MODIFIED MESSENGER RIBONUCLEIC ACID ENCODING HUMAN PROPIONYL-COENZYME A CARBOXYLASE ALPHA AND BETA SUBUNITS ENCAPSULATED INTO LIPID NANOPARTICLES for Propionic acidemia

Inclusion criteria

• {"criterion_text":"- 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;\n- 10. Body weight ≥3 kg at Screening\n- 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.\n- 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.\n- 2. ≥ 1 year of age at the time of consent/assent if enrolled after the first 2 participants in Part 1;\n- 3. Confirmed diagnosis of PA based on diagnosis by MGT via central laboratory (PCCA and/or PCCB mutations);\n- 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;\n- 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.\n- 6. (Part 2 only) At least one documented MDE in the 12-month period before consent.\n- 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.\n- 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].\n- 9. <1 year of age at the time of first dose."}

Exclusion criteria

• {"criterion_text":"- 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;\n- 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;\n- 3. QTc > 480 ms using Bazett's correction;\n- 4. In female participants of reproductive potential, a positive pregnancy test;\n- 5. Pregnant or breastfeeding;\n- 6. Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association Classification;\n- 7. History of organ transplantation or planned organ transplantation during the period of study participation;\n- 8. Hypersensitivity to acetaminophen/paracetamol and/or ibuprofen or H1/H2 receptor blockers;\n- 9. History of hypersensitivity to any component of the mRNA-3927;\n- 18. Previously received gene therapy for PA.\n- 10. History of anaphylaxis/anaphylactoid reaction or severe hypersensitivity with infusions;\n- 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;\n- 12. Major surgical procedure within 30 days before the Screening Visit (excludes central line, port, or feeding tube placement);\n- 13. Enrollment in the study is not deemed to be of clinical benefit, in the opinion of the Investigator;\n- 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;\n- 15. No longer applicable.\n- 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.\n- 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."}

Primary endpoints

• {"endpoint_text":"- Part 1: Incidence and severity of AEs (including mRNA-3927-related and not related AEs), SAEs, and AEs leading to treatment discontinuation","definition_or_measurement_approach":"Incidence and severity of adverse events will be recorded, including attribution to mRNA-3927, serious adverse events (SAEs), and AEs causing treatment discontinuation; standard AE/SAE reporting per protocol."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Annualized frequency of metabolic decompensation events (MDEs) adjudicated by the Clinical Events Committee (CEC) during the 12-month treatment period compared with pretreatment period; change in annualized rate is the primary efficacy measure."}
• {"endpoint_text":"- Part 3: Incidence and severity of TEAEs, SAEs, AESIs (eg, IRR and hypersensitivity), and TEAEs leading to treatment discontinuation","definition_or_measurement_approach":"Treatment-emergent adverse events (TEAEs), SAEs, and adverse events of special interest (AESIs) such as infusion-related reactions (IRR) and hypersensitivity will be recorded and graded according to protocol-defined criteria; incidence and severity summarized."}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Measurement of blood biomarkers 2-MC and 3-HP pre- and post-dose; pharmacodynamic (PD) parameters including Emax, AUEC, and response duration estimated."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Pharmacokinetic (PK) parameters for PCCA/PCCB mRNAs and exposure metrics (Cmax, tmax, AUC, t½, CL, Vz, Vss); measurement of SM-86; immunogenicity assessed by ADA/APA presence and titers."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Annualized frequency of MDE-related hospitalizations adjudicated by CEC during 12-month treatment vs pretreatment period."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Annualized frequency of PA-related hospitalizations adjudicated by CEC during 12-month treatment vs pretreatment."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Annualized frequency comparisons stratified by MDE severity grades (Grade 1–3), adjudicated by CEC."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Patient-centred outcomes: change from baseline in PedsQL total and physical function scores and MMAPAQ-PSS at Week 52, using validated instruments."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Distribution of participants by IGA-S severity categories at Week 52 and proportion meeting improvement thresholds on IGA-I."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Annualized frequency of PA-related urgent healthcare encounters (CEC-adjudicated) during 12-month treatment vs pretreatment; PD assessments as secondary measures."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Blood biomarkers 3-HP and 2-MC measured pre- and post-treatment; PD parameter estimation including AUC_Below_B, AUC_Net_B, and Emax."}
• {"endpoint_text":"- 7. Part 2- Secondary: Safety -Incidence and severity of TEAEs, SAEs, AESIs (eg, IRR and hypersensitivity), and TEAEs leading to treatment discontinuation","definition_or_measurement_approach":"Safety endpoints: incidence and severity of TEAEs, SAEs, AESIs (e.g., IRR, hypersensitivity), and TEAEs causing discontinuation."}
• {"endpoint_text":"- 8. Part 3 - Key Secondary: - Annualized frequency of CEC-adjudicated MDEs during the 12 month Treatment Period.","definition_or_measurement_approach":"Annualized frequency of CEC-adjudicated MDEs during 12-month treatment in Part 3."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Annualized frequencies of MDE-related and PA-related hospitalizations adjudicated by CEC during 12-month treatment."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Annualized MDE frequency by severity grade; change in patient-centred outcomes including PedsQL Physical Function score."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Patient-reported outcome measures (MMAPAQ-PSS, PedsQL) and IGA severity/improvement categorizations at Week 52."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Annualized frequency of PA-related urgent healthcare encounters adjudicated by CEC; PD biomarker changes (3-HP, 2-MC) measured pre/post dosing."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Estimation of PD parameters for 3-HP and 2-MC (AUC_Below_B, AUC_Net_B, Emax) after administration."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"PK parameter estimation for PCCA/PCCB mRNAs and for SM-86/OL-56 (AUC, Cmax, tmax, etc.) in Part 3."}

Methods

• Study website and trial listing (central study website support provided by Longboat Clinical Limited) — public trial listing materials and study brochures provided.
• Physician-to-physician outreach (PI-to-Physician letters) — targeted to clinicians in participating countries (documents available IT/FR/ES/NL).
• Patient invitation letters and Trial Listing materials (patient invitation-to-trial letters, posters, tear-off posters) distributed at sites and in clinics (country-specific materials available).
• GP letters and local clinic outreach (GP letters for Italy and other localised materials).
• Site support and retention programs (Praxis Communications / Praxis Retention Site Support Program; study retention materials provided to sites).
• Printed materials and local-language brochures/fact sheets (Clinical Trial Brochure, Study Welcome Brochure, Part-specific visit guides) for target audiences (patients, parents, caregivers) in country-specific languages (Italian, French, Spanish, Dutch).
• Home health care visits as appropriate (Home health care services provided by Professional Case Management Clinical Trials LLC).
• Provision of iPads for eCOA and digital data capture (Medidata) to support remote data collection and participant-reported outcomes.

Italy

Earliest CTIS Part Ii Submission Date

12-03-2024

Latest Decision Or Authorization Date

25-03-2025

Processing Time Days

378

Number Of Sites

1

Number Of Participants

2

France

Earliest CTIS Part Ii Submission Date

12-03-2024

Latest Decision Or Authorization Date

24-10-2025

Processing Time Days

591

Number Of Sites

2

Number Of Participants

8

Spain

Earliest CTIS Part Ii Submission Date

22-12-2023

Latest Decision Or Authorization Date

28-10-2025

Processing Time Days

676

Number Of Sites

4

Number Of Participants

20

Netherlands

Earliest CTIS Part Ii Submission Date

15-03-2024

Latest Decision Or Authorization Date

28-10-2025

Processing Time Days

592

Number Of Sites

2

Number Of Participants

2

Primary sponsor

Full Name

Moderna Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Pharmaceutical Product Development LLC (PPD)

Responsibilities

Central lab, laboratory sample management, bioanalytical analysis; pharmacovigilance and global central labs; distribution and operational support depending on entry

Name

Bioclinica Inc.

Responsibilities

ECHO imaging interpretation

Name

Charles River Laboratories International Inc.

Responsibilities

Bioanalytical laboratory analysis

Name

Icon Development Solutions LLC

Responsibilities

exit interviews

Name

PPD Development Ireland Limited / PPD Global Central Labs / PPD Global Limited

Responsibilities

distribution of supplies, biomarker storage, pharmacovigilance and central lab services

Name

Endpoint Clinical Inc.

Responsibilities

operational support (sponsor duty code 3)

Name

Fisher Clinical Services GmbH / Fisher Clinical Services Inc.

Responsibilities

IP depot, QP, packaging/labeling, distribution and returns/reconciliation

Third parties

• {"country":"United States","full_name":"Professional Case Management Clinical Trials LLC","duties_or_roles":"Home health care services","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"Sponsor duty code 3 (unspecified in record)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Arup Laboratories Inc.","duties_or_roles":"lab testing - secondary biomarkers amino acids","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"IP Depot and QP ( packaging/labelling, distribution (including QP and depot setup), returns/reconciliation)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"ECHO imaging interpretation","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Ireland","full_name":"Longboat Clinical Limited","duties_or_roles":"Study website, site staff education","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"Central Lab, Laboratory sample management, bioanalytical analysis","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fisher Clinical Services Inc.","duties_or_roles":"IP Depot and QP ( packaging/labelling, distribution (including QP and depot setup), returns/reconciliation)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"provision of iPads for eCOA; additional duty code 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Praxis Communications LLC","duties_or_roles":"provides trial educational toolkits for both sites and patients, provision of retention materials","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Charles River Laboratories International Inc.","duties_or_roles":"Bioanalytical laboratory analysis","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"PPD Development Ireland Limited","duties_or_roles":"distribution of non-IP ancillary supplies","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"provision of ECG machines and supplies and central ECG reading","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Ppd Inc.","duties_or_roles":"Bioanalytical laboratory analyses","organisation_type":"Pharmaceutical company"}
• {"country":"Finland","full_name":"Blueprint Genetics Oy","duties_or_roles":"Genetic testing","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"multiple duties including pharmacovigilance-related and operational support (codes 1,11,2,5,6 listed)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Gray Consulting Inc.","duties_or_roles":"Patient travel, logistic and reimbursement","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"Biomarker sample long term storage","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"PPD Global Limited","duties_or_roles":"Pharmacovigilance; additional duty code 8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC (alternate entry)","duties_or_roles":"burden assessment review calls; other support functions","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Icon Development Solutions LLC","duties_or_roles":"exit interviews","organisation_type":"Pharmaceutical company"}