Virus World

Strategy may offer alternative to daily antiretrovirals.  Individuals with HIV who began taking antiretroviral therapy (ART) in the early stages of infection achieved a lengthy period of HIV suppression without ART after receiving two broadly neutralizing anti-HIV antibodies (bNAbs), according to a small study published today in the journal Nature. The findings suggest that combination bNAb therapy might offer a future alternative to daily ART for people living with HIV. The research was conducted by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, in collaboration with researchers at the NIH Clinical Center; the Maple Leaf Medical Clinic in Toronto; the Frederick National Laboratory for Cancer Research; Harvard Medical School, Boston; and The Rockefeller University, New York City. Although oral antiretrovirals are highly effective at keeping HIV levels under control, it can be difficult for some people with HIV to adhere to a daily medication regimen. Additionally, the medicines can present long-term side effects from lifetime usage and create the possibility for the development of drug-resistant virus. In previous research, single bNAbs showed only limited success in keeping virus levels low partly because bNAb-resistant HIV either already existed or emerged in the individual. To address this problem, researchers in the NIAID Laboratory of Immunoregulation tested a dual combination of bNAbs—called 3BNC117 and 10-1074—targeting different parts of the surface of HIV.

The researchers conducted a two-component clinical trial between September 2018 and January 2021. The first component was a Phase 1 randomized, placebo-controlled trial involving 14 participants with HIV. These individuals had started ART during the early phase of their infection. They were taken off antiretrovirals shortly after receiving their first infusion of the combination bNAbs or placebo. Participants received up to eight bNAb or placebo infusions—two in the first month and once monthly thereafter—for 24 weeks. HIV levels and CD4 T-cell counts were measured every two weeks.  The purpose of the study was to see if treatment with the bNAbs could suppress HIV in the absence of ART. None of the seven participants who received the bNAb treatment had to restart ART before 28 weeks post-infusion compared to six of the seven participants who received placebo. The median duration of time off antiretrovirals was 39.6 weeks (bNAb group) and 9.4 weeks (placebo), respectively. The second component of the study involved bNAb infusions in a group of 5 study participants who were not taking ART but still maintained low levels of HIV. In this smaller group, only two of the five study participants maintained complete suppression of the virus for an average of 41.7 weeks following the bNAb transfusions.

The authors note that the bNAb combination was ineffective in suppressing HIV if participants harbored virus resistant to either or both experimental antibodies before receiving the infusions. The presence of pre-existing antibody-resistant HIV poses a major challenge going forward, according to the authors. No safety issues occurred in the study, and the infusions were well-tolerated. The study authors conclude that the combination bNAb therapy can be highly effective in suppressing HIV in the absence of ART for extended periods, provided that antibody-resistant virus is not present at the time individuals begin antibody treatment. Larger studies are needed to confirm the findings, but as next-generation bNAbs with increased potency and durability become available, “there is reason to believe that infrequent administration (i.e., twice a year) of such antibodies, possibly along with a long-acting injectable antiretroviral drug, could lead to ART-free HIV suppression for extended periods (years) in infected individuals,” the authors wrote.

Research Cited Published in Nature (June 1, 2022):

https://doi.org/10.1038/s41586-022-04797-9 

The FDA halted the use of two monoclonal antibody treatments for COVID-19 because they are not effective against the omicron variant of SARS-CoV-2, which now accounts for almost all U.S. cases. The FDA revised the emergency use authorizations for the two treatments bamlanivimab and etesevimab administered together, and the cocktail of casirivimab and imdevimab. Their use will now be limited to infections that are likely to have been caused by a variant that is susceptible to the treatments. “Because data show these treatments are highly unlikely to be active against the omicron variant, which is circulating at a very high frequency throughout the United States, these treatments are not authorized for use in any U.S. states, territories, and jurisdictions at this time,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press release. Cavazzoni said this will avoid exposing patients to side effects from treatments “that are not expected to provide benefit to patients who have been infected with or exposed to the omicron variant.” She said the treatments may be reauthorized in regions where patients are likely to be infected or exposed to a susceptible variant, or if they are proven affective against future variants. The FDA noted that there are several other therapies that are expected to work against omicron, including Paxlovid, sotrovimab, remdesivir and molnupiravir.

BACKGROUND

The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days.

METHODS

In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase–polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183.

RESULTS

A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19–related deaths occurred, all in the placebo group.

CONCLUSIONS

A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725. opens in new tab.)

Published in NEJM (April 20, 2022):

https://doi.org/10.1056/NEJMoa2116620 

AstraZeneca's antibody cocktail against COVID-19, which has proven to work as a preventative shot in the non-infected, was also shown to save lives and prevent severe disease when given as treatment within a week of first symptoms.  The drug, a combination of two antibodies called AZD7442, reduced the risk of severe COVID-19 or death by 50% in non-hospitalised patients who have had symptoms for seven days or less, the Anglo-Swedish drugmaker said on Monday. The risk reduction was even better in patients who started therapy within just five days of initial symptoms, but AstraZeneca joins an already crowded field of medicines that were shown to prevent deterioration in patients with mild disease when given soon after diagnosis. AstraZeneca executive Mene Pangalos said in a media call that the treatment results would mainly underscore the potential future use as a non-vaccine prevention.FWN2R716N "If and when this is approved it will be used in the treatment setting as well. But the real differentiator for this antibody is going to be in the prophylactic setting," he said.

Similar therapies made with a class of drugs called monoclonal antibodies are being developed by Regeneron (REGN.O), Eli Lilly (LLY.N) and GlaxoSmithKline (GSK.L) with partner Vir (VIR.O). These therapies are approved for emergency use in the United States for treating mild-to-moderate COVID-19. Regeneron's therapy showed 72% protection against symptomatic infection in the first week, and 93% after that. GSK-Vir's showed a 79% reduction in the risk of hospitalisation or death due to any cause, while Eli Lilly's therapy showed a 70% reduction in viral load at day seven compared to a placebo. Merck & Co Inc (MRK.N), in turn, is emphasising the convenience of use of its anti-COVID-19 tablet, which cut the risk of having to got to hospital or of dying by 50% in a trial of early-stage patients who had at least one risk factor.

Merck, collaborating with Ridgeback Biotherapeutics, on Monday applied for U.S. emergency clearance for the oral drug. read more AstraZeneca, whose COVID-19 vaccine has been widely used across the globe, asked U.S. regulators last week to grant emergency use authorisation for AZD7442 as a preventative shot. read more

As such, it is designed to protect people who do not have a strong enough immune response to vaccines, primarily those who have received organ transplants or who are in cancer care. If full market clearance is obtained after any emergency approval the market could widen, for instance, to include crew and passengers of a cruise ship, said Pangalos. "You can say the same for people who don't want to be vaccinated but want an antibody," he added. AstraZeneca said it is submitting the new treatment data on AZD7442 to global health regulators. The trial took place across 13 countries and involved more than 900 adult participants, 90% of whom suffered from conditions that made the particularly vulnerable to COVID-19, such as cancer and diabetes. One half receiving AZD7442 and the rest a placebo. Full trial results will be submitted for publication in a peer-reviewed journal, AstraZeneca said. AZD7442 contains laboratory-made antibodies designed to linger in the body for months to contain the virus in case of an infection. A vaccine, in contrast, relies on an intact immune system to develop targeted antibodies and infection-fighting cells. While Monday's results cover the use of AZD7442 in non-hospitalised patients, a separate trial is also studying its use as a treatment for hospitalised COVID-19 patients. Reporting by Ludwig Burger in Frankfurt, Yadarisa Shabong in Bengaluru; Editing by Saumyadeb Chakrabarty, Kirsten Donovan and Alexander Smith

AstraZeneca Press Release (Oct. 11, 2021):

https://www.astrazeneca.com/media-centre/press-releases/2021/azd7442-phiii-trial-positive-in-covid-outpatients.html