Switch from Existing Antivirals to Brincidofovir Leads to Improving Renal Function

Transcription

1 Switch from Existing Antivirals to Brincidofovir Leads to Improving Renal Function Marion Morrison MD 1, Robin Avery MD 2, Eun Kwak MD 3, Tom Brundage MS 1, Herve Mommeja-Marin MD World Transplant Congress San Francisco, CA, USA Oral Abstracts Session: Infectious Complications Post Kidney Transplantation Tuesday, 29Jul2014, 4:48 PM 1 Chimerix, Inc., Durham, NC, 2 Johns Hopkins, Department of Medicine, Infectious Diseases, Baltimore, MD, 3 University of Pittsburgh, Department of Medicine, Infectious Diseases, Pittsburgh, PA 1

2 DISCLOSURES Marion E. Morrison, MD Senior Medical Director, Clinical Research Chimerix, Inc. Durham, NC I have a relevant financial relationship with respect to the content of this presentation as follows: 1. Chimerix, Inc. 2. Employee and ownership interest in stocks 2

3 Brincidofovir (BCV, CMX001) Investigational antiviral in Phase 3 development Nucleotide analog: class with known safety, efficacy and high barrier to resistance with strong precedent in antivirals (HIV, HBV, HCV, HSV) Proprietary lipid technology allows oral, twice-weekly dosing, while avoiding renal toxicity associated with intravenous cidofovir administration Brincidofovir is the first potential antiviral for prevention of CMV with the safety to be able to be used in HCT* recipients who are at very high risk for drug-related toxicities. *HCT = Hematopoietic Cell Transplant 3

4 In Vitro Brincidofovir Concentrates the Active Antiviral in the Cells Where Viruses Replicate 4

5 Brincidofovir (BCV, CMX001) BCV is in Phase 3 development for Prevention of CMV post-hct (Study 301, SUPPRESS) Treatment of adenovirus infection (Study 304) Solid organ transplant (SOT) trial design in progress Safety database (>1000 subjects) shows no hematologic or renal toxicity to date, which differentiates BCV from cidofovir Lack of hematologic toxicity supports initiation of BCV in the immediate posttransplant period, regardless of engraftment BCV is not a substrate of hoat1 (human organic anionic transporter), is not concentrated in the renal tubular cells, and is thus incapable of causing hoat1- mediated renal toxicity 5

6 Dose-Related Improvement in Renal Function as Measured by egfr over time, in Phase 2 Trial No evidence of nephrotoxicity 6

7 Brincidofovir: In Vitro Antiviral Activity Against All 5 Families of dsdna viruses Pathogenic to Humans 7

8 CMX : Expanded Access Study Open-label trial of BCV for treatment of subjects with serious or lifethreatening infection with one or more dsdna viruses, and no other therapeutic options Of total 210 subjects enrolled (adults and pediatrics) 152 (72%) were HCT recipients 33 (16%) were SOT recipients 25 (12%) were non-transplant patients Reasons for enrollment Lack of Efficacy/Resistance 48% Nephrotoxicity* (history of/at risk for) 25% Other/Not given 18% *For the purposes of this analysis, if both nephrotoxicity and myelotoxicity were provided as reasons for enrollment, the subjects were included in the nephrotoxicity calculation only. Myelotoxicity* (history of/at risk for) 6% BCV treatment duration was highly variable (range: 1 to 24 weeks) 8

9 Analysis of Baseline and On-treatment Renal Function (estimated GFR) Analysis Population Study 350 Subjects with baseline and on-treatment GFR data Subjects with prior CDV or FOS use Subjects with no concomitant CDV or FOS use (N=66) Maximum on-treatment egfr was compared to Baseline egfr Time to maximum on-treatment egfr assessed Median duration of BCV treatment, 4.5 weeks 9

10 Demographics and Baseline Characteristics Prior CDV or FOS, but No Concomitant CDV or FOS N=66 Age median, years 36.0 < (32%) (68%) Female, % 23 (35%) White, % 49 (74%) Transplant HCT 49 (74%) SOT 10 (15%) None 7 (11%) Days from Transplant median 98.0 Baseline egfr median, ml/min/1.73m <30 13 (20%) 30 - <60 16 (24%) 60 - <90 10 (15%) (41%) 10

11 % of Subjects >80% Subjects on Prior, but No Concomitant CDV or FOS Had Improvement in GFR During Brincidofovir Treatment GFR Improvement from baseline >0 ml/min >5 ml/min >10mL/min >20 ml/min 0 All (N=66) BL GFR <60 ml/min (N=29) BL GFR <30 ml/min (N=13) >40% of all subjects had GFR improvement of >20 ml/min Improvement in GFR was seen in subjects with baseline GFR <30 ml/min, consistent with severe renal impairment Median time to max GFR: 2 wks (range: 1 8 wks) 11

12 % of Subjects >80% Subjects on Prior, but No Concomitant CDV Had Improvement in GFR During Brincidofovir Treatment GFR Improvement from Baseline >0 ml/min >5 ml/min >10mL/min >20 ml/min 0 All (N=37) BL GFR <60 ml/min (N=14) BL GFR <30 ml/min (N=6) The majority of subjects had improvement in GFR of >10 ml/min regardless of baseline GFR All subjects with severe renal impairment at baseline had improvement in GFR, and >60% had improvement of >20 ml/min Median time to max GFR: 2 wks (range: 1 8 wks) 12

13 Conclusions CMX data support lack of BCV nephrotoxicity, despite highly complex and extremely ill population Greater than 80% of subjects with prior CDV or FOS treatment had improvement in GFR during BCV treatment These data are consistent with data from Phase 2 CMV prevention/preemption trial, which suggested BCV may protect GFR In the Phase 2 study, BCV treatment was associated with greater GFR improvement than placebo in subjects with BKV viruria Further study of BCV in kidney transplant recipients, and other patients at high risk of renal impairment is warranted 13

14 Acknowledgement The CMX Expanded Access Study was funded in whole or in part with Federal funds from the Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under Contract No. HHSO1002O C. 14