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What’s Up with Bleeding 2012 Michael Recht, MD, PhD Director, The Hemophilia Center Oregon Health & Science University.

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Presentation on theme: "What’s Up with Bleeding 2012 Michael Recht, MD, PhD Director, The Hemophilia Center Oregon Health & Science University."— Presentation transcript:

1 What’s Up with Bleeding 2012 Michael Recht, MD, PhD Director, The Hemophilia Center Oregon Health & Science University

2 Disclosures Research funding directly to OHSU from – NovoNordisk – Baxter – Biogen Idec – Pfizer

3 Agenda Bio-engineering of coagulation proteins – Chemical modification – Fusion to protein conjugates Alternative hemostatic approaches Gene transfer

4 History of hemophilia The existence of hemophilia has been known for centuries—first mentioned in the Talmud ~2000 years ago – “If she circumcised her first child and he died, and a second one also died, she must not circumcise her third child”

5 History of hemophilia therapy Prior to the 1940’s-supportive care and whole blood transfusion – Low concentration of factors VIII and IX – Individuals suffered significant pain and morbidity – Average lifespan 27 years 1964-Judith Graham Pool described method to produce cryoprecipitate – Rich in FVIII and fibrinogen – Beginning of home infusions – Average lifespan 40 years

6 History of hemophilia therapy 1970’s-plasma-derived factor concentrates – Pools of 20,000+ donors – Made school, work, and travel possible – Average lifespan 60 years

7 However…. Hepatitis B and C were known to be in plasma supply Thought to be an “acceptable” risk in light of drastic improvement in quality of life First individual with hemophilia that died from HIV infection reported in 1982 – Only retrospectively was it discovered that plasma- derived factor was vector – HIV was isolated in 1984 – Heat treatment of plasma-derived factor became standard practice in 1985

8 Recombinant factor VIII FVIII gene sequenced and cloned in 1984 First clinical trial of recombinant FVIII concentrate reported in 1990 First recombinant FVIII concentrate marketed for clinical use in 1992

9 Recombinant factor IX Human FIX gene was cloned in 1982 Minor differences in post-translational sulfation between recombinant FIX and plasma derived FIX 30% lower in vivo recovery of recombinant FIX Became available for clinical use in 1994

10 Engineering of coagulation proteins Impetus derives from clinical limitations of current therapies – Require IV access – Must be given repeatedly due to short half-lives – Associated with development of inhibitory antibodies 30% of patients with hemophilia A <5% of patients with hemophilia B (though associated with anaphylaxis) – Available therapy for those with inhibitors is suboptimal

11 Rational design of new products Increase half-life Improve ease of delivery Reduce immunogenicity Increase potency

12 Wish list Characteristic Relevance to all hemostatic therapies Relevance to bioengineered coagulation factors Least invasive mode of administrationxx Least requirement for dose manipulationxx Maximal half-lifex Lowest immunogenicityx Highest tolerabilityxx Lowest thrombogenicityx Lowest cost over a lifetimexx Fogarty, Hematology 2011

13 Chemical modification

14 PEGylation Covalent conjugation of polyethylene glycol (PEG) to a therapeutic protein – Creates “cloud” around protein – Shields from exposure to: Proteolytic enzymes Clearance receptors Immune effector cells Effective at prolonging half-life of many other biopharmaceuticals – Interferon – Asparaginase – G-CSF

15 PEGylation concerns PEG polymers may interfere with the peptide interaction with substrates, reducing activity Randomly PEGylated B-domain-deleted recombinant factor VIII Interaction of FVIII with vWF ConjugateSpecific activityProtein able to bind vWF rFVIII15 u/mg98% Conjugate #17.0 u/mg43% Conjugate #25.3 u/mg26% Rostin, Bioconjugate Chem, 2000

16 Site-directed PEGylation Mei, Blood, 2010

17 Glyco-PEGylation Recombinant factor VIIa (Ghosh, J Thromb Haemost, 2009) – Increased factor X cleavage at lower concentrations – Reduced interaction with phospholipids – NN7128-three phase 1/2 clinical trials complete Recombinant factor IX – Equivalent potency to recombinant factor IX – Better duration of hemostasis after bleeding challenge

18 Glyco-PEGylation Recombinant factor IX – Equivalent potency to recombinant factor IX – Better duration of hemostasis after bleeding challenge in mice – Half-life prolonged to 93 hours Negrier, Blood, 2011

19 Liposomal PEGylation (PEGLip) Liposomes are small vesicles consisting of a phospholipid bilayer surrounding aqueous interior PEGylation of the liposome decreases clearance No difference in clotting or other laboratory parameters between study drug and standard recombinant factor VIII concentrate. There was a trend towards fewer bleeding episodes 14 days after infusion of PEGLip-recFVIII concentrate Pulled from further trials Powell, J Thromb Haemost, 2008

20 Long term use of PEGylated proteins Accumulation of PEG polymers has been documented in some preclinical studies Whether accumulation will be evident in those receiving these medications over a life- time is unknown In other compounds, anti-PEG antibodies have been demonstrated

21 Fusion to protein conjugates

22 rFVIII:Fc-IgG fusion (rFVIIIFc) IgG molecule has a prolonged t 1/2 secondary to continual recycling Fc domain of IgG is a “natural” molecule with no known toxicity rFVIIIFc is a single molecule of rFVIII covalently linked to human IgG 1 Fc domain Compared to full length rFVIII, rFVIIIFc had a 1.7-fold longer t 1/2 Powell, Blood, 2012 preprint

23 rFIX:Fc-IgG fusion (rFIXFc) Same technology as used in rFVIIIFc Compared to rFIX, t 1/2 was extended from 18 hours to 60 hours Shapiro, Blood, 2012 preprint

24 Prophylaxis schedule with rFIXFc Shapiro, Blood, 2012 preprint

25 Alternative hemostatic approaches Non-peptide molecules may provide opportunities to enhance hemostasis in bleeding disorders patients These molecules have the potential for oral or subcutaneous administration

26 Aptamers Ribosomal or deoxyribosomal oligonucleic acids that can be produced to any length or 3D conformation Allow binding to an unlimited array of physiologic targets

27 ARC19499 Aptamer antagonist of tissue factor pathway inhibitor Improved thrombin generation in plasma from subjects with FVIII deficiency Improved clot times as measured by thromboelastography in monkeys depleted of FVIII Waters, Blood, 2009

28 Fucoidans Also known as non-anticoagulant-sulfated polysaccharides (NASPs) Heterogeneously sized anionic compounds that derive from marine plants (brown seaweed) Have demonstrated pharmacologic activity: – Anti-cancer – Anti-inflammatory – Anti-angiogenesis – Anti-coagulant

29 AV513 Fucoidan with anti-TFPI activity Fed to hemophilia A dogs: – Improved clotting time as measured by TEG – Improved cuticle bleeding time Phase 1 trial of BAX513 in healthy subjects is underway Prasad, Blood, 2008

30 Read-through of nonsense mutations Nonsense mutations (premature termination codons [PCTs]) account for 11% of known mutations in severe hemophilia First described in 1964, new compounds are being developed to promote ribosomal read- through of PCTs Has been shown to be safe and effective in restoring the cystic fibrosis and Duchenne muscular dystrophy proteins

31 Ataluren (PCT124) No major adverse events reported in CF or Duchenne MD Currently phase 2 trial of 28 day treatment cycle with Ataluren in hemophilia A and B is recruiting patients

32 AAV-vector mediated gene transfer in hemophilia B AAV8 vector – Packaged as complementary dimers within single virion  mediate transgene expression at higher levels than single-stranded AAV vectors – AAV8 has lower seroprevalence that previous AAV vectors  decreased humoral immunity – Since AAV8 has tropism for liver, able to administer via peripheral vein Nathwani, NEJM, 2011

33 Study design Inclusion Criteria years of age Factor IX activity < 1% No history of inhibitor or anaphylaxis to FIX No immunity to AAV8 Dose level cohorts Cohort 1: 2 x vg/kg Cohort 2: 6 x vg/kg Cohort 3: 2 x vg/kg

34 Results AAV-mediated expression of FIX at 2-11% of baseline levels was observed in all participants Four of the six discontinued FIX prophylaxis In the other two, time between prophylactic infusions has increased Both participants receiving highest dose had asymptomatic elevations of AST treated with short course of prednisone

35 Results Nathwani, NEJM, 2011

36 Conclusions Peripheral vein infusion of AAV8 vector resulted in FIX expression at levels sufficient to improve bleeding phenotype with few side effects Immune-mediated clearance of AAV- transduced hepatocytes remains a concern

37 Benefits of correcting hemostatic defect in hemophilia Reduced mortality and morbidity Reduced joint bleeding and hemophilic arthropathy Improved joint health, mobility, and physical activity Improved patient perception of disease state Improved quality of life Improved tolerability of antithrombotic medications Improved tolerability of invasive procedures Fogarty, Hematology 2011

38 Benefits of novel therapeutics Prophylaxis – Half of US treatment centers do not follow the advice of MASAC of NHF to start three times weekly prophylaxis in those with severe hemophilia – Requirement of frequent infusions and need for central venous access in children most common reason given – Fewer infusions and non-intravenous alternatives may improve adherence and long term outcome

39 Benefits of novel therapeutics Joint health – Early three times weekly prophylaxis has been demonstrated to protect the joints of children with severe hemophilia A – Follow-up to the initial study is ongoing, but preliminary data indicate that this protective effect continues into adolesence – Decreasing infusion frequency may increase adherence

40 Benefits of novel therapeutics Quality of life – QoL increases in children with severe hemophilia A on prophylaxis compared to those receiving factor on-demand – The potential impact of improved hemostasis with new products is substantial Decreased missed work or school Decreased pain

41 Questions?

42 Conclusions Great strides have been made in the treatment of hemophilia – Understanding of the inherent limitations of currently available therapies – Unmet clinical needs of the affected population Novel agents hold promise for: – Improved safety and efficacy – Improved joint health – Improved quality of life – Increased tolerability

43 Contact information The Hemophilia Center at OHSU – (office) – (fax) –


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