Hemophilia Emerging Therapies - January 2024

by Dr. David Clark

There is a huge amount of new product development going on in hemophilia B.  The potential new products can be separated into three categories, 1) improved factor products, 2) rebalancing agents and 3) gene therapy.  These updates are divided into those three categories.  Within each category, the entries are generally listed in order of the names of the organizations developing the product.

IMPROVED FACTOR PRODUCTS

These are improved versions of the factor products that most people with hemophilia B are currently using, also including products for inhibitor treatment.  The improvements include longer half-lives and delivery by subcutaneous injection.  This section also includes updates on some of the current products on the market.

Expert Opinion on HEMA Biologics’ Sevenfact for Inhibitor Treatment

8/21/23  A group of U.S. researchers recently published an expert opinion on the use of HEMA Biologics’ Sevenfact product for treatment of hemophilia A and B patients with inhibitors.  Sevenfact, licensed in 2020, is a recombinant activated factor VII (FVIIa) product that joins two other bypassing agents, NovoSeven and FEIBA, currently available for inhibitor treatment.  Bypassing agents induce clotting in inhibitor patients by bypassing the factor VIII/factor IX step in the clotting cascade.  FEIBA is a plasma-derived mixture of activated clotting factors (including FVIIa), while Sevenfact and NovoSeven are recombinant versions of FVIIa.

Sevenfact is produced in the milk of transgenic rabbits which gives it a different glycosylation pattern than NovoSeven, which is produced in cell culture from baby hamster kidney (BHK) cells.  Glycosylation refers to chains of carbohydrate (sugar) molecules that are attached to many mammalian proteins.  Sevenfact and NovoSeven have identical protein backbone structures but with different carbohydrate chains attached.  That small difference seems to make a difference in how the products perform.  For instance, Sevenfact appears to exhibit enhanced binding to activated platelets, which may help improve clotting.  It also appears to inhibit protein C activation, which reduces the amount of anticoagulant activity at the site of the clot.

So, does this mean that Sevenfact is better than NovoSeven?  Not at all!  Remember that every patient is different.  Some inhibitor patients will do better on NovoSeven and some will do better on Sevenfact.  Some will see no real difference.  Note that FEIBA is not used as often for hemophilia B inhibitor patients because it contains factor IX, to which many B inhibitor patients develop an allergy.

One of the important issues that this article points out is that research on inhibitor treatment for hemophilia patients is decreasing.  The majority of inhibitor patients have hemophilia A and are now being treated with Hemlibra.  There are so few inhibitor patients with hemophilia B that it is becoming difficult to recruit enough subjects for a meaningful clinical study.  Fortunately, most of the rebalancing agents (see below) being developed also work for inhibitor patients, so inhibitor patient’s standard method of treatment may be changing (and improving).  [Pipe SW et al., Expert Review of Hematology, 16(10), 715-729, 2023]

REBALANCING AGENTS

Rebalancing agents tweak the clotting system to restore the balance so the blood clots when it should and doesn’t clot when it shouldn’t.  The clotting system is a complex system of clotting factors that promote clotting and anticoagulants that inhibit clotting.  In a person without a bleeding disorder, the system is in balance, so it produces clots as needed.  In hemophilia, with the loss of some clotting factor activity, the system is unbalanced; there is too much anticoagulant activity keeping the blood from clotting.  Rebalancing agents mainly reduce or inhibit the activity of anticoagulants in the system.  Most of these agents work to help restore clotting in people with hemophilia A or B, with or without inhibitors.

Pfizer’s Marstacimab Licensure Expected in Late 2024 in U.S.

12/11/23  Pfizer is developing marstacimab, a rebalancing agent that inhibits tissue factor pathway inhibitor to restore clotting.  Marstacimab is a once-weekly subcutaneous treatment delivered via an auto-injector pen for treatment of hemophilia A and B patients, with or without inhibitors.  They have completed their clinical studies (described in the previous issue) and submitted their license applications to the FDA in the U.S. and to the EMA in Europe.  The FDA has set an action date for their response in the last quarter of 2024.  The EMA response is expected in the first quarter of 2025.  [Docwirenews article 1/11/24]

GENE AND CELL THERAPY

Gene therapy is the process of inserting new, functional factor IX genes into the body to allow it to produce its own factor IX.  Cell therapy is the transplantation of whole cells that have been modified to perform a specific function such as producing factor IX.

FDA Developing Pilot Program for Collaborative Review of Gene Therapy Products

1/12/24  The U.S. FDA is working on a pilot project to explore the possibility of concurrent collaborative review for gene therapy products with other global regulators.  The goal will be for various worldwide regulatory bodies to share in the review of new gene therapy products, instead of each country reviewing the applications separately.  One field that should be positively affected by the project is rare diseases.  Where there are only a few patients with a rare disease in a country, it may be difficult for a company to pursue licensure.  Pooling the data and regulatory reviews is expected to make it easier for countries to approve products for rare diseases.  [RAPS article 1/12/24]

Pfizer’s Beqvez Gene Therapy Approved in Canada

1/3/24  Pfizer is developing Beqvez (fidanacogene elaparvovec), a gene therapy for hemophilia B that is delivered by an adeno-associated virus (AAV) vector and uses the Padua high-activity factor IX gene.  They announced that Canada has approved the product.  Licensure is also pending in the U.S. and Europe.  The FDA has set a decision date in the second quarter of 2024.  [Biospace artic