New factor concentrates on the way to the market

Transcription

1 New factor concentrates on the way to the market ISCB, Copenhagen, 1 September 2015 John R. Hess, MD, MPH, FACP, FAAAS Professor of Laboratory Medicine and Hematology Medical Director, Transfusion Service, Harborview MC U of Washington School of Medicine, Seattle

2 Disclosure Statement U.S. Patent #6,825,323, Hess, "Compositions for treatment of hemorrhaging with activated factor VIIa in combination with fibrinogen European Patent U.S. Patent #8,932,560, Dowling, Hess, Bochicchio, & Ragavan Advanced Functional Biocompatible Polymeric Matrix used as a Hemostatic Agent and System for Damaged Tissues and Cells. Now US FDA 510K approved as Hemogrip.

3 Why do we need better blood products?

4 From Hess & Holcomb, Resuscitating PROPPRly, Transfusion 2015 Jun 1:1:1 RBC in AS 180 ml RBC 10 ml anticoagulant 35 ml plasma 100 ml AS FFP WBD Plts In plasma RBC in AS 65% plasma, 90K plts, Hct 29% (INR 1.31, PTT 42, circ plts 63K) FFP 200 ml plasma 50 ml anticoagulant 1:1:2 FFP WBD Plts In plasma RBC in AS RBC in AS WBD Plts In plasma 55+ billion platelets 10 ml anticoagulant 40 ml plasma 52% plasma, 60K plts, Hct 38% (INR 1.55, PTT 50, circ plts 42K) Armand and Hess, Transfus Med Rev 2003; Kornblith et al. J Trauma 2014

5 Better Hemorrhage Control Grade V liver injury % mortality % mortality Damage control surgery Saline/RBC resuscitation Survivors - open wounds Damage control resuscitation Hypotensive management 68% non-operative control

6 Conventional Blood Components Pathogen Reduced Blood Components 1:1:1 180 ml RBC 9 ml CPD 36 ml plasma 100 ml AS No licensed pathogen reduced RBC component FFP PR 65% plasma, 80K plts, Hct 29% INR 1.31, PTT 1.4, circ plts 48K 1:1:2 200 ml plasma 50 ml CPD FFP PR 192 ml plasma 48mL CPD 10 water -18% coagulant activity FFP PR 53% plasma, 53K plts, Hct 36% INR 1.55, PTT 50, circ plts 32K PR 1:1: plts 21 ml ACD 279 ml plasma plts 20 ml ACD 265 ml plasma 14 ml of AS -30% plt recovery or activity FFP PR 52% plasma, 80K plts, Hct 29% INR 1.57, PTT 51, circ plts 34K

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8 The Coagulation Cascade Hoffman 2003

9 J Trauma, In 20,000 direct admissions to the U. Miami trauma center: An abnormal PT was common (28%) and predicted a 35% excess mortality An abnormal PTT was uncommon (8%) but predicted a 426% excess mortality Normal PT Abnormal PT Normal PTT Abnormal PTT

10 Making Coagulation Factors From pooled plasma Cold ethanol (Cohn) fractionation for fibrinogen & XIII Cryoprecipitation for VIII & vwf Ca ++ columns for Vit K factors II, VII, IX, X as 4-factor PCCs From cell culture rviii rix rviia rxiiiα rvwf riia In development V, XI fibrinogen

11 Buying Coagulation Factors You can buy Factors I and XIII as fibrinogen concentrate for $1000/g or $3 / IU You can buy Factors II, VII, IX and X as 4- factor PCC for $6500/dose or $2/IU You can buy Factor VIII/vWf for $1.20/IU You can buy recombinant Factors VIIa, VIII, and IX separately for $1/IU You cannot buy Factors V or XI

12 New long-acting anti-hemophilia factors New long-acting Factor VIIIs compatible with 2-3 times a week dosing (rather than every 8 hours) New long-acting Factor IXs compatible with 1 time a week dosing (rather than every 12 hours)

13 Factor XI concentrate Hemoleven from Laboratoire Français de Fractionnement since Made by plasma fractionation with cation exchange and nanofiltration. Available only for named patients with homozygous XI deficiency (<0.2 IU/mL). Effective and safe in target population in small series.

14 Recombinant factor XIIIα Tretten by Novo Nordisk is a recombinant factor XIIIα (alpha sub unit) made in yeast cells since Indicated for alpha subunit factor XIII deficiency as most congenitally deficient patients have the beta subunit. Not useful in other groups.

15 ScienceTranslational Medicine 2015 Vol 7 Issue ra29 BIOENGINEERING A synthetic fibrin cross-linking polymer for modulating clot properties and inducing hemostasis Leslie W. Chan,1 Xu Wang,2 Hua Wei,1 Lilo D. Pozzo,3 Nathan J. White,2* Suzie H. Pun1* Injectable short chain polymer with pendant cyclic hydrophobic polypeptides deploys by breaking a disulfide bond and binds and crosslinks fibrin to stabilize fibrin polymer structure.

16 Hemogrip Chitosan is poly n- acetyl glucosamine. It can be recovered from shrimp shells It can be modified to improve its interaction with cell membranes

17 HM-chitosan can convert blood to a gel independent of coagulation It also interacts with tissue

18 Untreated blood unstained smear RBC in unmodified chitosan RBC in HM chitosan

19 HM-chitosan can stop bleeding HM-chitosan gels the cells, not the plasma, so it works in the face of coagulopathy Washed cells Plasma

20 Reversal of HM chitosan cytoadhesion with α-cyclodextrin

21 Newer NAG Bandages N-acetyl glucosamine (NAG) modified to improve tissue adhesion (more aliphatic sidechains) Photo Matt Dowling / Srini Ragavan, U of MD School of Engineering

22 HM-chitosan can be gel cast and freeze dried as sponge-like bandages

23 Unlike chitosan, hm-chitosan does not saturate and fail Femoral artery injury in swine Decastro et al, J Trauma 2012

24 Femoral artery injury in swine DeCastro et al. J Trauma 2012; 72:899

25 Hemostatic foam for intracavitary use With direct spraying onto a grade 5 swine liver injury, blood loss is reduced 90% compared to the chitosan control.

26 Conclusions Blood products used in hemostatic ratios with TXA work well. Plasma products are at best a partial solution at this time and will remain an expensive dream. Biotech products hold important promise For prehospital care As triage tools As adjuncts to surgical care

27 Collaborators Dry Fibrin Sealant Bandage John Holcomb Martin MacPhee HM-Chitosan bandage and Foam Hemostatic hydrogels Matt Dowling Srini Raghavan Brendan Casey, Adam Behrens, Peter Kofinas

28 Thank you over, Blood Cells

29 The Coagulation Cascade