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Pipeline Update: Short Notes on New Anti-HIV Drugs in Development

October 2006

The Phases of Drug Development

  • Phase I studies are small and are designed to get information about a new drug's safety and how people respond to different doses. These studies are generally the first time a new drug is given to people, so they include a small number of people (around 10-30), are short in duration (around 1-8 weeks), and often will test a variety of doses.
  • Phase II studies involve more people (around 30-200 people) and last somewhat longer (12-48 weeks). Sometimes Phase II studies examine different doses of a drug and look for specific drug-drug interactions. In HIV, these studies will often reveal early information about whether a drug is active against HIV.
  • Expanded Access Programs (sometimes called parallel track) are programs that provide early access to drugs that show promise in Phase II studies. They also help build a database about a drug's side effects, and therefore its safety. While there aren't hard and fast rules, these programs will often open at the end of Phase II studies or during Phase III studies once the Phase III study is fully recruited. In HIV, they have typically been designed to provide access to new drugs to people who have few options and who don't qualify for other ongoing studies.
  • Phase III studies are larger (several hundred to a thousand or more people) and last longer (minimally 24 weeks to several years). In addition to looking at drug safety and side effects, Phase III studies look for conclusive evidence of a drug's effectiveness. These are usually the pivotal studies that determine whether a drug is approved.

Project Inform follows HIV drug development closely, in order to provide people living with HIV accurate and up-to-date information on new drugs as they work their way through the development process. HIV treatment activists use the term pipeline to refer to the collection of all experimental HIV drugs. This article provides a very brief overview of each of the most promising drugs now in the pipeline. See this sidebar for more information on the phases of clinical studies.


Integrase Inhibitors

MK-0518 is the first of an entirely new class of drug, called integrase inhibitors, being developed by Merck. It is currently in Phase III studies. Encouraging data on MK-0518 in people who have used anti-HIV therapy (called treatment experienced people) were presented at the 2006 Conference on Retroviruses and Opportunistic Infections (CROI). This study showed the drug to be remarkably effective in reducing viral load in people who were highly resistant to nearly all other anti-HIV drugs.

More data, this time in people taking anti-HIV medications for the first time, were presented at the 2006 International AIDS Conference (IAC). Still more was presented at Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in September 2006. Some of the more striking data shows that the drug appears to reduce viral load more quickly than other potent anti-HIV drugs.

Yet another promising observation, from a study that compared a regimen based on MK-0518 to one based on the popular drug efavirenz, concluded that people treated with MK-0518 showed lower levels in serum cholesterol and triglycerides, while efavirenz like most other NNRTIs and protease inhibitors (PIs), increased both. This is considered a welcome change since many people who take anti-HIV drugs experience problems of increased cholesterol.

While there is still much to learn about MK-0518, so far it looks exceptionally potent and well tolerated. The drug is taken as a single pill twice a day and, unlike most PIs, it does not require using Norvir (ritonavir) as a booster. Merck recently announced the opening of their expanded access program. We expect data to be submitted to the Food and Drug Administration (FDA) for consideration for approval in 2007.

GS-9137 is a competing integrase inhibitor being developed by Gilead Sciences. It is currently in Phase II studies. Data were presented earlier this year from a Phase I study in HIV-negative people. A Phase II study in HIV-positive people, comparing GS-9137 to Norvir-boosted PIs, is fully enrolled. This drug is taken once daily but requires Norvir as a booster.

The integrase inhibitor currently known as 364735 is being developed by GlaxoSmithKline and Shionogi. The completion of its Phase I studies was announced at the 2006 IAC. Data are expected sometime in 2007.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Etravirine (TMC-125) is being developed by Tibotec Therapeutics and is currently in Phase III studies. Data thus far suggest it is effective against HIV that is resistant to the available NNRTIs, like Sustiva (efavirenz) and Viramune (nevirapine). In addition to its stand-alone Phase III program, etravirine is being studied together with the recently approved PI Prezista (darunavir, TMC-114), in a landmark study called DUET. While this drug is designed to overcome resistance to other NNRTIs, research has shown that HIV that develops resistance to etravirine is also resistant to Tibotec's other experimental NNRTI, rilpivarine (TMC-278). Thus, if people use etravirine now and eventually develop resistance, rilpivarine will unlikely be an option for them in the future. An expanded access program for etravirine opened recently and the details are posted here.

Tibotec Therapeutics' rilpivarine (TMC-278) is currently in Phase II studies. Data were presented at the 2006 CROI showing adequate levels of drug in the blood (called pharmacokinetics) and that HIV had difficulty developing resistance to the drug. Like Tibotec's etravirine, rilpivarine is designed to overcome resistance to the approved NNRTIs. Little is known about the strength or side effects of rilpivarine yet. A Phase II study in treatment experienced people has fully enrolled, and data are expected in 2007.

BILR-355 is being developed by Boehringer Ingelheim and is currently in Phase I/II studies. Early data suggest it will work against HIV that is resistant to the approved NNRTIs. A Phase II study in people on a failing anti-HIV drug regimen is ongoing. BILR-355 must be taken with a booster dose of Norvir. No information is yet available on whether BILR-355 is cross-resistant with etravirine and rilpivarine.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Racivir is being developed by Pharmasset and is currently in Phase II studies. This drug is very similar to Epivir (lamivudine, 3TC) and Emtriva (emtricitabine, FTC). Racivir is active against the hepatitis B virus as well as HIV. Early research suggests that it takes longer for HIV to develop resistance to racivir than to either Epivir or Emtriva. If more research confirms this, it might make racivir an attractive alternative to those drugs for first line therapy. There is an ongoing Phase II study evaluating racivir in people with Epivir-resistant HIV.

Elvucitabine is being developed by Achillion and is currently in phase II studies. In 2005, early information suggested that this might be the first anti-HIV drug taken once a week, although currently it is being studied as once a day. At the higher doses (50mg and 100mg weekly) being studied once a week, the drug proved too toxic, dangerously suppressing the development of new cells in the bone marrow (called bone marrow toxicity). This hampered drug development and the company is now studying it at lower doses (5mg and 10mg) daily, where hopefully this side effect won't be a problem.

Apricitabine (AVX754) is being developed by Avexa Pharmaceuticals and is currently in two ongoing Phase II studies. One is an extension of an earlier study and is looking at safety and tolerability of long-term use in people who had completed the earlier study. The second is examining several doses of apricitabine in people whose HIV shows evidence of the M184V mutation, which is associated with resistance to the NRTIs Epivir and Emtriva. Earlier research showed people who took different doses of apricitabine averaged between 1 and 1.6 log reductions in HIV levels, which is similar to the levels of viral suppression seen with drugs like Epivir.

Entry Inhibitors

Maraviroc (UK-427-887) is a type of entry inhibitor called a CCR5 inhibitor. It is being developed by Pfizer Pharmaceuticals and is currently in Phase III studies. Maraviroc is expected to be the first-in-class CCR5 drug when it is approved. Results from studies so far have shown that it works well both in people new to HIV treatment and treatment experienced people.

One of the concerns with all drugs that interfere with CCR5 is that using them may force HIV to begin using another entry point called CXCR4. HIV that uses CXCR4 has been associated with more rapid disease progression. Data from studies thus far have suggested that this feared switch is happening only rarely and that it hasn't been associated with more rapid disease progression.

One of the open questions about maraviroc and other co-receptor (CCR5 and CXCR4) inhibitor drugs is whether and how to use lab tests to determine who could best benefit from them. This blood test is called a tropism assay. A presentation at the 2006 IAC suggested that maraviroc could be used safely in people with HIV that uses both receptors -- called dual tropic virus.

An expanded access for maraviroc is being developed. Details on this program will be posted on Project Inform's website when they are known.

Vicriviroc (Schering-D) is another CCR5 inhibitor. It is being developed by Schering-Plough and is currently in Phase II studies. Research has been slowed by underwhelming results and concerns about the rate of cancers seen in people taking the drug. In late 2005 a study comparing vicriviroc (together with approved anti-HIV drugs) to Sustiva (also together with approved anti-HIV drugs) was halted because significantly more people taking vicriviroc experienced rises in viral load, compared to those on Sustiva. More recently, a presentation at the 2006 IAC showed good reductions in viral load for people taking vicriviroc. However, of concern was the higher rate of cancers seen in the people taking the drug. The rates were not considered high enough for the study to be halted.

There are several ongoing studies of vicriviroc. A Phase II study is looking at two doses (20mg and 30mg once a day) of vicriviroc together with more traditional anti-HIV therapies (often called optimized background anti-HIV therapy as in these studies researchers work with volunteers to devise potent regimens with the existing drugs) in people with resistance to other HIV drugs. Another planned study, that is not yet enrolling volunteers, is a Phase III study which will look at vicriviroc in people with dual tropic HIV.

TNX-355 is a type of entry inhibitor called an attachment inhibitor. It is being developed by Tanox Pharmaceuticals and is currently in Phase II studies. It is a kind of immune system protein, called a monoclonal antibody (mAb). This particular artificial antibody aims to stop HIV from attaching to the CD4+ receptor that it uses to enter cells. It is given through a needle placed in a vein in the arm, every two weeks. This route of delivery -- called intravenous (IV) infusion -- likely will restrict its use to people with extensive treatment experience and a lack of other treatment options.

Data presented thus far on TNX-355 have been somewhat confusing. In addition to only modest reductions in HIV levels, there was a lack of a dose dependant response. Typically the more of a drug that is given to a person, the larger the anti-HIV reductions they experience. This hasn't been the case with TNX-355. While the full implications of this finding aren't yet understood, it raises questions for activists and researchers alike. A final concern about TNX-355 is what it is likely to cost if approved, which is expected to be quite high.

Such concerns, however, should not prevent researchers and companies from studying drugs like this. We do not yet know where the next real advance might come from or what pathways of research will eventually lead to a cure. Some approaches, such as drugs that require IV infusion or might be unduly expensive, may still have an important role to play in the overall progress of AIDS research.

New production methods can perhaps overcome pricing issues, while newer formulations may result in less frequent dosing. For example, the current version of Fuzeon (enfuvirtide, T20) requires two daily injections. This has been an obstacle for many people. But things that were learned while developing the original drug have now led to the testing of a second generation product that may require dosing only once a week.

Conceptually, dosing once a month may someday become possible. Thus, we must be careful not to reject new approaches simply because their first generation products are less than ideal. First generation protease inhibitors weren't so good either, but the current generation is proving to be far superior.

PRO-140 is another monoclonal antibody, but this one is more like maraviroc and vicriviroc in that it is a CCR5 inhibitor. PRO 140, from Progenics Pharmaceuticals, is currently in Phase IB. Like TNX-355, it is given through IV infusion. The exact dosing and dosing schedule have yet to be determined.

Data presented earlier this year show that at the highest dose given to volunteers (5mg/Kg), PRO-140 remained attached to cells 60 days after infusion. It is not yet clear what this means about how often the drug will need to be given to patients, but surely it won't require daily dosing. Ongoing studies will help choose an optimum dose and schedule for infusion. Because it is given through an IV, it is likely to be restricted to people with extensive treatment experience. There is also concern about its cost if it is approved, as other drugs of this type are quite expensive.

Protease Inhibitors

PPL-100 is being developed by Ambrilia Biopharma and is just entering Phase I studies. Data from test tube and animal studies suggest it might work against HIV that is resistant to other PIs.

Brecanavir (GW640385) is being developed by GlaxoSmithKline and is currently in Phase II studies. Brecanavir must be taken with a booster dose of Norvir. Early data have been encouraging. Results from a 48-week, 31-person open label study (where participants knew they were taking the drug) of brecanavir plus two NRTIs were presented in 2005. After 24 weeks most people had viral loads below 50 copies. Average reductions in viral load ranged from over 3 logs in people taking HIV drugs for the first time, to just over 2 logs in people with protease resistant HIV. Phase II studies are ongoing now.

Other Types of Anti-HIV Drugs

KP-1461 is a new type of anti-HIV drug, called a mutagenic nucleoside competitor reverse transcriptase inhibitor. It is being developed by Koronis Pharmaceuticals and is currently in Phase I studies. Unlike other anti-HIV drugs that seek to limit HIV's ability to mutate, KP-1461 works by accelerating its mutations. The ultimate goal is to force HIV to gather so many mutations that it is no longer able to replicate -- something called terminal mutagenesis. This drug is just entering human studies, so little is known to date. This drug's unique mechanism raises difficult questions about how it will be studied and evaluated. It's definitely research to watch.

Bevirimat is a maturation inhibitor (MI) being developed by Panacos Pharmaceuticals. It is currently in Phase II study. Maturation inhibitors work near the same point in HIV's replication cycle as PIs. While PIs work by physically blocking the protease enzyme, MIs like bevirimat, work by attaching to immature HIV proteins and preventing the protease from cutting them up. Data from a Phase II study showed that people taking 200mgs of bevirimat once a day averaged about a 1 log reduction in HIV levels. A Phase II study in treatment experienced people is enrolling now.

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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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