Intravenous Brincidofovir as an Antiviral for Treatment of Progressive Multifocal Leukoencephalopathy: A Pilot Study

Background: Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal brain infection caused by the JC virus. The JC virus is common. More than half of adults have been exposed to it. Most people do not get sick from the JC virus, but in people with weakened immune systems, it can cause PML. Brincidofovir (BCV) is an antiviral drug approved to treat smallpox. Researchers want to know if it can help people with PML. Objective: To test BCV in people with PML. Eligibility: People aged 18 years or older with PML. Design: Participants will be screened. They will have a physical exam with blood tests. They will have an imaging scan of the brain with contrast dye. They will have a lumbar puncture (spinal tap): A thin needle will be inserted into their lower back to draw out a sample of the fluid around their spinal cord. BCV will be given through a tube attached to a needle inserted into a vein. Participants will receive the drug 2 times a week for 4 weeks (this is 1 cycle). If the drug is helping them, they may have up to 3 drug cycles (12 weeks). Imaging scans, spinal taps, and other tests will be repeated after every 4 weeks of treatment. Participants will have 6 follow-up visits in 1 year after treatment ends. The imaging scan, spinal tap, and other tests will be repeated at each visit.

* INCLUSION CRITERIA: * Able to provide informed consent or have a designated legally authorized representative (LAR) to provide consent * Stated willingness to comply with study procedures and to participate for the duration of the study including follow-up * Actively progressing, clinically definite or probable PML (2013 AAN Consensus Diagnostic Criteria) * Positive PCR for JCPyV in CSF * Age 18 or older * Medically stable and able to tolerate travel to NIH * Participants of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study EXCLUSION CRITERIA: * ALT or AST \> 5 x the ULN, total bilirubin \> 3 mg/dL (SI: \>51 micromol/L), or spontaneous prothrombin time-international normalized ratio (PT-INR) \> 2 x ULN within 7 days prior to Day 1 * An estimated glomerular filtration rate of \< 30 mL/min within 7 days prior to Day 1 * Hypersensitivity to CDV or to BCV or its formulation excipients, or prior intolerance to these agents that, in the opinion of the investigator, would pose an unacceptable safety risk. * Active CNS disease other than PML that, in the opinion of the investigator, would confound study assessments or pose an unacceptable safety risk. * Contraindication to MRI (including cardiac pacemakers and some infusion pumps, other metallic implants, metallic foreign objects) * Medical contraindication to LP * Positive pregnancy test or nursing