PI Perspective #48

March 2009     View PDF     En español

Two newcomers may challenge ritonavir's position as the only booster for HIV therapy

Two companies announced development of boosters, or pharmaceutical enhancers, that could replace ritonavir's sole position in that role. These enhancers, when used to treat HIV disease, increase the level of other HIV drugs in the blood, thereby bolstering their potency by increasing the length of time those drugs remain active and at optimal levels to fight HIV.

Currently, ritonavir is co-formulated as a booster with lopinavir and sold as Kaletra, but it's also recommended as a booster for other protease inhibitors to augment their anti-HIV activity. However, ritonavir has a rather long list of troublesome side effects and drug interactions. The prospect of having other boosting compounds to choose from without these confounding side effects from ritonavir would be welcomed by many.

Both companies report that their compounds are not active against HIV, as is ritonavir. Also, while both compounds seem to inhibit the same liver enzyme (P450 [CYP3A]) as ritonavir, their sponsors claim they do this in a more specific way, which they contend will be beneficial at the end of the day. Moreover, it's asserted that these compounds will not affect lipid or glucose levels, which hopefully will result in fewer metabolic changes and fewer cases of elevated blood fats or insulin resistance. Only further study will whether either of these claims is true.

Gilead's GS-9350

Gilead Sciences reported results from two phase I proof-of-concept studies of GS-9350 and theorized on its possible co-formulation with their experimental integrase inhibitor, elvitegravir. Gilead is positioning GS-9350 to be co-formulated with elvitegravir and their combination pill Truvada (tenofovir + emtricitabine) as a single pill competitor to Atripla. Atripla is currently the only one-pill, once-a-day regimen. Atripla contains 2 NRTIs and 1 NNRTI while Gilead's proposed combination is an integrase inhibitor combined with 2 NRTIs plus the booster.

A single and 14-day multiple dose escalating study compared 18 people taking 50, 100 or 200mg of GS-9305 once a day to 18 people on 100mg ritonavir on the ability of the drug to block P450. The two higher doses performed at equal levels to ritonavir. No one experienced grade 4 adverse events or grade 3 or 4 lab abnormalities. The GS-9305 did not appear to impact fats (lipids) or sugar (glucose).

In the partially randomized study (GS-236-0101), GS 9350 was given together with elvitegravir and Truvada in 44 volunteers. The regimen was compared to ritonavir + elvitegravir + Truvada at 100 and 150mg doses of GS 9350. The 150mg dose was comparable in effect as ritonavir. The only grade 3 or 4 adverse event occurred in one volunteer.

Gilead is planning to start this year a phase II study of this one-pill, once daily regimen in people going on first line therapy. The company is also planning to study GS-9350 as a booster for several protease inhibitors such as Prezista (darunavir) and has already started lab study of the booster with Reyataz (atazanavir).

Sequoia's SPI-452

In laboratory studies, SPI-452 by Sequoia Pharmaceuticals shows no added HIV activity and comparable activity to ritonavir when combined with 8 protease inhibitors in addition to an HCV drug. Like Gilead's compound, SPI-452 showed strong inhibition of the P450 enzyme.

Phase I of the first proof-of-concept study (0452-001) followed 47 people divided into 6 groups, with each group getting doses ranging from 25–600mg. Phase II included 10 volunteers in each of two arms comparing three different once-a-day regimens: SPI-452 + saquinavir, saquinavir + placebo, or placebo + placebo.

From these two phases of the first study, the compound was considered generally safe though 19 people experienced 1 or more adverse events such as headache, which were usually mild. Based on the results, the 25, 50 and 200mg doses were moved forward into a second proof of concept study in regimens with darunavir and atazanavir. In the second study, 45 experienced 1 or more adverse events such as headache, nausea or diarrhea.

Combining the data from both studies, the company reported that the compound appears to boost the activity of the protease inhibitors Prezista and Reyataz comparable to ritonavir while also being a potent inhibitor of P450. And, like Gilead's compound, SPI-452 seems to have a tolerable side effects profile and does not significantly alter lipid levels.

The results show promise for long overdue competitors to ritonavir. Though these proof-of-concept studies may not result in an actual booster for another year or two, they nevertheless represent a positive step in improving the safety and efficacy of HIV drugs taken today.