Transcript Treatment of Hemophilia: What's in the Pipeline?

Treatment of Hemophilia:
What’s in the Pipeline?
Kerry Hege, MD
Indiana University School of Medicine, Indianapolis, Indiana
A REPORT FROM THE 65TH ANNUAL MEETING OF THE NATIONAL HEMOPHILIA FOUNDATION (NHF 2013)
AND THE 55TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY (ASH 2013)
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Treatment of Hemophilia:
Past, Present, and Future
The past four
decades have
witnessed
great strides
in hemophilia
therapy.
Franchini M, Mannucci C. Orphanet J Rare Dis. 2012;7:2
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Goals of the Hemophilia Pipeline

Improving patient outcomes with more effective
bleeding control and preservation of joint function

Reducing the burden of factor administration through
reduction in dosing frequency and more cost-effective
therapy

Individualizing therapy by adapting to individual
pharmacokinetics and personalizing treatment
regimens based on variability of bleeding phenotype,
and lifestyle

Identifying, monitoring, and preventing age-related
comorbidities

Developing a cure for hemophilia through gene therapy
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Recombinant Factors in Clinical Trials
Note: Since this table was published, the US Food and Drug Administration approved the use of recombinant factor IX Fc
fusion protein (rFIXFc; Alprolix) in adults and children with hemophilia B.
Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84; Pipe SW. What's in the pipeline? NHF 2013;
ClinicalTrials.gov Web site: http://clinicaltrials.gov
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Bioengineering Approaches
Bioengineering approaches to extending the half-life of
recombinant coagulation factors have employed several
strategies, including:

Reduction of exposure to clearance receptors
through PEGylation with polyethylene glycol (PEG)

Rescue of endocytosed proteins from intracellular
degredation by Fc fusion and albumin fusion
proteins

Enhanced interactions with von Willebrand factor
(vWF)
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PEGylation
PEGylation improves
drug efficacy via the
covalent attachment of
polyethylene glycol
molecules (PEG) to the
protein of interest—in
this case, recombinant
factor proteins.
Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84
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PEGylated Liposomes
Another approach to
prolonging the half-life
of recombinant factor
proteins is by attaching
them to the outer surface
of PEGylated liposomes
via noncovalent binding.
Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84
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Polysialylation
When polysialic acid
polymers are attached to
recombinant factor
proteins, they attract
water and produce a
watery “cloud” that
surrounds the protein to
protect it from clearance
receptors, proteolytic
enzymes, and immunemediating cells.
Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84
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Fc Fusion
Fusion of recombinant
factor to the
crystallizable fragment
(Fc) portion of
immunoglobulin G
protects the factor
protein from lysosomal
degradation via
interactions with
neonatal Fc receptors
when internalized by
endothelial cells.
Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84
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Albumin Fusion
Albumin fusion binds
human albumin to factor
protein, lengthening its
half-life, protecting it
from proteolytic
degradation, and
shielding the factor
protein from exposure to
immune-mediating cells,
further prolonging its
half-life and decreasing
its immunogenicity.
Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84
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Enhanced Interactions with vWF

The primary determinant of the half-life of FVIII is
interaction with vWF, which naturally protects it
from degradation.

A unique recombinant, single-chain rFVIII (CSL627)
has shown improved stability and higher affinity for
vWF when compared with other rFVIII proteins.

In preclinical studies, CSL627 has demonstrated
safety and efficacy with hemostatic activity
equivalent to that of full-length rFVIII formulations.

The novel single-chain design provides for higher
intrinsic stability and affinity for vWF.
Pabinger-Fasching I, Pipe S. Thromb Res. 2013;131:S1; Zollner SB et al. Thromb Res. 2013;132:280
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Bispecific Antibodies
In addition to improving factor
proteins themselves, a novel
approach has been taken to
replace FVIII cofactor function
by a small molecule, creating a
bispecific antibody capable of
mimicking activated factor VIII
(FVIIIa) activity. In preclinical
studies, this bispecific antibody
to FIXa and FX (hBS23) had a
terminal half-life of 14 days and
a subcutaneous bioavailability
of nearly 100%.
Lillicrap D. Nat Med. 2012;18:1460; Kitazawa T et al. Nat Med. 2012;18:1570
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Gene Therapy

Hemophilia makes a good candidate for gene
therapy because it represents a monogenetic disease
that requires the production of only a small fraction
of normal factor activity to ameliorate or cure the
bleeding phenotype in hemophilia.

The most recent human trials of gene therapy in
patients with hemophilia have achieved long-term
expression of therapeutic factor levels.

The field is exploring ways to improve gene delivery,
minimize vector immunogenicity, prolong gene
expression, and raise factor activity levels.
High KA. J Thromb Haemost. 2011;9(suppl 1):2; High KA. Blood. 2012;120:4482; Chuah MK et al. J Thromb
Haemost. 2013;11:99
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Where Are We Today?

At least three different FIX products created using
three different bioengineering approaches reveal
terminal half-lives as much as fivefold greater than
those of standard rFIX products.

The available data on novel recombinant FVIII
products, also using different engineering methods,
show terminal half-lives up to 1.8 times longer than
those of standard rFVIII products.

Randomized clinical trials are currently underway to
determine whether the extended half-lives of these
new recombinant products will translate into fewer
factor infusions, as much as two weeks apart.
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Conclusion
Early pharmacokinetic data for new factor products are
promising, but ultimately the ongoing phase 1–3 trials
will establish what effect these new products will really
have on:

Patient’s individual dosing schedules

Overall use of factor replacement products

Patient adherence to factor replacement therapy

Inhibitor development

Need for venous access

And the overall cost of factor replacement therapy
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