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-)
See also
Hemophilia Therapies in the Pipeline (2015-)
