IND-enabling studies for hemophilia A gene-editing therapy to advance
In preclinical studies, MGX-001 led to sustained increase in FVIII activity
Metagenomi, which is developing MGX-001, a gene-editing therapy for hemophilia A, is preparing to initiate investigational new drug (IND)-enabling activities that seek to support the therapy’s transition from preclinical to clinical testing.
The move is backed by preclinical studies in nonhuman primates that show the treatment led to a sustained increase in the activity of factor VIII (FVIII), the missing clotting protein in hemophilia A, over a year. Data will be presented at the American Society of Hematology (ASH) meeting, December 7-10, in San Diego.
The company has begun manufacturing activities to support IND-enabling studies of MGX-001 and remains on track to request authorization to test the therapy in patients in 2026.
“Our strong pace of innovation and execution continued in the third quarter, highlighted by the nomination of our first [development candidate], MGX-001, intended as a one-time curative gene editing therapeutic for both adults and children with hemophilia A,” Brian C. Thomas, PhD, Metagenomi’s CEO and founder, said in a company press release.
Hemophilia A is caused by mutations in the F8 gene that impair the production or activity of FVIII, which is needed for blood to clot. Its absence increases patients’ susceptibility to excessive and prolonged bleeding episodes.
How does MGX-001 work in hemophilia A?
MGX-001 delivers a functional version of F8 by packaging it into a harmless adeno-associated virus (AAV) that targets the liver, where most clotting factors are produced. It also delivers lipid nanoparticles, or small particles made up of fatty molecules that contain a guide RNA and a messenger RNA that carry instructions for producing an enzyme that can cut DNA, called a nuclease.
The guide RNA is a small molecule that’s designed to direct the nuclease to a specific region within the gene encoding albumin, where it will cut into its DNA sequence to enable the F8 gene to be inserted. Albumin is the most abundant protein in plasma, the liquid portion of blood, that normally transports other substances through the bloodstream.
This approach should lead to a sustained increase in FVIII activity, normalizing blood clotting and preventing bleeds with hemophilia A.
In a preclinical study, three nonhuman primates were treated with a single dose into their veins, or intravenously, of the AAV containing the F8 gene, followed by a single intravenous dose of the nanoparticles a month later. The treatment was generally well tolerated by the animals, leading to a moderate, but temporary, increase in liver enzymes.
Consistent with previous findings, updated results to be presented at ASH showed the therapy led to sustained FVIII activity levels over a year that were sufficient for a functional cure. Specifically, between nine and 12 months after the nanoparticles were administered, two animals had normal or nearly normal FVIII activity levels and the third had levels in the mild hemophilia range.
“This preclinical study provided an important validation of our gene-editing platform, supporting our potential to overcome a key limitation of gene therapies that have struggled to achieve long-term persistence of Factor VIII expression in patients,” Thomas said.
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