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The 2009 Pipeline Report

tagline 2009 August

TAG’s Annual Review of What’s New

The Pipeline Report is a concise compendium of new drugs and technologies with the potential to benefit people living with HIV within the next few years.

By Bob Huff

TAG’s annual pipeline report for 2009 was distributed in July at the Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town, South Africa, where eager attendees snatched up 2,000 copies during the three-day meeting. The 90-page booklet is popular because it provides an easyto- read overview of drugs, vaccines, and diagnostics that are being developed for HIV, viral hepatitis, and tuberculosis. Here are some highlights.

HIV Drugs in Development

The antiretroviral (ARV) drug pipeline for 2009 shows—as TAG’s executive director Mark Harrington explains in the report’s introduction—a lull in new drugs to treat HIV after an unusually active period of drug approvals during 2007 and 2008. Aside from a few specialty drugs (bevirimat, ibalizumab) moving into late-stage clinical trials that might be important for people with few remaining treatment options, the most significant progress may come in the form of new, more tolerable, and more convenient combinations of drugs in singlepill formulations. Four new drugs that boost blood levels of certain ARVs are moving through the pipeline, and these could facilitate a breakthrough in how several protease inhibitors (PIs) are offered in the future. Currently many of these drugs— such as Prezista, Reyataz, and Lexiva— depend on Abbott Laboratories’ Norvir for boosting. Alternative boosters could break the Norvir monopoly and allow all-inone boosted PI tablets as well as a boosted integrase inhibitor from Gilead.

The drug in the pipeline likely to first achieve approval is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) from Tibotec called rilpivirine. The drug is being groomed to compete with efavirenz as a first-line treatment choice and offers the potentially important advantage of having fewer side effects. In late-breaking news from the Cape Town conference, it was announced that Tibotec and Gilead are teaming up to create a singletablet regimen containing rilpivirine plus Gilead’s Truvada combination of the nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir and emtricitabine. This once-a-day pill will compete with Atripla, the highly popular single-tablet regimen containing efavirenz plus Truvada, a collaboration between BMS and Gilead. Gilead’s integrase inhibitor elvitegravir, now in advanced phase III trials, will also be offered in a single-pill regimen containing a booster plus Truvada.

Vicriviroc, a CCR5 antagonist HIV entry inhibitor from Schering-Plough, is also working its way through advanced trials and will likely be the second approved drug in this class. Maraviroc, the first CCR5 blocker, approved in 2007, experienced only limited uptake by physicians due partially to a requirement for an expensive diagnostic test to identify patients who are likely to respond to the drug. However, simpler and cheaper tests are starting to come to market, and this barrier may soon be removed.

Some of the biggest ARV buzz coming out of the Cape Town conference was over the new GlaxoSmithKline (GSK) integrase inhibitor, now entering phase II trials. At the end of a ten-day trial of the drug alone, the majority of patients receiving the highest dose had an undetectable viral load. No resistance was seen in this short study and the only side-effect complaint was headache. GSK, in a joint venture with Pfizer, has formed a new, independent company to do its HIV drug development and marketing work. This consolidation of forces, alongside the collaborations among other HIV drug companies, gives hope that the current lull in the pipeline may be followed by some creative new developments in ARV therapy.

Hepatitis B Drug Development

The hepatitis B virus (HBV) infects more that 400 million people in the world and is a leading cause of liver disease; yet, as TAG’s Lei Chou reports in the 2009 Pipeline Report, drug development for HBV has come to a “virtual standstill” in the past year.

Part of this has to do with scientific difficulties in discovering and testing safe and effective new HBV drugs, but the main reason must be due to the paltry amount of money spent on research. Though six drugs have been approved to treat HBV, several of them from the NRTI class— which are also used to treat HIV—have been rendered ineffective due to widespread resistance. People who have taken earlier, less potent versions of these drugs may have compromised responses to the newer ones.

One of the more promising drug approaches being tested employs the HIV combination Truvada. Otherwise, the HBV drug development pathway is littered with failures. The development of the NRTI clevudine, a front-running HBV drug candidate in 2008, has been canceled due to potentially dangerous side effects. Hopes for using an approved drug, telbivudine, in combination with pegylated interferon to achieve better treatment responses were dashed due to increased rates of nerve damage that occurred in the study.

Other, more novel approaches to treating HBV using immune modulators and therapeutic vaccines are under active investigation, but studies are going slow. News on using gamma interferon to clear the virus may be forthcoming in late 2009.

With the central questions of when to start HBV therapy and how long to continue it still unanswered, the field is all but mired in stagnation. One bright spot, though, is the establishment of a new clinical trials network for HBV funded by the National Institutes of Health that expects to begin clinical research later in 2009.

While TAG’s pipeline report usually covers the burgeoning drug development scene for hepatitis C virus (HCV), this year that report will appear in a separate booklet.

Tuberculosis Drug Development

After 40 years with no new class of drugs approved for treating tuberculosis, there are finally signs that new agents may soon contribute to improving cure rates for this age-old disease. Current treatments are effective, but they fall short when used in the real world due to resistance, toxicity, inconvenience, and interactions with other medications—and these problems are exacerbated in people with HIV and in children. Yet, notes TAG’s Claire Wingfield, “while there are currently more new compounds being investigated to treat TB than there have been for decades, there are still too few sponsors and too few resources dedicated to moving these products through the drug development pipeline.”

If 400 million people infected with HBV sounds like a vast number, consider that perhaps 2 billion people may have a latent tuberculosis infection. Most of them will never have TB symptoms, but the risk of developing active TB is far greater for people with HIV. Six to twelve months of single-drug treatment with isoniazid is effective at reducing this risk, yet this regimen is not widely prescribed. Studies are under way to shorten the treatment duration by using combinations of drugs.

If active TB is diagnosed or suspected, current treatments are effective—as long as the TB organism is susceptible to the drugs. The main focus of clinical trials for drug-susceptible TB is on shortening the time individuals must take their drugs; the goal is to reduce the number of patients who stop therapy before they are cured.

The big news in TB drug development, however, comes from a handful of drugs from new classes with novel mechanisms of action against TB—drugs that are also effective against TB that is resistant to the conventional drugs. Multidrug-resistant TB is a dangerous and deadly problem that has begun to appear in the past five years wherever TB outbreaks occur, often overlapping in places with high HIV prevalence. Because untreated and untreatable TB can be rapidly fatal in a person with HIV, the urgency to develop new classes of drugs has pushed industry to take up the challenge. TAG lists two new drugs from Tibotec and Otsuka that are specifically being developed to treat drug resistant TB.

Yet, as Wingfield warns, because there have been so few large clinical trials for new TB drugs in the past 40 years there are few people with experience in developing new TB drugs that meet modern regulatory standards. Greater investment in research going forward— not only for discovering and developing new drugs but on finding the best ways to test these drugs and then put them into clinical practice—will be increasingly critical if TB is to be controlled within the next few decades.

Tuberculosis Diagnostics in Development

If the lack of new drugs to treat TB seems like a daunting problem, consider that the main technique for diagnosing active TB infection was developed over 125 years ago and is only reliable about half the time. Furthermore, while there are new DNAbased technologies that can be used to diagnose TB with greater confidence, these are mostly useless outside of well-equipped laboratories and are of no use in most developing-world settings—the very places that TB is rampant. In fact, as TAG’s TB project director Javid Syed reports, there is only one product under development that appears to be appropriate for use in rural heath care settings—places without reliable electricity or running water that are often far from urban centers. This product, a skin patch from Sequella, is applied to the arm. If a localized inflammation appears within three or four days an immune reaction to TB has occurred, which is diagnostic of a prior TB infection. As simple as that sounds, there are still many unanswered questions about the patch that ongoing research must address.

For settings with an intermediate level of resources, such as regional hospitals and larger clinics, many more techniques and products are under investigation to help improve current methods of microscopically examining stained sputum samples to identify TB organisms coughed up from the lungs. Many of these advances aim to make the diagnostic process more efficient. But even if diagnostic methods can be improved, simply obtaining a sputum sample that contains a sufficient amount of TB will likely remain a hit-or-miss process.

There is also a long list of techniques and products being developed for use in hightech laboratories, though most will have little relevance to a person who has had to walk a day and a half to visit a part-time village clinic. Even a patch test that takes four days falls short. What’s needed are point-of-care dipstick tests that can identify active TB and tell a doctor or nurse if the organism will respond to conventional drugs or if special drugs are required to control a drug-resistant strain. No product in the current TB diagnostics pipeline comes close to meeting these requirements.

Tuberculosis Vaccines in Development

As with any disease that affects millions of people, the most cost-effective intervention will be one that prevents infection or allows the body’s immune system to resist or control an infection. This is why vaccines are the holy grail of infectious disease—one shot (and maybe a booster or two) and you are protected for life. There is an effective vaccine for tuberculosis called Bacille Calmette- Guérin (BCG), and while it is a lifesaver, it falls far short of the ideal. BCG given to children does not protect against pulmonary TB and the protection it provides against disease in the rest of the body only lasts until adolescence. Still, it is estimated that BCG immunization saves the lives of 40,000 children per year. Because scientists are building on the modest success of BCG, there is a relatively robust effort to discover and develop better TB vaccines—though initial steps aim for incremental progress. Each of the four new vaccine candidates listed in TAG’s report is a booster designed to enhance the effectiveness of BCG. Farther down the line come candidates intended as improved versions of BCG. Overall there may be 50 vaccine candidates in the pipeline, notes TAG’s Wingfield. As with TB treatments and diagnostics, this work could go faster if it received adequate research investment. Wingfield notes that an estimated $1 billion gap exists in just the funding required to test the most advanced TB vaccine candidates in largescale clinical trials to prove that they work and can save lives.

Immune-Based Therapies and Preventive Technologies in Development

Lack of investment is not necessarily the problem for preventive vaccines and other technologies in restricting the transmission of HIV. As TAG’s Richard Jefferys notes, after the failure of Merck’s vaccine candidate in a large trial in 2007 (which seemed to make some vaccinated volunteers more susceptible to HIV infection), scientists have been scrambling to reorient the field away from its premature focus on product development and back toward basic scientific investigations about HIV, the immune system, and how the two interact over time. After years of commitment to developing vaccines that activate the T-cell wing of the immune system, the pendulum may be swinging toward stepping up research on understanding and enhancing B-cell immunity, which involves provoking antibody responses to infectious agents, and to exploring advanced concepts of vaccination that involve genetic manipulation of immunity.

Vaccines and other treatments that affect the immune system are also being explored for their potential to help people who are already infected with HIV control their virus without drugs. But the news on this front has also been bleak. A nearly decade-long study of the immune system messenger IL-2 to boost the T-cell counts of people with HIV and AIDS finally ended in failure in 2009. Efforts to substitute immune control of HIV for antiviral drugs are up against a formidable barrier, since ARVs are so thoroughly effective and since even incomplete viral suppression has now been associated with health risks. Still, researchers continue to investigate the reasons why some people naturally manage to control HIV and live long lives without significant immune deterioration or disease.

The extraordinary efficacy of antiretroviral drugs is shaping the development of other approaches to HIV prevention. The development of microbicides— vaginally or rectally applied gels to prevent transmission of HIV via mucosal surfaces—has regained momentum after a few setbacks with early products. Older microbicide candidates create physical barriers or alter the chemistry of the vaginal environment to limit HIV transmission. The newer and more promising generation of microbicides will likely contain antiretroviral drugs to halt an HIV infection from taking root. Clinical trials of some of the newer candidates are in progress.

As Jefferys notes in his introduction, “The biomedical approach to HIV prevention generating the most optimism is pre-exposure prophylaxis (PrEP).” PrEP involves taking antiretroviral medications—either episodically or on an ongoing basis—by people who do not have HIV but who are at risk for becoming infected. Currently, Viread (tenofovir) and Truvada (the combination pill that contains tenofovir plus emtricitabine) are in clinical trials, but several other newer antiretrovirals with minimal toxicity are under consideration. Obviously, tolerability of the drug is a major requirement for PrEP since it will be taken by people without disease. Approaches like PrEP and microbicides fall far short of the ideal “one-shot protection for life” that a vaccine might promise, but for targeted communities with high rates of HIV transmission these products might help stem the tide of what remains an epidemic out of control.

Overall, the product pipelines covered in TAG’s 2009 report show slow progress being made in bringing new technologies to bear on the HIV epidemic. When and if these developments will make a significant impact is uncertain. Economic recession and a flagging sense of urgency among the funders of research and health care could prove to be a larger impediment to achieving widescale lifesaving changes than either the daunting scientific or regulatory barriers.

TAG’s 2009 Pipeline Report is available online.