BRINCIDOFOVIR WAS USED TO SUCCESSFULLY TREAT ADENOVIRUS INFECTIONS IN SOLID ORGAN TRANSPLANT RECIPIENTS AND OTHER IMMUNOCOMPROMISED PATIENTS Diana F. Florescu, MD 1, Michael S. Grimley, MD 2, Genovefa A. Papanicolaou, MD 3, Vinod K. Prasad, MD, FRCP 4, Enrikas Vainorius, MD 5, Greg Chittick 5, Thomas M. Brundage, MS 5, W. Garrett Nichols, MD, MS 5 1 Univ Nebraska Med Center, Omaha, 2 Cincinnati Children's Hosp Center, Cincinnati, 3 Memorial-Sloan Kettering Cancer Center, New York, 4 Duke Univ Med Center, Durham, 5 Chimerix, Inc., Durham, USA
Disclosure Statement Diana F. Florescu, M.D. Associate Professor Internal Medicine Department Division of Infectious Diseases Director, Transplant Infectious Diseases Research Associate Director, Transplant Infectious Diseases Program University of Nebraska Medical Center, Omaha, Nebraska, USA I have financial relationship(s) with: Advisory Board: Chimerix; Merck; Oxford Other (Trial investigator): Chimerix; Merck; Oxford; Astellas; Shire My presentation includes discussion of brincidofovir (also CMX1), an investigational medicine being developed by Chimerix, Inc. 2
Adenovirus: An Important Cause of Mortality & Morbidity Incidence of adenovirus (AdV) infection in solid organ transplant (SOT) recipients is less well defined than in hematopoietic cell transplant (HCT) recipients, mainly due to lack of systematic screening Estimated at approx. 5 to 1% of SOT recipients Most infections occur within 3 months of transplantation Incidence higher among pediatric SOT recipients Factors increasing risk of progression to AdV disease: Isolation of virus early after transplantation Persistent isolation of virus Isolation of virus from more than one site High initial viral load Intensification of immunosuppression regimen No FDA-approved treatment for AdV 3 Sandkovsky, et al. Curr Infect Dis Rep. 214;16:416-24. Tebruegge & Curtis. Ped Infect Dis J. 212 Jun;31(6):626-7.
Brincidofovir (BCV, CMX1) BCV is a broad spectrum antiviral with high in vitro potency against all AdV subtypes tested 1 Active form is cidofovir diphosphate Orally bioavailable lipid conjugate of cidofovir BCV is absorbed in small intestine, circulates in blood as BCV and readily crosses cell membranes Intracellular cleavage of BCV allows cidofovir to be delivered directly to the site of viral replication Increases antiviral potency Low risk of nephrotoxicity or myelotoxicity 2-4 High barrier to viral resistance 4 1. Bae A, et al. Presented at BMT Tandem 216. 2. Morrison M, et al. Presented at the World Transplant Congress, July 214. 3. Grimley M, et al. Presented at the EBMT meeting, April 213. 4. Tippin T, et al. Ther Drug Monit. 216;38:777-86.
AdVise: Study Overview AdVise (CMX1-34; NCT28736) was an open-label, multicenter study to evaluate BCV for AdV in pediatric and adult patients BCV suspension or tablets were administered orally twice weekly (BIW) for 12 weeks (extensions permitted for ongoing or recurrent infection) Dose: 1 mg BIW for 5 kg, 2 mg/kg BIW for <5 kg Cohorts A and B (allogeneic HCT recipients weighing <12 kg with asymptomatic viremia/localized infection or disseminated disease; N= 158) described previously 1 Cohort C (N = 43): all other patients regardless of disease status, including: SOT recipients (n = 18) Other immunocompromised patients (n = 25): Chemotherapy (n=1) Known or suspected primary immune deficiency (n=6) Autologous HCT (n=5) Allogeneic HCT weighing >12 kg (n=1) Fibromyalgia on steroid therapy, (n=1) Myocarditis (n=1) Former pre-term infant with chronic lung disease (n=1) Final analysis of outcomes at 36 weeks post-first BCV dose 5 1. Prasad VK, et al. Presented at BMT Tandem 217.
Baseline Characteristics All Cohort C Patients (N=43) Adult (n=4) SOT Pediatric (n=14) Adult (n=9) Other Pediatric (n=16) Median (Range) Age (yrs) 4 (<1 76) 43 (21 58) 4 (<1 17) 45 (22 76) 1 (<1 13) White Race 27 (63) 4 (1) 8 (57) 6 (67) 9 (56) Male 27 (63) 3 (75) 9 (64) 3 (33) 12 (75) Prior CDV within 3 Days: None reported <1 mg/kg, cumulative dose 1 mg/kg, cumulative dose 28 (65) 11 (26) 4 (9) 2 (5) 2 (5) 11 (79) 2 (14) 1 (7) 7 (78) 2 (22) 8 (5) 5 (31) 3 (19) Symptomatic AdV Disease 26 (6) 4 (1) 8 (57) 4 (44) 1 (63) Median (Range) AdV Viremia (log 1 c/ml) Median (Range) Days from AdV Diagnosis Urine AdV Respiratory AdV Stool AdV 3.3 (ND 1.) 3. (ND 3.3) 3.6 (ND 1.) 2.4 (ND 7.2) 3.5 (ND 8.1) 7 (1 247) 6 (6 16) 7 (2 16) 7 (1 247) 11 (2 48) 17 (4) 27 (63) 29 (67) 1 (25) 2 (5) 3 (75) 5 (36) 5 (36) 11 (79) 4 (44) 7 (78) 7 (78) 7 (44) 13 (81) 8 (5) 6 All values are n (%) unless otherwise stated. Abbreviations: CDV, cidofovir; ND, not detected; c/ml, copies/milliliter.
Solid Organ Transplant Characteristics Small bowel most common transplant preceding AdV in SOT: All Cohort C SOT Patients (N=18) Adult SOT Patients (n=4) Pediatric SOT Patients (n=14) Organ(s) Transplanted Heart Lung Thymus Kidney ± Pancreas Liver ± Pancreas/Small Bowel Small Bowel 1 (6) 3 (17) 1 (6) 3 (17) 9 (5) 1 (6) 1 (25) 2 (5) 1 (25) 1 (7) 2 (14) 1 (7) 1 (7) 8 (57) 1 (7) Days Since Transplant List or Median (Range) 39 (2-9342) 29, 31, 1625 & 9342 39 (2 111) 7 All values are n (%) unless otherwise stated.
Brincidofovir Treatment Treatment Duration (days) Number of BCV Doses All Cohort C Patients (N=43) Solid Organ Transplant Adult (n=4) Pediatric (n=14) Adult (n=9) Other Pediatric (n=16) Median (Range) 29 (1 244) 24 (8 26) 78 (15 244) 19 (1 88) 37 (1 166) Median (Range) 9 ( 1 5) 8 (3 8) 19 (5 5) 6 (1 25) 12 (1 48) Completed Not completed 13 (3) 3 (7) 4 (1) 6 (43) 8 (57) 1 (11) 8 (89) 6 (38) 1 (63) Treatment Course Disposition Reason: Adverse event Death Physician decision Other 7 (16) 7 (16) 12 (28) 4 (9) 2 (5) 2 (5) 2 (14) 5 (36) 1 (7) 4 (44) 1 (11) 2 (22) 1 (11) 1 (6) 4 (25) 3 (19) 2 (13) Concurrent Reduction in Immune Suppression (through Week 4)* 9 (21) 5 (36) 1 (11) 3 (19) Although prescribed duration of therapy was long per protocol (12+ weeks), virus was rapidly cleared 8 All values are n (%) unless otherwise stated. * Based on review of reported immunosuppressant medication use through 4 weeks post-first BCV dose.
Adverse Events of Interest All Cohort C Patients (N=43) Solid Organ Transplant Adult (n=4) Pediatric (n=14) Adult (n=9) Other Pediatric (n=16) Gastrointestinal AEs, Grade 3* Laboratory Test AEs, Grade 3* Abdominal pain 1 (2) 1 (7) Diarrhea 5 (12) 1 (25) 3 (21) 1 (6) Nausea 1 (2) 1 (11) Vomiting 2 (5) 1 (11) 1 (6) ALT increased 3 (7) 2 (14) 1 (11) AST increased 2 (5) 2 (14) Bilirubin increased 2 (5) 2 (14) AEs leading to BCV discontinuation 1 (23) 2 (5) 5 (56) 3 (19) Event(s) leading to discontinuation in individual subjects Diarrhea Diarrhea + Abdominal pain Abdominal pain ALT increased C. difficile colitis Septic shock Visceral arterial ischemia Adenoviral hepatitis Klebsiella sepsis Respiratory failure 9 * Treatment-emergent events (through last BCV dose + 7 days) assessed using CTCAE grading scales, version 4.3. All values are n (%) unless otherwise stated. Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase
Rapid Antiviral Response to Brincidofovir Therapy Subjects with Baseline Viremia (n=3) Undetectable or 2 log 1 decrease in AdV viremia any time on treatment, n (%) 22 (73) Days to undetectable or 2 log 1 decrease, median (IQR), n=22 15 (8 22) Undetectable AdV viremia at end of treatment, n (%) 18 (6) 1 Plot presents values during BCV dosing up to 7 days after last dose. AdV DNA in plasma assayed using 75 Adenovirus quantitative real-time PCR test (Viracor-IBT Laboratories); lower limit of detection, 1 copies/ml. Abbreviations: IQR, interquartile range.
Overall Survival by Age Group and Transplant Status 79% (11/14) 75% (3/4) 63% (1/16) 56% (5/9) 6/43 (14%) patients had cause of death reported as AdV related 11
Rapid Virologic Response to BCV after 2 Weeks was Associated with Improved Survival at Week 36 n=21 with Baseline AdV viremia 3log 1 copies/ml 13 / 21 (62%) had a 2 log 1 drop or were undetectable at Week 2 1 / 13 (8%) of virologic responders died prior to Week 36 4 / 8 (5%) of virologic non-responders died prior to Week 36 Mortality model: Responders vs Non-responders: HR 8. (.8 75.8), p=.7 Pediatrics vs. Adults: HR.6 (.1 3.7), p=.56 SOT vs Other: HR.6 (.1 3.8), p=.56 12 All values are n/n (%). Abbreviations: HR, hazard ratio. A Cox model incorporating age group and solid organ transplant was used to compare mortality at 36 weeks in responders and non-responders. Responders are defined as subjects who achieved undetectable viremia or 2 log 1 decrease at Week 2, with non-responders defined as subjects who did not achieve either.
Lower Viral Burden with BCV Associated with Improved Survival Time-averaged area under the viremia-time curve (AAUC; DNA copies/ml) is a virologic endpoint that can quantify severity of disease in acute lytic viral infections such as AdV 1-2 Lower AdV viral burden with BCV is associated with increased survival 3 In Cohort C patients (N = 22) with clinically relevant viremia at baseline ( 3 log 1 copies/ml), decreased AAUC over 12 weeks (1-2 nd vs. 3-4 th quartiles) positively correlated with survival at Week 36 13 1 Heim A. Expert Rev Anti Infect Ther. 211;9:943-5; 2 DeVincenzo J, et al. N Engl J Med. 214;371:711-22 ; 3 Brundage T, et al. Presented at BMT Tandem 218
Conclusions Oral brincidofovir rapidly cleared AdV viremia in this diverse population of immunocompromised patients Lower AdV burden (as measured by AAUC -12 weeks for viremia) was correlated with improved survival There are no other drugs for AdV currently in development These data support further study of short-course oral brincidofovir in patients with adenovirus infection 14
Acknowledgments The authors would like to thank the patients, their families, and study center personnel who participated in the study. 15