Biotech is driving hemophilia towards what the experts have termed the ‘precipice of a therapeutic revolution.’ From gene therapy to antibodies, here is the most exciting hemophilia treatment technology that promises to change the lives of patients suffering from the disease within the upcoming years.

Hemophilia is a genetic disorder that impairs blood clotting. When one of the genes encoding for clotting factors is absent or deficient, a simple injury can turn into a serious health risk. Since these genes are located on the X chromosome, the disease is much more common in males than females.

In numbers, the disease afflicts more than 187,000 people worldwide. The most frequent form, hemophilia A, affects the clotting factor VIII in over 150,000 patients. The second, hemophilia B affects over 30,000 people with factor IX deficiency.

hemophilia clotting factors

3D structure of clotting factor VIII (left) and IX (right)

There is currently no cure for hemophilia, once known as the mysterious ‘Royal Disease‘ that monarchs across Europe inherited from Queen Victoria. People living with this disease may require up to 3 infusions per week of clotting factors as a prophylactic therapy, as well as emergency treatment in case of an injury. Still, patients experience repeated bleeding episodes, and in 30% of severe hemophilia A cases, they develop inhibitory antibodies against the recombinant clotting factors that make them unresponsive to the standard hemophilia treatment.

The biotech industry is changing these circumstances by targeting the hemophilia market, expected to hit €14B by 2024. A number of technologies including therapeutic antibodies, RNAi and cell therapy are fighting to become the go-to treatment; gene therapy might be the first.

Why Gene Therapy?

Gene therapy offers the promise of correcting genetic diseases with a one-off treatment by delivering a functional DNA copy, commonly using viral vectors. Of all the diseases out there, many biotechs have decided to focus their gene therapies in hemophilia. To understand why we talked with Matt Kapusta, CEO of uniQure, a Dutch biotech leading its development.

It proved to be a strong and relatively easy proof-of-concept indication,” says Kapusta. The key aspects are that the disease is monogenic, drug delivery to the liver is simple, and results are easily measured through well-characterized biomarkers that make measuring results easy.

hemophilia treatment biotech innovation

For patients and healthcare providers, this technology could significantly reduce expenses. “The cost of the replacement therapy alone, excluding logistics, distribution and nursing care, is between 300k and 400k dollars per year,” says Kapusta. “A product like ours that has demonstrated 6.5 years of durability could save up to $3M.”

The Biotech Battlefield

Several biotechs are racing to launch the first gene therapy for hemophilia. Shire, which until recently was leading the race in hemophilia B, dropped its program last year because of inconsistent results and is now turning to hemophilia A using the same technology. This move has placed Spark Therapeutics and uniQure on the lead.

We have a very good shot at being the first to market in hemophilia B,” says Kapusta. UniQure is getting ready to start regulatory processes and aims at running a pivotal trial by 2018.

Traditionally, pharma has gone after the bigger hemophilia A market, leaving hemophilia B for biotechs. In the case of gene therapy, this trend is also based on the molecular biology behind the disease. The gene coding for the factor IX protein is simply smaller than that for factor VIII, and therefore easier to fit in the viral vectors used for gene delivery.

This has not discouraged biotechs from tackling hemophilia A though, with BioMarin on top as the first company that reached clinical trials. To overcome the size limit, it has deleted a region from the factor VIII protein that is not necessary for clotting.

Gene therapy is not a perfect solution, though. In some cases, patients can develop immunity against a particular viral vector or foreign DNA sequences. Bioverativ, a spin-off from Biogen, is trying to circumvent this problem by using lentiviruses, which are less immunogenic and protect the DNA cargo by inserting it the host genome.

For its part, Sangamo Biosciences has opted for an in vivo genome editing therapy. Its viral vectors also deliver zinc finger nucleases that insert the desired gene in the host genome. However, both strategies have toxicity and mutagenesis risks associated with the insertion of foreign DNA.

Ditch the Viruses, here comes Cell Therapy

Promethera wants to get rid of the problems associated with viral vectors and make way for cell therapy instead. CEO John Tchelingerian told us, “pharma companies are starting to understand that viral vectors are not the ‘magic bullet’ to make gene therapies work in the long run.

Promethera’s Hepastem technology grows cells from the liver of healthy donors that are then injected into patients with liver disease. Now, the Belgian company is interested in combining Hepastem with genetic constructs to create a safer delivery system.

hemophilia treatment cell therapy

We plan to attract strategic partnerships around our program in hemophilia B, and potentially hemophilia A,” commented Tchelingerian. Although still in early research stage, this hemophilia treatment could make a big difference for patients in which gene therapy does not prove effective.

What else is out there?

Since gene therapy is not for everyone and cell carriers are still far from the market, what other options are there to improve hemophilia treatment?

Sanofi and Alnylam have decided to bid for RNAi therapy. Their candidate fitusiran, which could start Phase III trials soon, blocks the anticoagulant protein antithrombin. However, some are skeptical about the technology after failures from companies like Roche, Merck, Abbott and Alnylam itself.

Other biotechs like Sobi, Bioverativ or Glycotope are aiming for coagulant factors with an extended half-life, which could reduce dosing and protect patients from spontaneous bleeding. Meanwhile, Apitope is developing a drug that can treat and prevent resistance to coagulant factor infusions in up to 96% of cases.

hemophilia treatment biotech innovation

But Roche seems to have one of the most promising candidates. ACE910 (emicizumab) is an antibody that mimics the factor VIII protein with a half-life of 4 to 5 weeks that is effective in patients with resistance.

Emicizumab is easier, simpler and faster,” Guy Young from the Children’s Hospital Los Angeles told Nature. “I think it has the potential to be transformational for patients – really, truly, life-altering.”

With these characteristics, the big pharma could bench Novo Nordisk’s NovoEight, a recombinant factor VIII launched in 2014. Although results from clinical trials raised safety concerns, development will continue and according to Bloomberg, the drug could bring Roche over €600M in sales in 2021.

What’s next?

Unfortunately, a cure for hemophilia doesn’t still seem feasible yet. “Our gene therapy was never intended to be a cure, which would entail restoring close to 100% of Factor IX activity, and it’s highly unlikely that we or others would get to that level,” admitted uniQure’s CEO, Matt Kapusta. “So we’re trying to transition patients with severe hemophilia to a mild disease.” For patients, this will mean getting rid of frequent infusions and significantly improving their quality of life.

The sheer numbers of innovative hemophilia treatment hint at a brighter future for patients in the next few years. In the words of Jan Hartmann and Stacy Croteau from Harvard Medical School, “hemophilia is now at the precipice of a therapeutic revolution.

According to their paper in the American Journal of Hematology, these innovations “address gaps in our current approach to hemophilia management but do not provide a one-size fits all opportunity.” Therefore, the next step will be individualized treatments where each patient is matched with the most suitable therapy.


Update 26/01/2017: included uniQure in the hemophilia A table

Images from Jarun Ontakrai, Molekuul_be, Kanowa, interphasesolution, Crevis /Shutterstock

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  • Prof. Dollar

    @Clare: In the tabel with product candidates for Hemophilia A you did not include uniQure’s Hemophilia A program (currently pre-clinical). Have you done this deliberately? And in consultation with uniQure?

    • Hi there, it was definitely not intentional, the article has been updated to include uniQure’s candidate program. Thanks for the heads up!

  • Colombowala Zulkef

    It is quite informative artical. It give the understanding that there will be more then one theory to treat hemophilia A. And it will be applied as per patient body acceptance.

  • bloodclot

    At the end, consistent and predictable outcomes are the keys to the success. I’d not treat a patient with an unknown outcomes and the possibility of immune responses.