RealTalk MS – Episode 440

"An MS Specialist's Response to the FDA"
Host: Jon Strum
Guest: Dr. William Conte
Release Date: February 2, 2026

Episode Overview

In this episode, Jon Strum dives into a contentious recent decision by the FDA: the issuance of a Complete Response Letter (CRL) declining approval of tolebrutinib, a novel investigational disease-modifying therapy for multiple sclerosis (MS). Dr. William Conte—a principal investigator on the pivotal Phase 3 trial—joins the show to offer a clinician’s reaction, dissect the FDA’s rationale, and amplify the urgent unmet needs of people with progressive MS. The conversation deeply explores the science, patient perspectives, regulatory inconsistencies, and what needs to change for future drug approvals.

Key Discussion Points & Insights

1. The Shock of the FDA’s Decision

• Dr. Conte’s Reaction:
  • Dr. Conte describes being “angry” and “confused” by the FDA's reversal after what had been promising communications and a highly positive Phase 3 study.
  • Quote:

    "Initially it was a big confusion. Then in early January, I actually was able to access the actual complete response letter...I actually was angry after reading it by some of the statements..." — Dr. Conte (06:46)

2. Unmet Needs in Secondary Progressive MS (SPMS)

• Explanation of Progression:
  • Dr. Conte details the distinction between relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA), highlighting that most therapies only address relapses, not ongoing progression.
  • Patients “aren’t relapsing anymore,” but still report worsening symptoms—this is the “big unmet need.”
  • Quote:

    "Why am I feeling slower? Why is my walking slower? Why is my fatigue getting worse?... That's what progression is." — Dr. Conte (09:24)

3. FDA’s Use of Outdated Definitions

• Obsolete Criteria:
  • The FDA referred to progression independent of relapse activity (PIRA) as “an emerging construct” and relied on a 2014 paper for definitions, disregarding recent international consensus papers and current clinical understanding.
  • Quote:

    "It was just really bizarre to say it was an emerging concept...this consensus paper came out after this big meeting and it's... ignored." — Dr. Conte (11:25)

• Implications for Future Trials:
  • This stance jeopardizes not only tolebrutinib but also other ongoing studies using modern criteria.

4. Clinical Trial Endpoints and MRI Findings

• FDA Objections:
  • The FDA criticized inclusion of patients with “asymptomatic enhancing lesions,” questioning if they fit the SPMS profile.
  • Dr. Conte explains that while enhancing lesions are more typical of relapsing MS, strict trial criteria ensured these participants had clinically defined progression.
  • Counterpoint:
    • Similar issues existed in prior successful trials (e.g., ocrelizumab), which were nonetheless approved.
    • Quote:

      "The only other FDA drug approved for progressive MS...had 30% of patients in their phase 3 trial that had enhancing lesions...Why the change?" — Dr. Conte (18:24)

5. Safety Concerns: Liver Injury

• FDA’s Focus:
  • One fatal case of drug-induced liver injury (DILI) led to heightened FDA worry, though all subsequent cases were reversible with monitoring.
• Comparison with Existing Therapies:
  • Dr. Conte argues that other approved MS drugs have greater risk for liver enzyme elevations or other serious complications.
  • The risk/benefit balance should consider what happens to patients left untreated.
  • Quote:

    "...most patients would take a small risk of drug induced liver injury, given the stakes, what's at stake?" — Dr. Conte (37:35)

• Monitoring Feasibility:
  • While weekly testing is burdensome, there is ample precedent in MS care for rigorous lab monitoring protocols.

6. Equity & Access: FDA’s Concern on Drug-Naïve Participants

• FDA Issues:
  • The FDA highlighted that 25% of trial participants were treatment-naïve, implying bias or non-representativeness.
• Conte’s Rebuttal:
  • Dr. Conte says this mirrors the reality for underserved patients who face diagnosis and access delays.
  • Quote:

    “The worst case scenario... we see this a lot with my underserved patients, is that...they're gaslighted into saying, no, it's something else, not MS.” — Dr. Conte (32:11)

7. Call for Regulatory Modernization & Patient-Centeredness

• Changing Definitions:
  • The rigid reliance on old disease constructs blinds FDA reviewers to real-world disease evolution and patient needs.
• The Greater Harm:
  • Delayed treatments are themselves a “side effect,” as untreated progression is irreversible.
  • Quote:

    "What is the risk of doing nothing with these patients?" — Dr. Conte (24:10)

8. Final Takeaways & Lessons for the FDA

• Critical Lesson:
  • The FDA should update its understanding of MS and consider modern progression science and lived patient experience.
  • Dr. Conte favors moving beyond rigid “secondary progressive” labels to more functional clinical definitions.
• Memorable Quote:

  “If they're having this issue with this phenotype definition, just go back to this trial design, look at the inclusion criteria. Maybe we just need...don't even use the term SPMS then, if that's the hold up here.” — Dr. Conte (36:06)

Notable Quotes & Moments

• “There was initially a shock...then I actually was angry after reading it [the FDA letter]...” — Dr. Conte (06:46)
• “Patients aren’t relapsing anymore...But why, why am I feeling slower?...That’s what progression is.” — Dr. Conte (09:24)
• “It was just really bizarre to say it [PIRA] was an emerging concept...they just ignored [the 2024 consensus paper]...” — Dr. Conte (11:25)
• “The only other FDA drug approved for progressive MS...had 30% of patients in their phase 3 trial that had enhancing lesions...Why the change?” — Dr. Conte (18:24)
• “What is the risk of doing nothing with these patients?” — Dr. Conte (24:10)
• “We see this a lot...where, you know, at the most benign level, a patient minimizes their symptoms...the worst case is, they're gaslighted into saying, no, it's something else, not MS.” — Dr. Conte (32:11)
• “If [the definition of SPMS] is the hold up here...don’t even use the term SPMS then.” — Dr. Conte (36:06)

Important Timestamps

• 05:33 – Dr. Conte’s emotional response to the FDA decision
• 08:21 – Unmet needs in progressive MS explained
• 10:50 – FDA’s statements on PIRA criticized as outdated
• 13:00 – The effect of using obsolete definitions on innovative drug evaluation
• 15:01 – Debate on clinical trial inclusion of patients with enhancing lesions
• 18:47 – Discussion on safety and liver injury concerns
• 24:10 – Balancing risk: danger of undertreating MS
• 27:48 – Feasibility and history of frequent lab monitoring
• 30:23 – Equity and access mishandlings in FDA’s criticism
• 34:20 – Dr. Conte’s message to the FDA: Move to modern disease understanding

Tone & Language

The episode is candid, technical yet accessible, and deeply empathetic. Dr. Conte blends rigorous science with heartfelt advocacy for his patients, making complex regulatory and medical issues tangible for anyone living with or affected by MS.

This episode is essential listening for MS patients, caregivers, advocates, and anyone interested in how regulatory decisions impact real lives and scientific progress.