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Two New Drugs-- HE2000 and AG1459, a new NNRTI

June 12, 1999

This week I met with officials from Hollis-Eden Pharmaceuticals to talk about their new drug called HE2000. It is not an antiretroviral but works by affecting the host. The host is the person with HIV and their immune system. According to company officials HE2000 likely has several mechanisms of action all of which affect the host’s ability in dealing with HIV. HE2000 is supposed to provide support to host cells in limiting HIV activity. Hollis-Eden believes they have characterized one or two mechanisms of action but not others. The mechanism of action of other drugs are not always fully known so, in my opinion, this alone should not discourage interest in this drug. Company officials have said that HE2000 is a synthetic glucocorticoid and is not known to interact with viral proteins or nucleic acids. They’ve said it is believed HE2000 acts by a "novel mechanism of action on the host’s cellular biochemistry interfering with the viruses’ metabolic requirements". In the end, what matters is the clinical effect of HE2000 on individuals with HIV. Because it is a new class of drug, cross-resistance to current classes of HIV drugs are not expected. This would be welcomed by individuals needing salvage therapy. The administration of HE2000 and the rationale for its dosing are novel. Initial human studies have recently started in South Africa. A few sites in the USA are starting up. HE2000 is administered by subcutaneous injection once a day for 5 days separated by 4-7 weeks of no administration before another 5-day administration period. This type of administration has benefits compared to daily dosing of the current regimens.

Company officials showed me HE2000’s antiviral activity in SHIV infected monkeys who were well progressed in their disease. SHIV is a combination of SIV and HIV. One monkey did not respond well but had a very high baseline viral load. Several other monkeys had viral load reductions ranging from 0.5 to 1.5 log from baseline. Although there was no effect on CD4, the monkey’s general health improved and median weight increased on average 0.35 kg (9%).

At the 12th Intl Conference on Antiviral Research in Jerusalem, Israel on March 21-26, 1999 Hollis-Eden officials reported data from a study of 6 pigtailed macaques infected with SHIV. The monkeys had a virulent or potent form of HIV. Three monkeys received sub-q HE2000 daily for ten days at 1, 2, or 3 mg/kg and 5 mg/kg every other day for 20 days. Three animals inoculated with HIV and not treated with drug served as historical controls in this survival study. The 3 monkeys given HE2000 lived longer. The 3 untreated monkeys had an average time to death of 193 days while the HE2000 treated monkeys survived for >350 days and remain in good health. They were sick monkeys in declining health prior to the study. The monkey’s baseline viral load ranged from 2x106 to 7x107 (>2 million).

Company officials showed me graphs where viral load declined but increased about 7 weeks after treatment stopped. Thus, the periodic 5 day dosing cycle. Company officials reported that the depth and duration of viral response varied with the dosing parameters.

Data from the human study being currently conducted in South Africa is expected to be available for presentation at the ICAAC meeting in San Francisco in late September. Again, what matters is if HE2000 results in clinical benefit by reducing viral load and improving the immune system.

In Los Angeles, Agouron Pharma hosted a small meeting with community advocates and writers to discuss their plans for their two new drugs. AG1549 is a NNRTI, which they hope will have antiviral activity against NNRTI resistant virus. So individuals who have resistance to currently used NNRTIs would hopefully be able to benefit from this drug. Human studies are starting now and will eventually test the ability of this drug to suppress NNRTI resistant virus. In vitro data shows that AG1549 can suppress such resistant virus. This data was initially reported by Agouron at last September’s ICAAC meeting and is posted to the NATAP web site (click here to view it).

At this same meeting Agouron discussed AG1776, their new protease inhibitor. Again in vitro data suggests this PI may suppress HIV resistant to the currently used protease inhibitors. It is, however, important to remember that if a person remains on a failing protease inhibitor regimen this allows ongoing viral replication. Resistance develops and mutations accumulate. The more mutations that accumulate the less likely a person is to respond to a subsequent protease inhibitor. Proposed study designs for AG1776 were presented by Agouron and discussed by community and company officials at this LA meeting.

Also discussed were study designs for Remune. As you may know Remune is a therapeutic vaccine. Fred Valentine, MD, of NYU Medical Center, reported data at the Geneva World AIDS Conference from a small study showing that HIV specific CD4 cells directed at HIV were generated by giving individuals with chronic HIV Remune after deep viral load suppression to undetectable or close to undetectable by HAART. Previously, many researchers thought individuals with chronic HIV infection could not generate these HIV specific CD4s.Small studies by Bruce Walker and Eric Rosenberg at Massachusetts General Hospital suggest that individuals treated during acute infection (shortly after HIV infection) with HAART preserved their HIV specific CD4s, which researchers feel would otherwise fade. Walker and colleagues feel this preservation of HIV specific CD4s is responsible for long term non-progressors preserving their health, immune system and long-term suppression of HIV.

In the end all the matters is if the addition of Remune to HAART results in improved clinical benefit to patients. Studies will ask volunteers to stop their HAART to see if Remune stimulated an immune response capable of controlling HIV. In addition, we want to see if Remune+HAART improves the antiviral effect when compared to HAART alone. Will viral load stay suppressed longer with Remune+HAART than with HAART alone? Will viral load be more deeply suppressed with Remune+HAART? Other parameters will also be followed?