The title of a recent New York Times story—They thought hemophilia was a ‘lifelong thing’; they may be wrong—captures the majority sentiment of reporting over the past year on the promising results of early gene therapy trials.
These stories have led to many questions and so to provide some context and perspective on the now and the next in treatment, NHF turned to Stacy E. Croteau, MD, MMS, a past NHF-Baxter Fellow. Dr. Croteau is a pediatric hematologist and clinical researcher at Boston Children’s Hospital and the Boston Hemophilia Center, where she specializes in bleeding and clotting disorders. She serves as the director of the Hemophilia/VWD program at Boston Children’s and assistant professor of pediatrics at Harvard Medical School, and is a primary investigator for several industry-sponsored and investigator-initiated clinical trials.
Dr. Croteau, what one word captures this moment in bleeding disorders treatment research and development?
Transformative. While we can’t yet make a blanket statement that each of these new and prospective therapies will be effective for all hemophilia patients, we do see mounting evidence that gene therapy and emicizumab (Hemlibra) are transforming the disease phenotype for subsets of hemophilia patients—meaning a reduction in how often they bleed, how often they need treatment, and also in their experience of the day-to-day burden of hemophilia. This is true for individuals participating in gene therapy trials who’ve achieved and maintained normal (or higher than normal) factor levels as well as those with levels even in the mild deficiency range—15-20 percent of normal blood levels of factor VIII or IX. Patients have been able to completely abandon their routine prophylactic infusions, which is life-altering for any patient and especially for those who’ve been burdened by more frequent infusions and/or bleed events due to more rapid clearance of infused factor compared to others. Now they can head off to work or school without needing to budget extra time to infuse or worrying about the potential bleed risk of typical daily activities.
For hemophilia A patients with inhibitors, the availability of emicizumab has really transformed our ability to achieve good bleed prophylaxis. As a clinician who takes care of a broad spectrum of bleeding disorders patients, it’s been amazing to hear stories of how some patients have effectively kicked their wheelchairs to the curb because now they can walk more than a few feet without having a hip or knee bleed, or even intense pain. Of course, that hasn’t been the outcome for every patient, but for a majority of them, it has. One can’t really overstate the positive impact the availability of this new therapy has had on the lives of those patients who for years, decades in some cases, struggled with factor VIII inhibitors.
What recent developments in research and treatment excite you most?
Big picture, what really excites me is the diverse approach of these investigational therapies. I mentioned gene therapy and emicizumab for inhibitor patients (now also available for hemophilia A patients without inhibitors), but there are other novel therapies that interfere with the coagulation cascade in other ways to promote clotting. These alternate therapies may be helpful for the groups of hemophilia patients we’ve already mentioned, but importantly can help others also such as hemophilia B patients with inhibitors, who are now rising to the top as one of the subgroups with the greatest unmet need. In aggregate, hopefully many of these novel therapies will ultimately provide improved long-term health outcomes for all or most bleeding disorders patients. By more effectively being able to individualize care, we hope to further improve bleed prevention, reduce the burden of disease and improvement musculo-skeletal and other clinical outcomes over the patient’s lifespan.
Can you comment on the prospect of gene therapy as a once-in-a-lifetime treatment?
At this stage it’s hard to know whether adeno-associated virus (AAV) gene therapy for hemophilia will be a once-in-a lifetime treatment. To some degree this will be influenced by when in the lifetime one receives the treatment. So far, the reported pre-clinical and early phase human studies have not clearly demonstrated waning factor levels over time, but we need a longer observation period to really know how effectively the genes that make it into those liver cells—the hepatocytes—will be maintained over time and able to continue the desired FVIII or FIX protein production. So while it isn’t a guarantee that the current gene therapies being studied will yield substantial improvements in factor level and a lifelong cure, the clinical trials and biology studies underway are encouraging and helping us learn a lot about this type of therapy and ways it can be further optimized or tailored to patients in the future.
When people use the term “cure,” in some ways perhaps it’s truly in the eye of the beholder. In a strict definition-type way, one could look at the term “cure” to mean achieving factor VIII or IX levels within the normal range that are sustained over a lifetime after treatment. This is the ideal. At the same time, even if patients go from undetectable factor levels to sustaining factor VIII or IX levels of 15, 20 or 25 percent, it would dramatically change their lives and their medical management, moving them closer to the goal of normalcy. And in the end, that’s our ambition as researchers and healthcare professionals—to ensure that people with bleeding disorders can live happy, healthy and productive lives.
