CMX001 in Post-transplant Patients With BK Virus Viruria

This was a randomized, double-blind, multiple-dose placebo-controlled study of oral brincidofovir (BCV) in hematopoietic stem cell transplant and renal transplant recipients with BK virus infection.

Subjects received blinded study medication for a total of 5 doses in 1 of the following regimens:

• 10 mg BCV administered twice weekly (BIW) on Days 0, 3, 7, 10, 14.
• 20 mg BCV administered once weekly (QW) on Days 0, 7, and 14 and placebo administered on Days 3 or 10.
• Placebo administered BIW on Days 0, 3, 7, 10 ,14.
• 40 mg BCV administered QW on Days 0, 7, 14, 21, and 28.
• Placebo administered QW on Days 0, 7, 14, 21, and 28.

Inclusion criteria

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

• Aged between 18 to 75 years, inclusive. Males must have been able and willing to use adequate contraceptive methods throughout the study and for 3 months after the final dose. Females must have been post-menopausal, surgically sterile, or willing to use adequate contraception for the duration of the study (screening through the Day 48 visit).
• Were renal or hematopoietic stem cell transplant patients who met the following criteria:

• Renal transplant patients who:

• Were at least 28 days post transplant;
• Were in stable condition with hemoglobin >10 g/100 mL;
• Had no evidence of graft rejection (i.e., serum creatinine was not increasing [±30%], creatinine clearance was not decreasing);
• Were on a stable immunosuppressant regimen for at least 14 days prior to dosing.
• Had either urine levels of BK virus DNA ≥10^4 copies/mL without viremia or plasma levels of BK virus DNA <10^4 copies/mL (with or without viruria).
• Stem cell transplant patients who:

• Were a minimum of 3 days post documentation of successful engraftment as evidenced by an absolute neutrophil count >500 cells/mm3;
• Had urine levels of BKV ≥10^4 copies/mL.
• Had GFR >30 mL/min.
• Were able to swallow tablets.
• Were willing and able to understand and provide written informed consent.
• Were willing and able to participate in all required study activities for the duration of the study (including ingestion of oral medication).

Exclusion criteria

Any of the following was regarded as a criterion for exclusion from the trial:

• Females who were currently nursing or pregnant.
• Were using illicit drugs or abusing alcohol.
• Had hypersensitivity to cidofovir or brincidofovir.
• Had received aminoglycosides (intravenously) or NSAIDS (except as given for cardioprotective treatment) within 7 days prior to enrollment; had received leflunomide, cidofovir, or any other medication for treatment of BK virus infection or disease within 14 days prior to enrollment; had received any investigational drug (including maribavir) within 30 days prior to enrollment.
• Were HIV positive (results must have been obtained within 1 year prior to dosing); had active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection as evidenced by plasma levels of HCV RNA or HBV DNA, respectively.
• Were renal transplant patients with evidence of biopsy proven acute rejection in the 3 weeks prior to enrollment. This exclusion criterion applied only to those patients for whom a biopsy was performed within the 3 weeks prior to enrollment.
• Were stem cell transplant patients who:

• Had cystitis ≥Grade 3 National Cancer Institute, Common Terminology Criteria for Adverse Events version 3.0.
• Had Grade 3 or 4 graft versus host disease (GVHD).
• Had untreated or uncontrolled Grade 2 GVHD.
• Had received ganciclovir or valganciclovir within 14 days prior to enrollment.
• Had mucositis that prevented ingestion of oral medication.
• Had hypotony, uveitis, or retinitis or any intraocular pathology that would have predisposed the patient to any one of these conditions.
• Had unstable or poorly controlled diabetes, defined as having frequent hypoglycemic and/or hyperglycemic events on a daily basis (brittle diabetes), with fluctuating short acting insulin requirements daily, or requiring unpredictable insulin supplementation to oral hypoglycemic agents on a regular basis.
• Had bilirubin >2.5 x the upper limit of normal.
• Had cardiovascular disease which, in the opinion of the investigator, would have interfered with the conduct of the study.
• Had any of the following autoimmune diseases: Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid, celiac disease, dermatomyositis, active Goodpasture's syndrome, idiopathic thrombocytopenic purpura, active lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, polymyositis, primary biliary cirrhosis, vasculitis, Wegener's granulomatosis.
• Had active malignancies (with the exception of basal cell carcinoma or the condition under treatment for hematopoietic stem cell transplant patients).
• Had concurrent or ongoing ≥Grade 2 gastrointestinal symptoms including nausea, vomiting, diarrhea, constipation, or gastroenteritis. Patients with active gastrointestinal disease including inflammatory bowel disease, irritable bowel syndrome, or celiac sprue.
• Had any other condition including abnormal laboratory values that would have, in the judgement of the investigator, put the subject at increased risk for participating in the trial, or interfered with the conduct of the trial.