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Entry Inhibitors: The Ups and Downs of Drug Development

By Lynda Dee

Spring 2006

I have been an AIDS activist since 1986 but just when I thought I'd seen it all, the seesaw phenomenon that is drug development caught me off-balance again. Entry inhibitors (EIs) have made HIV drug development an even more dangerous roller coaster ride for both companies and people with HIV. Here is one activist's take on the history of another "promising new class" of HIV drugs.


A "Cleaner" Drug?

The story of EIs begins ten years ago, when researchers began finding people who had been exposed to HIV many times but had never been infected. The mystery was solved when, in 1996, they reported that these individuals lacked a CCR5 receptor on their T cells. Turns out that HIV attaches not only to the CD4 receptor on T cells, but also to a co-receptor: either CCR5 (R5) or CXCR4 (X4). People lacking this co-receptor weren't getting infected, no matter how much unsafe sex they had.

This led to hopes of new HIV vaccine approaches and to a new class of drugs: EIs. These drugs were designed to "clog up" the R5 or X4 co-receptors. If an EI was effective, HIV could attach to the CD4 receptor, but it couldn't "unlock" the cell's coat since the co-receptor was blocked by an EI. The drugs worked in the test tube, promising fewer side effects and potent viral suppression, even in people resistant to many approved HIV drugs. But as we've seen in the past, the anticipation may have far exceeded the actual event.

This new class of drugs presents many challenges with respect to safety and side effects. Initially, we were peppered with the concept that these drugs would be "cleaner" than previous drugs like protease inhibitors (PIs). My first thought was, "Where have I heard that before?" Because EIs should prevent HIV from actually entering uninfected cells, the theory was that they would lower HIV replication without affecting healthy cells.

Researchers initially suggested that EIs should be tested only in people with early HIV disease due to fears that if the R5 receptors were blocked, HIV would shift to using X4 receptors, perhaps leading to faster HIV progression. This sounded only too familiar to long-time activists. Years before, other elite researchers had told us that all new drugs should be studied in antiviral-naive patients so we could better prove just how effective the newer drugs were. They swore we that would thwart the development of promising new drugs by studying them in people who were too sick to actually show real benefit. We were told we should forgo studying new drugs in the people who needed them the most.

Treatment activists didn't go for that line then, and we didn't this time either. We insisted that the FDA force companies to study these drugs in all patient populations before they became more widely available after FDA approval. This has resulted in another unforeseeable turn of events and a divergence of opinion between US and European activists, which I'll explain further when we discuss the specific drugs.

There were other safety issues that also needed to be addressed. Theoretically, EIs might cause immune system interactions that will result in the proliferation of other pathogens in the blood, including well-known opportunistic infections and deadly new cancers. Resulting immune complications are of paramount concern even if these drugs are supposed to be "clean" in and of themselves.


BMS 806: Too Many Pills

The EI saga began with a compound from Bristol-Myers Squibb (BMS) that was initially further along than the rest of the pack. In test-tube studies, BMS 806 inhibited the first step in HIV entry by binding with a part of the HIV envelope, gp120. Since it bound with HIV, not a CD4 cell, it was hoped that this compound would block HIV entry regardless of whether the virus used the X4 or R5 co-receptor.

In 2002, BMS was the leader in this field and claimed that BMS 806 had a tolerable safety profile and no cross-resistance to other approved HIV drugs. It was also orally bioavailable -- a tablet, not an injection like Roche's Fuzeon, which causes injection site reactions in 98% of cases and costs over $20,000 a year.

But four years later, BMS has not produced a usable version of 806. They haven't been able to solve the problem of how to get enough drug into the bloodstream without requiring an unacceptable number of pills too many times each day.


Aplaviroc: Liver Toxicity

GlaxoSmithKline (Glaxo) also had an entry inhibitor -- GW873140, or aplaviroc -- that it purchased from a Japanese drug company. But development was discontinued due to liver toxicity. A small number of people in early trials were seeing abnormalities in three different indicators of liver function increase simultaneously: ALT, AST and bilirubin. This phenomenon, known as Hy's Law, can predict permanent liver damage. Glaxo immediately stopped the studies, and is to be commended for acting swiftly to ensure patient safety. (Remember, these were the drugs that weren't supposed to have any side effects.) Meanwhile, another one bites the dust!


Vicriviroc: Potency Problems

Schering Plough was initially developing SCH C, another R5 attachment inhibitor. But this compound was shelved after EKGs of patients showed QT irregularities (heartbeat abnormalities). Schering decided to proceed with development of SCH D, now known as vicriviroc (VCV). Schering claimed this compound was more potent and did not cause life-threatening heart problems. As an added benefit, it was taken only once a day. In 2003, VCV had not yet been studied in the clinic but was said to offer "great promise."

Unfortunately, we once again learned the hard way that all drugs offer great promise until they are tested in people. When large numbers of people begin using new drugs, more issues are bound to develop. For example, soon after meeting with activists and telling us how rosy everything looked with VCV, Schering announced that the lowest dose in the Phase II trial was dropped after the Data Safety Monitoring Board (DSMB) saw viral load breakthroughs. Then, the DSMB (a group of experts that reviews blinded studies to ensure patient safety) recommended closing the study entirely because of viral load breakthroughs at all three doses. We still don't know why viral breakthrough occurred, but Schering is hoping that higher doses will do the trick.

It should be noted that the VCV study in treatment-experienced patients is continuing, even though cancers have developed in five patients, including four lymphoma patients and one patient with stomach adenocarcinoma. Let's hope VCV will continue to hold its own against Sustiva and Combivir in this population, without making them sicker than they already were.

Schering is requesting FDA approval to start larger Phase III trials with higher doses of VCV, but the company may be required to go back to the drawing board with another Phase II study to find the correct dose. Restarting a Phase II study will add at least two years to VCV development. Moreover, higher doses of VCV may cause new and unforeseen side effects.


Maraviroc: The Liver Transplant Scare

Next we have Pfizer's UK 427, now known as maraviroc (MVC). Because of all the foregoing tales of woe, MVC is further along in development than the other EIs. MVC blocks viral replication at the point of membrane fusion by preventing the gp120 viral envelope from binding to the R5 co-receptor. The really good news about this compound is that unlike VCV, MVC does not need to be boosted by Norvir, the side-effect-ridden, extremely expensive Abbott PI .

This is probably the most complicated and unclear EI story of all. Apparently, a woman in one of Pfizer's international trials needed a liver transplant after receiving MVC. This case was disclosed at a scientific conference in Europe and caused transcontinental panic. Coupled with the liver toxicity resulting from the Glaxo EI, this case made people fear that liver toxicity might be a problem with the entire class of EIs, a problem that would result in the discontinuation of all EIs.

But -- you guessed it -- this case is far from clear. We may never know what caused the need for this liver transplant, as many confounding factors were present. Did MVC cause the liver damage? Was it MVC or MVC plus the INH she was taking to prevent TB that caused the problem? Or was it MVC, INH, and poor medical care? Apparently, she was given INH -- which is highly liver toxic -- to prevent TB, without any indication that she was at risk for TB (other than the country she came from). Further, she was given Tylenol -- also liver toxic -- for initial symptoms and IV Tylenol after hospitalization. The patient also had hepatitis C, although her HCV viral load was undetectable. So, we have a patient who probably had a compromised liver, receiving two drugs known to be toxic to the liver (INH and Tylenol) and an investigational drug (MVC). Who's to say for sure what actually caused the liver damage that led to the liver transplant?

What's even more concerning is that in addition to the liver transplant incident, Pfizer's DSMB recently recommended that the lowest dose of MVC + Combivir in its study in people who had never taken anti-HIV drugs be stopped because the Sustiva + Combivir arm was outperforming the MVC arm. Is this deja vu? Let's hope the higher doses of MVC keep performing well against Sustiva.

It is important to note that the MVC + Combivir vs. Sustiva + Combivir study in treatment-experienced patients is continuing, with MVC holding its own against Sustiva so far. It should also be noted that Sustiva + Combivir is one of the best first-line regimens we have against HIV. Bet Pfizer is now very happy that the FDA forced them take our recommendation and study MVC in later-stage patients, too.


The European Conflict

Many European AIDS activists firmly believe that newer drugs like MVC should not be studied in naive patients, especially if they have a CD4 count below 200. They fear that not enough is known about these compounds and that patients below 200 should not be exposed to the unknown risk and potentially suboptimal benefit of new drugs when other, more tried-and-true regimens are available. When reviewing the protocol, many U.S. activists thought it would be better to study these drugs in all populations before they received FDA approval. We believed that most physicians would not subject their patients with CD4 counts below 200 to experimental agents when over 20 HIV drugs were readily available. Enter the previously described "perfect storm" liver transplant scenario, and yet another controversial trial design question gathered steam: is it appropriate to study new agents in people who are at risk of serious illness but who have proven treatment options remaining?


AMD 11070: The Lone X4 Inhibitor

Can we inhibit the potentially more dangerous X4 virus? AMD 3100, an X4 coreceptor inhibitor, was being studied by AnorMed, but trials were also halted due to life-threatening adverse events. AnorMed is proceeding with AMD 11070, which does not have the same dangerous toxicity profile as 3100. Unfortunately, the current AMD 11070 study (ACTG A5210) opened in November of 2004 but has still accrued only four of the required 48 patients necessary, largely because people must stay in the hospital for 10 days. Although the protocol team continues to make amendments that should help enrollment, at this rate it won't be fully enrolled until 2030. Hopefully, the X4 shift may not be as dangerous as once anticipated because other already marketed antivirals may effectively inhibit X4 virus.


Tropism Assays

As if that weren't enough, we are far from understanding the previously mentioned, potentially dangerous shift from R5 to X4 virus. It now seems that R5 inhibition may serve merely to make already existing X4 virus more visible to currently available tests. Maybe significant amounts of dual-tropic HIV (virus that can use either the R5 or X4 receptor) were already present before initiation of EI therapy. Of course, we would know a lot more about this issue if the only approved tropism assay was better able to detect the presence of R5 and/or X4 virus.

Presently, there is only one company producing a tropism assay, Monogram Biosciences. More companies involved in assay development would undoubtedly translate into more, possibly better and less expensive assays. But it seems that many of the funding sources have dried up as a result of the poor trial results discussed earlier. Unfortunately, the Monogram assay leaves a lot to be desired. It is very expensive -- between $800 to $1,200 per test. It is also a very labor-intensive process that requires that a patient have a viral load over 500. And it cannot detect virus that makes up less than 10% of the viral population. This means that plenty of the more dangerous X4 virus may be present, but undetectable with the current technology.


Where Does This Leave EIs?

It appears we may need to reconsider the role of EIs. They may end up being merely add-on drugs, instead of the anchor drugs (like Sustiva and Kaletra) we had hoped for. Further study will describe more fully the risk/benefit ratio of these compounds. Will they have potent and sustained anti-HIV activity? If they do, the resulting benefit must be weighed against what other side effects develop and the unknown factor of their long-term effects on the immune system's other regulatory functions. Maybe these drugs will end up being added to regimens used only by treatment-experienced patients who have burned through all other therapies and who are willing to take more risk.

But there is yet another issue. In all studies so far, we have seen substantial variation among patients in sensitivity to EIs. What factors will predict this patient variability? How many years of study will it take to sort out these strategic issues? Just when will we know how to use these drugs effectively in the real world? Is your head spinning yet?

In any event, it seems that the new integrase inhibitors being developed by Merck and Gilead Sciences may overtake EI development. Merck's MK 518 began Phase III trials in March. Although 518 needs to be taken twice daily, it does not require Norvir boosting and Merck says it is extremely effective against many types of HIV drug-resistant virus. Merck claims that this "promising" new drug will present much less risk than the EIs. Where have I heard that before?

Lynda Dee is a long-time activist and member of AIDS Action Baltimore, AIDS Treatment Activist Coalition, and Treatment Action Group.


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