Just before Christmas, The U.S. Food and Drug Administration (FDA) gave an unwanted gift to ViiV Healthcare, a division of GlaxoSmithKline (GSK), when it refused to approve the company’s much-anticipated long-acting HIV injection.
The injectable, known under the working title Cabenuva, is composed of GSK’s integrase strand transfer inhibitor cabotegravir and Johnson & Johnson’s NNRTI rilpivirine, currently sold as Edurant in its tablet form. The hope is that the two-drug Cabenuva would be injected into the muscle once a month, as an alternative to daily oral medications to control the virus, which could improve adherence and prevent “pill fatigue.”
In an email, Audrey Abernathy, a spokesperson for ViiV Healthcare, said that FDA’s reasons for rejecting the regimen right now, given in the complete response letter related to Chemistry Manufacturing and Controls (CMC), were not due to safety issues. “There is no change to the safety profile of the products used in clinical trials to date,” Abernathy wrote. Without elaborating on the FDA’s concerns, Abernathy said those concerns did not require more clinical data and that the company will “work closely with the FDA to determine the appropriate next steps for this New Drug Application.”
The FDA’s rejection came as a surprise, because studies showed Cabenuva to be effective at suppressing HIV for people whose viral load is suppressed and who are not resistant to cabotegravir or rilpivirine. The global ATLAS (Antiretroviral Therapy as Long-Acting Suppression) and FLAIR (First Long-Acting Injectable Regimen) pivotal phase 3 studies included more than 1,100 patients from 16 countries and concluded that the combination of cabotegravir and rilpivirine, injected monthly, was as effective as a daily, oral, three-drug regimen in maintaining viral suppression throughout the 48-week study period. The results were presented at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI).
In August 2019, ViiV Healthcare touted a phase 3 study showing the injectable regimen was effective when administered up to every two months.
Melanie Thompson, M.D., principal investigator of the AIDS Research Consortium of Atlanta, told TheBodyPro that there’s no reason not to believe ViiV’s statement that the FDA rejection of Cabenuva was not about safety or efficacy.
“Immediately upon the announcement, there was much concern on social media about the safety of the drugs,” Thompson said. “But given the results of the clinical trials, that is not an issue. The FDA most likely was not satisfied with the chemical or manufacturing process.”
Thompson added that most people not involved with clinical trials don’t know all the things that the FDA looks for. “The FDA could have been clearer in its announcement so that the general public didn’t think, ‘Oh no, it’s not safe.’”
Paul Volberding, M.D., Professor Emeritus of Medicine at UCSF and Director of the AIDS Research Institute, agrees it was likely that a technicality led to the FDA’s rejection. He told TheBodyPro that an injectable, when approved, could improve adherence for certain patients.
“People who are not taking other meds, or who are living in unstable housing, where their belongings are not secure, or people who find it difficult to take oral medications, a long-acting injectable could help,” he said. “And [an injectable] would be good for people who might not want others to know that they have HIV.” People with chaotic life situations or mental health issues, those who might not remember to take a daily pill, could also benefit, he added.
“But if someone is not adherent to injectables, there is a risk of resistance,” Volberding said, noting that many people who could be helped—including those who are homeless or housing insecure—might find it difficult to travel to the nearest clinic once a month for an injection.
Though injectable treatment isn’t yet available for HIV, long-acting injectables have been used in other areas of medicine, including drugs for birth control and schizophrenia.
There are some other unknowns about a long-acting injectable HIV treatment, Thompson said. “We need some details about pricing and discounts, and its impact on Ryan White and [the AIDS Drug Assistance Program] ADAP. Also, who will pick up the cost of administering these meds? It requires personnel to administer, and that costs money. Some busy clinics are already strapped and can barely take care of existing patient loads.”
Injectable treatment for HIV is much further advanced than the also-touted injectables for pre-exposure prophylaxis (PrEP). The first large-scale clinical trial for a long-acting injectable PrEP began in December 2016, and results are expected next year.
As for injectable antiretroviral drugs for treatment, the assumption in the HIV/AIDS research community is that they’re coming, and FDA approval will happen.
“We may look back on this period in 10 years and say these were awkward first steps,” Thompson said. “But [injectables] represent an incremental advance. And there are many in clinical trials, so we are likely to get more than one injectable long-acting drug.”