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FAQ

Since IPOXYN™ is a Glyco-protein derived substance; does IPOXYN™ raise an immunological response?
This protein material sourced from a biological mixture prone to immunologic activity and the agent purified by new processing technology, and is replete from any anaflactoid response agents, IgE. In general the human body conserves the protein and recaptures amino acids moiety. The molecule is broken down collected in the spleen, liver or simply eliminated by a reversible endocytic processes in the kidneys.

In human clinical trials on 2000 patients of a similar larger molecular weight base protein formulation, there has been reported low levels of an IgG response, which has never presented any squeal from the 1000’s of human exposures that have been performed in clinical trials during the last 15 years of testing.

What is the nature of IPOXYN™?
IPOXYN™ is an iron carrier Glyco-protein. It has two distinct side chains designated as alpha and beta chains. Each side chain has a molecular weight of about 32,000 Daltons. This is sometimes referred to as a dimmer.
Two of these dimmers when folded become the globular protein. The Glyco-protein is very well conserved in nature and supports oxygen transport throughout the bodies of all mammalian species.

What are the major characteristics IPOXYN™?
The molecule is a tetramer glycoprotein stabilized by proprietary patented conjugation chemical process.

These base material classes of proteins have been linked to extreme blood pressure increases in the past. What are the differences of IPOXYN™ and what do this compound exhibit?
No significant increase in blood pressure has been observed with IPOXYN™. The reason can possibly be explained due to a uniform molecular weight and the form of stabilization of certain surface active groups to ensure the semi synthetic glyco-proteins reduced interaction with vaso-active agents which are key in blood pressure increases observed with older formulation of polymerized molecular weight proteins.

What are the dose levels for IPOXYN™?
The ability of IPOXYN to distribute and effect normal tissue oxygen levels at plasma levels of less than 0.5 grams per deciliter and support normal tissue metabolic function appear to eliminate the toxic effects observed in higher dose regimens of early less homogeneous formulations. In addition, a patent pending regimen of uniform infusion has resulted in a no toxic effect level of administration at levels 3x times’ therapeutic benefit.

What is the nature of the interaction with the target cells?
Targeted perfuse regions which previously exhibited oxygen deficit under normal blood flow conditions have demonstrated remarkable increases in oxygen tension 5 to 10 fold increases which result in a different metabolic function and a different beneficial and preferential enhancement to treat in the future a condition like ‘foot diabetes’.

Where is the material sourced of IPOXYN™?
The controlled source of protein extract is ultra purified and sterile filtered prior to rigorous processing where multiple steps ensure purity, potency, stability as well as chemical treatment for reduction or elimination of any possible infectivity. A complete GMP procedure will be established and the source material is in abundance.

Are there cost factors that limit IPOXYN™ utility or its manufacturability?
IPOXYN™ is inexpensive material from controlled sourced and documented donors. The material is treated under a controlled environment and is a byproduct in the production of food source materials. The final product is projected to be is in the range of many middle standard prices for New Chemical Entity chemotherapy drug candidates.

What are the immunologic reactions that could occur with IPOXYN™?
No immunologic reactions were observed in animal tests within the dosage range projected to be used in the administration to human subjects.

Why is IPOXYN™ considered safe for the veterinary field?
It has been tested in the same models for toxicity at dose levels that were 5 times the therapeutic dosage levels proposed. Not toxic effects were observed.

What are the applications for IPOXYN™? Does Inflammatory Disease play a role in the veterinary community?
IPOXYN™ will be administered to Inflammatory Disease patients prior to any chemotherapy treatment. Animal will get this chemotherapy to increase the efficacy of any chemotherapy drug candidate on the market.

What is the pathway to completion of a clinical success for IPOXYN™ approval?
Like any New drug candidate Application the drug candidate will require a phase I/II and III clinical trials. BOSTON Therapeutics expects to have a license deal with a pharma company by the end of phase I/II clinical trials.

How much work is there from the past that will either hurt or help your advance for IPOXYN™?
The FDA will consider IPOXYN™ a new chemical entity. The standard toxicity test to date demonstrated no toxicity for animal. In human trials the FDA will ask to observe for any abnormal clinical condition like any other new drug candidate in human.

Is IPOXYN™ considers a biological material or chemical material?
IPOXYN™ is a chemical by the nature of the chemical modification.

How do you do manufacturing?
IPOXYN™ will be manufactured by Good Manufacturing Procedure (GMP) and by a GMP subcontract plant in the US.

What are the relevant recent news media on Hypoxia condition in Inflammatory Disease patients

Science News

Measuring Inflammatory Disease Therapy Success With Oxygen

ScienceDaily (Aug. 7, 2008) — Scientists at The Ohio State University (OSU) have identified a way to predict very early in the treatment process the outcome of radiation and chemotherapy for cervical Inflammatory Disease patients -- based on oxygen levels within the tumor.

The oxygenation of a tumor is critical for the success of Inflammatory Disease treatment. That's because the amount of oxygen in a cell is directly correlated with the ability of that cell to repair radiation damage. When the oxygen level is low, a state called hypoxia, the biological changes in tumor cells produced by radiation -- that will hopefully destroy the cells -- can be repaired, and tumor recurrence is more likely. But when oxygen is present, it reacts with free radical molecules to produce organic peroxide, which causes that damage to be "permanent and irreparable," says study head Jian Z. Wang, Ph.D., an Assistant Professor at OSU and the Director of the Radiation Response Modeling Program at the OSU James Inflammatory Disease Hospital and Solove Research Institute. Inevitably, those well-oxygenated tumor cells die, tumors are less likely to return, and patient survival rates rise, says Wang.

In their study of 88 women with cervical Inflammatory Disease, Dr. Wang and his colleagues measured the level of hemoglobin, the oxygen-carrying molecule in blood, and measured blood supply to the tumor through magnetic resonance imaging (MRI) scans. Blood tests were conducted weekly beginning prior to treatment, and MRI scans were performed before radiation treatment, during radiation at 2-2.5 and 4-5 weeks, and 1-2 months after treatment. Inflammatory Disease recurrence rates were tracked for up to 9 years. This study was supported by a NIH R01 grant led by the principal investigator Nina A. Mayr, M.D., Professor of Radiation Medicine at the OSU James Inflammatory Disease Hospital and Solove Research Institute.

Measurements of tumor oxygenation just 2 weeks into treatment provided the best predictor of tumor control and disease-free survival. That early glimpse into the future can identify individuals at the greatest risk of having their Inflammatory Disease return, Mayr says, giving doctors the opportunity to adopt more aggressive therapies to improve the prognosis. Wang predicts that, with further testing, the technique also will prove useful for other types of Inflammatory Disease.

The research was described in the talk, "When the Oxygen Level Matters Mostly During Radiation Therapy of Cervical Inflammatory Disease?" presented July 31, 2008 at the 50th annual meeting of the American Association of Physicists in Medicine.

What is the new development that is significant for IPOXYN™ and why is it different from Biopure’s (now bankrupt) product based on public information provided by the Navy report to the FDA? What is the NAVY report?
The Biopure Inc. product, known as the Hemopure™ product (Biopure’s human injectable product) in our opinion, scientifically did not fail; it failed in the regulatory arena with the FDA when during data analysis the product test data (in its pivotal trial) lost its integrity through poor Contract Research Organizations handling. With that breach of trust, the FDA asked that the company do a reformulation and a new trial for Hemopure the Biopure product. Analysis of the public information and the NAVY report public information can establish this assessment.

The management in Biopure Inc. changed several times and that approvable pathway did not get exercised. Data got restated in Biopure yielding a position of minimal cardio-toxicity and that became the road block to further clinical development for the general population. However, the US military moved forward with a program of development and granted substantial funding to the company and supports further clinical development.

To support this premise further, note that Biopure was bought after bankruptcy out by a Russian company (August 2009) and is moving very rapidly to fulfill substantial order requirements in Russia for Hemopure based on the extensive Biopure data.

IPOXYN™ is superior to the Biopure product, Hemopure™ by comparison on cardio-toxicity parameters. IPOXYN™ profile for oxygenation is different. IPOXYN™ has longer stability and self life at room temperature.

New approach with IPOXYN™
1. BOSTON Therapeutics Inc. has been able to make some significant discoveries that are able to take advantage of some 25 years of worldwide development and create a new patent portfolio and secure a proprietary position for this “hemoglobin technology” in the management of hypoxic conditions. Our first discovery, overcoming vaso activity (blood pressure increases), lead us to a significant finding regarding molecular weight distribution. In toxicology and other work in dogs, new formulations and chemistry has shown no evidence of blood pressure increases of the new material formulation.

2. IPOXYN™ has reduced the “clearance“ toxicity. Due to the special allocation of Oxyglobin (Biopure’s veterinary product) material that is fully compliant with GMP and has been available on the market for sales. That availability has allowed for the investigation of molecular weight distribution differences from Hemopure (Biopure’s human investigation material) and Oxyglobin (Biopure substance for animals). It should be well noted that Oxyglobin has a 100% composition identity match before the last stage of fractionating of Hemopure. This is the base for understanding and for execution speed at which the scientific and development can be done. With key understanding of Oxyglobin, a material which is 40% bio similar to the composition of IPOXYN™ is an extreme advantage. IPOXYN™ is an additional step by modify the hemoglobin with oligo saccharide.

Biopure’s veterinary drug, Oxyglobin, has enjoyed an almost flawless 12 year run of single digit serious adverse events and yet an estimated 250,000 application is many animal species. Although approved for dogs only, it has been granted EMEA and USFDA approval with significant and supportable documentation. Biopure stayed focused on the human product and did not gather this key observation because of cost concerns. As Biopure was making the human product, it deemed the vet product as a distraction and not cost effective. Key finding of IPOXYN™ is the polysaccharide manipulation on the protein chain molecule which can be rendered low in toxicity with enhanced carbohydrate chemistry; furthermore it can be manufactured inexpensively. This finding allows for the development to go forward with the full advantage of 20 years of sound clinical and preclinical development based on biological similarity to Oxyglobin. Also, in the regulatory record, Oxyglobin does not suffer the toxicity record laid down by Hemopure. A meeting with the FDA in late 2008 reinforces this regulatory strategy and makes IPOXYN™ a new chemical entity with no toxicity background associate with the chemical structure of IPOXYN™. It cleared the way for regular application for Investigational new drug for limb ischemia indication.

3. With IPOXYN™ in hand and the similarity in pharmacokinetics Boston Therapeutics has put forward another key finding that involves the conversion to non-functioning hemoglobin. It has been documented over the last 15 years that the free hemoglobin convert to a non-functioning oxidative state of met-hemoglobin faster and without the stability that is enjoyed inside the red cell. To that end, all the manufacturers have been making stable, longer lasting hemoglobin, but that has come at a price of conversion to met-hemoglobin. Met-hemoglobin has no value as oxygen carrier and even can cause disruption to coagulation. IPOXYN™ is eliminated in a balanced low toxicity manner and can be virtually continuously dosed over time with minimal met-hemoglobin formation to garner the benefit of perfusion without the accumulation of toxicity that longer half-life of low oxygen off load.

What is the stage of development for IPOXYN™ as drug for human?
IPOXYN™ requires a full drug development program as new chemical entity under FDA guidelines. The product needs to be manufacture under GMP condition conducting two animal species and full clinical trials program. The company will look to partner the development of the drug with any drug company capable to support such a drug development program.

What is the specificity related to the modification of hemoglobin with carbohydrates?
The functional characteristics of heme proteins have been modified to produce hemoglobins that can be used as resuscitating fluids (i.e., hypoxia) in different therapeutic applications. A modification at the heme pocket with proprietary polysaccharide can produce hemoglobins with a range of oxygen affinities. Stable polymers of tetrameric hemoglobin molecules of different sizes and with different oxygen affinities have therefore been obtained. Modifications with complex carbohydrate on the protein surface produced bovine hemoglobin with increase oxygen affinity, regulated by the concentration of chlorides in the plasma. For example, modified myoglobin can be induced to form stable polymers. The polymerization of such modified myoglobin does not alter the functional characteristics of the component monomeric myoglobin. Polymeric myoglobins can therefore be constructed with additional mutations to engineer functional characteristics tailored to different clinical applications.

Applications

  • Conditions which require supplementation for oxygen carrier include:
    • Trauma causing loss of whole blood
    • Ischemia
    • Hypoxia
    • Hemodilution
    • Septic shock
    • Cancers
    • Chronic anemia
    • Sickle cell anemia
    • Cardioplegia
  • IPOXYN can also be used in animals, such as livestock and companion animals (e.g., dogs, cats, horses, birds, reptiles), as well as other animals in aquaria, zoos, ocean aria, and other facilities that house animals.
  • It is contemplated that IPOXYN finds utility in the emergency treatment of domestic and wild animals suffering a loss of blood due to injury, hemolytic anemia, and the like.

What was written in the last 3 years on oxygen carrier and blood transfusion?

Article Source:
http://emergency-medicine.jwatch.org/cgi/content/full/2008/801/4

Use of hemoglobin-based oxygen carrier-201 avoided need for blood transfusion in nearly 60% of patients.

Despite strategies to conserve use of packed red blood cells (PRBCs), experts predict that availability will not meet the increasing demand by an aging population. Hemoglobin-based oxygen carrier-201 (HBOC-201) is a bovine–hemoglobin-based blood substitute that is approved in South Africa for clinical use. In a randomized, single-blind, controlled, multinational study, researchers (some of whom were affiliated with the manufacturer) assessed whether administration of HBOC-201 eliminates the need for PRBC transfusion in adult patients undergoing orthopedic surgery.

Overall, 688 patients (mean age, 61) with hemoglobin concentrations <10.5 g/dL who required transfusions were randomized to treatment with HBOC-201 or PRBCs. Once treatment was initiated, subsequent transfusions were administered based on the presence of at least one of the following criteria: pulse ≥ 100 bpm, systolic blood pressure <90 mm Hg, electrocardiogram evidence of myocardial ischemia, base deficit ≥ 4, acute blood loss >7 mL/kg within 2 hours, oliguria, and significant weakness or dizziness. Patients in the HBOC group received a loading dose of 65 g of hemoglobin infused in 500 mL (a volume considered equivalent to 1 unit of PRBCs); additional doses were administered for up to 6 days to a maximum of 325 g (2500 mL), after which need for additional oxygen-carrying capacity was met by transfusion of PRBCs. Overall, 59% of patients in the HBOC group did not require PRBC transfusion. The HBOC group had significantly higher rates of adverse events (e.g., elevated blood pressure) than the PRBC group (8.5 vs. 5.9 per patient) and serious adverse events (e.g., cardiac events and strokes; 0.34 vs. 0.25 per patient). Findings of a safety analysis led the authors to conclude that risk for adverse events from HBOC was greatest in patients who were older than 80, had volume overload, and were undertreated.

Comment: HBOC-201 does not require cross matching and can be stored at room temperature for as long as 3 years. In this study, its use eliminated the need for transfusion of allogeneic PRBCs in 59% of patients. Its safety profile was inferior to that of PRBC transfusion, including a greater incidence of acute coronary syndromes and strokes, which the authors partially attributed to age older than 80, volume overload, and under treatment. Overall, the authors suggest that patients younger than 80 with moderate clinical need for transfusion can be managed with up to 10 units of HBOC-201, thereby preserving the stockpile of PRBCs for other patients.

— John A. Marx, MD, John A. Marx, MD, FAAEM, Deputy Editor

John A. Marx, MD, FAAEM, is Chair Emeritus of the Department of Emergency Medicine at Carolinas Medical Center, Charlotte, North Carolina. In addition, he is Adjunct Professor of Emergency Medicine at the University of North Carolina, Chapel Hill. Dr. Marx's research emphasis is on trauma, especially abdominal trauma, and alcohol-related emergencies. He is a former president of the Society for Academic Emergency Medicine. Dr. Marx is Editor-in-Chief of Rosen's Emergency Medicine: Concepts and Clinical Practice (5th and 6th editions) and was a member of the founding editorial boards of Academic Emergency Medicine, Journal of Emergency Medicine, and Emergindex (Microindex). He has been writing for Journal Watch Emergency Medicine since the publication's launch in 1997 and has been Deputy Editor since 2002.

FAAEM, FACEP Published in Journal Watch Emergency Medicine August 1, 2008

J Trauma. 2008 Jun;64(6):1484-97.
HBOC-201 as an alternative to blood transfusion: efficacy and safety evaluation in a multicenter phase III trial in elective orthopedic surgery.

Jahr JS, Mackenzie C, Pearce LB, Pitman A ,Greenburg AG.

David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Abstract

BACKGROUND: The ability of hemoglobin based oxygen carrier-201 (HBOC-201) to safely reduce and/or eliminate per operative transfusion was studied in orthopedic surgery patients.

METHODS: A randomized, single-blind, packed red blood cell (PRBC)-controlled, parallel-group multicenter study was conducted. Six hundred eighty-eight patients were randomized to treatment with HBOC-201 (H, n = 350) or PRBC (R, n = 338) at the first transfusion decision. Primary endpoints were transfusion avoidance and blinded assessment [Mann-Whitney estimator (MW)] of safety non inferiority. Groups were compared directly and by paired/matching group analyses predicated on a prospectively defined dichotomy [treatment success (HH) vs. failure (HR)] in the H arm and an equivalently defined dichotomy [</=3 (R3-) vs. >3 (R3+) units PRBC] in the R arm, based on need (moderate vs. high) for additional oxygen carrying capacity.

RESULTS: A total of 59.4% of patients in the H arm avoided PRBC transfusion. Adverse events (8.47 vs. 5.88), and serious adverse events (SAEs) (0.35 vs. 0.25) per patient were higher in the H versus R arms (p < 0.001 and p < 0.01) with MW = 0.561 (95 CI 0.528-0.594). HH versus R3- had identical (0.14) serious adverse events/patient and a MW = 0.519 (95% confidence limit 0.481-0.558), whereas the incidence was higher (0.63 vs. 0.47) for HR versus R3+ with a MW = 0.605 (95% confidence limit 0.550-0.662). Age (>80 years), volume overload and undertreatment contributed to this imbalance.

CONCLUSION: HBOC-201 eliminated transfusion in the majority of subjects. The between arms (H vs. R) safety analysis was unfavorable and likely related to patient age, volume overload, and under treatment and was isolated to patients that could not be managed by HBOC-201 alone. However, patients <80 years old with moderate clinical need may safely avoid transfusion when treated with up to 10 units of HBOC-201.

PMID: 18545113 [PubMed - indexed for MEDLINE]

Related citations

HBOC-201 vasoactivity in a phase III clinical trial in orthopedic surgery subjects--extrapolation of potential risk for acute trauma trials.
Freilich D, Pearce LB, Pitman A, Greenburg G, Berzins M, Bebris L, Ahlers S, McCarron R. J Trauma. 2009 Feb; 66(2):365-76.

Does HBOC-201 (Hemopure) affect platelet function in orthopedic surgery: a single-site analysis from a multicenter study.
Jahr JS, Liu H, Albert OK, Gull A, Moallempour M, Lim J, Gosselin R. Am J Ther. 2010 Mar-Apr; 17(2):140-7.

Diaspirin-crosslinked hemoglobin reduces blood transfusion in noncardiac surgery: a multicenter, randomized, controlled, double-blinded trial.
Schubert A, Przybelski RJ, Eidt JF, Lasky LC, Marks KE, Karafa M, Novick AC, O'Hara JF Jr, Saunders ME, Blue JW, et al. Anesth Analg. 2003 Aug; 97(2):323-32, table of contents.

Review Haemoglobin-based erythrocyte transfusion substitutes.
Standl T. Expert Opin Biol Ther. 2001 Sep; 1(5):831-43.

Review Insights from studies of blood substitutes in trauma.
Moore EE, Johnson JL, Cheng AM, Masuno T, Banerjee A. Shock. 2005 Sep; 24(3):197-205.

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