Anti-HIV Candidates in the Pipeline
In the past year or so, the HIV drug pipeline seemed to slow to a trickle, with only one new approval, tenofovir (Viread). But the future is beginning to look brighter. Several agents that entered the pipeline years ago will soon emerge, including T-20 (Fuzeon) -- the first in an entirely new class of fusion inhibitor drugs (see "Entry Inhibitors: The Bouncers at the Door"). Further back in the development process are a slew of candidates in existing drug classes, along with many more that attack HIV by completely new mechanisms.
The drug development process is long and complex. Keeping track of agents as they make their way through the pipeline can be a challenge as drug names change, pharmaceutical companies merge, and studies are suspended and restarted. Candidates are frequently withdrawn due to toxicity or lack of effectiveness in early trials, and all too often, once-promising agents seem to stall in the pipeline or disappear with little or no explanation.
Despite growing concerns about resistance and side effects, research into the existing drug classes is far from dead.
Among the new protease inhibitors (PIs) in development is TMC-114 from Tibotec-Virco that was designed to be active against HIV that is resistant to older PIs. This agent has shown good in vitro (test tube) activity against both wild-type and resistant HIV. Phase I/II studies are underway.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are well represented in the current crop of candidates, including Capravirine (formerly known as AG-1549 and S-1153, now owned by Pfizer), discussed in "Next Generation Drugs in Existing Classes". Calanolide A, produced by Sarawak MediChem, is derived from a rainforest plant. It is active against HIV in the laboratory and produced viral load reductions in early human trials. Calanolide B is in preclinical testing in conjunction with the National Cancer Institute. MIV-150, under joint development by Chiron and Sweden's Medivir, is in Phase I studies. Roche and Medivir expect to begin Phase I trials of MV026048 this year.
On the nucleoside analog (NRTI) front, alovudine (MIV-310 or FLT, being developed by Medivir) is actually an old drug making a comeback. Like AZT (which it resembles structurally), alovudine can cause low blood cell counts, but appears tolerable at low doses. Early Phase II trial results indicate that it's active against multidrug-resistant HIV. Stampidine, being developed by the Parker Hughes Institute, is a new and improved Zerit (d4T) derivative that looks stronger in laboratory studies. Toxicity was rare in rodent studies, but given the many side effects of Zerit, its sister bears close monitoring. Other NRTIs in the pipeline include SPD-754 (a chemical cousin of the abandoned dOTC) and the new puridine analog SPD-761 TP, both under development by Shire Pharmaceuticals, as well as GS-7340, a prodrug of tenofovir being developed by Gilead. (A prodrug is a compound related to a drug that requires additional processing in the body before it becomes active.)
While additional drugs in old classes continue to be developed, promise also lies with drugs that work in completely different ways. Each basic science discovery about how HIV infects cells and replicates opens doors for possible new treatments.
HIV entry inhibitors are receiving the most hype. The process of HIV entry into cells requires three steps -- attachment, co-receptor binding, and fusion -- and there are drug candidates that act at each step. Bristol-Myers Squibb's BMS-806 inhibits the attachment step by binding to HIV's gp120 protein and preventing it from grabbing on to CD4 cells. Study results presented at recent conferences indicate that the drug has strong activity against HIV, including virus that is resistant to other classes of antiretrovirals. Animal studies to date have not aroused safety concerns, and human studies are set to begin soon. Since BMS-806 is a small molecule, it probably can be taken orally rather than injected. TNX-355, produced by Tanox, is a monoclonal antibody (a genetically engineered antibody that recognizes a single protein) that inhibits HIV attachment by binding to host cell CD4 receptors; Phase I clinical trials are newly underway.
Chemokine antagonists inhibit the middle step by preventing HIV from binding with one of two co-receptors -- CCR5 or CXCR4 -- which allow the virus to enter host cells. Several CCR5 antagonists are in the pipeline. PRO-140, under development by Progenics, is a monoclonal antibody that has been shown to block HIV infection of cells in the laboratory and to lower viral load in animal studies. Other CCR5 blocker candidates include Pfizer's UK-427-857 and Schering-Plough's SCH-D, a reportedly more potent successor to SCH-C (see "Entry Inhibitors: The Bouncers at the Door"). Development of the first CXCR4 inhibitor to gain widespread attention, AnorMED's AMD-3100, was halted in 2001 due to poor effectiveness and possible heart toxicity.
HIV that uses CXCR4 co-receptors was once widely thought to cause more rapid disease progression than virus that uses CCR5. Although this theory has recently been reevaluated, some researchers remain concerned that agents that block CCR5 might encourage more aggressive HIV that can still use CXCR4. On the other hand, CXCR4 antagonists may cause a shift toward the less aggressive strains that use CCR5. Combining CCR5 and CXCR4 blockers could prevent HIV from switching back and forth between targets. GlaxoSmithKline is even looking at an agent called vMIP-II that appears to block multiple co-receptors. Unfortunately, because chemokines have other functions in the body, agents that block their activity could potentially lead to serious side effects.
Finally, Lexigen's fusion inhibitor FP-21399 appears to be well tolerated in Phase I studies, although many people developed a bluish skin and urine color. SJ-3366, being developed by South Korea's Samjin, inhibits entry after HIV attaches to CD4 cells, but its exact mechanism is unknown; this agent also acts as an NNRTI once HIV is inside a cell.
After HIV enters a host cell, it must splice its genetic material into the human DNA in the cell nucleus in order to replicate. The HIV enzyme called integrase is required for this process. Several experimental integrase inhibitors are under study, but development of this class has been slow. Integrase is the last of HIV's three enzymes -- after reverse transcriptase and protease -- to be successfully targeted by a drug.
Diketobutanoic (diketo) acids interfere with the final step in the process of assembling and transferring HIV DNA into host cell DNA. S-1360 (GW810781), under development by Japan's Shionogi and GlaxoSmithKline, is furthest along in clinical trials. Results from laboratory studies indicate that the agent is active against a variety of HIV strains (including multidrug-resistant strains) and works well with other classes of drugs. Early Phase I data reported at recent conferences suggest the drug can be taken orally and has low toxicity, but it may not work well in the body due to plasma binding (a process in which a drug attaches to proteins in the blood, making it unavailable where it's needed). Merck has also developed a series of diketo acid compounds. The earliest agents had poor pharmacokinetic properties (not enough drug was getting into cells), but later candidates appear more promising. Recent data show that L-870,810 is active in vitro against multidrug-resistant HIV, and L-870,812 lowered viral load in rhesus monkeys. Phase I human trials of L-870,810 are underway.
Before HIV can integrate its genetic material into a host cell, it must uncoat itself, or remove its envelope to release the proteins and enzymes inside. After integration, new viral components are produced and assembled, and then bud out through the host cell membrane to become complete virions (virus particles). All of these steps present potential drug targets.
HIV's nucleocapsid core, which contains its RNA (genetic material), is held together by protein structures called zinc fingers. Zinc finger inhibitors interfere with the packaging of RNA into new virions. Disruption of the nucleocapsid leads to the production of dysfunctional virus that cannot infect new cells. Azodicarbonamide (ADA), under development by Hubriphar in Belgium, is the most advanced zinc finger inhibitor. Results of Phase I/II trials showed moderate activity against HIV. But while HIV may be unable to function without zinc fingers, the same might be true of the human body. Such agents may have serious side effects; kidney toxicity and glucose intolerance were seen in early studies. GPG-NH2, from Sweden's Tripep, also interferes with the assembly of HIV's p24 nucleocapsid protein. It has shown anti-HIV activity in laboratory studies and good absorption and safety in early clinical trials.
AXD-455, being developed by Germany's Axxima, works by blocking the action of an enzyme called eIF-5A that transports viral genetic material from the host cell nucleus to the main body of the cell for processing and assembly. In vitro studies showed anti-HIV activity, and the agent is undergoing early clinical trials in Europe. Panacos' PA-457, a betulinic acid derivative, appears to inhibit HIV assembly and budding. Laboratory studies show that it's effective against different strains of the virus. NeoR is a Tat inhibitor that interferes with one of HIV's three regulatory proteins. Agents that target the other two regulatory proteins -- Nef and Rev -- are possible future drug development prospects.
New classes of anti-HIV drugs -- and new drugs in existing classes -- represent the best hope for people with HIV, especially those who have exhausted current therapies. Even people whose HIV is resistant to drugs in all three existing classes stand to benefit from new agents now in the pipeline. And drugs that work by different mechanisms may produce fewer side effects. But even with the best new agents, resistance remains a major concern. It will likely remain the case that the best treatment strategy involves use of multiple drugs that attack HIV from different angles.
Liz Highleyman is a San Francisco-based freelance medical writer, writing for the Bulletin of Experimental Treatments for AIDS (BETA), POZ and the Hepatitis C Support Project's HCV Advocate.
This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.