MK-0518 demonstrates potent efficacy in patients with triple-class resistant virus: 24 week results
Edwin DeJesus, for thebody.com
This is the third major international HIV-related conference this year (including 13th Conference on Retroviruses and Opportunistic Infections [CROI] in Denver and the XVI International AIDS Conference this past August in Toronto) in which impressive data have been presented on the safety and efficacy of MK-0518 on various patient populations.
Integrase is an HIV enzyme that allows the 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 new target makes 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. The primary metabolism is via glucuronidation (UGT1A1), and it is not a potent inhibitor or inducer of CYP3A4; thus it does not require ritonavir (RTV, Norvir) boosting. For the same reason, the expected pharmacokinetics interactions are minimal. In fact, several pharmacokinetic drug interaction studies presented at this conference demonstrated very small changes on the MK-0518 pharmacokinetics when coadministered with efavirenz (EFV, Sustiva, Stocrin), ritonavir, tipranavir (TPV, Aptivus) or tenofovir DF (TDF, Viread), which did no 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 had been initially presented at CROI this past February. In fact, I also reported on that study.  At ICAAC we had the opportunity to view the 24-week results of this multicenter, international study  in which almost 200 heavily treatment-experienced patients with widespread HIV drug resistance were randomised to three different twice-daily dosages of MK-0518 (200 mg, 400 mg, 600 mg) versus placebo, plus an optimised background regimen.
The phenotypic susceptibility score in almost 50% of patients was 0, and 20-28% of the patients used enfuvirtide (EFN, 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 lack of efficacy in comparison to 67% in the placebo arm. Discontinuation due to adverse events was rare.
Table 1: Virological responses at 24 weeks
|n||MK-1054 200mg||MK-1054 400mg||MK-1054 600mg||Placebo|
|% >1 log10||77||80||80||18|
|% <400 copies/mL||70||73||71||16|
|% <50 copies/mL||65||57||67||14|
This chart above summarizes the proportion of patients achieving HIV RNA below 50 copies/mL in an ITT analysis. The responses seen with all dosages studied are superior to the responses seen with placebo and an optimised background regimen.
On the 400-mg twice-daily group, which is the dose that has already been selected for further development, 69% of the patients with a PSS = 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 not of enfuvirtide, it appears that enfuvirtide improved the MK-0518 response by an approximate 20% in all groups studied. All dosages were very well tolerated.
These are remarkable results for a drug that appears to be not only extremely well tolerated, but has minimal drug interactions. Merck already opened an early expanded access to make this very promising agent available for the most needed population. The efficacy and safety of MK-0518 is also being evaluated in a head-to-head naive study against efavirenz, both using tenofovir DF/emtricitabine FDC (Truvada as backbone). This drug has a lot of potential to change treatment paradigms in the next few years. Its efficacy is clear; but data is 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.
- 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 Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract A-373.
- 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 Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract A-374.
- 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 Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract A-375.
- DeJesus E. Coverage of the 13th Conference on Retroviruses and Opportunistic Infections for The Body PRO.
- Grinsztejn B, Nguyen B, Katlama C. 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 Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1670b.