The XVI International AIDS Conferences are not often the stage for treatment breakthroughs, the last big one coming with the advent of HAART (highly active anti-retroviral therapy) in Vancouver in 1996. In Toronto there were limited updates on new drugs that are showing promise in clinical research but this year the focus fell on prevention technologies—a needed shift in attention and awareness. Still, AIDS treatment activists are beginning to realize that a new treatment paradigm may be on the horizon as cumulative information comes forward on better drugs and new drug classes.
Integrase Inhibitor MK0518
Despite the scant information from Toronto, the pipeline is active for many of us who need new and different treatment options. Probably the most exciting example is the new integrase inhibitor known thus far as MK0518, or 518. There are high hopes for this drug based on the current research, as it appears to work very well in people who are treatment experienced.
The drug looks so good that a new Expanded Access Program (EAP) was announced in Toronto and started screening September 11th (providers can enroll patients who qualify at www.earmrk.com, 1-877-EARMRK1). Merck has moved swiftly and responsibly in order to provide this new class to those who need it.
The company now wants to show that the drug works in those who have never taken HIV drugs before (treatment naïve). One Late Breaker session presented the latest information about 518 in a Phase II, 48-week study that compared four doses of 518 vs. Sustiva, both combined with Viread and Epivir in about 200 treatment-naïve people. 24-week interim analysis showed that all arms showed similar effectiveness at lowering virus levels by more than a 2.2 log drop from an average 4.7 log at baseline.
Similarly, CD4 numbers increased an average of 75-135 cells. There was a similar safety profile in all arms with less central nervous system adverse events in the 518 arms. The major differences seen in this study were the number of participants who achieved rapid viral suppression in the 518 arms compared to the Sustiva arm.
While this analysis didn’t prove superiority of 518, the results show that it will move forward as a strong competitor in people taking HIV meds for the first time, perhaps shaping a new paradigm shift towards a new background class.
CCR5 Antagonist Maraviroc
The next candidate nearing approval is maraviroc, the CCR5 antagonist from Pfizer. Studies have thus far shown this to be an effective therapy in treatment-experienced participants. But the company wants to prove that a shift in tropism to a co-receptor associated with late stage disease (CXCR4, or X4) is not occurring using a small pilot study looking at people with both R5– and R4–containing viruses.
This is the $64,000 question that everyone is waiting to answer, since most people living with more advanced HIV have dual/mixed tropism and use of this new class has begged the question whether it would be safe to use in this population. But so far no serious problems have been associated with a shift to R4–containing virus when the CCR5 co-receptor is blocked.
A study presented in a Late Breaker session was a 24-week analysis comparing maraviroc once daily vs. maraviroc twice daily vs. a placebo-containing optimized background regimen in treatment-experienced participants who had dual/mixed tropic viruses. Similar viral load responses were seen in all arms, although CD4 cells were higher in the maraviroc arms in this analysis. Adverse events were similar in all groups, suggesting maraviroc is not any more toxic than compared background therapies. Further work will have to be done to prove if in fact this drug can be effective in this particular population. We’ll hold out to the 48-week results to see if there may be different results.
CCR5 Antagonist Vicriviroc
Vicriviroc is Schering-Plough’s version of a CCR5 antagonist. In Toronto a Phase II Adult AIDS Clinical Trials Group (AACTG) study was presented to evaluate different doses of this compound at a 24-week time point. The effectiveness of the two CCR5 antagonists furthest along in the research pipeline is similar when combined with optimized background regimens, but vicriviroc has to be “boosted” by Norvir, which will mean a lower dose of the drug will be used.
In this two-part study after 14 days of vicriviroc plus a failing background regimen, an average 1 log decrease in baseline viral load was seen. Participants then switched to an optimized background regimen and saw further decreases in viral load between 1.5-1.8 log. Malignancies seen in this study have been a concern with this drug class, which the company claims are not related to vicriviroc, but it remains to be seen whether or not CCR5 antagonism may affect the body’s responses in other ways.
Monoclonal Antibody TNX-355
Another entry inhibitor in development works with a different mechanism than other entry inhibitors. The drug is called TNX-355, a monoclonal antibody infused every two weeks that blocks the CD4 receptor, therefore preventing viral entry into the cell. In Toronto the compound showed a durable response in a 48-week study in treatment-experienced participants who combined TNX-355 with an optimized background regimen.
This was an ongoing study that provided added information on the effectiveness of the compound, making it yet another possibility for those who have fewer HIV treatment options. Compared to a placebo arm, two doses being studied were more effective in reducing virus levels in the blood.
Interestingly, the lower 10 mg per kg dose showed a greater virus reduction, though more advanced participants were randomized to the higher 15 mg per kg. This drug is viewed as a likely candidate because it will not interact with other medicines, and so far there are few side effects. TNX-355 provides hope as it is the first HIV monoclonal antibody that has reached this level of research. Despite the fact that it is infused, it will only be given at least every two weeks and it might have additive affects for those without treatment options.
Other Drugs
While newer classes seem to be highlighted in this article, other older drug classes are being refined and new discoveries may be leading to safer, easier to take, and more potent drugs that have the potential to out-do the older drugs.
One such drug, TMC125, is showing promise as a therapy against NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant virus. Development of this drug has reached the point that it is in several drug interaction and resistance substudies that are important to do, but not highlighted at a major HIV conference. 48-week data showed that this new NNRTI is potent and appears to hold its effectiveness with mutations present from older NNRTI’s. In this heavily pre-treated NNRTI-experienced population, the drug appears safe and hearty. It should be almost ready for use through Expanded Access, promised by its maker, Tibotec, although it is unclear whether it can be used with Merck’s 518 due to unknown drug interactions.
There is great interest to improve upon Fuzeon, a fusion inhibitor, so that it does not have to be injected twice daily. Two fusion inhibitor candidates presented in Toronto have shown to have longer half-lives, staying in the body longer so that the possibility of weekly injections may be possible. The candidates also appear to be just as potent against Fuzeon susceptible viruses and 150-200 times more potent with Fuzeon resistance. More hurdles have to be met to see if even an injection every two weeks will have a place in the new treatment paradigm where newer classes may overshadow the need for injectibles.
Where protease inhibitors (PIs) were all the buzz 10 years ago in AIDS meetings, now they are getting less exposure simply because newer classes are being studied. Brecanavir is a protease inhibitor that should be effective in PI resistance. One study showed that the drug remains effective in laboratory HIV strains resistant to four older protease inhibitors.
Given the effectiveness of Prezista, a new protease inhibitor that was recently approved to treat protease resistance, more new protease inhibitors may be akin to “always a bridesmaid, never a bride,” waiting on the pharmacy shelves withering away into obscurity, especially in light of the new classes that may be more potent, safer, and easier to take. |
