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Being Alive
From the 5th National Conference on Retroviruses New Drugs In the Pipeline
Chris Griffin
March 5, 1998
Being Alive 1998 Mar 5: 2

On the last day of the Conference Dr. Scott Hammer of the Harvard Medical School presented an excellent talk called "New Agents on the Horizon" in which he summarized what we can expect to see emerging from the new drug development pipeline in the near and distant future.

These new weapons in the anti-HIV arsenal will include drugs in all three of the familiar antiretroviral classes-protease inhibitors (PIs), and both nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs).

Some of these drugs will become FDA-approved and widely available fairly soon, and are already available through various clinical trials (the PI amprenavir, the NRTIs abacavir and adefovir, and the NNRTI efavirenz). Others are in the earliest stages of development, still undergoing laboratory appraisals, and safety tests in animals and in humans.

Dr. Hammer also described some compounds, under investigation but still far from practical use, which aim to attack HIV in ways different from the drugs we already have, and therefore could be effective against antiviral-resistant strains of the virus. Chemokine receptor antagonists, fusion inhibitors, and drugs that target "zinc fingers": just some of the singular ways scientists hope to interfere with and interrupt the replication cycle of the virus.

Earlier in the Conference Dr. W. Gary Tarpley of Pharmacia and Upjohn urgently called for bold and resolute focus on the development of new agents to attack HIV. "With a pathogen like HIV," he stated, "which has established itself throughout the world, which initiates a chronic and permanent infection and which has tremendous replicating potential if unleashed by incomplete suppression, I think we must prepare for a future scenario in which, over time, this virus will learn to evade all the current drugs we have." Many of these new drugs will play a crucial role in "salvage therapy," presenting additional options to people who have already been through all of the currently-available antivirals and whose viral loads are rebounding. Several trials are underway to assess the effectiveness of various combinations in people who have experienced viral rebound while on the various regimens of HAART. We should be hearing more about this through the coming year.

(Hydroxyurea, an inexpensive generic drug that has been in use more than 30 years, is currently getting a lot of attention. Several studies are showing it to be especially effective against HIV in combination with other antiretrovirals. For a discussion of hydroxyurea, click here.) The following is a summary of what we can look forward to in 1998 and beyond, as described in Dr. Hammer's talk and in other Conference sessions and posters.

Protease Inhibitors Fortovase (saquinavir soft-gel, Hoffman-La Roche). Strictly speaking, this reformulation of saquinavir is not exactly a "new" drug, but it is an improvement over the original hard-gel version of the drug. Taken at twice the dose of the older Invirase, Fortovase is more efficiently metabolized, permitting a total drug exposure in the body that is eight times greater than before. Simply put, a lot more of the drug makes it into the blood stream. The relative weakness of Invirase compared to other protease inhibitors is overcome with Fortovase, which is as potent as the other available PIs. Fortovase is now FDA-approved and available from U.S. pharmacies.

For some time now, Invirase (hard-gel saquinavir) has been used by some people in combination with ritonavir. Hoffman-La Roche has indicated that Invirase will be phased out, leaving only Fortovase on the market. People who have been doing well on the ritonavir/saquinavir combination understandably do not want to make any change, and have logged protests with the company. In a meeting at the Conference, a company spokesperson stated that Invirase will be made available to these people, although not necessarily through pharmacies.

Fortovase is also being used currently in combination with Agouron's nelfinavir (Viracept), with encouraging reports of significantly lowered viral load. Amprenavir (formerly known as 141W94, Glaxo Wellcome). Like nelfinavir, amprenavir is an adaptation of the basic, highly effective and HIV-specific molecular structure of saquinavir, altered to achieve greater availability in the body and to less resemble the molecular shape of saquinavir so as to better avoid viral resistance.

Several reports at the Conference dealt with amprenavir in combination with other antiretrovirals. Results showed that amprenavir in combination with either indinavir, nelfinavir or saquinavir produced impressive decreases in viremia (viral activity). Another study showed that when amprenavir was used as monotherapy resistance formed quickly. Amprenavir in combination with the NRTI abacavir (see below) proved effective in a very limited and small pilot study of seven patients over four weeks, resulting in a median 2-log drop in viral load and an increase of CD4s of 114. But another study of people who were highly experienced with antiretrovirals and PIs proved disappointing, showing viral rebound within three months.

Most common side effects of this two-drug combination were diarrhea, nausea, headache and rash, not dissimilar to other PI side effects. It is unclear at this time whether amprenavir will indeed prove effective against PI-resistant viruses. Its role in salvage therapy (treating people whose viral load is rebounding despite the use of HAART) is currently being evaluated.

New Protease Inhibitors With Novel Mechanisms ABT-378 (Abbott Labs). This promises to be one of the most powerful protease inhibitors developed so far. At this time it has been tested only in vitro (in test tube) and in rats; in those tests it has proven to be ten times more potent than ritonavir (Norvir). Abbott says it has a synergistic effect when used with ritonavir. Resistance profiles suggest that people with extensive exposure to previous PIs should remain at least partially sensitive to ABT-378, and people previously treated with saquinavir should remain wholly sensitive.

PNU-140690 (Pharmacia & Upjohn), Bristol Myers 232632, Parke-Davis 178390. These three drugs aim to disrupt the HIV replication process in a way different from the "peptide-class" of PIs with which we are already familiar (saquinavir, indinavir, ritonavir and nelfinavir, as well as amprenavir and ABT-378). Because of their different mechanism for blocking reproduction, these drugs could prove highly effective against PI-resistant strains of HIV.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Abacavir (formerly 1592U89, Glaxo Wellcome). Now in Phase II/III clinical trials, this nucleoside analog has shown synergy with other RTIs in vitro, and is the only NRTI that equals AZT's ability to penetrate the central nervous system. There appears to be no cross-resistance with AZT or d4T, but resistance to 3TC is likely.

Abacavir is up to three times more active than AZT, and in monotherapy trials has resulted in significant viral load reductions of two logs.

As noted in the pages of the Newsletter before, an adverse reaction to abacavir has been reported in 3% of patients, characterized by fever, malaise, nausea, vomiting and rash. These side effects do abate once the drug is discontinued, but attempts to go back on the drug have resulted in exaggerated life-threatening reactions, including one death.

Abacavir is now available through an expanded access program. Further expanded trials of abacavir, in combination with other antivirals including protease inhibitors, are under way. We expect soon to learn more about this potentially valuable drug.

Adefovir (formerly PMEA, brand name Preveon, Gilead Sciences). This nucleoside analog's mechanism is different from other NRTIs and therefore has the potential for being effective against HAART-resistant HIV. In lab studies, adefovir is also effective against many herpes viruses, including herpes simplex types 1 and 2, CMV and hepatitis B. A major asset of this drug is that it needs to be taken only once a day.

A Phase II/III trial is now underway, and Gilead has an expanded access program, available to people who have been failed by or are intolerant of combination therapy with at least two commercially available nucleosides and at least one protease inhibitor. "In addition, the treating physician must be unable to construct a viable regimen based on current treatment guidelines and the patient's previous antiretroviral use." Exceptions to Gilead's current CD4 and viral load requirements will be favorably considered. For information on the Adefovir Expanded Access Program call 800.gilead.5.

FTC. This nucleoside analog, now in Phase I/II clinical trials, resembles 3TC but is ten times more powerful (in the test tube). It looks to have the same resistance profile as 3TC, and researchers believe it will work synergistically with AZT, d4T, indinavir, efavirenz and others.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz (brand name Sustiva, formerly DMP-266, DuPont Merck). This NNRTI has shown particularly good activity against strains of HIV resistant to NRTIs and to indinavir, and has shown good effectiveness against strains resistant to the NNRTIs nevirapine and delavirdine as well.

Resistance studies reveal that efavirenz, like the other NNRTIs, should always be used in combination with NRTIs and/or protease inhibitors.

In combination with indinavir, efavirenz resulted in a mean decrease in viral load of 4.75 logs; in a 24-week study, 95% of the participants had viral loads under 500, and their CD4 counts increased by a mean of 199. Limited clinical efficacy studies suggest that efavirenz is significantly more potent than either nevirapine or delavirdine.

Side effects include rash and light-headedness, symptoms which tend to go away in days or sometimes weeks.

DuPont Merck recently made its eligibility requirements more flexible for the Efavirenz Expanded Access Program, allowing people who are highly experienced on HAART to have a CD4 count less than 400 (up from their previous requirement of 50), and a rebounding viral load. For more information call 800.998.6854. MKC-442 (Triangle Pharmaceuticals). In early stage of development. Clinical trials have recently started: preliminary results show the potential for a 1.4 log decline in viral load.

Way Out There: New Drugs, New Approaches As can be clearly seen by the above summary, anti-HIV drugs available now and in the immediate future belong to two classes: those that target the reverse transcriptase or the protease enzymes of the virus. New approaches are going to be necessary to avoid cross-resistant variants of HIV and the eventual "failure" of currently-available versions of HAART. Several new approaches are being explored.

Integrase inhibitors For some time we've heard of integrase inhibitors, which would target a third vital enzyme of the virus's replication mechanism. These drugs have been slow to evolve, however. It is not known how effective they will be, but it is unlikely that there would be any cross-resistance between integrase inhibitors and the existing classes of antiretrovirals. The human body does not possess such an enzyme; therefore, it is expected that inhibition of the HIV integrase would be safe and not cause adverse effects.

Zinc Finger Inhibitors HIV contains a structure called "zinc fingers" which cannot readily change by mutation; that is, the virus would find it difficult if not impossible to mutate around and form resistance to a drug which targeted these "zinc fingers." The hope is that a drug that attacks the virus at this crucial structure would permanently disable the virus's replication. Such a drug is now in early human testing.

T-20 This genetically engineered peptide is designed to target a specific step in the process by which HIV attaches to a cell in the course of infecting that cell. It has already been shown to substantially reduce viral load, and it is unlikely to have cross-resistance with our current batch of treatments. Therefore, T-20 may be highly effective in people who have been heavily treated with HAART and are experiencing drug failure and viral rebound. This drug may not be especially practical for anyone other than those with literally no other options: it will probably have to be given by continuous intravenous infusion. In clinical trials it is being administered via a small computerized pump with a flexible catheter, something used successfully in diabetes treatment. It is doubtful that any but the most desperate patients would be interested in undergoing this kind of therapy.

Two more drugs have gained the attention of researchers, although little is known about their mechanisms or potential for effectively fighting HIV. TCN (triciribine) has been shown to be an inhibitor of HIV, but exactly how it does that is still under examination. AMD-3100, being developed by Johnson Murphy, is seen as a potential weapon against the virus's chemokine receptor.

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