Cloudbreak

Immunotherapy Discovery Platform

The Cloudbreak immunotherapy discovery platform has the potential to do for infectious disease what immunotherapy has done for cancer — Cloudbreak is a fundamentally new approach for the treatment of infectious disease that, in a single molecule, pairs potent antimicrobials with agents that redirect the immune system to destroy fungal, bacterial and viral pathogens.

The modular composition of Cloudbreak compounds allows for rapid exploration of combinations of targeting moiety (TM), effector moiety (EM), and linker domains, potentially enabling efficient discovery of anti-infective components with the desired potency, specificity and physical properties.

Cloudbreak Platform Overview

The design of the Cloudbreak immunotherapy platform recognizes that most infectious disease is due to a temporary deficiency in the function of the immune system. Our Cloudbreak candidates are designed to address this deficiency by recruiting components of the patient’s immune system to the site of infection. Cloudbreak supports the engineering of bi-specific agents that simultaneously target and destroy the pathogen while priming the immune system to generate a more effective anti-infective response.

We are initially developing Cloudbreak candidates for the prevention and treatment of serious Gram-negative bacterial infections.

Potential Platform Advantages

The Cloudbreak immunotherapy discovery platform is similar to certain cancer immunotherapies in that it uses components with two binding sites, one that binds to a cell surface target and a second that binds to specific receptors on immune cells – with the added benefit that the cell surface targeting group can be designed to destroy the pathogen.

Our Cloudbreak candidates have the potential to feature the following attributes:

  • Small or large molecule components with well-defined targets and efficient testing
  • Selective binding to pathogens to amplify their immunogenicity (recognition by the immune system) and thereby efficiently recruit the innate or adaptive immune system to assist in the rapid eradication of the pathogen
  • Use as adjunctive therapy along with standard of care regimens
  • Broad applicability in the treatment and prevention of infectious diseases

CD201

CD201 is a novel, bispecific antimicrobial immunotherapy being developed for the treatment of multi-drug resistant (MDR) bacterial infections, including those caused by MCR-1-producing pathogens.

CD201 may circumvent existing bacterial resistance mechanisms and introduce a new mechanism of immune-mediated killing, potentially providing a novel tool for fighting MDR pathogens. These include pathogens resistant to carbapenems, a staple, standard-of-care therapy for Gram-negative infections, as well as colistin, an antibiotic used as last-resort therapy.

ADC

Cloudbreak Antibody Drug Conjugates (ADC) offer several added benefits over small molecule approaches for use as highly effective countermeasures against MDR bacterial infections.

Different from traditional antibiotics, the Cloudbreak ADCs physically link the pathogen and the immune component to eradicate pathogens via dual killing mechanisms. The engagement of specific innate immune system components confers potential to largely limit resistance development in target pathogens. Furthermore, by linking to an antibody Fc, ADCs possess extended half-lives to support once-weekly or bi-weekly dosing, making them well suited as both immunoprophylactic and immunotherapeutic agents to prevent and treat life-threatening multidrug-resistant Gram-negative infections.

Advantages of Gram-negative Antimicrobial Antibody Drug Conjugate (ADC)
1
Direct kill: novel TMs tightly bind LPS and kill bacteria – KAPE spectrum
2
Immunomodulatory: Fc recruits and initiates an innate immune system response
3
Superior PK/ADME: Antibody-like PK, receptor mediated transport to lung, limited kidney exposures
4
Potentiation: Enhances permeability of standard of care therapeutics to provide additional efficacy
5
Protection from septic shock: Attenuation of sepsis response through LPS scavenging

CARB-X Award

CARB-X (Combating Antibiotic Resistant Bacteria Accelerator) is the world’s largest public-private partnership focused on antibacterials, created by the U.S. Department of Health and Human Services (HHS), Biomedical Advanced Research and Development Authority (BARDA) and the National Institute of Allergy and Infectious Diseases (NIAID). CARB-X is funded by BARDA and the London-based Wellcome Trust, a global charitable foundation, and administered by the Boston University School of Law.

In March of 2017, Cidara received a grant for up to $6.9 million from CARB-X to advance the development of its antibiotic immunotherapy, CD201, for the treatment of life-threatening multi-drug resistant (MDR) Gram-negative bacterial infections. Following a competitive review process, CARB-X selected Cidara’s CD201 product candidate for its first phase of funding awarded to companies with pre-clinical development projects in the area of antibiotic-resistant infections, a serious global health threat. Under the grant, CARB-X will provide up to $3.9 million in base funding and up to $3.0 million in additional funding through Phase 1, linked to the successful progression of the project through milestones established by CARB-X.

To be considered, the clinical project must target one of the deadly antibiotic-resistant bacteria on the Serious or Urgent Threat List prepared by the U.S. Centers for Disease Control and Prevention (CDC) or appear on the Priority Pathogens list published by the World Health Organization (WHO). The first projects selected for the Powered by CARB-X portfolio focus on Gram-negative bacteria, which are responsible for half of all healthcare associated infections many of which are resistant to multiple drugs.

The rise in drug-resistant bacteria is a growing public health concern. In the U.S. alone, the CDC estimates that 23,000 people die each year from drug-resistant infections, with related healthcare costs of approximately $20 to $25 billion. In addition, a recent CDC report highlighted the urgent need for novel antibacterials that are effective against Gram-negative bacteria.

Gram-negative Bacterial Infections

Gram-negative pathogens are responsible for half of all healthcare associated infections (HAIs). The CDC estimates that there were 1.7 million HAIs in the U.S. and the estimated number of death associated with HAIs were 99,000, costing the U.S. health care system $20B per year. Gram-negative pathogens are the primary cause of hospital-acquired infections in the ICU. While mortality due to these infections is already high, infections caused by MDR strains result in significantly higher mortality and hospital length of stay when compared to those caused by susceptible strains.

While new antibiotics introduced over the past 15 years have made significant progress in the fight against resistant Gram-positive bacteria, including MRSA, a recent CDC report highlighted the urgent need for novel antibacterials that are effective against Gram-negative bacteria, particularly carbapenem-resistant Enterobacteriaceae (CRE), MDR-Acinetobacter baumannii and Pseudomonas aeruginosa. Several recently approved or late-stage antibacterials provide adequate coverage of less resistant forms of CRE and P. aeruginosa, but significant spectrum gaps remain.

Immunocompromised patients are at significantly higher risk of developing a MDR Gram-negative infection and have inadequate immune systems to adequately fight the infections. Novel agents are needed that provide both an antibacterial effect in addition to leveraging the remaining immune system to help clear the infection. New resistance mechanisms, such as the emergence of the mcr-1 resistance gene have rendered even toxic last line agents ineffective.

Mortality Rate by Susceptibility of Pathogen

Mortality rates are much higher in patients with resistant bacteria compared to susceptible strains.

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