Important note: Information in this article was accurate in April 2000. The state of the art may have changed since the publication date.Entry inhibitors, a prominent new class of antiretroviral drugs, were a focus of numerous presentations at the 7th Conference on Retroviruses and Opportunistic Infections (CROI), with several groups reporting pre-clinical and clinical data on candidates.
For an in-depth report on all the news from CROI, see "Conference Coverage" in this issue.
Antiretroviral drugs are the current backbone of HIV/AIDS treatment, in spite of existing and emerging side effects associated especially with long-term use, and in spite of persistent questions about the best ways to use them including when to start (antiretroviral treatment), what to start with, and when to switch.
All 16 antiretroviral formulations approved by the U.S. Food and Drug Administration (FDA) fall into three classes: nucleoside analogs, non-nucleoside analogs, and protease inhibitors. Approved drugs to date target the HIV-1 enzymes reverse transcriptase (the nucleoside and non-nucleoside inhibitors) and protease; the goal of current antiretrovirals is to impede those two enzymes at the point in the HIV replication cycle where they are needed, thereby slowing or stopping the (replicative) cycle.
During the process of cell infection, HIV attaches to a target cell such as a CD4 cell and, via a series of complex interactions, enters it. Once inside the cell, HIV's RNA genome is transcribed (process early in protein synthesis and replication by which genetic information is "converted" for use as a template for the production of new proteins) into DNA by reverse transcriptase (RT). The genetic product of that step is transcribed to more RNA, which is translated into proteins, some of which must at that stage be cut by protease enzymes in order to be active. Again, all currently available antiretroviral agents work by attacking intracellular HIV in order to prevent its replication.
It has long been thought that a combination of drugs targeted at different steps in the viral life cycle or targeted at different aspects of the same step will result in a more effective therapeutic approach to inhibiting viral growth and replication.
Today, especially as more and more people develop HIV resistance to existing antiretrovirals from all three currently available classes, there is a pressing need to discover new drugs that combat HIV in novel ways, i.e., new drug classes, including those that will act at new steps in the infection process. The development of new anti-HIV medications is a major goal of research in both the public (government-funded) and the private (the pharmaceutical industry) sectors.
Entry inhibitors belong to a new class of antiretroviral drugs and target a new step(s) in the life cycle of HIV. Specifically, they are compounds designed to disrupt HIV-1 replicative functions not yet targeted by approved antiretrovirals: most prominently, HIV-1 cell fusion and entry. A broad category of drugs under investigation, entry inhibitors include fusion inhibitors (the focus of this article), attachment inhibitors, and co-receptor inhibitors. Only the fusion inhibitors have advanced to clinical trials; candidates from the other two classes are still in preclinical (laboratory) studies.
All drugs in the class of entry inhibitors work by blocking the ability of HIV to successfully enter and thereby infect a target cell. Fusion inhibitors work by attacking the virus itself; some of the less advanced candidates work with the cells that HIV targets.
The rationale for these drugs derives from x-ray crystallographic, structural studies that permit improved understanding of the interactions between HIV and host (human) cells. Cells are by design resistant to infection by viruses and other microbes; the steps a virus undergoes to successfully infect a cell are many and complex.
Successful infection of a cell requires HIV to bind and to fuse with cell receptors in a series of steps, followed by entry. Binding and fusion involve interactions between HIV glycoproteins (gp) 120 and 41, CD4 cell receptors, and secondary receptors on the target cell, often referred to as chemokine receptors; the two primary co-receptors are CCR5 (R5) and CXCR4 (R4). CD4 cells exhibit ("express") both CCR5 and CXCR4. Other key immune system cells, monocytes and macrophages, which are also frequent targets of HIV, generally express CXCR4 but not CCR5.
In the initial binding process, HIV gp120 binds to the CD4 cell receptor, inducing changes in gp120 that cause it to bind to the chemokine receptor, either CCR5 or CXCR4.
Current knowledge of binding and entry processes has permitted the identification of a number of new, potential targets for antiretroviral drugs, including CD4 cell binding, chemokine receptor binding, and gp41-mediated fusion. A number of candidate drugs have been developed, including soluble CD4, fusion inhibitors, and chemokine receptor antagonists.
The theory behind soluble CD4 was that it would inhibit viral binding on CD4 cell receptors on target cells by blocking a specific, gp120-CD4 interaction between HIV and the target cell. While this approach did well in studies using laboratory strains of HIV, it did less well when tested with clinical HIV strains in vivo (in the body), where it became clear that extremely high--too high--concentrations of the substance would be needed to inhibit viral entry into cells and thus replication.
To date, fusion inhibitors are the type of entry inhibitor that have advanced furthest in the research and development (R&D) process.
Trimeris, a biopharmaceutical company called based in Durham, NC, has two fusion inhibitors in development. (Last July, Roche joined forces with Trimeris for development and marketing of the agents.) Both candidates successfully inhibit HIV fusion with host cells and have advanced to clinical trials. In addition, both agents have been granted "fast track" status by the FDA for treating HIV positive individuals.
The candidate out in front, T-20, has demonstrated promising anti-HIV activity throughout its development so far. (See the January 1999 issue of BETA for an earlier report on the drug.) T-20 is a 36-amino acid synthetic peptide that binds to the HIV protein gp41. In studies to date, T-20 consistently inhibits both wild-type (the normal type of a virus or other organism before genetic mutation takes place) virus and virus that is resistant to other approved antiretrovirals. In laboratory studies, T-20 appears to be synergistic (when combined, the effects of component parts are enhanced) with other anti-HIV agents.
T-20 is administered as a subcutaneous (under the skin) self-injection twice daily in a dose of 50 mg. T-20 is reportedly well tolerated; adverse events observed include irritation at the injection site, headache, nausea, fever, weakness, diarrhea, and dizziness. Thus far, two clinical trials have been completed (TRI-100 and TRI-300), and a Phase III trial is being planned and should begin enrolling sometime this year.
This past September Jay Lalezari, MD, of Quest Clinical Research in San Francisco presented 16-week data at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) on T-20's utility in a group of heavily pretreated (with antiretrovirals) people.
Participants had taken a median of 11 prior anti-HIV drugs; 93% had taken drugs from all three anti-HIV drug classes. After genotypic testing, participants began a new multi-drug salvage regimen that included T-20. At study entry, participants had a median viral load of 4.9 log copies/mL and a median CD4 cell count of 70 cells/mm3; 93% had resistance to at least one protease inhibitor and 87% had resistance to NNRTIs or NRTIs. In this study, T-20 at a dose of 50 mg was self-injected subcutaneously twice daily, as an addition to participants' established drug regimens (which were chosen after receiving the results of genotypic resistance testing).
At 16 weeks, 20 people had an undetectable viral load (fewer than 400 copies/mL) and 13 others had had a one-log copies/mL decrease in viral load. Overall the drug was well tolerated; the most common side effect was a reaction at the injection site. Serious side effects occurred in 7% but no one dropped out due to adverse reactions. According to investigators, the groups' overall response was comparable to the response to "mega-HAART" seen in heavily treatment-experienced persons.
At the 7th CROI, Samuel Hopkins, MD, of Trimeris presented 32-week, follow-up results from the same cohort. (Again, all participants had extensive prior antiretroviral experience.) Forty-six people were available for analysis at 32 weeks; those on treatment at that point showed approximately one log copies/mL reduction in viral load. According to Hopkins, T-20 continued to be safe and effective for most people at all dose levels.
Martin Hirsch, MD, of Massachussetts General Hospital in Boston led a team that studied the combination of T-20 and the CXCR4 inhibitor AMD 3100 (see below) in vitro (in test tube models). Clinical studies will evaluate whether the high level of synergism observed in vitro will also occur in vivo.
Data from cumulative studies of T-20 provide clinical evidence that the strategy behind fusion inhibitors (blocking membrane fusion and viral entry) is sound. Currently, a protocol for a Phase III trial is being drafted, with enrollment expected to begin by mid-2000. Trimeris is working on a new formulation of T-20 that they believe will be twice as concentrated as the earlier formulation and that might therefore require a person to receive fewer injections. The new formulation also is reported to cause less irritation.
On March 14, Trimeris and Hoffmann-La Roche announced that a Phase II clinical study (T20-208) of two novel alternative formulations had begun; up to 60 people will receive daily subcutaneous injections of the new formulations, in addition to their (oral) antiretroviral regimens.
Sponsored by the National Institute of Allergy and Infectious Disease (NIAID), a Phase I/II dose-escalating study of T-20 in children 3-12 years of age is currently enrolling at several sites around the nation. A Trimeris-sponsored Phase II trial assessing three doses of T-20 in combination with abacavir (Ziagen), amprenavir (Agenerase), ritonavir (Norvir), and efavirenz (Sustiva) in adults is also still enrolling at several sites; for more information including eligiblity criteria and sites, contact Trimeris at 919/419-6050 or ACTIS at 1-800-TRIALS-A.
Trimeris' second fusion inhibitor, T-1249, is similar to T-20 in many ways; it is a 39-amino acid synthetic peptide and it also binds to gp41, although in a different region than T-20. Laboratory studies suggest that T-1249 is a potent inhibitor of cell fusion in both laboratory and clinical viral strains. The agent also appears active against HIV that is resistant to AZT (Retrovir), saquinavir (Fortovase), and also to T-20. T-1249 appears likely to have some activity against HIV-2, as well as HIV-1. Like T-20, T-1249 is taken either by either intravenous or subcutaneous injection. Compared with T-20, T-1249 has double the half-life (the time it takes for an original amount of the drug to be decreased by half).
Currently, a Phase I/II trial is underway that is comparing once-daily vs twice-daily subcutaneous injections at five dose levels. Seventy-two people will be enrolled. Dose assignment will escalate in response to safety data gathered first at the lowest level. The treatment phase of the study lasts for two weeks, during which the drug is given on an outpatient basis. Eligibility criteria include an HIV viral load greater than 5,000 copies/mL. Sites are Birmingham, AL; Boston, MA; Chapel Hill, NC; Denver, CO; Houston, TX; New York, NY (two sites); Stanford, CA; and Tampa, FL.
At the 39th ICAAC in San Francisco this past autumn, Progenics Pharmaceuticals presented results of Phase I trials of its fusion inhibitor, PRO 542. PRO 542 binds to HIV's gp120. In the study presented at ICAAC, 15 participants received a single injection of the drug in one of four doses. According to investigator Jeffrey Jacobson, MD, from Mt. Sinai Medical Center in New York, a single dose of PRO 542 was well tolerated and achieved significant antiviral activity; a large, Phase II trial is being planned.
Drugs designed to prevent HIV from binding to the chemokine receptors on target cells, a crucial aspect of cell entry and infection, are also being developed. CCR5 and CXCR4, the two main co-receptors on human cells used by HIV, are the two that experimental agents primarily seek to block. Inhibitors aimed at CCR5 and CXCR4 are currently in preclinical development.
In primary and early infection, HIV seems to preferentially use the CCR5 chemokine receptor to enter cells, i.e., early on, CCR5-using virus predominates. Over time, with HIV disease progression, a switch occurs and the virus becomes syncytium-inducing (a more virulent form) and skilled at using both co-receptors for cell entry and infection. Thus, one obstacle in the development of CCR5 inhibitors is the presence of alternative pathways for virus entry, i.e., "R5" viruses can evolve their receptor specificity and enter cells via other chemokine receptors--CXCR4, in particular.
Although these concerns are still hypothetical, since R4 viruses are thought to be more virulent, this limitation may prove significant, and researchers are scrutinizing ways to prevent their CCR5 inhibitors from causing HIV to switch from a CCR5- to a CXCR4-type receptor. Phase I/II studies should provide some elucidation.
Another R&D challenge relates to the fact that there are natural chemokines or ligands (molecules that attach to HIV co-receptors) that help block HIV infection by themselves binding to the receptors. Natural ligands for CCR5 include the chemokines RANTES, MIP-1alpha, and MIP-1beta. A derivative of the chemokine RANTES, called AOP-RANTES, has even been shown to inhibit HIV in vitro (but was inactive in a small clinical trial). The challenge to researchers is to design drugs that will not inhibit natural ligands, which not only play a role in the body's natural immune defense against HIV but may be needed to fulfill other physiological functions.
Progenics Pharmaceuticals is developing PRO 140, a monoclonal antibody that binds to CCR5. In vitro studies of PRO 140 indicate that it can effectively inhibit viral replication in a variety of cell lines.
Schering-Plough is actively developing a CCR5 antagonist, still in preclinical studies, known as SCH-C. This candidate's oral bioavailability eliminates the need for injection or intravenous infusion. In vitro studies suggest that the agent is very potent and highly active. At the 7th CROI, Bahige Baroudy of the Schering-Plough Research Institute in Kenilworth, NJ, described the progress of the agent thus far. SCH-C appears to inhibit HIV-1 in mononuclear cells and to prevent HIV from entering into CD4 and CCR5-expressing cells. SCH-C also seems to be potentiated (i.e., it becomes even more potent) when used with AZT (Retrovir) and indinavir (Crixivan).
AnorMED, a Canadian company, is developing a substance designed to prevent HIV from binding to the CXCR4 receptor. At the 7th CROI, Erik De Clercq, MD, from the Rega Institute in Leuven, Belgium, reviewed the development of bicyclams or AMD 3100. AMD 3100 is not a brand- new compound; ten years ago it was described in the literature as having antiviral activity against both HIV-1 and HIV-2. Since then, more has been learned about its mechanism of action and it is now known to be an antagonist of CXCR4 that works by interrupting the interaction between gp120 and CXCR4. From in vitro studies, resistance of HIV to AMD 3100 appears to develop slowly.
Human trials of AMD 3100 have already begun. A Phase I single-dose, dose-escalation trial has been completed, in which 13 subjects took 24 doses intravenously, subcutaneously, or orally, at doses ranging from 10 to 80 micrograms/kg. Investigators found that the drug was well tolerated. Currently a Phase Ib/IIa dose-escalating trial is underway, in which people with greater than 50 CD4 cells/mm3 and greater than 5,000 HIV RNA copies/mL are receiving 10 days of continuous infusion of AMD 3100.
Other candidates at early preclinical stages of R&D include ALX40-4C and T-22, both of which block CXCR4-using virus. A CCR5 receptor antagonist drug called TAK-779 is also under development by Takeda Chemical Industries. On March 27, Consensus Pharmaceuticals, a Massachusetts biotechnology company, was awarded a Phase I Small Business Research grant from NIAID to fund the continuance of a drug discovery program designed to target the CCR5 receptor--an indication of broad support for this approach from the respected scientific community.
These new agents offer new treatment options for people who have exhausted current options. Progress thus far is encouraging, although even for those relatively advanced candidates, more data are needed on long-term potency and efficacy and on such issues as side effects and drug resistance.
One looming drawback may well be the high cost of manufacturing these agents, which will undoubtedly be transmitted to consumers. Another detriment for consumers is that several of the candidates are large molecules that require administration by injection. Some researchers believe that the identification of these potentially beneficial molecules may provide clues to finding smaller, more manageable molecules which when developed could be taken orally. At present, there is widespread agreement that the principles behind these agents' development are sound.
Leslie Hanna is Editor of BETA.
Bolognesi, D. and others. Development and clinical evaluation of T-20, the first member of a novel class of antiretroviral agents that inhibit membrane fusion. 7th Conference on Retroviruses and Opportunistic Infections (CROI). San Francisco, CA. January 30-February 2, 2000. Abstract and oral presentation S16.
Baroudy, B. A small molecule antagonist of CCR5 that effectively inhibits HIV-1 potential as a novel antiretroviral agent. 7th CROI. Oral presentation S17.
DiMassimo, B. and others. Effects of peptide-induced humoral responses and preexisting antibodies in non-human primates and HIV-infected patients following chronic administration of T-20, 7th CROI. Abstract and poster presentation 502.
Dragic, T. and others. TAK-799, a specific inhibitor of HIV-1 entry, binds within a pocket formed by the trans-membran domains of CCR5. 7th CROI. Abstract 498.
Kilby, J.M. and others. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry, Nat Med 1998 Nov;4(11):1302-7.
Lalezari, J. and others. Sixteen week analysis of heavily pre-treated patients receiving T-20 as a component of multi-drug salvage therapy. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 1999. San Francisco, CA. Abstract LB-18.
Richman, D. Nailing down another HIV target, : Nat Med 1998 Nov;4(11):1232-3.
Saag, M. and others. A short-term assessment of the safety, pharmacokinetics, and antiviral activity of T-20, an inhibitor of gp41 membrane fusion. 35th Annual Meeting of the Infectious Disease Society of America. September 1997. Abstract 771.
Schols, D. and others. Bicyclams as CXCR4 antagonists. 7th CROI. Abstract S18.
Tremblay, C. and others. Strong in vitro synergy observed between the fusion inhibitor T-20 and a CXCR4 blocker, AMD-3100. 7th CROI. Abstract 500.
000410
BE000409
Copyright © 2000 - San Francisco AIDS Foundation. Reproduced by permission. Reproduction of this article (other than one copy for personal reference) must be cleared through BETA: PO Box 426182, San Francisco, CA 94142-6182. Tel: 415 487 8060 Fax: 415 487 8069 URL: http://www.sfaf.org/beta E-mail: beta@sfaf.org
ÆGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2000. This material is designed to support, not replace, the relationship that exists between you and your doctor.
ÆGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1990, 2000. ÆGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on ÆGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of ÆGIS and the Sisters of Saint. Elizabeth of Hungary, or the party credited as the provider of the content.