A global HIV prevention study comparing a long-acting injectable antiretroviral from Viiv Healthcare Ltd. to a daily pill from Gilead Sciences Inc. has stopped early after Viiv's cabotegravir proved 69% more effective than the current standard of care, Gilead's Truvada (emtricitabine/tenofovir), in preventing HIV acquisition (95% CI 41%-84%).

Kimberly Smith, head of R&D, Viiv

With FDA approval for Gilead's Descovy (emtricitabine and tenofovir alafenamide) in 2019, some Americans gained a second once-daily option for HIV1 pre-exposure prophylaxis, though not without controversy. Yet, with an estimated 1.7 million people still newly diagnosed with HIV each year, "we're obviously not winning at the prevention game. We need better tools," Viiv's head of research & development, Kimberly Smith, told BioWorld.

"We know that Truvada works very well for individuals that take it consistently. But if you're not consistent at taking it, then you may be vulnerable," Smith said. "Whereas with cabotegravir, if you show up to the clinic and get your shot, you're good for two months," she said.

The study, run by the HIV Prevention Trials Network, enrolled HIV-negative men who have sex with men and transgender women who have sex with men, participants considered at risk for HIV acquisition. Two-thirds of them were under 30 years of age, and 12% were transgender women. Half of the participants in the U.S. identified as black or African American. Among them, 50 people acquired HIV. Twelve of them were on cabotegravir and 38 of them were on Truvada, translating to an HIV incidence rate of 0.38% (95% confidence interval [CI] 0.20%-0.66%) in the cabotegravir group and 1.21% (95% CI 0.86%-1.66%) in the Truvada group.

Adherence to Truvada during the study was high, based on a random subset sampling that detected tenofovir (> 0.31 ng/ml) in 87% of all samples tested, further highlighting the stark contrast between the two arms.

After completing an interim analysis of the study's data, a data safety monitoring board (DSMB) concluded the trial had "definitively shown cabotegravir was not only noninferior, but actually very, very close to superior," Smith said. Accordingly, the trial was stopped and all participants in the Truvada arm will be offered long-acting cabotegravir.

Viiv, an HIV specialist established in November 2009 by Glaxosmithkline plc and Pfizer Inc., has already sought the FDA's blessing for cabotegravir as part of a once-monthly, non-fixed-dose combination treatment for HIV with the long-acting non-nucleoside reverse transcriptase inhibitor rilpivirine, a product of Johnson & Johnson. The combination was already approved by Health Canada under the trade name Cabenuva in March. But in the U.S., it received a complete response letter in December 2019 over a manufacturing issue. Smith said Viiv's team expects to refile the Cabenuva NDA at midyear, positioning it for a potential FDA approval either later this year or early next year. An MAA remains under consideration in Europe.

A crucial class

HIV integrase strand transfer inhibitors are a class of drugs that block the virus' ability to integrate itself into a host genome. The first to win FDA approval was Merck & Co. Inc.'s Isentress (raltegravir) in October 2007. Since then, they've become an essential tool in the fight against the virus and more plentiful, too: Both Viiv's Tivicay (dolutegravir) and Vitekta (elvitegravir) have entered the U.S. and global markets, broadening patients' options and, in Tivicay's case, generating billions in revenue for Viiv.

Like Gilead's Biktarvy (bictegravir), a medicine the FDA has approved in a fixed-dose combination with the nucleoside analogue reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide fumarate as Biktarvy, cabotegravir is a second-generation integrase inhibitor, which, while having a similar mechanism of action to first-generation drugs of the class, pose a higher barrier to emergent viral resistance and somewhat higher potency.

According to Cortellis, the number of people who are newly infected with HIV is continuing to decline in most parts of the world, and access to HIV treatments in low- and middle-income countries has increased, while the percentage of people living with HIV who are not receiving antiretroviral therapy has decreased to about 41.2%. Still, substantial need remains. For instance, according to the CDC, while African Americans accounted for 13% of the U.S. population in 2018, they comprised 42% of the 37,832 new HIV diagnoses in the nation and its dependent areas.

In addition to HPTN 083, the DSMB also reviewed data from HPTN 084, a trial evaluating cabotegravir in more than 3,000 sexually active women in seven African countries to date.

"If approved, a new injectable agent, such as long-acting cabotegravir administered every two months, could play an important role in reducing HIV transmission and helping to end the HIV epidemic," said Myron Cohen, co-principal investigator of the HPTN.

No Comments