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A Look Ahead at This Year's Drug Approvals

April 2007

The year 2007 is shaping up to be a busy one for anti-HIV drug development. By year's end at least two and possibly three new anti-HIV drugs will be approved. It's not only the number of new drugs that is significant. Two of them -- maraviroc and raltegravir -- will be the first of their types to gain FDA approval. The third drug, etravirine, represents a much needed second chance for many people whose virus has become resistant to an entire class of drugs. This article reviews these three drugs, focusing on how each differs from the current drugs and how it may fit strategically into the treatment of HIV.


Maraviroc: The First CCR5 Inhibitor Drug

Maraviroc, developed by Pfizer, is expected to gain FDA approval in late spring of 2007. Pfizer submitted data to the FDA in December 2006. The FDA has a six-month window to rule on a drug once it's submitted, so a decision must be reached no later than June 2007. Typically the FDA rules near the end of that window; however, it has scheduled a hearing before the Antiviral Advisory Committee in late April. It's possible that this might lead to maraviroc's approval shortly thereafter.

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Maraviroc attempts to block HIV from entering an immune cell. It does this by attaching to a protein called CCR5 that is part of the surface, or membrane, of the cell. This protein, often just called R5, is a co-receptor that HIV uses to enter cells. By attaching to R5, maraviroc -- and other drugs like it -- seeks to keep HIV from attaching to the protein and thus prevents the virus from entering the cell.

Any drug that works by stopping HIV from getting inside immune cells is called an entry inhibitor, or EI for short. One approved EI is on the market now, called Fuzeon (enfuvirtide, T20). Fuzeon interferes with a different step in HIV's entry into cells. This is important because HIV that has become resistant to Fuzeon won't typically be resistant to maraviroc, or other R5 inhibitor drugs. Unlike Fuzeon, which is given as two injections per day, maraviroc is taken as a pill twice a day. However, when Fuzeon and maraviroc are used together, HIV's entry is blocked in two ways, which may make for a good combination.

Most, but not all, HIV uses R5 to enter CD4+ cells. Some HIV uses another protein called CXCR4, or X4 for short. Almost everyone in early HIV disease has HIV that uses R5 (referred to as R5 HIV). Some percentage of people's virus will shift over time to use X4. This happens most often in more advanced HIV disease. Some think that X4 virus is more aggressive and speeds up disease progression. Others think it might be an outcome, rather than the cause, of disease progression.

Further complicating matters, people can have HIV that only uses R5 (called R5-tropic), only uses X4 (X4-tropic), uses either R5 or X4 (dual-tropic), or both R5 and X4 (mixed-tropic). Additionally, people with X4 HIV don't always have a more aggressive form of disease. Therefore, it's difficult to draw any hard conclusions other than to say that blocking whichever receptor that HIV uses is a good thing.

Maraviroc is only expected to be useful for people with R5 HIV. A lab test, developed by Monogram Biosciences (formerly Virologic), can distinguish these different types of HIV. This test, called Trofile, will probably be required before a person is given maraviroc, or any R5 inhibitor drug.

Before the 2007 Conference on Retroviruses and Opportunistic Infections (CROI), less was known about maraviroc this close to FDA approval than is typically the case. This is because Pfizer was allowed to combine their Phase II and III programs. Typically these stages are done separately. This shortened the time it took for maraviroc to advance through the FDA approval process. It also reduced the amount of data available to Project Inform and other treatment activists to review ahead of approval.

Maraviroc might be more useful for people who have never taken anti-HIV drugs, or are on their second regimen. Unfortunately there will be little, if any, data on maraviroc being used in these groups. This will probably make some doctors hesitate to prescribe it for people earlier in HIV disease.

Some doctors and activists have raised a different concern about maraviroc and other drugs like it. Maraviroc would become one of the few drugs not to target HIV, but rather the cells of the immune system. R5 has many roles in the immune system, and it is not known what problems blocking it might have for a person's immune function and health in the long-term. While nothing alarming has been reported from studies so far, there are unresolved concerns about long-term use. One encouraging sign is that people who are born with a defective gene that prevents their cells from producing R5 don't seem to have any unusual health problems.

An expanded access program (EAP) for maraviroc began enrolling in February 2007. It is open to people with limited treatment options because of drug resistance or intolerance. (To enroll, check www.maraviroceap.com.) Visit Project Inform's website throughout spring 2007 for regular updates on maraviroc as it progresses toward its anticipated FDA approval.


Raltegravir: The First Integrase Inhibitor

Following fairly closely on the heels of maraviroc is another new kind of anti-HIV drug. Raltegravir, formerly known as MK-0518 from Merck, is set to become the first of a new type of drug called an integrase inhibitor, or simply II. Merck is expected to submit raltegravir to the FDA early in the second quarter of 2007, with approval likely to follow at most six months later.

Integrase is an enzyme (a kind of protein) that HIV uses to combine its own genes with the genes of an immune cell. A drug that successfully stops this step in the HIV replication cycle has long been sought. Three companies, Merck, Gilead and GlaxoSmithKline (GSK), have IIs in human studies, with Merck's drug the closest to approval. Both Merck and GSK had other IIs that failed to pan out. Several other companies, including Ambilia, Avexa and Bristol-Myers Squibb, have IIs in pre-clinical development. Merck and Gilead are also working on second generation IIs.

Raltegravir has generated a good deal of excitement, beginning at the 2006 CROI. Data from one study in treatment experienced people showed the largest average reduction in viral load ever seen in this group of people. Two more compelling studies were presented later in 2006.

One, presented at the International AIDS Conference in Toronto, looked at raltegravir in people taking anti-HIV drugs for the first time. This study showed that people had more rapid reductions in viral load on raltegravir than people taking a regimen based on Sustiva (efavirenz). This is significant because other studies, including a large, well controlled study presented at the 2007 CROI, show that the more quickly a drug reduces viral load, the longer it continues to work before developing resistance.

A second study, presented at the 2006 ICAAC, compared the effects of raltegravir on the kinds of fats that circulate in the blood, called lipids. This study found that, compared to people on a Sustiva regimen who experienced higher lipid levels, people taking a raltegravir regimen actually saw a small but significant decrease in lipids.

In developing raltegravir, Merck bucked a long-standing trend among companies that develop new anti-HIV drugs. Most newer drugs have been studied first in treatment experienced people and then maybe later in people taking anti-HIV drugs for the first time. Merck decided for a more-or-less parallel development plan, studying it in both groups of people at the same time. The studies in treatment experienced people are somewhat further along than those in people new to treatment.

When the FDA rules on raltegravir later in 2007, one interesting question will be the exact nature of the approval. Often anti-HIV drugs are approved by the FDA only in select groups of people. For example, maraviroc will likely be approved for people with R5 HIV only. The early data suggest it's both powerful and well tolerated. If, as expected the studies in people new to therapy aren't done by the time the FDA makes its decision, there will likely be debate over this issue.

Some will argue that the data are only complete for treatment experienced people, so the approval should be only for them. Others are likely to argue that the drug appears powerful, and moreover well tolerated. Since all drugs that have worked well in treatment experienced people have worked at least as well (and usually better) in people taking anti-HIV drugs for the first time, the drug should be given a broader, more inclusive approval.

More data on raltegravir are expected during the next two years. It is available now in an EAP for people who are resistant to at least one drug in each of the three main classes of drugs. For more information about the raltegravir EAP, go to www.benchmrk.com. Remember though that the drug was previously known as MK-018.


Etravirine: The First Second-Generation NNRTI

Etravirine (formerly TMC-125) is an experimental NNRTI (non-nucleoside reverse transcriptase inhibitor) being developed by Tibotec Therapeutics. Unlike maraviroc and raltegravir, which are set to become the first drugs of their kind, etravirine is the same type as Sustiva, Viramune (nevirapine) and Rescriptor (delavirdine).

Etravirine is different from the older NNRTIs in one important way: it remains active to some degree against HIV that's resistant to the other NNRTIs. One of the main drawbacks to the NNRTIs has been that HIV that develops resistance to Sustiva is also very likely to be resistant to Viramune and Rescriptor. Moreover, resistance to NNRTIs can develop from a single change in HIV's genes. The result is that most people get one shot at using an NNRTI.

Etravirine was designed to work against HIV that is resistant to the older NNRTIs, and results from several studies have been published. They suggest that etravirine is a potent anti-HIV drug, reducing viral loads between 1 and 2 logs. It seems to cause more diarrhea than the other NNRTIs, and it can cause a rash like the others as well.

Unlike maraviroc and raltegravir, where major questions remain on who exactly will use those drugs, etravirine's role in anti-HIV therapy is fairly clear. It will likely be used by people who have taken and become resistant to the older NNRTIs. However, one significant controversy remains. It appears that people whose virus has developed more than two NNRTI mutations do not respond as well as people with two or fewer.

Etravirine is available now in an EAP. For more information on it, see Expanded Access Program Opens for Etravirine.


Conclusions

There is little doubt that 2007 will be an important year in anti-HIV drug development. It's expected that the first drugs from two new classes will debut. While unlikely to gain approval in 2007 the first second generation drug from another important class will near approval. This news is especially good for people with a lot of experience taking anti-HIV drugs, who might be running short on options. Each of these three new drugs will be used by this group, to varying degrees. Two of them, maraviroc and raltegravir, show promise for a much broader group of people.

While there's much to be excited about this year, the news might not be as good for the next few. GSK recently announced the end of their experimental PI brecanavir. (See GSK Puts the Brakes on Brecanavir for more information.) TNX-355, another type of entry inhibitor, faces an uncertain future due in equal parts to underwhelming results from studies and the purchase of the company developing it. (See Saving the Best for Last? for more information.) Also facing serious questions are Schering's R5 inhibitor drug vicriviroc and Panacos' maturation inhibitor bevirimat.

This leaves a relatively thin group of new drugs possible for approval in 2008-2010. Of note will be Gilead's integrase inhibitor elvitegravir (formerly GS-913), Tibotec's follow-up NNRTI rilpivarine (TMC-278), and possibly the NRTIs elvucitabine from Achillion and apricitabine from Avexa.

For now, however, the news is very promising. For years, many treatment experienced people faced the prospect of adding only one new active drug at a time. Fairly soon there will be as many as four new drugs -- including the PI Prezista (darunavir, TMC-114) approved in late 2006 -- for treatment experienced people to construct a potent regimen. This is an extraordinary and unprecedented opportunity for people who have otherwise run out of options or become resistant to most of the other drugs. Never before have people in these situations had the chance to construct a new regimen with three or four drugs they've never used before.

People need to make careful and wise use of this opportunity. If they do, it should be possible for the great majority to reach undetectable levels of viral load. This opportunity will unlikely be repeated again in the foreseeable future. While there's some uncertainty about the future, Project Inform remains committed to spurring the development of new, innovative and effective therapies to treat, and one day to cure, HIV/AIDS.





  
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This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.
 

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