Multiple Sclerosis Research Repository

Dear Dr. Hafler:

Thank you for your response.  I will respond to your statements individually.

1. “Clearly, the efficacy of B cell depletion is significantly efficacious in early autoimmune MS while it is less helpful in progressive disease.”: 

1. Some researchers argue that MS is not a primary autoimmune disease and that this is the reason that the MS DMTs have not shown efficacy against progression.  Here is one such example: https://pubmed.ncbi.nlm.nih.gov/15477520/

2. If by “significantly efficacious in early autoimmune MS” you mean that the B cell depleting DMTs (referred to as “high efficacy” DMTs, which I utterly and very strongly disagree with; I feel this is another misrepresentative, misleading, and untrue term) are efficacious against relapses and conventional MRI activity, I will agree that the evidence supports this assertion.  However, as I indicated in my initial email to you, the evidence also shows that relapses and relapse-associated worsening (RAW) barely contribute to progression in MS and that there is only a weak to moderate association between lesions and progression in MS.  I am happy to provide my research citations supporting these assertions.  What, then, is the significance of a DMT being efficacious against these manifestations of MS (relapses and conventional MRI activity) if these DMTs fail to be efficacious against progression and disability accumulation and likely fail to delay the transition of those with RRMs to SPMS?

I think the question MS experts should be focusing on is trying to understand the discrepancy between the efficacy of the DMTs (including the B cell depletion DMTs) against relapses and conventional MRI activity vs. their lack of efficacy against progression.  This seems to clearly indicate that there are different underlying pathological mechanisms between relapses and conventional MRI activity vs. progression (inflammatory vs. neurodegenerative pathology).  This discrepancy further supports the assertion that the inflammatory and neurodegenerative pathologies are at least partially independent in MS.  

3. Even Genentech’s own information states that relapses do not contribute to progression in MS: 

  “Disease Progression in Multiple Sclerosis”: Genentech (2024)

-relapses were not associated with long-term disability worsening or confirmed disability worsening

-data were consistent with 2 simultaneous processes: focal demyelinating lesions and a more diffuse process that contributes to brain and spinal cord atrophy: this is largely independent of relapses or focal lesion formation and may be the most important contributor to long-term MS disability 

-PIRA was seen early in the MS disease course in a cohort study; 66% had at least 1 PIRA event; 31% developed PIRA within the first 5 years of the disease; 34% had all of their CDA episodes qualify for RAW; 26x greater risk of developing severe disability (EDSS 6) in patients with PIRA within the first 5 years of MS compared with patients whose first PIRA appeared later in the disease course

I have yet to see any evidence that any of the DMTs, including the b cell depleting DMTs, show any significant efficacy against PIRA.  I will offer one example below: 

“Real-world evidence of ocrelizumab-treated relapsing multiple sclerosis cohort shows changes in progression independent of relapse activity mirroring phase 3 trials” by J Ingwersen et al

-”Mean follow-up time was 29 months (range 6 to 51 months). 23.5% developed CDA under ocrelizumab therapy (n = 23). Of those, the majority developed PIRA (87.0% of CDA, n = 20) rather than RAW (13.0% of CDA, n = 3). An exploratory investigation using Cox proportional hazards ratios revealed two possible factors associated with an increased probability of developing PIRA: a shorter disease duration prior to ocrelizumab (p = 0.02) and a lower number of previous DMTs prior to ocrelizumab (p = 0.04). Our data show that in ocrelizumab-treated RRMS patients, the main driver of disability accumulation is PIRA rather than RAW.”

-”Using data from the pivotal phase 3 randomized controlled trials (RCTs) OPERA I and OPERA II, Kappos et al. investigated RAW and PIRA contributions to the disability accumulation of ocrelizumab-treated vs. interferon-treated patients.  They found that (A) PIRA was responsible for most of the disability accumulation rather than RAW irrespective of the treatment arm (later confirmed by the findings of Lublin et al.) and (B) ocrelizumab was superior in preventing PIRA compared to interferon. However, it was less effective in preventing PIRA than RAW.”

-”In both the interferon and ocrelizumab groups, PIRA (rather than RAW) was responsible for 80–90% of the clinical worsening…”

-”our data contributes to the notion that in typical RRMS patients under effective, immune-directed therapy PIRA is the primary driver of disability progression rather than RAW.”

4. “…while it is less helpful in progressive disease”: I will again refer to you to the FDA approval documentation for Ocrevus as well as the following study which found that Ocrevus and rituximab were not effective at slowing progression in PPMS: https://www.neurology.org/doi/10.1212/WNL.0000000000209886.  

Regarding the FDA Ocrevus approval documentation specifically relative to PPMS, I cannot recapitulate the entirety of the information here, but much of it was presented in my FDA Citizen Petition that I included the link for in my initial email to you.  

2) “…these experiments strongly suggest that B cell depletion appears to be working on the likely underlying mechanisms of the disease”: 

1. I strongly disagree, because the B cell depletion DMTs are not showing efficacy against progression
2. What do you consider “the likely underlying mechanisms of the disease to be?”  Only the inflammatory pathology?  What about the neurodegenerative pathology?  There is research that indicates that the inflammatory and neurodegenerative pathologies are at least partially separate in MS.  None of the current DMTs, including the B cell depletion DMTs, are showing efficacy against the neurodegenerative (PIRA) pathology.  

3. It may really “boil down” to whether one views MS as primarily relapses and conventional MRI activity; if this is the case, one could make the argument that the B cell depletion DMTs “appear to be working on the underlying mechanisms of the disease.”  However, there is so much research and evidence that suggests that MS is SO MUCH MORE than relapses and conventional MRI activity.  Some examples include (but are not limited to): synapse loss and dysfunction; motor neuron loss and dysfunction; cellular metabolic and mitochondrial dysfunction; etc.  There is even a sub-type of MS without white matter demyelination (myelocortical MS).  There is damage to unmyelinated axons as well, such as those in the PRNL.  The list could go on. 

3) I will review your paper in the J of Clinical Investigation when time permits, but for now, I refer you again to the research and literature that argues against MS being a primary autoimmune disease.  If this is the case (which I believe it likely is), affecting regulatory T cells may very well not have much effect on the disease course, especially progression.   The researchers Dr. Abhijit Chaudhuri and Peter O. Behan have published numerous works containing this argument.  The other issue is that much of what is believed about MS pathology appears to come from the EAE model, which has very significant differences from MS in humans.  

4) Regarding your standing by your comments about Dr. Bar-Or, I again refer to the significant deficiencies and issues that the FDA found with the ORATORIO trial, which Dr. Bar-Or was part of.  I will include some “highlights” below:

1.  The FDA’s Cross-Discipline Team Leader Review (the Cross-Discipline Team Leader was Dr. John R. Marler) stated that the FDA’s Recommended Indication for Ocrelizumab was only “The treatment of patients with relapsing forms of multiple sclerosis (RMS)”, despite the “Applicant’s Proposed Indication” of: “Relapsing and primary progressive forms of multiple sclerosis.”

2. From “Cross-Discipline Team Leader Review, Clinical and Statistical Reviews of Efficacy (Reference ID: 4019179”:
   1. “Credibility of a trial’s results can be lost in small increments…the review team became aware of problems with the results, the trial conduct, and the protocol that significantly diminished the review team’s confidence in the results of the trial.  Table 14, below, enumerates the more significant of these weaknesses” (p 38)
   2. These “more significant of these weaknesses” were:
      1. Imputation of primary outcome events
      2. No treatment benefit for female patients
      3. Lack of treatment effect after 18 weeks as seen in Kaplan-Meier curve of primary outcome
      4. High rate of dropout and missing outcomes
      5. Determination of Baseline Primary Outcome Measure of Baseline after Recorded Time of Randomization and Infusion (p 39)
   3. “Without changing the protocol, the applicant increased the sample size in the PPMS trial by 102 patients from 630 to 732.  The trial results would be negative if the analysis uses the first 630 patients (p=0.0087)” (p 39)
   4. “The [greyed out] identified 18 problems; 6 major, and one critical (the over-enrollment mentioned above).  Other problems included the quality system, conduct and management (over-enrollment, vendor management, primary endpoint), data management (design and requirements of electronic data capture), and monitoring and auditing.  The inspection team concludes that the PPMS trial ‘was not conducted fully in line with the requirements of the applicable European directives, guidelines and national legislation” (p 40). 
   5. “The trial protocol did not adequately control bias” (p 44)
   6. “Some unusual features of the trial results may be due, in part, to a small treatment effect and a high and unbalanced loss of primary outcome data” (p 44) 
   7. “The number of patients with missing possible outcomes exceeded the absolute difference observed in the trial (maximum of 7.1% absolute difference in Kaplan-Meier estimate and minimum dropout rate of 20%).  For these reasons, the trial does not contain a sufficient quantum of evidence to have confidence that the results are accurate.  One could possibly explain these unusual results by simple chance, but that same argument would apply to the primary outcome as well.  An adequate trial would not be likely to have these uncertainties.” (p 44)
   8. “This review concludes that it would be reasonable to decide that the WA25046 trial is not adequate or well-controlled” (p 45)
   9. “The conclusion of this review is that the PPMS Trial WA25046 does not provide persuasive evidence of effectiveness” (p 45)
   10. “The conclusion of this review is that the PPMS trial is not a single multicenter study of excellent design that provides highly reliable and statistically strong evidence of an important clinical benefit as described in the Guidance on Clinical Evidence quoted above” (p 46)
   11. “Dr. Rodichok and Dr. Yan agree that the evidence to support an effect on disability progression in PPMS from trial WA25046 is weak” (p 54)
   12. “For PPMS, this review agrees with Dr. Rodichok that the evidence is not convincing that ocrelizumab is effective and with Dr. Yan that the evidence of effectiveness is weak, particularly in women” (p 55)

Just as you “stand by [your] comments on Amit, one of the most talented and dedicated scientist I have trained,” I stand by my view and assertion that Dr. Bar-Or’s active participation in the ORATORIO clinical trial for PPMS (WA25046) casts significant doubts, concerns, and questions on your comments.

Respectfully Submitted: