No abstract

Background AVCs (antiviral Fc-conjugates) are novel, long-acting immunotherapeutic conjugates of potent antivirals conjugated to the Fc domain of human IgG1. CD377, an AVC development candidate for the prevention and treatment of influenza A and B, comprises multiple copies of a novel neuraminidase inhibitor conjugated to IgG1 Fc. CD377 demonstrated potent, broad-spectrum activity in vitro and in lethal mouse models. Herein, we characterize the activity of CD377 on viral lung burden in lethal mouse models and in a ferret model of influenza A (H1N1) infection. Methods BALB/c mice were challenged intranasally with 3 x 102 PFU of influenza A/PR/8/1934 (H1N1) or with 3 x 104 PFU A/CA/07/2009 (H1N1)pdm. Ferrets were challenged sub-lethally at 1 x 106 PFU with influenza A/CA/07/2009 (H1N1)pdm. A single dose of CD377 was given 2 h post-challenge in the mouse (subcutaneous dose ranging from 0.1 – 3 mg/kg) or 24 h prior to challenge in the ferret (intravenous dose ranging from 0.3 – 30 mg/kg). In mice, oral oseltamivir was given at 5 mg/kg (human equivalent dose, HED) or at 50 mg/kg BID x 4 days starting at 2 h post-challenge and in ferrets at 20 mg/kg (4x HED) BID x 4 days starting at 4 h prior to infection. Viral burden was determined on day 4 (mouse) or days 2 and 4 (ferret) post-challenge by plaque assay. Results In mice, CD377 demonstrated dose-dependent reduction in viral lung burden (1.1 logs at 0.1 mg/kg, 2.1 logs at 0.3 mg/kg, 3.1 logs at 1 mg/kg and 3.6 logs at 3 mg/kg) compared to PBS against influenza A/PR/8/1934 (H1N1) (Fig. 1A). In the same study, oseltamivir reduced viral lung burden only by 0.8 logs at both 5 mg/kg (HED) and 50 mg/kg. No significant reduction in lung burden was observed between negative controls, PBS and hIgG1 Fc. Similarly, CD377 demonstrated a dose-dependent, multi-log reduction in viral lung burden against influenza A/CA/07/2009 (H1N1)pdm (Fig. 1B). In ferrets, CD377 reduced viral load with dose dependency at days 2 (Fig. 1C) and 4 post-infection (Fig. 1D). CD377 at 3 mg/kg or higher dose was superior compared to oseltamivir at 4x HED on days 2 and 4 post-challenge. Conclusion CD377 demonstrated superior viral load reduction compared to oseltamivir in lethal influenza A (H1N1) mouse and ferret models. These data support further development of CD377 for prevention and treatment of influenza infection. Disclosures Simon Döhrmann, PhD, Cidara Therapeutics (Shareholder) Amanda Almaguer, Bachelors, Cidara Therapeutics, Inc. (Employee, Shareholder) Nicholas Dedeic, n/a, Cidara Therapeutics (Employee) Karin Amundson, BSc, Cidara Therapeutics (Shareholder) Thomas P. Brady, PhD Chemistry, Cidara Therapeutics (Employee) Alain Noncovich, PhD, Cidara Therapeutics (Shareholder) Grayson Hough, MS - Chemistry, Cidara Therapeutics (Employee) Allen Borchardt, PhD, Cidara Therapeutics (Employee) Jeffrey B. Locke, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Jason Cole, PhD, Cidara Therapeutics (Shareholder) James Levin, PhD, Cidara Therapeutics (Shareholder) Les Tari, PhD, Cidara Therapeutics (Shareholder)

Background CD377 is a novel antiviral Fc-conjugate (AVC) development candidate for influenza prevention and treatment, comprising multiple copies of a novel potent small-molecule antiviral and the Fc domain of human IgG1. CD377 was designed as a stable, long-acting molecule for treatment and prevention of influenza A and B. Studies were conducted to characterize CD377 stability/pharmacokinetics (PK), single-dose efficacy in influenza models, and safety/toxicology. Methods PK in the mouse (1-100 mg/kg), rat (5-50 mg/kg), ferret (3 mg/kg), and monkey (5-20 mg/kg) were studied by sampling plasma over a 1-2 week interval. Plasma levels of intact molecule and total Fc were measured by neuraminidase (NA)-capture and Fc-capture with Fc-detection ELISA, respectively. Two-week safety/toxicology (bodyweight, coagulation, clinical signs, chemistries, hematology, cytokines, urinalsis, histopathology) was evaluated in monkeys (5-20 mg/kg on days 1 and 8). Prophylaxis efficacy was studied in a lethal influenza mouse model using a single dose of CD377 (0.3–3 mg/kg) 28 days prior to intranasal (IN) challenge with 3x the LD95 of A/California/07/2009 (H1N1)pdm, A/Hong Kong/1/68 (H3N2), or B/Malaysia (Victoria lineage). Treatment efficacy was studied in a similar mouse model using a single dose of CD377 (0.3–3 mg/kg) administered 2 hours after IN challenge with A/CA/12/2012 (H1N1)pdm. Results Plasma concentrations measured by Fc-capture/Fc-detection and NA-capture/Fc-detection were comparable, indicating that CD377 remained intact in vivo. In species tested, CD377 t1/2 was 3–10 days. Dose proportional increases in exposure were observed, notably from 1–100 mg/kg in mouse. High bioavailability (77%) was observed after subcutaneous (SC) or intramuscular (IM) administration. A single SC dose of 1 mg/kg administered 28 days prior to infection provided 100% protection against H1N1, B, and H3N2 subtypes in mouse (Fig. 1). Treatment efficacy was observed with a single 0.3 mg/kg IM dose. The 2-week monkey toxicology study showed no adverse effects. Figure 1. Efficacy (Survival and Body Weight) of CD377 in a 28-Day Prevention Model Against Influenza H1N1, H3N2, and B Subtypes in Mouse (IN infection challenge on Day t=0 and CD377 dosed t–28 days). Conclusion The stability and safety of CD377, together with its long half-life and efficacy with a single dose, support the potential of CD377 as a long-acting, novel AVC for the prevention and treatment of influenza. Disclosures Voon Ong, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) James Levin, PhD, Cidara Therapeutics (Shareholder) Allen Borchardt, PhD, Cidara Therapeutics (Employee) Thomas P. Brady, PhD Chemistry, Cidara Therapeutics (Employee) Thanh Lam, PhD, Cidara Therapeutics (Shareholder) Alain Noncovich, PhD, Cidara Therapeutics (Shareholder) Joanne Fortier, BSc, Cidara Therapeutics (Employee, Shareholder) Karin Amundson, B.S., Cidara Therapeutics (Shareholder) Jeffrey B. Locke, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Amanda Almaguer, Bachelors, Cidara Therapeutics, Inc. (Employee, Shareholder) Nicholas Dedeic, n/a, Cidara Therapeutics (Employee) Grayson Hough, MS - Chemistry, Cidara Therapeutics (Employee) Jason Cole, PhD, Cidara Therapeutics (Shareholder) Simon Döhrmann, PhD, Cidara Therapeutics (Shareholder) Rajvir Grewal, n/a, Cidara Therapeutics, Inc. (Employee, Shareholder) Elizabeth Abelovski, B.S., Cidara Therapeutics (Shareholder) James M. Balkovec, PhD, Cidara Therapeutics (Consultant, Shareholder) Ken Bartizal, PhD, Cidara Therapeutics, Inc. (Consultant, Shareholder) Les Tari, PhD, Cidara Therapeutics (Shareholder)