A Global, Phase 1/2, Open-label, Dose Optimization Study to Evaluate the Safety, Pharmacodynamics, and Pharmacokinetics of mRNA-3927 in Participants with Propionic Acidemia
- Trial ID
- 2022-502910-10-00
- Protocol
- mRNA-3927-P101
- Sponsor
- Moderna Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and tolerability of mRNA-3927 in participants with **Propionic Acidemia** (PA). This is crucial for determining the potential risks associated with the treatment and ensuring that it is safe for further clinical use. Additionally, the study aims to assess the efficacy of mRNA-3927 by comparing the frequency of metabolic decompensation events (MDEs) to the standard of care, which is vital for understanding the therapeutic potential of mRNA-3927 in managing PA.
The secondary objectives include:
- Characterizing the pharmacodynamic (PD) responses of mRNA-3927 by monitoring changes in blood levels of 2-methylcitrate (2-MC) and 3-hydroxypropionate (3-HP) after single and repeated administrations.
- Characterizing the pharmacokinetics (PK) of mRNA-3927, including single-dose and repeated-dose assessments.
- Evaluating the immunogenicity of mRNA-3927.
- Assessing SM-86 exposure after single and repeated doses.
- Evaluating changes in signs, symptoms, health-related quality of life (HRQoL), and global assessments.
- Assessing the efficacy of mRNA-3927 in terms of PA-related hospitalizations and urgent healthcare encounters.
- Evaluating the safety and tolerability of mRNA-3927 in repeated doses.
Participants
The clinical trial involves a total of **25 participants** diagnosed with **Propionic Acidemia**. The study population includes both male and female subjects, with an age range starting from **1 year** and extending to adults, as indicated by the inclusion of age categories **2** and **3**. Participants were selected based on a confirmed diagnosis of Propionic Acidemia through molecular genetic testing, specifically identifying mutations in **PCCA** and/or **PCCB** genes. The trial includes a vulnerable population, as it involves individuals with a rare metabolic disorder. Participants are required to have a body weight of at least **3 kg** at screening and must have experienced at least one documented Propionic Acidemia-related event prior to screening. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are capable of complying with study-related assessments, and for those of reproductive potential, the use of highly effective contraception is mandated during the study and for three months following the last administration of the investigational product. The trial aims to evaluate the safety, tolerability, and efficacy of **mRNA-3927** in this specific patient population.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the safety, pharmacodynamics, and pharmacokinetics of **mRNA-3927** in participants diagnosed with **Propionic Acidemia**. The trial is structured into three parts, each with specific objectives: Part 1 focuses on evaluating the safety and tolerability of mRNA-3927, Part 2 assesses the efficacy of mRNA-3927 by comparing the frequency of metabolic decompensation events (MDEs) to the standard of care, and Part 3 re-evaluates the safety and tolerability. The trial is expected to commence recruitment on January 1, 2025, and conclude by January 30, 2027, with an overall duration of approximately two years.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, body weight, and a confirmed diagnosis of Propionic Acidemia through molecular genetic testing. Following the screening, participants will be randomized and receive the investigational product or control. Regular follow-up visits will be scheduled to monitor safety, collect pharmacokinetic and pharmacodynamic data, and assess the frequency of MDEs. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.
The expected length of participant involvement in the trial is approximately 12 months, with conditions for early termination including the occurrence of severe adverse events (AEs) or serious adverse events (SAEs) that necessitate discontinuation of treatment. Primary endpoints include the incidence and severity of AEs, SAEs, and treatment-emergent adverse events (TEAEs), while secondary endpoints focus on changes in blood biomarkers and pharmacokinetic parameters. The trial aims to provide comprehensive data on the safety and efficacy of mRNA-3927 in managing Propionic Acidemia, contributing to the development of advanced therapeutic options for this rare metabolic disorder.
Treatment
The clinical trial involves the administration of **mRNA-3927**, an experimental medication formulated as a **dispersion for injection**. This investigational product contains **modified messenger ribonucleic acid** encoding human propionyl-coenzyme A carboxylase alpha and beta subunits, encapsulated into lipid nanoparticles. The medication is administered via the **intravenous** route. The dosing schedule and frequency of administration are determined based on the study protocol, with careful monitoring of participant compliance to ensure adherence to the treatment regimen.
In addition to the experimental treatment, the study includes several non-experimental treatments. **Famotidine** is used as an auxiliary medication, classified as an H2-receptor antagonist. It is administered in an **oral** pharmaceutical form, with the specific dosage and frequency determined by the standard-of-care guidelines.
**Ibuprofen lysine** is another auxiliary treatment, categorized as an anti-inflammatory agent. It is provided in an **oral** form, with dosing aligned with standard medical practices for managing inflammation and pain.
**Cetirizine dihydrochloride** and **pseudoephedrine hydrochloride** are administered together as an antihistamine combination. This auxiliary treatment is also given **orally**, with dosing schedules based on established therapeutic protocols for managing allergic symptoms.
**Paracetamol**, combined with **buclizine hydrochloride** and **codeine phosphate**, serves as an analgesic auxiliary treatment. This combination is administered **orally**, with dosing tailored to the participant's needs for pain management, following standard analgesic guidelines.
An **electrolyte solution** containing **potassium chloride**, **sodium hydrogen carbonate**, and **sodium chloride** is administered **intravenously** as an auxiliary treatment. This solution is used to maintain electrolyte balance, with dosing adjusted according to the participant's clinical requirements.
Lastly, **dexamethasone acetate**, a corticosteroid, is provided as an auxiliary treatment. It is administered **intravenously**, with dosing and frequency determined by the clinical condition being addressed, in accordance with standard corticosteroid therapy practices.
Efficacy
The efficacy of mRNA-3927 in the clinical trial will be assessed primarily by evaluating the frequency of metabolic decompensation events (MDEs) in participants with **Propionic Acidemia**. The primary endpoint for Part 2 of the trial is the annualized MDE frequency after 12 months of treatment, compared to the standard of care. Secondary efficacy endpoints include changes from baseline in patient-reported outcomes such as the Pediatric Quality of Life Inventory (PedsQL™) Physical Function score and the Metabolic and Mitochondrial Associated Patient Assessment Questionnaire-Patient Symptom Score (MMAPAQ-PSS) total score. Additionally, the trial will assess the annualized frequency of PA-related hospitalizations and urgent healthcare encounters after 12 months of treatment.
Biomarker levels, including 3-hydroxypropionic acid (3-HP) and 2-methylcitrate (2-MC), will be measured to evaluate pharmacodynamic (PD) parameters. These measurements will be taken from baseline (pretreatment levels) to postdose levels after single and repeated administrations of mRNA-3927. The estimation of PD parameters will include Emax, area under the effect curve (AUEC), and duration of response. Pharmacokinetic (PK) parameters of PCCA and PCCB mRNAs, such as Cmax, tmax, AUC, t½, CL, Vz, and Vss, will also be estimated. The presence and titers of anti-drug antibodies (ADA) against anti-PEG and anti-PCC will be measured to assess immunogenicity. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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;
- ≥ 1 year of age at the time of consent/assent if enrolled after the first 2 participants in Part 1;
- Confirmed diagnosis of PA based on diagnosis by MGT via central laboratory (PCCA and/or PCCB mutations);
- 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;
- 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.
- (Part 2 only) At least one documented MDE in the 12-month period before consent.
- 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.
- 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].
- <1 year of age at the time of first dose.
- Body weight ≥3 kg at Screening
- 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.
- 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
- 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;
- History of anaphylaxis/anaphylactoid reaction or severe hypersensitivity with infusions;
- 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;
- Major surgical procedure within 30 days before the Screening Visit (excludes central line, port, or feeding tube placement);
- Enrollment in the study is not deemed to be of clinical benefit, in the opinion of the Investigator;
- Other condition that in the Investigator's opinion could interfere with interpretation of study results or limit the participant's participation in the study;
- No longer applicable.
- (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.
- 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.
- 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;
- QTc > 480 ms using Bazett's correction;
- In female participants of reproductive potential, a positive pregnancy test;
- Pregnant or breastfeeding;
- Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association Classification;
- History of organ transplantation or planned organ transplantation during the period of study participation;
- Hypersensitivity to acetaminophen/paracetamol and/or ibuprofen or H1/H2 receptor blockers;
- History of hypersensitivity to any component of the mRNA-3927;
- Previously received gene therapy for PA.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Jan 2025 | 8 |
 Italy | Not Recruiting | 01 Jan 2025 | 2 |
 The Netherlands | Not Recruiting | 01 Jan 2025 | — |
 Spain | Not Recruiting | 01 Jan 2025 | 20 |
| Netherlands | — | — | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
FAMOTIDINE | Other | PHF00009MIG | ORAL | — | — | SCP127871 |
SODIUM CHLORIDE | Other | PHF00169MIG | INTRAVENOUS | — | — | SCP12712712 |
CETIRIZINE | Other | PHF00212MIG | ORAL | — | — | SCP127887 |
IBUPROFEN | Other | PHF00082MIG | ORAL | — | — | SCP1153989 |
DEXAMETHASONE | Other | PHF00245MIG | INTRAVENOUS | — | — | SCP10332310 |
mRNA-3927 | Test | DISPERSION FOR INJECTION | INTRAVENOUS | — | — | PRD10256168 |
PARACETAMOL | Other | PHF00082MIG | ORAL | — | — | SCP1081917 |