About

Using proprietary technology, the Company has developed two hemoglobin-based products: Hemopure® (Hemoglobin Glutamer 250) for human application and Oxyglobin® (Hemoglobin Glutamer 200) for veterinary application.

Both Hemopure® and Oxyglobin® are room temperature stable, universally compatible, and specifically formulated for different applications such as organ preservation in transplantation, transfusion when blood is not an option, etc.

The founders and senior management team of Hemoglobin Oxygen Therapeutics LLC have significant experience in the pharmaceutical industry including more than 150 years experience in the development and manufacture of hemoglobin solutions.

The Company’s research and development laboratories and state-of-the-art bioprocessing facility are located 35 miles north of Philadelphia in Souderton, PA.

When our products are infused into the bloodstream, the chemically stabilized hemoglobin molecules carry oxygen in the plasma (the fluid part of blood) and can also facilitate the release of oxygen from remaining red blood cells (RBC), thereby increasing diffusion of oxygen to tissues. If necessary, this effect can be extended over time by repeat dosing to provide a continuous oxygen bridge until the patients receive other appropriate therapy.

Hemoglobin, the native protein responsible for transporting oxygen is normally contained within circulating RBCs. However, our products consist of hemoglobin that has been extracted from the RBCs of cattle and then purified, chemically cross-linked for stability and formulated in a balanced salt solution similar to Lactated Ringer's Solution.

On a gram-for-gram basis, stabilized hemoglobin molecules in our products hold the same amount of oxygen as the hemoglobin molecules in RBCs, but with a higher P50 (40 mM Hg), they release the oxygen more readily. In addition, data from preclinical studies suggest that introducing our products into the bloodstream may help RBCs offload more oxygen to the tissues than they would otherwise.

Scientific advisory board

HbO2 Therapeutics collaborates with several institutions and key opinion leader clinicians specializing in areas such as oxygen therapeutics, transfusion medicine, trauma resuscitation, emergency medicine, organ transplantation, and cardiology.

Management

Led by a team with decades of success

Brian Dawson has over 25 years experience working with the development and commercialization of Hemopure and Oxyglobin. In this position with Hemoglobin Oxygen Therapeutics LLC, Mr. Dawson is responsible for the transition of the manufacturing process and components from the Cambridge, MA manufacturing facility to the Souderton, PA manufacturing facility. Mr. Dawson started his career with Biopure in 1989 and held several positions in manufacturing operations offering broad qualifications in all facets of production, maintenance, calibration, supply chain, process engineering, validation, environmental control, anaerobic aseptic filling, packaging, microbiology and capacity management. The scope of Mr. Dawson’s experience encompasses preclinical research and development phase through product approval and marketing. He is successful in streamlining production processes, accelerating performance, reducing costs, and meeting time-critical industry demands. Brian was Director of Operations for both Biopure and OPK Biotech LLC, and has a BA from North Adams State College (Massachusetts College of Liberal Arts).

Mr. Leibensperger has 18 years of experience in Biopharmaceutical Manufacturing and Operations Management. He was an original team member with Biopure Corp. that helped bring Oxyglobin® and Hemopure® production to full scale and an integral part of achieving FDA and EMA GMP approval for manufacturing facilities. Bruce has had direct responsibilities for addressing FDA, EMA, and MHRA regulatory agencies. Most recently served as a Plant Director at OPK Biotech LLC and was responsible for restart operations. Employing Lean Manufacturing principles, the OPK Biotech Souderton Facility was fully operational ahead of schedule and gained VMD approval for veterinary product marketing. Previously, he served as a Biomaterials Manufacturing Manager at Globus Medical Inc. where he managed restructuring of department personnel and multiple production lines including polymer-based bone void implants, and spinal implant devices that gained both FDA and EU marketing approval. Mr. Leibensperger has a B.S. degree in Biology from Susquehanna University.

Gregory Dubé has 30 years of industry experience in drug research and development including positions of increasing responsibility in large pharma, small pharma, biotechnology and start-up firms, including management roles at Biopure and OPK Biotech. He has a deep understanding of the physical, biochemical and pharmacological properties of hemoglobin-based oxygen carriers (HBOCs) and has significant experience in the design and conduct of preclinical and clinical studies to evaluate HBOCs across a wide range of medical indications, including hemorrhagic trauma/shock, anemia and myocardial ischemia/reperfusion injury. Dr. Dubé has a doctorate in pharmacology and cell biophysics and completed a postdoctoral fellowship at Duke University School of Medicine, Division of Cardiology.

Ms Zafirelis has more than 20 years of multinational regulatory and clinical operations experience. She has a BA from University of Massachusetts and a MBA from the University of Southern California, Marshall School of Business.

Mr. Pitman has 20 years of broad based pharmaceutical and healthcare US experience with a strong background in mathematics, statistics and logistics. Previously he has taught courses in mathematics, logic, computer sciences and statistics at various colleges, including the University of Kharkov, Ukraine, Soviet Union. He earned a Master of Science with Honors in mathematics at Kharkov State University, USSR.

Former CEO of OPK Biotech LLC which developed the first approved HBOC for human use. Mr. Kowalski is a veteran of the investment banking industry, holding numerous senior positions with firms such as Bankers Trust, where he was Vice Chairman of Europe, the Middle East and Africa, Building offices in Russia, Eastern Europe, Turkey and Israel. He was global head of emerging market investment banking for Credit Suisse and CEO of Rose Square Capital an advisory firm with offices in London, Kiev, and Moscow. Mr. Kowalksi was chairman of the largest bank by capital in Russia. Mr. Kowalski is on the board of The Rollicking Crew University of Michigan Endowed Scholarship Fund, Shorts International and a member of the Clinton Global Initiative, Prague Society and Global Panel. Mr. Kowalski holds a BA in Economics from the University of Michigan.

Mr. Zafirelis has more than 25 years of CEO experience in private and public companies, including start-up ventures and turnaround situations. He has an extensive background in the biotech and medical device industries, with broad knowledge of oxygen therapeutic and cardiovascular products. Mr. Zafirelis was part of the original team at Biopure that led the development and approval of Oxyglobin®, the veterinary oxygen carrier, by the FDA and EMA. He has led two cardiac device companies, Medquest and Cardiacassist, and has substantial experience in the approval of new biologics and devices with regulators worldwide. Mr. Zafirelis has an MS in Chemistry and an MBA from the University of Southern California.

Mr. Serov has over 20 years of experience in the Investment Banking industry. He spent most of his career in London running such groups as capital markets, structured products, and advisory. Mr. Serov has worked at Bankers Trust, Rose Square Capital, Dresdner Kleinwort Benson, and Renaissance Capital. Before joining Hemoglobin Oxygen Therapeutics, he was heading up coverage for corporate clients and financial institutions at Sberbank, the largest Russian bank. Mr. Serov has a BA in Mathematics and Economics from Connecticut College.

Manufacturing

Source of hemoglobin

The active biological component in Hemopure® is polymerized bovine hemoglobin. Its manufacture consists of hemoglobin purification, chemical polymerization, and final packaging by sterile filtration. The Company collects fresh whole bovine blood from certified managed herds less than 30 months of age and includes documentation of the animal’s country of origin (USA) and their health monitoring. The program is under the supervision of a qualified veterinarian. Any animals sick or medically treated within 60 days before slaughter are not eligible for shipment and collection. Finally, there is a post-mortem inspection of each animal by a qualified US Department of Agriculture (USDA) inspector.

Manufacturing process

Manufacture of the products occurs in four major steps: first, bovine blood is collected and processed to remove plasma; second, the hemoglobin protein is removed from then red blood cells; third, the hemoglobin is purified of other red cell proteins; and fourth, the purified hemoglobin is stabilized by the addition of a cross-linking agent to form hemoglobin polymers, or proteins bound together. For the human product, an additional filtering step removes the unbound hemoglobin molecules. For both products, the polymers are then placed in a solution suitable for infusion. Finally, the products are put through sterilizing filters and into sterile bags.

The company's facilities have a validated process with an annual production capacity of 100,000 hemoglobin glutamer-250 (bovine) (HBOC-201) units (250 ml/unit) or approximately 350,000 Oxyglobin® units (125 ml/unit) or 700,000 of the smaller Oxyglobin® units (60 ml/unit), or any combination thereof. Much of the engineering and design has been completed for a potential future manufacturing facility designed to produce 500,000 HBOC-201 units per year.

Validation and product safety

The process has been validated, in accordance with regulatory agency guidelines, to remove potential pathogens in the raw material. Examples of pathogens include bacteria, viruses, such as those leading to hepatitis and AIDS, and the transmissible spongiform encephalopathy (TSE) agents that cause rare neurological disorders, such as "mad cow disease" and its human equivalent.

Health and regulatory authorities have given guidance directed at three factors to control these diseases: source of animals, nature of tissue used and manufacturing process. These three factors are addressed by supplier contracts that maintain traceable records on animal origin, health, feed and care, and by the validated blood collection and manufacturing processes.

Safety assurance is provided by:

  • Managed herds in which the animals' country of origin, feed, age and health are monitored;
  • Clearance studies that have demonstrated that our manufacturing process removes or inactivates potential pathogens;
  • External experts' analyses of the capability of our process to remove or inactivate pathogens;
  • Adherence with worldwide industry and regulatory standards;
  • Approval of our products and the process to manufacture them by multiple regulatory agencies.

Oxygen carrying solutions

Why an oxygen carrying solution?

Oxygen deprivation, even for several minutes, can result in cell damage, organ dysfunction and, if prolonged, death. Hemoglobin, the native protein responsible for transporting oxygen, is normally contained within circulating red blood cells (RBC). An RBC transfusion is the standard therapy for anemia resulting from blood loss or other disorders. Sources of RBCs for transfusions include stored supplies of donated blood (allogeneic blood) or of the recipient’s own pre-donated blood.

Unfortunately, there are frequently shortages of blood due to its limited shelf life and complications from blood typing such that blood is not available.1, 2 Shortages can become severe during crisis and, in some cases, blood is not an option.3 Many patients refuse blood transfusions on religious grounds,4 are alloimmunized, or simply prefer to avoid allogeneic blood transfusions, and as the population ages, the need for blood-intensive surgical procedures will increase sharply.

As such, an oxygen carrying solution might be needed when blood is either not available or not an option.

An oxygen bridge solution

A hemoglobin carrying oxygen (HBOC) solution can act as an oxygen bridge during acute anemia as a support to when the patient can begin making his own RBCs or to when suitable blood becomes available. These products encompass the management of patients in many situations, whether from blood-loss, ischemic conditions or other situations of oxygen deficiency.

They might provide benefit both in early or in late intervention, both systemically when there has been major blood loss or locally when blood flow is lost to a specific area. These products do not treat or cure a disease state, but support the basic metabolic function that is essential to sustain life. Our drugs support the metabolism by providing an oxygen bridge treatment that allows the body to produce new RBCs or fight disease, whatever the case may be.

Literature:
Research areas

HbO Therapeutics' research strategy focuses on the development of our products as an oxygen bridge solution or treatment to help stabilize patients and prevent tissue damage or organ dysfunction associated with oxygen deprivation.

The pre-clinical and clinical research has shown our products may be beneficial due to its rapid release of oxygen and small molecular size in ischemic conditions where there is a shortage of oxygen due to decrease or lack of red blood cell flow to an organ or area of the body due to obstructed or constricted blood vessels. The Company is currently assessing the products' safety and feasibility in such conditions. Victims of trauma may have massive bleeding resulting in rapid loss of blood volume and oxygen-carrying capacity. Patient blood typing and blood handling requirements, particularly refrigeration, limit the feasibility of using red blood cell transfusions in pre-hospital emergency treatment. To stabilize blood pressure in these patients, emergency caregivers administer intravenous fluids, such as Lactated Ringer's Solution or saline. Both of which restore blood volume, but do not restore oxygen-carrying capacity. Our products’ oxygen-carrying capacity may provide time for the patient to be transported successfully to where blood and better care is available.

Organs for transplant are harvested and maintained chilled without any oxygen supply, leading to organ ischemia. Perfusion with our product, used for its oxygen-carrying ability, may eliminate or reduce organ ischemia, maintaining a viable organ for improved patient outcomes and allowing for a greater window of time to get a healthier organ to the recipient.

Hemopure

Hemopure is supplied in 250-ml units as a sterile solution of approximately 32.5 g total purified, glutaraldehyde-polymerized, bovine hemoglobin (Hb) in an iso-oncotic balanced modified Ringer’s lactate solution at a pH of 7.6 to 7.9. It is stored at room temperature (2 to 30oC) for up to three years.

Hemopure can be administered immediately and is compatible with all blood types; blood-type testing and cross-matching is unnecessary. It does not require warming or reconstitution prior to administration and can be administered through a standard intravenous line.

Upon administration, it immediately transports oxygen to tissues served by blood flow and, because of the relatively small molecular diameter, has the potential of transporting oxygen through constricted or partially blocked blood vessels via the movement of plasma through tissues in which red blood cell (RBC) flow is restricted. Hemopure has an oxygen dissociation curve that is right-shifted with a P50 of 40 mmHg, compared to 27 mmHg for corpuscular hemoglobin.

Normal blood flow

Anemic blood flow

Oxyglobin

Hemopure is manufactured from a plentiful and well-controlled source material, bovine hemoglobin. Only cattle from the United States are utilized as donors, and an extensive herd-management program ensures that only certified disease-free animals less than 30 months of age are used to provide the hemoglobin.

The extraction and purification process used in production has been validated for the removal of potential contaminants including plasma proteins, red blood cell stroma, endotoxin, bacteria, viruses and the agents that are thought to cause transmissible spongiform encephalopathies such as bovine spongiform encephalopathy (BSE) and variant Creutzfeld-Jakob disease (vCJD). This process produces a sterile, pyrogen-free balanced salt solution containing glutaraldehyde cross-linked bovine hemoglobin polymers, which range in size from 130 to 500 kDa and have an average molecular weight of 250 kDa.

hemopure

In contrast to human hemoglobin whose oxygen affinity relies on adequate levels of 2,3-bisphosphoglycerate, the affinity of bovine hemoglobin for oxygen is regulated by the concentration of chloride ions in the plasma. It has a dose-dependent intravascular half-life of 19 to 24 hours.

Hemopure and RBCs containing the same concentration of hemoglobin, have the same oxygen carrying capacity (1.39 mL O2/g Hb). A unit of packed red blood cells (pRBC) typically has a higher hemoglobin concentration (26-32 g/dl) than does Hemopure (13.1 g/dl) and, therefore, has a higher oxygen carrying capacity (= higher efficacy) than does Hemopure.

For this reason, and because units of pRBC (250-300 mL) and Hemopure (250 mL) may have different volumes, Hemopure should not be considered a unit-for-unit alternative to pRBC. Rather, the clinical need for oxygen carrying capacity and the total circulating hemoglobin concentration (RBC Hb + plasma Hb) should guide determination of Hemopure dose. Achieving a particular target total Hb concentration will require a larger number of Hemopure units than pRBC units.

Numerous in vivo and in vitro pharmacology and toxicology studies have been performed on Hemopure over a period of more than 15 years. These studies have defined the pharmacological and toxicological properties of Hemopure in a variety of animal models ranging from ischemia, hemorrhagic shock, and cardiac arrest and include the appropriate complement of toxicology studies.

Hemopure has been administered to more than 800 human subjects in 22 completed clinical trials, including red blood cell-controlled trials in elective surgical patients where the product was administered at doses up to 300 g (10 units). Hemopure eliminated or reduced the requirement for allogeneic blood transfusions. Results from two red blood cell-controlled trials in general and orthopedic surgery have been published and are listed in the literature.

hemopure

Infection risk

Risk of exposure to any infection with Hemopure is effectively nil and certainly many orders of magnitude less than the potential infective risk of receiving several units of human blood.

hemopure

Transmissible Spongiform Encephalopathy (TSE) transmission, mad cows disease, has been independently evaluated and judged safe by the European Directorate for Quality Medicines (EDQM), and they have issued a Certificate of Suitability for Hemopure. Potential microbial contamination is monitored by bioburden and endotoxin testing performed throughout the processing of the drug substance.

The extensive filtration, chemical purification and polymerization process used to manufacture Hemopure removes and inactivates possible bacterial and viral contaminants. This has been demonstrated by viral clearance studies which have been carried out during the various production phases of Hemopure. Both RNA and DNA viruses, as well as enveloped and non-enveloped viruses have been shown to be cleared by the proprietary production process.

A herd management program ensures that the source material, bovine whole blood, is collected from animals that meet strict safety requirements. Suppliers maintain adequate records to document sourcing (USA and Canada only), age (less than 30 months), appropriate feed, health and vaccination programs, and animals must pass USDA inspection for use as beef for human consumption. OPK Biotech maintains separate facilities for the collection of its source material and a process designed to assure efficient, clean collection of a pharmaceutical raw material.

The extensive filtration, chemical purification and polymerization process used to manufacture Hemopure removes and inactivates possible bacterial and viral contaminants. This has been demonstrated by viral clearance studies which have been carried out during the various production phases of Hemopure. Both RNA and DNA viruses, as well as enveloped and non-enveloped viruses have been shown to be cleared by the proprietary production process.

A herd management program ensures that the source material, bovine whole blood, is collected from animals that meet strict safety requirements. Suppliers maintain adequate records to document sourcing (USA and Canada only), age (less than 30 months), appropriate feed, health and vaccination programs, and animals must pass USDA inspection for use as beef for human consumption. OPK Biotech maintains separate facilities for the collection of its source material and a process designed to assure efficient, clean collection of a pharmaceutical raw material.

Oxyglobin

The product is indicated for the treatment of canine anemia regardless of the cause. Anemia is a potentially life-threatening condition that affects millions of dogs each year. Oxyglobin was introduced to U.S. veterinarians in 1998. Since that time, the product has been used by thousands of veterinarians nationwide to treat various critical conditions.

Other than a blood transfusion, Oxyglobin is the only treatment that provides immediate relief from the clinical signs of anemia in dogs. The most common side effects of Oxyglobin are transient discoloration of skin, mucous membranes and urine.

Circulatory overload is an uncommon but important side effect. Other adverse reactions such as vomiting and melena (dark colored feces) have occurred. Based on data from more than 800 case studies nationwide, Oxyglobin is being used both as an oxygen carrying fluid therapy and as an alternative to red blood cell transfusion (e.g., massive blood loss, immune-mediated hemolytic anemia, etc.).

Normal blood flow

Anemic blood flow

Oxyglobin

Other than a blood transfusion, Oxyglobin is the only treatment that provides immediate relief from the clinical signs of anemia in dogs. The most common side effects of Oxyglobin are transient discoloration of skin, mucous membranes and urine. Circulatory overload is an uncommon but important side effect.

The extraction and purification process used in production has been validated for the removal of potential contaminants including plasma proteins, red blood cell stroma, endotoxin, bacteria, viruses and the agents that are thought to cause transmissible spongiform encephalopathies such as bovine spongiform encephalopathy (BSE) and variant Creutzfeld-Jakob disease (vCJD). This process produces a sterile, pyrogen-free balanced salt solution containing glutaraldehyde cross-linked bovine hemoglobin polymers, which range in size from 130 to 500 kDa and have an average molecular weight of 250 kDa.

Other adverse reactions such as vomiting and melena (dark colored feces) have occurred. Based on data from more than 800 case studies nationwide, Oxyglobin is being used both as an oxygen carrying fluid therapy and as an alternative to red blood cell transfusion (e.g., massive blood loss, immune-mediated hemolytic anemia, etc.).

Oxyglobin is a sterile, intravenously administered solution consisting of chemically stabilized hemoglobin (the protein that carries oxygen) in a balanced salt solution. Unlike blood, it does not contain red blood cells. Instead, it contains cross-linked hemoglobin molecules (several tetramers bound together) that circulate in plasma and immediately transport oxygen to tissues upon infusion.

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hbo main office

674 Souder Road
Souderton, PA 18964
+1 (267) 382 0064
info@hbo2therapeutics.com