Molecules for Health, Inc., Presents Findings of Novel HIV/AIDS Therapy

Mol4hlth * 5 18-72 5-7896 MoIh~h *S1'75~79WY326199 06-30PM n 215 Molecules For Health, Inc. Cancer Drug Research & Development 800 E. Leigh Street, Suite 208A Virginia Biotechnology Research Park Richmond, VA 23219 Phone: [phone] Fax: [phone] E-mail: Mol4Hlthgvabiotech.com March 22, 1999 FOR IMMEDIATE RELEASE FOR MORE INFORMATION, CONTACT: Howard Elford, PhD: [phone] Molecules for Health, Inc., Presents Findings of Novel HIV/AIDS Therapy Jerusalem, Israel -- Molecules for Health, Inc., (MFH), a privately owned biopharmaceutical company, is presenting results of preclinical studies of its lead compound, Didox, a ribonucleotide reductase inhibitor with potent antiviral activity against HIV. At the 12th International Conference on Antiviral Research here, MFH announced that studies in a mouse model found Didox to be more potent and less toxic than another ribonucleotide reductase inhibitor, hydroxyurea. The severe combined immunodeficiency (SCID-hu) mouse model is believed to be an ideal animal system in which to investigate the efficacy of anti-HIV drugs because the mice have human blood cells that are susceptible to infection by HIV. SCID-hu mice, exposed to high levels of infectious HIV, were treated with either Didox at a dose of 450 mg/ kg or hydroxyurea at a dose of 600 mg/ kg. Didox significantly reduced the amount of infectious HIV titers - from 4.8 x 103 TCID50/ 106 cells to 2.2 x 101 TCID50/ 106 cells. (TCID50 is the 50% tissue culture infectious dose per one million cells.) Comparisons with hydroxyurea 111111II5111111111 11 111111111 5571095.0291.051

Mol4hith * 518-725o7696 t3/26I99 06-31 PM D3/ showed that Didox had two-fold greater anti-HIV activity; hydroxyurea only reduced viral titers to 2.7 x 10 TCID50/106 cells. Evaluation of the HIV RNA data - the key piece of data now used to establish anti-HIV efficacy in human clinical trials and widely used in clinical practice to determine whether HIV replication is under control in patients on antiretroviral therapy - revealed that results were consistent with the TCID50 data. In lymph nodes, the average HIV RNA logio copies per one million cells was reduced from 1.6 x 106 per 106 cells (untreated mice) to undetectable levels (Didox-treated mice). Hydroxyurea-treated mice had only a small effect, reducing HIV RNA to 2.6 x 105 per 106 cells. In peritoneal cells, the average HIV RNA loglo copies per one million cells was reduced from 4.5 x 105 per 106 cells (untreated mice) to 5.1 x 101 copies per 106 cells (Didox-treated mice). Hydroxyurea-treated mice, again, had only a small effect, reducing HIV RNA to 6.2 x 104 per 106 cells. Additional studies examined the effect of combination antiretroviral therapy consisting of either Didox and the nucleoside reverse transcriptase inhibitor, didanosine (ddl or Videx~), or hydroxyurea and ddl. Both combination regimens were highly effective in suppressing HIV replication in SCID-hu mice; HIV RNA copies per one million cells were undetectable with both combination treatments. Didox treatment also had a positive effect on the immune response of HIVinfected mice. Treatment with Didox, either alone or in combination with ddl, resulted in a significant increase in the CD4: CD8 cell ratio. (Both CD4+ and CD8+ lymphocytes, perhaps the most important cells in the body's immune response against pathogens like HIV, are known to be severely affected by HIV

Mol4hith V 5 1 &72 5-7896 MoIhlt * 16725896VI326I99 06-31PM D 4/5 infection.) Although treatment with hydroxyurea, alone and in combination with ddl, also led to an improved CD4:CD8 ratio, the magnitude of improvement was considerably less than that associated with Didox treatment. Together, these findings indicate that Didox, a newly developed compound, may be a potent single-agent component of combination therapy regimens for HIV/ AIDS. Unlike the currently marketed HIV/ AIDS drugs, all of which directly attack viral enzymes, Didox and related compounds being developed by MFH target and inhibit ribonucleotide reductase - one of the cellular enzymes that HIV usurps for its continued replication. The targeting of a cellular enzyme may mean drug resistance is less likely to occur with the ribonucleotide reductase inhibitor drugs. By interfering with this cellular enzyme, Didox and other drugs in this class inhibit the production of deoxynucleotides and thus viral DNA synthesis. In addition, Didox and related compounds reduce cellular deoxynucleotide levels, which is believed to enhance the effectiveness of the currently approved nucleoside reverse transcriptase inhibitors (NRTIs), including ddl, when the two types of anti-HIV drugs are coadministered. Didox and its related compounds represent a promising new approach to HIV/ AIDS treatment - a high priority of the drug development efforts at Molecules For Health, Inc. The immediate goal of the funded studies are to determine the full potential of two leading MFH compounds, Didox and Trimidox, used alone and in combination with NRTIs such as ddl, d4T, 3TC, or ZDV, as well as with the protease inhibitor, nelfinavir. Although Didox is predicted to show single-agent activity, based on results in the SCID-hu mouse

Mol4hith V 518-725-7896 MofNi 3 *75.7ftY326199 06-32 PM D515 model, the future for Didox is its use in combination with other antiretroviral agents in protocols for North America, Western Europe, Japan, and Korea. Importantly, in areas virtually lacking healthcare funds, where the HIV/AIDS epidemic continues to rage, a low cost single-agent treatment for HIV, including one that can be used in HIV-infected pregnant women, would be a significant single contribution to the HIV/ AIDS treatment armamentarium there. A near-term goal of MFH is to conduct a clinical trial of Didox both alone and in combination with ddl. Single-agent studies in humans are needed to define the safety, tolerability, and pharmacokinetic profile of Didox. Didox is also currently be investigated as a cancer treatment and is in early clinical trials. Drug development is being extended to other diseases in which free radicals play a role, such as ischemia reperfusion injury, brain injury and degeneration, and sickle cell anemia. These research studies are based on demonstrated free radical scavenging capacity of Didox and related compounds in animal models. The abstract of the preclinical studies of Didox, presented at the 12th International Conference on Antiviral Research in Jerusalem, Israel (21-26 March 1999), is published in the journal Antiviral Research. Molecules for Health, Inc., received a $750,000 Small Business Innovative Research (SBIR) grant from the National Institutes of Health in 1998 to develop a series of new anti-AIDS drugs based on compounds invented by the company. ft

Mol4hlth 3 518-725-7896 203/26199 06-30PM Dn1/5 1 - DATE: Friday, March 26, 1999 TO: Jon Cohen, Science FAX: [phone] FROM: Mol4hith PAGES: 5 MEMO Jon, Howard Elford will be back from Jerusalem April 8th He'll be attending the Apr 18-19 HIV immune meeting in DC if you want to catch him there Good story here