Tuesday morning’s State of the Art session on “longer-acting clotting factor concentrates” highlighted recent advances in therapeutics for hemophilia, with a focus on existing and evolving approaches to treatment. Jerry S. Powell, medical director, coagulation, for CSL Behring, discussed, among other topics,  a factor VIII (FVIII) fusion protein. Andreas Tiede of Hannover Medical School, Germany, discussed half-life extended FVIII for hemophilia A, and Etienne Sokal of Université Catholique de Louvain, Brussels, Belgium, presented cutting-edge research on hepatic stem cells and related microparticles for the treatment of hemophilia.

From left, Jerry S. Powell, Andreas Tiede, and Etienne Sokal

From left, Jerry S. Powell, Andreas Tiede, and Etienne Sokal

Recently approved recombinant (r) FVIII-Fc and rFIX-Fc, with improved pharmacokinetic properties – including extended half-life – represent major therapeutic advances for patients with hemophilia, and punctuate more than three decades of remarkable progress, Powell said.

More than 700 patients have participated in clinical trials that have demonstrated the safety of these treatments, with a range of improvement over prior therapies. Many study participants required fewer infusions to prevent spontaneous bleeding or to treat bleeding episodes. Other studies of extended half-life FIX products have completed phase 3 clinical trials – also with promising results, and efforts continue with respect to improving upon existing therapies and to develop new therapies.

While additional studies are needed to tease out subtle differences between the newer products and to enable predictions about which patients will benefit most or least, it is clear that the treatments are safe and that patients appreciate their added benefits.

Tiede focused on the newer extended half-life products, including those currently in development. He discussed Fc fusion (Eloctate, Elocta, and efmoroctocog alfa), the addition of polyethylene glycol (turoctocog alfa pegol – N8-GP, BAY 94-9027, and BAX 855), and a single-chain construct (CSL627). He reviewed the characteristics and potential benefits of each, as well as findings from early clinical trials, which suggest a 1.5-fold prolonged half-life that may allow for modest reductions in injection frequency for prophylaxis in many patients.

Extended half-life FVIII products could improve trough levels during prophylaxis. This may be of particular benefit for those who fail to achieve at least 1% trough levels with conventional regimens, and for those who need higher trough levels because of frequent bleeding, the presence of target joints, or higher physical activity, according to Tiede.

Sustained production of endogenous FVIII or FIX by a patient’s own cells could represent curative treatment for hemophilia, according to Sokal.

Stem cells expanded in vitro can provide de novo protein synthesis; successful implantation of the cells could induce a steady-state production of low quantities of factors that may allow a patient to maintain levels required to prevent spontaneous bleeding, he explained.

Liver-derived mesenchymal stem cells are being assessed in clinical trials for inborn errors of metabolism. Sokal described his promising results in children with inherited metabolic disorders. These cells now are being considered for hemophilia, given their capacity to produce FVIII and FIX in cell culture. With in vivo transplantation of these cells, the mechanism of action involves not only direct engraftment of the FVIII- and FIX-producing stem cells, but possibly the transfer of genetic material incorporated into extracellular vesicles and exosomes, he said.

Powell disclosed that, during the writing of his state of the art manuscript, he retired as professor of hematology and oncology at the University of California Davis and accepted a position as medical director, coagulation, for CSL Behring, which manufactures products for hemophilia, including two products mentioned in the manuscript. Tiede disclosed that he received research support, lecture fees and honoraria for consultancy from Baxter, Bayer, Biogen Idec, CSL Behring, Novo Nordisk and Swedish Orphan Biovitrium. Sokal founded the spin-off biotech issued from his laboratory at the Université Catholique de Louvain (Promethera Biosciences), is a consultant for the company and receives honoraria. He also is entitled to founding shares from the university.

By Sharon Worcester |June 23, 2015