Anti-influenza Agents Inspired by Immunotherapy

Given the urgent need for compounds that can effectively prevent and treat influenza, San Diego-based Cidara Therapeutics are working to develop antiviral conjugates.

Using their propietary Cloudbreak technology, Cidara generate compounds that attack influenza. Cidara hope that their lead candidate, a neutralizing antiviral agent connected to a human antibody fragment, will provide direct and sustained antiviral activity.

Cidara recently presented their preclinical findings at the 29th European Congress of Clinical Microbiology & Infectious Diseases, and we spoke to Les Tari, PhD, Senior Vice President, Research, to find out more.

Michele Wilson (MW): Why is there a need to find new antiviral candidates? What are the main limitations of current flu vaccines and treatments?

Les Tari (LT): Vaccines play a critical role in public health, however, in the case of influenza, vaccine efficacy is far from desired, especially in the elderly and very young. Influenza vaccines are still only about 40 percent effective, and their ability to protect against the flu declines as the season extends and different strains emerge.

Additionally, vaccine efficacy wanes dramatically over a relatively short time. Current antiviral treatments for the flu, which include neuraminidase inhibitors and the recently approved endonuclease inhibitor, baloxavir, have one or more of the following limitations: short half-life, high susceptibility to resistance, multi-dose regimens, or limited routes of administration. Therefore, there is an urgent need to develop new antiviral candidates that have the ability to effectively prevent and treat influenza.

Cidara Therapeutics’ antiviral Fc-conjugates (AVCs), which are generated from our proprietary Cloudbreak immunotherapy platform, are being developed for both the prevention and treatment of influenza.

Cidara’s AVCs are not vaccines, monoclonal antibodies or traditional antivirals. They are novel, Fc-conjugates designed to provide a direct and sustained antiviral effect for months, in addition to engaging the immune system, for effective prevention and treatment of the flu. 

MW: Can you explain the concept behind Cloudbreak technology?

LT: Cidara was founded on the Cloudbreak concept to combat infectious disease. In most infectious disease, the problem stems from a deficiency in the immune system to recognize and eliminate the invading pathogen. With the Cloudbreak antiviral program, our aim is to overcome the deficiencies in the immune system to recognize and eliminate influenza by combining potent surface-acting antiviral agents with immune engagers in one molecule.

In our molecules, known as AVCs, we engage the immune system by stably fusing multiple copies of the antiviral agent to the Fc domain of an IgG1 antibody. Our antiviral agents are engineered carefully to target specific, highly conserved regions on the virus surface. By adding the synergistic immune-mediated killing mechanism to the action of the antiviral, we see enhanced activity which should also minimize the probability of developing resistance. Additional benefits of this strategy are improved potency of the antiviral due to the multivalent presentation on the Fc, and a dramatic improvement in half-life compared to conventional small molecule approaches.

MW: What mechanisms do antiviral conjugates use to neutralize viruses? 

LT: Our Cloudbreak AVCs are designed to counter infection in two ways, by inhibiting viral replication/cell-to-cell transmission and by focusing the immune system at the site of infection. 

MW: If successful, how do you visualize AVCs fitting in with vaccine schedules? Would they replace or complement vaccines?

LT: We believe that our AVCs have the potential to protect for an entire flu season with a single dose, with or without concurrent vaccination, and also provide a highly potent treatment for seasonal and pandemic influenza.

Also, since our AVCs possess potent intrinsic antiviral activity even in the absence of immune engagement, they could protect patient populations with compromised immune systems, where vaccines typically do not perform well.

MW: What have you learnt so far about your lead candidate, CB-012? 

LT: In preclinical studies, our lead AVC candidate, CB-012, demonstrated broad-spectrum coverage of influenza A and B viruses and superior in vitro activity compared with the standard-of-care antiviral, oseltamivir. Single low doses of CB-012 provided 100% protection in multiple lethal influenza A and B infection models in mice. CB-012 demonstrates a long half-life in mice, rats and primates, which translates to a long duration of action for influenza prevention.

A single, low dose of CB-012 was able to protect mice from mortality when administered 28 days prior to infection in a lethal mouse influenza A model. In a treatment study, the post-infection dosing window for CB-012 was expanded up to 72 hours compared with oseltamivir, which lost its ability to protect when administered beyond 24 hours post-infection.

Based on these promising results and additional ongoing research, we believe CB-012 has the potential to provide a long duration of action which means it could be dosed once or twice a flu season, with or without vaccines, to provide universal influenza protection for seasonal and pandemic use.

Les Tari was speaking to Michele Wilson, Science Writer for Technology Networks