MS Physician Newsletter October 2019

Multiple sclerosis (MS) is an autoimmune disease in which the immune system misrecognizes part of the brain called myelin.

by Dr. David C. Weisman, MD

Multiple sclerosis (MS) is an autoimmune disease in which the immune system misrecognizes part of the brain called myelin. The immune system attacks the myelin in patches (that’s the sclerosis part of MS, the patches feel hard on pathology relative to the rest of the brain). When the myelin is damaged, it cannot protect nerve cells. So if the myelin behind the eye is damaged, vision is lost. If the myelin that protects nerves sending signals to the legs is damaged, the legs get weak. We call these events “relapses.” Sometimes they get better, but sometimes not. We can see these patches on MRI where they are called “demyelinating lesions” (myelin used to be there; demyelination removed it).

MS is a random, unpredictable, and cruel disease, mostly affecting younger people.

Before the new medications became available, there were many patients whose MS seemed utterly unaffected by the injections of older medications, even if they were able to tolerate them. When I was a resident, we took care of a young woman — exactly my age at the time, 25 — who suffered relapse after relapse. Her MRI showed horrible changes. She failed every medication on the market. In desperation, our senior neurologist, a famous MS doctor and researcher, even tried chemotherapy. Ultimately, she was left in a nearly comatose state, paralyzed, entirely bedbound, using a stomach tube and a tracheotomy for breathing. The neurology team, once focused on making her better, became her hospice team, focused on easing her suffering as she died.

That was the state of medicine in and around 2002. Who could have predicted the next two decades? The field has had amazing success. Why? Well, the MRI provides an obvious, intuitive, and reliable biomarker for the disease. Partially as a result of the robust power of the MRI, and also thanks to legions of basic scientists and doctors who have studied the immune system over their lives, MS has many excellent medication options.

These medications center around modulating the immune system, to make it less ‘angry’ at the myelin. The oldest, Copaxone (glatiramer), acts like a vaccine, providing the immune system with random and ever-changing myelin molecules, thus desensitizing and distracting the angry cells.

Tysabri (natalizumab) prevents immune cells from entering the brain. So the cells can be as angry as they want, but they cannot attack the myelin because they cannot enter the brain or spinal cord. Tysabri works so well, for so many patients with a history of aggressive MS, doctors began speaking of patients who had No Evidence of Disease Activity (NEDA): no evidence of disease clinically and by MRI.1 Tysabri shuts down all immune activity in the brain for both good (less MS lesions) and bad (more brain infections). This medication is not for everyone.

ANA Research Center began working on the next wave of MS medications in 2011. At that time, we were asked to help develop ocrelizumab, an unproven drug without FDA approval. It worked in a unique manner: by depleting a type of immune cells called the CD20 B-cell. These cells seem to sit at the causal center of a lot of evil in MS: they make auto-antibodies, they present myelin as being harmful, and they make inflammatory molecules. But the effect of reducing CD20 cells was not well known. This was a fundamental risk for the drug company as well, because this part of the immune system had not been targeted in the past, but Genentech and Roche sponsored a preliminary trial, giving it a 15% chance of success. The unmet need of patients warranted a risky move.

A handful of subjects at our site agreed to participate. The drug was being compared to an older, three-time-a-week injection with significant side effects. It was a stunning success.2 When the data was collected, those in the ocrelizumab arm had double the NEDA, half the relapses, and 94% less MRI activity. They also had very few ill effects from an altered immune system. Thanks to this data, the FDA approved the drug, which has helped tens of thousands of MS patients worldwide.

ANA Research Center continues to investigate other lines of inquiry. We are working on oral drugs that try to deactivate B-cells. The future of this field is to enable NEDA for all patients, and to work on remyelination, covering the damaged areas of myelin with new growth. New molecules appear promising in this regard.

I come back to the bedbound young patient with MS and wonder if she would have responded to ocrelizumab, wonder if a novel remyelinating drug could have wrapped her spinal cord in myelin and allowed her to get out of bed. Given the strides we’ve made so far, I have little doubt that patients like her, with nearly fulminant MS, will be saved.

1 Havrdova E, Galetta S, Hutchinson M, Stefoski D, Bates D, Polman CH, O’Connor PW, Giovannoni G, Phillips JT, Lublin FD, Pace A, Kim R, Hyde R Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009 Mar; 8(3):254-60.
2 Hauser SL1, Bar-Or A1, Comi G1, Giovannoni G1, Hartung HP1, Hemmer B1, Lublin F1, Montalban X1, Rammohan KW1, Selmaj K1, Traboulsee A1, Wolinsky JS1, Arnold DL1, Klingelschmitt G1, Masterman D1, Fontoura P1, Belachew S1, Chin P1, Mairon N1, Garren H1, Kappos L1; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234.

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