ProfG asked do we give up the idea of IRT dosing for ocrelizumab?
I suspect that eventually a trial will happen. Sadly however, I will have given up the will to live by then:-(.
Why do this?. Simple…..to look at safety.
If you continually deplete B cells there is an increased, albeit a small increase, in the risk of serious infections eventually happening. This is all well and dandy…until you are the individual that has the serious infection…then it’s serious. However, as speculation based on biology seems to give some people diarrhrea at the thought of believing the as yet unproven.….. I am afraid you are going to have to wait until someone (neuro) does this and evidence mounts.
This is what has been happening with natalizumab. The four weekly dosing schedule is being extended, because it seems to be reducing the risk of progressive multifocal leukoencephalopathy. Here they look at an 8 week dosing schedule. In study people have been dosing every two months and have been doing OK. It is funny that during the COVID-19 era the entended dosing interval was accepted as it kept you out of hospital (to reduce chance of COVID-19 infection) for infusions. This is not ony important for you but I believe it tells us something fundemental about MS relapses. It is keeps MS at bay so it is keeping the MS causing cells out of the brain, but if it is stopping PML, it is allowing the important anti-viral immune survellience to enter to kick some viral butt.
Guess what the answer to this question was?
This was presented over a year ago, but as it questions the role of CD4 T cells maybe we won’t see it surface for a while if at all, as it is not what the T cell immunologists want to hear. Maybe when the work is repeated it is the CD4 T cell after all. Let’s wait and see.
So one way to keep you out of hospital is to reduce the dose frequency
Does Extended Interval Dosing Natalizumab Preserve Effectiveness in Multiple Sclerosis? A 7 Year-Retrospective Observational Study.Riancho J, Setien S, Sánchez de la Torre JR, Torres-Barquin M, Misiego M, Pérez JL, Castillo-Triviño T, Menéndez-García C, Delgado-Alvarado M.Front Immunol. 2021 Mar 25;12:614715.
The extended interval dosing (EID) of natalizumab has been suggested to be associated with a reduced risk of progressive multifocal leukoencephalopathy (PML) and short-term preservation of efficacy but its long-term effectiveness remain unknown. We aimed to determine the long-term effectiveness and safety of natalizumab in an EID setting in a cohort of patients with multiple sclerosis (MS) treated for more than 7 years. We conducted an observational retrospective cohort study, including 39 (34 female, 5 male) patients with clinically definite relapsing-MS, initially treated with standard interval dosing (SID) of natalizumab (mean time 54 months [SD29]) who were then switched to EID, every 8 weeks (mean time 76 months [SD13]). The main outcome measures included the following: i) annualized relapse rate (ARR), ii) radiological activity, iii) disability progression, and iv) NEDA-3 no evidence of disease activity index. EID preserved ARR, radiological activity, and prevented disability worsening during follow-up. The proportion of patients maintaining their NEDA-3 status after 24, 48, and 72 months of natalizumab administration in EID was 94%, 73%, and 70%, respectively. Stratified analysis according to history of drug therapy showed that the EID of natalizumab was slightly more effective in naïve patients than in those previously treated with other immunosuppressive drugs. No cases of PML or other severe adverse reactions were reported. In conclusion, long-term therapy with natalizumab in an EID setting following an SID regimen maintained its disease-modifying activity, and was safe and well tolerated for over 7 years. These encouraging observational results need to be confirmed in controlled clinical trials.
The other way is to use a dosing regime that does not require hospitalisation. So avoiding infusion, which takes a few hours, can be limited by injection under the skin, taking a few seconds. This has safety merit, but the cynic in me wonders if the natalizumab infusion patent is coming to an end, and this change in dose creates a new one. I speculate without knowledge either way and frankly it doesn’t matter either way to me.
This study (below) was presented a few years ago and I found the information in clinical trial.gov a few months ago. I was going to publish it but was waiting to give it to a student as a literature review project. Anyway the information has now surfaced so not need to bother and the injection of natalizumab under the skin is just as effective as natalizumab into the blood in terms of inhibiting relapse
A randomized study of natalizumab dosing regimens for relapsing-remitting multiple sclerosis.Trojano M, Ramió-Torrentà L, Grimaldi LM, Lubetzki C, Schippling S, Evans KC, Ren Z, Muralidharan KK, Licata S, Gafson AR.Mult Scler. 2021 Apr 6:13524585211003020.
Background: REFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing-remitting multiple sclerosis (RRMS) patients.
Objective: To examine the efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients.
Methods: Clinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for greater or equal to 12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60.
Results: In total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; Greater than or equal to 39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable.
Conclusion: Natalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety.
No need for an infusion and guess what, this approach has already been approved by the European Medicines Agency, it was approved for use in children by this route. So once NICE approved, it could be the end of the Natalizumabers once a month/six week Coffee morning with a “Sip and a (infusion) drip”. It will be in-out and no time to shake it all about. I guess with time you will do the injection at home.
Ofatumumab has also gained European Approval so another subcutaneous injection coming your way. Will this knock ocrelizumab off its perch? Will they (natalizumab, ofatumumab) cause anti-drug antibodies?….As for the former it is not my concern, but I will put money on the latter evemntually occuring in some, albeit probably a limited number of people, as injecting stuff under the skin is a sensitizing route. However, in the natalizumab trial (above) they say it doesn’t happen and the occurence in the ofatumumab trial was very low too.
Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.