Cloudbreak Antiviral Conjugate Demonstrates Potent In Vitro Activity

Influenza prevention and treatment may be getting an upgrade as Cidara Therapeutics unveils Cloudbreak, a novel immunotherapy approach using antiviral conjugates (AVC) that could provide powerful protection against influenza A and B infections.

The US Centers for Disease Control and Prevention estimates that 48.8 million people experienced flu illness during the 2017-2018 season, leading to 959,000 hospitalizations and 79,400 deaths. Although the flu vaccine is the best way to prevent flu illness, the vaccine was just 36% effective overall in 2017-2018.

Cidara investigators developed CB-012, a stable conjugate of a highly potent antiviral agent linked to human IgG1 Fc, and are evaluating the asset for the treatment and prevention of seasonal and pandemic influenza A and B infections. The results were presented in an oral session at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2019), where Leslie Tari, PhD, senior vice president of research at Cidara, sat down with Contagion® to discuss Cloudbreak and antiviral conjugates (see video).

The research team compared the activity of CB-012 in a viral growth inhibition assay using infected A549 cells with oseltamivir for A/WSN/33 H1N1, A/Wyoming/3/03 H3N2, and A/California/04/09 H1N1 pandemic viruses. Efficacy of CB-012 was measured in a lethal influenza infection model (A/Texas/36/91 H1N1) in mice. A single intravenous dose of CB-012 administered 4 hours before infection was compared with 5 once-daily oral doses of oseltamivir and controls.

Compared with oseltamivir, CB-012 demonstrated potent activity against seasonal and pandemic influenza A strains. At 10 nM, CB-012 reduced the amount of released infectious virus in the supernatant 10- to 3,000-fold more efficiently than oseltamivir at 1000 nM.

CB-012 achieved potent inhibition of viral growth compared with oseltamivir in vitro and offered full protection at single doses ≥0.4 mg/kg in a lethal prophylactic mouse influenza infection model. The asset demonstrated extended systemic exposure, with a half-life of 10 days in mice.

“The high potency and low clearance of CB-012 may offer robust protection from influenza for a large portion of the flu season with a single dose, regardless of patient immune status,” the investigators concluded.

According to research team, Cloudbreak combines a potent antimicrobial that directly targets a pathogen with an immunological effector moiety that engages the immune system, providing elimination of the pathogen via multiple neutralizing mechanisms.

“With molecules like this, we’re not looking to replace vaccines, which play a critical role in public health,” Tari told Contagion® in a previous interview. “What we know is that vaccine efficacy is far from excellent, especially in the elderly and very young. Our vision is that 1 to 2 subcutaneous doses of our AVCs could prevent influenza in humans for an entire flu season, with or without concomitant vaccine administration—and cover strains that are missed by the vaccine in any given year. And since our AVCs possess potent intrinsic antiviral activity even in the absence of immune engagement, we can also protect patient populations with compromised immune systems, where vaccines don’t perform well.”

The study, “Cloudbreak: A Novel Approach for the Treatment and Prevention of Influenza Virus,” was presented in an oral session on Monday, April 15, 2019, at ECCMID 2019 in Amsterdam, the Netherlands.