Merck-Gilead Drug Duel Is Heating Up

Drug Details

To that end, Merck and Gilead have developed drugs that fight HIV by inhibiting integrase. Specifically, integrase is the enzyme responsible for allowing viral DNA to enter the nucleus of the host cell and integrate into the host cell genome. Clinical data presented so far by both companies have excited HIV researchers because integrase inhibitors appear to be very effective in fighting the virus with fewer side effects than current HIV medicines.

Merck's drug goes by the name MK0518. At the CROI meeting, Merck will present for the first time clinical data from two phase III studies testing MK0158 in combination with other HIV drugs in treatment-experienced HIV patients. Said another way, these are patients in whom the virus has developed resistance to certain current HIV drugs.

Merck has already announced plans to seek approval of MK0158 with the Food and Drug Administration in the middle of the year. MK0518 could be approved and on the market by early next year, if Merck proceeds on plan.

Gilead's integrase inhibitor is called GS 9137. At CROI, data will be presented from a phase IIb study of GS 9137, also in treatment-experienced HIV patients. Gilead has already stated that it will start phase III studies of GS 9137 in mid-2007. If so, data should be available in mid-2008 and the drug could be approved in early 2009.

As in all HIV drug studies, the efficacy of both integrase inhibitors will be measured by the reduction in viral load. The gold standard is the percentage of patients who reach the detection limit of less than 50 copies per millileter. Such patients are deemed to have "undetectable" viral loads. Because current HIV treatment regimens get patients to undetectable levels, the safety profile of new HIV drugs is also very important, if not more important.

In Merck's phase IIb study, previously announced, between 57% and 67% of patients taking MK0518 were able to reduce their viral load to undetectable levels, compared with 14% of placebo patients. For the most part, this is the efficacy standard with which Gilead's GS 9137 will be compared when its data are presented next week. (Some differences in the design and conduct of the Gilead study will make comparison difficult.)

On the safety side, both drugs have looked relatively clean, although a handful of patients in previous MK0158 studies developed potential liver toxicity while on the drug. Any signal of future problems with liver toxicity with be carefully scrutinized in the Merck data to be presented next week.

Apart from that, the major difference between the two drugs is the way they are administered. Merck's MK0518 is taken twice daily; Gilead's GS9137 is taken once a day, although it must be given with a 100 milligram dose of ritonavir, another HIV drug that helps boost the therapeutic effect.

The race to get the first integrase inhibitor approved is not a winner-take-all game. As I said, safety and tolerability of the drugs is just as important as efficacy. And while Merck's drug now appears headed toward first approval and sale, doctors will be most likely to prescribe it to patients in combination with Gilead's core HIV regimen, Truvada. (Merck's phase III studies of MK0518 use Gilead's Truvada as the backbone regimen for patients.)

And because GS 9137 is a once-daily pill, Gilead could co-formulate it with Truvada to create a single-pill therapy. Gilead did just that recently with Atripla, which combines Truvada with the Bristol-Myers Squibb(BMY Quote) drug Sustiva. Generally speaking, HIV patients prefer once-daily treatment regimens.

Below is a chart, recreated in part from a Jefferies & Co. report, that compares the drugs from Merck and Gilead Sciences:

HIV-1 Integrase Inhibitors: MK0158 vs. GS 9137
Product	MK0158	GS 9137
Company	Merck	Gilead Sciences
Dosing	Twice daily (BID)	Once daily (QD)
Status	Phase III begain in early 2006 (400 mg BID); NDA filing in 2Q '07 (for treatment-experienced patients); salvage indication.	Phase II 24-week efficacy and 48-week safety data in 1H '07; phase III to begin in mid-2007; potential approval by late-2008.
Reported/To-be-reported data	Phase IIB (n=179); interim results	Phase II (n=282)
Dose	200 mg, 400 mg or 600 mg (BID) of MK 0518 or placebo (BID); all arms with optimized background therapy including protease inhibitors.	50 mg, 125 mg of GS9137 boosted with 100 mg of ritonavir (QD) or placebo. All arms with optimized background therapy, including protease inhibitors.
Patient characteristics	Prior use of ARTs for median of nine years for all groups; resistant to at least one each NRTI, NNRTI and PI; baseline viral load = mean of 4.6-4.8 log1o copies/ml; baseline CD4 counts = mean of 220-274 cells/uL.	Failed at least one class of ART and resistant to at least one PI (heavily treatment-experienced.)
Placebo:Drug	undisclosed	undisclosed
Length of study	48-week study with 24-week efficacy endpoint	48-week study with 24-week efficacy endpoint
Primary endpoint	viral load reduction below 400 copies/ml and 50 copies/ml	Time-weighted average change in viral load from baseline
Data at 24 weeks	less than 50 copies/ml: 57-67% for all doses vs. 14% for placebo; less than 400 copies: 70-73% for all doses vs. 16% for placebo	TBA
Adverse events	Generally well tolerated (comparable to placebo arm); most common AEs: diarrhea, nausea, fatigue, headache, itching. Four patients dropped due to AEs.	TBA
Source: Jefferies & Co.