Unmasking Multiple Sclerosis

Emily BurkeBiologics, Biotech Basics, Clinical Trials, Drug Development, Drug Targets, Mechanism of Action, Monoclonal Antibodies, Small Molecule Drugs, The WEEKLY

 Many Channels Available To Impede MS Progression

Continuing our series on central nervous system (CNS) disorders—previously covering Alzheimer’s and Huntington’s—we pivot to unmask Multiple Sclerosis this week. Famous faces suffering from Multiple Sclerosis (MS) include former talk show host Montel Williams and Sopranos star Jamie-Lynn Sigler. MS typically occurs in susceptible individuals between the ages of 20 and 50, and there are an estimated 2.3 million cases worldwide according to the MS Society.

Both a neurological disorder and autoimmune disease, MS originates as an immune-derived attack on the myelin sheath surrounding the axon portion of the neuron. With this insulating layer damaged, the electrical signal relied upon by neurons for communication loses the ability to push data forward. Initial symptoms vary due to the particular part of the nervous system affected. Neurons all along the front lines of communication are under threat, so symptoms can include motor, sensory, or visual problems.

About 85% of MS cases are relapsing-remitting (RRMS), meaning periods of recovery followed by remission are seen between clearly defined periods of new or increasing neurologic symptoms. Those afflicted with RRMS usually transition into secondary progressive MS, experiencing an accumulation of disability over time. Primary progressive MS, in contrast, exhibits a worsening of neurologic function from the onset of symptoms.  In both cases, significant loss in mobility continue as neurons lose their ability to send data.

Unplugging The Roots

The identification of susceptibility genes, or genes that increase the odds of developing a disease, have contributed to the framework for understanding MS. The direct cause, however, is largely unknown.

What we do know:

  • First, white blood cells (WBCs) must mistakenly label the myelin sheath as a “foreign invader.” Since MS typically doesn’t develop until age 20 or older, one theory points to these rogue WBCs being activated by a viral infection.
  • Second, a breach in the blood-brain barrier (BBB), the protective network of blood vessels preventing potentially harmful substances from entering the brain. Exactly what elicits this compromise is not fully understood, but generalized inflammation—possibly triggered by a viral infection—is thought to play a role, in part because certain anti-inflammatory medications (see below) appear to lessen the permeability

Other theories:

  • Hormones may be involved—MS is more common in women than men by a three to one ratio.
  • Geography may play a factor—there is a higher incidence of cases the farther north one travels from the equator. Since sunlight is required for the sufficient production of vitamin D, it’s speculated the fat-soluble vitamin may protect predisposed individuals.

The ultimate expression of the disease is likely the result of a combination of genetic and environmental factors.

Injectables Blunt The Immune Response

Although there is no cure for MS, there are a number of drugs on the market that can slow its progression. Most work by blunting the immune system’s attack on the CNS. MS sufferers switch between different drugs as the course of their disease worsens.

One of the most common first-line treatments for RRMS is recombinant interferon-beta: Avonex and Plegridy by Biogen (Cambridge, MA), Rebif  by EMD/Serono (Darmstadt, Germany) and Pfizer (New York, NY), Extavia by Novartis (Basel Switzerland), and Betaseron by Bayer (Leverkusen, Germany). Interferon-beta is a signaling molecule that reduces the overall levels of inflammatory agents in the brain. Patients on interferon-beta therapy experience an increase in the integrity of their BBB, resulting in fewer myelin sheath attacking WBCs entering the brain. Recent studies suggest interferon-beta may increase the production of nerve growth factor, improving neuronal survival.

Copaxone, marketed by Sandoz (Holzkirchen, Upper Bavaria, Germany), consists of four amino acids—glutamate, lysine, alanine, tyrosine—that constitute a large percentage of the myelin protein, which compose the myelin sheath. This injectable is thought to act as a decoy of sorts to the immune system—white blood cells that would normally attack the myelin sheath attack Copaxone instead.

Two monoclonal antibodies are available to treat MS. Sanofi’s (Paris, France) Lemtrada binds to a protein on the surface of T-cells, one type of WBC thought to be a key player in attacking the myelin sheath. A Lemtrada-bound T-cell is targeted for destruction by other WBCs, thereby reducing the number of T-cells available to destroy the myelin sheath. Biogen’s (Cambridge, MA) Tysabri helps to prevent T-cells from entering the brain by binding to proteins called VCAM1 on the surface of the blood vessels making up the BBB. In order for myelin-attacking T-cells to cross the BBB, they must attach to these VCAM1 proteins and “pull” themselves through. With Tysabri in place, the T-cells cannot attach to the VCAM1 proteins, and are denied entry into the brain.

Small Molecule Fighters

Until 2010, injectable drugs (listed above) were the only option. With the approval of Novertis’ Gilenya, MS medication in pill form arrived. Gilenya works by binding to a receptor on the surface of T-cells that prevents them from leaving the lymph nodes. Thus, they are unable to enter the brain to weaken the myelin sheath.

Two years later, a second oral MS drug, Sanofi’s Aubagio, entered the market. Aubagio works by inhibiting the growth of actively dividing cells—including activated T-cells.

In 2013, much excitement surrounded the approval of Biogen’s oral MS medicine, Tecfidera. Clinical trials suggested it was at least as effective and had a better safety profile than other MS drugs. While the exact mechanism of action for Tecfidera is not known, it has anti-inflammatory properties and activates the expression of antioxidant proteins, which may explain its neuroprotective effects.

In The Clinic

MS drug discovery and development is very active. Here are just a few of the highlights:

Daclizumab: Monoclonal antibody that binds to a receptor on the surface of T-cells, preventing them from becoming fully activated. Regulatory filings completed. Developed by Biogen and AbbVie (North Chicago, IL).
Ocrelizumab: Monoclonal antibody targeting B-cells for destruction. Previously, B-cells were not thought to play a role in MS pathology, but the apparent clinical efficacy of Ocrelizumab suggests they might. Currently in Phase III clinical testing. Developed by Biogen and Roche (Basel, Switzerland).
Anti-LINGO-1: LINGO is a protein that appears to inhibit myelination when it binds to its receptor on nerve cells. Anti-LINGO is a monoclonal antibody attempting to stop this inhibition. Data from animal studies suggest it may even trigger re-myelination. If proven to work in humans, it will be the first MS drug to directly fix the myelin sheath. Currently in Phase II clinical testing. Developed by Biogen.
MN-166: Oral medication that suppresses the production of pro-inflammatory signaling molecules and increases the production of anti-inflammatory signaling molecules. In Phase II clinical testing. Developed by MediciNova (La Jolla, CA).
MultiStem: Athersys (Cleveland, OH) is in preclinical development of this “off-the-shelf” adult stem cell platform for the treatment of MS where tissue matching isn’t required for treatment.