Antiretroviral Pipeline: New-Drug Reports from Retroviruses Conference

by John S. James

Summary: The three experimental drugs most discussed at the important 11th Conference on Retroviruses and Opportunistic Infections (February 8-11, San Francisco) were: BMS-488043, a new kind of entry inhibitor; Reverset, a nucleoside analog active against most resistant viruses; and Schering D, which blocks viral attachment to the CCR5 co-receptor on the cell.

Other compounds discussed included PA-457, SPD-754, GW873140, GW678248, SN1212/1461, TMC114, TNX-355, PRO140, UK-427,857, AK602, KRH-2731, mifepristone (RU-486), and chloroquine.

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Three experimental antiretrovirals (BMS-488043, Reverset, and Schering D) were most discussed at the 11th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2004 in San Francisco. They received attention because they reported significant data from human HIV trials, and because they were highlighted in the conference program and press materials.

Other antiretrovirals presented at the conference (see above) were at least as interesting, but at an earlier stage of development. We expect to report later on many of them later.

BMS-488043: New Mechanism to Stop HIV Entry

This new compound from Bristol-Myers Squibb works differently from any approved drug; therefore, cross-resistance with existing drugs would not be expected. BM-488043 prevents the first step of infection, by attaching to the gp120 protein on the virus and blocking its attachment to the CD4 receptor on the cell.(1-3)

Note that the approved drug T-20 (Fuzeon) blocks viral fusion with the cell at a later step in the attachment process; since the two drugs work at different steps of HIV entry into cells, cross-resistance is unlikely. Also, BMS-488043 is a small-molecule drug candidate, so it will be much less expensive to manufacture than T-20. It can be given orally, and can reach blood concentrations in healthy human volunteers about 10 times greater than what is expected to be needed to block HIV replication.

Shortly before the conference the company received "proof of principle" that the drug can reduce HIV in people: data showing that the compound did lower viral load and appeared to be safe, in an 8-day trial in 30 HIV-positive volunteers.

Reverset: Nucleoside Analog Active Against Resistant Viruses

Reverset is a nucleoside analog (in the same class as AZT, 3TC, abacavir, tenofovir, and others), but is active against most of the viruses resistant to the approved antiretrovirals, as well as against wild-type, non-resistant virus. A small (30-volunteer, 10-day) trial reported at the Retroviruses conference found that the drug appeared to be safe, and caused an average 1.7 log (98%) drop in HIV viral load.(4) Reverset can be taken once a day, and laboratory tests did not find evidence of mitochondrial toxicity, believed to cause the neuropathy and other side effects of some antiretrovirals.

Reverset was invented at Emory University and developed by Pharmasset, (http://www.pharmasset.com/), which recently entered into a licensing agreement with Incyte Corporation (http://www.incyte.com/) to co-develop Reverset. Before the recently completed trial, it had been tested for safety in 56 HIV-positive volunteers.

Schering D: Targeting CCR5 Virus

After HIV attaches to the CD4 receptor on a human cell, it must then attach to a co-receptor -- usually either CCR5 or CXCR4. Almost always the virus that first infects a person uses CCR5; later, CXCR4 virus will evolve in some but not all patients. Different drugs are now being developed to target viral attachment to each of these co-receptors.

Schering D (SCH D), which blocks attachment to the CCR5 co-receptor, is an improvement over Schering C. It is active against HIV at about one tenth the concentration needed of Schering C, and appears to be safe in trials so far.

At the Retroviruses conference, results were reported from a trial of 48 patients treated for 14 days with one of three different doses of Schering D, or with a placebo. Viral load reductions were about one log at the lowest dose tested, 1.6 logs at the highest dose.(5)

References

Note: Unless otherwise stated, all references refer to the 11th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2004, in San Francisco. You can see these abstracts at the official conference site:
http://www.retroconference.org/2004/home.htm

(click on 'Search Abstracts'). You may want to find the abstract by searching in the Abstract Title field for an important word. Another way is to search in the Presentation Number field for the abstract number. In case the search only shows a few lines of the result, try a different Web browser.

1. G Hanna, J Lalezari, J Hellinger and others. Antiviral activity, safety, and tolerability of a novel, oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, February 8-11, 2004 [abstract 141]

2. PF Lin, HT Ho, YF Gong, and others. Characterization of a small molecule HIV-1 attachment inhibitor BMS-488043: virology, resistance and mechanism of action. [abstract 534]

3. G Hanna, J-H Yan, W Fiske, T Masterson, D Zhang, and D Grasela. Safety, tolerability, and pharmacokinetics of a novel, small-molecule HIV-1 attachment inhibitor, BMS-488043, after single and multiple oral doses in healthy subjects. [abstract 535]

4. RL Murphy, D Schurmann, A Beard, L Cartee, RF Schinazi, and MJ Otto. Tolerance and potent anti-HIV-1 activity of Reverset following 10 days of mono-therapy in treatment-naive individuals. [abstract 137]

5. D Schurmann, R Rouzier, R Nougarede, and others. SCH D: Antiviral activity of a CCR5 receptor antagonist. [abstract 140LB]

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