Conference Coverage
INDIANAPOLIS—Investigators are conducting clinical trials of various drugs that may slow clinical worsening in patients with progressive multiple sclerosis (MS), according to an overview provided at the 2015 CMSC Annual Meeting. Two such agents, anti-LINGO-1 antibody and rHIgM22 monoclonal antibody, are under active development in early clinical trials.
“Treatments that promote remyelination are going to prove to be the most effective way to prevent or treat progressive MS,” said Dennis Bourdette, MD, Roy and Eulalia Swank Family Research Professor and Chairman of the Department of Neurology at Oregon Health & Science University (OHSU) School of Medicine in Portland. Investigators are developing cell-based, large-molecule (ie, biologic), and small-molecule (ie, chemically manufactured) therapies that could promote remyelination.
Cell-Based Therapies
One potential treatment is to inject oligodendrocyte precursor cells (OPCs) into the brain and spinal cord. These OPCs then could become oligodendrocytes and produce myelin. Researchers in New York state under the leadership of Drs. Steven Goldman and Burk Jubelt are preparing for a phase I trial of this technique. They plan to use embryonic OPCs and are working with the FDA to establish the appropriate controls for the study.
Current surgical technology should allow the team to inject human OPCs into the brain safely, said Dr. Bourdette. “Researchers have shown that human embryonic-derived OPCs injected into the brains of rodents that have hypomyelination caused by a genetic defect will migrate long distances and myelinate axons.” The goal is for the OPCs to migrate into areas of demyelination in the brain of people with MS and remyelinate axons.
But how far the OPCs will migrate and whether this technique will succeed are open questions, added Dr. Bourdette. The brain of a patient with MS already has OPCs, and adding more OPCs may not promote remyelination, he said. “It might be an approach that is particularly useful, though, in people who are disabled from large plaques in the cervical cord.”
Large-Molecule Approaches
Another approach to promoting remyelination is to block the protein LINGO, which inhibits the differentiation of OPCs into oligodendrocytes. Biogen has developed an anti-LINGO-1 monoclonal antibody that appeared to promote remyelination in patients with optic neuritis during a small phase II trial. Investigators currently are studying this monoclonal antibody in patients with relapsing MS.
A group of investigators at the Mayo Clinic have developed recombinant human IgM22 antibody that promotes OPC differentiation and remyelination in animal models. The drug’s safety has been assessed in a phase I trial. Because the anti-LINGO antibody and the human IgM22 are large molecules, they will not penetrate the brain easily, said Dr. Bourdette. Large doses of these medicines thus will be required to achieve a therapeutic effect.
Small Molecules in Development
Small molecules also could stimulate OPC differentiation. These drugs can be modified to enhance their ability to penetrate the CNS, in contrast with large molecules.
One class of drugs that researchers are studying is thyromimetic medicines, which seek to simulate the effects of thyroid hormone. Thyroid hormone is necessary for OPCs to differentiate into oligodendrocytes and to promote myelination. Patients with hypothyroidism do not produce the normal amount of myelin. Investigators use thyroid hormone to promote OPC differentiation in vitro, and the drug is a potential treatment for patients with MS.
Peter Calabresi, MD, Director of the Division of Neuroimmunology at Johns Hopkins University in Baltimore, and colleagues are preparing to begin a trial of thyroid hormone for promoting remyelination in patients with MS. Although the approach seems promising, “the problem is that you may have to make patients thyrotoxic in order to get enough of thyroid to be beneficial,” said Dr. Bourdette. Thyroid hormone also can be cardiotoxic.
Thyromimetic drugs may represent a better approach, said Dr. Bourdette. These drugs are modifications of the thyroid hormone that have preferential activity for the thyroid hormone receptors on oligodendrocytes, which differ from those on the heart. Investigators thus can make thyromimetic drugs with differential affinities for the brain and OPC. Thomas Scanlan, PhD, Director of the Program in Chemical Biology at OHSU, and colleagues created a thyromimetic drug as a means of lowering cholesterol with minimal effects on the heart. This drug can stimulate OPCs. Researchers at OHSU now are studying the agent in a mouse model of demyelination. “The drug does accelerate remyelination in the mouse model, but not as well as the thyroid hormone,” said Dr. Bourdette. The investigators hypothesize that the thyromimetic drug does not penetrate the brain effectively, and they are modifying the drug to improve its ability to enter the brain.
