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Not Nearly Enough

By Bob Huff

In the midst of a “golden age” of abundant antiretroviral treatments some worry that our “embarrasment of riches” will leave us wanting unless we continue the search for better drugs.

TAG’s Antiretroviral (ARV) Pipeline Report is usually a story about what’s new and what’s coming in the world of experimental HIV drugs—and the story typically ends with FDA approval. In 2008, with only a few new drug candidates in the pipeline, the bigger story may be what’s happening (or not happening) with three drugs that were approved during the past 12 months.

Merck’s raltegravir, approved in October 2007, seems to be a star that shines brighter day by day. Prior to approval it was an object of giddy speculation by the medical elite, some of whom called it a “wonder drug.” And it enjoyed a glittering debut among people with multidrug-resistant HIV who, for the first time in many years, found a regimen able to durably suppress their virus. (Many of them apparently even felt comfortable enough to drop the inconvenient injectable Fuzeon—a potentially catastrophic development for Trimeris and Roche, makers of Fuzeon; this development has also led some to speculate that future Pipeline Reports may become obituaries.) Some observers warn, however, that this “golden age” of viral pansuppression may not last as a growing number of individuals on the newer drugs experience loss of viral control due to resistance and require even newer options. Unless the pipeline is refilled, their options may be few.

Yet for now, at least, some clinical investigators seem content with taking a breather and enjoying the lighter burden in their clinics. One editorial even termed current options “an embarrassment of riches” (Hirschel 2008).* There is a worrisome aspect to this, however, if the complacency expressed by some clinicians and investigators regarding the need for improved first-line regimens manifests as reluctance to participate in clinical trials for better drugs.

The other important new drug of 2007, Pfizer’s maraviroc, approved in August, has not fared as well as raltegravir, and while not a candidate for the obituary column it may one day find itself adrift if Pfizer decides to cast off its involvement with HIV. Sales of maraviroc have been far below expectation, mainly because the drug faces formidable barriers to acceptance in clinical practice. Currently, using maraviroc requires an expensive and slow-to-report blood test that indicates baseline viral susceptibility to the drug—and susceptibility rates fall to about 50 percent in people with long time infections and lower CD4 counts. Because such an assay does not catch everyone who lacks susceptibility, there is a risk of loss of viral control—and possible loss of the rest of the regimen due to resistance. Then there are worries about the safety unknowns of maraviroc’s novel mechanism that targets the host rather than the virus. Finally, a high state of nervousness at the FDA over the Vioxx drug safety scandal likely contributed to a black box warning about liver damage based on one episode with maraviroc and multiple cases with a different, subsequently discontinued drug in the same class.

Still, an intriguing result of early clinical trials provides optimism for the use of maraviroc and other treatments in the CCR5 inhibitor class. It’s been observed that some patients who lacked susceptibility to the drug and obtained no virologic benefit from it still had paradoxical increases in CD4 counts. Because the CCR5 inhibitors attach to signaling proteins on CD4 immune cells, there is some speculation that they may have immune modulation activity independent of their antiviral effect. Another explanation may be that the specific suppression of HIV that uses CCR5—even if it is not the dominant strain as measured by viral load—helps protect against CD4 cell loss. If this turns out to be the case, then the need for a susceptibility assay may be jettisoned, as CCR5 antagonists are prescribed to quell a particularly toxic form of HIV, whether it shows up in the viral load or not. Until recently there were five CCR5 inhibitors under development, though this number was reduced by one when Incyte discontinued its candidate, INCB9741, in 2008. We may expect that this number will shrink further in the future.

Another less heralded drug approval, in January 2008, was that of the NNRTI etravirine, from Tibotec. This drug is active against many—but not all—NNRTI-resistance mutations that arise with efavirenz and nevirapine, and it was approved for treatmentexperienced patients with resistance problems. Etravirine followed an unusual development path since it was most always paired in clinical trials with Tibotec’s protease inhibitor darunavir. While offering two experimental agents was a step forward in clinical trial practice and provided people with few treatment options extra protections while in the study, it also meant that there was little data produced on using etravirine in any other context than with darunavir. It turns out that there are a complicated set of interactions when etravirine is combined with several other drugs. Nevertheless, it works well with darunavir, tenofovir, and raltegravir, and these combinations may be all anyone really needs. Unfortunately for Tibotec, neither etravirine nor darunavir have been as widely embraced by clinicians as had been hoped. Rilpivirine, another NNRTI from Tibotec being developed as a firstline drug, has finally initiated phase III studies at 25mg/day after a long delay.

With the success of raltegravir (and the disappointment of maraviroc) the gold rush in ARV development has shifted to the integrase inhibitor class. Next in the pipeline is elvitegravir, a candidate from Gilead Sciences with once-daily dosing potential when combined with the pharmacologic booster ritonavir. At first glance, the need for ritonavir seems like a drawback (Abbott Laboratories only offers an inferior and expensive form of the drug— part of a market-protection scheme for its Kaletra product), but new thinking about ARV development looks to the regimen, not just the drug. Due to favorable drug interactions between elvitegravir and the Bristol-Myers Squibb (BMS) protease inhibitor atazanavir, Gilead may be wellpositioned to offer the first all-in-one NRTI-sparing regimen. A successful cooperative venture between Gilead and BMS resulted in the wildly successful single-pill version of efavirenz, tenofovir, and emtricitabine called Atripla. Since BMS also makes atazanavir, the precedent is in place for a nextgeneration powerhouse with access to a boosting agent being the main sticking point. Gilead and Pfizer are both said to be working on boosting agents to replace ritonavir.

This brings us to another trend in ARV manufacturing. Due largely to Abbott’s monopoly on ritonavir, the United States may soon fall behind the rest of the world in the variety of ARV formulations available to its citizens. The Indian generic pharmaceutical industry operates under a set of patent laws that protect the process for manufacturing drugs but not the final drug product itself. This means the industry has become skilled at inventing new processes, and as a result has been able to supply ARVs to mass treatment programs in Africa at a cost of under $200 per year per person. Millions of people are alive today because of low-cost, high-quality Indian-made ARVs made possible by this patent system. However, this system is changing, and Indian generic drug makers may be prevented from manufacturing certain newer drugs such as atazanavir and raltegravir without permission. Yet because the need for ARVs is so great and continues to grow (some plans call for treating ten million additional people within the next few years), patent holders such as Gilead have issued licenses that allow the Indian companies to produce and sell tenofovir in Africa with few restrictions. Looking ahead, these Indian drug companies are already planning to produce novel all-inone regimens of generic ritonavir-boosted atazanavir/tenofovir/lamivudine, and even raltegravir/atazanavir/ritonavir. The generics are ready to release a heat-stable version of ritonavir (which Abbott has not yet done) and will be able to combine it with a drug like atazanavir in smart, convenient combinations that may never become available in the United States.

The Current Pipeline

Of ARVs in phase II or beyond, only one drug currently appears to have the staying power needed to make it to the finish line—and not before 2010. Gilead has the money and experience to move its integrase inhibitor elvitegravir forward, and it has a strategy and a market waiting for it when it emerges. What it doesn’t have is heatstable ritonavir available in 25mg doses (a quarter of the Abbott dose and all that is required by elvitegravir) or a substitute pharmacologic booster.

After many years of setbacks and missteps, Schering’s CCR5 blocker vicriviroc may continue to limp forward, but the rationale for investing in large phase III trials seems slim given the dismal performance of maraviroc during its first year on the market.

Tibotec’s rilpivirine could be a very important drug for the developing world due to its compact 25mg dosing, which would make it cheap and easy to put into single-pill regimens. But potency may be an issue, since rilpivirine suppressed HIV at a slower rate than did efavirenz in a head-to-head trial (although by 48 and 96 weeks its performance was equivalent to efavirenz, with fewer side effects). Still, after seeing the unprecedented rapidity with which raltegravir suppresses HIV, there may be a perception that the bar for antiviral activity has been set higher.

Beviramat, a novel maturation inhibitor, once had its day as a bright and promising newcomer. That luster is now long gone, however, as the drug has suffered problems with formulation, unconvincing trial results, and missteps by an underresourced small pharmaceutical company trying to go it alone. Tiny companies like Panacos must inevitably partner with a larger company if they hope to get a drug through expensive phase III trials. That no big pharmaceutical partner has appeared to take beviramat forward means that most of them had a look at the drug and decided to pass.

KP-1451 is a (very) novel compound from Koronis, another smallpharmaceutical start-up. The idea is that the molecule incorporates into the growing HIV DNA chain during reverse transcription, but instead of terminating the chain, as do NRTIs, it flips its identity to an alternate base, thereby introducing a point mutation that is integrated and propagated as the virus replicates. Eventually these randomly inserted mutations accumulate and lead the virus to extinction. This has worked in the test tube, but the drug has yet to decisively impact HIV levels in actual persons. Until that happens, this drug survives only on hope. Larger phase II trials are being enrolled now.

TNX-355 is a promising idea from a small company that may have been lost in a corporate shuffle. The drug is a monoclonal antibody that prevents HIV from attaching to the CD4 receptor on target cells. Its developer, Tanox, was acquired by Genentech, which then shipped the drug off to Biogen, where it awaits a development plan. A drawback is the need for infusion, although one dose might last for a full month. The drug would occupy a niche market at best.

With only one or two drugs in the pipeline that have a strong chance of emerging by 2010, the outlook for new HIV agents looks bleak. If we seek hope in compounds still in phase I trials we may not be reassured. Merck undoubtedly has a follow-on integrase inhibitor with oncedaily dosing properties; GlaxoSmithKline also has an integrase candidate on tap, as may others, since this is where the action is.

A surfeit of CCR5 blockers (where the action used to be) is already starting to become apparent. Incyte canceled its CCR5 program, though newcomer Tobira has entered the scene with two candidates. Pfizer has a follow-on to maraviroc, but it is hard to imagine the company giving it much attention after maraviroc’s poor showing. A couple of monoclonal antibody CCR5 blockers are on the books at Progenics and Human Genome Sciences, but they are not causing much buzz. Development of a CXCR4 blocker, which might make a nice companion to its CCR5 cousin, has at present been suspended by Genzyme.

New and improved versions of wellestablished classes, such as NNRTIs and protease inhibitors, may be a safer bet. Pfizer and Boehringer-Ingelheim each have an NNRTI in the early pipeline, though whether either of these companies—which have each suffered significant disappointments in the marketplace recently—will stick with them, or even with HIV treatment, remains to be seen. Smaller companies, such as Ardea, are also working on NNRTIs.

The protease inhibitor class may still have some life in it if compounds from Merck and promising newcomer Sequoia gain traction.

Finally, there are a gaggle of NRTI molecules from small companies that have been languishing for several years at early development stages; none seem poised for greatness. Still, despite great enthusiasm for NRTI-sparing regimens, a good, clean NRTI active against current NRTI mutations might find a happy home in a fixed-dose combination pill from Merck or Gilead.

HIV Drug Pipeline in 2008

Phase II or III

  • Rilpivirine (TMC278), NNRTI; Tibotec, phase III
  • Vicriviroc, CCR5 antagonist; Schering, phase III
  • Elvitegravir, integrase inhibitor; Gilead, phase II
  • Bevirimat, maturation inhibitor; Panacos, phase II
  • KP-1451, viral decay accelerator; Koronis, phase II
  • TNX-355, CD4 blocker, Biogen Idec, phase II
  • Apricitabine, NRTI; Avexa, phase IIb
  • Amdoxovir, NRTI; RFS Pharma, phase II

TAG’s complete 2008 Pipeline Report, including vaccines and drugs for TB and hepatitis, will be avialable in July.

* Bernard Hirschel, M.D., and Alexandra Calmy, M.D. Editorial: Initial Treatment for HIV Infection—An Embarrassment of Riches. New England Journal of Medicine 358, no. 20 (2008): 2170-2172.

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