Potential Gene Therapy GENV-HEM Earns Orphan Drug Status

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by Marta Figueiredo PhD |

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The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to GENV-HEM, GeneVentiv Therapeutics’ investigational gene therapy for hemophilia A and B patients, with or without clotting factor inhibitors.

Orphan drug designation is given to treatment candidates that have the potential to be safe and effective treating rare diseases, defined as those affecting fewer than 200,000 people in the U.S. The decision is meant to expedite GENV-HEM’s clinical development by providing regulatory support and financial benefits, as well as a seven-year marketing exclusivity period upon regulatory approval.

“With no approved gene therapies for hemophilia patients with inhibitors, we are dedicated to driving GENV-HEM forward as the first gene therapy for both hemophilia A or B with or without inhibitors,” Damon Race, GeneVentiv’s CEO, said in a press release.

Benjamin Samelson-Jones, MD, PhD, of the Children’s Hospital of Philadelphia’s division of hematology and a member of GeneVentiv’s scientific advisory board, said GENV-HEM “combines a novel bypassing strategy with the accumulating clinical experience of AAV [adeno-associated virus] gene transfer.”

“It is designed to improve [bleeding cessation] by circumventing missing upstream clotting factors, such as factor VIII or IX, as well as inhibitory antibodies,” Samelson-Jones added.

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Current gold-standard treatment for hemophilia A and B consists of replacement therapy, which involves supplying patients with the blood clotting protein they are missing — either factor VIII (FVIII) in the case of hemophilia A or factor IX (FIX) in the case of hemophilia B.

However, about 20–30% of severe hemophilia A patients and up to 10% of those with severe hemophilia B develop inhibitors, which are neutralizing antibodies, against the delivered clotting factor, limiting its effectiveness and, in worst cases, rendering it useless.

Administered directly into the bloodstream via a single infusion, GENV-HEM is the first gene therapy developed for both hemophilia A and B, regardless of the presence of clotting factor inhibitors.

It uses a modified and harmless version of the AAV variant 8 to deliver a patent-pending, bioengineered gene providing instructions for making an activated form of factor V (FVa) to liver cells, the main producers of clotting factors in the body. FVa is part of a common pathway in the blood-clotting cascade, functioning downstream of FVIII and FIX to prevent or stop bleeds.

As such, by increasing the levels of FVa, GENV-HEM has the potential to restore normal blood clotting without the need for FVIII or FIX in patients with hemophilia A or B with or without clotting factor inhibitors.

In preclinical studies, a single dose of GENV-HEM prevented bleeds in animal models of hemophilia, regardless of the presence of clotting factor inhibitors.

“This unique approach focused on the “bypass” strategy using FVa variant by AAV liver gene therapy has the potential to simplify the treatment of severe hemophilia,” said Valder Arruda, MD, PhD, also of the Children’s Hospital of Philadelphia’s division of hematology and chairman of GeneVentiv’s scientific advisory board.

The therapy also may “provide an innovative intervention for hemophilia A with refractory inhibitors to FVIII or those [with] hemophilia B with inhibitors to FIX with contraindication of FIX protein/transgene exposure FIX, which are certainly challenging clinical scenarios,” Arruda added.