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Staying Ahead Of Disability Progression In Multiple Sclerosis

Staying Ahead Of Disability Progression In Multiple Sclerosis

In its earliest stages, multiple sclerosis (MS) can be difficult to diagnose, with many people having symptoms such as unexplained fatigue, urgent need to urinate, depression, and short-term memory loss for years prior to their diagnosis.1 And in most cases, the disease continues to evolve in unpredictable and often subtle ways — making treatment a perpetual challenge.

MS is an autoimmune disease in which the immune system attacks myelin, the protective coating that surrounds neurons in the brain, spinal cord, and optic nerves. Around 85 percent of people living with MS develop recurrent immune attacks, called relapses. Relapse symptoms range from visual loss out of one eye to numbness and weakness in extremities to spinning sensations and double vision. These unpredictable neurological attacks can worsen rapidly over a few days to several weeks, and recovery may not be complete, which means people living with MS may experience vastly different symptoms.

As people living with MS age, some may start to develop progressively worsening impairment, which is thought to be caused by the accumulation of permanent nerve damage in the central nervous system (neurodegeneration). This disability progression can be assessed by a measurement scale called the Expanded Disability Status Scale (EDSS), which can detect changes over time like muscle weakness, balance problems, and difficulty with multitasking or short-term memory.2 This increasing disability progression that many people with the disease eventually experience may signal a shift from the inflammatory stage of relapsing MS (RMS) to the progressive stage.3

“Evidence supports that injury to the brain and spinal cord can occur early in the disease, which leaves people living with MS at risk for future disability,” says Barry Singer, M.D., Director of The MS Center for Innovations in Care at Missouri Baptist Medical Center, St. Louis. “A major goal for MS treatment is trying to protect the nervous system as much as possible, as soon as possible, in order to slow down disease progression.”

According to Dr. Singer, a comprehensive, holistic approach can be used to address the many components of a person’s life that are impacted by the disease. “Alleviating key symptoms such as fatigue, nerve pain, cramping, and bladder issues has helped many of my patients continue their passions. Great care requires a tailored, collaborative team approach including MS nurses, therapists and subspecialists. A focus on overall wellness is highly important including diet, exercise, mental health, cognitive health, and social connections.”

Traditional approaches to detecting this transition from relapsing MS to early disease progression—such as tracking changes in physical strength and coordination over time—often miss its onset. Evidence of disease progression can include extremely subtle broader symptoms from the EDSS such as mild cognitive decline, trouble with memory or concentration, and other neurologic changes related to MS that are not as easy to measure as changes in physical function.4 As a result, until recently, minimal clinical trial research had specifically focused on patients transitioning to a progressive stage of RMS called active secondary progressive MS (SPMS).5 Recognizing the need to better treat this transition, Novartis researchers concluded that it was crucial to investigate this pivotal moment in the MS disease journey.

“Patients at this stage of RMS are difficult to identify, and there has not been a lot of research in this patient population. Novartis recognized it was time to change the conversation around disease progression by focusing on this critical transition period,” says Dharmesh Patel, M.D., Vice President, Neuroscience Medical Unit Head, Novartis.

Recent diagnostic innovations have enabled scientists to detect and measure subtle signs of disability progression among patients with RMS.6 Novartis used some of these new approaches to identify and follow RMS patients in the earlier stages of disability progression in the EXPAND clinical trial, the largest Phase 3 study of SPMS patients to date,7 which eventually led to the U.S. Food and Drug Administration’s 2019 approval of the oral drug Mayzent® (siponimod). Mayzent is the first and only pill studied and proven to delay disability progression in people with RMS whose disease was more progressed.*

“The EXPAND trial looked at a patient population that’s reflective of a large group of my own MS patients, and those for whom we haven’t had a lot of treatment options historically,” says Dr. Singer. “When discussing therapies to slow down disability progression, it’s important to have evidence from a large clinical trial that supports what we are trying to do in real-world clinical practice.”

The EXPAND trial zeroed in on disability progression by including only those patients who had experienced consistent symptom worsening for three months or more, but not the return to baseline that characterizes the earlier stages of the disease. It assessed disability progression by measuring eight key areas of the EDSS, reflecting changes in cognitive and physical function.

“This trial showed, for the first time, that these transitional or progressive patients do benefit from a specific therapy,” says Dr. Patel. “Mayzent showed consistent benefits in this patient population.”

Physicians, people with RMS, and researchers have always known that the disease does not proceed in a strictly stepwise way.8 The EXPAND trial confirmed that the transition to SPMS is gradual, and that inflammation overlaps with nerve damage. We still need additional rigorous research and disease monitoring methods that detect subtle and gradual changes, especially in cognitive functions, which can be difficult to track in daily life. This will allow physicians to further hone in on the right medicines or combinations of medicines to use—including traditional MS disease-modifying treatments—at the right time.

We also need to better understand the biological mechanisms that underlie RMS progression, so researchers can develop new treatments that slow it. According to both Dr. Singer and Dr. Patel, an emerging research path is around brain cells called microglia, which may have the potential to address both inflammatory and neurodegenerative components to fight MS,9 and on finding ways to restore the protective nerve cell coating that is steadily lost in progressive forms of the disease.

“At Novartis, we constantly strive to address unmet needs in every disease area that we study,” says Dr. Patel. “By better understanding the drivers of nerve damage in MS, we have the potential to give patients who confront advancing disability even more possibilities and hope for a healthier future.”

*Mean EDSS score of 5.4

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