Preclinical data bring human trial launch closer for MGX-001
Primate study shows treatment restores clotting factor in hemophilia A
Data from non-human primates suggest gene-editing therapy MGX-001 may be able to restore clinically meaningful levels of factor VIII (FVIII) after a single dose, supporting its potential as a one-time treatment for hemophilia A.
Developer Metagenomi expects to meet with health authorities later this year to develop a strategy for the therapy’s development process and to file an investigational new drug application seeking approval for a clinical trial in late 2006.
“Our new data builds upon an earlier study demonstrating durable and stable FVIII activity in NHPs [non-human primates] over an approximately 19-month study, giving us confidence that our novel approach has the potential to be a curative, one-and-done treatment for patients suffering from hemophilia A,” Jian Irish, PhD, president and CEO of Metagenomi, said in a company press release.
Hemophilia A is caused by mutations in the F8 gene, which provides instructions for making clotting factor VIII (FVIII). Without enough FVIII, the blood cannot clot normally, leading to frequent or prolonged bleeding episodes that may damage joints and tissues over time.
MGX-001 aims to correct this underlying problem by enabling the liver, the body’s primary source of clotting factors, to produce its own functional FVIII.
‘A potentially lifelong cure’
The treatment uses a two-part system: an engineered adeno-associated virus (AAV) delivers a working F8 gene, while lipid nanoparticles (LNPs) provide a guide RNA and a DNA-cutting enzyme, or nuclease, to insert that gene into a highly active region of the genome known as the albumin locus. Once inserted, the new gene may allow liver cells to make FVIII at levels high enough to prevent spontaneous bleeds.
Instead of temporarily replacing or mimicking the missing clotting factor, “MGX-001 enables endogenous production of FVIII for hemostatic regulation and restores the body’s own ability to produce FVIII for a potentially lifelong cure,” Irish said.
Researchers tested MGX-001 in 24 non-human primates. Animals received one of six AAV doses ranging from 5.0 × 10¹¹ to 4.0 × 10¹³ vector genomes per kilogram (vg/kg), followed by an LNP dose of 0.2, 0.6, or 2.0 mg/kg. All animals received corticosteroids before both components.
Across the five highest AAV doses, animals reached therapeutic FVIII activity, defined as 50% to 150% of normal human FVIII levels. In one group, where the LNP dose was administered at 0.6 mg/kg and AAV doses varied between 1.6 × 10¹² and 4 × 10¹³ vg/kg, the average FVIII activity ranged from 49% to 81% of normal. When the AAV dose was fixed at 5 × 10¹² vg/kg and the LNP dose varied, FVIII activity ranged from 17% to 72%.
The proposed clinical dose — AAV 5 × 10¹² vg/kg plus LNP 0.6 mg/kg — yielded an average FVIII level of 49%, with individual results ranging from 29.3% to 59.5%. No animals exceeded the upper safety limit of 150%, and no off-target genome edits were detected.
“We are highly encouraged by the dose range finding results observed in this study where we have seen clear dose-dependent activity across both the AAV and LNP components of MGX-001, resulting in therapeutically relevant FVIII activity in each animal treated in all but the lowest AAV dose,” Irish said.
Aside from temporary liver-enzyme elevations at the highest LNP dose, MGX-001 was well tolerated.
Hematology consultant Glenn F. Pierce, MD, PhD, said the therapy could meaningfully expand options for people with hemophilia A. “The MGX-001 approach represents a potential paradigm shift for the treatment of hemophilia A patients who, even with currently approved therapies, are subject to rare but serious spontaneous bleeding events and must always ensure access to their treatment,” Pierce said. “As a physician scientist, drug developer, and former hemophilia A patient myself, I can speak firsthand to the impact that a potential one-and-done curative treatment can have in enabling a new standard of life with a hemophilia-free mindset.”
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