Elizabeth A. Lakota, Pharm.D., M.S.Institute for Clinical Pharmacodynamics, Inc.242 BroadwaySchenectady, NY 12305Telephone: (518) 631-8100Fax: (518) 631-8199E-mail: elakota@icpd.com

Pharmacokinetic-Pharmacodynamic Analyses to Provide Rezafungin Prophylaxis Dose Selection Support for Invasive Fungal Infections in Blood and Bone Marrow Transplant Patients

CONCLUSIONS

RESULTS

American Society of Hematology, San Diego, CA. December 1-4, 2019

RESULTS

REFERENCES

INTRODUCTION

E.A. Lakota1, S. Flanagan2, T. Sandison2, J. Brown3, C.M. Rubino1

1Institute for Clinical Pharmacodynamics, Inc., Schenectady, NY, USA; 2Cidara Therapeutics, San Diego, CA, USA, 3Stanford University Medical Center, Division of Blood and Marrow Transplant, Stanford, CA, USA

METHODS

1. Sandison T, Ong V, Lee J, Thye D. 2017. Safety and Pharmacokinetics of CD101 IV, a Novel Echinocandin, in Healthy Adults. Antimicrob Agents Chemother 6:e01627-16.

2. Ong V, Bartizal K, Cushion M, Miesel L, Lopez SR. Antifungal Prophylaxis with CD101 in Immunosuprreseed Mouse Models of Candidiasis, Aspergillosis, and Pneumocystis Pneumonia (PCP). Abstract 9645. 22nd Congress of the European Hematology Association. Madrid, ES. June 22-25, 2017.

3. Lakota EA, Ong V, Flanagan S, Rubino CM. 2018. Population Pharmacokinetic Analyses for Rezafungin(CD101) Efficacy Using Phase 1 Data. Antimicrob Agents Chemother 62:e02603-17.

4. Flanagan S, Sandison T, Locke JB, Ong V, Ye G, Bartizal K, Daruwala P. 2018. CD101 prophylactic dose rationale for prevention of Aspergillus, Candida, and Pneumocystis Infections. Biol Blood Marrow Transplant 24:S389–S390.

5. Pfaller MA, Messer, SA Rhomberg PR, Schaefer BA, Castanheira M. Activity of a Long-Acting Echinocandin Rezafungin Tested against Invasive Fungal Isolates Collected Worldwide. Abstract 2400. IDWeek 2018. San Francisco, CA. October 3-7, 2018.

• Rezafungin is a novel antifungal of the echinocandin class being developed as a single agent for the prevention of invasive fungal infections (IFIs) caused by Candida, Aspergillus, and Pneumocystis species in patients at high risk of infection.

• Rezafungin exhibits an exceptionally long half-life (~133 h) which enables the administration of once-weekly dosing regimens [1].

• Treatment efficacy in a mouse Pneumocystis model is achieved at a human equivalent dose of <50 mg once-weekly [2].

• A dose of 400 mg, followed by 200 mg once-weekly achieved >90% target attainment for treatment of Candida [3].

• Although lower doses of rezafungin might be useful for prevention of Pneumocystis and Candida infections, prevention of invasive aspergillosis in immunosuppressed populations is often considered more challenging.

OBJECTIVES• Pharmacokinetic-pharmacodynamic simulations were

performed, at the dosing regimen for treatment of Candida, to evaluate the appropriateness of rezafunginfor prophylaxis against A. fumigatus among blood and bone marrow transplant (BMT) patients.

Population Pharmacokinetic Model• Data from the two Phase 1 trials used previously to

develop the population pharmacokinetic (PK) model were pooled with data from an additional Phase 1 trial and the Phase 2 STRIVE trial data in patients with candidemia and/or invasive candidiasis. CD101.IV.1.01 Evaluated single intravenous (IV ) doses ranging

from 50 – 400 mgCD101.IV.1.02 Evaluated multiple weekly IV doses ranging from

100 – 400 mgCD101.IV.1.06 Evaluated single IV doses ranging from 600 – 1400

mgCD101.IV.2.03 Treatment Arm 1: 400 mg once-weekly x 2 (STRIVE) weeks, optional additional weekly doses

Treatment Arm 2: 400 mg once-weekly x 1 week followed by 200 mg once-weekly x 1 week, optional additional weekly doses

• The population PK model was refined using NONMEM Version 7.2.

• The ability of covariates such as body size, age, sex, albumin, creatinine clearance, and infection status to explain a portion of the interindividual variability on select PK parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001).

METHODS

Monte Carlo Simulations• Baseline demographic data were available from 100

patients who underwent a BMT at Stanford Medical Center. • Using this dataset and the developed population PK model,

a Monte Carlo simulation (n=2,000) was conducted to simulate expected rezafungin concentration-time profiles in BMT patients following administration of rezafungin 400 mg IV on Week 1 then 200 mg IV weekly x11. o A human plasma protein binding estimate of 97.4% was used [4].

• Free-drug concentration-time profiles were evaluated relative to the maximum observed A. fumigatus minimal effective concentration to inhibit 100% of isolates tested (MEC100) from surveillance data collected in 2017 [5] shown in Table 1.

• These data provide support for a weekly rezafungin dosing regimen for the prevention of A. fumigatus infections among BMT patients.

• The effectiveness of antifungal prophylactic regimens are frequently limited due to pill burden, adherence, safety, tolerability, and drug interactions.

• In addition to the excellent safety, tolerability, and lack of drug interactions exhibited by echinocandin agents, rezafungin’s favorable PK profile presents the opportunity to mitigate the typical challenges faced when administering IFI prophylaxis in BMT patients.

Figure 3. Rezafungin free-drug plasma concentration-time profiles by week relative to A. fumigatus MEC100

Table 1. Rezafungin MEC distributions for A. fumigatus based on isolates collected in the international SENTRY AntifungalSurveillance Program

Pathogen (N)

No. of occurrences by MEC (mg/L)(cumulative % inhibited)a

≤0.008 0.015 0.03 MEC50 MEC90 MEC100

A. fumigatus(60)

25 (41.7) 29 (90.0) 6 (100) 0.015 0.015 0.03

a. Based on data for clinical isolates described in reference 5.

RESULTSPopulation Pharmacokinetic Model• The final population PK model was a linear, four-

compartment model with zero order IV input. • The model provided precise and unbiased fits to the

observed data (Figure 1).

Population Pharmacokinetic Model• Albumin, sex, infection status, and body surface area

were all found to be significant covariates.o Mean parameter estimates for an infected male subject with

an albumin concentration of 4.2 g/dL and body surface area of 1.83 m2: CL = 0.254 L/h, Vc = 16.4 L, CLd1 = 18.2 L/h, Vp1 = 14.6 L, CLd2 = 0.541 L/h, Vp2 = 18.0 L, CLd3 = 0.0743 L/h, Vp3 = 13.6 L.

o Differences in predicted median area under the concentration time curve (AUC) across a wide range of covariate values were modest (Figure 2).

Figure 1. Observed versus model predicted rezafunginconcentrations

Figure 2. Forrest plot of covariate effects on rezafungin Week 1 plasma AUC

• Across simulated subjects, exposures were highest during Week 1 (Table 3).

• Following administration of rezafungin 400 mg IV on Week 1 then 200 mg IV weekly x11, free-drug plasma concentration-time profiles for Weeks 1, 2, and 12 relative to the A. fumigatus MEC100 (0.03 mg/L) are displayed in Figure 3.

• As shown in Table 4, through Week 12, >90% of simulated patients had rezafungin free-drug concentrations above the MEC100 value for the entire dosing interval (one week). This result was ≥99.8% when based on the MEC90.

Variable Median (Range) N (%)

Age (years) 58 (19 – 75) —

Weight (kg) 73.7 (41.6 – 133) —

Height (cm) 169 (142 – 193) —

BSA (m2) 1.84 (1.27 – 2.61) —

BMI (kg/m2) 26.4 (17.1 – 48.5) —

Albumin (g/dL) 3.35 (1.80 – 4.43) —

Female — 39 (39%)

Allograft Transplant — 87 (87%)

Regimen WeekTotal-Drug Weekly AUC (mg•h/L)

Mean (SD) Median (10th,90th

percentile)

400 mg Week 1 followed by 200 mg

Weekly

1 919 (210) 896 (664, 1202)

4 709 (178) 688 (493, 952)

12 701 (198) 626 (470, 973)

MEC Value Week Percent of Simulated Patients with %T>MEC = 100%

0.015a

1 100%4 99.9%12 99.8%

0.03b

1 98.0%4 92.0%12 90.2%

a. MEC90 value for A. fumigatus based on SENTRY 2017 data.b. MEC100value for A. fumigatus based on SENTRY 2017 data.Table 2. Summary statistics for patient demographics

Table 3. Summary statistics for simulated plasma weekly AUC

Table 4. Percent probability of achieving free-drug plasma concentrations above select MEC values for the entire dosing period (%T>MEC=100%)

Monte Carlo Simulations• The demographic dataset utilized for the simulations

contained 100 BMT patients (Table 2).