Last updated on April 23, 2014 at 20:10 EDT

Pro Bono Bio Announces the Successful Development of Subcutaneous and Long-Acting Blood Factors VIIa,VIII and IX for the Treatment of Haemophilia

September 10, 2012

LONDON and MOSCOW, September 11, 2012 /PRNewswire/ –

Subcutaneous blood factors expected to revolutionise the treatment paradigm

of haemophiliac patients worldwide

Pro Bono Bio Group plc (“PBB”), the international healthcare group, announces the
successful conclusion of a series of pre-clinical trials in haemophiliac subjects
conducted with the world’s first long acting blood Factors VIIa, VIII and IX capable of
subcutaneous administration. The results of these trials are of great importance as these
novel long-acting, subcutaneous blood factors are expected to revolutionise the treatment
paradigm for haemophilia sufferers worldwide. The availability of PBB’s subcutaneous blood
factors would make self-administration by patients at home much easier leading to a
significant improvement in treatment compliance and reduction in healthcare system costs
by avoiding the need for regular IV infusions.

Key findings from the 8 trials with 6 products conducted at the University of Alabama

        - PBB's current subcutaneous form of FVIIa achieved up to 3 days of
          haemostatic cover providing the prospect of sustained prophylactic treatment for
          haemophilia A patients who suffer an immune response to FVIII meaning that FVIII is no
          longer a viable therapy for them.
        - PBB's current intravenous form of Factor VIIa achieved a 12x extension of
          haemostasis over current commercially available products. This means it could offer
          significant advantages in trauma applications in hospitals where haemostatic cover can
          be maintained for the duration of long operations and post-operation, without the
          current need for multiple administrations and related complications.
        - PBB's subcutaneous form of Factor VIII for haemophilia A achieved a
          circulating dose level of 20% of the intravenous version and also maintained
          haemostasis for 72 hours, meaning that it is already suitable for twice-weekly dosing
          and will be able to be administered at higher subcutaneous doses enabling once weekly
          dosing or better.
        - PBB's subcutaneous form of FIX for haemophilia B maintained haemostasis for 10
          days meaning that it is already suitable for dosing less frequently than once per
        - PBB expects to optimise these products so that each one will provide
          haemostatic cover for at least a week and possibly two weeks from a single
          subcutaneous injection (with circulating blood factor maximum dose levels ("Cmax") in
          line with the Malmo Protocol).

Following these successful trials PBB now has 6 blood factor products under
development of which 3 can be administered subcutaneously and 3 by intravenous (“IV”)
injection. Each of these blood factor products has proven efficacy in a sophisticated
combination of in vivo trials in naturally haemophiliac subjects and in vitro assays.
PBB’s novel improved blood factors utilise the epitope-cloaking property of PEG to prevent
the products from being rapidly detected and destroyed by the patient’s own immune system
before the product has had a chance to fulfil its therapeutic potential. This property has
already been demonstrated by PBB in a haemophilia B dog. Work is underway to demonstrate
that PBB’s other blood factor products are similarly “immune-silent”.

PBB intends to optimise these products, confident that effective prophylactic cover
will now be possible with each of these blood factors via a once-a-week regimen of shallow
subcutaneous injections.

Professor Ted Tuddenham, emeritus Professor of Haemophilia at University College
London and former Director of the Haemophilia Centre at the Royal Free Hospital, a pioneer
in the development of gene therapy treatments for haemophilia commented “I consider these
products to be a vital breakthrough by PBB as the availability of subcutaneous and long
acting blood factors will dramatically improve the quality of life and treatment regimes
for haemophilia sufferers. There is a clear and present need for these products, which in
the longer term, will continue to augment potential gene therapy options.”

John Mayo, CEO of PBB said, “This is great news. These new, improved blood factors
have the potential to revolutionise the quality of life for haemophilia sufferers. These
new products also have huge commercial potential. It is medically, morally and
commercially important that these products get to market as quickly as possible.”

Further Information

Overview of PBB’s blood factor technology

PBB has been able to generate these improved blood factors that retain their efficacy
and have a longer half life while being capable of subcutaneous administration by
attaching an inert molecule of polyethylene glycol (“PEG”) to each individual blood factor
molecule in a precise location remote from the active site on each blood factor. PBB’s
technology has been applied and tested successfully on several recombinant and plasma
sourced blood factor proteins.

        - PBB has enhanced the performance of blood factors by pioneering the
          PEGylation of these proteins with TheraPEG(TM) technology, developed independently by
          Polytherics Ltd.
        - The recombinant human protein molecules are conjugated to a polyethylene
          glycol ("PEG") molecule. TheraPEG(TM) technology is uniquely successful where previous
          attempts to PEGylate blood factors have failed, by carefully locating PEG remotely
          from the active site on each protein, and by covering epitopes which otherwise trigger
          an immune response.
        - The careful individual pegylation of each molecule ensures that, molecule by
          molecule, the blood factors are made more water soluble. This enables subcutaneous
          delivery and allows the products to be formulated with less polysorbate, reducing the
          total amount of polyethylene glycol administered to a patient (when compared to
          conventional prophylaxis).
        - PBB has substantial intellectual property around these products, including
          exclusive global licences to TheraPEG(TM) in relation to these blood factors, in
          addition to PBB's own patents.

Summary observations from PBB’s blood factor trials

Subcutaneous delivery

PBB achieved a world first in correcting the whole-blood clotting times of naturally
haemophilic dogs to normal via a low-volume subcutaneous injection. As expected,
unmodified proteins that were administered subcutaneously in the same studies (and at
equivalent dose levels) were ineffective in providing haemostatic cover.

                   Naked                             Expected PBB
                  protein   PBB protein Extension of    Protein
         Blood  Haemostatic Haemostatic duration of   Haemostatic   Subcutaneous
        Factor   cover (i)   cover (i)  Haemostasis      Cover     Bioavailability
         FVIIa     0 hrs      72 hrs    --lemniscate   168+ hrs    89%
         FVIII     0 hrs      72 hrs    --lemniscate   168+ hrs    40% (ii)
          FIX      0 hrs      240 hrs   --lemniscate    336 hrs    86%

(i) The duration of “cover” is the time over which a whole blood clotting time of less
than 12 minutes could be maintained

(ii) FVIII bioavailability figure reflects a minimum measurement (based on assays for
the existing native protein) that is expected to improve as PBB develops specific assays
for the new, improved protein.

Further extensions in duration of cover with the subcutaneous products are confidently
expected since the Cmax of the subcutaneous products is significantly lower than for the
intravenous products, providing plenty of scope for safe dose increases and further
product optimisation.

Intravenous delivery

Long-acting intravenous products are ideal for trauma applications including surgical
and post-surgical treatment. PBB’s modified blood factors clearly outperformed the
currently available products (naked protein) in all trials.

                                   Current PBB               Expected PBB
                   Naked protein     protein    Extension of   Protein
          Blood     Haemostatic    Haemostatic  duration of  Haemostatic
         Factor      cover (i)      cover (i)   Haemostasis     Cover
          FVIIa        8 hrs          96hrs         12x        168 hrs
          FVIII        24 hrs         96 hrs         4x        168 hrs
           FIX         72 hrs        240 hrs         3x        336 hrs

(i) The duration of “cover” is the time over which a whole blood clotting time of less
than 12 minutes could be maintained

PBB is confident that with regular product optimisation normal haemostatic cover of at
least one week will be achieved for all 3 blood factors, both intravenously and

These improved blood factors make possible, for the first-time, a subcutaneous,
long-acting prophylactic regime that would lead to substantial improvements to the quality
of life for haemophiliacs. Ease of administration, easier home use and a more convenient
dosing regimen will result in improved compliance, thereby reducing the occurrence of
micro-bleeds into the joints (leading to premature joint degradation), avoidance of
vascular damage by high-volume intravenous dosage and a smoother and more consistent
plasma concentration profile, giving a better prediction of the therapeutic benefit of
these factors over time, benefitting patients and caregivers alike.

Notes to Editors

About Pro Bono Bio Group plc

Pro Bono Bio Group plc (“PBB”) is an international healthcare company, which partners
with leading scientists, eminent physicians and specialist service providers, to ensure we
have access to the best talent available to develop products that target key unmet medical
needs. PBB’s approach is designed to create and bring to market important new therapies
which will improve the lives of patients worldwide.

Pro Bono Bio launched its first medicine, FLEXISEQ(TM) for the treatment of pain
associated with osteoarthritis in 2012 in Germany. Dermatology products, ROSSOSEQ and
EXOSEQ, are scheduled to launch later this year.

About Haemophilia

Haemophilia A is the genetic disorder which causes an absence of the naturally
occurring blood Factor VIII. Protein replacement therapy can be prophylactic (75%+ of
patients in Western markets) or in response to bleeding events (greater in developing
markets). The value of the global market for Factor VIII products in 2010 was circa $5bn.

Haemophilia B is the genetic disorder which causes an absence of the naturally
occurring blood Factor IX. Protein replacement therapy can be prophylactic (75%+ of
patients in Western markets) or event-driven (greater in developing markets). The value of
the global market for Factor IX products in 2010 was circa $1bn.

Factor VIIa is needed as a substitute for Factor VIII when some (circa 30% of)
haemophilia A patients develop an immune response to injected Factor VIII, thereby
limiting its effectiveness. It is also used for the acute treatment of bleeding associated
with major trauma and in some surgical settings. The value of the global FVIIa market in
2010 was estimated at circa $1.6bn.

For Media and Analyst Enquiries: David Dible, Citigate Dewe Rogerson, +44-207-638-9571

SOURCE Pro Bono Bio

Source: PR Newswire