determined by reduction in frequency of MDEs
Part 3: Evaluate the safety and tolerability of mRNA-3927

Secondary objectives 2

1. Part 1: - Characterize the PD responses of mRNA-3927 as determined by changes in blood 2-MC and 3-HP after single and repeated administrations of mRNA-3927 - Characterize the single-dose and repeated-dose PK of mRNA-3927 - Assessment of SM-86 exposure after single and repeated dose - Evaluate the immunogenicity of mRNA-3927 Part 2 - Secondary: Efficacy - Demonstrate the efficacy of mRNA-3927 as assessed by reduction in the frequency of MDE-related hospitalizations. - Demonstrate the efficacy of mRNA-3927 as assessed by reduction in the frequency of PA-related hospitalizations - Evaluate the efficacy of mRNA-3927 as determined by the severity of MDEs - Evaluate the efficacy of mRNA-3927 as assessed by PCOA - Evaluate the efficacy of mRNA-3927 as assessed by PA-related urgent healthcare encounters. Part 2 - Secondary: PD - Characterize the PD responses to mRNA-3927 as determined by changes in blood 2-MC and 3-HP after single and repeated administrations of mRNA-3927 Part 2 - Secondary: Safety - Evaluate the safety and tolerability of mRNA-3927
2. Part 3 Part 3 - Secondary Efficacy: - Evaluate the efficacy of mRNA-3927 as determined by the frequency of MDEs - Evaluate the efficacy of mRNA-3927 as assessed by the frequency of MDE-related hospitalizations - Evaluate efficacy of mRNA-3927 as assessed by PA-related hospitalizations. - Evaluate the efficacy of mRNA-3927 as determined by the severity of MDEs - Evaluate changes in signs, symptoms in global assessments - Evaluate the efficacy of mRNA-3927 as assessed by PA-related urgent healthcare encounters. Part 3 - Secondary: PD - Characterize the PD responses of mRNA-3927 as determined by changes in blood 2-MC and 3-HP after single and repeated administrations of mRNA-3927 Part 3 - Secondary: PK - Characterize the repeated-dose PK of mRNA-3927 - Assessment of SM-86 and OL-56 exposure after single and repeated dose

Conditions and MedDRA coding

Propionic Acidemia

Study design 7 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, The Spanish Agency Of Medicines And Medical Devices, Health Canada, Medicines And Healthcare Products Regulatory Agency, Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-375240-PIP20-23

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Participants ≥1 Year of Age 1. ≥ 8 years of age at the time of consent/assent if enrolled as 1 of the first 2 participants in Part 1;
2. 2. ≥ 1 year of age at the time of consent/assent if enrolled after the first 2 participants in Part 1;
3. 3. Confirmed diagnosis of PA based on diagnosis by MGT via central laboratory (PCCA and/or PCCB mutations);
4. 4. Participant and/or legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulations and willing and able to comply with study-related assessments;
5. 5. Sexually active females of childbearing potential and sexually active males of reproductive potential agree to use a highly effective method of contraception during study treatment and for 3 months following the last administration of mRNA-3927.
6. 6. (Part 2 only) At least one documented MDE in the 12-month period before consent.
7. Participants <1 Year of Age 7. Identification by newborn screening shortly after birth or having suspected PA by presenting with a spectrum of metabolic symptoms (as defined by the criteria below), and having a sibling diagnosed with PA. Participant may enter the Screening Period while awaiting genetic testing results, provided that all other eligibility criteria are met but would not be enrolled until diagnosis of PA is confirmed.
8. 8. For infants in the NICU only: ≥37 weeks gestational age at the time of birth without other conditions/comorbidities that in the opinion of the Investigator may interfere with the interpretation of study results. [Note: Infants <37 weeks gestational age who are no longer neonates at the time of Screening and are thriving independently are eligible].
9. 9. <1 year of age at the time of first dose.
10. 10. Body weight ≥3 kg at Screening
11. 11. At least 1 documented PA-related event prior to Screening defined as the following criteria: • Clinical signs of metabolic deterioration consistent with PA (eg, vomiting, not feeding well/poor suck, heavy breathing, lethargy, absence of proper perfusion, abnormal movements including bicycling, abnormal tone, low body temperature, seizure[s]), OR • Meeting the criteria of MDE definition, OR • Evidence of laboratory abnormalities as evidenced by at least one of the following: − Metabolic acidosis with elevated anion gap. − Acute hyperammonemia. − Neutropenia or thrombocytopenia.
12. 12. Legally authorized representative is willing and able to provide informed consent as mandated by local regulations and willing and able to comply with study-related assessments.

Exclusion criteria 18

1. 1. Participants of all Ages. Any individual with laboratory abnormalities considered to be clinically significant (eg, markedly out of range, associated with clinical symptoms) in the Investigator or Sponsor’s opinion that could interfere with or limit the participation in the study;
2. 10. History of anaphylaxis/anaphylactoid reaction or severe hypersensitivity with infusions;
3. 11. Participation in another clinical study of another investigational agent within 30 days before study entry or within 5 elimination half-lives of the investigational agent, whichever is longer;
4. 12. Major surgical procedure within 30 days before the Screening Visit (excludes central line, port, or feeding tube placement);
5. 13. Enrollment in the study is not deemed to be of clinical benefit, in the opinion of the Investigator;
6. 14. Other condition that in the Investigator's opinion could interfere with interpretation of study results or limit the participant's participation in the study;
7. 15. No longer applicable.
8. 16. (Part 2 only) History of hepatitis B (known positive HBsAg), HCV, or HIV (positive HIV-1/HIV-2 antibodies). Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg are eligible. Participants with history of positive results for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
9. 17. Other clinically significant conditions that in the Investigator’s opinion could interfere with the safety of the participant, the interpretation of study results, or limit the participation in the study.
10. 2. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, as estimated by Schwartz formula for participants < 18 years of age (Schwartz et al 2012) or by the Chronic Kidney Disease Epidemiology Collaboration creatinine-based formula for participants ≥ 18 years of age or for participants of all ages receiving chronic dialysis;
11. 3. QTc > 480 ms using Bazett's correction;
12. 4. In female participants of reproductive potential, a positive pregnancy test;
13. 5. Pregnant or breastfeeding;
14. 6. Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association Classification;
15. 7. History of organ transplantation or planned organ transplantation during the period of study participation;
16. 8. Hypersensitivity to acetaminophen/paracetamol and/or ibuprofen or H1/H2 receptor blockers;
17. 9. History of hypersensitivity to any component of the mRNA-3927;
18. 18. Previously received gene therapy for PA.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part 1: Incidence and severity of AEs (including mRNA-3927-related and not related AEs), SAEs, and AEs leading to treatment discontinuation
2. Part 2: Change in annualized frequency of CEC-adjudicated MDEs during the 12-month Treatment Period with mRNA-3927 compared to the annualized frequency of CEC-adjudicated MDE during the Pretreatment Period
3. Part 3: Incidence and severity of TEAEs, SAEs, AESIs (eg, IRR and hypersensitivity), and TEAEs leading to treatment discontinuation

Secondary endpoints 17

1. 1. Part 1: -Change in blood 2-MC and 3-HP levels from baseline (pretreatment levels) to postdose levels measured after single and repeated administrations of mRNA-3927 -Estimation of PD parameters from baseline after single and repeated administration of mRNA-3927, including Emax, AUEC, and duration of response
2. 2. Part 1: -Estimation of PK parameters of PCCA and PCCB mRNAs, including Cmax, tmax, AUC, t½, CL, Vz, and Vss -Measurement of SM-86 after single and repeated dosing -Presence and titers of ADA against anti-PEG and APA against anti-PCC
3. 3. Part 2 - Secondary: Efficacy Change in annualized frequency of CEC-adjudicated MDE-related hospitalizations during the 12-month Treatment Period with mRNA-3927 compared to the annualized frequency of CEC-adjudicated MDE-related hospitalizations during the Pretreatment Period
4. 3 Cont.: Change in annualized frequency of CEC-adjudicated PA-related hospitalizations during the 12-month Treatment Period with mRNA-3927 compared to the annualized frequency of CEC-adjudicated PA-related hospitalizations during the Pretreatment Perioda
5. 4. • Change in annualized frequency of CECadjudicated MDEs during the 12-month Treatment Period with mRNA-3927 compared to the annualized frequency of CEC-adjudicated MDEs during the Pretreatment Period by the following severity grades: Grade 1, Grade 2, Grade 3
6. 4 Cont.: Change from Baseline in PedsQLTM total score and Physical Function Score at Week 52 • Change from Baseline in MMAPAQ-PSS total score at Week 52
7. 5. Proportions of patients distributed into ‘mild’ ‘moderate’ and ‘severe’ categories based on IGA-S severity levels at Week 52Proportion of participants meeting ‘modestly improved’ or ‘much improved’ in IGA-I at Week 52
8. 5 Cont.: Change in annualized frequency of CECadjudicated PA-related urgent healthcare encounters during the 12-month Treatment Period with mRNA-3927 compared to the annualized frequency of PA-related urgent healthcare encounters during the Pretreatment Period Secondary: PD
9. 6. Change in blood biomarkers including 3-HP and 2-MC from baseline (pretreatment levels) to posttreatment levels measured afteradministrations of mRNA-3927 -Estimation of PD parameters of blood 3-HP and 2-MC after administration of mRNA-3927, including AUC_Below_B,AUC_Net_B, and Emax
10. 7. Part 2- Secondary: Safety -Incidence and severity of TEAEs, SAEs, AESIs (eg, IRR and hypersensitivity), and TEAEs leading to treatment discontinuation
11. 8. Part 3 - Key Secondary: - Annualized frequency of CEC-adjudicated MDEs during the 12 month Treatment Period.
12. 8 Cont.: Annualized frequency of CEC-adjudicated MDE-related hospitalization during the 12 month Treatment Period - Annualized frequency of CEC-adjudicated PA-related hospitalization during the 12-month Treatment Period
13. 9. - Annualized frequency of CEC-adjudicated MDE during the 12 month Treatment Period by the following MDE severity grades: Grade 1, Grade 2, Grade 3 • Change from baseline in PCOAs: - PedsQL Physical Function score
14. 9 Cont.: MMAPAQ-PSS total score - PedsQL total score • Proportions of patients distributed into ‘mild’ ‘moderate’ and ‘severe’ categories based on IGA-S severity levels at Week 52. Proportion of participants meeting ‘modestly improved’ or ‘much improved’ in IGA-I.
15. 10. Annualized frequency of CEC-adjudicated PA-related urgent healthcare encounters during the 12-month Treatment Period. Secondary: PD - Change in blood biomarkers including 3-HP and 2-MC from baseline (pretreatment levels) to postdose levels measured after single and repeated administrations of mRNA-3927
16. 10 Cont.: Estimation of PD parameters of blood 3-HP and 2-MC after administration of mRNA-3927, including AUC_Below_B, AUC_Net_B, and Emax.
17. 11. Part 3 - Secondary: PK - Estimation of PK parameters of PCCA and PCCB mRNAs, including Cmax, tmax, AUC, t½, CL, Vz, and Vss Estimation of PK parameters of SM-86 and OL-56, including AUC, Cmax, tmax.

Investigational products

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

Test 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Moderna Inc.

Sponsor organisation

Moderna Inc.

Address

325 Binney Street

City

Cambridge

Postcode

02142-1038

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 22

Locations

4 EU/EEA countries · 9 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

Temporary halts 6 · Art. 38 CTR

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

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

Documents 176 files

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

Application history

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