© 2014 Direct One Communications, Inc. All rights reserved. 1 Treatment of Hemophilia: What’s in the Pipeline? Kerry Hege, MD Indiana University School

© 2014 Direct One Communications, Inc. All rights reserved. 1

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)


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


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


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


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)


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


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.



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 immune-mediating cells. Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84


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.


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.


Enhanced Interactions with vWF

Pabinger-Fasching I, Pipe S. Thromb Res. 2013;131:S1; Zollner SB et al. Thromb Res. 2013;132:280

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.


Bispecific Antibodies

Lillicrap D. Nat Med. 2012;18:1460; Kitazawa T et al. Nat Med. 2012;18:1570

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%.


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


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.


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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© 2014 Direct One Communications, Inc. All rights reserved. 1 Treatment of Hemophilia: What’s in the Pipeline? Kerry Hege, MD Indiana University School