Hemophilia Medical Research Update
The American Society of Hematology (ASH) held its annual meeting in December in San Diego. Two research presentations caught our attention.
Earlier this year, the Survey of Inhibitors in Plasma-Products Exposed Toddlers (SIPPET) study reported that previously-untreated hemophilia patients had a significantly higher incidence of inhibitors when treated with recombinant factor VIII than those treated with plasma-derived factor VIII containing von Willebrand factor. This has generated much debate and interest. One presentation at ASH explored differences in two types of recombinant factor products. Recombinant factor VIII products are produced by human genes placed in either Chinese hamster ovary (CHO) cells or baby hamster kidney (BHK) cells. A presentation by Jesse Lai of Queen's University, Canada, looked at whether factor produced by CHO or BHK cells are more likely to provoke an immune response and create inhibitors. Hemophilia mice were injected with recombinant factor VIII products under their skin (subcutaneously) and into a vein (intravenously) and their immune response measured. When injected under the skin, the researchers found that 100% of the mice that received BHK-produced factor VIII developed inhibitors vs 37% of those that received CHO-produced factor. This difference was not seen in the mice injected intravenously though the mice receiving BHK-produced factor did produce higher amounts of immunoglobulin specific to factor VIII. The researchers concluded that BHK-produced recombinant FVIII has properties that affect the immune system differently in hemophilia A mice compared to CHO-produced rFVIII. They are conducting continued research to understand these differences.
Dr. Margaret Ragni of the University of Pittsburgh reported the latest findings from the clinical trials of fitusiran being conducted in several countries. Fitusiran is a treatment for hemophilia that does not involve putting factor VIII or IX into the body. It is a drug that is injected under the skin that targets the body’s natural anticoagulant, antithrombin. It improves the way the body makes thrombin for blood clotting and decreases bleeding in patients with hemophilia. As of July 2016, a total of 25 hemophilia patients (without inhibitors) have been enrolled in the study. Of these, 16 of these patients have completed three months of monthly injections and have gone on to the Phase 1/2 extension study where they receive a fixed monthly fitusiran dose of 50mg or 80mg. There have been no serious adverse events related to fitusiran and no unwanted blood clots. Of the patients receiving the higher dose of 80 mg, 70% (7 out of 10) of patients were bleed-free and 90% (9 out of 10) of patients experienced zero spontaneous bleeds. Because this drug can potentially be given under the skin (no more searching for a vein), once a month, to people with hemophilia A or B with and without inhibitors, there is much excitement and interest in its development.
Thank you to the National Hemophilia Foundation for this gene therapy update. At a conference in January, BioMarin Pharmaceutical, Inc., reported on their ongoing phase 1/2 clinical study of BMN 270, gene therapy for hemophilia A. Like the St. Jude gene therapy clinical trials, BMN 270 uses adeno-associated viruses (AAVs) as delivery vehicles, or vectors, to carry the factor VIII protein gene into the body. The purpose of the trial, the recruitment for which is still ongoing, is to evaluate the safety and efficacy of BMN 270 in up to 15 individuals with severe hemophilia A. To date, a total of nine patients have received a single dose of the therapy and seven of those have been treated at the highest dose. As of the December 9, 2016, data cutoff, patients had been followed-up from 34 to 50 weeks. Data based on each patient’s most recent reading showed that six of seven patients in the high- dose group continue to have FVIII levels above 50%, while the seventh continues to be more than 15%. These percentages effectively shift these patients’ FVIII severity levels from severe (less than 1%), to mild (5%-40%) or normal (50%-150%). Even a modest boost in FVIII levels for an individual with hemophilia A can lead to a significant reduction in bleeding complications and have a dramatic impact on quality of life.
For the six patients at the high dose and previously on a FVIII prophylactic treatment regimen, the mean annualized bleeding rate (ABR) dropped 91% from 16.3 before receiving BMN 270 to 1.5 beginning two weeks after receiving the therapy. For those same six patients, the mean annualized FVIII infusions fell 98% from 136.7 to 2.9.
In addition, six of the seven patients in the high-dose group had normal aminotransferase (ALT) range, and one patient had a mild elevation. ALT can be used to screen for adverse effects on liver function. Some of the early trial patients did experience elevated ATL levels, therefore investigators initially decided to administer prophylactic corticosteroids (steroid hormones) to all the patients. Patients successfully tapered off steroids with no lasting significant impact on FVIII expression or ALT levels. The requirement for prophylactic corticosteroids has been since removed for all newly enrolled patients in the study.
“These data continue to show promising evidence that restoration of clotting function can be achieved by gene therapy,” said John Pasi, PhD, FRCP, Professor of Haemostasis and Thrombosis at Barts and the London School of Medicine and Dentistry. He is the primary investigator for the BMN 270 Phase 1/2 clinical trial. “The increase in Factor VIII levels we have seen has the potential to stop patients' bleeding and has changed how we think about treating hemophilia. For the first time we can truly start considering the opportunity for our patients to live a more normal life.”