Haematology – Haemophilia A
In haematology, Ascension has a promising late stage pipeline targeting haemophilia A, a genetic disorder which leaves a patient at risk of uncontrolled bleeding due to a lack of certain blood clotting factors. Haemophilia A is the most common form, affecting around 80% of patients with a complete absence or a lack of functioning Factor VIII (FVIII). The disease has a prevalence rate of about 1 in 5,000 men and can be categorised from mild to severe depending on the actual level of functioning FVIII in the body.
Unpleasant intravenous injections
Replacement FVIII proteins – whether plasma derived or recombinant – have traditionally been administered directly into the blood stream of haemophiliacs via intravenous (“IV”) injection. This route of administration is unpleasant, can require trained medical assistance (so is not optimised for home therapy) and potentially damaging to the structure of the vein long-term. These drawbacks can result in reduced compliance by patients and are less conducive to the development of regular, prophylactic care regimes, leaving patients open to the danger of bleeds and the resulting healthcare costs of dealing with such ad hoc incidents.
PEGylation technologies problems
In order to move towards a better form of prophylaxis, companies have worked to develop “long-lasting” versions of blood factors with a longer half-life in the body. This has involved the use of well-known technologies such as PEGylation or the creation of fusion proteins to protect the injected protein from being degraded and excreted from the body. Such technologies are able to extend the life of the proteins for several days, allowing a form of prophylaxis, but come with their own problems.
Fusion proteins concentration and dosing inconsistencies
Chief among these is that they rely of the injection of a large bolus of product that gradually degrades over several days. The initial bolus far exceeds the requirements of the individual and is wasteful; conversely after several days the concentration in the blood may have dropped below a critical level (1-2%), leaving the patient in danger of having a bleeding episode. The subsequent re-injection of a bolus of material generates an exaggerated “sawtooth” profile of protein concentration in the blood (see figure), which is either far above or below the preferred concentration for most of the dosing interval.
Our solution: Subcutaneously (“SQ”) administered FVIII
The development of subcutaneously (“SQ”) administered FVIII by Ascension addresses several of the short comings seen with previous products and leads the way to improved prophylaxis. Contrary to the attempt to reduce the number of (inconvenient) IV injections to a smaller number of (inconvenient) higher dose administrations, the SQ approach will see daily, lower dose injections delivered through a narrow needle into the subcutaneous tissue. Once there, the proteins leach out of this SQ depot through the interstitial fluids into the lymph and thence into the bloodstream. Once there they form a second circulating depot, protected from degradation by the technologies employed in their delivery.
The benefits of our approach
This “twin depot” approach provides a sustained release effect of the protein into the blood and should enable a controlled level of protein to be maintained in the blood (see figure) of around 10% of normal, giving the patient effective prophylaxis with a minimum of inconvenience. Payors will also benefit from the improved control and compliance leading to better outcomes as well as a reduction in the overall use of costly FVIII. In order to deliver blood factors subcutaneously, Ascension had to solve several problems:
- Make the protein water soluble, so that it does not stick to the tissues when it is injected and is carried via the lymph into the blood stream
- The injection medium must have a low viscosity capable of being injected via the typical subcutaneous needle
- Once inside the body, the protein should neither cause an immunologic response (i.e. cause antibodies to be generated against it), nor should it be detectable by extant antibodies.
Our core development programmes
The replacement FVIII market is worth about $6.5bn a year, with a further $2bn being spent to treat haemophilia A patients that have developed antibody inhibitors to FVIII. These market values are purely the cost of the products and do not take into account the cost of doctors and nurses administering IV injections, rather than patients self-administering subcutaneous injections at home.
Ascension has three core development programmes: PBB-8-IN, FVIII for HA patients with inhibitors; PBB-8-SQ, subcutaneous FVIII administration for HA patients and PBB-8-CH, a liposomal formulation to boost patients own FVIII. Ascension’s Chaperones have been proven to work with both recombinant (rFVIII) and plasma-derived pdFVIII) Factor VIII.