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

10 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML) are disorders that affect the central nervous system (CNS). The CNS includes the brain, spinal cord, and optic nerves. Both diseases can cause muscle weakness and impair vision, speech, and coordination. Researchers are working to better understand how MS and PML affect the CNS. Objective: To test whether an experimental radioactive tracer (minibody) can help positron emission tomography (PET) scans detect certain immune cells in the CNS of people with MS and PML. Eligibility: People aged 18 years and older with MS or PML. Design: Participants will come to the clinic for at least 3 visits over 4 to 6 weeks. Participants will undergo testing. They will have a physical and neurological exam. They will have blood tests and tests of their heart function. They will have a magnetic resonance imaging (MRI) scan of the brain. They may have a spinal tap: Their lower back will be numbed, and a needle will be inserted between the bones of the spine to withdraw fluid from around the spinal cord. Minibody is given through a tube with a needle placed in a vein in the arm. This takes 5 to 10 minutes. Participants will have heart function tests before and after receiving the minibody. Participants will return the next day for the PET scan. They will lie on a table that moves through a doughnut-shaped machine. This scan will take about 1 hour. Participants with PML may opt to repeat the minibody infusion and the PET scan within 6 months.

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 data supports the effectiveness of the drug 89Zr-Df-crefmirlimab for treating multiple sclerosis?

Research shows that zirconium-89 labeled antibodies, like those used in 89Zr-Df-crefmirlimab, can effectively target specific cells in the body, as seen in studies with mice that have a condition similar to multiple sclerosis. This suggests that the drug might help in visualizing and targeting areas of inflammation in multiple sclerosis. ^{1 2 3 4 5}

How does the radioactive tracer treatment for multiple sclerosis differ from other treatments?

The radioactive tracer treatment for multiple sclerosis is unique because it involves using a radioactive substance to potentially track and target disease activity, which is different from existing treatments that primarily focus on modulating the immune system or reducing inflammation. ^{6 7 8 9 10}

Research Team

Daniel S Reich, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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: Multiple Sclerosis Experimental Treatment 1 Intervention

MS cohort- Three 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

Who Is Running the Clinical Trial?

National Institute of Neurological Disorders and Stroke (NINDS)

Lead Sponsor

Trials

1,403

Recruited

655,000+

Findings from Research

(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 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]

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]

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 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]

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]

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]

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 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]

References

1. Switzerland 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? [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

89Zr-Immuno-PET with Immune Checkpoint Inhibitors: Measuring Target Engagement in Healthy Organs. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS. [2022]

4. Switzerland 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. [2020]

5. England pubmed.ncbi.nlm.nih.gov

89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetic drug evaluation of daclizumab for the treatment of relapsing-remitting multiple sclerosis. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Bioavailability of Monomethyl Fumarate Following a Single Oral Dose of Bafiertam™ (Monomethyl Fumarate) or Tecfidera® (Dimethyl Fumarate). [2022]

9. New Zealand 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. [2023]

10. New Zealand pubmed.ncbi.nlm.nih.gov

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