Pharmacists Remain at the Center of MS Care as Perspectives on Pathophysiology Change

As the multiple sclerosis (MS) landscape continues to evolve, pharmacists are more important than ever, said Pharmacy Times Peer Exchange video series moderator Jacquelyn Bainbridge, PharmD, BS Pharm, FCCP, MSCS, professor and vice chair for research and scholarship, neurology pharmacy, in the Department of Clinical Pharmacy and Department of Neurology at Colorado University Anschutz-Skaggs School of Pharmacy and Pharmaceutical Sciences. During the discussions, Bainbridge and her fellow panelists emphasize the importance of biomarker-driven diagnostics and disability detection, and they describe how pharmacists can reaffirm their role as key players in MS management.

How Is Experts’ Understanding of MS Progression Changing?

The understanding of MS is now shifting from a series of distinct phenotypes (eg, relapsing-remitting or secondary progressive MS) toward a continuous disease spectrum, explained Kiranpal Singh Sangha, PharmD, clinical pharmacy specialist at the University of Cincinnati. This evolving view recognizes that underlying neurological damage and neurodegeneration begin at disease onset, even if clinical symptoms do not manifest until much later.

A central component of this shift is the concept of progression independent of relapse activity (PIRA), which describes a steady worsening of neurological symptoms that occurs in the absence of relapses. According to Ryan Fuller, PharmD, clinical pharmacy specialist at the Hospital of the University of Pennsylvania, this progression is now believed to begin at the onset of the disease and to continue throughout its course. As a result, health care professionals are increasingly focused on “smoldering” MS, a persistent degenerative process that may not be well captured by standard MRI imaging.

Further, the understanding of the pathology driving this progression has also advanced, distinguishing between 2 types of inflammation: focal inflammation, which is historically associated with relapsing disease and involves peripheral immune cells crossing the blood-brain barrier to cause large, visible lesions on MRIs; and neuroinflammation, a persistent, low-grade, and widespread inflammation within the central nervous system (CNS) that is driven by resident cells.

To address these challenges, the criteria for monitoring progression are being expanded. The McDonald diagnostic criteria were recently updated to include the optic nerve as a topographic sign, and clinicians are using new biomarkers, such as paramagnetic rim lesions, to track activated microglia and slowly expanding lesions. Additionally, there is a growing emphasis on monitoring cognitive disability alongside physical symptoms, using composite tools such as the Symbol Digit Modalities Test (SDMT) for cognitive speed and the Nine-Hole Peg Test for upper extremity function.

“I think the current treatments available are very lacking in their efficacy to manage neuroinflammation, and we see that in the clinic with patients, particularly [those who] have had MS for a number of years,” explained Fuller. “Even if they’re on treatments that are good at controlling focal inflammation, we continue to see this progression in PIRA, and these patients are the ones [for whom] we all hope for new treatments. And we know that they’re looking forward to new treatments being available.”

Current Treatment Landscape

These shifts are redefining treatment priorities. Although existing therapies are effective at controlling focal inflammation and relapses, there is a significant unmet need for treatments targeting neuroinflammation within the CNS. This has led to the investigation of small molecules, such as Bruton tyrosine kinase (BTK) inhibitors, which can cross the blood-brain barrier to modulate B cells and microglia directly. Unlike many existing disease-modifying therapies (DMTs) that are too large to penetrate the CNS, BTK inhibitors can directly modulate B cells and innate immune cells, [such as] microglia, which are key drivers of disease progression and smoldering MS.

Notably, fenebrutinib (Genentech) is currently being evaluated in phase 3 clinical trials for both relapsing and progressive forms of MS. In relapsing MS, the FENhance 2 study (NCT04586023)¹ demonstrated that fenebrutinib met its primary end point by significantly reducing relapse rates compared with teriflunomide (Aubagio; Genzyme Corporation). In primary progressive MS (PPMS), the phase 3 FENtrepid trial (NCT04544449)² compared fenebrutinib with ocrelizumab (Ocrevus; Genentech, Inc), with top-line results indicating that fenebrutinib was noninferior to ocrelizumab in delaying or preventing disability progression over approximately 120 weeks. Although these efficacy data are promising, the panelists note they are awaiting more detailed demographic data and a clearer understanding of its safety profile, particularly regarding liver health.

“[Treating MS] is [about] balancing efficacy with safety—it’s always a risk-benefit analysis. And…efficacy data [for fenebrutinib] look promising…[and I’m] very excited about the PPMS population having another treatment option,” emphasized Aimee Banks, PharmD, clinical pharmacy specialist at Vanderbilt University Medical Center. “We’ll have to see how the safety data look in the end.”

Other BTK inhibitors provide additional context for the development of this therapeutic class. Tolebrutinib (Sanofi), evaluated in the phase 3 HERCULES trial (NCT04411641),³ which focused on nonrelapsing secondary progressive MS, demonstrated a 31% reduction in 6-month disability progression compared with placebo, with 8.6% of patients showing sustained disability improvement. Evobrutinib (Merck KGaA), an earlier BTK inhibitor, showed modest effects on slowly expanding lesions and microglia; however, in the phase 3 evolutionRMS 1 (NCT04338022)⁴ and evolutionRMS 2 (NCT04338061)⁵ trials, it did not demonstrate a dramatic impact on disability outcomes compared with teriflunomide, partly because, according to Sangha, the patients in the teriflunomide group “[performed] better than the investigators expected.”

The panelists emphasized that a significant concern for the BTK inhibitor class is hepatotoxicity. In one trial, approximately 0.5% of patients experienced severe elevations in liver enzymes—over 20 times the normal limit—leading to 1 death following a liver transplant. As a result, health care professionals anticipate that, if these drugs were to receive FDA approval, they will require rigorous monitoring, potentially including weekly liver function tests for the first 3 months of treatment.

Regardless of some of the possible adverse events, Banks notes that BTK inhibitors are expected to fill a major unmet need in the progressive MS population, where few treatment options currently exist. Because they do not fully deplete B cells, they may offer a safer alternative for older patients who face a higher risk of infection with traditional B-cell depleters. There is also interest in their potential use in combination with other therapies, such as following a high-potency induction therapy with a B-cell depleter to maintain long-term control of CNS inflammation.

The Pharmacist’s Role in MS Management

Pharmacists play an increasingly essential and multifaceted role within the interdisciplinary MS care team, serving as medication experts, patient educators, and clinical coordinators. Their involvement is particularly critical as the MS treatment landscape expands to over 20 DMTs, each with varying mechanisms and administration requirements.

The pharmacist’s role spans several key areas of patient management. In patient education and lifestyle management, pharmacists spend significant time explaining the risks and benefits of various DMTs, helping patients navigate “myriad…different medications” to reach a preferred option through shared clinical decision-making. They also provide pathophysiology education, helping patients understand the difference between relapsing and progressive biology, which can reduce fear and validate the experiences of those with steadily worsening symptoms. In addition, pharmacists address adherence and administration challenges (eg, pill burden with oral therapies, proper refrigeration, injection techniques for self-injectables), as well as the logistical complexities of frequent infusion schedules. They also identify unique household considerations, such as ensuring expensive medications are stored safely and not mistaken for other items.

Further, pharmacists are at the forefront of Risk Evaluation and Mitigation Strategies for high-risk drugs such as natalizumab (Tysabri; Biogen Inc) and alemtuzumab (Lemtrada; Genzyme Corporation), ensuring patients are properly enrolled, educated about risks such as progressive multifocal leukoencephalopathy, and adherent to the required monitoring. Bainbridge explains that a key responsibility is overseeing laboratory testing, as pharmacists often “own” the process of ensuring appropriate labs are ordered and reviewed, recognizing that routine tests from primary care providers may not include the specific markers required for MS DMTs. They also triage abnormalities and, in some settings, operate under collaborative practice agreements to independently order labs and respond to results, improving efficiency and reducing administrative burden on physicians.

Pharmacists also play a critical role in navigating access to treatment. They manage the complex prior authorization process by documenting patient goals and prior treatment failures to support drug approval. As insurers increasingly require more specific coding for MS phenotypes per the International Classification of Diseases, Tenth Revision, such as distinguishing between active and inactive secondary progressive MS, pharmacists ensure that clinical documentation accurately reflects disease status to prevent barriers to access. As new therapies emerge, many of which may require intensive monitoring, the pharmacist’s role in coordinating this high-touch, safety-focused care is expected to become even more indispensable.

In tracking disability and disease progression, pharmacists contribute to both objective and subjective assessments. They help monitor physical and cognitive function using composite tools such as the Nine-Hole Peg Test for upper extremity function, the Timed 25-Foot Walk for ambulation, and the SDMT for cognitive processing speed. Additionally, they capture patient-reported outcomes through specialty pharmacy interactions, asking targeted questions to better understand how patients perceive fatigue, memory, and overall function.

“It’s an exciting time…every year there are new breakthroughs. We have new medications that we’re using now, and that are going to be on the table soon. And we also have seen pharmacists around the country starting to develop their own practice in these neurology clinics, which is also exciting. I think the number of new medications and medications that we’ve been using speaks to the need and the value of having a pharmacist in the clinic,” Fuller said.

Millad Sobhanian, PharmD, clinical pharmacy specialist at the University of Maryland Medical Center, echoed this sentiment: “Hopefully, we start to see this second explosion of therapies and growth within the progressive field…and I think it’s exciting to see how pharmacy is just going to continue to grow and evolve alongside it.”

Watch the full Peer Exchange series here.

REFERENCES

1. Study to evaluate the efficacy and safety of fenebrutinib compared with teriflunomide in relapsing multiple sclerosis (RMS) (FENhance 2). ClinicalTrials.gov. Updated March 16, 2026. Accessed March 25, 2026. https://clinicaltrials.gov/study/NCT04586023

2. A study to evaluate the efficacy and safety of fenebrutinib compared with ocrelizumab in adult participants with primary progressive multiple sclerosis (FENtrepid). ClinicalTrials.gov. Updated December 24, 2025. Accessed March 25, 2026. https://clinicaltrials.gov/study/NCT04544449

3. Nonrelapsing secondary progressive multiple sclerosis (NRSPMS) study of Bruton’s tyrosine kinase (BTK) inhibitor tolebrutinib (SAR442168) (HERCULES) (HERCULES). ClinicalTrials.gov. Updated July 2, 2025. Accessed March 25, 2026. https://clinicaltrials.gov/study/NCT04411641

4. Study of evobrutinib in participants with RMS (evolutionRMS 1). ClinicalTrials.gov. Updated June 12, 2025. Accessed March 25, 2026. https://clinicaltrials.gov/study/NCT04338022

5. Study of evobrutinib in participants with RMS (evolutionRMS 2). ClinicalTrials.gov. Updated March 21, 2025. Accessed March 25, 2026. https://clinicaltrials.gov/study/NCT04338061