Our knowledge of hemophilia is slowly moving forward, and new therapies are set to soon replace or complement existing ones. Indeed, if we would take a look back at medical history, we should be proud that any treatment for hemophilia exists at all; it used to be an incurable disease in which prevention of bruising and injury was the only method to limit its clinical symptoms. It also played a major part in ending the Romanov dynasty in Russia when the only son in the family developed hemophilia — but that’s a story for another day.
In this article, we will be discussing some of the new breakthroughs in hemophilia treatment as detailed in a study recently published in Biologics. In epic fashion, the authors begin by tracing the progress of hemophilia treatment as being remarkable in the “first 20 years of the third millennium,” with progress truly picking up speed with our ability to fractionalize plasma in 1946. It was this breakthrough that allowed scientists to develop replacement therapy, which is the mainstay of hemophilia treatment today.
Indeed, given the long history of hemophilia eluding physicians, it is remarkable how replacement therapy finally offered concrete hope of a relatively normal life. It is also worth mentioning here how advancements in genetics allowed us to finally understand how it is inherited — through the X chromosome, thus explaining why males suffer the most severe forms of the disease.
Replacement therapy itself is made possible by our understanding that hemophilia A (HA) and hemophilia B (HB) are caused by a partial or total lack of coagulation factors (VIII for HA and FIX for HB). If hemophilia is caused by a lack of coagulation factors, the strategy is just to replace them and the problem is solved, right? Well, it wasn’t quite so straightforward. There were hiccups along the way, most significantly in the transfer of viruses from the blood donor to the recipient, but by the end of the 20th century, significant improvements in the manufacturing and safety of replacement therapy were made, based on 3 factors:
- Better screening of infection for blood donors
- New concentrates developed through DNA-recombinant technologies
- The implementation of virucidal methods in the manufacturing process.
The goal of replacement therapy was to prevent excessive bleeding after an injury, which can be extremely painful and potentially fatal. Initially, replacement therapy was administered on an on-demand basis, meaning it was given after an occurrence of bleeding. However, scientists soon discovered that significant damage to joints or muscles occurs even just a few hours after bleeding, causing patients to experience arthropathy and muscle atrophy severe enough to limit movement. This caused the treatment paradigm to shift from on-demand therapy toward prophylaxis.
Multiple studies have shown that prophylaxis works. For example, studies found that continuous, early prophylaxis prevented joint damage in children and decreased the annualized bleeding rate. The decrease in the frequency of bleeding then has the knock-on effect of avoiding further deterioration of muscles or joints caused by a previous episode of bleeding.
The main difficulty with prophylaxis treatment is the frequency of IV infusions needed. For FVIII, it is every 2 to 3 days and for FIX concentrates, it is every 5 to 7 days. To reduce the burden of treatment on patients, the pharmaceutical industry is turning its attention toward prolonging plasma half-life and extending the intervals needed between injections.
Other Therapeutic Approaches
Since hemophilia is a disease of the coagulation pathways, our increased understanding of them has made non-replacement therapies possible. “The coagulation system is a complex mechanism in which procoagulant and anticoagulant proteins determine the correct coagulation balance,” the authors of the study wrote. Therefore, hemophilia treatment can be viewed as a delicate balancing act between increasing coagulation and inhibiting anticoagulation pathways. This is exactly what non-replacement therapies seek to do.
Emicizumab is a humanized antibody specific for both FIXa and FX that works by increasing coagulation. Because its function depends on phospholipids, it targets sites of bleeding. Fitusiran, an antithrombin RNA interference molecule, and concizumab, a humanized IgG4 antibody monoclonal selective for the second Kunitz domain of tissue factor pathway inhibitor (TFPI), both work by dampening the anti-coagulation pathway. Studies have shown that both fitusiran and concizumab are effective in reducing thrombotic events.
Gene Therapy: A Better Alternative?
The common problem of all the treatment methods mentioned above is that they require repeated administration, thus limiting the patient’s ability to live life with much spontaneity. Of course, they should be highly regarded in that they allow patients to live at all; before replacement therapy was available, for example, male patients often died young.
However, what if there was an even better alternative — a chance for patients to live relatively free and normal lives, without the need for repeated infusions? “The ultimate goal for hemophilia treatments should be a “functional cure” and “health equity,” the authors of the study wrote. And gene therapy offers that hope due to its single-administration paradigm.
Researchers have been working furiously to make gene therapy a viable treatment alternative. Current studies focus on exploring various means for transgene delivery, including nonviral techniques as well as viral-mediated delivery. The latest research focuses on the r-adeno-associated virus (rAAV) as a preferred delivery method. The challenge of getting gene therapy right is to ensure that it is safe, predictable, and durable, and ultimately impacts patients’ lives in a meaningful way.
Reasons For Optimism
It was not too long ago that hemophilia was considered a fatal disease, a ticking time bomb, just like diabetes. Advancements in medicine mean that both diseases are no longer considered fatal, but the burden of treatment remains. As genetics slowly take center stage in the world of medical research, we have every reason to be optimistic that diseases such as hemophilia will one day be considered a mere inconvenience, such as being born short. When that day comes, the reproach of hemophilia on humanity will be wiped clean.
Marchesini E, Morfini M, Valentino L. Recent advances in the treatment of hemophilia: a review. Biologics. Published online June 15, 2021. doi:10.2147/BTT.S252580
Schramm W. The history of haemophilia – a short review. Thromb Res. 2014;134 Suppl 1:S4-9. doi:10.1016/j.thromres.2013.10.020.