Clinical trial NCT04159103: Open-Label Study of mRNA-3927 in Participants With Propionic Acidemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Propionic Acidemia
Keywords: mRNA-3927
Propionic Aciduria
Metabolism, Inborn Errors
Genetic Diseases
Inborn Amino Acid Metabolism, Inborn Errors
Acidosis
Acid-Base Imbalance
Metabolic Diseases
Organic Acidemias
Moderna
mRNA
Lead sponsor: ModernaTX, Inc.
Sponsor class: INDUSTRY
First posted: 2019-11-12
Enrollment: 68
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This First-in-Human (FIH) Phase 1/2 study is designed to characterize the safety, tolerability, and pharmacological activity (as assessed by biomarker measurements) and to determine the optimal dose of mRNA-3927 in participants with genetically confirmed propionic acidemia (PA). After establishing a dose with acceptable safety and pharmacodynamic (PD) response in a Dose Optimization Group (Part 1) in participants ≥1 year of age, additional participants will be enrolled into the study in a Dose Expansion Group (Part 2) to allow for further characterization of the efficacy, safety, and PD of mRNA-3927. Part 3 will evaluate the safety, efficacy and PD response of mRNA-3927 in infants (\<1 year of age).

Detailed description: During the Dose Optimization Stage, after each dose cohort is fully enrolled (≥1 year of age), , and the dose-limiting toxicity (DLT) observation window of at least 14 days is complete for the final participant in that cohort, the Sponsor will review the totality of available safety data in conjunction with all available PK/PD data. Based on this review, the Sponsor will recommend a revised dose and/or dosing interval. The Sponsor will abide by predefined constraints as to the maximum percentage change in dose and dose interval. A maximum of 9 cohorts will be enrolled in Part 1 (Dose Optimization).

Upon establishment of a dose with acceptable safety and PD activity in a Dose Optimization Part (Part 1), additional participants (≥1 year of age) will be enrolled into the study in a Dose Expansion Part (Part 2) to allow for further characterization of the safety, efficacy, and PD of mRNA-3927. Part 3 will evaluate the safety, efficacy and PD response in infants (\<1 year of age).

Participants in all the phases will participate in a predosing observational period, followed by a treatment period, and then a follow-up period after withdrawal of treatment.

Eligibility criteria: Inclusion Criteria:

Participants ≥1 year of age are eligible to be included in the study only if all of the following criteria apply:

* ≥ 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.
* Confirmed diagnosis of PA based on diagnosis by molecular genetic testing (PCCA and/or PCCB mutations).
* Part 2 only: At least one documented MDE in the 12-month period before consent.

Participants \<1 Year of Age :

* Identification by newborn screening shortly after birth or having suspected PA by presenting with a spectrum of metabolic symptoms, 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.
* ≥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.
* 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 (decreased pH) with high anion gap, or compensated metabolic acidosis (reduced bicarbonate, or base deficit, or reduced PaCO2 or increased lactate) with high anion gap.
* Acute hyperammonemia.
* Neutropenia or thrombocytopenia.

Exclusion Criteria:

Participants of all ages are excluded from the study if during Screening any of the following criteria apply:

* Any individual with laboratory abnormalities achieving theresholds defined in the protocol
* Estimated glomerular filtration rate (eGFR) \<30 milliliters (mL)/minute/1.73 square meter (m\^2) for participants of all ages receiving chronic dialysis.
* History of organ transplantation or planned organ transplantation during the period of study participation.
* Corrected QT interval (QTc) \>480 milliseconds (ms) using Bazett's correction.
* Grade 3 or 4 heart failure according to the Modified Ross Heart Failure Classification for Children or the New York Heart Association Classification.
* Pregnant or breastfeeding.
* 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 outcomes:
measure: Part 1: Number of Participants with an Adverse Event (AE), Serious AE (SAE) and AE Leading to Discontinuation
timeFrame: Day 1 (initial mRNA-3927 dose) up to Week 150 (End of Study)
measure: Part 2: Number of Metabolic Decompensation Events (MDEs)
timeFrame: Day 1 up to Week 53
measure: Part 3: Number of Participants with Treatment- emergent Adverse Event (TEAEs), SAEs, AEs of Special Interest and TEAEs Leading to Discontinuation
timeFrame: Day 1 up to Week 82
Secondary outcomes:
measure: Part 1: Change From Baseline in Plasma 2-Methylcitrate (2-MC) and 3-Hydroxypropionic Acid (3-HP) Levels After Single and Repeated Administrations of mRNA-3927
timeFrame: Baseline up to Week 40
measure: Part 1: Maximum Observed Effect (Emax) of 2-MC and 3-HP after Single and Repeated Administrations of mRNA-3927
timeFrame: Baseline up to Week 40
measure: Part 1: Area Under the Effect Versus Time Curve (AUEC) of 2-MC and 3-HP after Single and Repeated Administrations of mRNA-3927
timeFrame: Baseline up to Week 40
measure: Part 1: Duration of Response (DOR) after Single and Repeated Administrations of mRNA-3927
timeFrame: Baseline up to Week 40
measure: Part 1: Maximum Observed Concentration (Cmax) of Propionyl-CoA Carboxylase Subunit α (PCCA) and Propionyl-CoA Carboxylase Subunit β (PCCB) mRNAs
timeFrame: Day 1 through Day 22
measure: Part 1: Time of Cmax (Tmax) of PCCA and PCCB mRNAs
timeFrame: Day 1 through Day 22
measure: Part 1: Area Under the Plasma Concentration-Time Curve (AUC) of PCCA and PCCB mRNAs
timeFrame: Day 1 through Day 22
measure: Part 1: SM-86 Concentration after Single and Repeated Administrations of mRNA-3927
timeFrame: Day 1 through Day 8
measure: Part 1: Frequency of Anti-Polyethylene Glycol Antibodies
timeFrame: Day 1 (initial mRNA-3927 dose) up to Week 150 (End of Study)
measure: Part 2: Number of PA-related Hospitalizations
timeFrame: Day 1 up to Week 53
measure: Part 2: Change from Baseline in Pediatric Quality of Life Inventory (PedsQL) Physical Function Score
timeFrame: Baseline, Week 53
measure: Part 2: Change from Baseline in Methylmalonic Acidemia and Propionic Acidemia Questionnaire - Proximal Signs and Symptoms (MMAPAQ-PSS) Total Score
timeFrame: Baseline, Week 53
measure: Part 3: Change from Baseline in PedsQL Physical Function Score
timeFrame: Baseline, Week 53
measure: Part 3: Change from Baseline in MMAPAQ-PSS Total Score
timeFrame: Baseline, Week 53
measure: Part 3: Number of MDEs
timeFrame: Day 1 up to Week 53
measure: Part 3: Number of PA-related Hospitalizations
timeFrame: Day 1 up to Week 53
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Stanford
country: United States
facility: Lucile Packard Children's Hospital Stanford
state: California
city: Baltimore
country: United States
facility: Johns Hopkins Hospital, Adult Outpatient Clinical Research Unit
state: Maryland
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospitals
state: Michigan
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai - Clinical Research Unit
state: New York
city: Durham
country: United States
facility: Duke University Medical System (Duke Health)
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia (CHOP)
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Edmonton
country: Canada
facility: Stollery Children's Hospital University of Alberta
state: Alberta
city: Toronto
country: Canada
facility: Hospital For Sick Children
state: Ontario
city: Toyoake-shi
country: Japan
facility: Fujita Health University Hospital
state: Aichi
city: Sendai-Shi
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham NHS Foundation Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust
Study officials:
References: