The Food and Drug Administration (FDA) has issued a complete response letter to ViiV Healthcare declining approval of the long-acting injectable antiretroviral (ARV) regimen Cabenuva (cabotegravir/rilpivirine). The federal agency’s decision involved concerns regarding the two-drug regimen’s chemistry and manufacturing controls.

According to ViiV, the pharmaceutical company will work closely with the FDA to determine what’s needed to get Cabenuva approved.

This surprise move—the FDA has rarely declined approval for new ARV applications—puts off what was to be the launch of a new era of HIV treatment, which for nearly a quarter century has been based on all-oral regimens of daily pills. For people who have trouble adhering to such regimens, long-acting injectable treatment may one day offer a better way to ensure they keep their virus fully suppressed. 

Cabenuva requires a monthly clinic visit to receive an intramuscular (into the muscle) injection by a health care provider.

The regimen contains Janssen’s non-nucleoside reverse transcriptase inhibitor rilpivirine, which is sold in daily oral pill form as Edurant, and ViiV’s new integrase inhibitor cabotegravir. ViiV has also applied for approval of a daily pill form of cabotegravir to serve as an oral lead-in to the injectable regimen.

In clinical trials, to start Cabenuva treatment, people with HIV first took a daily oral regimen of Edurant and cabotegravir before transitioning to monthly injections. During this period, they were monitored for safety. The long-acting formulation has a long “tail,” meaning that it can linger in the body for months. So if individuals were to have a bad reaction to either of the drugs in the regimen while on the injectable version, they could only wait for the drug to slowly dissipate.

ViiV’s FDA application was based on findings from the Phase III ATLAS and FLAIR studies, which were presented in March at the 2019 Conference on Retroviruses and Opportunistic Infections in Seattle. ATLAS included people who were already taking standard oral ARV treatment before entering the trial, while FLAIR included treatment first-timers.

Between them, the trials had more than 1,100 HIV-positive participants from 16 nations. After 48 weeks of treatment, Cabenuva suppressed the virus as effectively as a standard daily oral triple-ARV regimen.

Cabenuva proved well tolerated, and the trial participants reported high levels of satisfaction with the regimen, greatly preferring it to taking daily pills. The treatment was commonly associated with injection site reactions, including pain. But these effects were generally mild or moderate and resolved quickly. Just 1% of the trial members withdrew from the studies because of such reactions.

To read a press release about the FDA’s decision, click here.