March 7, 2011
At CROI 2011, Joe Eron, M.D., presented new dosing and efficacy phase 2b data on the experimental integrase inhibitor dolutegravir (also known as S/GSK1349572 or just "572"), under development by GlaxoSmithKline (GSK).
Prior data were presented in Vienna, Austria, at the XVIII International AIDS Conference from VIKING I, a cohort of HIV-infected volunteers with resistance to the integrase inhibitor raltegravir (RAL, Isentress) who replaced their raltegravir with 50 mg of dolutegravir once a day. The study showed that patients with one or more Q148+ associated integrase mutations had reduced activity to the drug. As a result, GSK decided to recruit a second cohort of patients who took 50 mg twice a day in hopes that the increased blood levels would overcome some of this lower efficacy. (Despite a long half-life supporting once-daily dosing, the lack of a dose proportional increase in exposure above 50 mg precluded using 100 mg once daily instead of 50 mg twice daily.) Interim results from that new cohort, called VIKING II, were presented at CROI 2011.
Adult patients with HIV-1 RNA at or above 1,000 copies/mL showing genotypic resistance to raltegravir and to at least two other antiretroviral classes received 50 mg twice daily of dolutegravir while continuing their failing regimen (without raltegravir) to day 11, after which the background regimen was optimized with another active agent. Unlike the previously presented 50-mg once-daily cohort (VIKING I), eligibility for VIKING II required at least one fully active antiretroviral for day 11 optimization.
Dolutegravir was generally well tolerated: Mild to moderate diarrhea was the most common adverse event (n = 6), while one patient experienced two severe adverse events (demyelinating polyneuropathy at day 23 and diabetes mellitus at day 79), both of which were considered unrelated to the study drug.
Although the day 11 responses were numerically better in cohort II, the baseline fold change range in virus susceptibility to dolutegravir for cohort II was more limited due to extensive raltegravir-related mutations. Of the patients taking the 50-mg twice-daily dose, 46% had one or more Q148+ associated mutations that were associated with reduced response to the prior, 50-mg once-daily dose in cohort I. Longer-term (24-week) assessments in this phase 2b study are ongoing.
The data from cohort II provide promise for patients with extensive raltegravir resistance. However, many of these patients are in deep salvage with no remaining active antiretrovirals to construct a viable regimen, so even if dolutegravir works for them, they will still be faced with the challenge of finding another active agent. Fortunately, several companies are currently collaborating on an upcoming expanded access program that will allow these patients, who are at higher risk of disease progression and death, to obtain more than one active investigational drug without waiting three years for all of them to be approved. I will write about this project in future articles.
In addition to its evaluation in multidrug-resistant patients, dolutegravir will also be tested in treatment-naive patients in an upcoming head-to-head phase 3 trial with raltegravir (using a background of abacavir/lamivudine [ABC/3TC, Epzicom, Kivexa] or tenofovir/emtricitabine [TDF/FTC, Truvada]). When I first saw this study design schema, I thought it curious that GSK decided to include its nucleoside fixed-dose combination drug abacavir/lamivudine in its upcoming studies with dolutegravir, considering the combo drug's lack of preferred status in the U.S. Department of Health and Human Services (DHHS)'s antiretroviral treatment guidelines.
This decision started to make sense when GSK recently made an announcement that it will coformulate dolutegravir with abacavir/lamivudine in a pill called 572-Trii. This coformulation will likely compete with other once-a-day pills aimed at treatment-naive patients, including efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC, Atripla), the Quad pill that is in development and the rilpivirine/tenofovir/emtricitabine pill that is also in development.
However, the development of 572-Trii for approval as a first-line treatment still seemed risky, due to some compelling studies that had previously linked abacavir (ABC, Ziagen) to cardiovascular risk in patients with HIV. Even though other studies found conflicting results, these data were what compelled the DHHS antiretroviral guidelines panel to drop abacavir from its list of recommended nucleosides for treatment-naive, HIV-infected patients. Given this, how could GSK ensure that its future 572-Trii coformulation found a prominent place among those recommended first-line regimens?
In answer to my question, the U.S. Food and Drug Administration (FDA) presented a surprising poster on March 2 that reported no evidence of an association between abacavir and an increased risk of myocardial infarction. (I provide a more robust summary of that poster in this article.)
It is yet unknown if this new FDA report will enable abacavir to regain the "preferred" position in first-line treatment guidelines. But whatever the outcome will be for that nucleoside, the decision to pursue the new 572-Trii coformulation for treatment-naive patients may provide one more option in the growing arsenal of once-daily pills. Hopefully, this new competition among companies in the once-daily market will generate better pricing and worldwide access.
As the abacavir story unfolds, we await more efficacy and safety data in the next few months on dolutegravir's use in both treatment-naive and treatment-experienced patients.
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