TREATMENT OF ADENOVIRUS INFECTION IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTPATIENTS WITH BRINCIDOFOVIR: 24 WEEK INTERIM RESULTS FROM THE AdVise TRIALM. Grimley1; G. Papanicolaou2; V.K. Prasad3; G. Marón4; T. Brundage5; E. Vainorius5; G. Chittick5; and G. Nichols5 for the AdVise Clinical Investigators

1Cincinnati Children’s Hospital, Cincinnati, OH, USA; 2Memorial Sloan Kettering Cancer Center, NY, NY, USA; 3Duke University Medical Center, Durham, NC, USA; 4St Jude Children’s Research Hospital, Memphis, TN, USA; 5Chimerix, Durham, NC, USA

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Adenovirus: Epidemiology and Treatment Options

§ Adenovirus (AdV) infection is an important cause of morbidity and mortality following hematopoietic cell transplant (HCT) – In untreated HCT recipients, mortality rates of up to 26% have

been reported in patients with localized infection and 50-100% in patients with AdV pneumonia and disseminated disease

– Death generally occurs in the first 60 days after diagnosis1–3

§ No approved treatment– Intravenous (IV) gamma globulins and a reduction in immune

suppression may be used, with or without off-label use of IV cidofovir4–6

– IV cidofovir is associated with significant dose-limiting nephrotoxicity in up to 50% of patients7, as well as myelotoxicity, which can be a direct threat to the hematopoietic graft

1. Feghoul L, et al. Clin Microbiol Infect 2015;21:701–9. 2. Lion T. Clin Microbiol Rev 2014;27:441–62. 3. Mynarek M, et al. Biol Blood Marrow Transplant 2014;20:250–6. 4. Yusuf U, et al. Transplantation 2006;81:1398–404. 5. Muller WJ, et al. Clin Infect Dis

2005;41:1812–6. 6. Neofytos D, et al. Biol Blood Marrow Transplant 2007;13:74–81. 7. Lalezari JP, et al. Ann Intern Med 1997;126:257–63.

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Brincidofovir (BCV, CMX001)

§ BCV is a broad-spectrum antiviral with high in vitro potency against all AdV subtypes

§ Intracellular cleavage of BCV allows cidofovir to be delivered directly to the site of viral replication, improving antiviral efficacy and limiting plasma cidofovir exposure

§ BCV is not associated with nephrotoxicity or myelotoxicity1,2

§ BCV has shown promise as:– Pre-emptive treatment of asymptomatic AdV viremia in allogeneic

HCT (allo-HCT) recipients in a placebo-controlled Phase 2 study – Treatment for serious AdV infection or disease under

compassionate use regulations3–6

1. Papanicolaou G, et al. Presented at the European Society for Blood and Marrow Transplantation (EBMT) meeting, April 2014. 2. Morrison M, et al. Presented at the World Transplant Congress, July 2014. 3. Grimley M, et al. Presented at the EBMT meeting,

April 2013. 4. Florescu DF, et al. Biol Blood Marrow Transplant 2012;18:731–8. 5. Grimley M, et al. Presented at BMT Tandem, February 2014. 6. Prasad VK, et al. Presented at BMT Tandem, February 2014.

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AdVise: Study Overview and Objectives

§ AdVise was an open-label, multicenter study to evaluate BCV treatment of AdV infection in ~200 pediatric and adult patients– Primary endpoint: all-cause mortality at Day 60 following initiation

of BCV in allo-HCT recipients with disseminated AdV disease§ Enrolled subjects were assigned to one of three cohorts:

– Cohort A: Allo-HCT recipients at risk of progression to disseminated AdV disease (either localized AdV infection or asymptomatic viremia)

– Cohort B: Allo-HCT recipients with disseminated AdV disease– Cohort C: All other patients with serious AdV infections

§ Data in this presentation: interim analysis of outcomes at 24 weeks post-first BCV dose in the 158 allo-HCT recipients (Cohorts A & B)– Includes ~12 weeks of off-treatment follow-up

§ BCV suspension or tablets was administered twice weekly (BIW) for 12 weeks– An additional 12 weeks of BCV was allowed in patients with

ongoing or recurrent infection – After completing treatment, all patients were followed until Week 36

§ Patients weighing ≥50 kg received BCV 100 mg BIW; patients weighing <50 kg received weight-based doses of 2 mg/kg (not-to-exceed 100 mg) BIW

§ Concurrent use of IV cidofovir, leflunomide, vidarabine, ribavirin, anti-AdV vaccines, and cell-based therapies was prohibited

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AdVise: Study Treatment

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AdVise: Study Procedures

§ Plasma for analysis of AdV DNA viremia was collected at screening, pre-dose on Day 1 (baseline), Day 4, weekly throughout the treatment phase, and at post-treatment follow-up visits on Weeks 13, 14, 16, 18, 20, 22, 24, 28, 32, and 36– AdV DNA viremia was measured by quantitative polymerase

chain reaction (AdV 7500 qPCR, Viracor-IBT Laboratories, Lee’s Summit, MO, USA) with a lower limit of detection of 100 c/mL and lower limit of quantification (LLOQ) of 190 c/mL

§ All patients were monitored for adverse events (AEs) and underwent regular safety monitoring, including routine clinical laboratory safety assessments, assessment of renal function, targeted physical examination, and vital signs measurements, throughout the treatment and post-treatment phases

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AdVise: Baseline Characteristics (N=158)

All values are n (%) unless otherwise stated. Cohort A had localized AdV infection or asymptomatic viremia. Cohort B had disseminated disease. AdV, adenovirus; ALC, absolute lymphocyte count; BKV, BK virus; CDV, cidofovir; CMV,

cytomegalovirus; GvHD, graft-versus-host disease; SD, standard deviation.

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AdVise: Transplant Details (N=158)

All values are n (%). Cohort A had localized AdV infection or asymptomatic viremia. Cohort B had disseminated disease.* Excludes 1 adult patient in Cohort A who received a mismatched, unrelated HCT, with no other details provided.

ATG, anti-thymocyte globulin; HCT, hematopoietic cell transplant.

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AdVise: Half of Subjects Did Not Complete Treatment Course, Reflecting the Significant Mortality Risk of AdV

All values are n (%) unless otherwise stated. Cohort A had localized AdV infection or asymptomatic viremia. Cohort B had disseminated disease. BCV, brincidofovir; SD, standard deviation.

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AdVise: Mortality was Lower in Pediatric vs Adult Patients and Cohort A vs B

Cohort A had localized adenovirus infection or asymptomatic viremia. Cohort B had disseminated disease.

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AdVise: AdV-related Mortality at Week 24 was Low, Particularly in Pediatric Subjects

• AdV-related mortality at Week 24 in allo-HCT recipients with disseminated AdV was 14% in pediatric patients and 46% in adults, reflecting later diagnosis and more severe co-morbidities in adults.

• Mortality assessments were not mutually exclusive: the endpoint adjudication committee could select more than one contributing factor, with relapse-associated mortality assigned priority in the analysis.

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AdVise: Rapid Declines in AdV Viremia were Observed, Particularly in Pediatric Subjects

All values are n (%) unless otherwise stated.Cohort A had localized AdV infection or asymptomatic viremia. Cohort B had disseminated disease.

AdV, adenovirus; NE, non-estimable.

• A last on-treatment value of undetectable AdV viremia was achieved in 61% of subjects in Cohort A, and 49% of subjects in Cohort B.

• At Week 4, declines of ≥2 log10 c/mL or undetectable AdV viremia were seen in 76% of all pediatric patients, and in 44% of all adult patients.

• In patients with baseline CD4 counts <50 cells/μL, 55% in Cohort A and 52% in Cohort B had ≥2 log10 c/mL decline or undetectable AdV at Week 4.

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AdVise: Rapid Virologic Response was Associated with Improved Survival at Week 24 in Both Pediatric and Adult Patients

All values are n/N (%).A Cox model incorporating age group was used to compare mortality at 24 weeks in responders and non-responders.

Responders are defined as patients who achieved a decrease of ≥2 log10 c/mL or undetectable AdV viremia at Week 4, or undetectable viremia at Week 6, with non-responders defined as patients who did not achieve the specified cut-off.

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AdVise: Few Treatment-Emergent Adverse Events Led to Discontinuation, Particularly in Pediatric Subjects

All values are n (%).Cohort A had localized adenovirus infection or asymptomatic viremia. Cohort B had disseminated disease.

AE, adverse event; TEAE, treatment-emergent adverse event.

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AdVise: <20% Mortality in Pediatric Patients Enrolled in 4th Quartile: More Rapid AdV Diagnosis and BCV Initiation

• The first subjects at each participating site experienced delays between diagnosis and initiation of BCV (IRB approval, etc.)

• More rapid diagnosis of AdV and initiation of BCV led to a much lower overall mortality in the 4th quartile of subjects enrolled

• Two fatal events in the 4th quartile occurred prior to achieving steady-state BCV concentrations

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AdVise: Conclusions

§All-cause and AdV-associated mortality were lower in pediatric patients than in adult patients– Screening for AdV in pediatric allo-HCT leads to earlier diagnosis

§Rapid declines in AdV viral load were observed with BCV, even in HCT recipients with low CD4 counts at baseline– In patients with disseminated disease, rapid virologic response at

4 or 6 weeks was associated with better overall survival– These findings confirm the observations made in patients who were

treated for serious AdV infection through emergency investigational new drug (EIND) and expanded access regulations in the US, in which suppression of AdV viral load in BCV recipients led to reductions in AdV-related symptoms and associated mortality1-4

1. Grimley M, et al. Presented at the EBMT meeting, April 2013. 2. Florescu DF, et al. Biol Blood Marrow Transplant 2012;18:731–8. 3. Grimley M, et al. Presented at BMT Tandem, February 2014.

4. Prasad VK, et al. Presented at BMT Tandem, February 2014.

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AdVise: Conclusions

§A period effect was demonstrated when enrollment period was included as a covariate – Lower mortality was observed in Cohort B pediatric patients enrolled

in the 4th quartile compared with those enrolled at the beginning of the study; differences were less pronounced in adults

– Rapid diagnosis of AdV and ability to begin BCV without delay appear to drive improved mortality

§BCV was better tolerated in pediatric patients– A low discontinuation rate due to AEs was seen in pediatric subjects – No new safety concerns were identified

§These data support the continued development of BCV as a potential therapeutic for AdV

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Acknowledgments

§The authors would like to thank the patients, their families, and study center personnel who participated in the study.