Cloudbreak

Anti-infective Immunotherapy Platform

The Cloudbreak platform is a fundamentally new approach to the fight against life-threatening infectious disease that provides potent antimicrobial activity and immune system engagement in a single molecule. Our lead Cloudbreak candidates are Antiviral Fc-Conjugates (AVCs) for the prevention and treatment of influenza. The Cloudbreak platform has enabled us to expand the development of AVCs to target other life-threatening viruses.

Cloudbreak

Anti-infective Immunotherapy Platform

The Cloudbreak platform is a fundamentally new approach to the fight against life-threatening infectious disease that provides potent antimicrobial activity and immune system engagement in a single molecule. Our lead Cloudbreak candidates are Antiviral Fc-Conjugates (AVCs) for the prevention and treatment of influenza. The Cloudbreak platform has enabled us to expand the development of AVCs to target other life-threatening viruses.

Cloudbreak Platform Overview

The Cloudbreak platform recognizes that most infectious disease results when a microbial pathogen is able to evade or overcome the host immune system. Our Cloudbreak candidates are designed to counter infection in two ways, by directly targeting and destroying invading pathogens and by focusing the immune system at the site of infection. In this way, Cloudbreak anti-infective candidates are similar to certain cancer immunotherapies that unlock the potential of the immune system to destroy cancer cells.

Multimodal Mechanism of Action from a Single Molecule

Cloudbreak candidates targeting viral infections are called Antiviral Fc-Conjugates (AVCs), single molecules consisting of two distinct moieties with discrete, yet complementary mechanisms of action:

  • Targeting Moiety (TM): Novel and highly potent small molecule that binds surface targets on the pathogen to directly destroy it and/or inhibit replication.
  • Effector Moiety (EM): Fragment crystallizable (Fc) region of human IgG1 antibodies, which was selected to maximize engagement of the human immune system via Fc-gamma (Fcγ) receptors and for its long half-life.

AVCs not only mediate pathogen clearance through a multimodal mechanism of action but also have potential for months of activity with a single dose.

Cloudbreak AVC Program Overview

Cidara seeks to develop AVCs against influenza that provide direct, sustained antiviral effect as well as immune system engagement, for effective prevention and treatment of disease. This is a potentially transformative approach to influenza, distinct from current therapies. AVCs are not vaccines, small-molecule drugs, or monoclonal antibodies. AVCs are novel, Fc-conjugates with the following features:

  • Multimodal mechanism of action: Potent, direct antiviral activity and immune system engagement
  • Strong target binding: High affinity to an essential, conserved target on the virus surface
  • Long duration of action: Months of protection from disease with a single dose
  • Rapid onset: Rapid distribution to site of infection for treatment of disease

Collectively, these features of AVCs provide several potential advantages.

Potential Advantages of Cloudbreak Antiviral Fc Conjugates (AVCs)

  • Broad-Spectrum, Universal Coverage: Cloudbreak AVCs have demonstrated activity against pandemic and seasonal influenza A and B viruses, including resistant (e.g. oseltamivir-resistant H1N1) and strains with high pandemic potential (e.g. H5N1 , H7N9)
  • Superior Resistance Profile: AVCs may be less prone to viral resistance, by virtue of the AVC multimodal mechanism of action
  • Protection for High-Risk Populations: Unlike vaccines, the potent intrinsic activity of the AVCs should provide antiviral protection independent of immune system status. Even in immune-compromised patients, AVCs can focus the existing immune system at the site of infection
  • Seasonal and Pandemic Readiness: AVCs are well-suited for immediate and robust response to influenza challenges by providing rapid onset of protection and coverage of strains that may have been missed by the seasonal vaccine. Moreover, AVCs are not subject to the lengthy and unpredictable process of vaccine manufacturing
  • Long Duration of Action: A single AVC dose may protect from influenza for an entire season

Cloudbreak AVC Development Candidate CB-012: Preclinical Highlights

CB-012 outperforms oseltamivir in vitro

Plaque reduction in infected A549 cells

CB-012 demonstrated broad-spectrum coverage of influenza A and B viruses and superior in vitro activity compared with standard-of-care antiviral oseltamivir

CB-012 is efficacious against multiple influenza A and B strains, including drug resistant pandemic strain

Five mice per cohort CB-012 dosed four hours prior to infection.
*Dosing in the B/Malaysia study was initiated two hours post-infection.

One dose of CB-012 was 100% protective against influenza A and B viruses, while a five-day regimen of oseltamivir was not

CB-012 improves treatment window versus Tamiflu®

Lethal influenza model (H1N1: TX/36/91 in mice); single dose of CB-012 improves treatment window vs 10 doses (BID) of Tamiflu®.

Five mice per cohort Tamiflu® dosed BID for five days in each cohort.

In this in vivo study, the post-infection dosing window for CB-012 was expanded up to 72 hours compared with Tamiflu® (oseltamivir), which loses its ability to protect when administered beyond 24 hours post-infection

Extended half-life translates to long duration of action

Lethal influenza prevention model (H1N1: TX/36/91 in mice); CB-012 dosed once 28 days prior to viral challenge.

Five mice per cohort.

A single dose of CB-012 provided protection against and treatment of H1N1, H3N2, and Tamiflu® (oseltamivir) resistant H1N1-related infections

Influenza Virus

Influenza, or flu, is a virus that causes upper respiratory infection. The influenza virus can cause mild to severe illness, and at times can lead to influenza-related death. Young children, the elderly (people aged > 65 years and older), pregnant women, and immunocompromised patients are at higher risk of serious complications resulting from influenza infection, but even healthy people are at risk of infection with seasonal flu.

As many as 646,000 people may die from influenza-related illness each year worldwide. The annual burden of influenza in the U.S. results in approximately one million hospitalizations and emergency department visits and up to $11.7 billion in medical costs, with an additional $13.6 billion per year in lost earnings.

For the 2017-2018 season, the CDC estimates almost 50 million people in the U.S. became ill from influenza and almost 80,000 people died, making it one of the most severe seasons in recent history.

Prevention

Currently, the only preventive measure against influenza for most people is the seasonal influenza vaccine. While the influenza vaccine is critical to global health, it has limited vaccine effectiveness (VE) and must be redesigned every year based on a prediction for the next season’s dominant circulating strains. In recent years, the VE has varied significantly, with an average 40%. Even if not fully protective, vaccination reduces severity and influenza-related complications. Nevertheless, low VE results in more patients who are at risk of serious complications resulting from influenza and who must rely on a limited number of therapeutic options.

Treatment

Currently, four drugs for treating influenza are recommended by the CDC:

  • Oseltamivir phosphate (Tamiflu®)
  • Zanamivir (Relenza®)
  • Peramivir (Rapivab®)
  • Baloxavir marboxil (Xofluza)

These drugs include neuraminidase inhibitors and the recently approved endonuclease inhibitor, baloxavir. All of these drugs have one or more of the following limitations: short half-life, high susceptibility to resistance, multi-dose regimens, and limited routes of administration.

Older antiviral medications, such as amantadine and rimantadine, are no longer recommended due to high levels of resistance.

For more information about influenza, visit the CDC website here.

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