Phase 2 Study to Evaluate Brincidofovir for the Prevention of Adenovirus Disease

A Randomized, Placebo-controlled, Multi-site Phase 2 Study Evaluating the Safety and Efficacy of Preemptive Treatment With CMX001 for the Prevention of Adenovirus Disease Following Hematopoietic Stem Cell Transplantation

This study was designed to assess the safety and efficacy of preemptive treatment with oral brincidofovir (BCV), as compared to placebo, for the prevention of adenovirus (AdV) disease in recipients of hematopoietic stem cell transplantation (HCT) with asymptomatic AdV viremia.

This was a Phase 2, randomized, multicenter, placebo-controlled study for pediatric and adult subjects who had undergone hematopoietic stem cell transplantation (HCT) and who had been identified as having asymptomatic adenovirus (AdV) viremia [i.e., had detectable AdV DNA in plasma based on polymerase chain reaction testing performed at the local laboratory with no AdV disease symptoms]. The primary objectives of the study were to assess the safety and tolerability of oral brincidofovir (BCV), and to estimate the treatment failure rate based on an efficacy endpoint with 2 different dosing regimens of oral BCV versus placebo.

Inclusion Criteria

For inclusion into the study, subjects were required to fulfill all of the following criteria:

1. Were males or female aged ≥3 months to ≤75 years.
2. Received an allogeneic hematopoietic stem cell transplant (HCT).
3. Had positive serum adenovirus (AdV) PCR (>100 copies/mL) as measured by the central laboratory (unless the subject developed AdV disease while participating in the prescreening activities and after concurrence from the Chimerix medical monitor or designee).
4. Was on dialysis during treatment if he/she had an estimated glomerular filtration rate (eGFR) ≤30 mL/minute.
5. Subject or guardian(s) were willing to comply with the protocol.
6. Subject or guardian(s) were willing and able to understand the informed consent/assent.
7. Female subjects of child-bearing potential must have had a negative pregnancy test and must have agreed to use 2 acceptable methods of birth control throughout the study with at least 1 being a barrier method. Sexually active males of procreation potential must have been able and willing to se a reliable and medically approved contraceptive method throughout the study. At least 1 barrier method of contraception must have been used.

Exclusion Criteria

Subjects meeting any of the following exclusion criteria were excluded from participation in the study:

1. Had possible, probable, or definitive AdV disease (unless the subject developed probable or definitive AdV disease while participating in prescreening activities and after concurrence from he Chimerix medical monitor or designee).
2. Had suspected gut graft versus host disease that was not biopsy-proven (subjects with a biopsy performed were included in the study).
3. Had an eGFR ≤30 mL/minute and was not currently on dialysis.
4. Had an alanine aminotransferase or aspartate aminotransferase >5 x the upper limit of normal (ULN), total bilirubin ≥2 x the ULN, or conjugated (direct) bilirubin ≥1.5 x the ULN.
5. Had a condition that prevented oral dosing of study drug.
6. Was HIV antibody positive, based upon available medical records.
7. Had ocular hypotony, uveitis, or retinitis or any other intraocular pathology that would have predisposed the subject to 1 of these conditions.
8. Had participated in another clinical study of an investigational drug/biologic or was exposed to an investigational drug/biologic within 30 days of enrollment without the prior written approval of the Chimerix medical monitor or designee. For subjects who were participating in any clinical study involving non-investigational drugs and/or biologics, the investigator must have obtained approval from the Chimerix medical monitor or designee prior to enrolling the subject.
9. Was pregnant or breast-feeding or intended to conceive during the course of the study, including the follow-up period after drug discontinuation.
10. Had known immunologic hypersensitivity to cidofovir (CDV) or brincidofovir (BCV) drug or any of its excipients.
11. Had a history of illicit drug use or alcohol abuse within the previous 6 months.
12. Had any medical condition that, in the opinion of the investigator, might have interfered with the subject's participation in the study, posed an added risk for the subject, or confounded the assessment of the subject (e.g. severe cardiovascular, central nervous system or pulmonary disease).
13. Received BCV, CDV, ribavirin, or leflunomide within the previous 14 days.
14. Was receiving or was anticipated to need treatment with digoxin that could not have been withheld for the duration of BCV therapy.

Any exemptions to the protocol inclusion or exclusion criteria, as applicable, for subjects who developed probably or definitive AdV disease while participating in prescreening activities must have been discussed with and approved by the Chimerix medical monitor or designee before the subject was allowed to receive open-label BCV therapy.