When neurologist Robert Fox first diagnoses a patient with progressive multiple sclerosis (MS) — a form of the disease marked by a slow, gradual worsening of symptoms — he cannot offer much hope of a cure. “I'm very blunt with patients,” says Fox, who is medical director at the Cleveland Clinic's Mellen Center for Multiple Sclerosis Treatment and Research in Ohio. “We don't have a therapy to slow down this train.”

Significant strides have been made in treating MS: there are now eight approved treatments that can reduce its severity and progression. But all of these are for relapsing–remitting MS, a form of the disease marked by unpredictable attacks of new or returning symptoms, followed by periods of either complete remission or a condition slightly worse than before the episode. About 85% of MS patients are in this category. But the treatments cannot help the hundreds of thousands of people with the progressive form of the disease, which is characterized by a steady physical decline.

The recent achievements in drug development highlight this glaring gap in the ability to fight the disease. Drug after drug has been approved for relapsing–remitting MS, but none has made an impact in patients with the progressive form. “In progressive MS, we have zero approved therapies,” Fox says. “Therein lies the unmet need.”

Patients with the progressive form of MS are being left behind. Credit: Huntstock, Inc / Alamy

This gap “is the biggest frustration that I hear from people with MS”, says Timothy Coetzee, chief research officer at the National Multiple Sclerosis Society in New York. Coetzee says that promoting research on progressive MS is currently the main thrust of the organization's funding efforts. The focus of this research is to gain a better understanding of the underlying biology that drives the insidious progression of the disease in these patients.

Finding the cause

MS has a notoriously unpredictable course: two patients with the same diagnosis can have different disease progression, symptoms and severity. People often initially become aware of their disease when they experience a symptomatic attack, which can range from mild numbness or tingling to difficulty with vision or balance, to severe weakness. Attacks can last for several days or weeks, and might take months to subside fully. Many people with such relapsing–remitting MS, however, find that after years or decades, the periodic relapses give way to a gradual decline in function, known as secondary progressive MS. A few patients skip the cycle of attacks and remission entirely, and only experience a gradual, steady decline, called primary progressive MS. About 5% of patients have the progressive form as well as occasional attacks; this is called progressive–relapsing MS. At the heart of the treatment gap is a fundamental question: what makes progressive MS different to relapsing–remitting MS?

The underlying cause of MS is an overactive immune system that destroys its own tissues — specifically, the myelin sheath that surrounds and protects the long axons of neurons in the central nervous system. The process is marked by an inflammatory reaction along the myelin sheath. Current therapies target this inflammation, which is thought to be the primary cause of relapses and the most important player in disease progression for most patients in the early stages of disease. But along with this inflammation and myelin loss is a gradual deterioration of the axons that the myelin protects; it is this neurodegeneration that causes permanent damage. It was once assumed that degeneration was a result of the inflammatory process, but research has since shown that it begins early in the disease and represents a separate process (see The X factor).

There is growing evidence that inflammation plays only a minor role in progressive MS, which seems to be driven by neurodegeneration. Research suggests that the treatments fail in progressive MS because they are targeting the wrong problem. As support for this theory, Fox cites the drug rituximab, a cancer and arthritis medication that has also shown promise for relapsing MS. Like many other drugs before it, rituximab failed overall in a phase II trial in progressive patients, although it did help one subgroup: young subjects who had signs of active inflammation.

If a different biological process underlies progressive MS, then treating it requires a new approach. “We're really not going to get on top of this until we prevent the degeneration that occurs and develop drugs that protect the neurons,” says Alan Thompson, dean of brain sciences at University College London in the United Kingdom. That goal puts progressive MS in the same territory as other neurodegenerative disorders such as Alzheimer's diseases, which are notoriously difficult to treat.

Trials and tribulations

Developing treatments for progressive MS — as with other neurodegenerative diseases — is complicated by the difficulty of designing and conducting clinical trials. Measuring the clinical effects of a drug is straightforward for relapsing–remitting MS, because researchers can track relapse episodes and evaluate whether a drug is reducing their number, frequency and severity. But it is much harder to evaluate a drug's effectiveness in a progressive condition in which symptoms worsen slowly over the course of months and years.

The relapsing–remitting form of MS can also be evaluated by magnetic resonance imaging (MRI), which is used to measure lesions in the brain and spinal cord. The number of new lesions far outstrips the occurrence of relapses, so MRI provides a more convenient measure and so far has been highly predictive of clinical efficacy. Using imaging as a biomarker, pharmaceutical companies are able to conduct relatively small, short phase II trials of drug candidates, helping them target investment in larger, lengthier and more expensive phase III trials. The result, Fox says, is a system for developing drugs for relapsing–remitting MS that is streamlined and successful.

Progressive MS poses a greater challenge for drug development. Standard MRI illuminates areas of inflammation but does not necessarily capture the neurodegenerative pathology. Progress is being made, however. More sophisticated types of MRI, such as magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI), can pinpoint degeneration in the axons of neurons more specifically than conventional MRI can. But so far, these techniques, which require more skill to interpret, have not been widely used because they have not yet been standardized for making quantitative measurements in clinical trials.

A better understanding of the biological underpinnings of progressive MS could help. “The research community is on the cusp of making some significant advances in the neurological basis of the disease,” Coetzee says. “'Progressive' is used as one word, but it's a big word, and it encompasses a lot of different experiences.” For example, Coetzee says, the pathology of progressive MS in someone who has just transitioned from relapsing–remitting MS might be different to that in someone who has had progressive MS for a long time. Figuring out the mechanisms behind these different experiences, he says, should lead to more effective treatments.

The pharmaceutical industry has recently turned its attention to addressing the lack of treatment options for people with progressive MS. Several treatments are currently in clinical trials, including existing drugs for relapsing MS as well as experimental therapies.

Treating symptoms

Even though there are currently no drugs to treat progressive MS, patients can still work towards recovery, says Fox. Indeed, after bluntly telling patients there are no available treatments to slow the advance of progressive MS, he quickly gives them a more positive message: they can take action to manage their symptoms and improve their quality of life.

There is a large and growing arsenal of resources for treating the symptoms of MS with drugs, rehabilitation and exercise. “We're talking about quality of life, managing symptoms and restoring or at least maintaining function,” says Nicholas LaRocca, vice-president of health-care delivery and policy research at the National Multiple Sclerosis Society. “There's really been a resurgence in interest in research to address the symptoms in MS.” The reasons, he says, are twofold. First, “we have a variety of disease-modifying therapies that are partially effective, but that don't stop the disease in its tracks,” he says. And second, because of that, “we need to address the here and now — that is, the symptoms and quality of life”.

Rehabilitation once focused solely on helping a patient recover from an injury or illness, LaRocca says, and a progressive disease such as MS was considered a hopeless cause. But the past few decades have seen “a tremendous blossoming” of rehabilitation therapy for MS patients. It now includes the goal of maintaining function and maximizing abilities in the face of a progressive disease, just as it does for other neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease. People with progressive MS are now given help to manage their disease-specific challenges and symptoms by speech pathologists, occupational therapists and psychologists. Exercise therapy is also a major focus — MS patients used to be cautioned against exercise, because it was thought to be of no use and even to worsen symptoms, but it is now seen as a primary intervention to improve quality of life.

People with progressive MS suffer from a host of symptoms that interfere with daily living, including spasticity and tremor, leg cramps, difficulty walking or maintaining balance, fatigue, depression, bowel and bladder dysfunction, sexual dysfunction and cognitive impairments. Drugs are available to treat many, but not all, of these problems, and pharmaceutical companies are increasingly recognizing that symptomatic treatment is another unmet medical need in MS. In 2010, the US Food and Drug Administration (FDA) approved dalfampridine to improve walking in people with all forms of MS — the first drug specifically approved to treat a symptom of the disease. Another medication, Nuedexta, was approved in 2010 for treating uncontrollable laughing and crying, a rare symptom in people with MS and another neurodegenerative condition, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Botox has been specifically indicated for two MS symptoms: hyperactivity of the bladder wall and spasticity of the upper limbs. Many other drugs are used to treat MS but are not specifically indicated for it. Thompson says that certain symptoms, such as bladder dysfunction, are now easy to treat, but that the medical tools available for others — including fatigue and unsteadiness — are “far from adequate”.

Rehabilitation and symptom management can vastly improve the experience of living with progressive MS while patients wait for science to find new treatments. The key to making those discoveries is to tease apart the mechanisms responsible for the degeneration of the central nervous system. Only then will Fox and other doctors be able to tell their patients that they can slow the unrelenting course of this train — or even stop it in its tracks.