MS Living Well: Key Info from Multiple Sclerosis Experts

Episode: Secondary Progressive MS: Next Chapter
Date: May 20, 2025
Host(s): Barry Singer, MD & Jamie Holloman, MD
Guests: Dr. Christopher Legank

Episode Overview

This episode kicks off season seven with an in-depth exploration of secondary progressive multiple sclerosis (SPMS), highlighting new clinical insights, evolving therapeutics, and practical management tips for patients and caregivers. Dr. Barry Singer and new co-host Dr. Jamie Holloman focus on understanding progression in MS, the impact of disease modifying therapies (DMTs), and exciting new drug developments. Later in the episode, Dr. Christopher Legank shares a clinical and personal perspective on managing progressive symptoms.

Key Discussion Points & Insights

1. Defining Progression in MS

[01:42 - 05:06]

• Progression Defined

  • Most patients (about 85%) start with relapsing-remitting MS (RRMS), characterized by attacks (relapses) followed by recovery.
  • Progression refers to gradually worsening symptoms—weakness, balance, cognition—without clear recovery.
  • Transition from RRMS to SPMS is variable, ranging from 7 to 40 years; early treatment reduces risk of progression.

• Two Types of Worsening:

  • Relapse-Associated Worsening (RAW): Worsening after an MS relapse.
  • Progression Independent of Relapse Activity (PIRA): Gradual worsening not tied to relapses, especially hard to treat.

  "The harder part to treat is what we call PIRA—progression independent of relapse activity. And this is when you’re not having relapses, but things are slowly getting worse."
  —Dr. Barry Singer [02:53]

2. Pathophysiology of Progression

[05:06 - 07:35]

• Damage goes beyond myelin to include axons (nerve fibers).
• Chronic inflammation—driven by microglia and B cells—plays a persistent role:
  • Microglia form a rim around brain lesions, fueling ongoing inflammation.
  • Chronic B-cell clusters in the meninges sustain low-level immune attack.
• Age-related neurodegeneration: Brain volume loss accelerates in MS, making early, effective treatment crucial for long-term function.

3. Current and Emerging Treatments for SPMS

[07:35 - 18:22]

• Existing Therapies:

  • Beta-interferons: Early trials showed limited benefits; effectiveness higher in younger, less advanced patients.
  • Siponimod (Mayzent): 21% reduction in progression risk in SPMS (EXPAND trial); side effects include liver enzyme elevation, hypertension, eye swelling (macular edema), increased shingles risk.
  • Ocrevus (ocrelizumab): Effective in primary progressive MS; 24% reduction in disability progression, now approved for “active” SPMS (with ongoing relapses/MRI activity). No dedicated phase III trials yet for SPMS with B-cell treatments.

• Bruton's Tyrosine Kinase (BTK) Inhibitors—Focus on Tolebrutinib:

  • How It Works: Orally administered, blocks BTK, a target in B cells and microglia (the cells implicated in chronic inflammation within the brain).
  • Advantage: Penetrates the CNS more effectively than traditional antibody therapies due to smaller molecular size.

Notable Clinical Trials

• HERCULES (SPMS):

  • 31% reduction in disability progression with tolebrutinib; 8.6% saw confirmed disability improvement.
  • Modest MRI lesion reduction but increased respiratory infection and elevated liver enzymes.
  • Patient profile: Older, long disease duration, few/no recent relapses.

• GEMINI 1 & 2 (Relapsing MS):

  • Compared to teriflunomide: No major relapse rate difference; tolebrutinib showed a 29% relative benefit in slowing disability progression.

"Patients on tolebrutinib were less likely to have progression of disability. This was a 31% benefit."
—Dr. Barry Singer [12:48]

• Projected Availability:
  • Tolebrutinib is under expedited FDA review, with decisions expected by September 2025.

4. Clinical Approach to Progressive Symptoms: Interview with Dr. Christopher Legank

[19:08 - 35:36]

• Personal Motivation:

  • Both Dr. Legank and Dr. Holloman have close family affected by MS, influencing their empathetic approach to care.

• Differentiating Causes of Progressive Symptoms:

  • True MS progression vs. stress-induced worsening vs. other medical issues (e.g., vitamin deficiencies, thyroid, depression, anxiety).
  • Careful history, laboratory workup, and MRI (including spinal cord imaging) are central to the assessment.
  • Many symptoms (e.g., fatigue, cognitive decline, walking difficulty) may be due to factors other than direct disease progression.

"Progressive symptoms can also be due to stress... which, fortunately, can be reversed if we deal with the cumulative stressors."
—Dr. Christopher Legank [20:48]

• Management Strategy:

  • Treat underlying contributors—fatigue, sleep disorders, deconditioning, depression.
  • Personalized recommendations for increasing activity (e.g., walking, aquatic therapy, cooling strategies for heat sensitivity).
  • Medications for Fatigue:
    • Modafinil/Armodafinil (Provigil/Nuvigil) and (in some cases) stimulants for symptom control.

• Objective Measures:

  • Functional tests like the 25-foot walk help track changes.
  • Look for confounding factors like arthritis or neuropathy.

• Addressing Walking Difficulties:

  • Consider medications like dalfampridine (Ampyra), which improves neural conduction and endurance.

"Dalfampridine or Ampyra is terribly underutilized. It can actually improve strength, improve walking by improving signaling through scar tissue and by blocking potassium channels."
—Dr. Christopher Legank [29:23]

• Changing DMTs:
  • Only after thorough review and if objective disease progression is detected; set realistic expectations ("goal is stabilization, not reversal").
  • Caution with generic DMTs: Dr. Legank strongly opposes substitution due to bioequivalence concerns.

5. Future Therapies and Hope

[33:35 - 35:06]

• BTK Inhibitors: Ongoing studies may further expand their role in progressive MS.
• Fraxalumab: Under study for targeting CD40 ligand on B cells, with possible implications for Epstein-Barr virus (EBV)–driven progression.
• Non-pharmaceutical approaches: Biological vs chronological age—exercise as a key intervention to slow progression.

"Not every sixty-year-old's the same. A person's biological age is maybe different than their chronological age...the fountain of youth of treatment there is exercise."
—Dr. Christopher Legank [34:36]

Memorable Quotes

• On describing progression to patients:

  "Frankly, they tell me...I'm just not doing as well. I'm having a harder time walking...some of our patients will talk about, they could walk two miles before their foot would drop, and now...just a mile."
  —Dr. Barry Singer [04:10]

• On new therapies:

  "One day it would be nice to have a little bit of combination treatment: one drug that's very effective for progression and one that's very good at shutting down new contrast enhancing lesions."
  —Dr. Barry Singer [17:19]

• On patient and caregiver education:

  "There might be a little bit of an education gap where family members might think...the patient just isn't motivated, which is really heartbreaking when you hear it."
  —Dr. Jamie Holloman [27:17]

Important Timestamps

• [01:42] – Defining progression in MS
• [02:53] – PIRA vs. RAW and complexity in measuring progression
• [05:12] – Underlying mechanisms of progression
• [07:35] – Review of therapeutic options and clinical trial insights
• [11:29] – Mechanism and benefits of BTK inhibitors, especially tolebrutinib
• [12:48] – HERCULES trial results for tolebrutinib
• [15:38] – GEMINI trial results for relapsing MS
• [18:22] – FDA review timeline for tolebrutinib
• [19:43] – Introduction to Dr. Legank and his motivation
• [20:48 – 31:21] – Clinical approach to evaluating and managing progressive MS symptoms
• [29:23] – Underutilized walking medications: dalfampridine
• [33:35] – Future research (BTK inhibitors, fraxalumab, exercise)

Conclusion

This episode delivers an authoritative, hopeful, and practical update on secondary progressive MS—from how progression is identified and experienced, to which therapies offer measurable benefit or are in the research pipeline, and how care teams can differentiate true progression from treatable mimics or stressors. Balancing the latest science with lived expertise, the hosts and their guest urge early intervention, nuanced assessment, and ongoing innovation—leaving listeners with actionable insights and a sense of realism, but also optimism for the next chapter in SPMS care.