New Hemophilia Treatments: Subcutaneous Injection

Early results offer potential to transform bleeding disorders treatment
Author: Sarah M. Aldridge, MS

Update: On September 7, 2017, Alnylam announced it was halting dosing in all ongoing fitusiran studies following the death of a patient participating in the study.

 

Jabbing your vein or that of a terrified toddler is not the ideal way to deliver factor product. Besides the needle phobia and the pain, there are other potential issues. One is the inconvenience and the cost. And then there’s the reality that only half of adults keep to their prophylactic regimen.

If you’ve ever wondered if there’s a better way to deliver factor, you’re not alone. Researchers are finding that one way may be as close as your skin, and investigators are optimistic about the clinical trials to date involving humans.

What is subcutaneous injection?

Subcutaneous injections go through the layer of the skin called the cutis, which comprises the epidermis and dermis. With few sensory receptors below the cutis, injections are nearly painless. Common sites include the upper arm and top of the thigh. Some vaccines and drugs, such as insulin, are already delivered in this manner.

So far, Alnylam Pharmaceuticals, Inc., based in Cambridge, Massachusetts, and Chugai Pharmaceutical Co., Ltd., of Tokyo, have had promising results from phase 1 and 2 studies of subcutaneous products to treat hemophilia. Both companies presented their findings at the World Federation of Hemophilia’s World Congress in July 2016 in Orlando, Florida. And both use different strategies to achieve the goal of hemostasis, stopping bleeding after an injury and preventing bleeds.

How they work

Alnylam’s product is called fitusiran, or ALN-AT3. The AT stands for antithrombin, a protein produced by the liver to prevent clotting. Fitusiran is an RNA-interfering (RNAi) molecule. It turns off, or silences, RNA activity that normally leads to the production of AT. By pushing the mute button on AT, levels of thrombin, an enzyme that helps platelets clump, rise, initiating the steps leading to clot formation.

Chugai’s product emicizumab uses a different mechanism. It is a bispecific antibody, an artificial protein combining two antibodies in one molecule. It binds to factors IXa and factor X (hence its alternative name ACE910), fulfilling the normal role of the missing factor VIII in the clotting process.

How they fared

In these early trials, patients were divided into groups, each receiving different amounts of the drugs. Fitusiran was given monthly to people with hemophilia A or B, with or without an inhibitor. Emicizumab was given weekly to subjects with hemophilia A, with or without an inhibitor. Bleeding was well-controlled in the majority of subjects in both trials, with annualized bleeding rates falling to 0 in several of the groups. No thromboses, or blood clots, formed in the subjects and no inhibitor antibodies developed.

Both pharmaceutical companies plan to expand the clinical trials of these products in 2017. Alnylam will initiate a study in children and teens. Chugai will test its product using a monthly injection schedule.

The benefits of using such innovative therapies have broad implications, says Margaret Ragni, MD, MPH, professor of medicine and clinical translational science in the Division of Hematology/Oncology at the University of Pittsburgh Medical Center. “We’re actually going to understand the coagulation system a lot more by exploring these new pathways,” Ragni says. She is director of the Hemophilia Center of Western Pennsylvania, one of the sites for the initial clinical trial of fitusiran. “If we can understand coagulation better, we’ll be able to design even better drugs.”