SEPTEMBER 1998

NUMBER ONE

WHAT LIES AHEAD

What's in the Pipeline
New drugs to control and flush out HIV.

NRTIs. Five new NRTI drugs are in early testing, including F-ddA (U.S. Bioscience/Phase II), a ddI-like drug that has good data on cross-resistance. FTC (Triangle Pharmacueuticals/Phase I/II) appears potent in animal and early human studies, while a sister Triangle compound, DAPD (Phase I planned), works against HIV and hepatitis B. BCH-10652 (BioChem Pharma/Phase I) is a potent 3TC-like drug against HIV strains resistant to AZT, 3TC, indinavir and saquinavir in lab tests. D-D4FC (Emory University) is a 3TC-like drug.

NNRTIs. Only one drug is in Phase II/III: Triangle's MKC-442 works well with other HIV drugs but since it is a cytochrome p450 inducer, it may interact with other drugs broken down by p450 liver metabolic pathways. Calinolide (Sarawak MediChem/Northwest Kinetics) is a compound made from a natural source that is being studied in Phase I tests against resistant HIV strains. Other upstarts: PNU 142721 (Pharmacia & UpJohn); S-1183 (Agouron)-all in early trials-and UC-781 (Uniroyal).

Nucleotide Analog RTIs. Gilead's potent oral pro drug, Bis (Poc) PMPA, is in Phase II trials, while an IV version is being tested to prevent maternal transmission of HIV and a PMPA topical gel is a candidate for HIV prophylaxis-a preventive drug.

Protease Inhibitors. Glaxo Wellcome's potent amprenavir (also called 141W94) is now available through expanded access as salvage therapy (900 mg twice a day), but be aware: It's a p450 inhibitor and substrate, so it could interact with other HIV drugs. Abbott's potent new ABT-378 goes into larger, Phase III testing in humans early next year; it's also a p450 processed drug as are most PIs. Novel non-peptidic protease drugs have a different structure than other PIs and include Tipranavir (Pharmacia & UpJohn, also called PNU 140690) that's being tested in protease-resistant and drug-naive subjects in early clinical trials, Parke Davis' PD-178390 and Bristol Myers-Squibb's BMS-232632. Triangle's new DMP-450 is a cyclic urea compound, while Japan Energy Corporation is testing JE-2147 (also called KNI 764) now licensed to Agouron.

Fusion Inhibitors (FI), Integrase Inhibitors (II) and Zinc Finger Inhibitors (ZFI). These new classes of drugs are aimed at other HIV enzymes besides protease. FIs include a monoclonal antibody by Progenic Pharmaceutical's called PRO 452 (in Phase II) and Trimeris' potent petide, T-20 (in Phase I). Integrase inhibitors include Zintevir (also called AR-177) by Aronex. Fuji ImmunoPharmaceutical's FP-21399 is a zinc finger inhibitor. CI-1012 (Parke Davis), ADA (Tassignon & Associates), and diathane are ZFIs being studied at the NCI.

Chemokines and Co-Receptor Blockers. Compounds that target the CCR-5 and CXCR4 chemokine co-receptors on T-cells are in early testing, as are other agents listed here that block HIV from binding to cells or reproducing. Candidates include AMD-3100 (AnorMed), a bicyclam CXCR4 blocker; Rantes (Glaxo Wellcome), a CCR-5 blocker; Pharmacia and UpJohn's NSC 651016 distamycin analog which works against drug-resistant HIV strains in lab tests; Gem 92 (Hybridon), an antisense oligonucleotide; Temacrazine, a potent transcription inhibitor of the bistriazoloacridone drug class; Didox and Trimodox (Molecules for Health), new ribonucleotide reductase inhibitors like hydroxyurea.

Gene Therapy. It sounds very futuristic, but HIV gene therapy is at hand using altered genes inserted into cells that can cripple HIV's ability to reproduce. Contenders include Tat/Rev ribozyme gene therapy (Ribozyme Pharmaceutical/Chiron); ev M0 (Systemix); HGTV43 (Enzo), a new antisense gene therapy technology; Cell Genesys products; Vpr Thera Technologies; and RNA decoys.

Anti-HIV Monoclonal Antibodies/Cytokines. Studies show neutralizing molecules to HIV and pro-inflammatory molecules called cytokines can either block a T-cell from expressing HIV or flush out the virus from a dormant cell. Keep your eye on OKT- 3/Orthoclone (Ortho), a promising monoclonal antibody being tested by Dr. David Ho at the Aaron Diamond AIDS Research Center that appears capable of flushing HIV from latent HIV reservoirs, and on Tanox Biosystems' AD-439 and AD-519, already in Phase II tests. HRG214 is a neutralizing antibody by Now Probe/Probe USA. An immunotoxin, DAB389CD4 is being looked at in Europe.

Immune-Based Therapy. High hopes are riding on Remune, the renamed Salk vaccine that boosts specific HIV T-helper and CTL-immune responses (see "HIV Remission: The New Goal"). Other non-HIV drugs like foscarnet and cyclosporin, an immunosuppressant, show potential as anti-HIV agents.

• Enrolling clinical trials of drugs for treating HIV