DOVATO: label updates to include new indication and long-term data

FDA approved changes to the DOVATO (dolutegravir/lamivudine) product labeling to include a new indication and provide longer term (96 week) safety and efficacy data from the GEMINI 1 and 2 trials. A summary of the major changes to the product labeling is as follows: INDICATIONS AND USAGE DOVATO is to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DOVATO. ADVERSE REACTIONS This section was updated to provide the 96-week safety data from GEMINI-1 and 3 trials. Compared to the Week 48 data, the rates of adverse events leading to discontinuation increased from 2% to 3% at Week 96. The rates for the adverse reactions (all grades) reported in > 2% of subjects in any treatment group remained the same, with one exception, anxiety was added and reported in 2% and 1% of subjects randomized to dolutegravir+lamivudine vs dolutegravir/lamivudine/tenofovir disoproxil fumarate, respectively. Minor changes were made to the Selected Laboratory Abnormalities table and mean change from baseline in fasted lipids table and text and changes in serum creatinine. Clinical Trials in Virologically Suppressed Adults subsection was added and includes: The safety of DOVATO in virologically suppressed adults was based on Week 48 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 200 weeks. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials CLINICAL STUDIES This section was updated with the 96-week data from GEMINI-1 and 2 and the 48-week data from TANGO as follows. Clinical Trial Results in HIV-1–Infected Adult Subjects with No Antiretroviral Treatment History Week 96 outcomes (including outcomes by key baseline covariates) for the pooled GEMINI-1 and GEMINI-2 trials are shown in Table 11. The results of the pooled analysis are consistent with the results from the individual trials, for which the secondary endpoint is the difference in proportion of subjects with plasma HIV-1 RNA <50 -4.9="" -6.4="" -9.8="" 0.0="" 2.7="" 84="" 88="" 89="" 90="" 96="" adjusted="" algorithm="" and="" any="" associated="" at="" based="" ci:="" copies="" difference="" div="" dolutegravir="" epivir="" for="" gemini-1="" gemini-2.="" gemini="" group="" had="" hiv-1="" in="" ml="" no="" nrtis.="" of="" on="" or="" plasma="" plus="" proportions="" receiving="" resistance="" respectively="" rna="" snapshot="" subjects="" substitutions="" the="" tivicay="" to="" treatment-emergent="" truvada.="" truvada="" versus="" was="" week="" were="" with="">

The primary endpoint was assessed at Week 48 and the virologic success rate was 91% in the group receiving TIVICAY plus EPIVIR and 93% in the group receiving TIVICAY plus TRUVADA, with a treatment difference of -1.7% (95% CI: -4.4%, 1.1%) in the pooled data. The results of the pooled analysis are similar to the individual trials, for which the primary endpoint (proportion of subjects with plasma HIV-1 RNA <50 -0.7="" -2.6="" 1.5="" 2.9="" 48="" adjusted="" algorithm="" and="" at="" based="" ci:="" copies="" difference="" div="" epivir="" for="" gemini-1="" gemini-2.="" met.="" ml="" on="" plus="" snapshot="" the="" tivicay="" truvada="" versus="" was="" week=""> Virologic outcomes by baseline CD4+ (cells/mm3) in GEMINI-1 and GEMINI-2 at Week 96 are shown in Table 12. In both trials, lower response rates (HIV-1 RNA <50 baseline="" cd4="" cells="" copies="" div="" findings="" hiv-1="" in="" irrespective="" ml="" mm3.="" observed="" of="" plasma="" rna.="" seen="" subjects="" these="" were="" with="">

The adjusted mean change from baseline in CD4+ cell count based on the pooled analysis at Week 96 was 269 cells/mm3 for the group receiving TIVICAY plus EPIVIR and 259 cells/mm3 for the group receiving TIVICAY plus TRUVADA. Clinical Trial Results in HIV-1–Infected Virologically Suppressed Adult Subjects Who Switched to DOVATO The efficacy of DOVATO in HIV-1–infected, antiretroviral treatment-experienced, virologically suppressed subjects is supported by data from a 200-week, Phase 3, randomized, open-label, multicenter, parallel-group, non-inferiority controlled trial (TANGO). A total of 741 adult HIV-1–infected subjects who were on a stable suppressive TBR received treatment in the trial. Subjects were randomized in a 1:1 ratio to receive DOVATO once daily or continue with their TBR for up to 200 weeks. Randomization was stratified by baseline third-agent class (protease inhibitor [PI], INSTI, or non-nucleoside reverse transcriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA ≥50 copies/mL (virologic non-response) at Week 48 (Snapshot algorithm adjusting for randomization stratification factor). At baseline, the median age of subjects was 39 years, 8% were female, 21% non-white, 5% were CDC Class C (AIDS), and 98% of subjects had baseline CD4+ cell count ≥200 cells/mm3; these characteristics were similar between treatment arms. Subjects receiving DOVATO and a TBR had been on an antiretroviral regimen for a median of 2.8 and 2.9 years, respectively, prior to Day 1. Most subjects were on an integrase inhibitor-based TBR (78% and 80% of subjects who received DOVATO and a TBR, respectively). In the primary analysis, <1 13="" 48="" able="" algorithm="" arms="" at="" based="" both="" copies="" div="" experiencing="" failure="" in="" ml="" of="" on="" rna="" snapshot="" subjects="" the="" virologic="" week="">

In TANGO, treatment outcomes between treatment arms were similar across the stratification factor, baseline third-agent class (PI, INSTI, or NNRTI), and across subgroups by age, sex, race, baseline CD4+ cell count, CDC HIV disease stage, and countries. The median change from baseline in CD4+ count at Week 48 was 22.5 cells/mm3 in subjects who switched to DOVATO and 11.0 cells/mm3 in subjects who stayed on the TBR.

The label will soon be available at Drugs@FDA or DailyMed. Kimberly Struble Division of Antivirals Food and Drug Administration