Hemophilia: A Physician’s Perspective

STEVEN PIPE, MD, medical director of the Pediatric Hemophilia and Coagulation Disorders Program at the University of Michigan, has been researching the structure and function of the factor VIII (FVIII) protein and its secretion pathway to improve the manufacture of its recombinant form. He is a member of the National Hemophilia Foundation’s Medical and Scientific Advisory Council.

BSTQ: What are the most significant health challenges for individuals living with severe hemophilia?

Dr. Pipe: The primary complication is recurrent bleeding, primarily into joints (hemarthrosis). Though acute bleeding can be arrested by replacing missing clotting factor through intravenous infusions, repeated bleeding leads to progressive joint injury and, ultimately, a crippling and painful chronic arthropathy. Bleeding can be effectively prevented through prophylactic infusions of the clotting factors; preventing bleeding preserves joint health over subsequent decades.

An important complication of clotting factor replacement therapy is up to 30 percent of patients with severe hemophilia A (FVIII deficiency) will develop an immune response and make an antibody that inhibits the function of the clotting FVIII. This makes it impossible to treat or prevent their bleeding with FVIII replacement.

Their acute bleeding has to be managed with alternative clotting factors (bypassing agents) that are less effective for acute bleed management and prophylaxis. Thus, developing inhibitors increases a patient’s risk for serious acute bleeding, including death, and leads to increased hospitalizations and a higher incidence of joint disease.

Finally, our older patients (older than 35 years) still suffer from the legacy of blood contamination from HIV and hepatitis C in the early 1980s. This affected up to 90 percent of the severe hemophilia population, and it remains a significant comorbidity affecting the health of the older population of patients.

BSTQ: How have treatment options evolved?

Dr. Pipe: In part, due to infections associated with clotting factors obtained through plasma fractionation, recombinant technologies led to the development of recombinant clotting factors. These synthetic facsimiles of FVIII and factor IX (FIX) have proved to be safe and efficacious, and in the developed world have become the standard of care for replacement therapy. Moreover, the recombinant platform has allowed for targeted bioengineering of the molecules to alter the properties of the FVIII or FIX. The most successful innovations have resulted in longer half-lives of clotting factors. These extended half-life factors have led to improved joint outcomes, increased physical activity levels and reduced infusion frequency.

BSTQ: Tell us about your work with gene therapy and why it holds significant promise.

Dr. Pipe: Because hemophilia is a monogenic disease — that is, it is due to a mutation in a single gene resulting in loss of a single protein, either FVIII or FIX — it is amenable for genetic therapies that effectively replace a working copy of the gene. This has made hemophilia an attractive candidate for gene therapy. Many avenues have been explored over the past 30 years. However, the most promising platform is packaging of the gene coding for either FVIII or FIX protein into a recombinant viral vector. The virus serves as the vehicle to deliver the gene into the target cell, typically the liver, where the gene remains and accesses the normal machinery to produce the proteins and restore plasma levels of either FVIII or FIX to levels sufficient to prevent bleeding.

The proof-of-principle clinical trial was reported in 2011 using an adeno-associated virus vector to deliver the gene for FIX in severe hemophilia B. Men achieved durable expression of FIX such that they no longer required clotting factor prophylaxis and have maintained low bleeding rates. Since then, additional Phase I/IIb clinical trials have shown the ability to produce levels of FVIII or FIX that are in the “curative” range. These programs are now moving to Phase III trials.

BSTQ: What’s next in terms of bleeding disorder research?

Dr. Pipe: Besides the novel substitution therapy, emicizumab, several additional research programs aim to treat hemophilia through alternative methodologies. Each of these pipeline programs is targeting the inhibitory pathways for coagulation. By targeting these pathways, blood clotting can be restored without needing to administer FVIII or FIX. These would have broad application for hemophilia A or B with and without inhibitors. It will be interesting to see in the years ahead how these will compare in safety and efficacy with gene therapy programs.