Once again, the new integrase inhibitor MK-0518 continues to wow us. It dominated the stage at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2006) in San Francisco. ICAAC 2006 is the third major international HIV-related conference this year (including the 13th Conference on Retroviruses and Opportunistic Infections [CROI 2006] in Denver and the XVI International AIDS Conference [AIDS 2006] this past August in Toronto) in which impressive data have been presented on the safety and efficacy of this compound in various patient populations.

Integrase is an HIV enzyme that allows the HIV virus to insert its genetic material into the DNA of human T cells. Integrase inhibitors block this important step in the viral life cycle, preventing the virus from replicating. This is a new target in the treatment of HIV, making this drug extremely attractive for use in patients who already have preexisting resistance to other HIV drug classes.

MK-0518 has an in vitro activity (IC95) of 33 nM + 23 nM in 50% human serum. It is primarily metabolized via glucuronidation (UGT1A1) and it is not a potent inhibitor or inducer of CYP3A4; thus it does not require boosting with ritonavir (RTV, Norvir). For the same reason, the expected pharmacokinetic interactions are minimal. In fact, several pharmacokinetic drug interaction studies presented at ICAAC 2006 demonstrated very small changes in the pharmacokinetics of MK-0518 when coadministered with efavirenz (EFV, Sustiva, Stocrin), ritonavir, tipranavir (TPV, Aptivus) or tenofovir (TDF, Viread), which did not require dosing modification.^1-3

But the most relevant information presented at this conference on MK-0518 is a follow-up of the study of MK-0518 in treatment-experienced patients. The results of this trial were initially presented at CROI this past February. (In fact, I also reported on that study.⁴) At ICAAC, we had the opportunity to view the 24-week results of this multicenter, international study⁵ in which almost 200 heavily treatment-experienced patients with widespread HIV drug resistance were randomized to three different twice-daily dosages of MK-0518 (200 mg, 400 mg and 600 mg) plus an optimized background regimen versus placebo.

The phenotypic susceptibility score in almost 50% of the patients was 0, and 20% to 28% of the patients used enfuvirtide (T-20, Fuzeon) for the first time as part of their optimized background regimen. Approximately 17% of the patients in the treatment groups discontinued the study due to a lack of efficacy in comparison to 67% in the placebo arm. Discontinuation due to adverse events was rare.

Slide by Beatrice Grinsztejn, M.D.; reprinted with permission.

The chart above summarizes the proportion of patients achieving an HIV-RNA level below 50 copies/mL in an intent-to-treat (ITT) analysis. The responses seen with all dosages studied are superior to the responses seen with placebo plus an optimized background regimen.

In the group taking the twice-daily, 400-mg dose of MK-0518, which is the dose that has already been selected for further development, 69% of the patients with a phenotypic susceptibility score of 0 achieved viral loads below 400 copies/mL (in comparison to none in the placebo group). When these results are further stratified by the use or non-use of enfuvirtide, it appears that the use of enfuvirtide improved the MK-0518 response by an approximate 20% in all groups studied. All dosages were very well tolerated.

Slide by Beatrice Grinsztejn, M.D.; reprinted with permission.

Slide by Beatrice Grinsztejn, M.D.; reprinted with permission.

These are remarkable results for a drug that appears to not only be extremely well tolerated, but also has minimal drug interactions. Merck already opened an early expanded access program to make this very promising agent available to those most in need. The efficacy and safety of MK-0518 is also being evaluated in a head-to-head, naive study against efavirenz, both using tenofovir/emtricitabine (TDF/FTC, Truvada) as their backbone regimen. MK-0518 has a lot of potential to change treatment paradigms in the next few years. Its efficacy is clear, but data are now needed on sustained virologic responses beyond 24 weeks, resistance, sequentiability and safety. While we all wait for these data to come, it is extremely difficult not to get too excited about this promising drug.

Footnotes

1. Iwamoto M, Wenning LA, Petry AS, et al. Minimal effect of ritonavir (RTV) and efavirenz (EFV) on the pharmacokinetics (PK) of MK-0518. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract A-373.

2. Wenning LA, Hanley H, Stone J, et al. Effect of tipranavir + ritonavir (TPV + RTV) on pharmacokinetics of MK-0518. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract A-374.

3. Wenning LA, Friedman E, Kost JT, et al. Lack of a significant drug interaction between MK-0518 and Tenofovir Disoproxil Fumarate (TDF). In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract A-375.

4. DeJesus E. HIV antiretroviral agents in development. The Body/The Body Pro. March 30, 2006.

5. Grinsztejn B, Nguyen B, Katlama C, et al. Potent efficacy of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus: 24-week data. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1670b.
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