#ISTH2020 – Gene Therapy BAY 2599023 Showing Steady FVIII Activity, Safety in Trial

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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A single dose of the investigational gene therapy BAY 2599023 safely promotes a sustained production of factor VIII (FVIII),  effectively preventing spontaneous bleeds in people with severe hemophilia A, a Phase 1/2 trial shows.

Two of the six patients treated to date in this clinical study, both given the therapy at lowest dose, are still showing FVIII activity at more than one year post-treatment, its investigators report.

Trial findings, “First-in-Human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A: Safety and FVIII Activity Results,” were presented at the recent 2020 Virtual Congress of the International Society on Thrombosis and Haemostasis (ISTH). The presentation was given by Steven Wesley Pipe, MD, with the University of Michigan.

BAY 2599023, formerly known as DTX201, is an experimental gene therapy for hemophilia A that is being developed by Bayer in collaboration with Ultragenyx Pharmaceuticals.

It uses a modified, harmless version of an adeno-associated virus (AAV), called AAVhu37, to deliver a shorter, but functional, copy of F8 — the gene that provides instructions to make FVIII, the blood clotting protein missing in people with hemophilia A — to liver cells. This shorter gene version is known as B-domain deleted human FVIII.

The AAVhu37 viral vector was selected for BAY 2599023 due to its ability to specifically target liver cells, where blood clotting factors are made, and its low risk of leading to the production of neutralizing antibodies.

Like other forms of gene therapy, BAY 2599023 aims to restore and maintain the production of FVIII over long periods of time, to lessen and possibly stop the need for repeated FVIII infusions to prevent spontaneous bleeds.

The safety, tolerability and effectiveness of single increasing doses of BAY 2599023 are currently being investigated in a dose-finding Phase 1/2 trial (NCT03588299) enrolling about 30 men with severe hemophilia A without FVIII inhibitors. The study is either recruiting or soon will be recruiting eligible patients at various sites across the U.S. and Europe.

Enrolled patients are being assigned to one of four increasing doses of BAY 2599023 — 0.5 x 1013 gene copies per kilogram (GC/kg), 1.0 x 1013 GC/kg, 2.0 x 1013 GC/kg, and 4.0 x 1013 GC/kg.

The study’s main goal is to assess the incidence and severity of adverse events in the year after dosing. Secondary goals include measuring changes in FVIII activity levels for up to five years following treatment.

Data on the first two patients given the lowest dose of BAY 2599023 showed the therapy to be safe, and that it  effectively increased FVIII levels, reducing or preventing the occurrence of bleeds.

Pipe at ISTH presented data on six men, given the gene therapy at one of three doses: 0.5 x 1013 GC/kg, 1 x 1013 GC/kg, or 2.0 x 1013 GC/kg.

A dose response was observed across all three groups, with FVIII levels increasing rapidly within eight to 12 weeks post-dosing and being maintained in those first treated for more than 16 months.

Two men who received the lowest dose (0.5 × 1013 GC/kg) of BAY 2599023 saw their FVIII activity levels increase to 5%–20% and experienced no serious adverse events or treatment-related adverse events in the year following dosing. One has been off prophylaxis for about seven months, data showed.

Two other patients treated at the low-medium dose of 1.0 × 1013 GC/kg saw their FVIII activity levels increase to 8%–40% after 28 weeks of follow-up. Neither is currently using a prophylactic to avoid bleeds.

One man had a mild elevation in the levels of liver enzymes, a sign of inflammation and possible liver damage. This was resolved with corticosteroids, and did not affect FVIII activity.

The two final patients with data, who both received the high-medium dose (2.0 × 1013 GC/kg) of BAY 2599023, stopped prophylaxis one month before a follow-up at week 10 after treatment. No spontaneous bleeds were seen after discontinuing prophylactic use and achieving stable activity levels of FVIII.

Both these men also had a mild-to-moderate elevation liver enzymes levels, which were again resolved with corticosteroids. A traumatic bleeding episode in one of these patients was resolved without additional FVIII treatment. No other adverse events or treatment-related serious adverse events were reported.

“BAY 2599023 delivers early measurable FVIII expression [activity] levels sustained over time … with evidence of hemostatic [bleeding prevention] efficacy,” the researchers wrote.

These early findings provide proof-of-concept for the use of BAY 2599023 to reduce and prevent bleeds in people with severe hemophilia A, they added.