Virus World

NIH-funded research networks provide evidence on cabotegravir and rilpivirine in additional populations. Long-acting, injectable antiretroviral therapy (ART) suppressed HIV replication better than oral ART in people who had previously experienced challenges taking daily oral regimens and was found safe in adolescents with HIV viral suppression, according to two studies presented today at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) in Denver. Both studies were sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, in collaboration with other NIH institutes.

“The HIV community is just beginning to unpack the enormous potential of long-acting antiretroviral medications for HIV treatment and prevention, and we need population-specific data for everyone to benefit,” said NIAID Director Jeanne Marrazzo, M.D., M.P.H. “These findings open up new possibilities for millions of people with HIV, particularly those whose health suffers due to challenges of daily pill taking.”

NIH funded this research to build on the clinical trials that underpinned the Food and Drug Administration approval(link is external) of long-acting cabotegravir and rilpivirine in 2021 for people with a consistent history of viral suppression. The studies were conducted in collaboration with ViiV Healthcare and Johnson & Johnson and intended to provide evidence on the use of the drug regimen in populations for whom limited data exist....

Long-acting injectable cabotegravir plus rilpivirine effectively maintained viral suppression of HIV among adults with or without a 1-month oral lead-in phase, according to the results of a study published in The Lancet HIV. The FDA approved the once-monthly injectable regimen, branded as Cabenuva, in January.  “This is the longest follow-up data on people who have received long-acting injectable cabotegravir plus rilpivirine as part of a phase 3 clinical trial,” Chloe Orkin, MBBCh, professor, consultant physician and HIV research lead at Queen Mary University of London and Barts Health, told Healio. “It provides reassurance on durability.” The new results are from the FLAIR study an ongoing phase 3, randomized, open-label, multicenter trial that previously reported improved treatment satisfaction compared with daily ART at 96 weeks. Orkin and colleagues assessed 124-week safety, tolerability and durability of the regimen among ART-naive participants who were virologically suppressed during the 20-week induction phase with standard of care. They randomly assigned the participants in a 1:1 ratio to continue the standard of care oral regimen or switch to the long-acting regimen in the 100-week maintenance phase. According to the study, randomization was stratified by sex at birth and baseline HIV-1 RNA. Participants in the treatment group received cabotegravir plus rilpivirine once daily for at least 4 weeks before their first injection. They could choose to continue long-acting cabotegravir (400 mg) plus rilpivirine (600 mg) every 4 weeks from week 100 or withdraw.

Study endpoints for week 124 included plasma HIV-1 RNA of at least 50 copies/mL or less than 50 copies/mL, confirmed virological failure — HIV-1 RNA measured at 200 copies/mL or higher two times in a row — safety and tolerability. According to the study, at week 100, 232 (92%) of 253 participants transitioned to long-acting cabotegravir plus rilpivirine in the extension phase (111 in the direct-to-injection group and 121 in the oral lead-in group), whereas 243 of the 283 who were randomly assigned to the long-acting therapy group continued the long-acting regimen into the extension phase. Orkin and colleagues found that one participant in each extension switch group HIV-1 RNA of 50 or more copies/mL, whereas 110 participants in the direct-to-injection group and 113 in the oral lead-in group remained suppressed at the week 124 check-in. The researchers said the lower suppression rates in the oral lead-in group were driven by nonvirological reasons. Additionally, the study showed that among people in the randomly assigned long-acting group, 227 participants remained suppressed. Adverse events leading to withdrawal occurred in three participants in the extension switch population and two in the oral lead-in group after 24 weeks of therapy, and in 15 people in the randomly assigned long-acting group, with injection site reactions being the most common. “Long-acting injectable cabotegravir and rilpivrine was effective and safe over 124 weeks of treatment,” Orkin concluded. “The outcomes were good in those people who chose not to have the oral lead-in.”

Original research published in The Lancet HIV (Oct. 14, 2021):

https://doi.org/10.1016/S2352-3018(21)00184-3

HPTN 083 is the first study to compare the efficacy of CAB LA to daily oral TDF/FTC for HIV PrEP. HPTN 083 enrolled 4,570 cisgender men who have sex with men (MSM) and transgender women (TGW) who have sex with men at 43 sites in Argentina, Brazil, Peru, United States, South Africa, Thailand and Vietnam. For many people, taking a daily pill can be challenging. The development of safe and effective long acting alternative agents for HIV PrEP would increase HIV prevention choices and help those who find taking a daily pill challenging. Some people also may find periodic injections to be a more discreet form of HIV PrEP than daily pills and may prefer CAB LA for that reason.

Participants were assigned randomly (by chance) to either the CAB or oral TDF/FTC group. Neither the participants nor the study team knows who was in which group. Participants in each group received both injections and oral tablets – each participant received one active drug and one placebo (no active drug) in order to maintain the blinded nature of the study. Participants were randomized to one of two study arms and included three steps: Step 1 consisted of 5 weeks of daily oral CAB and a TDF/FTC placebo or 5 weeks of daily oral TDF/FTC and an oral CAB placebo; Step 2 consisted of 148 weeks of intramuscular CAB LA 600 mg every 8 weeks plus daily oral TDF/FTC placebo or 148 weeks of daily oral TDF/FTC plus an intramuscular CAB LA placebo every 8 weeks ; and Step 3 consisted of an open-label daily oral TDF/FTC for 48 weeks after participants completed Step 2.

On May 14, 2020 a Data and Safety Monitoring Board (DSMB) reviewed HPTN 083 study data and recommended that the blinded part of the study be stopped early for successfully meeting its specified objectives. The study results showed that CAB LA, administered every eight weeks, provided high efficacy compared to TDF/FTC. A total of 50 incident HIV infections occurred in HPTN 083, with 38 incident HIV infections in the TDF/FTC arm (incidence rate 1.21%) and 12 incident HIV infections in the CAB arm (incidence rate 0.38%): in other words, approximately three times the number of incident HIV infections were in the TDF/FTC arm than in the CAB arm. The study sponsor, the U.S. National Institute of Allergy and Infectious Diseases (NIAID), approved the decision to stop the blinded part of the study.

The FDA on Monday approved ViiV Healthcare’s cabotegravir as the first long-acting injectable for HIV PrEP. The medication, which will be known as Apretude, is administered every 2 months after two initial injections that are given 1 month apart. The FDA approved it for at-risk adults and adolescents weighing at least 77 pounds.  Debra Birnkrant, MD, who heads the Division of Antivirals in the FDA’s Center for Drug Evaluation and Research, said the approval “adds an important tool in the effort to end the HIV epidemic by providing the first option to prevent HIV that does not involve taking a daily pill.” “This injection ... will be critical to addressing the HIV epidemic in the U.S., including helping high-risk individuals and certain groups where adherence to daily medication has been a major challenge or not a realistic option,” Birnkrant said in a news release. Anticipating the approval, the CDC included a section on prescribing cabotegravir in its updated clinical practice guideline for HIV PrEP published 2 weeks ago. The CDC also recommended for the first time that clinicians tell all sexually active adult and adolescent patients about HIV PrEP in light of evidence that only around 25% of the 1.2 million people in the United States who met the indication for PrEP in 2020 were prescribed it.

The FDA approval was based on study findings that showed cabotegravir administered every 8 weeks prevented HIV infection. Two trials provided the data: one that was conducted among transgender women and cisgender men who have sex with men, and a second trial that included only cisgender women. “People who are vulnerable to acquiring HIV, especially those in Black and Latinx communities who are disproportionately impacted in the U.S., may want options beyond daily oral pills. That’s why ViiV Healthcare is proud that Apretude was studied in one of the most diverse and comprehensive HIV prevention trial programs to date, which also included some of the largest numbers of transgender women and Black men who have sex with men ever enrolled in an HIV prevention trial,” ViiV CEO Deborah Waterhouse said in a statement. Cabotegravir was already part of the first FDA-approved long-acting injectable regimen for HIV treatment, Cabenuva, which also includes rilpivirine.

FDA Press Release (Dec. 20, 2021):

https://www.fda.gov/news-events/press-announcements/fda-approves-first-injectable-treatment-hiv-pre-exposure-prevention 

"Having this treatment available for some patients provides an alternative for managing this chronic condition," said FDA's John Farley.  In a move that could transform HIV treatment, the Food and Drug Administration has approved a monthly injectable medication, a regimen designed to rival pills that must be taken daily. The newly approved medicine, which is called Cabenuva, represents a significant advance in treating what continues to be a highly infectious disease. In 2018, for instance, there were approximately 36,400 newly infected patients living with HIV in the U.S., according to the Centers for Disease Control and Prevention. About 1.7 million people worldwide became newly infected in 2019, according to UNAIDS. Although several medicines exist for treating HIV, ViiV Healthcare is banking on the improved convenience of getting a monthly shot, even if it must be administered by a health care provider. The company, which is largely controlled by GlaxoSmithKline (GSK), gathered data showing nine of 10 patients in pivotal studies claimed to prefer the shot over taking pills each day.

“This approval will allow some patients the option of receiving once-monthly injections in lieu of a daily oral treatment regimen,” said John Farley, who heads the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, in a statement. “Having this treatment available for some patients provides an alternative for managing this chronic condition.” Two clinical studies of more than 1,100 patients from 16 countries found that Cabenuva was as effective in suppressing the virus as the daily, oral, three-drug regimens that were taken by patients throughout the 48-week study period. However, patients must first take an oral version of the injectable medicine and another pill for the first month before pivoting to monthly shots, according to the FDA.  The cost, however, is steep — the list, or wholesale, price is $3,960 a month, or more than $47,500 a year. The list price for the one-time initiation dose is $5,490. However, a ViiV spokeswoman explained that a 30-day oral “lead-in,” which is required as part of the approval, will be made available at no charge to patients. She also maintained the list price for the monthly shot is “within the range” of HIV treatment pills on the market today. There is also considerable competition from Gilead Sciences (GILD), which markets several HIV medicines. During 2019, its HIV treatment franchise generated $17.2 billion in revenue, a 12.5% year-over-year increase, and grabbed more than 80% of the market for patients starting HIV therapy, according to Cowen analyst Phil Nadeau. He expects HIV medication sales to hit $24.4 billion in 2025, but points to HIV prevention pills as big drivers of that increase. ViiV, meanwhile, is developing an every-other-month injectable in hopes of capturing a more substantial market share.

Last November, an interim analysis found cabotegravir – a component of Cabenuva – was 89% more effective in preventing infection among women than Truvada, a Gilead pill that must be taken daily and is the current standard of care. And a separate analysis released in July showed the every-other-month shot protected uninfected people by 66% more compared with Truvada in at-risk men and transgender women who have sex with men. “We see Cabenuva as the beginning of long-acting treatment for HIV,” said Kimberly Smith, who heads global research and medical strategy at ViiV, who expects to seek FDA approval for this version of the shot in coming weeks. “We’re opening the door with Cabenuva and will only create more hunger for other long-acting therapies. It really becomes a sort of anchor.” The approval, by the way, comes more than a year after ViiV hoped to win approval for the treatment. In late 2019, the FDA issued a so-called complete response letter and explained approval could not be granted at the time due to issues with chemistry, manufacturing and controls, which are used to determine safety, effectiveness and quality.

FDA News Release (Jan 21, 2021):

https://www.fda.gov/news-events/press-announcements/fda-approves-first-extended-release-injectable-drug-regimen-adults-living-hiv#

ViiV Healthcare announced that it has received a complete response letter (CRL) from the FDA, rejecting its marketing application for its long-acting, monthly injectable therapy for HIV. The combination treatment was touted by ViiV as a next generation HIV therapy, due to the fact that it could free people with the virus from taking daily oral pills. The monthly injection  is a combination of ViiV’s integrase inhibitor cabotegravir and Johnson & Johnson’s non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine.

ViiV – which is majority owned by GlaxoSmithKline – said that it “will work closely with the FDA to determine the appropriate next steps for this new drug application”. In the CRL, the FDA cited concerns regarding the treatment’s chemistry manufacturing and controls process, but there was no issues surrounding the safety of the product. This is a blow to ViiV, which has been vying for market share from Gilead. Both companies make billions of dollars each year from selling daily oral drugs for HIV, so this monthly injectable could have made a significant dent in Gilead’s sales. In previous trials testing the long-acting treatment, ViiV’s injectable was as effective as a standard three-drug oral regime at suppressing levels of HIV. Two trials, named ATLAS and FLAIR, formed the basis of the regulatory filings for the regimen. ATLAS involved patients who had been previously treated with long-acting antiretroviral therapy (ART), and showed that the combination injection matched standard therapy on viral suppression rates. Three patients treated with ViiV’s injectable (1%) demonstrated a failure to suppress HIV, while there were four cases on the oral therapy. FLAIR recruited newly-diagnosed patients and along with data showing non-inferiority to oral treatment, revealed a similar 1% rate of treatment failure, caused by the emergence of treatment resistance strains.

ViiV’s rival Gilead was the first company to bring a single-tablet triple therapy – Biktarvy – to market, and the former has been desperately pushing its own two-drug oral therapies through the pipeline to try and claim more market share. Gilead’s Biktarvy has grown quickly since its launch last year, and will most likely hit a $1bn-plus annual sales rate. According to GlobalData, the overall value of the HIV market is not expected to change dramatically in upcoming years, but there will be a predicted shift towards increased use of simpler, single-tablet regimens as the big-selling products change.