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New HIV Drug: FDA Approves Dolutegravir (Tivicay)

, by Reilly O'Neal

PillBottleSunburstCROPA new HIV drug—ViiV Healthcare’s next-generation integrase inhibitor dolutegravir, now marketed as Tivicay—is headed to pharmacy shelves following yesterday’s approval by the United States Food and Drug Administration.

Dolutegravir is only the second stand-alone integrase inhibitor to win FDA approval. (The integrase inhibitor elvitegravir is approved as part of the Stribild combo pill but is still under FDA review as a stand-alone agent.) Integrase inhibitors work by interrupting a critical stage of the viral lifecycle when the virus integrates its own genetic material with that of the human cell it is infecting. By stopping this key step, dolutegravir and other integrase inhibitors help suppress viral replication and keep HIV in check in the body.

Learn more about the science behind dolutegravir and other developments in the HIV drug pipeline.

The new drug’s approval follows a series of advanced clinical trials in which dolutegravir worked better than other HIV meds in people taking antiretrovirals for the first time and in those whose current therapy was no longer working. In these studies, drug-related adverse events (side effects) were similar between dolutegravir and the comparator medications, and the drug was generally safe and well tolerated. Dolutegravir also worked well in people whose virus had developed resistance to other HIV medications.

For people new to HIV treatment or with no prior use of integrase inhibitors, the indicated dose is one 50-mg pill once daily. A twice-daily 50-mg dose is indicated for those with known or suspected resistance to integrase inhibitors, as well as for people who are simultaneously taking the HIV meds efavirenz, fosamprenavir/ritonavir, or tipranavir/ritonavir, or the antiviral rifampin (medications that may affect how the body metabolizes dolutegravir). Complete prescribing information for dolutegravir is available online from ViiV Healthcare.

ViiV expects its new drug to hit pharmacy shelves in about two weeks. At upwards of $14,000 per year, the newly approved medication doesn’t come cheap; however, the response from advocates with the Fair Pricing Coalition has been fairly positive. “While the Fair Pricing Coalition (FPC) believes that all HIV drugs are priced too high, we are satisfied that ViiV Healthcare’s WAC price for Tivicay (dolutegravir), its new integrase inhibitor, is $14,105 per year, $1,037 less than its nearest competitor,” the group noted in a statement released August 13.

Looking for help paying for your HIV meds? Most pharma companies offer patient assistance programs. Click here to learn more about these important resources.

Given that clinical trials demonstrated the drug’s superior efficacy, and given that its low dose makes it a candidate for future combination pills, the pharmaceutical company could have been expected to price its new drug much higher, the FPC adds. “ViiV could easily have followed the pernicious industry model of charging what the market will bear,” stated coalition member David Evans. “While we are not condoning the exorbitant price of antiretroviral therapy, it is important to note that some other HIV companies have initially priced their new drugs with similar improvements much higher than their leading competitor.”

ViiV Healthcare’s  press release announcing the approval of dolutegravir—and detailing the studies supporting it—is excerpted below and can be found in full online.

ViiV Healthcare announces U.S. approval of Tivicay (dolutegravir) for the treatment of HIV-1

London, UK, 12 August, 2013

ViiV Healthcare is pleased to announce today that the U.S. Food and Drug Administration (FDA) has approved Tivicay (dolutegravir) 50-mg tablets. Tivicay is an integrase inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 in adults and children aged 12 years and older weighing at least 40 kg (approx. 88 lbs).

…The submission included data from four pivotal Phase III clinical trials that treated 2,557 adults (who received at least one dose of study medication) with HIV across the treatment spectrum; it also included data in children aged 12 years and older. Tivicay was used without a pharmacokinetic boosting agent. Tivicay can be taken with or without food and at any time of the day….

About the Phase III Clinical Trial Programme

SPRING-2 was a study evaluating once-daily Tivicay versus twice-daily raltegravir in 822 HIV-infected, treatment-naïve patients, in each case in combination with a fixed-dose dual-NRTI treatment. At week 48, the proportion of study participants who were virologically suppressed (HIV-1 RNA <50 c/mL) was 88% for the regimen containing Tivicay and 86% for the regimen containing raltegravir, meeting the 10% non-inferiority criteria. The tolerability of Tivicay was similar to that of raltegravir, with adverse events leading to withdrawal at 2% in both arms. There were no treatment-emergent adverse drug reactions of at least moderate intensity (Grades 2 to 4) and ≥2% frequency in the Tivicay or raltegravir arms in SPRING-2.

No treatment-emergent genotypic resistance to Tivicay or the background regimen was seen in the Tivicay arm in SPRING-2.

SINGLE was a study evaluating once-daily Tivicay plus abacavir/lamivudine versus the single tablet regimen Atripla in 833 HIV-infected, treatment-naïve patients. At 48 weeks, the proportion of study participants who were virologically suppressed (HIV-1 RNA <50 c/mL) was 88% for the Tivicay regimen and 81% for Atripla. This difference was statistically significant. Overall, 2% of subjects on the Tivicay-based regimen discontinued due to adverse events versus 10% of those receiving the Atripla regimen.

For Tivicay, treatment-emergent adverse drug reactions of at least moderate intensity (Grades 2 to 4) and ≥2% frequency in SINGLE were insomnia (3%) and headache (2%). Treatment-emergent adverse drug reactions of at least moderate intensity (Grades 2 to 4) and ≥2% frequency for Atripla were rash (6%), dizziness (5%), nausea (3%), and insomnia, abnormal dreams, headache, diarrhoea, and vertigo (2%).

No treatment-emergent genotypic resistance that resulted in reduced susceptibility to either Tivicay or the background regimen was seen in the Tivicay arm in SINGLE.

SAILING was a study evaluating once-daily Tivicay versus twice-daily raltegravir in 719 patients with HIV who were failing on current therapy, but had not been treated with an integrase inhibitor, in each case in combination with an investigator-selected background regimen consisting of up to two agents, including at least one fully active agent. At week 24, 79% of patients on the regimen containing Tivicay were virologically suppressed (HIV-1 RNA <50 c/mL) versus 70% of patients on the regimen containing raltegravir. This difference was statistically significant. Overall, the tolerability of Tivicay was similar to that of raltegravir, with adverse events leading to withdrawal at 2% for the Tivicay regimen versus 4% for the raltegravir regimen. There were no treatment-emergent adverse drug reactions of at least moderate intensity (Grades 2 to 4) and ≥2% frequency in the Tivicay arm. The only treatment-emergent adverse drug reaction of at least moderate intensity (Grades 2 to 4) and ≥2% frequency in the raltegravir arm was diarrhoea (2%). Viruses from five of 15 subjects in the Tivicay arm with post-baseline resistance data had evidence of treatment-emergent genetic changes (integrase substitutions). However, none of these patients had decreases in susceptibility to either Tivicay or raltegravir.

VIKING-3 was a study evaluating twice-daily Tivicay in 183 HIV-infected adults currently on medication whose HIV was resistant to multiple classes of HIV medicines, including integrase inhibitors (raltegravir and/or elvitegravir). In the study, mean HIV RNA levels declined by 1.4 log10 c/mL after seven days of treatment with the addition of Tivicay to their background regimen. The proportion of study participants who were subsequently virologically suppressed (HIV-1 RNA <50 c/mL) with the addition of Tivicay to their background regimen was 63% at week 24. However, poor virologic response was observed in subjects treated with Tivicay twice daily with an integrase strand transfer inhibitor (INSTI) resistance called Q148 plus two or more additional INSTI resistance substitutions. The rate of adverse events leading to discontinuation was 3% of subjects at week 24. Treatment-emergent adverse drug reactions in VIKING-3 were generally similar compared with observations with the once-daily, 50-mg dose in Phase III trials of adult patients…

Click here to read the full ViiV press release, including important safety information about dolutegravir (Tivicay).

Reilly O’Neal is a freelance writer and former editor of BETA.

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