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Hemoglobin-Based Oxygen Carriers: An Update

Hemoglobin-Based Oxygen Carriers: An Update. Salima Shaikh, MD Medical Director. California Blood Bank Society Annual Meeting Friday, May 5, 2017. Outline. Introduction to HBOCs Definition Rationale for use Brief history of HBOCs Types and mechanisms of action Complications

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Hemoglobin-Based Oxygen Carriers: An Update

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  1. Hemoglobin-Based Oxygen Carriers: An Update Salima Shaikh, MD Medical Director California Blood Bank Society Annual Meeting Friday, May 5, 2017

  2. Outline • Introduction to HBOCs • Definition • Rationale for use • Brief history of HBOCs • Types and mechanisms of action • Complications • Aftermath • Unlicensed HBOCs currently available • Types and mechanisms of action • Clinical trials • Expanded access ("compassionate use") • Summary

  3. Introduction • Blood transfusions  • Safer today than ever before, thanks to careful blood donor screening and advances in infectious disease testing • Overall supply has usually been adequate to meet patient need, despite periodic shortages • BUT old and new challenges exist that make blood substitutes attractive • Risk of transfusion transmitted diseases is not zero • Shrinking size of the donor base - age, health/travel deferrals, difficulty attracting and keeping young donors • Complicated logistics for blood transportation • Difficulties with providing rare or antigen-negative blood, O neg RBCs • RBCs must be crossmatch compatible • Short shelf life of RBCs (35-42 days) • Not all patients will accept RBC transfusions - Jehovah's witnesses • Blood shortages in civilian and military trauma situations

  4. An ideal "blood substitute" has been the holy grail of trauma medicine for over 100 years • Readily available • Long shelf life (years) • No refrigeration needed • Universal compatibility • Efficient and effective delivery of oxygen to tissues • Minimal to no adverse reactions or other complications • Accepted by all patients • Low cost

  5. Hemoglobin-based oxygen carriers (HBOCs)  • attempted to fill the role of universal blood substitute OR (more recently) an alternative when RBCs are not available or not an option • have hemoglobin as a component • have had varying characteristics and mechanisms of action through the years • have historically had unacceptable complications and fallen into disrepute for a while • have made a comeback recently (in terms of development), on a limited scale • are not FDA licensed at this time but some are available for "compassionate use"

  6. Brief History of HBOCs/blood substitutes • 150 years ago • T. Gaillard Thomas administered IV infusions of fresh cow's milk ("lacteal injections") to 3 patients • Due to similarities between milk and lymphatic chyle • One patient survived, 2 died • Thomas said their deaths were unrelated to transfusion and insisted that fresh milk is a good blood substitute • Early 20th century • Hemoglobin-based solutions were explored • Cell-free Hgb in lactated Ringer's solution • Abandoned due to significant renal dysfunction and hypertension in 5 of 14 patients • Amberson WR et al. Clinical experience with hemoglobin-saline solutions. J Appl Physiol. 1949; 1: 469-89.

  7. 1950s • US Navy transfused free Hgb solutions to 47 anemic, febrile sailors • All had complications, including renal dysfunction and hypertension • Renal toxicity due to: • Obstruction of renal tubules by Hgb and red cell stroma deposition • Heme pigment deposition • Decreased renal blood flow due to Hgb-induced vasoconstriction • Winslow RM. The results of 62 large-volume hemoglobin infusions in man. Hemoglobin-Based Red Cell Substitutes. Baltimore and London: Johns Hopkins University Press 1992: 177-8.

  8. 1960s • Red cell stroma-free Hgb solutions were developed • But the tetrameric Hgb was broken down into dimers in the body and eliminated by the kidneys (short half-life) • Free Hgb had high oxygen affinity so it couldn't offload O2 to the tissues effectively • New approach:  Stabilize and chemically modify Hgb • US Army experiments • Crosslinked Hgb with a chemical (BME), polymerized Hgb with glutaraldehyde, or coupled Hgb to dextran • Prevented dimerization and increased retention in blood vessels

  9. 1980s-90s • Development of some products was halted due to increased rates of cardiac arrest • Hemolink (Hemosol) • Optro (Somatogen) • Few products progressed to phase II and III clinical trials in humans in peer-reviewed journals • HemAssist (Baxter Corporation, Deerfield, IL) • PolyHeme (Northfield Laboratories, Evanston, IL) • Hemopure (Biopure Corporation, Cambridge, MA)

  10. Chen JY, Scerbo M, Kramer G. A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers. Clinics. 2009;64(8):803-13.

  11. HemAssist/DCLHb (Baxter) • Developed in conjunction with the US Army • Diaspirin cross-linked Hgb (DCLHb) - term used by Army • Source of Hgb was outdated human RBCs  • Pooled, washed, lysed, filtered • Deoxygenated, crosslinked with bis(3,5-dibromosalicyl) fumarate, reoxygenated

  12. Chen JY, Scerbo M, Kramer G. A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers. Clinics. 2009;64(8):803-13. • Trauma patient study 1: 24 of the 52 patients (46%) infused with HemAssist died, vs. 8 of 46 patients (17%) transfused with saline.  Cause attributed to vasopressor effects of HemAssist (Sloan EP et al. Diaspirin cross-linked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhage shock: A randomized controlled efficacy trial. JAMA 1999; 282(19): 1857-64) • Trauma patient study 2: Terminated early because there was no significant decrease in rates of multiorgan failure in the HemAssist group and other concerns (Kerner T et al. DCLHb for trauma patients with severe hemorrhagic shock: The European ‘onscene’multicenter study. Intensive Care Med 2003; 29: 347-49)

  13. PolyHeme/SFH-P (Northfield) • Developed in conjunction with the US Army • Crosslinked stroma-free Hgb with glutaraldehyde, then pyridoxylated final product • Large molecule will not extravasate into intracellular space • Nitric oxide causes vasodilation and free Hgb binds it, causing vasoconstriction • PolyHeme was theorized to have decreased binding of NO, leading to decreased vasoconstriction

  14. Chen JY, Scerbo M, Kramer G. A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers. Clinics. 2009;64(8):803-13. • Trauma patient study 2: 93% of PolyHeme patients had adverse effects including decreased cardiac output, anemia, fever, electrolyte imbalance vs. 88% in control group (Northfield. Northfield Laboratories reports results of pivotal Phase III trauma study [press release]. [Online] Evanston, IL: Business Wire; [updated 2007 May 23; cited 2007 June 14]. Available from: http://phx.corporate-ir.net/phoenix.zhtml?c=91374&p=irol-newsArticle&ID=1005951&highlight=)

  15. Hemopure/HBOC-201 (Biopure) • Highly purified bovine Hgb, polymerized with glutaraldehye • Inactivated potential contaminants such as cellular stroma, infectious agents, endotoxins

  16. Chen JY, Scerbo M, Kramer G. A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers. Clinics. 2009;64(8):803-13. • Complications included vasoconstriction, reduction in cardiac output, impaired oxygen delivery (similar to HemAssist and PolyHeme)

  17. What happened to these HBOCs? • HemAssist • Development of HemAssist stopped in late 1990s • Baxter eventually terminated their HBOC program • PolyHeme • May 2009 - FDA refused to approve PolyHeme • June 2009 - Northfield filed for bankruptcy • Hemopure • December 2006:  FDA denied Biopure's application to perform Phase III trauma trial • Development has continued

  18. 2008 Meta-analysis: Demise of HBOCs? JAMA. 2008;299(19):2304-2312

  19. Analyzed 16 RCTs (13 published) from 1980s to 2008 for data on incidence of death and myocardial infarction • RCTs included 5 HBOCs (PolyHeme, HemAssist, Hemopure, Hemospan, Hemolink) • Elective surgery, trauma, and stroke patients • None of the 13 published RCTs reported if a systematic review of either animal or clinical evidence was conducted • Significantly increased risk of death:  164 deaths In HBOC groups vs. 123 deaths in control groups (RR 1.30; 95% CI, 1.05-1.61) • 30% increase in mortality risk • Significantly increased risk of MI:  59 MIs in HBOC groups vs. 16 MIs in control groups (RR, 2.71; 95% CI, 1.67- 4.40) • 2.7 fold increase in MI risk

  20. Proposed that any new or existing HBOC should be subjected to preclinical studies in animal models that replicate the known toxicities of HBOCs (as demonstrated in humans) before further clinical trials are allowed to proceed • Admonished the FDA for not publicly releasing results of trials involving HBOCs that had not received approval • Chastised HBOC manufacturers for not publishing results of studies until 3-5 years after the studies had concluded

  21. JAMA Editorial • "A systematic review and synthesis of accumulating clinical trials should have detected early signs of deleterious effects" before further clinical trials were conducted • There may be an "underreporting of harm" • "Further phase 3 trials of HBOCs should not be conducted“ • Fergusson DA, McIntyre L. JAMA 2008; 299(19): 2324-26

  22. “Blood Substitutes: Time for a Deep Breath” • Editorial (Stowell C. Transfusion 2008;48:574-575) • Hgb in HBOC is not the same as Hgb in RBC • Biologically reactive molecule that reacts with NO and may generate O2-reactive species • Perhaps the RBC sequesters Hgb in a way that mitigates these properties • HBOCs do not all behave the same way • Different formulations lead to a spectrum of side effects • False sense of security from working with such a well known molecule (Hgb) may have led to premature clinical testing of HBOCs • Few HBOCs available for independent study • Slow recognition and reporting of toxicities, which are as yet incompletely understood • Embarrassing revelation that we do not fully understand O2 delivery and utilization, even under physiologic conditions

  23. Differences in oxygen delivery, vasoactivity, viscosity, colloid oncotic pressure associated with HBOCs vs. Hgb-RBC suggest that simple measures of oxygen supply (i.e. Hgb level) may not be adequate for comparison with RBC transfusion • "Physicochemical characteristics of the HBOCs may suit them for applications where RBCs are not useable (e.g., vasoocclusive crisis in sickle cell disease; tissue perfusion distal to partial thrombosis), which calls for entirely different criteria for efficacy"

  24. Re-thinking the role of HBOCs • Infectious and non-infectious disease risks of RBCs have been mitigated significantly, due to advances in donor ID testing and other measures (TRALI mitigation, diversion pouch, premedication with Tylenol or Benadryl, IgA deficient products, etc) • Editorial (Weiskopf RB. Hemoglobin-based oxygen carriers: Disclosed History and the Way Ahead: The Relativity of Safety. Anesthesia and Analgesia 2014; 119(4): 758-60) • “The aggregate risk of RBC transfusion is such that using it as a comparator in a clinical trial seeking to demonstrate the superiority of an HBOC would now be a near impossibility.“ • Asserts that the new focus of HBOCs should now be on: • Situations where RBC transfusion is not an option (owing to patient refusal or lack of availability) • sickle cell disease • organ protection after ischemia (reperfusion injury) • protection of individual organs for transplantation

  25. HBOCs: The Comeback • HBOC-201 (Biopure -> OPK Biotech -> HbO2 Therapeutics LLC, Souderton, PA) • Phase III RCT of HBOC-201 vs. RBCs in non-cardiac surgery patients (1998-99) • Hemelricjk JV et al. A Safety and Efficacy Evaluation of Hemoglobin-Based Oxygen Carrier HBOC-201 in a Randomized, Multicenter Red Blood Cell Controlled Trial in Noncardiac Surgery Patients. Anesthesia and Analgesia 2014; 119: 766-76. • Phase III RCT of HBOC-201 vs. RBCs in orthopedic surgery patients  • Jahr JS et al. HBOC-201 as an Alternative to Blood Transfusion: Efficacy and Safety Evaluation in a Multicenter Phase III Trial in Elective Orthopedic Surgery. J Trauma. 2008;64:1484 –1497 • Sanguinate (Prolong Pharmaceuticals LLC, South Plainfield, NJ) • Phase I trial of Sanguinate vs. saline (control) in healthy volunteers • Misra H et al. PEGylated Carboxyhemoglobin Bovine (SANGUINATE): Results of a Phase I Clinical Trial. Artificial Organs 2014, 38(8):702–707. • Phase Ib randomized trial of Sanguinate vs. hydroxyurea in adult sickle cell anemia patients • Misra H et al. A Phase Ib open label, randomized, safety study of SANGUINATETM in patients with sickle cell anemia. Rev Bras Hematol Hemoter 2017; 39(1): 20-27.

  26. J Trauma. 2008;64:1484 –1497 Objective:  Determine if HBOC-201 can safely reduce and/or eliminate perioperative RBC transfusion in orthopedic surgery patients

  27. HBOC-201 • Purified cell-free, glutaraldehyde crosslinked and polymerized bovine Hb in a modified lactated Ringer’s solution • 13 g/dL Hgb (30 –35 g Hb/250 mL unit) • pH 7.6 to 7.9 • P50 of 40 mm Hg • May be stored at room temperature (2–30°C) for up to 3 years • Does not require cross matching • Oxygen release independent of 2, 3-diphosphoglycerate • Circulatory half-life of 19 hours • Approved for human clinical use in South Africa

  28. Study population  • Male and female (nonpregnant/lactating) patients • 18 years or older • Undergoing nonemergency orthopedic surgery • Patients with American Society of Anesthesiology Class I, II, or III ratings who did not receive recombinant erythropoietin, predonated blood or had been scheduled for normovolemic hemodilution were included • Patients who were expected to require at least two units of PRBC transfusion before midnight of postoperative day 3 (POD 3)

  29. Study design • Patients were randomized to HBOC-201 or PRBC at the first transfusion decision based on transfusion need and Hgb < 10.5 g/dL • 688 patients from 46 study sites on three continents [United States (27 sites), Europe (2), Canada (2), and South Africa (15)] were randomized • 350 (50.9%) received HBOC-201 and 338 (49.1%) received PRBC • No differences between HBOC-201 and PRBC randomized groups in surgical procedure, age, gender, or race • No differences in medical comorbidities

  30. Additional treatment was permitted for up to 6 days using the same criteria • Patients randomized to HBOC-201 received • Loading dose of 65 g of Hgb(two 32.5 g units, a 500 mL infused volume considered equivalent in total dose of Hgbto one unit of PRBC • Up to an additional 260 g, to a maximum of 325 g (2,500 mL) • Patients in HBOC-201 arm received RBCs • After 325 g HBOC-201 were administered or after 6 days • For clinical need • No upper limit for the number of units of RBCs a patient could receive • Patients were evaluated before and after infusions • Days 2 through 6 • 24 hours and 48 hours after the final administration of HBOC-201 or PRBC • 6 weeks postoperatively • Laboratory measurements were obtained at screening, baseline, and at follow-up time periods • Primary efficacy endpoint: Elimination of the need for red cell transfusions in at least 35% of randomized patients

  31. Results • No significant differences in electrolyte and acid-base parameters, albumin, total bilirubin, alkaline phosphatase, lactate dehydrogenase and glutamyltransferase, glucose, CK-MB between treatment groups • Total protein was higher (p = 0.05) at follow-up in the HBOC-201 group • Creatinine:  12 patients (6%) in the HBOC-201 group versus 3 patients (2%) in the RBC group (p = 0.035) with a ≥ 25% increase over baseline elevations of creatinine levels • Higher incidence of patients with low level troponin elevations greater than 2.5 times the lower limit of detection in the HBOC group • A total of six MIs were reported in this study, four in the HBOC-201 and two in the RBC arm (p = 0.68). • Primary efficacy endpoint: Proportion of HBOC- 201 patients not receiving red cells • Day 1: 96.3% (lower 95% CL 94.3%) • Day 7: 67.0% (lower 95% CL 62.1%) • Week 6: 59.1% (lower 95% CL 54.0%).

  32. Jahr JS et al. J Trauma. 2008;64:1484 –1497 Patients requiring ongoing HBOC-201 treatment maintained a lower total Hgb (p = 0.05) than those given RBCs at any preinfusion and postinfusion point

  33. Adverse events and deaths • HBOC-201 group • 977 more adverse events vs. control group • 4.3% more subjects experienced ≥ 1 AE • Rate of AEs/patient was 44% higher (p = 0.03) • Most AEs • Skin and scleral discoloration often interpreted as jaundice, various GI effects, increased blood pressure • Elevated BP reported in 60 patients (17%) in the HBOC-201 arm vs. 22 (7%) in the RBC arm (p = 0.001) • Serious AEs • HBOC-201 group experienced 35 more SAEs, and the rate of AEs/ patient was 36% higher for the HBOC-201 group compared with control (p < 0.016) • Incidence of cardiac related SAEs was significantly higher (p =  0.014) in the HBOC-201 arm of the study. Cerebrovascular injuries (strokes) were reported in five patients in the HBOC-201 arm vs. none after RBC transfusion (p =  0.07) • Ten deaths occurred in patients receiving HBOC- 201 vs. six in the RBC group (p = 0.450). None were deemed due to the treatment. In subjects > 80 years of age there was a marked imbalance in mortality rate, 16.1% versus 3.9%, p = 0.20. For subjects ≤ 80 years of age, the mortality rate was identical in the two treatment arms (1.9%).

  34. Safety analysis • Imbalance in adverse outcomes was due to patient cohort with intense clinical needs and O2 needs that could not be met with HBOC alone • Three factors were the primary contributors: age, volume overload, and undertreatment • HBOC-201 should only be used in patients over age 80 when blood is not available • 43% of the cardiac SAEs and 50% (5 of 10) of the deaths occurred in patients 80 years of age or older • Pay attention to patient volume status when using HBOC-201 • Use diuretics when needed • Undertreatment was suggested by • Overall lower total Hb levels in HBOC-201 group • Magnitude and duration of anemia and cardiac ischemic AEs in HBOC-201 group

  35. Recommendations by authors • When the Maximum Surgical Blood Order Schedule predicts a “need” of 3 units of PRBCs or less in an elective orthopedic surgical patient less than 80 years of age • Up to 10 units of HBOC-201 can be used • When Maximum Surgical Blood Order Schedule predicts > 3 units RBCs may be needed • HBOC-201 may be used until RBCs are available • “When any form of RBC is not an option, treatment with HBOC-201 is appropriate and may be optimal”

  36. Anesthesia and Analgesia 2014; 119: 766-76

  37. Rev Bras Hematol Hemoter 2017; 39(1): 20-27 Objective:  To determine the safety of Sanguinate in clinically stable homozygous SCA patients

  38. Background • Sanguinate (PEGylated carboxyhemoglobin bovine) is a dual action carbon monoxide releasing/O2 transfer agent Misra H et al. PEGylated Carboxyhemoglobin Bovine (SANGUINATE): Results of a Phase I Clinical Trial. Artificial Organs 2014, 38(8):702–707. Small molecular size (120 kd): allows it to bypass obstructions which prevent the passage of red blood cells (RBCs), as it travels in plasma Release of CO: within 30 min to 2 hours after infusion, allowing O2 to bind. CO’s anti-vasoconstrictive properties mitigate elevations in BP O2 transfer: based on p50 of 7-15 mm Hg, which is between that of RBCs and ischemic tissue. As it moves in the plasma layer between RBCs and vessel wall, it acts as a conduit and transports O2 from RBCs to ischemic tissue. Storage and administration: 2-8 oC, 40 mg/mL IV

  39. Background (con’t) Artificial Organs 2014, 38(8):702–707 • An ascending dose study of three cohorts of eight healthy volunteers found no serious adverse events at doses of 80, 120 or 160mg/kg.  No serious treatment-related adverse effects and the drug showed dose-proportional pharmacokinetics.

  40. Study population (Sanguinate in SCA patients) • Conducted in two countries and four medical centers in Central and South America • Adult patients with confirmed SCA   • 18 years or older • Majority of patients were female (15) and of race designated ‘other’ (23 reported as Hispanic/Latino, and Black or mixed/multiracial) • baseline hemoglobin level >6 or <10 g/dL • taking hydroxyurea or not, but must have been dose stabilized for at least three months and able to discontinue hydroxyurea for seven days prior to randomization.  • Many exclusion criteria including chronic transfusion program (defined as regular transfusions every 2–8 weeks), acute chest syndrome, serious infections, allergies to hydroxyurea, history of clinically significant diseases and electrocardiogram (ECG) abnormalities • No remarkable differences between treatment groups in medical history

  41. Study design • 24 adult SCA patients (Hb SS) were randomized 2:1 to receive, unblinded: • Single 2-h intravenous infusion of SANGUINATE • Or a standard dose of hydroxyurea (HU) with 2h at resting stage. • First 12 patients were to receive either 160mg/kg of SANGUINATE (eight patients) or 15mg/kg of hydroxyurea (four patients), and the second 12 patients were to receive either 320mg/kg of SANGUINATE (eight patients) or 15mg/kg of hydroxyurea (four patients).  • Fifteen patients received SANGUINATE and seven patients received hydroxyurea. Two patients discontinued before receiving medications

  42. Results • Adverse events • More AEs were reported in the SANGUINATE groups than reported in the hydroxyurea groups. • Of the 44 reported adverse events in SANGUINATE-treated patients, 16 were from only two of the 15 patients. • 46 of the 51 reported adverse events involving pain (including headache). • Musculoskeletal and connective tissue disorder-related adverse events were the most commonly reported, with arthralgia accounting for ten (nine SANGUINATE, one hydroxyurea) of the 51 reports • Mean increases in systolic and diastolic arterial blood pressures (transient) were noted and not dose-dependent

  43. Lab results • No meaningful differences in lab results between treatment groups • Levels of direct (conjugated) bilirubin decreased on the day of dosing relative to baseline levels for the patients receiving SANGUINATE, which was not seen in the hydroxyurea treatment group • Chemical urinalysis test for presence of blood in the urine showed a treatment-specific (not dose-specific) difference following infusion with SANGUINATE. May be the result of the increased colloid-osmotic pressure produced by the infusion, causing an increase in forced glomerular filtration • Small transient increases in troponin I levels in three patients receiving SANGUINATE (320mg/kg) and in one patient receiving hydroxyurea. Not accompanied by any clinically identified or patient reported adverse experiences • Mean values for hemoglobin and hematocrit over time show that treatment with SANGUINATE does not provide an appreciable increase in quantity or concentration of hemoglobin in these patients • Pharmacokinetics were dose dependent

  44. Analysis • Size of the study population was too small to allow a calculation of statistical significance between treatment groups • Decrease in bilirubin and gamma-glutamyl transpeptidase may be due to the impact of SANGUINATE upon the red blood cell • SANGUINATE has been shown to ‘unsickle’ red blood cells in SCA patients in vitro (Jubin R, Buontemp P, Yglesias RA, Abuchowski A, Chen Y,Kazo G, et al. Rapid reversal of red blood cell sicklingpromoted by PEGylated carboxyhemoglobin bovine gastransfer properties. Abstract 1371. In: 56th ASH annualmeeting abstracts and program. 2014) • Perhaps improvement in RBC morphology reduces hemolysis and thereby impact these biochemical parameters • The clinical significance of the transient increases in troponin I levels seen in some of these patients is not clear • Transient effect of SANGUINATE on arterial pressure is believed to be due solely to its oncotic effect • Pharmacokinetic results found that SANGUINATE (160mg/kg) had a prolonged T1/2 in stable SCA patients (19.56h) compared to that found in healthy volunteers (13.75h). Possibly the clearance mechanism will be the same as the mechanism used to clear native hemoglobin following hemolysis. Because of the widespread hemolysis in SCA patients, this clearance mechanism would be preoccupied by the patient’s extensive cell-free hemoglobin, thus reducing the clearance rate of Sanguinate.

  45. Study Conclusions • This is a first in-patient study of patients with stable SCA with either 160mg/kg or 320mg/kg of SANGUINATE • While there were more adverse events in the SANGUINATE arm, they were mild and self-limited • No clear evidence of clinically meaningful safety concerns were identified • These results support further development of SANGUINATE for the treatment of SCA comorbidities and initiation of further clinical trials designed to optimize dosing and select appropriate endpoints to assess safety and efficacy.

  46. How to obtain HBOC-201 and Sanguinate under FDA expanded access (compassionate use) • FDA term for use of nonapproved pharmaceuticals and devices is the “Expanded Access” program • Revised in August 2009 to clarify previous regulations, capture and formalize previous informal programs, and allow for new types of expanded access for treatment use • To participate, a patient: • must have a serious or immediately life-threatening disease or condition for which there is no comparable or satisfactory alternative therapy • the potential benefit to the patient must outweigh the potential risks of the treatment • treatment with the investigational drug cannot interfere with a clinical investigation(s) that could support approval of the drug • For treatment of a single individual, FDA must determine that the patient cannot obtain the drug under another investigational new drug (IND) or protocol. • Reference:  Weiskopf RB. Hemoglobin-based oxygen carriers: compassionate use and compassionate clinical trials. Anesthesia and Analgesia 2010; 110(3): 659-62. • In June 2016, FDA also issued a guidance for industry to answer questions about the 2009 regulations, in Q and A format (FDA. Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers. Guidance for Industry. June 2016 Procedural)

  47. To obtain Sanguinate • Sanguinate IND has been approved by FDA • Contact Sanguinate, who will send you appropriate forms to be reviewed, signed, and returned • Interim Clinical Research agreement • Informed Consent • Protocol SGHY-001 and product brochure • Form FDA-1572 for SGHY-001 • Summary of patient's condition and how he/she meets inclusion criteria and not exclusion criteria • If Sanguinate grants approval, your pharmacy or BB will receive product in 24 hours (expedited)

  48. To obtain Hemopure/HBOC-201 • Contact HBO2 therapeutics and discuss patient's condition and reason for request • If manufacturer agrees to provide drug, call FDA to obtain IND application  • Call HBO2 Therapeutics with Emergency IND from FDA, which allows drug to be shipped • Your pharmacy or BB will receive drug in 12-24 hours (expedited) • Document independent physician assessment of patient need for drug • Within 5 calendar days, submit the following to FDA • Emergency IND documents • Informed Consent • Documented approval from HBO2 therapeutics to use drug • Within 15 days, submit supporting documentation to FDA (brief clinical history, rationale for using drug, treatment plan, etc.)

  49. HBOCs under evaluation in animal studies • Hemoxycarrier (Hemarina, Morlaix, France) • Extravascular Hgb found naturally in marine invertebrates • OxyVita (OxyVita Inc., New Windsor, NY) • Zero-linked polymerized bovine Hgb • MP4-CO (Sangart Inc., San Diego, CA) • Carboxylated, pegylated bovine Hgb • Polynitroxylated pegylated Hgb (PNPH)(Synzyme Technologies LLC, Irvine, CA) • Pegylated Hgb with nitroxide moieties • Hemoglobin Vesicles as artificial RBCs • Sakai H. Overview of potential clinical applications of hemoglobin vesicles (HbV) as artificial red cells, evidenced by preclinical studies of the academic research consortium. J. Funct. Biomater. 2017, 8, 10.

  50. Summary • HBOCs have had a long, troubled history due to unacceptable complications and mortality rates • No FDA-licensed HBOCs are currently available, but some HBOCs can be obtained for compassionate use under IND • New HBOCs continue to be developed but need evaluation in human clinical trials • Blood industry appears safe, for now

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