MS DMT Is your option going to be….anti-virals?….What’s happening with the imods?

M

I realise many of you are sick of the COVID-19 stuff, but it continues to come. We are now up to 210,000 COVID-19 papers and counting, which is twice th total MS literature. Believe it on not, early-on I was reading every paper every day, so I could understand what was going on and what was likely to happen to you, so I could pass that on to the clinical team in the front line. A thousand papers a day was really too much, but as we were locked-down it was either say F-it I’m off to get fit or binge watch “Game of Thrones” or T*ts and dragons as we know it after watching a few episodes.

You may ask why post of this stuff as we know it already and indeed, this paper below is another “first to show” that the seroconversion response is inhibited for fingoliomod and anti-CD20 and notably that there is a limited T cell response detectable after fingolimod.

Tortorella C, Aiello A, Gasperini C, Agrati C, Castilletti C, Ruggieri S, Meschi S, Matusali G, Colavita F, Farroni C, Cuzzi G, Cimini E, Tartaglia E, Vanini V, Prosperini L, Haggiag S, Galgani S, Quartuccio ME, Salmi A, Repele F, Gerarda Altera AM, Cristofanelli F, D’Abramo A, Bevilacqua N, Corpolongo A, Puro V, Vaia F, Capobianchi MR, Ippolito G, Nicastri E, Goletti D; INMI COVID-19 Vaccine Study Group. Humoral- and T-Cell-Specific Immune Responses to SARS-CoV-2 mRNA Vaccination in Patients With MS Using Different Disease-Modifying Therapies. Neurology. 2021 Nov 22:10.1212/WNL.0000000000013108. doi: 10.1212/WNL.0000000000013108. 

Results: We prospectively enrolled 186 vaccinated individuals: 78 HCWs and 108 MS patients. Twenty-eight MS patients were treated with IFN-β, 35 with fingolimod, 20 with cladribine, and 25 with ocrelizumab. A lower anti-RBD-antibody response rate was found in patients treated with ocrelizumab (40%, p<0.0001) and fingolimod (85.7%, p=0.0023) compared to HCWs and patients treated with cladribine or IFN-β. Anti-RBD-antibody median titer was lower in patients treated with ocrelizumab (p<0.0001), fingolimod (p<0.0001) and cladribine (p=0.010) compared to HCWs and IFN-β-treated patients. Importantly, serum neutralizing activity was present in all the HCWs tested and only in a minority of the fingolimod-treated patients (16.6%). T-cell-specific response was detected in the majority of MS patients (62%), albeit with significantly lower IFN-γ levels compared to HCWs. The lowest frequency of T-cell response was found in fingolimod-treated patients (14.3%). T-cell-specific response correlated with lymphocyte count and anti-RBD antibody titer (rho=0.554, p<0.0001 and rho=0.255, p=0.0078 respectively). Finally, IFN-γ T-cell response was mediated by both CD4+ and CD8+ T cells.

Conclusion: mRNA vaccines induce both humoral and cell-mediated specific immune responses against spike peptides in all HCWs and in the majority of MS patients. These results carry relevant implications for managing vaccinations suggesting to promote vaccination in all treated MS patients.

What is lacking is a unified view of what to do. It is clear to me on a basis of science that without a delay then there will not be an adequate antibody response to COVID-19 vaccine in many CD20-treated individuals. But will people go against the licence? Again and again we see a T cell response and therefore one suspects that it is easier to do nothing and if people get infected and do badly, there are always anti-virals. It looks like some antibodies may not be great against the omicron variant but this should not stop other agents working.

But what about the Sphingosine-1-phosphate modulators?

The big question is whether there really is a poor T and B cell response on fingolimod. Importantly if there is a difference what do you do? Many people on these drugs will have had their boosters by now and failed to make a response before any information surfaces. Will it be any different before round four?

I know that effort is being put into the other imods but what about poor old fingolimod. If there is a difference between fingolimod and the other imods, then as a choice you may stay clear and go for one of the newer variants. In the old cynical MD I may have had something to say about that…but I won’t go there.

However, there may well be a small difference. Some of this may relate to biology.

There is a relative consistency of results with fingolimod but how is it caused?

One issue for the T cells is are we comparing like for like. When we measure the T cell response in healthy controls we are measuring the response against at least 4 different subtypes of T cells, but due to the way fingolimod works is really removes two of those those types and certainly drops the number of the third type so one type predominates and one can ask would this subtype respond in the healthy controls.

Then we have to ask with such a poor T cell response why are we not seeing the hospitals fill up with people on fingolimod. Is there something different to a vaccine response against largely a RNA vaccine to one protein and a natural infection to a live virus. Here I suspect the answer maybe yes but some of the T cell response to the natural infection is not against Spike but against other viral targets and these include nucleocapsid. This is an target inside the virus and so it can’t be seen by antibodies until the virus liberates its contents.

COVID-19 Infection in Fingolimod- or Siponimod-Treated Patients: Case Series.Sullivan R, Kilaru A, Hemmer B, Campbell Cree BA, Greenberg BM, Kundu U, Hach T, DeLasHeras V, Ward BJ, Berger J.Neurol Neuroimmunol Neuroinflamm. 2021 ;9(1):e1092. doi: 10.1212/NXI.0000000000001092.

Background and objectives: A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod. Methods: We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020.

Results: As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients. Discussion: Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

Could there be a difference between fingolimod and the newer imods ozanimod, ponesimod and siponimod?

It is hard to tell because the number aren’t there but it could be possible? This could relate to the mechanisms of action of fingolimod verses the other imods.

The mechanism to inhibit MS is to stop white blood cells entering the blood and if they are not in the blood they can’t get into the brain. This is the basis for how all the imods work. This effect occurs because it is controlled by one of the Sphingosine-1-phophate receptors of which there are five.

S1PR1 controls lymphocyte exit from lymph glands it also controls white blood cells crossing the blood brain barrier, but if is problably part of the unwanted heart side effects following first dosing. As you can see S1P3 affects B cells could this influence vaccination. Maybe, but mouse B cells express alot more S1P3 can do human B cells. S1P4 is involved in the movement of innate immune cells. Could this affect vaccination? S1P5 is hoped to influence myelination, so are ozanimod, spionimod and ponesimod less likely to inhibt vaccine response. I suspect that some of the inhibition is due to S1P1 as it looks like ponesimod can inhibit vaccine responses in animals.

ECTRIMS 2021 P646
A short pause in ponesimod treatment completely restores the ability to mount post-vaccination antibody titers in
mice K. Spiller, R. Aras, M. deGuzman, E. Ramsburg, A. Bhattacharya. “Animals continuously maintained on ponesimod chow, including at the time of vaccine administration, had an attenuated antibody response compared to control mice (inhibition titres, ID50, 0.0012 vs. 0.0035) at 28 days post-vaccination. However, when the animals received a drug holiday around vaccination, they had neutralising antibody titres that were indistinguishable from control animals”.

So this suggests S1P1 controls antibody response, but is also suggests a solution.

ECTRIMS 2021 P940
Humoral immune response to COVID-19 mRNA (BNT162b2-Pfizer) vaccine in patients with multiple
sclerosis. D. Karussis, A. Karni, R. Milo, E. Staun-Ram, A. Miller. All patients treated with Interferon-β preparations, Dimethyl Fumarate, Alemtuzumab, Glatiramer Acetate, Natalizumab, Ofatumumab, Ponesimod, Siponimod or Teriflunomide were positive for IgG anti-spike antibodies (How many of each?), following vaccination or COVID19 disease. 90% of Cladribine-, 31% of Ocrelizumab- and 51% of Fingolimod-treated patients were IgG positive after vaccination,

Skorić et al. Humoral immune response to COVID-19 vaccines in people with secondary progressive multiple sclerosis treated with siponimod. Mult Scler rel Disord DOI:https://doi.org/10.1016/j.msard.2021.103435

In this study you can see that whilst the response is blunted, it is present in most individuals and some response was measurable in about 85% of people. They say “Despite all these studies showing blunted humoral response in patients treated with S1P receptor modulators, one should bear in mind that the majority of pwMS on these therapies make an unremarkable recovery from COVID-19, implying that innate and T-cell responses are functional”.

So is fingolimod more inhibitory without a head to head study, this is because we have seen that the effects you find are assay dependent.

Capone F, Lucchini M, Ferraro E, Bianco A, Rossi M, Cicia A, Cortese A, Cruciani A, De Arcangelis V, De Giglio L, Motolese F, Sancetta B, Mirabella M, Di Lazzaro V. Immunogenicity and safety of mRNA COVID-19 vaccines in people with multiple sclerosis treated with different disease-modifying therapies. Neurotherapeutics. 2021 Dec 3. doi: 10.1007/s13311-021-01165-9. “All patients in treatment with first-line DMTs, natalizumab, cladribine, and alemtuzumab, developed a measurable humoral response. In patients treated with ocrelizumab and fingolimod, the IgG level was significantly lower, but only some patients (22.2% for fingolimod and 66% for ocrelizumab) failed to develop a measurable humoral response. In the ocrelizumab group, the IgG level was positively correlated with the time from last infusion. No SARS-CoV-2 infections were reported after vaccination”.

So here 77.8% people treated with fingolimod made a response. Is this why people are doing OK if infected with COVID-19 virus. 

Furthermore the animal data suggests that a short drug holiday may allow an antibody response to develop better in animals treated with ponesimod. Are they doing this in humans?. I dont know but this is being studies in people treated with Siponimod

ECTRIMS 2021 P810 Assessing the immune response to SARS-CoV-2 mRNA vaccines in patients with secondary progressive multiple sclerosis treated with siponimod (AMA-VACC clinical trial) T. Ziemssen, B. Rauser, B. Ettle, M. Groth, T. Bopp.

Cohort 1 receives SARS-CoV-2 mRNA vaccination while continuing their current siponimod treatment, cohort 2 interrupts siponimod treatment for for the purpose of a full vaccination cycle and cohort 3 receives vaccination during continuous treatment with first-line DMTs (dimethylfumarate, glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. Primary endpoint is the rate of patients achieving seroconversion assessed by detection of neutralizing antibodies after SARS-CoV-2 mRNA vaccination. Furthermore, development of SARS-CoV-2 specific T-cells is evaluated in all patients. Results: Data will be available in summer 2021.

Summer has come and gone actually strike that in UK summer never came, at ECTRIMS data was presented that most people were making responses but there were too few drug-holiday individuals to comment too much but the data should be ready soon.

Again I think it is sad that most people will have had a boost before we know what to do.

COI: Multiple

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