Pompe Disease mRNA Therapy Receives FDA Orphan Drug Designation


Preclinical data showed a reduction of Gys1 mRNA and protein of more than 80% in multiple skeletal tissues.

Aro Biotherapeutics’ ABX1100, an investigational Centyrin-siRNA conjugate for the treatment of Pompe disease, has received orphan drug designation from the FDA.1 ABX1100 functions by inhibiting the muscle glycogen synthase1 (Gys1) gene to prevent the disease-associated build-up of glycogen in muscle tissue caused by a mutation in acid alpha-glucosidase (GAA), an enzyme that breaks down glycogen in muscle.

Preclinical mouse model data presented at the TIDES USA 2022 meeting indicated that a single dose of 3 mg/kg (siRNA) with tool mouse specific Centyrin-siRNA conjugate led to a reduction of Gys1 mRNA and protein of more than 80% in multiple skeletal tissues 1 month after dosing.2

Furthermore, repeat dose experimentation showed significant reductions of Gys1 mRNA, Gys1 protein, and glycogen in skeletal muscles at 6 weeks after the final dose. Notably, there was no measurable gene knockdown in liver tissue observed, indicating tissue selectivity.

“These data represent a significant milestone for Aro,” Susan Dillon, PhD, co-founder and chief executive officer, Aro Biotherapeutics, said in a May 2022 statement regarding the preclinical data.3 “We have made considerable progress in advancing our Centyrin-oligonucleotide platform and in building our pipeline of novel therapies. These robust data in Pompe disease give us further confidence that our platform, which enables tissue-specific delivery of oligonucleotides and other genetic drugs, has potential to address a broad array of diseases.”

It was also noted in the presentation of the preclinical data that Centyrin-siRNA conjugates were well tolerated in in vivo models and showed a lack of potential for immunogenicity in human T-cell screens.2

“In addition to the potency and durability demonstrated, we postulate that the relatively low molecular weight of Centyrin siRNA conjugates vs antibody siRNA conjugates affords additional advantages in terms of lower drug dose, and reduced potential for acute infusion reactions and immunogenicity,” Karyn O’Neil, PhD, co-founder and chief scientific officer, Aro Biotherapeutics, who presented the preclinical data, wrote in the presentation’s abstract.2 “In summary, our studies demonstrate efficient targeting of a Gys1 specific siRNA to skeletal muscle tissues, and compelling link between Gys1 mRNA, protein and glycogen reduction in a murine model of Pompe disease.”

O’Neil further indicated that, based on the promising preclinical data, the Centyrin-siRNA conjugates have potential for development as a monotherapy, or as a combination therapy with enzyme replacement therapy, which is the current standard of care for Pompe disease, but has drawbacks including a lack of specificity for the skeletal muscle and necessary every-other-week dosing with long infusion times.

The company expects that the therapy may enter clinical trials in the middle of 2023.1

“We are pleased to have received this designation and are gratified by the FDA’s recognition of the potential of ABX1100 to improve the lives of patients living with Pompe disease,” Mittie Doyle, MD, FACR, chief medical officer, Aro Biotherapeutics, said in a statement regarding the news.1 “We believe our novel treatment approach has the opportunity to address the great unmet need that exists in Pompe disease, and we are excited to advance ABX1100 to clinical trials in the coming year.”

1. Aro Biotherapeutics receives FDA orphan drug designation for ABX1100 for the treatment of Pompe disease. News release. Aro Biotherapeutics. August 10, 2022. https://www.arobiotx.com/aro-biotherapeutics-receives-fda 
2. O’Neil K. Centyrin-targeted siRNA conjugates demonstrate potential new therapeutic approach for reduction of skeletal muscle glycogen in Pompe disease. Presented at: TIDES USA 2022; May 11, 2022. Boston, MA. https://informaconnect.com/tides/speakers/karyn-oneil-phd/#delivery-of-macromolecules-room-104_centyrin-targeted-sirna-conjugates-demonstrate-potential-new-therapeutic-approach-for-reduction-of-skeletal-muscle-glycogen-in-pompe-disease
3. Aro Biotherapeutics to present new preclinical data highlighting the potential of Centyrin-siRNA conjugates for the treatment of Pompe disease. News release. Aro Biotherapeutics. May 11, 2022. https://www.arobiotx.com/aro-treatment-pompe 
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