Fact 1 – Siponimod (Novartis Pharmaceuticals) trialed for SPMS, but the FDA label sits as Clinically isolated syndrome (the first clinical episode), Relapsing-remitting MS, and active Secondary progressive MS.
Fact 2 – Ocrelizumab (Genentech, Roche Pharmaceuticals) trialed for RRMS/PPMS; the latter has been shown to be most efficacious in those with active disease and OCB+ (oligoclonal band positive on lumbar puncture). However, the FDA label simply sits as relapsing or primary progressive forms of MS. The UK NICE recommendation is for RRMS and treating earlier forms of primary progressive MS (PPMS) with imaging features characteristic of inflammatory activity in adults. Over this past week the NHS England Blue Teq forms (used for reimbursement of drug costs) was disclosed with the following specifications for PPMS: a) confirmation the patient has a disgnosis of early PPMS with active disease, defined by the appearance of new lesions confirmed by two MRI studies taken at least 6 months apart OR one or more gadolinium enhancing lesions on one MRI over the last three years; b) EDSS score; c) agreed at multidisciplinary team meeting; d) recording all of the above for audit purposes. This strikes me as very liberal, especially the unspecified EDSS (the EDSS score defines the degree of disability level in a PwMS) cutoff.
So what is going on? Why is there a disconnect between the original Pharma request (Sponsor) and the final approval specifications?
Opinion 1 – they think that neurologists are too stupid to join the dots, or too brain dead with managing their clinical load to think on their feet.
Opinion 2 – I favor this one more. The regulatory bodies/health providers realize that MS is simply one disease (within reason) and are not bothered by who (PwMS) receives the treatment at the end of the day, as long as it works.
Opinion 3 – This magnanimous offer may represent the proverbial carrot to entice Pharma to really push their game and start working across the board with MS as a single disease entity, and also to encourage new clinical trials into SPMS and PPMS.
This is not a multiple choice….
This week at ECTRIMS 2019 in Stockholm further analysis on Siponimod were presented. The focus was on whether Siponimod has any influence on the time to wheelchair use (EDSS ≥ 7.0). They measured the length of time until a person progresses to EDSS ≥ 7.0 based on sustained progression until the last assessment in the core part of the EXPAND study (up to 3 years). The most interesting was the multistate modelling performed on the overall population from the EXPAND trial (Siponimod N=1099, placebo N=546), Figure 1 below.
PwMS on Siponimod had a 21% reduction in the risk of transitioning from EDSS ≤ 5 to EDSS 5.5-6 and a 28% reduction from ≥ 6.5 to sustained EDSS ≥ 7 versus placebo. The slight increase in the risk of moving from EDSS scores of 5.5-6.0 to 6.5 was compensated by similar improvements in the other direction.
The 6.5 year Open label (where the treatment assignation is known) Ocrelizumab treatment of PPMS from the ORATORIO study was also presented. Unlike with Siponimod they were looking at Time to wheelchair (EDSS ≥ 7.0) (see Figure 2 below) and time to onset of ≥ 20% increase in the 9-hole peg test (9-HPT, a measure of upper limb function) for at least 24 weeks (see Figure 3 below). In the open label study everyone was on Ocrelizumab (those who were initially on placebo [PBO] were swapped to Ocrelizumab, and those originally on Ocrelizumab [OCR] continued on Ocrelizumab]).
From this you can conclude that disability progression outcomes favored those on earlier and continuous treatment with Ocrelizumab versus delayed initiation. Earlier initiation reduced the risk of becoming wheelchair confined by 42% versus those switched from placebo, and by 35% with worsening hand function for at least 24 weeks from placebo.
Is it therefore any surprise that the regulatory bodies and healthcare providers have approved these two treatments for early use, as well as for later on; in fact throughout the MS disease course?