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
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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
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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