BRINCIDOFOVIR WAS USED TO SUCCESSFULLY TREAT ADENOVIRUS INFECTIONS IN SOLID

ORGAN TRANSPLANT RECIPIENTS AND OTHER IMMUNOCOMPROMISED PATIENTS

Diana F. Florescu, MD1, Michael S. Grimley, MD2, Genovefa A. Papanicolaou, MD3, Vinod K. Prasad, MD, FRCP4, Enrikas Vainorius, MD5, Greg Chittick5, Thomas M. Brundage, MS5, W. Garrett Nichols, MD, MS5

1Univ Nebraska Med Center, Omaha, 2Cincinnati Children's Hosp Center, Cincinnati, 3Memorial-Sloan Kettering Cancer Center, New York, 4Duke Univ Med Center, Durham, 5Chimerix, Inc., Durham, USA

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Disclosure Statement

Diana F. Florescu, M.D.Associate ProfessorInternal Medicine DepartmentDivision of Infectious DiseasesDirector, Transplant Infectious Diseases ResearchAssociate Director, Transplant Infectious Diseases ProgramUniversity of Nebraska Medical Center, Omaha, Nebraska, USA

I have financial relationship(s) with:

Advisory Board: Chimerix; Merck; OxfordOther (Trial investigator): Chimerix; Merck; Oxford; Astellas; Shire

My presentation includes discussion of brincidofovir (also CMX001), an investigational medicine being developed by Chimerix, Inc.

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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 10% 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

Sandkovsky, et al. Curr Infect Dis Rep. 2014;16:416-24.Tebruegge & Curtis. Ped Infect Dis J. 2012 Jun;31(6):626-7.

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Brincidofovir (BCV, CMX001)

• BCV is a broad spectrum antiviral with high in vitro potency against all AdV subtypes tested1

• 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 myelotoxicity2-4

• High barrier to viral resistance

1. Bae A, et al. Presented at BMT Tandem 2016. 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. Tippin T, et al. Ther Drug Monit. 2016;38:777-86.

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AdVise: Study Overview

• AdVise (CMX001-304; NCT02087306) 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: 100 mg BIW for ≥50 kg, 2 mg/kg BIW for <50 kg

• Cohorts A and B (allogeneic HCT recipients weighing <120 kg with asymptomatic viremia/localized infection or disseminated disease; N= 158) described previously1

• Cohort C (N = 43): all other patients regardless of disease status, including:• SOT recipients (n = 18)• “Other” immunocompromised patients (n = 25):• Chemotherapy (n=10)• Known or suspected primary immune deficiency (n=6)• Autologous HCT (n=5)• Allogeneic HCT weighing >120 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 dose1. Prasad VK, et al. Presented at BMT Tandem 2017.

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Baseline Characteristics

All values are n (%) unless otherwise stated. Abbreviations: CDV, cidofovir; ND, not detected; c/mL, copies/milliliter.

All Cohort C Patients(N=43)

SOT Other

Adult(n=4)

Pediatric(n=14)

Adult(n=9)

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 (100) 8 (57) 6 (67) 9 (56)

Male 27 (63) 3 (75) 9 (64) 3 (33) 12 (75)

Prior CDV within 30 Days:None reported

<10 mg/kg, cumulative dose ≥10 mg/kg, cumulative dose

28 (65)11 (26)

4 (9)

2 (50)2 (50)

0

11 (79)2 (14)1 (7)

7 (78)2 (22)

0

8 (50)5 (31)3 (19)

Symptomatic AdV Disease 26 (60) 4 (100) 8 (57) 4 (44) 10 (63)

Median (Range) AdV Viremia (log10 c/mL)

3.3 (ND – 10.0) 3.0 (ND – 3.3) 3.6 (ND – 10.0) 2.4 (ND – 7.2) 3.5 (ND – 8.1)

Median (Range) Days from AdV Diagnosis

7 (1 – 247) 6 (6 – 16) 7 (2 – 16) 7 (1 – 247) 11 (2 – 48)

Urine AdVRespiratory AdVStool AdV

17 (40)27 (63)29 (67)

1 (25)2 (50)3 (75)

5 (36)5 (36)

11 (79)

4 (44)7 (78)7 (78)

7 (44)13 (81)8 (50)

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Solid Organ Transplant Characteristics

All values are n (%) unless otherwise stated.

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 (50)

1 (6)

0

1 (25)

0

2 (50)

1 (25)

0

1 (7)

2 (14)

1 (7)

1 (7)

8 (57)

1 (7)

Days Since Transplant List or Median (Range) 39 (20 - 9342)29, 31, 1625 &

934239 (20 – 1101)

• Small bowel most common transplant preceding AdV in SOT:

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Brincidofovir Treatment

All values are n (%) unless otherwise stated. * Based on review of reported immunosuppressant medication use through 4 weeks post-first BCV dose.

All Cohort C Patients(N=43)

Solid Organ Transplant Other

Adult(n=4)

Pediatric(n=14)

Adult(n=9)

Pediatric(n=16)

Treatment Duration (days) Median (Range) 29 (1 – 244) 24 (8 – 26) 78 (15 – 244) 19 (1 – 88) 37 (1 – 166)

Number of BCV Doses Median (Range) 9 ( 1 – 50) 8 (3 – 8) 19 (5 – 50) 6 (1 – 25) 12 (1 – 48)

Treatment Course Disposition

CompletedNot completed

Reason:Adverse event

DeathPhysician decision

Other

13 (30)30 (70)

7 (16)7 (16)

12 (28)4 (9)

04 (100)

2 (50)0

2 (50)0

6 (43)8 (57)

02 (14)5 (36)1 (7)

1 (11)8 (89)

4 (44)1 (11)2 (22)1 (11)

6 (38)10 (63)

1 (6)4 (25)3 (19)2 (13)

Concurrent Reduction in Immune Suppression (through Week 4)* 9 (21) 0 5 (36) 1 (11) 3 (19)

• Although prescribed duration of therapy was long per protocol (12+ weeks), virus was rapidly cleared

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Adverse Events of Interest

* Treatment-emergent events (through last BCV dose + 7 days) assessed using CTCAE grading scales, version 4.03.All values are n (%) unless otherwise stated. Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase

All Cohort C Patients(N=43)

Solid Organ Transplant Other

Adult(n=4)

Pediatric(n=14)

Adult(n=9)

Pediatric(n=16)

Gastrointestinal AEs, ≥Grade 3*

Abdominal pain 1 (2) 0 1 (7) 0 0

Diarrhea 5 (12) 1 (25) 3 (21) 0 1 (6)

Nausea 1 (2) 0 0 1 (11) 0

Vomiting 2 (5) 0 0 1 (11) 1 (6)

Laboratory Test AEs, ≥Grade 3*

ALT increased 3 (7) 0 2 (14) 1 (11) 0

AST increased 2 (5) 0 2 (14) 0 0

Bilirubin increased 2 (5) 0 2 (14) 0 0

AEs leading to BCV discontinuation 10 (23) 2 (50) 0 5 (56) 3 (19)

Event(s) leading to discontinuation inindividual subjects

Diarrhea

Diarrhea + Abdominal

pain

Abdominal pain

ALT increased

C. difficile colitis

Septic shock

Visceral arterial ischemia

Adenoviralhepatitis

Klebsiella sepsis

Respiratory failure

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Rapid Antiviral Response to Brincidofovir Therapy

Plot presents values during BCV dosing up to 7 days after last dose. AdV DNA in plasma assayed using 7500 Adenovirus quantitative real-time PCR test (Viracor-IBT Laboratories); lower limit of detection, 100 copies/mL. Abbreviations: IQR, interquartile range.

Subjects with Baseline Viremia (n=30)

Undetectable or ≥2 log10 decrease in AdV viremia any time on treatment, n (%) 22 (73)

Days to undetectable or ≥2 log10 decrease, median (IQR), n=22 15 (8 – 22)

Undetectable AdV viremia at end of treatment, n (%) 18 (60)

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Overall Survival by Age Group and Transplant Status

75% (3/4)

56% (5/9)

79% (11/14)

63% (10/16)

• 6/43 (14%) patients had cause of death reported as AdV related

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Rapid Virologic Response to BCV after 2 Weeks was Associated with Improved Survival at Week 36

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 log10 decrease at Week 2, with non-responders defined as subjects who did not achieve either.

• n=21 with Baseline AdV viremia ≥3log10 copies/mL • 13 / 21 (62%) had a ≥2 log10 drop or were undetectable at Week 2

• 1 / 13 (8%) of virologic responders died prior to Week 36• 4 / 8 (50%) of virologic non-responders died prior to Week 36

Mortality model:• Responders vs Non-responders:

HR 8.0 (0.8 – 75.8), p=0.07• Pediatrics vs. Adults:

HR 0.6 (0.1 – 3.7), p=0.56• SOT vs Other:

HR 0.6 (0.1 – 3.8), p=0.56

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Lower Viral Burden with BCV Associated with Improved Survival

1Heim A. Expert Rev Anti Infect Ther. 2011;9:943-5; 2DeVincenzo J, et al. N Engl J Med. 2014;371:711-22;

3Brundage T, et al. Presented at BMT Tandem 2018

• 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 AdV1-2

• Lower AdV viral burden with BCV is associated with increased survival3

• In Cohort C patients (N = 22) with clinically relevant viremia at baseline (≥3 log10copies/mL), decreased AAUC over 12 weeks (1-2nd vs. 3-4th quartiles) positively correlated with survival at Week 36

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Conclusions

•Oral brincidofovir rapidly cleared AdV viremia in this diverse population of immunocompromised patients

•Lower AdV burden (as measured by AAUC0-12 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

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Acknowledgments

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