Although the HIV drug development pipeline in 2009 appears robust if you go by the numbers -- at least a dozen agents are in later stages (phases II and III) of clinical testing -- there are no obvious miracle drugs on the horizon and little that seems likely to revolutionize treatment; only the next steps in the evolution of antiretroviral (ARV) therapy. This doesn't mean that incremental benefits cannot be revolutionary for some individuals who depend on ARVs -- even a slight improvement in gastrointestinal tolerability or mental clarity, for example, can allow someone to enter the job market, start dating again, or think about starting a family.
As good as current HIV drugs are, they are not ideal and not universally accessible. A new generation of HIV therapy is needed -- treatments that are more tolerable, less susceptible to resistance, more forgiving of dosing lapses, and that have wellunderstood long-term safety profiles. To continue expanding treatment for millions of people in the developing world, add requirements for compact regimens that can be produced and distributed inexpensively and used with minimal monitoring. The world needs better AIDS drugs, but the current ARV pipeline does not reflect that urgency.
Unfortunately, many clinicians in the United States and Europe are content with the current drugs and complacent about the need for developing the next generation of therapy. This means that some drug makers do not hear a compelling demand to make major investments in HIV research. In 2009 there has been consolidation among the big HIV drug makers -- Schering with Merck; Pfizer with GlaxoSmithKline -- and other companies, such as Roche and Abbott, are backing away from new research in the field. The 2009 pipeline chart is half populated by offerings from small pharmaceutical or biotech companies with drugs aimed at specialized, or niche markets at best.
It could be that the drugs in the AIDS pipeline with the most potential for bringing dramatic change are not anti-HIV drugs at all. Rather, they are new agents that slow the metabolism, boost blood levels, and improve the potency of certain ARVs. As of now the only pharmacokinetic (PK) enhancer on the market is ritonavir (Norvir) from Abbott Laboratories. Originally approved as an HIV protease inhibitor, the drug's metabolic inhibiting side effect turned out to be more useful than its antiviral properties, and it became an essential ingredient in Abbott's popular coformulated protease inhibitor Kaletra. However, ritonavir use has been associated with increased blood lipid levels and diarrhea. There are high expectations that new, specifically designed boosters from Gilead, Tibotec, Sequoia, and Pfizer will come with fewer unwelcome side effects. Abundant boosters should also make possible a greater variety of combination tablets and all-in-one regimens, as more companies team up to pack three drugs (plus a booster) into a single daily pill. Convenient, tolerable drugs make treatment easier to start and stick with, which leads to better long-term outcomes. With a trend to prescribing earlier in the disease and a widening campaign to test and treat tens of thousands of people who are infected but undiagnosed, these small advances can help make lifelong therapy a more palatable prospect.
Antiretroviral Drugs in Development, 2009
|Rilpivirine (TMC278)||NNRTI||Tibotec||Phase III|
|Vicriviroc||CCR5 antagonist||Schering||Phase III|
|Elvitegravir||Integrase inhibitor||Gilead||Phase III|
|Apricitabine (ATC)*||NRTI||Avexa||Phase II/III|
|Amdoxovir (DAPD)||NRTI (prodrug)||RFS Pharma||Phase II|
|Bevirimat*||Maturation inhibitor||Myriad||Phase II|
|TNX-355*||CD4 blocker||Biogen Idec||Phase II|
|GSK1349572*||Integrase inhibitor||GSK/Shionogi||Phase II|
|GSK1265744||Integrase inhibitor||GSK/Shionogi||Phase IIa|
|PRO 140*||CCR5 Blocker||Progenics||Phase II|
|Ibalizumab*||CD4 Blocker||TaiMed||Phase II|
|GS 9350||PK Booster||Gilead||Phase II|
|* Potential use against extensively drug resistant HIV?|
Gilead's GS 9350 booster is farthest along on this path. The drug is getting its first trial as part of an all-in-one regimen containing Gilead's integrase inhibitor, elvitegravir, plus the company's tenofovir and emtricitabine (Truvada) pressed into a single pill. The combo is being studied in a treatment-naive population with approval anticipated by 2011. Gilead has said it intends to make the new booster available as a stand-alone product and is willing to license the drug to other companies for use in coformulated products. Tibotec's underutilized protease inhibitor (PI) darunavir could get a big boost in the market if it can be bundled with a proprietary PK enhancer. Tibotec also has a new protease inhibitor in early clinical trials that is giving the home team booster a shot. The start-up company Sequoia, with its expertise in protease inhibitors, is another natural in this field. Even a generic version of saquinavir, a first-generation PI, may be a viable treatment if it is mated with a better booster; the drug goes off patent in 2010.
It is not clear how Pfizer can capitalize on its booster candidate, since none of its current HIV drugs requires boosting and the company has recently shifted most of its ARV research and marketing efforts to a new, HIV-focused joint venture with GlaxoSmithKline (GSK). GSK does have a PI on the market that requires boosting, and it may see an opportunity for synergy there. As for Abbott, the original booster maker, after raising the price of Norvir by 400% in 2003 and having indicated that it doesn't anticipate developing a follow-on to surpass Kaletra, the company seems (like so many others) to have shifted its focus to the search for a breakthrough hepatitis C antiviral treatment, content to let the maturing market for HIV drugs play itself out. After many years of delay, Abbott is preparing to release a new heat-stable tablet formulation of Norvir.
Nucleoside reverse transcriptase inhibitors (NRTIs, or "nukes") were the first class of antiretroviral drugs developed. The drugs work by stopping HIV from successfully copying its genetic material into DNA. But NRTIs can affect similar natural processes in the body, and they have been implicated in both severe and subtle toxicities. AZT, approved in 1987, remains a useful drug today, although newer and less toxic NRTIs now dominate the market.
A "nuke sparing" strategy to forgo the use of NRTIs is currently in vogue and is getting a test in several trials that marry a reliable protease inhibitor with a powerful but more resistance-prone integrase inhibitor. A few small studies have begun to report successful results. A preliminary analysis from a trial of Kaletra plus raltegravir versus Kaletra plus the NRTI-combination Truvada showed faster viral suppression using raltegravir but, oddly, slightly increased triglyceride and cholesterol levels in the NRTI sparing arm. Longer-term results from this and other studies are expected in 2010. Other variations include a clever pairing of raltegravir with twice-daily unboosted atazanavir -- sparing both NRTIs and ritonavir.
While there are a few new NRTIs in development, it is not clear how even the most promising ones -- like apricitabine (ATC), from the Australian company Avexa -- are likely to upset the treatment landscape. ATC has a unique resistance profile that overcomes the M184V mutation associated with lamivudine and emtricitabine resistance and it could represent an important salvage alternative. The drug recently completed a 96-week phase IIb study with no ATC resistance seen in a small number of patients, and is now enrolling a large phase III trial comparing ATC to lamivudine in treatment-experienced patients. However, the current dose of ATC is 800 mg twice daily, which will be limiting in terms of convenience and utility as a first-line drug.
Amdoxovir (DAPD), from RFS Pharma, a Georgia company started by serial NRTI entrepreneur Raymond F. Schinazi, has progressed to the phase II stage, though no currently enrolling studies are apparent. The drug has appeared on pipeline charts since 2002 -- enrolling just a few hundred people during that time, mainly in short-term, 10- to 15-day studies. Amdoxovir is expected to have activity against lamivudine-resistant HIV, though so far there is scant data in treatment-experienced patients to support that.
Aside from whether the nuke-sparing strategy is practical or not, such trials might discover some interesting facts about HIV and HIV therapy. Maybe nukes will be found essential for preventing neurological symptoms and improving response rates. Maybe the DNA chain terminators will be implicated in the apparent premature aging of people with HIV (see box, "Premature Aging and HIV?"). Since these effects may be subtle and the trials to investigate them will not be very large, we may not find any clear answers, and choosing to use nukes will remain a part of the art of medicine as doctors stick with what they know.
If the easy HIV targets (HIV's enzymes, reverse transcriptase and protease) seem temporarily played out, second-generation targets are still getting a lot of attention. Integrase inhibition attacks HIV's third enzyme (integrase), and with raltegravir the concept has ascended to the main stage.
Merck's wonder drug raltegravir (Isentress) impresses because it clearly lowers viral load faster than efavirenz and Kaletra. But what's not clear is how meaningful this talent is, since by 48 weeks suppression rates for these drugs seem comparable. The current theory is that all effective ARV regimens halt viral replication equally well, but because integrase inhibitors protect cells from getting infected in the first place there is less excess virus produced and viral loads fall faster.
Premature Aging and HIV?
There is a growing concern that people with HIV are showing signs of aging prematurely -- even when their virus is under control. Rates of cardiovascular problems, diabetes, bone frailty, and cognitive and neurological problems are increased in people who delay therapy too long, but increased incidence of these is also suspected in some who are treated and have no evident viral replication.
Chronic immune activation and inflammation may be responsible for some of the emerging non-AIDS disease seen in people with HIV. But stress, sleep loss, smoking, and genetics could also contribute. Because the epidemiology and pathogenesis of these fairly rare clinical events are poorly understood, it is difficult to identify any single cause for premature aging other than HIV. There may be multiple factors.
1. Early injury. If HIV causes irreparable damage to the immune balance within days of infection by wiping out a significant population of T cells in the gut and elsewhere, it is possible that a key part of an immune regulatory mechanism has been destroyed. Trials of treatment during acute HIV infection, and studies of people who become infected despite taking drugs for pre-exposure prophylaxis, may illuminate the impact of moderating the early damage.
2. Ongoing insult. Unsuppressed viral replication could cause ongoing damage to the body due to chronic immune activation and inflammation. It is possible that bacteria entering the body from the damaged gut contribute to systemic immune activation. Immune deficiency could be an end-stage outcome after years of accumulated damage. The large Strategic Timing of Antiretroviral Treatment trial of initiating treatment earlier versus later in the disease plans to track inflammation markers, which may shed light on the impact of arresting the damage sooner.
3. Low-level toxicity due to the release of HIV proteins despite suppression of replication. HIV proteins are released from viral reservoirs periodically (blips) even when the drugs are working. If some of these proteins (Tat, Vpr) cause errant signaling to the immune system, then improper immune responses may be sustained even in the absence of viable virus. Treatments to purge viral reservoirs might help turn down the production of these toxic proteins.
4. The drugs. Even though the current generation of ARV drugs are highly effective and relatively tolerable, very-long-term effects are not known. For example, almost everyone on therapy takes lamivudine or emtricitabine, yet there are few comparative safety data from randomized trials that might reveal subtle toxicities attributable to these ubiquitous drugs. NRTI-sparing studies now underway might help reveal if these drugs are associated with any of the wide range of symptoms of premature aging increasingly recognized in people with HIV.
Some unsettling news about raltegravir resistance came from a study in which people who were suppressed on Kaletra were switched to the integrase inhibitor to take advantage of its better lipid profile. Unfortunately, some of them had virologic breakthroughs after switching, likely due to an unmasking of underlying NRTI resistance. Besides underlining the durability of protease inhibitors, this reveals the fragility of raltegravir -- and possibly of other agents in the class -- if they are not fully supported in the regimen by active companion drugs.
The critical quality determining raltegravir resistance may be the "on" time during which an integrase inhibitor stays attached to the integrase enzyme in the preintegration complex. If the "on" time is longer than the life of the integration complex, the drug will be effective; but if a mutation in integrase shortens that time, the risk of viral breakthrough increases. If this proves to be the mechanism of resistance to integrase inhibitors, then perhaps more frequent dosing -- inconvenient as that may be -- could offer a way to rescue viral suppression using the same drug. Merck is developing a second-generation integrase inhibitor that purportedly has not only a longer "on" time but can be dosed only once a day.
Gilead's elvitegravir is moving forward in phase III trials and could be approved by 2010 in a solo formulation. Though it enjoys the advantage of once-daily dosing, the drug will require boosting, at first by ritonavir and then later by Gilead's proprietary GS 9350 booster. Elvitegravir is expected to come into its own when a boosted combination regimen in a single pill is ready for approval in 2011 or 2012. Gilead's QUAD study of the four-in-one combo has already begun enrollment.
GSK has completed extensive drug-to-drug interaction studies on its integrase inhibitor candidate, the Shionogi-discovered GSK1349572, but no larger phase II trial has begun yet. Now GSK appears to be starting a similar development program for a follow-up Shionogi drug, GSK1265744. Besides all the usual qualities required for success, to truly shine GSK's integrase inhibitor must demonstrate activity against virus that is resistant to raltegravir. New details about GSK1349572 will be reported at the International AIDS Society meeting in Cape Town, South Africa in July, 2009.
Rilpivirine, a nonnucleoside reverse transcriptase inhibitor (NNRTI) from Tibotec, has nearly everything in its favor: it is comparable to efavirenz without causing sleep disturbances or increased blood lipids; it is a once-daily drug; and it has low-milligram dosing, which could be ideal for use in low-cost regimens for the developing world. But heart rhythm abnormalities (QT prolongation) seen at higher doses resulted in Tibotec choosing (at the U.S. Food and Drug Administration's insistence, no doubt) the lowest dose studied in the phase II clinical trial. Unfortunately, this dose was not the natural first choice, and people on the 25 mg dose had more early virologic failures than those on the 75 mg dose, though suppression rates were equivalent at the end of the trial. The large phase III trials underway will definitively reveal if the lower dose is adequate.
Idenix has partnered with GSK to develop IDX889, an NNRTI expected to be active against virus resistant to the approved NNRTIs as well as to rilpivirine. Pfizer's UK-453,061 is in a phase II trial for treatment-experienced people with resistance mutations to first-generation NNRTIs and is up against efavirenz in another trial as first-line therapy. Between the integrase inhibitors and these NNRTIs, the GSK/ Pfizer joint venture is starting to look fat. With other NNRTI compounds from Ardea in earlier stages of development, there may be life left in this class yet.
With enfuvirtide and maraviroc, entry inhibition has been proven in two different ways, but each approach has been hobbled by inconveniences unrelated to efficacy -- injection and the need for an expensive screening assay, respectively.
One of the three drugs currently in advanced phase III trials is Schering's CCR5 antagonist vicriviroc, which, if approved, would become the second drug in the class after Pfizer's 2007 maraviroc. Unfortunately -- despite being a very effective and welltolerated drug -- maraviroc has been a bust in the marketplace, mainly because it came into the world in the shadow of raltegravir, and because before it could be prescribed, an expensive tropism test with a four- to five-week turnaround time was required to determine if a patient's virus was susceptible to the drug. By the time vicriviroc arrives, however, cheaper and easier-to-use tropism tests may be available. These drugs are relatively immune to resistance, and they seem to have unparalleled penetration into the brain. If there are advantages to these qualities, they have yet to be worked out. There is also a tantalizing observation that some people who gain no virologic benefit from maraviroc (because their virus is not susceptible) still experience an increase in CD4 cell count while on the drug. Schering likely shares Pfizer's hope that CCR5 blockers exert beneficial effects on functional immunity independent of their antiviral properties, but both companies will have to wait for much more data before making claims. In its phase III trial for first-line use, Schering has adopted the NRTI-sparing model, pitting vicriviroc plus boosted atazanavir against atazanavir plus Truvada. Vicriviroc is dosed at only 30 mg per day when paired with ritonavir.
Other potential drugs that restrict HIV entry, such as TaiMed's CD4 blocker ibalizumab (acquired from Tanox) and Progenics' anti-CCR5 agent PRO140, are monoclonal antibodies (mAbs). Both will require infusion directly into the blood since they can't be taken orally, though TaiMed is said to be working on an alternative route of administration. While infused mAbs may effectively stay in the blood for up to a month, which could be a boon for people with adherence problems, nothing beats the simplicity of a single daily tablet (ideally in unit dose packaging -- like birth control pills -- to boost adherence; see www.unitdose.org).
Maturation inhibitors would block a final stage in viral assembly, leaving newly formed viral particles inactive. Bevirimat was the first candidate in this class, though it had a long and tortured path in the hands of its initial maker Panacos. The class is getting a second chance at Myriad, a small Salt Lake City, Utah pharmaceutical company that has acquired bevirimat and will be developing it, backed up by two of its in-house antimaturation drugs. A big limitation is that a fairly common naturally occurring mutation in the HIV protease enzyme renders the virus resistant to bevirimat. A genotype test will likely be required to identify those whose HIV will be susceptible to the drug.
Bevirimat, ibalizumab, and apricitabine are virtually the only hope for people who desperately need at least two new drugs from new classes to overcome HIV with resistance to every other available drug. Such deep salvage patients are rare in 2009, but their need is no less great. Some are veteran volunteers of clinical trials and carry resistant strains as evidence of long treatment histories and one too many placebos. New access mechanisms are needed that will allow doctors to pair up two or more experimental drugs earlier than has heretofore been possible.
Recent studies of the dependencies of HIV replication on the human cellular machinery have produced an impressive list of proteins that could be potential drug targets. The trick will be to find which human proteins are uniquely required by the virus and which can be blocked without shutting down an essential function of the cell and causing serious side effects. Research is also needed on how to interrupt transitory protein-to-protein interactions that are far less specific and less critical than enzyme reactions for the life of the virus.
Some human gene products would act as natural antivirals if they weren't switched off by one of HIV's so called accessory proteins. For example, APOBEC3G would cause deleterious mutations in HIV DNA when the virus replicated if not for Vif, a small HIV protein that inactivates APOBEC3G. The trick would be to find a small molecule drug that can deactivate Vif and let the body do its own housekeeping on viral interlopers.
Integration is the point of no return in the HIV life cycle at which the viral genome is brought into an infected cell's nucleus and made a permanent guest of the host's DNA. Raltegravir blocks this stage by preventing the viral DNA from finishing the final stitch. A host protein called LEDGF/p75 is thought to help the HIV integration complex find the right place in the cell's genome at which to join the host DNA. Some have speculated that blocking LEDGF/p75 would be an effective strategy for blocking HIV replication. Chinese researchers, as well as scientists at Schering and CellVir have been exploring the potential for blocking LEDGF/p75.
Though the ARV pipeline in 2009 seems abundant, the drugs most likely to make it to market appear more like successors than revolutionaries. And the candidates in phase II and earlier stages cannot be counted on to be with us the next time this annual pipeline report comes out. The pharmaceutical industry will eventually turn its attention back to HIV -- hopefully before too many people develop resistance, side effects, or give up on therapy. As long as HIV requires lifelong treatment, people with HIV all over the world deserve treatments they can live with for a long, long time.