My inquiry:
Dear Dr./Mrs/Ms. Folkendt:
I am the relative of someone with Multiple Sclerosis (MS).
I have been reviewing the FDA approval documents for many of the DMTs (disease-modifying therapies) for MS and would like to begin by asking about one aspect, please.
The following section is quoted from the FDA approval documentation of Tysabri:
-”6.1.2 General Discussion of Endpoints: The clinical manifestations of MS include both relapses and progressive disability. The FDA has previously approved drugs for treatment of MS (see Section 2.2.1, Immune Modulators Approved for Treatment of MS) based on evidence of an effect on either the frequency of relapses, relapse rate or progression of disability. These previous approvals have been based on data from two years of study agent administration in clinical trials. The clinical meaningfulness of an effect on relapse rate after only one year of study agent administration is unclear (see review memorandum of Dr. Marc Walton). The current application is for accelerated approval of natalizumab based on an effect on relapse rate using data from less than two years of study agent administration. The applicant proposes that the effect on relapse rate at one year, as presented in this application, be be used as a surrogate that is reasonably likely to predict an effect on relapse rate at two years (see Section 2.5.4, Application for Accelerated Approval” (*underlining and bolding mine) (page 25)
I would like to focus on the following portion of the above-quoted information: “The clinical manifestations of MS include both relapses and progressive disability.”
Research shows that almost all of the progressive disability in MS comes from PIRA (progression independent of relapse activity). Therefore, when the FDA continues to approve MS DMTs on the basis of their efficacy against relapses/relapse frequency, it is extremely misrepresentative, inaccurate, misleading, and non-evidenced based.
I offer some evidence about PIRA below:
- “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
- “Contribution of relapse-associated worsening in overall disability accrual in patients with relapsing-onset multiple sclerosis: A mediation analysis” by Bo Chen et al
-”In relapsing-onset MS, PIRA is the major contributor to the irreversible disability accrual throughout the whole disease course…”
- “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
-”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…”
- “Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras” by Noemi Montobbio, PhdD et al
-”The average contribution of PIRA to overall EDSS progression, already predominant in patients diagnosed in 1980-1996 (78%)…and in 1997-2008 (76%)…was significantly increased….in patients diagnosed in later years (87%…)”
-”However, although clinical relapses are almost completely eliminated by modern high-efficacy DMTs, the underlying disability progression independent of relapse activity is far from being halted or reversed. Our results showed a progressive shift toward a mostly relapse-independent progression”
In light of this research and evidence, why does the FDA continue to allow relapse rate/frequency as the primary endpoint in MS DMT clinical trials, as the above research clearly indicates that relapses are not significant in terms of progressive disability in MS?
-The FDA’s response:
Dear Kaylin,
Thank you for writing to Sandra Folkendt, the Office of the Ombudsman, and the Patient-Focused Drug Development program staff. Your emails have been forwarded to the Division of Drug Information in the FDA’s Center for Drug Evaluation and Research (CDER) for response.
We have determined that your inquiry requires additional consultation time and research to ensure an accurate and complete response. We will respond as soon as we can. Thank you in advance for your patience.
Multiple Sclerosis Research Repository 