FDA Declines to Approve Cabotegravir/Rilpivirine

ViiV Healthcare has announced the receipt of a complete response letter (CRL) from the US Food and Drug Administration (FDA) for its new drug application for cabotegravir and rilpivirine long-acting injectable to treat HIV-1 in virologically suppressed adults.

Cabotegravir is an integrase strand transfer inhibitor developed by ViiV Healthcare and rilpivirine is a non-nucleoside reverse transcriptase inhibitor developed by Janssen Sciences. The cabotegravir and rilpivirine long-acting regimen is investigational and is not approved anywhere in the world.

According to the company, the reasons given in the CRL relate to chemistry manufacturing and controls. However, ViiV reports that there have been no reported safety issues related to chemistry manufacturing and controls and that there is no change to the safety profile of the products used in clinical trials to date.

In April, the FDA accepted the new drug application for the product.

The submission was based on the global ATLAS (Antiretroviral Therapy as Long-Acting Suppression) and FLAIR (First Long-Acting Injectable Regimen) phase 3 studies. Combined, the studies included more than 1100 patients from 16 countries and demonstrated that when injected monthly, cabotegravir/rilpivirine was as effective as a standard of care, daily, oral, 3-drug regimen in maintaining viral suppression throughout the 48-week study period. These results were presented in March at the 2019 Conference on Retroviruses and Opportunistic Infections.

In the ATLAS study, 308 patients were enrolled in the treatment arm and received oral cabotegravir 30 mg + rilpivirine 25 mg once daily for 4 weeks for safety monitoring. Then, the participants went on to receive single 3 mL loading doses of cabotegravir long-acting (LA) 600 mg (200 mg/mL) and rilpivirine long-acting 900 mg (300 mg/mL) via intramuscular injection, followed by 2 mL intramuscular injections every 4 + 1 weeks of cabotegravir LA 400 mg and rilpivirine long acting 600 mg.

At week 48, 5 participants (1.6%) in the cabotegravir/rilpivirine arm and 3 (1.0%) in the control arm had HIV-1 RNA >50 c/mL, meeting the primary endpoint of non-inferiority using the US Food and Drug Administration’s snapshot algorithm with a 6% non-inferiority margin.

The study investigators also report that the cabotegravir/rilpivirine arm was non-inferior to the current ART arm for the key secondary endpoint of HIV-1 RNA <50 c/mL (93% vs 95%). During the study 3 cabotegravir/rilpivirine group participants and 4 current ART group participants had confirmed virologic failure (CVF).

In the FLAIR study, 283 participants in the long-acting arm received an oral lead in of 30 mg of cabotegravir + 25 mg of rilpivirine once daily for 4 weeks to evaluate tolerability, before receiving cabotegravir/rilpivirine as an intramuscular long-acting injectable therapy. Six participants in the cabotegravir/rilpivirine arm (2.1%) and 7 in the DTG/ABC/3TC [dolutegravir/abacavir/lamivudine] arm (2.5%) met the primary endpoint of viral load >50 c/mL at 48 weeks by US Food and Drug Administration snapshot algorithm (non-inferiority margin 6%).

Secondary endpoints included safety, tolerability, and confirmed virologic failure. The investigators indicate that the key secondary endpoint of HIV-1 RNA <50 c/mL was achieved by 93.6% of the cabotegravir/rilpivirine arm and 93.3% of the DTG/ABC/3TC arm.

Confirmed virologic failure was observed in 4 participants (1.4%) in the cabotegravir/rilpivirine; 3 had mutations in the NNRTI + INSTI domains and 1 was not tested. In the DTG/ABC/3TC arm, 3 confirmed virologic failures, none of which had INSTI resistance.

At CROI, Contagion® spoke with Brian Woodfall, MD, global head of development at Janssen, about what long-acting injectables will offer patients living with HIV, if approved.

"Certain patient types and attributes of adherence in terms of lifestyle, may not always fit well with daily, oral regimens that need to be taken at a very high rate of adherence to be fully effective. So, for those patients who may have problems with adherence, an injectable that only needs to be given once a month — or maybe once every 2 months when we see further data coming out on the injectable treatments – would be an option for those patients which may provide an opportunity to have better overall treatment in the long run," Woodfall said.

ViiV Healthcare will work closely with the FDA to determine the appropriate next steps.