#ECTRIMS2021: ocrelizumab the game-changer

Barts-MS rose-tinted-odometer: ★★★★★★★
The first  7-star ‘Teal Blue Monday’ #367588

The next in the series of #ECTRIMS2021 long-term follow-up posts. This is the 7.5 year follow-up of the ocrelizumab OPERA 1&2 (relapsing MS) cohort. The efficacy data looks very impressive. 

  1. Annualised relapse rates well below one in 10 years or 0.1 p.a.

2. 82% of ocrelizumab treated subjects had no confirmed disability progression.

3. Less than 7% of ocrelizumab treated subjects needed a walking stick compared to 10% of subjects randomised to interferon for 2-years before switching to ocrelizumab. Sadly, the 2 years on interferon have come at a price; time really is brain and spinal cord. This data like most contemporary data sets make a strong case for flipping the pyramid. 

4. The safety of ocrelizumab looks similar to what it was 2-years ago. The risk of serious infections is 1.73 per 100 patient-years of follow-up; i.e. in 1,000 patients on ocrelizumab, 17 will have a serious infection per year. This needs to be balanced against the COVID-19 data showing a doubling of risk of severe COVID-19 in ocrelizumab-treated subjects and an ~80% chance of not seroconverting when being vaccinated with one of the COVID-19 vaccines.

Unfortunately, no end-organ damage data (brain volume loss) to present, but this will come in time.

It is clear that anti-CD20 therapies are a real game-changer when it comes to the management of MS; i.e. very high efficacy therapies, in terms of switching off MRI activity and relapses, with a relatively good short and long term safety profile. 

ECTRIMS-2021_OPERA-OLE-7.5-years-Poster_VA3-2

Giovannoni et al. Long-term  reduction  of  relapse  rate  and  confirmed  disability  progression  after  7.5  years  of ocrelizumab  treatment  in  patients  with  relapsing  multiple  sclerosis  in  the  OPERA  OLE. ECTRIMS 2021, P723. 

Introduction:  The  efficacy  and  safety  of  ocrelizumab  (OCR)  in  relapsing  multiple  sclerosis  (RMS)  were demonstrated  in  the  96-week  contro led  double-blind  period  (DBP)  of  the  Phase  I  OPERA  I  (NCT01247324) and  OPERA  I (NCT01412333)  trials.

Aims:  To  assess  the  efficacy  of  switching  from  interferon  (IFN)  β-1a  or  maintaining  OCR  therapy  on  disease activity  and  confirmed  disability  progression  (CDP)  after  5.5  years  of  fo low-up  in  the  open-label  extension (OLE)  of  OPERA  I  and  OPERA  I.

Methods:  In  the  DBP  of  OPERA  I  and OPERA  I, patients  were  randomised  to  receive  OCR  or  IFN  β-1a. Patients  completing  the  DBP  either  continued  OCR  (OCR-OCR)  or  switched  from  IFN  β-1a  to  OCR  (IFN-OCR) when  entering  the  OLE.  Adjusted  annualised  relapse  rate  (ARR),  time  to  onset  of  48-week  CDP  (CDP48)  and time  to  48-week  confirmed  Expanded  Disability  Status  Scale  score  ≥6.0  (time  to  require  a  walking  aid)  were analysed  up  to  Week  384.

Results:  Overa l,  76.3%  of  patients  who  entered  the  OLE  period  completed  OLE  Year  5.5.  Adjusted  ARR decreased  year-on-year  from  the  pre-switch  year  to  OLE  Year  5.5  in  IFN-OCR  switchers  (pre-switch,  0.20;  OLE Year  1,  0.10;  OLE  Year  5.5,  0.03)  and  was  maintained  at  low  levels  in  OCR-OCR  continuers  (pre-switch,  0.12; OLE  Year  1,  0.10;  OLE  Year  5.5,  0.03).  Rates  of  CDP48  were  lower  in  OCR-OCR  continuers  vs  IFN-OCR switchers  at  the  end  of  the  DBP  (4.1%  vs  8.5%  [Δ=4.4%;  p<0.001])  and  numerica ly  lower  at  OLE  Year  5.5 (17.9%  vs  21.5%  [Δ=3.5%;  p=0.118]).  Rates  of  patients  requiring  a  walking  aid  were  lower  in  OCR-OCR continuers  vs  IFN-OCR  switchers  at  the  end  of  the  DBP  (0.8%  vs  3.1%  [Δ=2.4%;  p=0.001])  and  numerica ly lower  at  OLE  Year  5.5  (6.6%  vs  9.5%  [Δ=2.9%;  p=0.060]).  Over  the  DBP  and  OLE  periods,  the  risk  of  CDP48 was  23%  lower  (overa l  percent  of  patients  with  CDP48  in  OCR-OCR  vs  IFN-OCR:  14.5%  vs  16.4%;  HR [95%CI]:  0.77  [0.60–0.98];  p=0.034)  and  the  risk  of  requiring  a  walking  aid  was  35%  lower  (overa l  percent  of patients  requiring  a  walking  aid  in  OCR-OCR  vs  IFN-OCR:  5.2%  vs  7.0%;  HR  [95%CI]:  0.65  [0.44–0.97]; p=0.034)  in  OCR-OCR  continuers  vs  IFN-OCR  switchers.

Conclusions:  Switching  from  IFN  β-1a  to  ocrelizumab  at  the  start  of  the  OLE  period  was  associated  with  a rapid  and  robust  reduction  in  ARR  that  was  maintained  through  the  5.5-year  fo low-up  of  the  OLE  period.Compared  with  patients  switching  to  ocrelizumab  at  the  OLE,  patients  initiating  ocrelizumab  2  years  earlier had  a  significantly  reduced  risk  of  requiring  a  walking  aid  and  48-week  CDP.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

#ECTRIMS2021: a potential cure?

Barts-MS rose-tinted-odometer: ★★★★★★★
A 7-Starred Bright Pink Sunday Special #ff007f

Some asked about the 10-year alemtuzumab follow-up data. Here are the headline results:

  1. 60% of subjects are free of disability worsening.

2. 50% had confirmed improvement in disability.

3. Annualized brain volume loss consistently below 0.2% (essentially normal).

4. Tragically, the trial subjects who were randomised to interferon-beta for the first 2-years never catch up; time really is brain and spinal cord.

As you will see these results are clouded by a 40% drop-out rate and hence may be enriched for responders. However, these results still support hitting MS early and hard with an IRT will result in a significant number of pwMS going into long-term remission. 

I did the TOPAZ exit assessments of a large number of study subjects for both the CARE-MS1 and CARE-MS2 cohorts and I have never seen so many people with MS living normal lives with no disability in long-term remission, but still carrying around the label of having MS.

Wouldn’t it be great to be able to tell some of these pwMS you are cured? 

GE115-21EB-ECTRIMS-2021_Giovannoni_TOPAZ-CARE-MS-II-Poster_vp03_27Sep2021

Knowing what MS can do to people and seeing these results who wouldn’t want to be treated with, or at least offered the option of being treated with, alemtuzumab or another IRT when they are diagnosed? 

Giovannoni et al. Early treatment with alemtuzumab maintains its efficacy on clinical and MRI disease activity outcomes, including slowing of brain volume loss, over 10 years in RRMS patients: CARE-MS II follow-up (TOPAZ Study). ECTRIMS 2021, P722.

Introduction: In CARE-MS II (NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved clinical/MRI outcomes versus SC IFNB-1a over 2 years (y) in RRMS patients with inadequate response to prior therapy and further minimised disease in a 4-y extension study (NCT00930553). Further follow-up was available in an additional 5-y extension, TOPAZ (NCT02255656).

Aims: Evaluate the efficacy and safety of alemtuzumab in CARE-MS II patients over 10 y.

Methods: At investigator discretion, patients in TOPAZ can receive additional alemtuzumab as needed for disease activity (≥12 months apart) or other disease-modifying therapy (DMT) at any time.

Results: Proportions of patients remaining on study after 10 y were 62% (271/435) among those treated initially with alemtuzumab in the core study and 73% (107/146) among those treated with SC IFNB-1a for 2 y before switching to alemtuzumab in the extensions. In the extension studies, 39% of the alemtuzumab group did not receive further treatment (alemtuzumab or other DMT). Among the alemtuzumab group over the combined core and extension studies, 71% of patients had stable/improved EDSS scores, the mean change in EDSS score was +0.34, 58% of patients were free of 6-month confirmed disability worsening, and 49% achieved 6-month confirmed disability improvement. In Y10, the annualised relapse rate was 0.11, 71% of patients were free of MRI disease activity, 92% were free of new gadolinium-enhancing lesions, and 72% were free of new/enlarging T2 hyperintense lesions. The median annual brain volume loss was ≤0.19% each year over Y3–10. Alemtuzumab had a consistent safety profile over 10 y, with the incidence of overall adverse events (AEs) and infections declining through Y10. Cumulative incidence of thyroid AEs was 44% and immune thrombocytopaenia was 4%. Efficacy and safety in SC IFNB-1a–treated patients from the core study who switched to alemtuzumab in the extension were consistent with those treated with alemtuzumab in both the core and extension.

Conclusions: Early treatment efficacy with alemtuzumab on clinical, MRI lesion, and brain volume outcomes was maintained over 10 y in CARE-MS II patients, with 62% remaining on study and 39% receiving no additional courses or other DMTs through Y10. Safety remained consistent and manageable over 10 y, with declining AE incidences over time, including a consistent reduction in autoimmune AE occurrence after Y3.

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

#ECTRIMS2021: how long does cladribine work?

Barts-MS rose-tinted-odometer: ★★★★★★★ 
A 7-Star Bright Yellow Saturday #FFFF00

How good is cladribine as an immune reconstitution therapy? 

The CLASSIC-MS study was our attempt to get back all the pwMS who had participated in the original phase 3 programme, from 15 years ago. The following poster is from my late-breaking poster at ECTRIMS and describes what has happened to the subjects from the CLARITY and CLARITY extension study and does not include subjects with clinically isolated syndrome from the ORACLE study. 

As you can see the subgroup of subjects from CLASSIC-MS is similar to the overall population of subjects in the original trial. Therefore we think these results are representative of the overall population.

The median time to follow-up in the CLASSIC-MS study was 10.9 years (range 9.3, 14.9). 

The remarkable observation is how few study subjects progressed (to be presented later in more detail) with less than 1 in 5 needing a walking aid to manage 100m. 

56% of cladribine treated subjects did not require a follow-on DMT compared to only 27% of subjects that were not treated with cladribine. These results indicate that the duration of action of cladribine may be much longer than we realise and is beginning to mirror what we see in clinical practice with this particular agent. 

Given this data and the other attributes of cladribine, it is going to be a serious contender for the go-to DMT at the bottom of the therapeutic pyramid on which to build an induction-maintenance strategy and combination therapies. 

Oral cladribine has several favourable attributes for managing MS, particularly during the COVID-19 pandemic:

  1. High-efficacy DMT allowing flipping of the pyramid
  2. Good COVID-19 outcomes 
  3. Oral therapy, therefore reduced hospital contacts
  4. No cell lysis syndrome or infusion-type reactions
  5. No pre-dosing with steroids
  6. Innate immunity intact
  7. Only moderate reduction in T-cell counts
  8. Less impact on CD8+ compared to CD4+ T-cells
  9. Antiviral immunity relatively intact
  10. Vaccine immunity intact
  11. Low monitoring requirements
  12. Small risk of lymphocyte count being less than 500/mm3
  13. CNS penetration targeting CNS resident B and T cells
  14. Post-dosing immune reconstitution
  15. Good seroconversion post-COVID-19 vaccination
  16. Cost-effective; providing value to the NHS

Giovannoni et al. Long-term efficacy for patients receiving cladribine tablets in CLARITY/CLARITY extension: Primary results from 9–15 years of follow-up in the CLASSIC-MS study. ECTRIMS 2021, P975.

Introduction: CLASSIC-MS (NCT03961204) was an exploratory, ambispective Phase IV study designed to evaluate the long-term efficacy of cladribine tablets (CladT) in the real-world setting, for patients with relapsing multiple sclerosis (RMS) who were previously enrolled to Phase III (parent) trials.Objectives: To report primary results for CLASSIC-MS in terms of long-term mobility and disability beyond the treatment courses that patients received in the parent trials, with the aim of informing future treatment approaches.

Methods: This analysis represents patients in CLASSIC-MS who participated in the Phase III CLARITY trial whether or not they participated in CLARITY Extension, and who had received ≥1 course of CladT or placebo. The primary objective of CLASSIC-MS was the evaluation of long-term mobility (no wheelchair use/bedridden; i.e. EDSS <7 in the 3 months prior to first visit in CLASSIC-MS). The main secondary objective was long-term disability status (no requirement for an ambulatory device; i.e. EDSS <6 any time since last parent study dose [LPSD]). Analyses are descriptive and shown in relation to exposed/never exposed to CladT in CLARITY.

Results: The CLASSIC-MS population who previously participated in CLARITY/CLARITY Extension comprised 435 patients with RMS (67.8% female; mean±SD EDSS score, 3.87±2.07 at CLASSIC-MS baseline), with a median time since LPSD of 10.9 (range 9.3–14.9) years and a median disease duration of 20.7 (range 13.9–46.5) years at CLASSIC-MS baseline. A total of 90.6% (n=394) were exposed to CladT during CLARITY/CLARITY Extension, including 160 patients who received the approved cumulative dose of 3.5 mg/kg over 2 years; the remaining 9.4% (n=41) were never exposed. The proportion of patients not using a wheelchair/bedridden in the 3 months prior to CLASSIC-MS (i.e. EDSS <7) was 90.0% of the CladT exposed cohort and 77.8% of the never exposed cohort. Regarding long-term disability status, the proportion of patients with no requirement for an ambulatory device (i.e. EDSS <6) was 81.2% of the CladT exposed and 75.6% of the never exposed cohorts, respectively.

Conclusions: Baseline patient characteristics suggest that patients enrolled in CLASSIC-MS were a representative sample of all patients included in the original parent studies. Reported findings for CLASSIC-MS, with a median of 10.9 years’ follow-up after CLARITY/CLARITY Extension, suggests sustained efficacy of CladT in terms of long-term mobility and disability status.

20210922-ECTRIMS-2021-CLASSIC-MS_Typeset-ePoster_v06

Disclaimer: Please note that I am the PI on the oral cladribine programme including the CLASSIC-MS study and have been involved with the development of oral cladribine as a DMT for MS since 2002. I was a member of the original advisory panel that Serono put in place when they decided to in-license the oral formulation for development. Therefore you need to interpret what I say about cladribine and oral cladribine very carefully. In short, I am likely to be very biased. 

Conflicts of Interest

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Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

A no-brainer?

Barts-MS rose-tinted-odometer: ★★★★★ (aquamarine on a very rainy Friday in London, #00FFBF) 

I recently had a patient of mine who has been desperate to be treated with alemtuzumab actually ask if he can change his mind and rather be referred for AHSCT (autologous hematopoietic stem cell transplantation). Why? Because the chances of being put into long term remission, and hence potentially being cured of having MS, seems to be much higher with AHSCT. This particular patient has no concerns about the risks associated with alemtuzumab or AHSCT. The most important concern on his radar is his long term outcome. He wants a healthy brain when he gets older.

This is why this most recent paper on the long term outcome of Italian patients who received AHSCT adds to the mounting evidence base of the effectiveness of AHSCT. In patients with relapsing-remitting treated with AHSCT, MS 86% and 71% were free of disability worsening at 5 and 10 years, respectively. These figures for patients with progressive MS were 71% and 57% at 5 and 10 years, respectively. 

The results are less impressive when using NEDA-3 status, i.e. no relapses, MRI activity or disability progression. For patients with RRMS, probabilities of achieving NEDA3 status were 62% at 5 years and 41% at 10 years, respectively. However, and importantly, in the subgroup of patients with RRMS who underwent AHSCT with the BEAM+ATG conditioning protocol, which is more aggressive, NEDA-3 status was achieved in 68% and 55% of subjects at 5 and 10 years, respectively. 

In subjects with progressive MS, NEDA-3 status was only achieved 51% and 37% of subjects at 5 and 10 years, respectively. 

On average, disability scores improved in relapsing-remitting subjects and got worse in subjects with progressive disease, which implies that AHSCT does not stop smouldering disease. However, almost all subjects had failed one or more DMTs prior to AHSCT. The latter is important. The average EDSS was ~6.0 and most patients had a disease duration of longer than 10 years. This makes me wonder how better the results would be if AHSCT was done earlier in the course of MS, i.e. before too much damage to the brain and spinal cord had accumulated. This is why we really need to test AHSCT as first-line therapy in MS. Could AHSCT done early stop/reverse or prevent the establishment of smouldering disease? In other words, does AHSCT cure people from having MS? This is why a trial of AHSCT in very early MS, i.e. as a first-line treatment, is a no-brainer to me.

Please note that three deaths occurred due to AHSCT, which was 1.4% of the entire study population. 

The take home messages are: 

  1. AHSCT is the most effective DMT we have for treating MS. 
  2. RRMS responds better to AHSCT than progressive MS.
  3. BEAM+ATG conditioning protocol is superior to cyclophosphamide-based protocols.
  4. Mortality remains relatively high with AHSCT.
  5. The results would be much better than this if patients had had AHSCT earlier in the course of their disease. 

I was criticised yesterday for suggesting lifestyle changes to pwMS when I had no idea what it was like to have MS. It was implied that unless you have lived with MS, i.e. the lived experience, I shouldn’t be making any lifestyle recommendations to pwMS particularly around weight loss and diet. What I can say is that I have treated and followed thousands of people with MS and I know enough that if I had MS I would have no hesitation in wanting to be treated first-line with AHSCT or alemtuzumab and to manage all the lifestyle issues I referred to in my post ‘ASK NOT‘. 

What underpins my decision to be treated with alemtuzumab and AHSCT first-line is the data missing from this paper on the end-organ; both of these treatments will on average normalise brain volume loss in treated subjects. In other words, these treatments are on top of the ladder when it comes to preventing end-organ damage. The downside of AHSCT is that the brain takes a significant neurotoxicity hit from the chemotherapy with accelerated brain volume loss in year one. In addition, there is also the high, but delayed secondary malignancy risk and high mortality risk associated with AHSCT that needs to be taken into account. Therefore, alemtuzumab probably wins out on safety as a potential first-line therapy. Please remember being treated with alemtuzumab does not exclude you from being treated with AHSCT at a later stage. 

Boffa et al. Long-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Neurology. 2021 Jan 20;10.1212/WNL.0000000000011461. doi: 10.1212/WNL.0000000000011461. 

Objective: To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplant in a large cohort of MS patients.

Methods: To be included, a minimum data set (consisting of age, MS phenotype, EDSS at baseline, information on transplant technology and at least 1 follow-up visit after transplant) was required.

Results: 210 patients were included [relapsing-remitting (RR)MS=122(58%)]. Median baseline EDSS was 6(1-9), mean follow-up was 6.2(±5.0) years. Among RRMS patients, disability worsening-free survival (95%CI) was 85.5%(76.9-94.1%) at 5 years and 71.3%(57.8-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0%(59.4-82.6%) and 57.2%(41.8-72.7%) at 5 and 10 years, respectively. In RRMS patients, EDSS significantly reduced after aHSCT [p=0.001; mean EDSS change per year -0.09 (95%CI=-0.15 to -0.04%)]. In RRMS patients, the use of the BEAM+ATG conditioning protocol was independently associated with a reduced risk of NEDA-3 failure [HR=0.27(0.14-0.50), p<0.001]. Three patients died within 100-days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.

Conclusions: aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM+ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.

Classification of evidence: This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.

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Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Fingolimod vs. Siponimod

Barts-MS rose-tinted-odometer: ★★ (mid-week sepia = #704214)

In my post on rebound disease activity in a person with secondary progressive MS switching from fingolimod to siponimod, someone asked whether there is any logic in switching DMTs within the class of S1P modulators. Two or three years ago I would have said no, but now I would say yes. There are well defined and clear differences between the two compounds that may explain their different effects as DMTs in people with more advanced or progressive MS (see figure and table below). 

The fact that fingolimod works on a broader spectrum of S1P receptors may explain why it has a greater effect on peripheral immune function, i.e. its action on S1P4 may explain why it disrupts antibody responses to new vaccines. S1P4 plays an important role in the functioning of germinal centres (GCs) in lymph nodes and other secondary lymphoid organs, i.e. so-called follicular T-helper cells use S1P4 for migration signals. If these cells can’t enter the GCs they can’t help B-cells make good antibody responses. I, therefore, predict that vaccine responses in response to the COVID-19 vaccines will be better preserved with siponimod, ozanimod and ponesimod because this new generation of S1P modulators has less or no activity on S1P4 receptors.  

Fingolimod needs to be phosphorylated to become active, in comparison siponimod is active already. This may explain why siponimod has greater activity on the S1P5 receptor within the central nervous system (CNS) and explains its greater apparent effects on cells within the central nervous system (CNS). It is clear that when you look at the results of the fingolimod in the PPMS trial there was very little evidence that fingolimod was having any effect on the end-organ, i.e. there was no impact on brain volume loss and no difference across any of the clinical endpoints in the PPMS trial. In comparison, siponimod has a clear CNS signal compared to placebo in subjects with SPMS. Compared to placebo, patients on siponimod have less whole brain, grey matter and thalamic volume loss, preservation of brain tissue integrity on MTR, an MRI marker of myelination, and these effects correlated with better preservation of cognition. On the downside, siponimod was associated with a small but significant risk of seizures, which seems to be more common than with fingolimod in adults with MS.  

I have interpreted these results as showing fingolimod as being a more powerful peripheral immunosuppressive therapy but has fewer direct CNS effects. In comparison, siponimod is likely to be less immunosuppressive, but have more direct CNS effects. So based on these differences I think there is a rationale for switching someone on fingolimod to siponimod who has more advanced MS or has transitioned to SPMS. The downside of this switch is that in the NHS you will have to label someone as having SPMS to be able to prescribe siponimod. Using our current criteria SPMS is a one-way street, i.e. once you are labelled as having SPMS you can’t be undiagnosed and converted back to RRMS. As there are no other DMTs currently licensed for SPMS you are therefore theoretically stuck with siponimod. This is why I refer to siponimod as the cul de sac DMT. 

The other issue is that to be eligible for siponimod you have to have active SPMS, i.e. relapses or MRI activity (new or enlarging lesions) in the last 2 years. Most people who develop SPMS on fingolimod have inactive SPMS, which means they are not eligible for siponimod. To become eligible under NHS England guidelines you would have to stop fingolimod and hope you develop rebound disease activity that will then allow you to be eligible for siponimod. I have previously stated that I think this is unethical based on our current biological understanding of MS. In any case, once you label someone as having SPMS on fingolimod you are meant to stop their fingolimod in the NHS; the latter is one of the NHS England’s stopping criteria.

So based on the above if you have transitioned to SPMS on fingolimod would you (1) want to switch to siponimod and (2) would you be prepared to stop fingolimod so that your SPMS became active, i.e. developed rebound disease activity? 

FingolimodSiponimod
MOA: Targets S1P1, S1P3, S1P4 & S1P5MOA: Targets S1P1 & S1P5
No baseline pharmacogenomicsBaseline pharmacogenomics (CYP2C9 genotyping)CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2 = 2 mg/dayCYP2C9 Genotypes *1/*3 or *2/*3  = 1 mg /dayModerate CYP2C9 and strong CYP3A4 inducers are not recommended (e.g. rifampin, carbamazepine) 
First dose monitoring for all patientsFirst dose monitoring in patients with certain pre-existing cardiac conditions
Half life of 6-9 daysHalf life of approximately 30 hours
Lymphocyte counts progressively return to normal range within 1-2 months of stopping therapy in most patientsLymphocyte counts return to the normal range within 10 days of stopping therapy in the vast majority (90%) of patients
Prodrug – needs to phosphorylatedActive compound no need for activation

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.