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2005 Pipeline Report

What’s in the Pipeline: New HIV Drugs, Vaccines, Microbicides, HCV and TB Treatments in Clinical Trials

By Rob Camp, Richard Jefferys, Tracy Swan & Javid Syed

Edited by Mark Harrington & Bob Huff

July 2005

From the Introduction:

This overview of the antiretroviral, vaccine, microbicide, immune-based therapy, and anti-HCV and TB drug pipeline (focusing on products that have advanced to clinical testing in humans) reveals the state of research on AIDS and its most common global co-infections in mid-2005. The news is mixed.

The antiretroviral (ARV) pipeline is surprisingly robust. Despite the availability of over 20 FDA approved anti-HIV drugs, a variety of companies both large and small continue to invest in a broad array of potential new competitors. At least seven drugs are in early phase I studies, six in phase I/II, and eleven in randomized phase II/III efficacy studies. Rob Camp’s ARV pipeline shows five nucleoside analogues, many of which are designed to treat virus resistant to 3TC or FTC. There are six non-nucleoside reverse transcriptase inhibitors (NNRTIs), including two from Tibotec, as well as the now moribund capravirine, an Agouron legacy at Pfizer. Two protease inhibitors are being studied, including Tibotec’s TMC-114/r, which is making a fast track for FDA accelerated approval filing in early 2006. It’s too soon to tell whether any of these drugs in existing, wellpopulated drug classes will be able to displace any of their well-established forebears. More exciting is the activity in the entry inhibitors family, including gp120 blockers from BMS, three hotly competitive CCR5 inhibitors from GSK, Pfizer and Schering, a slow-moving CXCR4 inhibitor from Anormed, and the high-tech, likely to be expensive even if effective PRO-542 CD4-IgG fusion protein, as well as TNX-355, an anti-CD4 monoclonal antibody from Tanox. Panacos has PA-457, a budding inhibitor, and Merck and Gilead have integrase inhibitors entering the clinic. Finally, BioInvent has a Tat protein inhibitor, and the morning after pill RU-486 (mifepristone) is being studied by the Adult AIDS Clinical Trials Group (AACTG) as a potential antiretroviral (it inhibits the interaction between HIV’s Vpr protein and cellular glucocorticoid receptors).

The new classes of drugs present hazards. No one knows whether the CCR5 blockers will accelerate a potentially catastrophic HIV phenotype switch to faster-replicating X4 strains. The only assay used to determine prevalence of R5 or X4 HIV strains, ViroLogics’ PhenoSense, is expensive, time-consuming and the company currently lacks the capacity to scale up the test if it becomes commercially necessary; moreover it could add $1,000 to the cost of the standard of care.

The current race to develop the CCR5 inhibitors, and the entry of other classes into clinical trials, demonstrates the scientific payoff from two decades of significant public and private investment in HIV research. This progress is now threatened by the flattening budget at NIH, which is scheduled to rise by just 2% next year. Industry consolidation and the departure of some companies from infectious disease research may also threaten future developments in this area.

Things are more sobering on the HIV vaccine front. As Richard Jefferys’ overview demonstrates, while there are 17 vaccine candidates in phase I, many utilize similar approaches. Just four vaccine candidates are in phase I/II. Hopes are moderate for the Merck adenovirus vector vaccine now in Phase IIb, which may be an improvement on previous vaccines in its ability to stimulate anti-HIV cell-mediated immunity (CMI), and are vanishingly low for the NIH/Department of Defense’s scientifically indefensible but logistically unstoppable ALVAC vCP1521 canarypox vector/AIDSVAX prime-boost vaccine trial now underway in Thailand at a cost of over $150 million. On the therapeutic side, at least 13 therapeutic vaccine candidates are in clinical trials. Many of the same issues impeding progress in preventive vaccines are also relevant here. The HIV vaccine field awaits a breakthrough in basic science, one which would be particularly available if it led to the development of a vaccine which conferred effective neutralizing antibodies against common HIV strains found in humans.

The HIV microbicide field, in contrast, is surprisingly robust, and has recently caught up with and overcome vaccines. At least four candidate microbicides are in phase III, five are in phase II, and six are in phase I. Their mechanisms of activity are heterogeneous, ranging from soaps to acidbuffering agents to seaweed derivatives to anti-HIV compounds. Perhaps the lack of validated animal models has actually sped entry of potential microbicides into human efficacy trials. The downside of several concurrent failed studies could be dangerous, but the need for new and effective prevention approaches validates the rapid movement in this field.

More controversial, yet supported by strong evidence from animal studies, is the use of tenofovir DF (Viread®) as pre-exposure prophylaxis (PrEP) to prevent sexual – and possibly parenteral – transmission of HIV. Small-to-medium sized phase II trials are underway in Atlanta and San Francisco, with larger phase II/III studies underway or planned in Botswana, Ghana, and possibly Thailand. These studies have been dogged by controversy, with the main issues being the adequacy or lack thereof of the pre-trial community consultation and informed consent, linkages to HIV treatment programs for those found to be infected at baseline or in the course of the study, and – in the case of Thailand – the lack of access to needle exchange in a study designed to examine HIV transmission among injecting drug users. PrEP studies have already been canceled in Cambodia and suspended in Cameroon. Hopefully a recent series of consultations in two African sites, Geneva, Seattle, and Thailand among research sponsors, community activists, and others will help resolve the outstanding issues to move this promising research forward.

Richard Jefferys also gives an overview of the twelve cytokines and gene therapy approaches which are in clinical trials, including the perennial interleukin-2 (IL-2), now in a large phase III trial in many countries, and five cellular and gene therapy approaches. More progress in this area depends on new insights into HIV pathogenesis and human immunology.

The hepatitis C virus (HCV) infects over 129 million people worldwide and has infected over 3.8 million people in the United States. HCV can lead to cirrhosis and liver cancer, and progresses more rapidly in HIV-positive people. End-stage liver disease from HCV has become one of the leading causes of death among people with HIV in the USA and parts of Europe. Current treatment for HCV relies on a combination of pegylated interferon and ribavirin. It appears to eradicate the virus in approximately 50% of those without HIV infection, but is far less effective for those with HIV, with HCV genotype 1, or African-Americans. Efficacy of current hepatitis C treatment is limited by a range of side effects and toxicities. The good news is that at least 17 candidate anti-HCV drugs are in clinical trials, most of them small molecules with new mechanisms of activity, but some new types and formulations of alpha interferon as well.

After forty years with no new major drugs, there are now six new candidate therapies in the clinical pipeline to treat tuberculosis (TB), an age-old killer which infects up to two billion people worldwide, causes disease in nine million, and kills two million each year. Javid Syed’s review of the TB drug pipeline shows that recent investment in TB research is beginning to pay off, with two fluoroquinolones (gati- and moxifloxacin) along with at least three novel drug classes. The new TB drugs offer the potential to shorten the six-month TB treatment regimen, to simplify co-administration of TB treatment with ART, and also to treat multi-drug resistant (MDR) TB. Since TB is the most common AIDS-related co-infection worldwide, and MDR-TB is rampant in former Soviet states and elsewhere in Asia, such new candidates are overdue.

I have already mentioned the danger current US funding cuts and industry trends pose to AIDS research. There are additional threats to the HIV, HCV, and TB pipelines. The National Institutes of Health (NIH) will spend over $2.7 billion this year on AIDS research. However, it spends little over $100 million on TB, and even less on HCV research. There is virtually no funding for clinical trials for TB and HCV drugs. Substantially increased public investment is needed not only in basic research on the interactions of HIV, TB, and HCV with the immune system, but on clinical trials infrastructure in the places and settings where these three epidemics are rampant. Co-infected people are often excluded from clinical trials.

Research is only part of what is needed to make life better for people living with HIV, TB, and/or HCV. These diseases target vulnerable people who often suffer from social exclusion and political discrimination. Current policies on drug use and sexual diversity are driving up infection rates. The current crisis caused by inadequate FDA oversight of approved drugs post-marketing also poses dangers to people who may benefit, but may also be harmed by new drugs. Stronger postmarketing surveillance systems, stronger FDA authority to mandate post-marketing studies when necessary, and curbs on irresponsible and uninformative direct-to-consumer advertising campaigns are also needed to ensure that new drugs, once they reach the market, continue to be studied to determine their effects in real-world populations.

We are encouraged that industry continues to invest in new drugs for HIV, TB, and HCV. But substantially increased public investment in basic and clinical science, free and universal access to effective prevention and treatment interventions, and a strong but flexible regulatory environment are all critical to assuring a healthy drug development pipeline and healthy use of the drugs after approval. And ultimately, none of this will be secured without informed communities who have access to the prevention, treatment, and information they need to live.