NGLY1 Deficiency

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.

Pictured: Entrance of Moderna's office in Massachusetts/iStock, hapabapa Moderna on Thursday announced that the FDA has selected its investigational methylmalonic acidemia therapy mRNA-3705 for the agency’s Support for Clinical Trials Advancing Rare Disease Therapeutics pilot program. First unveiled in September 2023, the FDA’s accelerator program for rare diseases—also known as START—is designed to give drugmakers “regular ad-hoc communication with FDA staff to address product-specific development issues,” such as trial design and choice of controls and patient populations. According to the START webpage, selected companies will also receive guidance regarding the use of non-clinical information to support their candidates as well as product characterization. To be eligible for START, participating companies must be developing gene or cell therapies for neurodegenerative or genetic metabolic rare diseases which are “likely to lead to significant disability or death within the first decade of life,” according to the FDA. Moderna’s mRNA-3705, which targets methylmalonic acidemia (MMA), fits the bill. MMA is a rare, life-threatening and heritable metabolic disorder characterized by the accumulation of acids and other toxic substances in the body, which in turn leads to metabolic crises and multi-organ damage. The condition is often diagnosed within the first few months from birth and has a heavy mortality and morbidity burden. There are currently no approved treatments for MMA. Most cases of MMA are caused by a deficiency in the MUT enzyme, which is found in the mitochondria and plays a crucial role in the breakdown of amino acids and fatty acids. Designed to be administered intravenously, mRNA-3705 addresses the underlying disease pathway in MMA by delivering a MUT-encoding mRNA molecule packed inside a proprietary lipid nanoparticle. Moderna’s candidate, which has won the FDA’s Orphan Drug, Rare Pediatric Disease and Fast Track designations, is being evaluated in a Phase I/II open-label study. The investigational therapy is meant for patients aged one year of age and older. Kyle Holen, head of development fortherapeutics and oncology at Moderna, said in a statement that the company is “excited” and “proud” that mRNA-3705 was selected for START, which will “enable enhanced communication with the U.S. FDA, resulting in acceleration of our development program.” Moderna is gearing up for a pivotal MMA study for mRNA-3705 this year. “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,” Holed said. Moderna now joins four other biopharma players that were also selected for START, which made announcements earlier this week. Denali Therapeutics is participating with its investigational enzyme replacement therapy for mucopolysaccharidosis type IIIA, while Grace Science’s gene therapy GS-100 for NGLY1 deficiency will also be part of the accelerator program. In addition, Larimar Therapeutics’ novel protein replacement therapy nomlabofusp for Friedrich’s ataxia and Neurogene’s developmental gene therapy NGN-401 for Rett syndrome have been selected for START. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.