Confirmed Disability Progression (CDP):
Measures the increase in a patient’s EDSS score that is sustained over a pre-determined time period, which means a patient’s physical disability has increased.
As more more drugs enter the MS market, the line between what drugs are used where (RRMS vs progressive MS) has begun to blur. This matter is further complicated by most of us not understanding the clinical trials that have preceeded these decisions. Moreover, some of our antipathy towards logically considering the wherefore and the what not’s of treatments is illogically hampered by the launch of MS drugs timed to the nearest international conference.
Dr Avasarala, from Lexington USA uses the example of the launch of different Sphingosine-1-phosphate (S1P1) modulators for different types of MS to nicely frame this lack of understanding.
Fingolimod, a first generation S1P1 modulator is licensed for RRMS, whilst Siponimod a follow on drug, but with a similar mode of action is licensed for CIS, RRMS (FDA approved) and active SPMS. FREEDOMS1 clinical trial of fingolimod with an entry level of MS participants at a low disability level (EDSS score of 2.0), had a reduced risk of CDP at 3 months and 6 months. Whilst, FREEDOMS2 clinical trial, similarly using fingolimod, doesn’t demonstrate a statistically significant effect on CDP at even the low EDSS ranges (EDSS score 2.0-2.5). The EXPAND trial using siponimod, on the other hand with MS participants with EDSS scores of 3.0-6.5, clearly has a statistically significant effect on the 3 month (21% risk reduction) and 6 month (26% risk reduction) CDP.
What really is going on here?
Your guess is good as mine.
I leave you with Dr Avasarala’s concluding remarks: At a time when more FDA-approved drugs are entering the market for MS patients, clarity concerning disability data are urgently needed since there is accumulating evidence that disability in MS probably begins at the time of diagnosis, even as early as the clinically isolated syndrome. Unless we untangle the maze of divergent data on disability, having availability of more FDA-approved drugs alone might not translate into successfully addressing disability concerns in patients. How the MOA of any drug addresses disability will likely drive treatment choices but that in turn depends on what specific patient phenotype that the drug was studied in.
Mult Scler Relat Disord. 2020 Sep 28;46:102529. doi: 10.1016/j.msard.2020.102529. Online ahead of print.
Discordant disability data in multiple sclerosis phase 3 studies among sphingosine-1- receptor modulator drugs
Fingolimod, Siponimod and Ozanimod are all sphingosine-1-phosphate (S1P1) receptor modulators, FDA-approved for use in multiple sclerosis (MS). Additionally, siponimod and ozanimod are sphingosine-1-receptor 5 (S1P5) receptor modulators that have better cardiac side-effect profile(s) than fingolimod. All 3 drugs have potential anti-inflammatory and immunomodulating activities and selectively target and bind to S1PR1 on lymphocytes, causing transient receptor activation followed by S1PR1 internalization and degradation. This results in the sequestration of lymphocytes in lymph nodes. By preventing egress of lymphocytes, these drugs reduce both the amount of circulating peripheral lymphocytes and the infiltration of lymphocytes into target tissues. The drugs are all classified as small molecules, have the ability to penetrate the blood-brain-barrier and are highly protein-bound. As to why the drug effects on disability are different between the drugs when their mechanism of action (MOA) is fundamentally similar remains unknown. Contributors to disability in MS patients, among others, include sub-pial lesions in the brain seen best using 7T MRIs, age of patient, involvement of the cord/infratentorial areas/brainstem, male gender, # of relapses in the first two years since diagnosis, and incomplete resolution of relapses. Of the 3 drugs, only siponimod is approved for the treatment of secondary progressive multiple sclerosis (SPMS) while all of them are approved for ‘relapsing forms of MS’. All 3 prevent lymphocyte egress from lymph nodes, central to their efficacy in MS. Since all 3 drugs have the same MOA except for cardiac side-effects which have no direct bearing on disability measures, what is it that separates one from each other in producing differential disease outcomes ?