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

Safety and Tolerability of 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.

Study Overview

• Status: Recruiting
• Conditions: Progressive Multifocal Leukoencephalopathy
• Intervention / Treatment: Drug: Brincidofovir

Detailed Description

Study Description:

This pilot study will test safety and tolerability of IV BCV as an antiviral treatment strategy for participants with PML, and will collect preliminary data on biological and clinical impact on PML disease course. Eighteen adults with PML from all causes will complete this study.

Following a standardized baseline evaluation and confirmation of PML diagnosis with positive JCPyV DNA detection in CSF, participants will receive IV BCV 20mg (or 0.4mg/kg if participant weighs<50kg) twice weekly in 4-week Infusion Cycles for up to 12 weeks total (3 Infusion Cycles). Enrollment of the first 3 participants will be staggered by 4 weeks.

At completion of each Infusion Cycle, participants will be evaluated monthly for 3 months to determine if they meet criteria for 1) redosing with additional 4-weeks of IV BCV, 2) initiation/continuation of Clinical Monitoring or 3) definition of Treatment Failure (leading to optional withdrawal from study and pursuit of rescue treatments). As long as less than 12 weeks of cumulative dosing have been pursued, redosing may be offered.

Upon completion of treatment, participants will be monitored for up to 12 months.

Objectives:

Primary Objective:

-To describe the safety and tolerability of IV BCV 20mg (or 0.4mg/kg if participant weighs<50kg) dosed twice weekly for a cumulative total of up to 12 weeks.

Secondary Objectives:

• To investigate kinetics and magnitude of antiviral effect of IV BCV on JCPyV load in CSF in participants with PML.
• To investigate effect of IV BCV on clinical and radiological PML disease course.

Exploratory Objectives:

-To investigate pharmacodynamics and effect of IV BCV in urine, blood and CSF.

Endpoints:

Primary Endpoint:

-Number of treatment-related adverse events (AEs) of Grade 3 severity or higher as determined by Common Terminology Criteria for Adverse Events (CTCAE 6.0)

Secondary Endpoints:

• Number of treatment-related AEs, irrespective of grade
• Change from baseline in JCPyV load in CSF at completion of Infusion Cycles 1, 2 and 3
• Proportion of participants with 0.25 log decline or greater in JCPyV load in CSF at completion of Infusion Cycles 1, 2 and 3
• Number of Infusion Cycles
• Time to increase in JCPyV load in CSF during monitoring phase
• Number of participants meeting criteria for Treatment Failure
• Change in performance measures and standardized disability rating scales from baseline to Month 6, 9 and 12 (or last assessment)
• Change in PML lesion burden by MRI from baseline to Month 3, 6, 9 and 12 (or last assessment)
• Survival at 3, 6, 9 and 12 months

Exploratory Endpoints:

-Exploratory measures in urine, blood and CSF to investigate pharmacodynamics of IV BCV, including virological and immunological changes in response to study intervention.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Irene CM Cortese, M.D.; Phone Number: (301) 496-1801; Email: corteseir@ninds.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: (800) 411-1222; Email: ccopr@nih.gov
      • Contact: Neuroimmunology Clinic; Phone Number: 301-496-3825; Email: corteseir@ninds.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:
• Able to provide informed 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Brincidofovir treatment arm; experimental treatment arm	Drug: Brincidofovir; intravenous administraion of anti-viral agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of treatment-related adverse events (AEs) of Grade 3 severity or higher as determined by Common Terminology Criteria for Adverse Events (CTCAE)	Over duration of trial participation

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of treatment-related AEs, regardless of severity	over duration of trial
Change from baseline in JCPyV load in CSF upon completion of each Treatment Block	at end of each treatment block
Proportion of patients with 0.25log decline or greater in JCPyV load in CSF upon completion of each Treatment Block	at end of each treatment block
Time to increase in JCPyV load in CSF during monitoring phase upon treatment completion	over duration of trial participation
Number of Treatment Blocks and duration of treatment phase	dependent on duration of participation: 1 month - 3 months
Number of patients meeting Treatment Failure Criteria	At end of each treatment block
Change from baseline in performance and standardized disability rating scales at 6, 9 and 12 months	6, 9 and 12 months
Change from baseline in PML lesion burden by brain MRI at 3, 6 9 and 12 months	3, 6, 9 and 12 months
Survival at 3, 6, 9 and 12 months	3, 6, 9 and 12 months

Collaborators and Investigators

• Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Irene CM Cortese, M.D., National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

General Publications

• Gosert R, Rinaldo CH, Wernli M, Major EO, Hirsch HH. CMX001 (1-O-hexadecyloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes. Antimicrob Agents Chemother. 2011 May;55(5):2129-36. doi: 10.1128/AAC.00046-11. Epub 2011 Mar 14.
• Jiang ZG, Cohen J, Marshall LJ, Major EO. Hexadecyloxypropyl-cidofovir (CMX001) suppresses JC virus replication in human fetal brain SVG cell cultures. Antimicrob Agents Chemother. 2010 Nov;54(11):4723-32. doi: 10.1128/AAC.00837-10. Epub 2010 Sep 7.
• Grimley MS, Chemaly RF, Englund JA, Kurtzberg J, Chittick G, Brundage TM, Bae A, Morrison ME, Prasad VK. Brincidofovir for Asymptomatic Adenovirus Viremia in Pediatric and Adult Allogeneic Hematopoietic Cell Transplant Recipients: A Randomized Placebo-Controlled Phase II Trial. Biol Blood Marrow Transplant. 2017 Mar;23(3):512-521. doi: 10.1016/j.bbmt.2016.12.621. Epub 2017 Jan 5.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): June 2, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: April 3, 2026
• First Submitted That Met QC Criteria: April 3, 2026
• First Posted (Actual): April 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: April 28, 2026

More Information

Terms related to this study

• Keywords: Safety and Tolerability of Intravenous Brincidofovir; safety, tolerability, brincidofovir, PML, JCV
• Additional Relevant MeSH Terms: Infectious Encephalitis; Neuroinflammatory Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Virus Diseases; Demyelinating Diseases; DNA Virus Infections; Slow Virus Diseases; Leukoencephalopathies; Encephalitis, Viral; Central Nervous System Viral Diseases; Central Nervous System Infections; Polyomavirus Infections; Encephalitis; Leukoencephalopathy, Progressive Multifocal; brincidofovir
• Other Study ID Numbers: 10002635; 002635-N

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No