2006 and 2007 may one day be remembered as true watershed years for people with advanced HIV disease. The approval of Prezista (darunavir) in spring 2006 and the introduction of the integrase inhibitor MK-0518 through expanded access have brightened the picture for people who have already used many anti-HIV therapies and classes of therapy and need new options.
Simply put, a great majority of people who might have given up hope of achieving "undetectable" viral load can now do so. Less certain, but also holding hope for treatment veterans, are the entry inhibitor maraviroc and the NNRTI etravirine. Etravirine is now available through expanded access for people who have failed other drugs in this class (Viramune [nevirapine], Rescriptor [delavirdine] and Sustiva [efavirenz]), while the announcement of a similar program for maraviroc is expected before the end of the year. While celebrating the very real victories that these drugs represent for people with HIV, a look deeper into the anti-HIV drug development pipeline raises new and difficult questions about the future of drug development for treatment experienced people.
For several years now, most companies seeking fast approval of new anti-HIV drugs have focused on people with extensive treatment experience -- a group sometimes called treatment experienced or more problematically salvage patients. Scientific, medical and financial factors made this strategy attractive for companies moving their experimental anti-HIV drugs through the Food and Drug Administration (FDA) approval process.
Companies would design studies around patients who were failing existing therapies and add either the new drug or a placebo to the regimens. If the added drug did more than a placebo, it was seen as proof of the drug's effectiveness. Could impressive results now from the two latest drugs change this model and force companies to find new ways to study their drugs? Whatever the answer, this new landscape raises important questions for companies, the FDA and activists about the future of drug development for treatment experienced people.
There was a time when activists fought tooth-and-nail with pharmaceutical companies to include treatment experienced people in their studies. Historically, companies had been hesitant to study their new drugs in this population, fearing the results would harm their drugs' chance at being approved by the FDA. This fear was not unfounded. People with more advanced HIV disease, especially those with extensive drug experience, tend to get less of a robust response to anti-HIV drugs than those earlier in disease or newer to treatment. Moreover, they tended to suffer more serious side effects because of their weakened condition. Still, they were the people who needed new and better drugs the most. Project Inform, along with other treatment activists, consistently raised the demand that new drugs be studied in these people.
It is a battle that activists and treatment experienced people largely won. The companies were made to see that scientifically, ethically and even financially it was to their advantage to study new drugs in treatment experienced people. In fact, the pendulum swung fairly far in this direction, where most recently approved HIV drugs were studied first in treatment experienced people. In some cases, like Aptivus (tipranavir) and Fuzeon (enfuvirtide, T20), the drugs are still used almost exclusively by treatment experienced people. In other cases, most notably Viread (tenofovir), the drugs are now used widely as part of first and second line therapy, even though it was first tested in salvage patients.
Two important economic factors drove this change. The first was the amount of time it takes to move a new drug through the FDA approval process. By studying a drug in treatment experienced people, this amount of time is shortened significantly. It takes less time to see if a therapy is working or adding something when given to people with few options and a high likelihood of HIV disease progression. The shortened time to approval has a significant impact on the amount of money a company needs to invest in a new drug. The faster it is approved, the less money the company spends. It also allows the company to begin recouping those costs by selling their drug earlier.
The second factor was the effectiveness of existing drugs for first line therapy. Drugs like Kaletra (lopinavir/ritonavir) and Sustiva -- combined with a backbone of two NRTIs -- were achieving very good results both in studies and in everyday medical practice. The perception developed that the market for first line therapy was crowded and offered little space for a new entrant and, indeed, little room for improvement.
It made sense scientifically and medically to study a new drug in treatment experienced people. This too stems from that same effectiveness of the first line drugs. To gain approval for first line therapy, a new drug would need to have similar, if not superior results to drugs, like Kaletra and Sustiva, already being given as part of first line therapy.
In terms of both potency and tolerance, the standards of success, for use in treatment experienced people are different than for first or second line therapy. The protease inhibitor Aptivus provides a good example of this. Its mediocre potency and troubling, sometimes dangerous side effects make it a poor choice for people with other options available to them. For people who have few options, the risks of liver problems, cerebral hemorrhage and the required high dose of Norvir (ritonavir) to boost it might be more acceptable. This is an example of the need to look at cost-benefit equations in context. Side effects and inconvenience that might be intolerable to a person with many choices, often looks very different to a person with fewer choices. (For more information, read the publication, Aptivus.)
This favorable landscape for studying new HIV drugs in treatment experienced people has led to the approval of some important new drugs and no doubt has saved lives. This landscape however is not fixed or static. It is based on an evolving set of variables, most importantly the strength and tolerability of the drugs already available. Two new drugs, the recently approved protease inhibitor Prezista (darunavir) and the experimental integrase inhibitor MK-0518 seem likely to bring significant changes to this equation.
Prezista was approved in Spring 2006 based on two large studies (POWER 1 and POWER 2), which compared it to other Norvir-boosted protease inhibitors in treatment experience people. The results from these studies were very promising; with more than three times as many people taking Prezista having a sustained reduction in viral load compared to those taking other boosted protease inhibitors. Prezista offered a real advantage for people who had developed resistance to most other protease inhibitors.
The results achieved with Prezista were, at the time, unprecedented. The volunteers in the two studies were highly treatment experienced, having taken drugs from the three major classes (PIs, NNRTIs and NRTIs), and having an average of three major PI-associated resistance mutations. By comparison, in a similar study of Aptivus for treatment experienced people, about half as many people had viral loads below 50 copies after 24 weeks (23% for Aptivus vs. 46% for Prezista). (For more information, read the publication, Prezista.)
Early results of studies of another new drug, called MK-0518, are equally good and possibly better. MK-0518 is one of a totally new kind of HIV drug called an integrase inhibitor, and as such, should be fully effective despite any and all resistance to previous drugs. Integrase inhibitors are drugs that stop HIV from combining its genetic material into a cell's own genes. There are several of these drugs in development, with MK-0518 the furthest along.
At the 2006 Conference on Retroviruses and Opportunistic Infections (CROI), researchers presented data on MK-0518 showing large decreases in viral load when the drug was given to treatment experienced people. In one study of treatment experienced people, 72% of people taking MK-0518 had viral loads below 50 after 16 weeks, compared to 16% of people taking a placebo. (Both groups took at least two other approved anti-HIV drugs.) The data raised the possibility that MK-0518 might well be the most potent drug to date for treatment experienced people.
Equally impressive and possibly more interesting was the rate at which people experienced drops in their viral loads. In a study presented at the 2006 International AIDS Conference (IAC), researchers presented data from another phase II trial, comparing MK-0518 to Sustiva [both plus Epivir (lamivudine) and Viread (tenofovir)] in people taking HIV drugs for the first time. While similar numbers of both groups ultimately achieved viral loads below 50 copies after 24 weeks, on average people taking MK-0518 achieved undetectable viral load more quickly. While more research is needed to fully understand this finding, most previous research has shown that the faster HIV viral load drops, the longer lasting the effect.
Yet another study, presented at ICAAC in San Francisco in September 2006, compared MK-0518 to Sustiva in an otherwise identical regimen and measured the effect of the two regimens on cholesterol levels. Hyperlipidemia, or abnormally high cholesterol levels, has been a common effect of most protease inhibitor regimens as well as regimens based on Sustiva. Hyperlipidemia is associated with many harmful side effects. After 24 weeks, the patients treated with MK-0518 actually showed a statistically significant reduction in cholesterol levels compared to those on Sustiva, who experienced the usual increase.
(Phase III studies are currently underway for MK-0518. On the final day of the 2006 IAC, Merck announced the opening of an expanded access program for MK-0518. For information on this program, see this page.)
The results from Prezista and MK-0518 make it clear that the bar has been raised for developing new drugs in treatment experienced people. The results from these two drugs make it clear that the picture for treatment experienced people looks better than ever. However, it is almost certain to substantially reduce the number of people failing all therapies. This is good for those people, but it will also greatly reduce the number of people in need of salvage studies and drugs for this use. The number of people in need of salvage therapy has been decreasing slowly for a number of years. These two new highly potent drugs seem likely to accelerate the decline. Again, good for the patients, not so good for companies trying to get drugs approved for salvage use.
A look at two drugs being studied in treatment experienced people shows the potential dilemma for the companies that are developing them, for the activist community and for the FDA.
TNX-355 is a kind of entry inhibitor, called a monoclonal antibody (mAb). TNX-355 is a protein that binds to another protein on the surface of immune system cells, called CD4+. HIV attaches to the CD4+ protein in order to enter an immune cell. TNX-355 attaches to the CD4+ protein in such a way that HIV can't.
TNX-355 is given by intravenous infusion every two weeks, likely restricting its use to treating experienced people. Tanox, the company developing TNX-355, is studying their drug exclusively in treatment experienced people. Unfortunately, the results seen so far do not compare favorably to Prezista or MK-0518. Studies of TNX-355 in treatment experienced people showed a maximum viral load reduction of around 1 log -- compared to almost 2 logs (10 times more) for MK-0518.
Bevirimat (PA-457), the first maturation inhibitor to be studied in people, faces some similar obstacles. Maturation inhibitors work at a similar place in the HIV replication cycle as protease inhibitors. While protease inhibitors work by attaching to the protease enzyme and blocking its activity, bevirimat works by attaching to the proteins that the enzyme cuts up (substrates) keeping them from being cut up by the protease enzyme.
Unlike TNX-355, bevirimat is a small molecule, so it can be given as a pill. Like TNX-355, results from early studies have shown moderate anti-HIV activity. In studies published so far, people taking bevirimat sustained about a 1 log reduction in viral load. This is similar to TNX-355, but less than what was seen with either Prezista or MK-0518. While larger studies continue, and are necessary to fully understand the strength and other characteristics of bevirimat, these early results raise the question of what role this drug will have for treatment experienced people.
The more important issue here is not the merits of bevirimat or TNX-355 but with the changing realities facing companies that seek to develop new HIV drugs, the FDA that decides on approval, and the activists who follow and influence the process. The simple, fast route for developing these drugs is going away and won't come back for quite some time. Many companies have shied away from developing new drugs for first line therapy, knowing they would have to study their new drug against the proven first line drugs Kaletra or Sustiva. A similar situation might now be developing for companies seeking to develop their drugs for treatment experienced people.
It remains to be seen how different companies, the activists or the FDA will respond to these changes. While it isn't hard to see that the landscape has changed, how exactly to respond to these changes is far less clear. For the companies, an honest evaluation of the potential for their drugs in this current climate is crucial. For the FDA a similar discussion of the standards to evaluate these new drugs is necessary. So too must the activists (Project Inform included) reevaluate and adjust our approaches to activism for treatment experienced people. This is not to suggest that drugs like these shouldn't be studied or developed, but only that new approaches to their development must be created.
The very real challenges of anti-HIV drug therapy for treatment experienced people remain. While the advances represented by Prezista and MK-0518 are welcome, far too little is known about these drugs. It will take more research, as well as the real world experience of people with HIV using these drugs to fully flesh out their strengths and weaknesses. Despite the development of these two new drugs, there will still be a need for new anti-HIV drugs, especially for treatment experienced people. It is undeniable that companies seeking to develop these new drugs face higher expectations than ever before. For people with HIV and the activist community, this is a good problem to have. Project Inform remains committed to facilitating the study and development of new drugs, especially for those who need them the most.