There is good news on the horizon for people needing new options for HIV therapy. At the 10th Conference on Retroviruses and Opportunistic Infections held in Boston in February, a bumper crop of new therapies was presented. Many of the drugs are from new classes, different from the existing HIV therapies now in the pharmacy. In addition, older approved drugs are being simplified and developed into better formulations. This news represents an important shift in HIV research and development. It provides hope for those who are drug resistant and experiencing a multitude of toxicities.
Even a year ago the pipeline for new drugs seemed to be running dry. Drug companies had merged and biotech firms had closed up shop. HIV drug development appeared to be in big trouble. But this March one new drug from a new class was approved and three others will be up for approval in the coming year. A number of drugs from different classes and some designed to work against resistant virus are showing promise, but are in very early stages of testing that will require very preliminary "proof of principle" studies before they can go further. Then, it's not clear how many of them will prove to be practical, safe and effective. So, the exciting news from Boston must be tempered with the reality that some of the drugs may fail and not make it past where they are now. Also, due to the rigorous studies the drugs have to go through, they may not be in wider access for several years, leaving a gap where there may be few options.
But overall the news is positive and is a bit of a pay-off for all the hard work AIDS treatment activists have done for the last several years. We'll see how everything plays out. In this article, I cover the "pipeline" drugs presented in Boston, and the ones that seem most interesting and exciting.
Fuzeon (also known as T-20, or enfuvirtide), from Roche/Trimeris, is the newest FDA-approved therapy that represents a breakthrough into a new era of HIV research and development. It is from a new class of anti-HIV drugs that works by blocking the fusion process of HIV entry into the human CD4 cell. It is a welcome addition to the existing available antivirals, but not without some significant issues. Access to Fuzeon may be extremely difficult to come by. It is the most expensive anti-AIDS drug thus far, twice the cost of the highest existing antiviral. ADAP (AIDS Drug Assistance Program), Medicaid, HMO's and other insurers may not add it to their formularies because they simply cannot afford it. To further complicate matters, it is delivered by twice daily subcutaneous (under the skin) injections and in studies so far most people experience reactions from those injections. Because of these issues it's clear that Fuzeon should only be used by a select population of people with indisputable need.
People should recognize that combined data from studies show 30% of people on Fuzeon went below 400 viral load at 48 weeks compared to 12% not receiving Fuzeon. Eighty percent of the treated individuals maintained an undetectable viral load at 48 weeks. This information should be looked at carefully as it shows that Fuzeon is not actually the breakthrough drug people may have thought. It may work best with those who have another active drug to add to an existing regimen. This begs the question of who should be able to access it given the expense, difficulty in administering and the side effects. Activists maintain that Fuzeon should be available to those who need it most, based on the fact they cannot construct a viable treatment regimen.
Atazanavir, from Bristol Myers-Squibb, is a protease inhibitor currently available in expanded access and next in line for approval. Its advantages are that it is a once-a-day therapy and may have less of an effect on cholesterol than other protease inhibitors. It has similar effectiveness as Viracept but may be cross-resistant to other protease inhibitors. While the resistance is different from available PIs and takes longer to develop, it's not clear if it will be any better than existing protease inhibitors.
Coviracil from Gilead/Triangle is a once-a day drug with an efficacy profile very similar to its close cousin Epivir. It may be less likely than Epivir to fail due to resistance, but may show more toxicity. Bottom line is that it is one more option for people with AIDS. Hopefully, Gilead will price the drug lower than Epivir.
Fosamprenavir (908) is a pro-drug of the current Agenerase from GlaxoSmithKline (it acts like Agenerase after it enters the body). A protease inhibitor, there are fewer pills required with this drug than with Agenerase. Boosted with low-dose ritonavir (Norvir), it is a potent addition to the available drugs. Unfortunately, the ritonavir boost causes side effects. A 48-week study presented in Boston showed it was more effective in those who were drug naive compared to Viracept. But in an interim analysis of a drug-experienced population compared to Kaletra, there was no discernible difference. Fosamprenavir may be a useful drug for those who cannot get access to Fuzeon (see "News Briefs
Boehringer-Ingelheim's tipranavir is possibly a more exciting protease inhibitor showing good effectiveness for people with drug resistant HIV. Studies in heavily treated people show at least a one log drop in viral load in two weeks. Phase III studies are beginning and an expanded access will follow in six to nine months. Like so many other protease inhibitors it will be co-administered with ritonavir due to the boosting effect. Diarrhea is the main side effect. Tipranavir may be an up-and-coming drug for people who are in dire need of a potent protease inhibitor to add to their combination.
There are several companies developing new protease inhibitors. This is an important area of research because PIs have shown to be the most potent anti-HIV drugs yet they have also caused more side effects, so a new chemical PI class is welcomed and needed.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have the highest incidence of failure because of resistance to HIV. There are several new NNRTIs in development that were picked from the drawing board because they are active against the current NNRTIs. TMC-125 from Tibotec is being studied in Phase II trials in Europe. So far the data looks compelling. Glaxo is screening a whole new class of non-nukes that won't be cross-resistant.
An interesting new class of drugs that target the integrase enzyme in virus replication are coming into the spotlight. Several years ago there was work being done with integrase inhibition but the first compound did not make it very far. Today there are two integrase inhibitors that have made it to clinical trials. They are S-1360 from GlaxoSmithKline/Shinogi that is in Phase I/II and Merck's L-870, 810 in early Phase I.
The science of entry inhibition was inspired by Fuzeon's success. Since that drug is proving to work, scientists are looking at all the different ways HIV attaches and enters the cell. Without all of the connecting mechanisms in place, the virus cannot attach, fuse and then finally enter and infect the cell. There are currently six classes that make up 12 different types of entry inhibitors in various stages of development, quite a bumper crop indeed.
One promising class is the CCR5 antagonists that seek to stop co-attachment of HIV to the CD4 cell. CCR5 co-receptors are a type of receptor that are associated with most people with HIV, so in theory, it is hoped they can work to stop attachment. The leading CCR5 inhibitors are Schering-Plough's SCH C and Pfizer's UK-427, 857. This technology holds great promise; however, one concern is that many other cells use the CCR5 co-receptor, so until more studies are done we won't know if the drugs will harm other cells.
Another attachment inhibitor compound is PRO-452 that works in conjunction with human antibodies to stop early attachment, before the fusion and entry steps. The only problem is that this drug is also delivered by subcutaneous injections.
Finally, Fuzeon's sister compound, T-1249, shows the most promise in early Phase II development in people who are resistant to Fuzeon. From studies so far, the drug shows a 1.12-log viral load drop in resistant trial participants. Studies show the longer you have T-20 resistance the less effective T-1249 will be.
One out of the ordinary development in Boston was the presentation of TNX-355, another new class of anti-HIV drugs. It is a monoclonal antibody that inhibits post binding on the CD4 cell. It is moving into Phase I in an open-label study. Its big drawback thus far is that it is given by a once monthly IV infusion. But as with Fuzeon, it may be a good drug for those who are multi-drug resistant. It is moving into dose escalation studies.
One final drug class under development and presented at the conference was what is being called a "maturation inhibitor." Panaco's PA-457 has only been studied in the laboratory but the company plans to submit their Investigational New Drug (IND) application to the FDA for clinical trials in a few months. This drug works by disrupting the new RNA that is budding out of the cell in its baby virion. However, how it does that is not entirely clear. This drug is a surprise because it is a totally new class that few expected.
Other drugs are coming down the pike including zinc finger inhibitors (remember those?), several cellular factor inhibitors, new protease inhibitors and nucleoside and non-nucleoside reverse transcriptase inhibitors. Also, we cannot forget the importance of treatment vaccines in development and other immune-based technologies that often get forgotten in the antiviral shuffle (see "Immune-Based Therapies at the Retrovirus Conference
This large group of AIDS drugs has promise, simply in the fact that there is so much new interest in developing therapies that work for more and more people who have become drug resistant. I asked Ben Cheng from the Forum for Collaborative HIV Research how many of the 59 drugs he lists being studied would end up useful and he replied, "Based on my very unscientific tracking of the drugs that have been presented at conferences (usually starting pre-clinical and have some in vitro activity), about 10-15% make it to market."
The pipeline for new HIV drugs is indeed impressive and hopeful for the people who have access. However, with the latest approval of Fuzeon, it is clear that new high technology drugs from this point on may be only available to a few people in developed countries, and not at all in the rest of the world.
The pricing of new classes of AIDS drugs must be monitored by the community. People with AIDS must continue to proactively monitor pharmaceutical pricing discussions during the development of all new drugs. There should be a demand for worldwide access to all new drugs from day one. It is simply our moral obligation. The American Foundation for AIDS Research has a telling advertisement that reads, "1 million treated for HIV ... 41 million to go."