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Dolutegravir Active against Raltegravir-resistant HIV, Granted FDA Priority Review

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ViiV Healthcare announced last week that the U.S. Food and Drug Administration has given a priority review designation for its investigational HIV integrase inhibitor dolutegravir, which has demonstrated good efficacy in both treatment-naive and treatment-experienced people.

Integrase inhibitors work by preventing HIV from inserting its genetic material into host cell chromosomes. Dolutegravir (formerly S/GSK1349572) is a once-daily integrase inhibitor that does not require pharmacokinetic boosting. Studies have shown that it is well-tolerated, has low potential for drug-drug interactions, and has a unique resistance profile.

As recently reported, the Phase 3 SPRING-2 study found that dolutegravir worked as well as the sole approved integrase inhibitor, raltegravir (Isentress), for people starting antiretroviral treatment for the first time. 

Now, 24-week results from a Phase 2b trial of treatment-experienced patients with raltegravir-resistant virus have been published in the March 1, 2013, advance edition of the Journal of Infectious Diseases.

Joseph Eron and fellow investigators with the VIKING Study Group enrolled HIV positive adults with genotypic evidence of raltegravir resistance. First, they received 50 mg oral dolutegravir either once-daily (Cohort I, 27 people) or twice-daily (Cohort II, 24 people) as "functional monotherapy" while continuing on their current failing antiretroviral regimen without raltegravir for 10 days. At that point, participants' background regimens were optimized if feasible for Cohort I, while people in Cohort II had to be able to include at least 1 fully active drug.

Most participants (93% in Cohort I, 75% in Cohort II) were men, about 80% were white, and the median age was 48 years. On average, they had been on antiretroviral therapy for about 14 years and had taken 16 drugs; about 80% were on failing raltegravir at baseline. Median CD4 T-cell counts were approximately 100 cells/mm3 in Cohort I and 200 cells/mm3 in Cohort II, indicating considerable immune suppression.

Results

  • Overall, rapid antiviral response was observed.
  • On day 11, 78% of participants in the once-daily cohort and 96% in the twice-daily cohort had HCV RNA < 400 copies/mL or at least a 0.7 log drop from baseline.
  • At week 24, 41% of participants in Cohort I and 75% in Cohort II had undetectable viral load < 50 copies/mL.
  • Emergence of further integrase resistance mutations was uncommon, occurring in fewer than 15% of patients.
  • Dolutegravir was generally safe and well-tolerated, with similar safety profiles in both dose arms.

"Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen," the study authors concluded. "These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to raltegravir."

While these were the first such results to be published in full, data from the Phase 3 VIKING-3 trial of treatment-experienced people with extensive drug resistance -- including to raltegravir -- were presented late last year at the International Congress on Drug Therapy in HIV Infection (HIV11) in Glasgow.

According to a recent ViiV press release, the FDA has assigned dolutegravir a Prescription Drug User Fee Act (PDUFA) target date of August 17, 2013. Priority review designation is granted to drugs that treat conditions with no existing adequate therapies or that have the potential to offer significant improvement over existing products on the market.

2/20/13

Reference

JJ Eron, B Clotet, J Durant, et al (VIKING Study Group). Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects with Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study. Journal of Infectious Diseases 207(5):740-748. March 1, 2013.

Other Source

ViiV Healthcare. ViiV Healthcare Announces FDA Priority Review Designation for Dolutegravir as a Potential Treatment for HIV Infection. Press release. February 15, 2013.