Effective and Safe Blood Substitutes: Effective and Safe Blood Substitutes: An Attainable Reality or Lost Cause?An Attainable Reality or Lost Cause?

Jonathan S. Jahr, MD Jonathan S. Jahr, MD Professor of Clinical Anesthesiology Professor of Clinical Anesthesiology

David Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLA

Hemosol Incorporated: Principle Investigator Hemosol Incorporated: Principle Investigator in two Phase II Trials, Speakers Bureau.in two Phase II Trials, Speakers Bureau.

Biopure Corporation: Principle Investigator in Biopure Corporation: Principle Investigator in two Phase II/III Trials, Speakers Bureau.two Phase II/III Trials, Speakers Bureau.

Alliance Corporation: Principle Investigator in Alliance Corporation: Principle Investigator in Phase I Trial.Phase I Trial.

Disclosure StatementDisclosure Statement

Risks of Allogeneic Blood Risks of Allogeneic Blood TransfusionsTransfusions

American Society of Anesthesiologists Practice American Society of Anesthesiologists Practice ParametersParameters

Practice Guidelines for Perioperative Blood Practice Guidelines for Perioperative Blood Transfusion and Adjuvant Therapies: An Updated Transfusion and Adjuvant Therapies: An Updated Report by the American Society of Anesthesiologists Report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Task Force on Perioperative Blood Transfusion and Adjuvant Therapies.Adjuvant Therapies.11

11 Anesthesiology Anesthesiology 2006; 105(1):198 2006; 105(1):198

Accepting Minimal Accepting Minimal Hemoglobin LevelsHemoglobin Levels

Acceptable Hemoglobins of 5 g/dL?

Weiskopf et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA 1998;279:217-21.

Ideal Characteristics of a Blood Ideal Characteristics of a Blood SubstituteSubstitute

•Jahr, et al. Jahr, et al. Am J TherAm J Ther 2002. Winslow, 2002. Winslow, Semin HematolSemin Hematol 2007 2007

Methods of Preparation of Modified Methods of Preparation of Modified Hemoglobin SolutionsHemoglobin Solutions

•Fromm, Fromm, Crit Care MedicineCrit Care Medicine 2000. Chang, 2000. Chang, Biotech Annu RevBiotech Annu Rev 1998 1998

MODEL OF AN HBOC WITH RAFFINOSE IN THE MODEL OF AN HBOC WITH RAFFINOSE IN THE 2-3 DPG POSITION (HEMOGLOBIN RAFFIMER)2-3 DPG POSITION (HEMOGLOBIN RAFFIMER)

Clinical Trials of HBOCsClinical Trials of HBOCs

Clinical Phase I, II, and III trials with Biopure's Clinical Phase I, II, and III trials with Biopure's Hemopure, Hemosol's Hemolink, and Alliance's Hemopure, Hemosol's Hemolink, and Alliance's Perflubron have produced useful data, although Perflubron have produced useful data, although both Hemosol and Alliance have not pursued both Hemosol and Alliance have not pursued these products, probably due to poor study these products, probably due to poor study designs in cardiac surgery models, and lack of designs in cardiac surgery models, and lack of cooperation with independent investigators cooperation with independent investigators (refusal to publish existing data, etc).(refusal to publish existing data, etc).1,21,2

11 Levy JH, Goodnough LT, Greilich PE, Parr GVS, Stewart RW, Gratz I, Wahr J, Williams J, Comunale ME, Doblar D, Silvay G, Cohen M, Jahr JS, Vlahakes Levy JH, Goodnough LT, Greilich PE, Parr GVS, Stewart RW, Gratz I, Wahr J, Williams J, Comunale ME, Doblar D, Silvay G, Cohen M, Jahr JS, Vlahakes GJ. Polymerized bovine hemoglobin solution as a replacement for allogeneic red blood cell transfusion after cardiac surgery: Results of a randomized, GJ. Polymerized bovine hemoglobin solution as a replacement for allogeneic red blood cell transfusion after cardiac surgery: Results of a randomized, double-blind trial. double-blind trial. The Journal of Thoracic and Cardiovascular SurgeryThe Journal of Thoracic and Cardiovascular Surgery 2002, 124:35-42. 2002, 124:35-42.

22 Jahr JS, Mackenzie C, Pearce B, Pitman A, Greenburg AG. HBOC-201 as an alternative to blood transfusion: efficacy and safety evaluation in a Jahr JS, Mackenzie C, Pearce B, Pitman A, Greenburg AG. HBOC-201 as an alternative to blood transfusion: efficacy and safety evaluation in a multicenter phase III trial in elective orthopedic surgery. multicenter phase III trial in elective orthopedic surgery. Journal of Trauma-Injury Infection & Critical CareJournal of Trauma-Injury Infection & Critical Care 2008; 64(6):1484-1497. 2008; 64(6):1484-1497.

BIOPURE’S HEMOPUREBIOPURE’S HEMOPURE

Approved for clinical anemia in South Approved for clinical anemia in South Africa in 2001Africa in 2001

Under FDA and UK reviewUnder FDA and UK review

Phase III Pivotal Study publishedPhase III Pivotal Study published

Efficacy proven, safety studiedEfficacy proven, safety studied

•Jahr, et al. Jahr, et al. J Trauma,J Trauma, 2008. Jahr, et al. Expert Opinion in 2008. Jahr, et al. Expert Opinion in Bio TherBio Ther, 2008, 2008

Northfield Laboratories’ Northfield Laboratories’ POLYHEMEPOLYHEME

Phase III Study completed, presented Phase III Study completed, presented only in abstract formonly in abstract form

FDA submission, 4FDA submission, 4thth quarter 2008 quarter 2008

Studied as resuscitation fluid, not oxygen Studied as resuscitation fluid, not oxygen therapeutic therapeutic

•Jahr, et al. Jahr, et al. I DrugsI Drugs, 2004. www.northfieldlabs.com, accessed on 9/23/08, 2004. www.northfieldlabs.com, accessed on 9/23/08

SANGART’S HEMOSPANSANGART’S HEMOSPAN

Phase II Trials completed.Phase II Trials completed.

Phase III Trials in EU completed.Phase III Trials in EU completed.

Use of product for hypotension in spinal Use of product for hypotension in spinal anesthesia for orthopedic surgery.anesthesia for orthopedic surgery.

PP50 50 = 6 mmHg= 6 mmHg

Hb = 5 g/dLHb = 5 g/dL

ViscosityViscosity

www.sangart.com, accessed 9/23/08, accessed 9/23/08

Future HBOCsFuture HBOCs

Oxyvita available in lyophylized formOxyvita available in lyophylized form

Hemosol Biopharma HRC 101Hemosol Biopharma HRC 101

•Jahr, et al. Jahr, et al. J Cardiothorac Vasc AnesthJ Cardiothorac Vasc Anesth, 2008. Crawford, et al. , 2008. Crawford, et al. AnesthesiologyAnesthesiology, 2007, 2007

Meta-AnalysisMeta-Analysis

A recent meta-analysis has compared A recent meta-analysis has compared mortality and morbidity of the current mortality and morbidity of the current products (Hemopure, PolyHeme, and products (Hemopure, PolyHeme, and Hemospan and older discontinued products, Hemospan and older discontinued products, Hemolink and HemeAssist) not to primary or Hemolink and HemeAssist) not to primary or secondary endpoints, but to mortality, all secondary endpoints, but to mortality, all derived from post-hoc subset data analysis.derived from post-hoc subset data analysis.1,21,2

11 Natanson C, Kern SJ, Lurie P, et al. Natanson C, Kern SJ, Lurie P, et al. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. meta-analysis. JAMAJAMA 2008; 299(19):2304-2312. 2008; 299(19):2304-2312.

22 Greenburg AG. Biopure refutes the JAMA meta-analysis - June 6, 2008, Greenburg AG. Biopure refutes the JAMA meta-analysis - June 6, 2008, www.biopure.com/,www.biopure.com/, accessed 9/17/2008. accessed 9/17/2008.