The ability of HIV to mutate antiretroviral agents, designed to inhibit its replication, has shown a tremendous increase in their numbers. This poses a significant problem for the drugs that are already in use and also for those in the pipeline. Effective treatment of HIV-infected patients is compromised by the toxicity of approved regimens, conferred resistance, and cross resistance.
Las Vegas, Neveda-based Samaritan Pharmaceuticals has in place an HIV drug development program whose tag line is "We LIV... to Save Lives." Three therapeutics headline Samaritan's HIV pipeline: SP01A (phase II/III); SP10); and SP003.

Samaritan is developing HIV therapeutics that facilitate maximal and durable suppression of viral replication, do not confer resistance, have a favorable safety profile, and are well tolerated.
Speaking to Technical Insights, Janet Greeson, CEO, Samaritan Pharmaceuticals Inc says, "Samaritan's HIV program focuses on unique and novel therapeutics that are highly efficacious, have a favorable safety profile, are well tolerated, do not confer resistance, and do not facilitate cross resistance."

Samaritan's HIV therapeutics have demonstrated significant promise in addressing these issues; offering the hope of a viable solution to an otherwise impending global pandemic.
Samaritan's novel HIV therapeutics have been identified as belonging to a new class of HIV antiviral drugs called entry inhibitors. These are unlike protease and transcriptase inhibitors in that there are several mechanisms by which an entry inhibitor may function and, as such, there are several distinct types of entry inhibitors.

Samaritan scientists observed correlations between cortisol levels in HIV-infected patients and the progression of their disease to AIDS. The scientists hypothesized that the HIV-associated dysregulation of cortisol levels may play a role in the pathophysiology of AIDS including the modulation of cell-mediated immunity. Experimental evidence suggested that cortisol and its receptors were critically involved at some level in the regulation of immune function in HIV infection. Therefore, it was reasonable to hypothesize that treatment with a cortisol-modulating agent may improve the immune function in HIV-infected patients.

The modulatory effect of the lead compound, SP01A, on the stress-induced corticosteroid increase may be related to a reduction of the expression of the key cholesterol synthesis enzyme 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase mRNA and reduces stress-induced synthesis of steroids in vitro and in vivo, leading to a reduction in cholesterol synthesis. Many observations have suggested that inhibitors of cholesterol synthesis inhibit cell fusion formation induced by HIV-l and that drugs extracting cholesterol from the cellular membrane exert an anti-HIV-1 effect, in vitro. The unique function of SP01A is that cholesterol synthesis inhibitors exhibited the ability to exert their effect at the cellular level.

Reports from the preclinical studies suggest that there is a modification of the cholesterol content of the host cell membrane due to SP01A's effect on cholesterol synthesis. This exerts a control over the replication process as the HIV-1 virus finds it difficult to enter and infect the cell. These observations were further supported during phase I/II clinical trials in which SP01A was administered to HIV-infected individuals who were currently on stable, approved antiretroviral therapies.

"SP01A was well tolerated and proved highly effective in reducing viral load and improving quality of life," adds Greeson.

Owing to the success of the studies and previous trials, the subjects under investigation are entering a phase IIb monotherapy study, and Samaritan is preparing to conduct a phase III clinical trial. Samaritan intends to file for accelerated approval during the phase III study.

SP-10 Second HIV Drug Development in Conjunction with SP01A
SP-10 is a drug discovered in Samaritan Laboratories in collaboration with Georgetown University. Preclinical studies report its mode of action to be by blocking the entry of HIV and other multi-drug resistant viruses from entering the host cells. Moreover, SP-10 has shown very low toxicity, suggesting that it lacks serious side effects. Toxicity and the development of drug resistance is a major problem with most current antivirals. All of the currently approved antivirals on the market demonstrate drug resistance.

Since SP-01A is intended to be administered in combination with current antiviral therapy for the indication of HIV drug resistance, Samaritan decided to pursue SP-10 as an overall antiviral for HIV that could be administered alone or in combination with the normally administered triple therapy for both HIV in general and drug resistance in particular.

In pursuing the preclinical development of SP01A as an antiviral for drug resistance, the researchers decided to simultaneously accumulate the same preclinical data required by the FDA for SP-10, although they intend to study SP-10 as a stand alone antiviral.

Preclinical data on SP-01A and SP-10 suggests that these compounds reduce HIV virus replication by modifying the structure of the host cell membrane, thus rendering it impossible for the HIV virus to enter and infect the cell. They both can be classified as oral entry inhibitors and could prove more effective than today's antiretroviral therapy because they would prevent HIV from invading healthy cells, rather than going after the virus when it might be too late as it has already inserted itself into these cells.

Specifically, the therapeutics (SP01A and SP-10) appear to inhibit fusion of the HIV viral envelope with the target CD4 cell membrane by extracting cholesterol from the CD4 cell membranes. Several observations have shown that HIV utilizes cholesterol enriched lipid rafts to facilitate the fusion of the HIV viral envelope with the CD4 cell membrane, analogous to the lock and key model. Here, the viral envelope can no longer engage the cell membrane because excess cholesterol has been removed from the cell membrane. This unique mechanism offers another advantage. Since Samaritan's therapeutics does not attack the virus directly, they appear not to be susceptible to the development of resistance. HIV is a simple virus with a tremendous ability to mutate around therapeutics that attempt to alter or disable its structure. This is an added advantage as these therapeutics do not threaten the integrity of the virus or its envelope; so there is no reason for the virus to mutate.

"The lack of toxicity observed with our HIV drugs suggests that patients will not experience treatment compliance problems due to their inability to tolerate the drugs," adds Greeson.
"Finally, the maximal viral load suppression observed among HIV-infected patients administered the recommended therapeutic dose of SP01A correlates well with its favorable safety profile and lack of conferred resistance to provide a novel antiviral therapeutic that uniquely addresses the greatest challenges associated with the treatment of HIV infection," adds Greeson.

The therapies from Samaritan targeting HIV include:
SP01A for HIV resistance (oral entry inhibitor): Samaritan intends to introduce SP01A as an adjuvant therapeutic to be used in combination with currently approved HAART therapies in HIV-infected patients with evidence of virologic failure (treatment failures). Samaritan has commenced "A Multi-Center Double-Blind, Randomized, Placebo-Controlled Study of Orally Administered SP-01A as Monotherapy Treatment of HIV-Infected Patients" trial to show the efficacy and decide the dosage data for further trials. This is also to further demonstrate efficacy as an antiviral and gather dosage data in preparation for later stage PIII clinical trials, assuming positive outcome data.

SP-10 for HIV resistance (oral entry inhibitor): This drug can be a standalone therapeutic or in combination with currently approved HAART therapies. Preclinical studies are ongoing in preparation for an Investigational New Drug (IND) application with the FDA.
SP-03 for HIV resistance (oral entry inhibitor): This is developed similar to SP-10.

SP01A--Mode of action: blocks the ability of the HIV virus to infect CD4+ cells. From phase I/II clinical trials, reports validated the reduction in viral infections and improvement in the quality of life. It exhibited a favorable safety profile, a well tolerated drug for those patients who experience resistance with other drugs.

This seems to a better mode of prevention as it prevents HIV from invading healthy cells rather than attacking the virus, which has already established itself in the cell. This property helps to deal with the resistance problem often encountered with generally available drugs.
The effective treatment of HIV-infected patients is compromised by the toxicity of approved regimens, conferred resistance, and cross resistance.

The following summarizes the breadth of Samaritan's intellectual property ownership:
(US Patent Application 20050085464) Composition of anti-HIV drugs and anti-cortisol compounds and method for decreasing the side effects of anti-HIV drugs in a human.

This invention is based, in part, upon the discovery that the use of an anti-HIV drug in combination with at least one cortisol blocker, such as procaine, reduces the side effects associated with anti-HIV drugs. The invention also relates to a method of treating the high cortisol catabolic effects of diseases such as AIDS in the HIV positive population and those with AIDS-related complexes by the administration of a cortisol blocker. The invention also discloses a composition comprising an anti-HIV drug and cortisol blocker. More specifically, the invention relates to a cortisol blocking composition, which comprises procaine, ascorbic acid and zinc heptahydrate.
(WO 2005/089453) Benzamide and Benzoate Anti-HIV Compounds.

This invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the infectivity of a pathogen such as a retrovirus toward mammalian cells is implicated, and inhibition of its infectivity is desired. Where there is a mammal in need of such therapy, this invention comprises administering an effective amount of procaine, procainamide, or an analog thereof that inhibits pathogenic infectivity, including pharmaceutically acceptable salts thereof.

(WO 2004/108076) Anti-HIV Benzamide Compounds
This invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the infectivity of a pathogen such as a retrovirus toward mammalian cells is implicated and inhibition of its infectivity is desired. Where there is a mammal in need of such therapy, this invention comprises administering an effective amount of an N-benzamide derivative of a piperazinyl amide of an amino thereof that inhibits pathogenic infectivity, including pharmaceutically acceptable salts thereof.

(WO 2005/112922) Benzamide Compounds.
This invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the infectivity of a pathogen such as a retrovirus toward mammalian cells is implicated and inhibition of its infectivity is desired. Where there is a mammal in need of such therapy, this invention comprises administering an effective amount of an N-benzamide derivative of a piperazinyl amide of an amino acid thereof that inhibits pathogenic infectivity, including pharmaceutically acceptable salts thereof. The invention also provides a therapeutic method for preventing or treating a neuropathological condition or symptom in a mammal, such as human, that comprises administering an effective amount of an N-benzamide derivative of a piperazinyl amide of an amino acid thereof that inhibits pathogenic infectivity, including pharmaceutically acceptable salts thereof, to a mammal in need of such therapy.

(WO 2005/000205) Methods and Compositions for Modulating Serum Cortisol Levels
This invention relates to cortisol-modulating compounds, including but not limited to benzamide and benzoic acid derivatives such as procaine and procaine derivatives, utilized in compositions and methods for treating cortisol-mediated disorders, including but not limited to age-related depression, hypertension, Alzheimer's disease, and acquired immunodeficiency syndrome.

Details:

Dr. Janet Greeson

CEO, Samaritan Pharmaceuticals Inc.

101 Convention Center Dr., Suite 310

Las Vegas, NV 89109

Phone:  702-735-7001

Fax:  702-737-7016

E-mail: greesonjan@aol.com

URL:  www.samaritanpharma.com

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