First 2 Adults with Severe Hemophilia A Respond Well to Gene Therapy in Clinical Trial

Bayer’s investigational gene therapy BAY 2599023 safely and effectively increased the levels of clotting factor VIII (FVIII) and prevented or lessened bleeding in the first two people with severe hemophilia A treated in a Phase 1/2 clinical trial, preliminary data show.

The ongoing trial (NCT03588299; 2017-000806-39) is enrolling up to 30 eligible adult patients. More information, including recruiting sites in the U.S. and Europe, is available here.

These early results will be presented in the poster, “First-in-human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A,” at the 61st American Society of Hematology (ASH) Annual Meeting & Exposition running Dec. 7-10 in Orlando, Florida.

BAY 2599023 — initially by Dimension Therapeutics as DTX201— is being developed by Bayer in collaboration with Ultragenyx Pharmaceuticals. The potential gene therapy aims to promote a sustained production of FVIII and overcome its deficit in hemophilia A patients, reducing or eliminating the need for prophylatic, or preventive, FVIII replacement therapy and the occurrence of bleeding events.

Administered as a single infusion, the therapy uses a modified and harmless version of the adeno-associated virus (AAV), called AAVhu37, to deliver a shorter but functional copy of the FVIII gene to liver cells, where clotting factors are produced. This version of the FVIII gene is known as B-domain deleted FVIII gene.

Preclinical studies showed that AAVhu37 effectively delivered the FVIII gene to liver cells, had a favorable distribution, and induced a durable FVIII production.

In addition, preclinical data showed that BAY 2599023 had a good safety profile, and the potential to promote FVIII production to levels considered to be therapeutic over a long period of time.

The ongoing, dose-establishing Phase 1/2 trial (NCT03588299; 2017-000806-39) is evaluating the safety, tolerability and early effectiveness of three ascending doses of BAY 2599023 in adult men with severe hemophilia A who have been treated with FVIII products.

It is the first clinical trial to evaluate a gene therapy based on the AAVhu37.

Up to 30 enrolled patients will be given a single intravenous infusion of one of three doses of BAY 2599023. The study’s primary goal is to measure safety through reports of adverse events. Secondary goals include measuring FVIII activity and assessing the number of patients who reach more than 5% of FVIII production at six and 12 months after treatment at the different doses.

Data on the first two men treated at BAY 2599023’s starting dose (0.5 x 10¹³ gene copies/kg) will be presented at the meeting. These men had more than 150 days of treatment with FVIII products, no history of FVIII inhibitors, and no detectable immune response against AAVhu37.

No adverse events were reported after more than 15 weeks of safety evaluations (about four months). Blood levels of liver enzymes also remained within a normal range, and either of these patients needed to be treated with corticosteroids.

The first man reached a stable FVIII production of around 5%, and was free of bleeding events or a need for prophylactic treatment for six weeks. The second patient, who had 99 bleeds in the year before receiving the gene therapy, reached a stable FVIII production of around 17%, and has been bleed-free for more than 5.5 months (at the time of data collection).

These preliminary data suggest that BAY 2599023 is safe and effective in promoting the production of FVIII and in reducing or preventing the occurrence of bleeding events and the need for prophylactic treatment, the researchers wrote.

“Overall, data generated from this first dose cohort demonstrate that successful translation from pre-clinical to clinical development and proof-of-mechanism for BAY 2599023 was achieved,” they concluded.