Barts-MS rose-tinted-odometer: ★★★★★
I have recently been criticised by a colleague for supporting the DODO (double-dose ocrelizumab study) and the ADIOS (adaptive dosing ocrelizumab study) studies. How you can I on the one hand support more ocrelizumab and on the other hand suggest reducing the dose in the longterm. I responded that it is all about timing and how you use anti–CD20 therapies.
You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which I hypothesise house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously.
However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to test using ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study.
In reality, if I could convince a national funding agency, a pharma company or wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 or vidofludimus (selective second-generation DHODH inhibitor,) HAART (highly-active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of ant-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will be derisking the long-term immunosuppression associated with anti-CD20 therapies and you should prevent the development of hypogammaglobulinaemia.
The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I need to explore (another task for my expanding ToDo list).
The good news is that Roche has bought into, and run, with the principle of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.
You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions. If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years.