Radioactive Tracer for Multiple Sclerosis

Overseen By Maria I Gaitan, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Disqualifiers: Pregnant, Lactating, Severe claustrophobia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new radioactive tracer, 89 Zr-Df-crefmirlimab, which may help doctors see immune cells in the brain and spinal cord more clearly during PET scans. The focus is on understanding multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML), both of which can cause muscle weakness and issues with vision, speech, and coordination. People with MS, PML, or other similar brain diseases affecting the blood-brain barrier (the protective layer around the brain) might be suitable candidates for this trial. Participants will attend several clinic visits, undergo PET scans, and complete other assessments over a few weeks. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What prior data suggests that this radioactive tracer is safe for use in humans?

Research shows that a substance called 89Zr-Df-crefmirlimab is being tested for safety in people with conditions like multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML). Earlier studies found that this substance is generally safe for imaging in humans. Participants in those studies did not experience major side effects, indicating its safety for use in PET scans. This suggests that people who received the substance tolerated it well without serious problems. However, since this is an early-stage trial, limited information is available, and researchers do not yet fully understand all possible side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the radioactive tracer 89 Zr-Df-crefmirlimab for multiple sclerosis because it offers a unique way to visualize and understand immune activity in the brain. Unlike standard treatments that directly target symptoms or inflammation, this tracer binds to CD8+ T cells, allowing doctors to see where and how these immune cells are active in the brain using PET/CT scans. This innovative approach could lead to more personalized treatment plans by providing detailed insights into the disease's progression and response to therapy.

What evidence suggests that this radioactive tracer is effective for detecting immune cells in the CNS of people with MS and PML?

Research shows that the radioactive tracer, 89Zr-Df-crefmirlimab, is under study for its ability to detect immune cells in the brain using PET scans. In this trial, participants with multiple sclerosis (MS), progressive multifocal leukoencephalopathy (PML), and other neuroinflammatory diseases with blood-brain barrier leakage will receive this tracer. Early results suggest that this tracer effectively identifies CD8+ T-cells, crucial immune cells involved in MS and other brain inflammation diseases. Previous studies have shown that 89Zr-Df-crefmirlimab is safe, with no major side effects reported. This tracer could help doctors better understand and monitor MS and PML by highlighting areas of immune activity in the brain and spinal cord. Overall, the evidence supports its potential effectiveness as a diagnostic tool for these conditions. ^{6 7 8 9 10}

Who Is on the Research Team?

Daniel S Reich, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Are You a Good Fit for This Trial?

Adults aged 18+ with Multiple Sclerosis or Progressive Multifocal Leukoencephalopathy can join. They must be part of existing NINDS studies, understand and agree to the study's consent form, follow all procedures, and women must use effective contraception. Excluded are pregnant or breastfeeding individuals, those who can't have MRI contrast or fit in scanners, and anyone with conditions that could affect their participation.

Inclusion Criteria

I have been diagnosed with PML or PML-IRIS based on clinical and lab tests.

PML Inclusion Criteria: Able to understand and willing to sign a written, informed consent document

Multiple Sclerosis Inclusion Criteria: Able to understand, and willing to sign, a written, informed consent document

Exclusion Criteria

Weighs > 350 lb (158 kg; weight limit for the scanner table) or is unable to fit within the MRI or PET imaging gantry

Pregnant or lactating

Contraindications for MRI gadolinium contrast administration or 3T MRI

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline and Initial Testing

Participants undergo baseline testing including physical and neurological exams, blood tests, heart function tests, and MRI scans.

1 week

1 visit (in-person)

Treatment and Imaging

Participants receive the minibody infusion followed by a PET/CT scan to detect CD8+ T cells in the CNS.

1 week

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with optional repeat imaging for PML cohort.

up to 6 months

Variable visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• 89 Zr-Df-crefmirlimab

Trial Overview The trial is testing a radioactive tracer called minibody (89 Zr-Df-crefmirlimab) used during PET scans to detect immune cells in the CNS of MS and PML patients. Participants will receive an infusion of minibody followed by PET scans over several visits spanning 4-6 weeks.

How Is the Trial Designed?

Group I: Progressive Multifocal Leukoencephalopathy Experimental Treatment 1 Intervention

PML cohort- Up to five study visits. (1) Baseline; (2) Day 0: MRI brain (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka "PET/CT tracer"); (3) Day 1: PET/CT scan; (4) Study visit 4 (optional; time-period between study visit 3 and 4 is variable): MRI brain (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka "PET/CT tracer") following clinical, radiological and/or laboratory-defined immune reconstitution (spontaneous or facilitated); (5) Study visit 5: PET/ CT scan

Group II: Other Neuroinflammatory diseases with BBB leakage Experimental Treatment 1 Intervention

Up to four study visits: (1) Baseline; (2) Day 0: MRI brain/spinal cord (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka "PET/CT tracer"); (3) Day 1: PET/CT scan(4) Optional Visit: PET/CT scan

Group III: Multiple Sclerosis Experimental Treatment 1 Intervention

MS cohort- Up to four study visits. (1) Baseline; (2) Day 0: MRI brain/spinal cord (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka"PET/CT tracer"); (3) Day 1: PET/CT scan(4) Optional Visit: PET/CT scan

Who Is Running the Clinical Trial?

National Institute of Neurological Disorders and Stroke (NINDS)

Lead Sponsor

Trials

1,403

Recruited

655,000+

Published Research Related to This Trial

In a study involving 35 patients, several immune-checkpoint-targeting monoclonal antibodies (mAbs) demonstrated target-specific uptake in the spleen, indicating effective engagement with their targets, particularly at lower mass doses.

The analysis revealed that as the mass doses of the mAbs increased, the uptake values (Ki) decreased, suggesting saturation effects and supporting the use of Patlak analysis to assess target engagement in PET imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

89Zr-Immuno-PET with Immune Checkpoint Inhibitors: Measuring Target Engagement in Healthy Organs. Miedema, IHC., Wijngaarden, JE., Pouw, JEE., et al.[2023]

A study involving 50 healthy subjects demonstrated that two Bafiertam™ capsules (each containing 95 mg of monomethyl fumarate) are bioequivalent to one Tecfidera® capsule (240 mg of dimethyl fumarate), meaning they deliver the same amount of the active drug to the body.

Both formulations were found to be safe and well tolerated, with flushing being the most common side effect reported in 60% of participants taking Bafiertam™ and 51% taking Tecfidera®.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Bioavailability of Monomethyl Fumarate Following a Single Oral Dose of Bafiertam™ (Monomethyl Fumarate) or Tecfidera® (Dimethyl Fumarate). Lategan, TW., Wang, L., Sprague, TN., et al.[2022]

In two phase III trials involving patients with active relapsing-remitting multiple sclerosis (RRMS), alemtuzumab was found to be more effective than subcutaneous interferon β-1a in reducing MRI measures of disease activity, including new and enlarging lesions over two years.

Alemtuzumab not only prevented increases in lesion volume but also significantly slowed brain volume loss compared to interferon β-1a, indicating its superior efficacy in managing RRMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS. Arnold, DL., Fisher, E., Brinar, VV., et al.[2022]

(89)Zr-immuno-PET is a promising imaging technique that can visualize and quantify the distribution of monoclonal antibodies (mAbs) in tumors, helping to predict their efficacy and toxicity based on initial clinical trials.

Initial studies have shown that (89)Zr-immuno-PET correlates with target expression levels in tumors, indicating its potential as a predictive biomarker for personalized treatment, particularly in HER2-positive breast cancer with trastuzumab-emtansine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immuno-Positron Emission Tomography with Zirconium-89-Labeled Monoclonal Antibodies in Oncology: What Can We Learn from Initial Clinical Trials? Jauw, YW., Menke-van der Houven van Oordt, CW., Hoekstra, OS., et al.[2022]

In a study involving 18 patients with advanced melanoma or non-small-cell lung cancer, the uptake of 89Zr-labeled pembrolizumab in tumors was found to correlate with treatment response and patient survival, suggesting it could be a useful predictor of therapy effectiveness.

The optimal dose for 89Zr-pembrolizumab was determined to be 5 mg, with the best imaging results observed on day 7 after administration, indicating a potential timeline for monitoring treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer. Kok, IC., Hooiveld, JS., van de Donk, PP., et al.[2022]

In a study involving 125 young adults with relapsing-remitting multiple sclerosis, those continuously treated with dimethyl fumarate (DMF) showed a significantly lower annualized relapse rate (ARR) of 0.24 compared to 0.56 in those who received placebo, indicating DMF's efficacy in reducing disease activity.

The safety profile of DMF in young adults was favorable, with most adverse events being mild to moderate, and a high percentage (81%) of patients on DMF showed no confirmed disability progression after approximately 7 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Dimethyl Fumarate in Young Adults with Relapsing-Remitting Multiple Sclerosis: Analysis of the DEFINE, CONFIRM, and ENDORSE Studies. Amezcua, L., Mao-Draayer, Y., Vargas, WS., et al.[2023]

Daclizumab is an effective treatment for relapsing forms of multiple sclerosis, showing superior results in reducing relapse rates and disease progression compared to interferon β-1a in the phase III DECIDE trial.

The drug is generally well tolerated, with manageable adverse effects, and ongoing studies suggest its efficacy can be maintained over the long term, making it a valuable alternative to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daclizumab: A Review in Relapsing Multiple Sclerosis. Shirley, M.[2022]

Daclizumab, a monoclonal antibody targeting CD25, effectively reduces relapse rates and disability progression in multiple sclerosis (MS) by modulating IL-2 signaling and blocking autoreactive T cell activation.

Clinical trials demonstrated that daclizumab has a favorable pharmacokinetic profile, with slow clearance and high bioavailability, making it a promising treatment option among new therapies for MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic drug evaluation of daclizumab for the treatment of relapsing-remitting multiple sclerosis. Patti, F., Chisari, CG., D'Amico, E., et al.[2018]

The study demonstrated that a novel zirconium-89 (89Zr)-labeled anti-CD20 monoclonal antibody effectively distributes to major organs and the central nervous system (CNS) in both control and experimental autoimmune encephalomyelitis (EAE) mice, indicating its potential for targeting B cells in multiple sclerosis treatment.

Subcutaneous (s.c.) administration of the antibody resulted in significantly higher tracer uptake in the draining lymph nodes and CNS regions (cerebellum and cerebrum) compared to intravenous (i.v.) administration, suggesting that the route of administration can influence the biodistribution and efficacy of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficient Distribution of a Novel Zirconium-89 Labeled Anti-cd20 Antibody Following Subcutaneous and Intravenous Administration in Control and Experimental Autoimmune Encephalomyelitis-Variant Mice. Migotto, MA., Mardon, K., Orian, J., et al.[2020]

In a Phase 1 trial involving 72 adults with stable multiple sclerosis, the monoclonal antibody rHIgM22 was found to be well tolerated with no significant safety concerns over a monitoring period of six months.

The pharmacokinetics of rHIgM22 showed linear dose-proportionality, and the drug was detected in cerebrospinal fluid (CSF), indicating its potential to reach the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis. Eisen, A., Greenberg, BM., Bowen, JD., et al.[2022]

Citations

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A phase II, open label, multi-center study of 89Zr-DF- ... A phase II, open label, multi-center study of 89Zr-DF-Crefmirlimab for CD8 positron emission tomography in patients with locally advanced or ...

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CD8 PET Imaging in Metastatic Solid Tumours This is a multi-center, single-arm trial designed to evaluate the safety and imaging characteristics of 89Zr-Df-crefmirlimab in patients with locally ...

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First-in-Humans Imaging with 89Zr-Df-IAB22M2C Anti-CD8 ... Results: 89Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically ...

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Zirconium 89 and Copper 64 for ImmunoPET: From Antibody ... Zirconium 89 ( 89 Zr) and Copper 64 ( 64 Cu) are radiometals with half-lives suitable for mAb labeling.

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Targeting Immune Imbalance in Multiple Sclerosis Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) characterized by inflammatory demyelination, ...

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Central Nervous System Uptake of Anti-CD8+ T Cell ... To assess the safety of 89Zr-Dfcrefmirlimab in participants with CNS disease. At each study visit. To determine whether 89Zr-Df-crefmirlimab uptake profile in ...

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Central Nervous System Uptake of Anti-CD8+ T Cell ... Multiple sclerosis (MS) and progressive multifocal ... Secondary Objectives: (1) To characterize safety and tolerability of 89Zr-Df-crefmirlimab ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31586002/

First-in-Humans Imaging with 89 Zr-Df-IAB22M2C Anti-CD8 ... 89 Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell-rich tissues.

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Zirconium (89Zr) crefmirlimab berdoxam View sample adverse effects data in our new Data Library! See the data. Improve decision support & research outcomes with our structured ...

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Crefmirlimab | Anti-CD8 Antibody Crefmirlimab is a humanized CD8 specific minibody. The minibody (Mb) maintains the specificity of full-length antibodies but has no immune effector functions ...