Presentation Notes in PDF Format
What is on the horizon in hemophilia treatment Jason Taylor, MD PhD Associate Director, The Hemophilia Center Oregon Health & Science University Portland VA Medical Center April 2015 Difficulties with hemophilia treatment today • • • • IV administration Short half‐life Inhibitor formation (Cost) Classic coagulation cascades Payel Bhattacharjee and Debasish Bhattacharyya (2014). An Insight into the Abnormal Fibrin Clots — Its Pathophysiological Roles, Fibrinolysis and Thrombolysis, Dr. Krasimir Kolev (Ed.) Bypassing agents Now: Extended half‐life factor • Fc‐receptor – Allows for recycling of factor • Pegylated factor – Reduced turnover • Single chain Factor VIII – Reduced turnover Extended half‐life factors ASH 2014 • Extended half‐life factors are safe and effective in children (short term studies) Extended half‐life factors ASH 2014 • Extended half‐life factors are safe and effective in children (short term studies) • Corollary abstract – Radioactive PEG injected into rats • 99% recovery at 7 days (urine and feces) • Most residual recovered in the skin followed by kidney and Liver • Thus PEG accumulation may not be significant Broader view of coagulation Clotting cascade Broader view of coagulation Platelets activation Clotting cascade Broader view of coagulation Platelets activation Clotting cascade Factor inactivation Broader view of coagulation Platelets activation Clotting cascade Factor inactivation Clot lysis Ways to reduce bleeding • • • • Increase factor Decrease factor inactivation Decrease clot breakdown Alter activity of platelets Novel way to increase factor ACE910: Replace the Function of FVIII • Antibody that replaces the role of FVIII – Binds FIXa to FX to form FXa – Subcutaneous injection up to every 4 weeks – Works in humans, Phase I/II • Reduces bleeding in those without inhibitor by 100% • Reduces bleeding in those with inhibitor 90‐100% • No evidence of antibody formation against the product Broader view of coagulation Prevention of factor inactivation – TFPI (Tissue factor pathway inhibitor) inhibitor • Dual valent inhibitor peptide • Subcutaneous injection • Currently in Phase I – Blocking Antithrombin production • siRNA • Subcutaneous injection, Phase I – 30% stable knockdown for 70 days Prevention of factor inactivation TFPI Antithrombin Preventing clot lysis – TAFI (Thrombin Activatable Fibrinolysis Inhibitor) mutants with a longer half‐life – Works in vivo in the presence of inhibitors in mice Preventing clot lysis c TAFI c Broader view of hemophilia treatment Clotting cascade Factor inactivation Clot lysis Advances with Inhibitors (in mice) • Inhibitors – Adding dexamethasone upfront may decrease inhibitor formation – Oral dosing of FIX reduces inhibitor formation – Targeting FVIII‐reactive B‐cells – Creating customized suppressor T‐cells Now back to patient… SIPPET TRIAL: Inhibitor Development in Previously Untreated Patients (PUPs) or Minimally Blood Component‐Treated Patients (MBCTPs) when exposed to vWF containing FVIII concentrates and to Recombinant FVIII SIPPET • Following for first 50 exposure days or 3 years • 300 participants • 77 centers, 19 countries (2 in the US) SIPPET • Fully accrued • Interim analysis, discussed at ASH 2014 – No danger signals – No evidence for futility • Stay tuned! Thanks Tangent: Advances in adoptive T‐cell Therapy • Designer T‐cells – Artificial Antigen presenting cells – Transgenic T‐cell Receptor • MHC‐dependent – Limited to patients with the same HLA as the insert • mixed TCR dimers (exogenous/endogenous) – Engineered disulfide bonds – TCR – Chimeric Antigen Receptors (CARs) Tangent: 2nd generation CARs Adding a co‐receptor signaling domain (2nd generation) increases cellular activation by an order of magnitude
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