HIV and Hepatitis.com Coverage of the
14th Annual Conference on Retroviruses
and Opportunistic Infections (14th CROI)
February 25 - 28, 2007, Los Angeles, CA
CCR5 Antagonist Maraviroc Shows Good Activity Against HIV in Two 24-week Studies

By Liz Highleyman

This week at the 14th Conference on Retroviruses and Opportunistic Infections in Los Angeles, researchers presented the latest data on 2 experimental antiretroviral drugs that work by novel mechanisms:

- Pfizer CCR5 antagonist maraviroc

- Merck integrase inhibitor raltegravir (formerly MK-0518)

In a press conference on Tuesday, John Mellors, MD, of the University of Pittsburgh said that the latest findings are the most exciting developments since the advent of protease inhibitors in the mid-1990s, especially for highly treatment-experienced patients.

Maraviroc Data

Researchers presented data from MOTIVATE-1 and MOTIVATE-2, identical randomized, controlled Phase IIb/III trials of heavily treatment-experienced subjects with triple-class antiretroviral resistance. MOTIVATE-1 included 601 participants in North America; MOTIVATE-2 included 475 subjects in Europe, Australia, and the U.S.

Participants across arms were generally similar. About 90% were men, with a mean age of about 45 years. The median CD4 cell count was 150-180 cells/mm3 and the mean HIV viral load was about 65,000 copies/mL.

Subjects were randomly assigned to receive oral maraviroc at doses of 150 mg once-daily (QD) or 150 mg twice-daily (BID), or else placebo, in combination with an optimized background regimen. Those whose background regimen included a boosted protease inhibitor, excluding tipranavir (Aptivus), or delavirdine received maraviroc QD; all others received the study drug BID. About 40% of patients were also taking enfuvirtide (T-20; Fuzeon); 62-76% in the various arms had 2 or fewer other active drugs in their regimens.

Results from 24 weeks of follow-up were available for all participants. Both studies are planned to continue through 48 weeks.

Results

• In both studies, virological response rates were about twice as high in the maraviroc arms compared with the placebo arms.

• After 24 weeks, 45.6-48.5% of patients in the maraviroc BID arms and 40.8-42.2% in the maraviroc QD arms achieved viral loads below 50 copies/mL, compared with 20.9-24.6% in the placebo arms (P < 0.0001).

• For HIV RNA below 400 copies/mL, the corresponding figures were 60.4-61.3%, 54.7-55.5%, 23.1-31.4% (P < 0.0001).

• The mean decreases in HIV RNA from baseline were:

- 1.95-1.97 log copies/mL in the maraviroc BID arms;
- 1.82-1.95 log copies/mL in the maraviroc QD arms;
- 0.93 1.03 log copies/mL in the placebo arms.

• Among patients with no active background drugs, in the 2 studies combined, 29% in the maraviroc BID arms, 18% in the maraviroc QD arms, and 3% in the pacebo arms achieved virological suppression.

• Response did not differ according to baseline viral load or use of enfuvirtide.

• Participants who also received enfuvirtide experienced improved virological response.

• CD4 cell counts increased from baseline by 102-111 and 107-112 cells/mm3 in the maraviroc BID and QD arms, respectively, compared with 52-64 cells/mm3 in the placebo arms.

• Fewer patients in the maraviroc arms experienced treatment failure compared with placebo.

• However, more patients in the maraviroc arm experienced a shift in HIV co-receptor usage from CCR5-tropic to CXCR4-tropic or dual/mixed tropism.

• Adverse event profiles were similar in both maraviroc arms and the placebo arm.

• 4% of patients discontinued due to adverse events in the maraviroc BID arm, and 5% in both the maraviroc QD and placebo arms.

Conclusion

The researchers concluded that both once-daily and twice-daily maraviroc "demonstrated significantly greater virologic suppression compared to placebo" when used in combination with optimized background therapy.

Side effects have been a concern with CCR5 antagonists, since the normal function the receptor and the consequences of blocking it long-term are not well understood. In these studies, there were no signs of significant liver toxicity, which led to the discontinuation of development of another CCR5 inhibitor candidate, aplaviroc, in 2005.

Pfizer has already applied for U.S. and European approval of maraviroc. The Food and Drug administration recently announced that the agency will Meet on April 24, 2007 to review the application.

03/02/07

References

M Nelson, G Fatkenheuer, I Konourina, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia and North America: 24 week results. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Los Angeles, February 25-28, 2007. Abstract 104aLB.

J Lalezari, J Goodrich, E DeJesus, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24 week results from a phase 2b/3 study in the US and Canada. 14th CROI. Los Angeles, February 25-28, 2007. Abstract 104bLB.












































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