New therapeutic developments in haemophilia

Extended Half-Life Factor VIII
In November 2015, the first extended half-life (EHL) factor VIII concentrate was licenced in Europe by the European Medicines Agency (EMA). In April 2016, the first two EHL factor IX concentrates were licenced by the EMA. Half-life is the amount of time it takes for the factor to decrease its circulating concentration by half, or 50%. It is calculated by taking a series of blood samples over a specified time span after infusing clotting factor, and then measuring how much factor remains in each sample. When graphed, these measurements are called pharmacokinetic (PK) curves and they show how rapidly your body eliminates factor. The half-life of factor may vary from product to product, and from person to person. It is, therefore, important to know how long a particular brand of factor lasts in your body, which may be significantly different from the average half-life of that brand, due to high variation from individual to individual. By knowing how quickly you eliminate factor from your blood, your haemophilia centre team can tailor a prophylactic dosing schedule specific to your needs.

For instance, if you want to achieve a 50% factor VIII level in a man weighing 80 kg, you would infuse 2000 IU of factor VIII.  Immediately after the factor VIII is infused, the level of circulating factor VIII in the body is at 50%. If the product has a 12-hour half-life, then about 12 hours later, the factor VIII level will be at 25%  (half has been eliminated) and 24 hours (or 2 half-lives) after the original injection, 12.5% is left.  Thirty-six hours after the infusion, 6.25% is remaining and two days after the initial injection, the factor VIII level is at 3.125%.

How does this work for a prolonged half-life product? If the half-life is on average 50% longer than 12 hours, say 18 hours, then 36 hours after the original injection (which resulted in a factor VIII level of 50%), factor VIII levels are reduced by two half-lives, so 12.5%% is left. Three days after the initial dose, factor VIII is at 3.125%. In other words, when using a prolonged half-life factor VIII product with an 18-hour half-life, you may be able to go an extra day between infusions, as compared to a standard product with a 12-hour half-life. In clinical practice, EHL factor VIII can be utilised to reduce the frequency of factor VIII prophylaxis from three times per week to twice a week. Alternatively, it can be used at the current frequency of infusion (i.e. three times per week) resulting in a higher trough level (the level below which the factor VIII does not fall) and therefore conferring greater protection from bleeding.

The first EHL FVIII licenced in Europe is Elocta, developed in the USA, by Biogen and marketed in Europe by SOBI, based in Sweden. This product was licenced in the USA about 18 months ago.  Elocta harnesses one of the body’s natural mechanisms to prolong the half-life of factor VIII. Clotting factors such as factor VIII are proteins, and each protein that circulates in the blood has a different half-life; some proteins last for a few hours, and others last for several weeks. Two proteins, in particular, albumin and an immune antibody called IgG, both last for a long time, more than 21 days. Many proteins in the blood are absorbed and broken down by endothelial cells, the cells that line the blood vessels. IgG usually manages to escape this process.  There is an area on the protein, called Fc, which allows the protein to bypass the breakdown process and causes the endothelial cell to eject the protein back into circulation. Scientists at Biogen took advantage of this fact and developed a recombinant form of factor VIII fused to an Fc molecule. With the Fc molecule attached to the factor, the endothelial cells treat the factor as if it were IgG, and eject the factor back into the bloodstream, extending its half-life (by effectively, recycling the factor VIII fused to Fc). The half-life of Elocta, and of the other EHL factor VIII products under development is approximately 50% longer than standard recombinant factor VIII products. Several children with haemophilia in Ireland participated in the phase 3 clinical trial for this product and the product is now being introduced for routine use for some children and adults in Ireland. Several other EHL factor VIII products are under development and in late stage clinical trials. Baxalta (now part of Shire), Bayer and Novo Nordisk are developing EHL factor VIII products where the factor VIII is linked to polyethylene glycol (PEG). This is a petroleum derivative which is found in a variety of products from cosmetics to food. (PEG will be familiar to some people with haemophilia, as in the past, one of the standard treatments for hepatitis C, included injections of Interferon fused to PEG, so called Peg Interferon). Another approach to prolonging the half-life of factor VIII involves making a slight change in the structure of the factor VIII molecule. Normally, factor VIII is synthesised in the liver as a single long protein, called a single-chain. When secreted from the cell, the single-chain factor VIII molecule is broken into two parts, or two chains. Factor VIII travels in the bloodstream as a two-chain molecule. In the approach used by CSL Behring, the two chains of factor VIII are bonded back together to form the more stable single-chain molecule. All of the EHL factor VIII products extend the half-life by approximately 50%.

Brian O\’Mahony,
Chief Executive,
July 2016