Stretching Time Extending the Life of Clotting Factors May Improve Quality of Life for People with Haemophilia

OUTLOOK HAEMOPHILIA WORLD FEDERATION OF HEMOPHILIA FEDERATION WORLD

Boys with haemophilia receive a blood-clotting factor by intravenous injection (also referred to as an infusion).

CLOTTING FACTORS Stretching time Extending the life of clotting factors may improve quality of life for people with haemophilia.

BY NEIL SAVAGE from the blood of people with the condi- plasma being replaced by clotting factors tion. These therapies could stretch the time manufactured through recombinant DNA- or the parents of a child born with between infusions to days or even weeks. The technology, eliminating the transmission of haemophilia, the diagnosis comes with first two such treatments were approved by viral diseases that had devastated the haemo- both good and bad news. The good news the US Food and Drug Administration (FDA) philiac community in the 1970s and 1980s. Fis that the child, at least if he (or rarely, she) earlier this year, and more are in the pipeline, But prophylactic treatment still has its prob- is born in the developed world, can expect a with some expected to be approved in 2015. lems. The clotting factors do not last very long near-normal lifespan, up from a mere 20 years As these therapies emerge, dealing with hae- in the body. Depending on the person, the in 1970. The bad is that the parents must teach mophilia will become less troublesome (see amount of factor VIII — the protein missing in themselves to find their child’s veins, insert a ‘Drugs to help the blood’). This could increase haemophilia A — in the bloodstream drops by needle and infuse him with a clotting factor compliance with treatment, reduce complica- half in a mere 8–12 hours. Factor IX — which to replace what he lacks. Parents must infuse tions — and perhaps even allow some people people with haemophilia B lack — lasts longer, a toddler as often as every other day, and chil- to live almost as if they were free of the disease. 18–24 hours. Those short half-lives mean that dren with haemophilia will have to continue Replacing the clotting ability lacking in most people with haemophilia must trans- that treatment for the rest of their lives. haemophilia has been the treatment since the fuse themselves every two or three days. And But treatment is getting easier. Down the 1840s, when attempts were made to treat peo- inserting a needle directly into a vein can be road, gene therapy and other approaches ple with the disease by transfusion with whole difficult. “Adherence to therapy is not great, look likely to bring longer-term treatments blood from people with normal clotting. By because you have to inject yourself, and it’s for patients with the rare bleeding disorder. the end of the 1960s, freeze-dried concentrates a hassle,” says David Lillicrap, a professor of For now, improvement in treatment lies in of clotting factors were available for home use, pathology and molecular medicine at Queen’s the emergence of new, longer-lasting replace- to prevent spontaneous bleeding. In the 1990s, University in Kingston, Ontario, Canada. ments for the blood-clotting factors missing treatment leapt forward again, with donated One 2001 study suggested that up to 40% of

people with severe haemophilia do not follow the prophylactic schedule1. Those people are DRUGS TO HELP THE BLOOD more likely to develop spontaneous bleeding A number of treatments to aid blood clotting are in clinical trials or have been approved this year. that causes joints to fill with blood and results Product Approach Company Half-life Status in progressive damage similar to arthritis. (hours) They can also develop intracranial bleeding, Factor VIII Eloctate Fc fusion Biogen Idec 20 FDA approved in June which can cause brain damage and even death. infusions (for protein 2014 Drug companies have responded with haemophilia A) BAX PEGylation Baxter International 19 Submission for approval clotting factors that last longer, making the Conventional 855 planned for late 2014 time between infusions greater. Biogen Idec, infusion half- BAY94- PEGylation Bayer 19 Submission for approval based in Cambridge, Massachusetts, has two life: 8-12 hours 9027 planned for mid-2015 such factors approved by the FDA this year. N8-GP PEGylation Novo Nordisk 19 Submission for approval Eloctate, for haemophilia A, was approved in planned for 2018 June and is recommended for an initial infu- Factor IX rIX-FP Albumin CSL Behring 92 In clinical sion once every four days, with a physician infusions (for fusion trials adjusting that up to five days or down to three haemophilia B) N9-GP PEGylation Novo Nordisk 110 Submission for approval as appropriate. Alprolix, the company’s treat- planned for 2015 ment for haemophilia B approved in March, Conventional infusion half- Alprolix Fc fusion Biogen Idec 87 FDA approved promises infusions once a week, and perhaps life: 18–24 protein in March 2014 every ten days or two weeks in some patients. hours Other versions of the clotting factors from FDA, US Food and Drug Administration. other drug developers are showing similar extensions of lifetimes. For factor VIII, Fc fusion extends the glycol (PEG) molecules (see ‘PEGyla- “It’s a big improvement,” says Timothy half-life from a maximum of about tion protection’). The PEG forms Nichols, a cardiologist and pathologist who 12 hours to about 18 hours. Factor a sort of ‘watery cloud’ around the BIOGEN IDEC studies haemophilia at the University of North IX, which has a longer half-life to protein, protecting it from various Carolina at Chapel Hill. “It’s not no treatment, begin with, shows a more dramatic mechanisms that would break it but it is a lot easier than sticking a needle in increase, from one day to five days. down; for instance, PEG prevents your kid three times a week.” Both the approved Biogen drugs the clotting factors from binding Steven Pipe, a paediatric haematologist at are based on Fc fusion. Similar to protein-specific receptors that the University of Michigan’s C. S. Mott Chil- fusion drugs have been on the would normally clear them away. dren’s Hospital in Ann Arbor, agrees that the market to treat other diseases for PEG is eventually flushed from the progress is significant. In particular, work many years, for example the rheu- body through the kidneys and liver, that is stretching the lifetime of factor IX by matoid arthritis drug Etanercept, but before then it gives the clotting three to five times is “really transformative”, he which was approved by the FDA factors a new lease of life. Three says. And because half-lives can vary between in 1998. Jerry Powell, the retired large drug companies — Bayer in patients, “at high doses, you could probably in director of the Hemophilia Treat- Coagulation Leverkusen, Germany, Baxter Inter- some individual cases get a month’s worth of ment Center at the University of factor IX, national in Deerfield, Illinois, and factor IX,” Pipe says. California, Davis, says that the used to treat the Danish company Novo Nordisk success of those drugs suggests that haemophilia B in Bagsvaerd — have all developed BORROWED TIME this is a safe approach to altering the PEGylated factor VIII with a half-life The trick to extending the half-lives of clotting factors. of roughly 19 hours. Baxter expects to submit clotting factors is to interfere with the body’s A similar approach, which is being pursued its product for regulatory approval by the end natural mechanisms for flushing them away. by CSL Behring, based in King of Prussia, of this year, Bayer next year, and Novo Nor- There are three very similar approaches, each Pennsylvania, is to fuse the clotting factors disk by 2018. of which extends half-life by about the same with albumin. Albumin is a major protein Novo Nordisk is also testing a PEGylated amount for the respective clotting factors. The of blood plasma and, like immunoglobulin, factor IX that has shown a half-life of 110 only real difference is between factor IX, for has a half-life of about 20 days. Phase I safety hours in clinical studies. The company says which the techniques are offering extensions studies of factor IX fused to albumin showed that it hopes to submit that drug for approval long enough to make a substantial difference a fivefold increase in half-life, up to about next year. in treatment, and factor VIII, for which the four days. Unfortunately, attempts to do the Up to now, tests have not shown much dif- improvement has been more modest. Unfor- same with factor VIII have been unsuccessful. ference, in safety or effectiveness, between tunately, haemophilia A, which is caused by Powell says that the albumin seems somehow the three approaches. There are concerns factor VIII deficiency, is about four times as to interfere with the normal activity of that that PEG might accumulate in the liver or common as haemophilia B. clotting factor. kidneys over years of use, but studies of PEG Two of the techniques piggyback on the “These are really big molecules,” he says. The have found it to have very low toxicity, and half-lives of other longer-lived proteins that activity of factor VIII in action, he adds, is so Powell thinks that those fears are exagger- occur naturally in the body. One such is immu- complex that it resembles a dancing elephant ated2. “PEG’s been around a long time, there’s noglobulin, a large Y-shaped protein with — too easily thrown off its rhythm when some- a lot of toxicology and all the toxicology indi- a half-life of about three weeks. The stem of thing else is attached. “If you put the wrong cates no concern,” Powell says. And if, as he the Y is known as the Fc region. When a clot- kind of contraption on the elephant, it doesn’t expects, gene therapy replaces these treat- ting protein is fused to an Fc region, the body dance as well.” ments in the next decade, patients will in any treats the clotting factor more like an immu- The third strategy takes a slightly different case not have lifetime exposure to PEG. noglobulin, and allows it to stick around for approach. Instead of marrying the clotting One barrier to haemophilia therapy is the longer, although not for as long as a complete proteins to a natural substance in the body, tendency of factor VIII to prompt the body immunoglobulin molecule. they are attached to synthetic polyethylene into producing anti-factor VIII antibodies,

27 NOVEMBER 2014 | VOL 515 | NATURE | S163 © 2014 Macmillan Publishers Limited. All rights reserved OUTLOOK HAEMOPHILIA known as inhibitors. For a person with provide benefits beyond the convenience haemophilia A, factor VIII is a foreign PEGylation protection of less-frequent infusions and the potential substance, and the immune system can see it increase in the number of people who stick to A key advance in haemophilia treatment is to as a threat. About 30% of people with haemo- prolong the e ectiveness of the injected their treatment regime. If people under treat- philia A develop inhibitors, and once they do, coagulation-promoting proteins (clotting factors) ment now keep to their current schedule with treating their bleeding becomes much more by shielding them from destruction. the extended-life products instead of taking difficult. Only about 4% of people with hae- fewer infusions, the increased concentra- mophilia B develop inhibitors to factor IX. BEFORE tion of clotting factors in their blood could There is a lot of worry, Pipe says, that alter- Unprotected molecule improve their quality of life even further. ing factor VIII to extend its half-life could Under normal circumstances, proteases and When patients have make the inhibitor problem worse. “Everyone protein-specic receptors break up the an infusion of clotting clotting factor and rapidly clear it from the “It is a lot treads lightly in the factor VIII field, because bloodstream. easier than factor every 48 hours, there is such a fear of immunogenicity with the concentration of Protease sticking a any change of the molecule,” he says. “There’s needle in clotting factor initially no question with the current strategies that all reaches 100% of normal of them have sort of hit a ceiling. If we’re really your kid three levels and stays there for Clotting times a week.” going to overcome that ceiling, you are going factor about 12 hours. For the to have to accept more dramatic changes to next 36 hours, it is high the molecule.” enough to be useful, but below normal. For PEG may prove helpful in that regard. Stud- Protein-specic receptor the last 6 to 8 hours, the level is very low, less ies dating back to the 1970s have shown that than 5%, Pipe says. Physicians try to keep the PEGylation can reduce the chances of a for- lowest level, the trough, from falling below 1% eign protein stimulating an immune reaction, AFTER of the amount a non-haemophiliac person has although the effect has not yet been proved in Microscopic shield circulating in their blood, enough to prevent people with haemophilia. “That’d be a huge In PEGylation, molecules of polyethylene spontaneous bleeding. breakthrough if that were true,” Powell says. glycol (PEG) are attached to the clotting factor. But if the trough level can be higher, it The PEG molecules bring with them water molecules, which shield the clotting factor might make life easier for the patients, allow- CONSTANT CASCADE from attack. ing them to, for instance, take up athletics One researcher might have worked out a way Water with less fear of injury. “Ideally, you’d like to avoid the inhibitor issue almost entirely, by Protease molecules to have zero bleeding,” Pipe says. “What is developing a different molecule to take the the threshold for that I don’t think anybody place of factor VIII in the clotting cascade. knows.” Still, there would be substantial ben- Normally, once activated by previous steps efit from a less-than-perfect level of clotting PEG in the cascade, factor VIII grabs hold of both Clotting factor. “If you could maintain a level of 10% factor IX and factor X, bringing them together factor or 15%, you would probably eliminate all to perform the next steps in the cascade. joint disease,” he says. Midori Shima, director of the Hemophilia Lillicrap hopes that the emergence of Center at Nara Medical University in Japan, several therapies means that it will make Protein-specic receptor has created a ‘bispecific’ antibody to do the economic sense for drug companies to pro- same job. vide treatments to poorer parts of the world Antibodies are immunoglobulins, and the Too big to discard that have not been able to afford them. “No upper arms of these Y-shaped proteins are The watery cloud makes the factors too big for longer are people thinking about these the kidneys’ ltration mechanism, so the designed to bind specifically to another mol- molecule circulates in the bloodstream for therapies being only Western European ecule. Shima has created an antibody with longer. and North American therapies,” he says. one arm that binds to factor IX and the other If pharmaceutical companies are pouring to factor X, pulling the two together so that money into this research, he thinks that it is the clotting cascade can continue. The bispe- at least in part because they can see a world- cific antibody has a half-life of about 30 days, wide profit benefit. much longer than the 12-hour upper limit of For all the advantages of these extended- factor VIII, Shima says. Chugai Pharmaceuti- life molecules, the researchers predict that cals, based in Tokyo, and Hoffman-La Roche, they will be supplanted in perhaps a decade based in Basel, Switzerland, are working on by advances in gene therapy, which will enable developing his findings into a treatment. people with haemophilia to produce their own The researchers have not yet released the clotting factors. But in the meantime, trading results of their phase II initial clinical trials, current therapies for longer-lasting ones can but Shima says that in the patients with hae- of the nature of the antibody, it does not have improve patients’ lives. “As a bridging therapy mophilia they looked at, bleeding frequency to be delivered intravenously, but instead can between the really good outcomes we have decreased dramatically. Among six people be injected under the skin, like insulin. “We currently and maybe a cure down the line,” says receiving the lowest dose of the treatment, think we can change the whole concept of hae- Pipe, “I think the extended-half-life molecules who had each had 20–60 episodes of bleeding mophilia treatment,” Shima says. are a perfect transition.” ■ in the 12 weeks before the trial, two had no Lillicrap agrees. “That bispecific antibody bleeding episodes at all during the 12 weeks would be hugely disruptive if it works,” he Neil Savage is a freelance writer based in of the trial. And out of 64 patients, only one says. “We’ll know within the next couple of Lowell, Massachusetts. developed an inhibitor. The team is planning years whether it delivers on the promise which 1. Hacker, M. R., Geraghty, S. & Manco-Johnson, M. a larger, phase III trial. so far it’s shown.” Haemophilia 7, 392–396 (2001). One bonus of this treatment is that because Treatments with extended half-lives may 2. Webster, R. et al. Drug Metab. Dispos. 35, 9–16 (2007).