Multiple Sclerosis Research Repository

August 18, 2025

To Drs. Sabatino Jr., Cree, and Hauser: 

I am writing this letter to provide feedback about your recent article entitled: 

“New Horizons for Multiple Sclerosis Therapy: 2025 and Beyond” by Joseph J. Sabatino Jr. MD, PhD; Bruce A.C. Cree MD, PhD, MAS; and Stephen L. Hauser MD” (published June 6, 2025) (link: https://onlinelibrary.wiley.com/doi/10.1002/ana.27270?af=R) 

I will structure this letter by noting some quotations from this article and then providing my feedback and/or questions about each quotation.  

1. -”Here, we summarize recent advances that have together transformed the disease from the most common crippler of young adults in the western world to its place today as a condition in which most newly diagnosed patients can anticipate lives free from disability”

-Commentary: What is your evidence of this claim (“…most newly diagnosed patients 

can anticipate lives free from disability”)?

1. The FDA labeling information in Section 14 (“Clinical Studies”) for almost all of the “DMTs” indicates that the “DMTs” (even the alleged “high-efficacy DMTs”) are FAR more efficacious against relapses and conventional brain MRI activity (spinal cord MRI assessments are not included in this information or most if not all MS “DMT” clinical trials) than the disability progression endpoints, which only measure “disability progression” narrowly (using EDSS only in most cases) over short-term durations of time, when we know from research that the average time to transition from RMS to SPMS (when most progression and disability accrue and do not remit) is anywhere from 10-21 years from the onset of the RMS disease course per natural history of MS studies (happy to provide citations for these studies upon request).  

2. There is no evidence that I am aware of that indicates that ANY of the current MS “DMTs” prevent disability progression.  The concept of “slowing progression” is problematic as well, as a person with MS’s progression cannot be predicted.  My understanding from reviewing the “DMT” FDA approval and labeling information and the clinical trial reports/results is that the evidence for some “DMTs” reduce the risk (very small absolute risks with high Numbers Needed to Treat (NNTs) of disability progression as measured by EDSS (usually 3-month CDP) over the short-term durations of these trials).  The longer-term OLE data is not meaningful, as there is no placebo or active comparator group; therefore, one could make the argument that a placebo and/or active comparator group could have had the same results as the treatment group.

3. TREAT-MS and DELIVER-MS studies: Examples of the fact that it is not known how early, aggressive treatment with an alleged “high-efficacy DMT” (keeping in mind that as far as I am aware, in the USA, there is no set criteria for what constitutes a “high-efficacy DMT”: in the UK, per the ABN, it is a DMT that reduces relapses by 50% or more)
   1. “The DELIVER-MS study seeks to answer the important question: does early treatment with highly effective DMT improve the prognosis for people with MS? This is an area of significant controversy, and no data currently exist to guide treatment choices for patients and clinicians.”
   2. TREAT-MS: “There is an unmet need to identify if specific treatment strategies during the relapsing-remitting phase of multiple sclerosis (MS) can prevent, delay, or reduce longer-term disability.”

4. From: “Effect of Early Treatment Intensity on Progression Independent of Relapse Activity and Disability Accumulation in Multiple Sclerosis by Jessica Jane Ye et al (https://pubmed.ncbi.nlm.nih.gov/40791714/): “While HEET reduces risk of RAW, it does not significantly affect the risk of PIRA, even in patients diagnosed before age 30. It also does not significantly affect the risk of sustaining an EDSS score ≥ 5.0, though may minimally decrease change in EDSS/year. This suggests inductive versus escalation strategies primarily influence patient outcomes by decreasing RAW, and underscores the need for emerging therapeutics to target PIRA, which continues to cause significant disability in patients on treatment.”

5. https://pmc.ncbi.nlm.nih.gov/articles/PMC6518998/

6. https://www.buffalo.edu/news/releases/2023/02/017.html

7. I asked Dr. Gavin Giovannoni about this claim, and his response was as follows: 

-“Re: “Do you agree with the very bold claim made there that “most newly diagnosed patients can anticipate lives free from disability,” even though (and the authors even concede to this in this same article, paradoxically and contradictorily) the alleged “high efficacy” DMTs are still not very effective (f at all) against PIRA/silent progression/neurodegeneration?”

No, I disagree with this statement, because our current treatments, outside of alemtuzumab and AHSCT, don’t stop smouldering disease; they delay it. Therefore, given sufficient time, most people with MS will develop some form of disability” (https://gavingiovannoni.substack.com/p/q-and-a-104-autonomic-dysfunction/comments)

8. From the Phase 3 tolebrutinib HERCULES trial, the data showed that 74% of those in the trial with naSPMS had been on DMTs yet unfortunately still progressed to naSPMS in times no longer than the natural history studies of untreated patients.  Yes, an argument can be made that not all of this 74% cohort were on “high efficacy DMTs,” but some were.  
9. -”Yet as noted above, it is also clear that progressive disease activity, while attenuated, persists in most patients, and is not adequately captured with current imaging and protein biomarker measures”

-Commentary: This statement contradicts your above claim that “most newly diagnosed patients can anticipate lives free from disability.”  

3. -”Patients receiving anti-CD20 therapy achieve year-to-year whole brain volume reductions that approximate age-matched healthy controls  (~0.4% annually) despite experiencing ongoing silent progression”

-Commentary: This statement contradicts your above claim that “most newly diagnosed patients can anticipate lives free from disability” in that you do admit that patients will still experience “ongoing silent progression.” 

4. -”Despite near complete control of lesion formation and relapses, the impact of B cell depletion therapy on confirmed disability progression (CDP) is approximately 40% in RMS and 30% (with OCR) in primary progressive progressive multiple sclerosis (PPMS) [77].  More complete control is sorely needed…data to date indicate that the benefits of anti-CD20 therapies against progression are not improved with higher dosing regimens, and alternative strategies will be required”

-Commentary: What source 77 (“The patient impact of 11 years of ocrelizumab treatment in multiple sclerosis: long-term data from the phase III OPERA and ORATORIO studies” by Hauser SL et al (2024) says is: 

1. “Ocrelizumab reduces the risk of reaching key clinical milestones”; PPMS (key clinical milestone: EDSS 7 or higher): Risk reduction with OCR-OCR vs PBO-OCR: 33%; and RMS (key clinical milestone: EDSS 6 or higher): Risk reduction with OCR-OCR vs IFN-OCR: 35%.  *These numbers are almost certainly relative risk reductions, not absolute risk reduction numbers.*

e) ”For MS, however, as noted earlier, no culprit antibodies have been identified

-Commentary: This calls into question the belief and view that MS is a primary autoimmune disease.  

g) -”…the absence of any known serologic antibodies associated with MS…”

-Commentary: This calls into question the belief and view that MS is a primary autoimmune disease.

h) -”Given the spectacular progress to date, it may not be presumptuous to contemplate the possibility that MS could be the first chronic autoimmune disease to be cured” 

-Commentary: Given the information I have presented and provided above, it seems outrageous to make a claim that “MS could be the first chronic autoimmune disease to be cured,” ESPECIALLY when one considers that the belief and view of MS as a primary autoimmune disease continues to remain an unproven hypothesis!  Furthermore, at present, there are not even “treatments” that halt progression, nor is the cause(s) and pathology of MS elucidated enough to even have meaningful treatments that are capable of halting progression.  

In closing, again, can you please provide your evidence for your above claim that “most newly diagnosed patients can anticipate lives free from disability”? 

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