Immune Technologies, LLC Product Description

I.          Executive Summary

Immune Technologies^TM, “LLC” (“the Company” and “IT”) is a Florida company that provides treatment technologies for viral, fungal, bacterial and protozoal diseases and health conditions, particularly HIV/AIDS and Rheumatoid Arthritis, based on a patented technology invented by its medical director, Stephen Herman, M.D.

The Company’s lead therapeutics are Alphamir ^TM, as a prescription-only medicine to combat HIV/AIDS, and Arthromir^TM for Rheumatoid Arthritis.  Both of these inventions utilize Trioxolane derivatives that, upon introduction to the body’s aqueous ambience, reduce and produce high-energy oxygen metabolites within the blood stream as well as activate certain receptor cells in the oropharyngeal cavity.  These receptor cells cause the body to produce CD4 cells that are the precursor cells to the evolvement of lymphocytes, and thereby modulate the natural immune process in the body.

On May 24^th, 2001, the Company received provisional two-year registrations for use of Alphamir^TM as a prescription-only medicine to combat HIV/AIDS and for Arthromir^TM for Rheumatoid Arthritis.  The two-year registrations are renewed in five-year intervals.  These approvals came after completing clinical trials at the Kenya Medical Research Institute.  Immune Technologies has provided updated clinical data to the Pharmacy Poisons Board at the one-year anniversary in May 2002.  These approvals allow the resultant medicines to be used as ethical drugs in 21 sub-Saharan African countries that are members of the East African Medical Conference.

AIDS IS OUR FOCUS:  In Africa, the number of people suffering from HIV/AIDS has reached upwards of 20,000,000 in 2002 and 42,000,000 worldwide.  These figures are expected to increase to nearly 100,000,000 by 2010.  With HIV/AIDS reaching pandemic magnitudes, the Company is focusing its product launch initiatives on HIV/AIDS in Africa and then to other countries, Europe and the United States. 

HOW WE ARE UNIQUE:  Our approach to combat disease is unique from the common practice of using antimicrobial agents that can be toxic; rather, it utilizes the basic science within the white blood cells, called ‘the respiratory burst.’  The respiratory burst is the process by which the body’s immune system produces bio-oxidants to destroy abnormal cells and invading microorganisms.  Trioxolane emulates this process by producing oxidative metabolites that are anti-microbial, immuno-stimulatory and non-toxic.  This approach reinforces the natural immune system in combating harmful agents and regulates the production of serotonin, prostaglandin and inflammatory interleukins.

SAFETY PROFILE:  AlphamirTM is a safe and non-toxic substance.  The safety profile was performed over a period of 6 years between 1988 and 1994 in four laboratories located in the United States, Cuba, and Kenya.   Three of the facilities were medical academic institutions (University of California at Irvine, Kenya Medical Research Institute, and University of Cuba, LaHabana) and the fourth was a professional contract research organization located in California.  Nineteen different safety and toxicity studies were performed including:  minimum inhibition concentration assays, minimum bacterial concentration assays, acute systemic toxicity, dermal toxicity, oral toxicity, ocular irritation, primary skin irritation, vaginal and rectal irritation, AMES mutagenesis assays, micronuclei in mouse bone marrow, and other topical studies were performed in order to substantiate the effectiveness, safety, and tolerability of AlphamirTM.  Of these nineteen studies, a total of 312 mice, 65 rats, and 70 rabbits were used in order to substantiate the safety of the product.  

IT CLINICAL TRIALS:  AlphamirTM and ArthromirTM’s clinical investigator is Davy Kiprotich Koech BSc, MS, PhD, Cbiol, MIBiol, FinstPM, SS, CuD (Hon.), OGW.  For the past 14 years, Dr. Davy Koech has served as Chief Research Officer and Director of the Kenya Medial Research Institute (KEMRI).  He is the author of 161 refereed journal publications in the fields of Leishnamiasis, Schistosomiasis, Malaria, AIDS, and numerous other diseases. Research physicians, under Dr. Koech’s direction, conducted anecdotal, Phase I, and Phase II HIV/AIDS and Rheumatoid Arthritis studies which were completed at KEMRI on a total of 176 patients.  From 1992-1993 a Phase I double blind clinical trial with 30 patients; 3 study arms with 10 patients each – Oropharyngeal, Suppository, and Control was performed for AIDS.  The immunological results were:  CD4+ lymphocyte levels in groups treated with AlphamirTM increased 100+% versus 0% change for the control group.  From 1999 - 2001 the AIDS Phase II Open label clinical trial with randomized dose ranging for efficacy, safety and tolerability of AlphamirTM was performed with 43 patients which consisted of 3 study arms at buccal dose levels of Group 1 - 100 mg, Group 2 - 200 mg, and Group 3 - 400 mg.  Results from   Group 1 showed consistent and steady rise in weight; 50% of patients showed significant rise in CD4+ count with 33% drop in viral load.  The successful results led both drugs to provisional fast tract registrations as a prescription medicine for ethical use with continued research efforts.  Follow-up continues with monthly viral loads and no adverse effects encountered.  Funds are needed to begin Phase III clinical trials administering Alphamir as monotherapy and in combination therapy with other drugs/therapies.

IT STRATEGY:  The Company will simultaneously focus its attention on significant distribution of Alphamir ^TM for HIV/AIDS and Arthromir ^TM for Rheumatoid Arthritis in Africa at very low costs while it looks to promote its products with a pharmaceutical partner in developed markets.  IT suggests that the only viable and effective approach to contain HIV/AIDS must include a comprehensive program to:

1)      administer a low-cost self-testing procedure which we will co-market;

2)      treat infected HIV/AIDS population with Alphamir; and

3)      administer a vaginal gel for the prevention of transmission which we are developing.       

The demand for the use of this treatment strategy is great enough to support incrementally larger requirements of funding.  At this time, we are actively pursuing funds for Phase III clinical trials, to execute this treatment strategy, and manufacture and distribute the products.  It should be noted that the best scientific evidence supports the fact that viral strains cannot develop resistance to Alphamir ^TM and this represents a major breakthrough in the ability to effectively control the AIDS pandemic.

PROBLEM AND SOLUTION:  IT is taking an integrated approach with a cost effective treatment program.  Estimates to treat the current 42 million plus infected people range from approximately $316 to $3,325 per year using presently available Highly Active Antiretroviral Treatment (HAART).  In addition, the cost of the medical infrastructure for distribution, monitoring and training necessary for use of these treatment programs is prohibitive throughout Africa.  IT is launching Alphamir ^TM with a cost of $205 per year per patient for an orally prescribed medication not requiring water to swallow.  Efforts are being made to bring those costs down substantially for Third World countries.  The dosage of 100 mg, 4 times a day (10 drops/25 mg under the tongue 4 times) is expected to be available in tablet form that melts in the mouth without water.

The Company’s proprietary technology is unique and is closely guarded.  The technology is protected by existing and future pending patents.  The process and use of Trioxolane is patented in the U.S.A., Mexico, and Canada.  Its use will offer the production of ethical drugs that will be further tested in clinical trials for the treatment of viral, bacterial, and fungal diseases. Subsequent patents are to be issued and will cover our invention internationally.

II.        Market Review

IT’s registrations are valid in twenty-one African countries that are members of the East African Medical Conference to fight the symptoms of HIV/AIDS and Rheumatoid Arthritis.  In Africa, the number of people suffering from HIV/AIDS has reached upwards of 20,000,000 in 2002 and 42,000,000 worldwide.  These figures are expected to increase to nearly 100,000,000 by 2010.  In 2001, five million people were newly infected, three million died of AIDS (8,000 people a day), leaving 13.2 million children orphaned and a death total of more than 21,800,000 people thus far. 

The Company plans to commence its efforts to obtain approval for the use of its products as ethical drugs in Europe, Asia, Latin America, and South America.  Simultaneously, Immune Technologies will begin IND discussions with the US Federal Drug Administration (FDA).  In the United States, it is reported that a new drug costs upward of $800,000,000 and 10 years to receive US FDA approval.  In comparison, to date, $10,000,000 and 14 years of research have gone into developing Alphamir ^TM.  The Company believes that once the efficacy of Alphamir ^TM is demonstrated aboard, combined with its track record in 600+ patients as safe and non-toxic, US FDA approval should be less expensive and fast tracked. 

III.       Competition

Presently there are numerous costly alternatives to Alphamir™ for treatment of HIV/AIDS in Africa.  Estimates to treat the current 20 million plus infected people range from approximately $316 to $3,325 per year using presently available Highly Active Antiretroviral Treatment (HAART).  In addition, the cost of the medical infrastructure for distribution, monitoring and training necessary for use of these treatment programs is prohibitive throughout Africa.

Our data suggests that Alphamir™ is equally or more effective than current treatments.  Clinical trials with Alphamir™ have shown no toxic effects and require minimal special training and monitoring.  We are confident that clinical trials of Alphamir™ will demonstrate that it can be used as an effective vaginal gel to prevent transmission of HIV.  This will be the only truly effective means of curbing the AIDS pandemic.  No other current technology has this potential.  In addition, the cost of our product is lower than the currently available treatments on the market.  Immune Technologies is also cost competitive when compared with the generic treatments known today.  Alphamir™ is 1/5^th the cost of the lowest offer from proprietary companies.

According to Kenyan government figures, only 2,500 out of 200,000 AIDS patients in Kenya are currently receiving antiretrovirals, (ARVs).  The drugs are only available in high-cost private hospitals such as the Aga Khan, the Nairobi, the Pandya Memorial Hospital, the private wing of the public Kenyatta National Hospital, and a few church-run hospitals."  While generic AIDS drugs are now allowed into Kenya under compulsory licensing provisions in the Industrial Property Act of July 2001, which came into force in May this year, one major problem is that a majority of the patients say that the drugs are not available.  Some patients are switching to other drugs and then developing resistance.  "We are going to end up with serious resistance and two years from today we might have no ARVs that we can use," Dr. John Wesongo of Nairobi's Mbagathi Hospital. 

Nicholas Otieno, who has been living with HIV/AIDS since 1992, speaks of the irregular supplies of ARVs, which can lead to HIV-resistance to the treatments.  "Since I started taking antiretroviral drugs last July, I have twice been unable to get my regular supply of Zerit.  Once I could get Epivir as a substitute, but that costs 4000 Kenya shillings (US$50) per month instead of the usual KES 440 (US$5) I pay for Zerit.  The other time I went without a substitute for two weeks."  Liza Kimbo of the Kenya Coalition for Access to Essential Medicines says the problem of drug shortages started last year when the five major drug companies lowered the prices of their AIDS drugs for Africa by between 50 -80%....it's the big five.  It's the companies that have provided these drugs at the beneficial prices are the ones that are then affected with the shortages.  Inter Press Service–April 23, 2002

Kenya has said yes to generic ARVs, but failed to win funds from the Global Fund for HIV/AIDS, TB & Malaria.  Upon approval, the government planned for 300,000 people in Kenya to receive generic drugs IF they received the funding.  Nairobi hopes that the generics will undercut the prices of branded ARVs, which despite manufacturers 'reductions' still cost US $850 a year for the cheapest triple therapy.  That is less than a tenth of the price in the developed world, but still too much for the 10 million people in Kenya who live on less than US $1 a day. 

Generic triple therapies including AZT, 3TC, and nevirapine are now down to prices of around US $295 a year but still dear in the African context.  Ellen Hoen, coordinator of the globalization section of the Medicines Sans Frontiers (MSF) campaign for access to essential medicines, knows of other courses costing only US $209.  It's still not low enough 'but the prices could go down further', she says.

The Ministry has already announced its intention to make a reapplication to the Global Fund when its board sits again in September.

IV.       Alphamir™ – Technology Overview

Immune Technologies, “LLC”, has developed an entirely new medicinal agent, Trioxolane, designated Alphamir™.  This agent was developed in response to the increasingly urgent need to treat the worldwide threat of viral epidemics, as well as to the increasing occurrence of antibiotic-resistant organisms.  We believe Alphamir™ is a major breakthrough in therapeutic medicine and its broad efficacy brings a new understanding of the human immune system and our natural disease fighting mechanisms.

The most broadly successful therapy for human disease is provided by our own immune system.  This includes all infectious, neoplastic, and autoimmune diseases.  An intact and functioning immune system maintains a disease-free state, while a suppressed or dysfunctional immune system leaves us susceptible to a wide spectrum of maladies, almost without restriction. 

The process by which Alphamir™ acts as a microbicidal agent is best explained through the understanding of the Respiratory Burst; the natural way our bodies fight microbes and tumor cells.  White blood cells produce high-energy bio-oxidants, to kill viruses, fungi, and bacteria and to modulate immune function.  Through significant in-vitro, pre-clinical and clinical research studies, Immune Technologies has demonstrated that Alphamir™ augments this natural process.

a.                  Biochemistry of Alphamir™

Phagocytes employ, as antimicrobial agents, a number of compounds generated by partial reduction of oxygen.  Oxygen is initially reduced to superoxide (O₂^-) by a membrane-associated flavoprotein.  This process occurs in a respiratory burst via glucose oxidation in the hexose monophosphate shunt.  Oxidized NADPH participates as follows:

(O₂ + NADPH yields 2O₂^- + NADP^- + H^-) subsequently by dismutation (superoxide dismutase) 2O₂^- + 2H⁺₂ yields O₂ + H₂O₂.  Present theory suggests that microbicidal action by phagocytes is mediated by myeloperoxidase that catalyzes the conversion of H₂O₂ and Cl^- to hypochlorous acid (HOCl).  In support of the effectiveness of this mechanism it is interesting to note that 2X10^-7 M of HOCl generated by 10⁶ neutrophils will destroy 15x10⁷ e.coli in milliseconds.  In short, neutrophils purposely generate large quantities of reactive oxidants for microbicidal purposes.  Interestingly, HOCl is the sole active ingredient in bleach.  HOCl quickly reacts with primary or secondary amines to form an additional family of microbicidal agents called chloramines. 

The term “respiratory burst” refers to a coordinated series of metabolic events that take place when phagocytes are exposed to appropriate stimuli.  This group of events underlies all oxygen-dependent killings by phagocytes. 

b.         The Basic Science

Alphamir^TM incorporates Trioxolane derivates that, upon introduction to the body’s aqueous ambience, reduce and produce high-energy oxygen metabolites within the blood stream as well as activate certain receptor cells in the pharyngeal cavity.  These receptor cells cause the body to produce cells that are the precursor cells to the evolvement of lymphocytes, and thereby modulate the natural immune process of the human body.

More specifically, Alphamir^TM acts in vivo through the production of free radicals.  Neutrophils and other phagocyte leukocytes can utilize these free radicals to produce multiple pathogenic toxins thus materially increasing the efficiency of the immune system to kill invading microorganisms.  In addition, these free radicals exert a strong direct microbiocidal effect even in the absence of leukocytes.  Free radicals also exert both an immunomodulatory and immunostimulatory effect by chemotactically signaling the immune system that a pathogen/leukocyte interaction is occurring.  Little is known as to how Alphamir^TM works on a molecular level.  Effects can be divided into long-term and short-term actions.  Short-term effects include such things as lysis of pathogenic organisms, abnormal cells, and toxins.  Alphamir^TM may have activity by destroying or blocking the activity of inflammatory agents such as prostaglandins. 

Long-term effects are mediated via immune system modulation and stimulation as well as enzyme system modulation.  It has been shown that uptake of these radicals in infected cells is preferential in a ratio of 4 to 1 with uninfected cells.  It appears that Alphamir^TM also plays a role in cell membrane stabilization.

c.                   Safety & Toxicity Studies  (Note:  A more robust explanation of the Safety & Toxicity Studies can be viewed in the Appendix A)

Alphamir^TM is a safe and non-toxic substance.  The safety profile was performed over a period of 6 years between 1988 and 1994 in four laboratories located in the United States, Cuba, and Kenya.  Three of the facilities were medical academic institutions (University of California Irvine, Kenya Medical Research Institute, and University of Cuba, La Habana ) and the fourth was a professional contract research organization located in California.  19 different safety and toxicity studies were performed including: Minimum Inhibition Concentration assays, Minimum Bacterial Concentration assays, acute systemic toxicity, dermal toxicity, oral toxicity, ocular irritation, primary skin irritation, vaginal and rectal irritation, AMES Mutagenesis assays, Micronuclei in Mouse Bone Marrow, and other topical studies were performed in order to substantiate the effectiveness, safety, and tolerability of Alphamir^TM.  Of these 19 studies, a total of 312 mice, 65 rats, and 70 rabbits were used in order to substantiate the safety of the product.  The following includes a summary of important results:

·        Alphamir^TM was considered non-irritant to ocular tissue in the rabbit. 

·        The product would be considered dermally non-toxic to the rabbit; the LD50 was greater than 2.3 ml/kg of body weight of a 1% (w/v) solution of the test article in the solvent. 

·        The product would be considered a slight irritant to the skin.

·        The oral, single dose, LD50 of Alphamir^TM was determined to be greater than 5,010 mg/kg body weight in the rat.

·        The results show that the rats can tolerate daily I.P. of Alphamir^TM at a dose of 214 mg/kg that is almost 25 times higher than that proposed for AIDS patients (8.7 mg/kg).  

·        Female rats given Alphamir^TM I.P. doses up to 63 mg (586 mg/kg) in 0.5 cc tolerate a higher dose level [63 mg (586 mg/kg)] than male rats.  The Alphamir^TM level tolerated by rats is at least 380 mg/kg. 

·        The result was an LD50 of Alphamir^TM in mice has been calculated to be 700 mg/kg.  The minimum tolerable dose is 600 mg/kg.

·        Medium lethal dose was not obtained because only one male rat died in 4 hours after a single oral dose larger than 5 g/kg.  Substances with a LD50 larger than 5 g/kg orally administered to rodents are considered as non-toxic or moderately toxic substances.  Thus, this pharmaceutical preparation of Alphamir^TM is practically non-toxic when orally administered.

·        Alphamir^TM does not show a mutagenic effect at any of the studied concentration for all strains included in AMES Test.  Because of the phenotypic characteristics of Salmonella stocks selected in the AMES Test, Alphamir^TM does not present a mutagenic effect of the kind of mutations due to a frame shift running nor to changes of base pairs. 

Toxic concentration values found in some strains do not correspond to the reported inhibitory concentrations for Alphamir^TM in several pathogenic bacteria.

·        No toxicity sign was observed during a period of 15 days in mice of both sexes, after being topically administered with a larger dose of 5000 mg/kg.  There was no sign of dermic irritation during the time of observation.  Alphamir^TM does not show any toxicity sign due to its topical administration in single doses to mice of both sexes.

d.                  The Clinical Investigator 

Davy Kiprotich Koech  BSc, MS, PhD, Cbiol, MIBiol, FinstPM, SS, CuD (Hon.), OGW:  Since 1989, Dr. Davy Koech has served as Chief Research Officer and Director of the Kenya Medical Research Institute.  He is the author of 161 refereed journal publications in the fields of Leishmaniasis, Schistosomiasis, Malaria, AIDS, and numerous other diseases.  He has performed research under numerous grants and programs with the World Health Organization’s Immunology Research and Training Centre, served as a Fulbright-Hays Scholar/Pharmacologist at Duquesne University, Montefiore Hospital (Department of Neurosurgery), and Harvard University Medical School (Departments of Medicine and Biological Chemistry).  Since 1988 Dr. Koech has served as a member of the World Health Organization’s Regional Panel of Experts on AIDS and as a member of the International Council for Infectious Diseases.  He was honored to receive the Presidential Award (State Investiture) of the Decoration of the Silver Star of Kenya (S.S.) in 1984 and the Presidential Award (State Investiture) of the Decoration of the Order of the Grand Warrior of Kenya in 1989 both in recognition of distinguished service rendered to his nation.  Dr. Koech is a member of Who’s Who in Science and a member of the International Who’s Who in Medicine.  Dr. Koech was also honored to receive the Medal of Honor commemorating distinguished lifelong achievements from the American Biographical Institute in 1987.

Dr. Koech received his BSc (Chemistry & Zoology) from the University of Nairobi in 1974, his MS (Pharmacology – Majored in Clinical Pharmacology) from Duquesne University in Pittsburgh, PA in 1977, and his Ph.D. (Medical Pathology, Immunology) from the University of Nairobi.  Dr. Koech is a member of the East African Society of Parasitologists, British Society for Immunology, British Transplantation Society, Institute of Biology (U.K.), Institute of Professional Managers and Administrators (Fellow), Britain, International Society of Infectious Diseases, Association of Physicians of East and Central Africa, and Kenya Association of Clinical Pathologists. 

e.        Phase I Clinical Trial – HIV/AIDS     Efficacy of Trioxolane Alphamir^TM In the Clinical Management of HIV Seropositive and Symptomatic Individuals – 1992-1993 

After sufficient safety and toxicity studies were performed, a Phase I study protocol was developed and deployed at the Kenya Medical Research Institute by physicians under the direction of its Chief Research Officer, Dr. Davy Koech.  This Phase I double blind 12 week clinical trial in consenting individuals infected with HIV-1 using Alphamir^TM was performed to evaluate the clinical efficacy and safety of Alphamir^TM in the management of symptoms associated with HIV infections and to assess the changes in immunological profiles in patients receiving the drug. 

Patients of either sex were included in the study who had symptoms of ARC or AIDS with laboratory confirmation of HIV seropositivity by both ELISA and Western Blot or the equivalent tests, were between the ages of 12-60 years old, had a Karnofsky performance score (KPS) of between 40-90, and gave informed consent to participate.  Patients under the age of 12, pregnant woman and lactating mothers, patients on specific anti-HIV medication such as AZT and interferon’s, those on systemic or local steroids, and patients with renal impairment were excluded from the study. 

The study divided the 30 patients into three groups of 10 patients each selected as described by the criteria above.  The Pharyngeal and Suppository Groups each received 125mg daily while the control received a placebo.  The results of the trial demonstrate a significant decline in clinical complaints with a substantial increase in CD4+ lymphocyte levels as compared to the controls where HIV related clinical complaints and CD4+ lymphocyte levels remained consistent or marginally depressed.  There were no adverse side effects reported.  Please see results below: