a study to assess safety, pharmacokinetics, and pharmacodynamics of mrna-3705 in participants with isolated methylmalonic acidemia

Conditions: Methylmalonic Acidemia

Summary: this is a study of mrna-3705 in participants with isolated elevated methylmalonic acid (mma) due to methylmalonyl-coenzyme a (coa) mutase (mut) deficiency. the main goal of the study is to assess safety, pharmacokinetics, and pharmacodynamics of mrna-3705.

this study comprises 2 parts: dose optimization part (part 1) followed by a dose expansion part (part 2). the study is designed to evaluate multiple doses and dosing intervals of mrna-3705. in both parts, after confirmation of eligibility, participants will enter an observation period (48 to 72 hours pre-dose) in part 1 and 24 hours before dose 1 in part 2), followed by the treatment period. participants who complete the treatment period, including the end of treatment (eot) visit, are offered participation in the mrna-3705 extension study. if the participant chooses to participate and meets eligibility criteria, they will be enrolled in the extension study; otherwise, they will transition to the follow-up part of the study (approximately 2-year follow-up in part 1 and 6-months follow-up in part 2).

Eligibility criteria:
key inclusion criteria: * participant has a body weight of ≥11.0 kilograms (kg) at the screening visit. * participant has a diagnosis of isolated mma due to mut deficiency confirmed by molecular genetic testing. * participant has a blood vitamin b12 level equal to or above the lower limit of normal (based on laboratory reference range) confirmed in the screening period. for those participants found to have an elevated blood vitamin b12 level, the participant may enter if, in the opinion of the investigator, the cause of the elevation is secondary to b12 supplementation. * participant or their legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulations and is 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 the study and for 3 months after the last administration of study drug. * (part 2 only) at least 1 documented mde in the 12-month period before consent. key exclusion criteria: * participant has a diagnosis of isolated mma cb1a, cb1b, or cb1d enzymatic subtypes or methylmalonyl-coa epimerase deficiency or combined mma with homocystinuria. * participant has previously received gene therapy for the treatment of mma. * participant has a history of organ transplantation or planned organ transplantation during the period of study participation. * participant has an active, unstable, or clinically significant medical condition not related to mma or history of noncompliance that, in the investigator's opinion, could potentiate the risk while participating in this study, interfere with the interpretation of study results, or limit the participant's participation in the study. this may include, but is not limited to, history of relevant food or drug allergies; history of cardiovascular, central nervous, gastrointestinal, or infectious disease; history of clinically significant pathology; and/or history of cancer. * (part 2 only) history of hepatitis b (known positive hepatitis b surface antigen \[hbsag\]), hepatitis c virus (hcv), or hiv (positive hiv1/hiv-2 antibodies). participants with a past or resolved hepatitis virus b (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.

Keywords: isolated methylmalonic acidemia isolated methylmalonic aciduria elevated methylmalonic acid (mma) metabolism, inborn errors genetic diseases moderna mrna mrna-3705