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Methylmalonic acidemia, or MMA, is a genetic liver condition that in most cases is caused by a deficiency in an enzyme called MUT. Moderna’s methylmalonic acidemia candidate, mRNA-3705, will be developed under the FDA’s START pilot program for rare disease, the company announced June 6. It joins therapies from Denali Therapeutics, Neurogene, Grace Sciences and Larimar Therapeutics in the initiative, which aims to do for rare disease drugs what Operation Warp Speed did for the COVID-19 vaccines. Methylmalonic acidemia, or MMA, is a genetic liver condition that in most cases is caused by a deficiency in an enzyme called MUT, which processes fatty acids. Without it, the acids build up and damage organs. The disease is usually diagnosed within the first few months of life, and there are currently no treatments. MRNA-3705 is an mRNA-based drug that encodes MUT, thereby restoring acid metabolism. It has orphan-drug, fast-track and rare pediatric disease designations from the FDA and is currently being tested in a 63-subject, phase 1/2 clinical trial.  Under START, mRNA-2705 will get extra attention from FDA officials, who will guide Moderna through product development issues like designing studies, choosing control groups and selecting the right patient population. The effort is being carried out by the agency’s Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research, which is selecting six participants total for the first iteration of the program, according to a September 2023 announcement from the FDA.  “This selection highlights the promise of Moderna’s innovative mRNA platform beyond vaccines and the potential this novel medicine may have in addressing the serious and unmet medical needs of MMA,” Kyle Holen, M.D., senior vice president and head of development in the therapeutics and oncology unit at Moderna, said in a press release. “Selection for this program will…[result] in acceleration of our development program as we prepare for pivotal study initiation for mRNA-3705 in 2024.” Moderna's other rare disease programs include drugs for propionic acidemia, glycogen storage disorder type 1a, ornithine transcarbamylase deficiency, phenylketonuria, Crigler-Najjar syndrome type 1 and cystic fibrosis. Also picked for the START program is Calico Life Sciences' eIF2B activator fosigotifator, which is under development for Vanishing White Matter disease. The condition is an ultra-rare disease of the brain's white matter caused by variations in an essential enzyme in the cells called eIF2B. This causes a reduction in enzymatic activity that can lead to chronic activation of the integrated stress response.  This causes the white matter to degenerate, causing symptoms such as impaired muscle movement, cognitive decline and seizures. Patients have a shortened life span.  Fosigotifator is being developed in a partnership between Calico and AbbVie through an agreement signed in 2014. 

Calico Life Sciences said its experimental therapy for an autosomal recessive brain disorder has been tapped for the FDA’s Support for clinical Trials  Advancing Rare disease Therapeutics (START) pilot programme. It's the seventh and final candidate to be announced for the new initiative, which is intended to speed up the development of mid- to late-stage drugs and biologics for rare diseases by enabling more frequent communication with the US regulator. The Alphabet-founded biotech, along with partner AbbVie, is currently evaluating fosigotifator (ABBV-CLS-7262) in a Phase Ib/II trial of patients with vanishing white matter (VWM) disease. The therapy targets eIF2B, a guanine nucleotide exchange factor that is essential for protein synthesis and a key regulator of the integrated stress response (ISR). Fosigotifator is also being developed separately for amyotrophic lateral sclerosis.In patients with VWM disease, an ultra-rare progressive leukoencephalopathy, chronic activation of the ISR causes white matter to degenerate and leads to impaired muscle movement, cognitive decline, seizures, and a shortened lifespan. There are no approved treatments for VWM disease.  "The inclusion of fosigotifator underscores the potential of this investigational therapy in addressing the unmet needs of individuals and families affected by vanishing white matter disease," said Calico CEO Arthur Levinson. Participating therapies in the pilot programme are split between drugs and biologics, with FDA’s Center for Drug Evaluation and Research (CDER) having selected three products for rare neurodegenerative conditions, and the regulator’s Center for Biologics Evaluation and Research (CBER) having picked four cell or gene therapies intended to treat a rare disease that is likely to lead to significant disability or death within the first decade of life. The other six candidates are Moderna’s mRNA-3705, an mRNA therapy for methylmalonic acidaemia; Larimar Therapeutics’ nomlabofusp, a protein replacement therapy for Friedreich’s ataxia; Grace Science’s GS-100, an AAV9 gene therapy for NGLY1 deficiency; Myrtelle’s rAAV-Olig001-ASPA, a gene therapy for Canavan disease; Denali Therapeutics’ DNL126, an enzyme replacement therapy for MPS IIIA; and Neurogene’s NGN-401, a gene therapy for Rett syndrome.

The FDA filled its second-to-last slot for a new rare disease accelerator with an mRNA therapy from Moderna, one of a dozen programmes that represent the biotech’s push to grow beyond its bread-and-butter of infectious diseases.The candidate, mRNA-3705, is in the Phase I/II Landmark trial to treat methylmalonic acidemia (MMA) due to methylmalonic-CoA mutase deficiency in patients one year and older. The metabolic disorder, for which there are no approved therapies, is associated with significant mortality and can currently only be treated with a liver or combined liver and kidney transplants.Kyle Holen, Moderna's head of development for its therapeutics and oncology unit, said that mRNA-2705’s inclusion in the pilot "highlights the promise of Moderna's innovative mRNA platform beyond vaccines and the potential this novel medicine may have in addressing the serious and unmet medical needs of MMA.” He added that the firm plans to start a pivotal trial of the candidate this year. Boosting drug developmentIt’s the sixth experimental treatment to be announced for the FDA’s pilot programme, dubbed Support for Clinical Trials Advancing Rare Disease Therapeutics (START). Intended to speed up the development of mid- to late-stage drugs and biologics for rare diseases, participants can receive frequent advice from and communicate regularly with the agency’s staff on development issues such as study design and patient enrollment. Launched in September of last year, the initiative is designed to ensure “promising treatments advance efficiently through regulatory milestones.”Participating therapies will be split between drugs and biologics, with FDA’s Center for Drug Evaluation and Research in charge of selecting three products for rare neurodegenerative conditions, and the regulator’s Center for Biologics Evaluation and Research (CBER) responsible for picking four cell or gene therapies intended to treat a rare disease that is likely to lead to significant disability or death within the first decade of life. The slate of candidates, which were first revealed at the end of May, includes Larimar Therapeutics’ nomlabofusp, a protein replacement therapy for Friedreich’s ataxia; Grace Science’s GS-100, an AAV9 gene therapy for NGLY1 deficiency; Myrtelle’s rAAV-Olig001-ASPA, a gene therapy for Canavan disease; Denali Therapeutics’ DNL126, an enzyme replacement therapy for MPS IIIA; and Neurogene’s NGN-401, a gene therapy for Rett syndrome.One participant has yet to be announced.