Evolution of Treatments- Then and Now (2014)

Hemophilia is a bleeding disorder.  In a hemophiliac blood clots significantly slower than a normal person.  Due to this blood accumulates in the local tissue internally until the clot forms.  This is noticeable primarily in joints but can occur in muscle, soft-tissue or within an organ (GI, intracranial).  If a bleed is not stemmed, it can be fatal. Hemophilia is an incurable condition today- historically considered transmitted via inheritance of a faulty gene by the male child from the mother.  However, over the last decade or so, hemophilia has been observed in families with no prior incidence.  This has been attributed to spontaneous gene mutation.  Moreover, there are sporadic cases of female hemophiliacs in the general population.

A number of proteins called 'Factors' work in tandem to form a blood clot.  The sequence of their actions is defined in what is known as the Coagulation Pathway or Cascade.  The Factors are designated by Roman Numerals ( I, II... , VIII, IX... and such).  A missing, inadequate or incomplete Factor due to the faulty gene can cause an unstable clot and a bleeding disorder.  Hemophilia is caused by a defect in the Factor VIII (FVIII,in Hemophilia A)  or Factor IX (FIX, Hemophilia B) gene leading to various levels of the circulating clotting protein.  Hemophilia is classified based on the levels of Factor as severe( < 1% of normal), moderate (1-5%) or mild (5-40%).

Historically, hemophilia has been treated by replacing the missing Factor, administered intravenously via an injection.  Treatments have evolved over the years starting with matched fresh blood, purified pooled plasma, fractionated plasma, freeze-dried concentrates (cryoprecipitate), and monoclonal antibody (mAb) purified protein.  The simple difference between these products was noticeable in the volume used and their purity.  In the 80s a large number of patients were infected with HIV and Hepatitis B and Hepatitis C from the use of pooled plasma products.  Safety of Factor was suspect. The next milestone, a significant step forward, in the treatment for hemophilia came from to the evolution of gene cloning and recombinant technology.  in 1992, FDA approved the first recombinant Factor VIII product for clinical use.  This antihemophilic Factor is a glycoprotein synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell line, followed by several stages of immunoaffinity chromatography including mAb directed to FVIII.  All manufacturers of FVIII jumped on the recombinant bandwagon and developed their own products.  The differences were primarily either in the active Factor domain expression or with the steps in the purification process.  Until the early 2000s these were the purest form of injectable Factor for clinical use.

The landmark availability of recombinant FVIII had one caveat.  All available Factors were using some form of human albumin in their manufacture.  This was present in the cell culture medium or used as a protein stabilizer.  The human albumin offered a theoretical chance of viral transmission and hence a safety concern.  The next generation of FVIII, approved in 2003, was the first human plasma/albumin free product.  This has been deemed the safest product in the hemophilia market.

While the safety concerns were being addressed by the laboratories and the pharmaceuticals, the overall patient care systems were also evolving.  Care that once required hospitalization or an out-patient visit had become home-based therapy.  A number of home-care pharmacy businesses became the middle-tier between manufacturers and patients. Patients were getting treatment from a local general physician or hematologist to a federally funded hemophilia treatment center (HTC).  The treatment regimen also changed from on-demand (episode based) to prophylactic (preventive) schedule of infusions.  Care went from specialist- patient interaction to a multi-disciplinary comprehensive care for hemophilia.  Hemophilia camps taught children to self-infuse at an early age.

With the safety concerns of antihemophilic products behind them the trend in the past decade has been to prolong the availability of active protein in circulation.  This is technically measured in terms of half-life (T _1/2) of the protein.  Half-life is the time required for the protein to reach half its original activity level.  For FVIII the T _1/2 is 8-12h.  To be effective the circulating Factor should be maintained at or above a certain level.  This is commonly termed the 'trough' value.  The trough various for different individuals based on their daily activity.  A 10% level is considered a good trough.  In order to maintain this Factor level a patient on prophylaxis has to infuse three times a week at the basic dose of 20U/kg body-weight.

This next advance in Factor therapy addressed the longevity of Factor in vivo.  Recently, in 2014, FVIII and FIX products with extended half-life was available.  These products had 1.5 -3.0 times longer half-life compared to current products.  Fc fusion-based technology, previously used with other drugs, was used in these Factor products.  This approach combined two molecular structures- a single molecule of recombinant Factor fused with the dimeric Fc domain of IgG1- was used to extend the half-life in a clinically usable way.

Treatment for hemophilia has come a long way over the last decades.  Progress has been made in terms of improvements in the volume, safety, storage temperature, portability and dosing regimen.  Simultaneously, various infusion devices have also been developed addressing the 'accidental pricks' danger to the patient or healthcare provider.  Several types of reconstitution devices are in the market, typically packaged with the Factor product.  The product development continues with more manufacturers entering the market with a dozen or more products in the pipeline or various phase of clinical trials.  Recent successes have been reported with gene therapy trials for Factor IX.


See also
Hemophilia Therapies in the Pipeline (2015-)