July 1, 2020 PAP-Q2-20-CL-018
Immunotherapies that rely on bispecific immune engagers have revolutionized the treatment of cancer. The concept involves the targeted delivery of toxic molecules to specific harmful cells without damaging healthy cells, resulting in a reduction of deleterious side effects.
Cidara Therapeutics was founded in late 2013 to develop novel treatments for infectious diseases that apply this same approach. Traditional therapies for infectious diseases involve molecules that are toxic to infectious agents. Unfortunately, many invading organisms mutate to evolve and develop resistance to the mechanisms of action of many of these drugs.
Taking the two-fold approach suggested by many immunotherapies should help address this issue. Bispecific engagers should be able to direct the delivery of the toxic agent while simultaneously activating the immune system against the infecting organisms.
First In early 2014, we had compelling in vitro data in hand, but it was too early to take the company public, so Cidara acquired a later-stage candidate in the newest class of antifungal agents. Rezafungin was ready to enter the clinic and had highly differentiating properties, most notably greater efficacy and a prolonged half-life, that allow once-per-week IV therapy rather than daily 1-hour infusions.
Invasive fungal disease (IFD) is a serious threat to millions of patients around the globe, resulting in more than 1.5 million deaths annually. IFD continues to be a global health issue, especially for critically ill patients in hospitals and patients with compromised immune systems. Current treatment alternatives for systemic fungal disease, including polyenes, azoles, and approved echinocandins, have significant limitations. Toxicities, drug–drug interactions, low or variable exposure, daily intravenous administration, and increasing resistance are all issues.
Rezafungin offers a potential new solution for patients and clinicians to resolve these significant limitations. It may facilitate shorter and less costly hospital stays while also serving as a single agent for prophylaxis of several fungal pathogens, displacing azoles and trimethoprim/sulfamethoxazole (TMP/SMX). The U.S. Food and Drug Administration has designated rezafungin as a Qualified Infectious Disease Product (QIDP) Fast Track Product and orphan drug for the treatment of candidemia and invasive candidiasis.
Currently, rezafungin is being studied as a first-line therapy for candidemia and invasive candidiasis and prophylaxis of invasive fungal disease, including diseases caused by Candida, Aspergillus, and Pneumocystis spp. Dose-escalation phase I studies established the safety and pharmacokinetic profile of rezafungin in healthy subjects. Our phase II STRIVE trial in the treatment of candidemia and invasive candidiasis provided compelling data and catalyzed the formation of a major partnership with European pharma company Mundipharma, which has licensed the rights to rezafungin outside of the United States and Japan. A pivotal global phase III registration trial (ReSTORE) was initiated in 2018, and a second (ReSPECT Prophylaxis) is planned for prophylaxis of invasive fungal disease.
While our rezafungin program advanced, we also incubated our proprietary Cloudbreak® bispecific immunotherapy program. Our current focus for this unique antibody–drug conjugate (ADC) program is on antiviral Fc conjugates (AVCs) that consist of a targeting domain (antiviral molecule) that neutralizes a virus directly and an effector domain (Fc antibody fragment) that engages a patient’s immune system to accelerate the elimination of the pathogen. As a result, these drugs provide potent antimicrobial activity and immune system engagement in a single molecule.
Cloudbreak candidates counter infection in two ways: by directly targeting and destroying invading pathogens and by focusing the immune system at the site of infection. The targeting moiety (TM) is a novel and highly potent small molecule that binds surface targets on the pathogen to directly destroy it and/or inhibit replication. The effector moiety (EM) comprises the fragment crystallizable (Fc) region of human IgG1 antibodies and was selected to maximize engagement of the human immune system via Fc-gamma (Fcγ) receptors and for its long half-life. AVCs have the combined benefit of providing rapid onset and protection as well as a long duration of action — up to many months of protection from a single dose.
Currently, Cidara is leveraging the Cloudbreak platform to develop multiple AVCs targeting influenza (flu), HIV, RSV, and coronaviruses. The goal is to develop AVCs that — through their multimodal mechanisms of action — provide direct, sustained antiviral effects and immune system engagement for effective prevention and treatment of disease. We believe that this approach is potentially transformative and definitely distinct from current therapies.
The same features of our AVC technology that make it attractive for the development of influenza vaccines make it well suited for the development of a COVID-19 vaccine.
Cidara’s lead candidate is for influenza, and preclinical results indicate that it could have the potential to even be more effective than a universal vaccine. There is a tremendous unmet need for flu treatments, given that the efficacy of the typical flu vaccine is generally just 40%, and there is a very limited treatment window for therapies (e.g., within 48 hours of symptom onset for Roche’s Tamiflu®). In addition, evolving flu strains are developing resistance to the four drugs that are available as flu therapies.
Cidara’s AVCs have several potential advantages for the prevention and treatment of flu. Cloudbreak AVCs have demonstrated activity against pandemic and seasonal influenza A and B viruses, including resistant strains (e.g., oseltamivir-resistant H1N1) and strains with high pandemic potential (e.g., H5N1, H7N9). The multimodal mechanism of action should also make AVCs less prone to viral resistance. In addition, AVCs should provide antiviral protection independent of immune system status, so even immunocompromised patients can be protected. Finally, because they provide rapid onset of protection, wide strain coverage, and long-term protection, they are well suited for immediate and robust response to seasonal and pandemic influenza.
Our lead molecule (CD377) is in preclinical development. This AVC targets part of the flu virus that has difficulty mutating and is essential for viral replication. As a result, it should protect against all known and unknown flu strains. With its two-fold mechanism, it is very potent, but it is safe enough to be administered every 3–6 months (via subcutaneous or intramuscular injection like the annual flu vaccine).
The Biomedical Advanced Research and Development Authority (BARDA) within the U.S. Department of Health and Human Services has expressed interest in Cidara’s AVC program for influenza. Once we have generated phase I trial data, there may be an opportunity to partner with BARDA on further development and manufacturing of CD377.
The same features of our AVC technology that make it attractive for the development of influenza vaccines make it well suited for the development of a COVID-19 vaccine. AVCs kill any virus present and provide immediate protection, rather than having to wait for antibodies to build up over a two-week period, both of which are crucial to treating patients and slowing the spread of the virus. Furthermore, the small size of AVCs compared with monoclonal antibodies allows rapid penetration into the lungs, the site typically first invaded by respiratory viruses.
Immediately following the release of the genetic sequence for the SARS-CoV-2 virus in early January 2020, Cidara began building an AVC that could serve as a COVID-19 vaccine. In the first half of April, we conducted in vitro testing of the vaccine candidate against a broad panel of different coronaviruses and then progressed to evaluation in animal models.
One bottleneck in the process was the lack of available in vitro and in vivo assays for the specific COVID-19 coronavirus strain. Testing was first performed against other known coronaviruses (SARS, MERS) and then against SARS-CoV-2 in late April.
Dr. Stein has been President, CEO, and Director of Cidara since January 2014. Previously, he was the CEO of Trius Therapeutics, Inc., from 2007 until its acquisition by Cubist Pharmaceuticals, Inc., in September 2013. Dr. Stein currently serves as a Director of Paratek Pharmaceuticals (NASDAQ: PRTK) and Ideaya Biosciences (NASDAQ: IDYA). Dr. Stein conducted his postdoctoral research as an Alexander Hollaender Distinguished Postdoctoral Fellow at the California Institute of Technology and his graduate work as a NASA Graduate Student Researcher Fellow at the University of California, San Diego.