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Why is gene therapy for hemophilia taking so long?



– The goal of gene therapy for hemophilia and other genetic diseases is to achieve long-term expression and levels adequate to improve the phenotype of disease, according to Katherine A. High, MD.

“Sometimes people ask me, ‘Why is it taking so long to develop these therapeutics?’ ” Dr. High said at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “The answer is that gene therapy vectors are arguably one of the most complex therapeutics yet developed.”

Dr. Katherine High Courtesy of Dr. Katherine High

Dr. Katherine High

Currently, gene therapy vectors consist of both a protein and a DNA/RNA component that must be precisely assembled. “Most vectors are engineered from viruses and it has taken time to understand and manage the human immune response, which was poorly predicted by animal models,” said Dr. High, a hematologist who is cofounder, president, and head of research and development at Philadelphia-based Spark Therapeutics. “It took 22 years from the first clinical trial of gene therapy vectors to the first licensed product.”

Spark Therapeutics is currently developing gene therapies for hemophilia A (SPK-8011) and hemophilia B (SPK-9001).

Hemostasis and thrombosis targets in gene therapy trials include hemophilia, as well as peripheral artery disease/claudication and congestive heart failure. In the latter, a prior phase 2b trial of adeno-associated virus (AAV) expressing SERCA2a did not support efficacy (Lancet 2016;387:1178-86), while a current trial of adenovirus 5–vector expressing adenylyl cyclase–type 6 is entering phase 3 study (NCT03360448).

To get a sense of how long it may take for a new class of therapeutics to become established, Dr. High noted that the first monoclonal antibody to be licensed was OKT3 (muromonab-CD3) in 1986, followed by abciximab in 1994, rituximab and daclizumab in 1997, and four additional products in 1998. By 2007, 8 of the top 20 biotech drugs were monoclonal antibodies.

Hemophilia has long been a favored gene therapy target because biology is in its favor. “It has a wide therapeutic window, it does not require tissue-specific expression of transgene, small and large animal models exist, and endpoints are well validated and easy to measure,” she said. “Thus, early gene-therapy clinical investigation since 1998 explored many strategies.”

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