MK-518

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January/February 2007

Brand Name: Not yet established

Common Name: MK-0518

Class: experimental integrase inhibitor

Standard Dose: 400 mg twice a day going into Phase III study, with or without food.

Manufacturer contact: Merck and Co.,
www.benchmrk.com, 1 (800) 850?3430

AIDSInfo: 1 (800) HIV?0440 (448?0440), www.aidsinfo.nih.gov

Potential side effects and toxicity:
Diarrhea, nausea, vomiting, fatigue, headache, flushing, and pruritus (itchy skin) seen in studies.

Potential drug interactions:
Reyataz increases blood levels of MK-0518, but early results showed similarly good results with or without Reyataz.

Tips:

MK-0518 (518 for short) is available through an Expanded Access Program (free drug before FDA approval for people in medical need). Call 1?888?577?8839 or visit www.earmrk.com. 518 is exciting for several reasons. The advocate word on 518 is that some advanced patients are having dramatic results and no side effects. Many people on long-time therapy are now undetectable for the first time. One doctor reported that patients at his clinic could not believe they had received 518 instead of a placebo (dummy pill). Also, 518 is one of the truly new drugs that advanced patients are in so desperate need of -- and it's not the only one, making 2007 an especially promising year (see article "The Time They Are A-Changing"). As the first drug in its class to be available, there won't be cross resistance (ineffectiveness) to other drugs. It doesn't have to be boosted with the dreaded Norvir like so many other new HIV drugs, has had no published interactions with other HIV drugs, and can be taken with or without food. Cholesterol and triglyceride blood levels haven't been increased (in preliminary 24 weeks results, the time in which some of the other HIV meds have shot these levels through the roof). It's shown more potency in early (two weeks) results in both people on therapy for the first time and those who were heavily treatment-experienced, compared to the gold-standard Sustiva. The idea of such early and amazing potency -- never seen with an HIV drug before -- is exciting.

Integrase inhibitors, as their name implies, inhibit integrase, one of the three different enzymes HIV has that it uses to multiply. The nucleoside and non-nucleoside drugs work on the virus's reverse transcriptase enzyme, the protease inhibitors work on its protease enzyme, and integrase inhibitors like 518 work on its integrase enzyme. HIV uses its integrase to put its viral DNA (genetic protein) into the DNA of the human cell.

Comparing MK-0518 to Sustiva, MK-0518 showed comparable rates of achieving HIV viral loads less than 50 copies. At weeks 4 and 8, the MK-0518 arms showed a more rapid decline of viral load (to less than 50 copies) with all doses compared to Sustiva, and the safety profile was similar. Between 85 and 95% (varies by dosage) had less than 50 viral load at 24 weeks.

In a separate study of 150 heavily-treated persons with extensive drug resistance, about 71% of the MK-0518 group overall had less than 400 viral load after 24 weeks on 518, with a range of 57% to 67% under 50 (varies by dosage). There was a 20% improvement in efficacy overall for all arms of the study for people who had never taken Fuzeon and were adding it to either their 518 regimen or their optimized background therapy without 518. In the group taking 518, first-time use of Fuzeon improved efficacy 50% (varies by dosage). This study of 0518 also saw a very sharp and rapid drop in viral load -- an average of approximately 2 logs in the first two weeks. In fact, 90?95% of these advanced patients who were taking Fuzeon for the first time had less than 400 viral load at the end of 24 weeks, an unheard of response in such an extensive drug resistant group, compared to 60?70% of the other people on 518. But adding the twice-daily and expensive injection drug is a steep price to pay for success -- or maybe not. The numbers were also small, and so more unreliable. There are also those other new drugs that could team up with 518 to make up two active new meds, as recommended when switching therapy after treatment failure.

Doctor

MK-0518 has created interest due to the impressive preliminary results reported from two well done studies involving both treatment-naive and treatment-experienced patients. Advantages of MK-0518 include no need for ritonavir boosting, activity against HIV resistant to other ARV classes, a relative lack of drug interactions (not metabolized via the hepatic p450 pathway), potency, and tolerability. For treatment-naive patients, in a comparison with efavirenz (92%) similar high rates of viral suppression (less than 50 copies/ml) were observed with the MK-0518 arms (85?95% for the various dosing arms) who more rapidly suppressed HIV levels. In that study tolerability was similar to efavirenz while MK-0518 had less lipid effect. In the treatment-experienced study utilizing a TORO-design (MK-0518 plus OBT versus OBT), the rate of high-level viral suppression (less than 50 copies/ml) was up to 67% (in the 600 mg BID) versus 14% in the placebo arms. Once again, use of enfuvirtide in enfuvirtide-naive patients identified a subset of patients who did particularly well. MK-0518 has generally been well tolerated. Side effects have included diarrhea, nausea, vomiting, fatigue, and headache (all at rates comparable to placebo or comparator arms). One patient discontinued therapy due to an increase in liver enzymes. An expanded access program is now open. Data on use with other new drugs (such as darunavir, maraviroc, and TMC-125) is urgently needed in order to optimize the benefit of having so many new drugs available within a short time frame. -- Keith Henry, MD

Activist

The new Merck integrase inhibitor is another drug that you want to pay close attention to in the coming year. Integrase has been one of the most difficult targets in the virus life cycle to develop a drug for. Although there are now several exciting candidates in development, Merck's is the furthest along, so the community is paying close attention to it. The Merck compound (like the others in its class currently being studied) works at preventing HIV DNA from being integrated in the nucleus of our T-cell. This is after it has gone through the reverse transcriptase process where the nukes and non-nukes work. Once HIV DNA gets into our nucleus, it basically programs our cell to start making more HIV. If we can interfere in this process, it may help to cripple the virus's ability to produce more HIV. What a concept! However, don't expect any miracles at this point. Data from the studies is good, but we still have a lot more to learn about this drug and the others in its class. At this writing the Merck drug is currently available to salvage patients via expanded access. -- Cathy Olufs



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