A new gear for the cascade: engineering an antibody to replace factor VIII
A novel treatment for the rare disease hemophilia reached a milestone for regulatory approval last month. With the FDA’s approval of priority review for ACE910, Roche and Chugai Pharmacueticals are on the cusp of delivering an entirely new approach to a long-lasting medical challenge.
Dreamt up in a Japanese lab by Chugai researchers, ACE910 is the result of a new approach to developing treatments for hemophilia A. In the process, the Chugai team invented an entirely new antibody that inserts itself into the blood clotting process.
Hemophilia A is caused by a deficiency of a protein called factor VIII which is an essential component of the blood clotting system. There have been amazing advances starting in the 1950s that have made it easier to replace this missing protein, from plasma transfers to cryo-precipitate to human plasma extraction to recombinant engineering.
However, major challenges remain. Factor VIII can only be delivered via an intravenous needle stick. Also the body quickly breaks down factor VIII so frequent dosing is required. And for about 1/3 of those undergoing treatment, their body’s immune system will attack factor VIII, rendering the protein ineffective and necessitating complicated second line treatments.
The difficulties of hemophilia treatment have only increased the potential rewards for the company that can bring a treatment to market. The size of the hemophilia pharmaceutical market is estimated to be in the tens of billions of dollars. Per person treatment costs typically range from one to two hundred thousands of dollars per year. The costs can be far higher for people receiving specialized treatment for inhibitors.
In labs around the world, there have been recent innovations to lengthen the half-life of factor VIII, to make changes to the structure of factor VIII to reduce immune reactions, and even genetic engineering to rewire the patient’s genome to produce factor VIII. What made the research effort at Chugai unique was the potential to get an entirely new treatment approach into market in a relatively short period of time.
The researchers at Chugai started with a hypothesis. Instead of replacing factor VIII, they attempted to generate a brand new protein that could serve as its replacement. This new protein would have to mimic the critical function of factor VIII in linking together two different proteins involved in the clotting of blood.
To understand how this works, it’s worth taking a look at the blood clotting process, or coagulation pathway, that the body initiates when a blood vessel is injured. The body must carefully regulate the clotting process to make sure a clot forms quickly but also stops quickly, thereby ensuring that the blood supply doesn’t get ensnared in a big blood clot. A series of proteins detects the bleeding and communicates with other proteins to orchestrate an elaborate process which eventually seals shut the blood vessel with platelets and fibrin. Factor VIII is a small but critical piece of this orchestration that sits beside two other proteins in the process.
The Chugai team thought they could find a completely different protein that would serve the same function in the chain of events. This protein would look completely different from factor VIII but would be able to bind to the adjacent proteins, specifically factor IXa (the ‘a’ stands for active) and factor X. According to their research, the team knew that it’s possible to create an artificial antibody with the property of being bispecific, meaning that the antibody can simultaneously bind to two different types of proteins, they just had to find the right one.
The researchers conducted a brute force method which involved testing 40,000 different antibodies. The testing revealed a lead candidate antibody that was able to connect to FIXa and FX and bring them into a spatial position that connected the appropriate catalytic site of FIXa to the cleavage site of FX.
Next, the research team began the laborious process of engineering the antibody to increase it’s effectiveness, make it patient-friendly to administer, and allow it to be manufactured at scale.
A crucial starting point was making sure that the antibody would bind to FIXa and FX, but not bind too tight. Otherwise, it would be unable to release the activated protein to facilitate the next step in the blood clotting process. To accomplish this, the team generated variants of the antibody by introducing mutations. One of these variants was tested in macaques with factor VIII deficiency and showed positive results, notably remaining effective even in those with inhibitors. A similar variant, named hBS910, showed the most promise. The hBS910 antibody became the basis for further development and evolved into ACE910.
Several improvements to the antibody were engineered to increase the convenience for patients including making it deliverable subcutaneously, instead of intravenously, and making it long-lasting between doses. Subcutaneous delivery is a natural benefit of the strategy of using an IgG antibody and the antibody was additionally formulated into a high concentration through a process of introducing further mutations. To increase the time between doses, neutralizing a positive charge on the antibody increased the half-life. Another mutation was introduced so that the antibody could be delivered in a liquid formulation without requiring reconstitution. The optimization process also included extensive testing for immune reactions and utilization of a common light chain to allow for large-scale manufacturing at clinical grade.
From this point, the research moved into clinical trials and regulatory approvals.
In 2014, Roche released promising findings from a human trial in Japan involving 3 cohorts of 6 patients.
In September of 2015, ACE910 received a FDA breakthrough therapy designation for hemophilia A to accelerate development and review.
In November 2015, Roche began a phase 3 clinical trial called HAVEN 1 which grew to include 109 partipants with a median age of 28 years, all of whom had a history of high titer inhibitors. The median exposure to emicizumab treatment was 24 weeks.
As published in the New England Journal of Medicine, the HAVEN 1 findings are very encouraging.
In the HAVEN 1 trial, once-weekly emicizumab prophylaxis that was administered subcutaneously in patients with hemophilia A with inhibitors was associated with a bleeding rate that was 87% lower than the rate with no prophylaxis. These findings were supported by substantially lower rates of other bleeding-related end points (events of spontaneous bleeding, joint bleeding, and target-joint bleeding as well as all bleeding events) with emicizumab prophylaxis than with no prophylaxis. A total of 63% of the participants who were randomly assigned to receive emicizumab prophylaxis had zero bleeding events during the trial.
A separate study called HAVEN 2 is focused on children and preliminary results are also encouraging. After a median observation time of 12 weeks, the study showed that only one of 19 children receiving emicizumab reported a treated bleed. There were no reported joint or muscle bleeds. The study is intended to enroll a total of 60 children.
The momentum of ACE910 (aka emicizumab) looks likely to carry straight through to FDA approval with an expected date of 2018. Regulatory approval is also in process in the European Union and Japan. The hemophilia A community have been waiting a long time for a treatment that’s less frequent, less intrusive, and isn’t effected by inhibitors.
