POZ IRELAND
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POZ IRELAND
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NEW DRUGS These drugs have not been approved for use against HIV. Maturation InhibitorsMaturation inhibitor shows anti-HIV activity in single dose pilot study 04.05 A phase I trial of PA-457, the first of a new class of antiviral drugs, demonstrated that single, oral doses show dose-related antiviral activity, and were safe and well tolerated. PA-457 retained activity in two patients with extensive resistance mutations. PA-457 is the first of a new class of drugs called maturation inhibitors, which block the conversion of the HIV-1 capsid precursor CA-SP1 (p25) to mature capsid protein (p24) resulting in the release of non-infectious virus particles. It has been shown to potently inhibit the HIV-1 replication, including strains resistant to currently prescribed drugs and is highly active in the SCID mouse model. This American-German, double-blind, placebo-controlled study assessed the antiviral response and pharmacokinetics of PA-457 following a single, oral dose. 24 HIV-positive patients with CD4 counts >200 cells/mm3 and plasma viral load of 5,000 to 250,000 copies/mL were divided into 4 groups of 6 people and each group was given a different single, oral dose: placebo, or 75mg, 150mg, or 250mg of PA-457. Data from 16 patients (4 in each group) were available for report. All doses were safe and well tolerated with no drug related adverse events. There were reductions in mean viral load in all three groups compared to the placebo group which was sustained for more than 10 days in the higher dose groups. Median maximum viral load reduction for each treatment group showed a dose-dependent relationship of –0.17 log, –0.27 log, –0.45 log and –0.51 log in the placebo, 75mg, 150mg and 250mg groups respectively (p < 0.05). Preexisting mutations in one patient with 210W, 103N, 181C, 77I, and 90M in the 250mg group produced a –0.73 log reduction. Another subject with 184V, 103N, 10I, and 77I in the 150mg group had a –0.53 log reduction. Attachment and Fusion InhibitorsThis is a new class of anti-HIV drugs. They are intended to protect cells from infection by HIV by preventing the virus from attaching to a new cell and breaking through the cell membrane. Researchers hope that these drugs can prevent infection of a cell by either free virus (in the blood) or by contact with an infected cell. Because digestive acids break them down, most of these drugs are given by injections or intravenous infusion. Fusion and attachment inhibitors in human trials include AMD070, BMS-488043, FP21399, GW873140, PRO 140 and PRO 542, Schering C, SCH 417690, TNX-355 and UK-427,857. AMD070 by AnorMed blocks the CXCR4 receptor on CD4 T-cells to inhibit HIV fusion. It is in Phase I/II trials. BMS-488043, is an attachment inhibitor in Phase II trials by Bristol Myers Squibb. It attaches to the virus, not the target cell. So far, it shows good strength against HIV and only minor side effects. FP21399 by Fuji Pharmaceuticals was tested for safety in a Phase I trial as a single infusion or a series of 4 weekly 1-hour intravenous infusions. The drug produced viral load decreases and CD4+ cell increases. Side effects were minor, including blue-tinted urine and temporary blue marks on the skin. There have been no recent reports on its status. GW873140 by GlaxoSmithKline is in Phase II studies. It appears to bind very tightly to CCR5 receptors on the cell surface. The main side effects are mild cramping, diarrhea and nausea. PRO 140 by Progenics Pharmaceuticals is in Phase I trials. It blocks fusion by binding to a receptor protein on the surface of CD4 cells. PRO 542 works in the same way. It is in Phase II trials. Schering C (SCH-C) and SCH 417690 (formerly called Schering D) by Schering Plough block the CCR5 receptor on CD4 cells. At present SCH-D looks more promising than SCH-C. There is some concern about heart irregularities with Schering C but not with Schering D. No serious toxicities have been seen with SCH-D in Phase I. TNX-355 by Tanox blocks the CD4 receptor. It is a genetically engineered drug, a "monoclonal antibody." It may be administered by intravenous infusion or as a twice-monthly injection. No significant side effects have shown up yet. It is entering Phase II trials. UK-427,857 by Pfizer blocks the CCR5 receptor. Pfizer will continue to develop it. It is in Phase II trials. After HIV's genetic code is changed from a single strand to a double strand by the reverse transcriptase enzyme, it gets inserted (integrated) into the genetic code of the infected cell. Then the HIV genetic code gets "read," producing new viruses. Scientists hope that integration will be another point in the HIV life cycle that can be targeted by drugs. The inner core of HIV is called the nucleocapsid. It is held together by structures called "zinc fingers." Zinc finger inhibitors (or zinc ejectors) are drugs that can break apart these structures and prevent the virus from functioning. Scientists believe that the nucleocapsid core cannot mutate very easily, so a drug that works against zinc fingers might be effective for a long time. Unfortunately, zinc fingers are not only used by the HIV virus. Drugs that attack them could have serious side effects. One zinc finger inhibitor -- azodicarbonamide (ADA) -- has been tested in a Phase I/II trial. Antisense DrugsThese are a "mirror image" of part of the HIV genetic code. The drug locks onto the virus to prevent it from functioning. One antisense drug, HGTV43 by Enzo Therapeutics, is starting Phase II trials.
Drugs No Longer in DevelopmentThe following drugs are no longer being developed for use against HIV: AMD3100 (fusion inhibitor) by AnorMed. BMS806 (attachment inhibitor) by Bristol-Myers Squibb, replaced by BMS488043. S-1360, GW810781(integrase inhibitors) by Shionogi and GlaxoSmithKline. T-1249 (fusion inhibitor) by Roche and Trimeris -- development was halted in early 2004.
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