Barts-MS rose-tinted-odometer: ★★★ Black and Gray Hurricane Friday, #000000 #d3d3d3
I was kindly invited by David Martin the CEO of the MS Trust to participate in a Parliamentary round table meeting on Multiple Sclerosis on Tuesday. The meeting was chaired by Helen Hayes MP, who impressed me immensely and reassured me that the Labour party has some serious talent and committed MPs on the backbenches.
The meeting highlighted the massive task ahead of us post-COVID in relation to MS services. COVID-19 has turned the perfect storm the MS community was facing before the pandemic into a category 5 hurricane. I am not sure if you are aware that during the pandemic there has been an approximately 30% reduction in patients with MS starting disease-modifying therapies (DMTs). Where are all these new patients? I suspect waiting to be referred into the service or stuck in diagnostic pathways.
In addition, to new patients waiting to be diagnosed there are patients with PPMS and SPMS waiting for MRI scans to assess if they have active progressive MS in the hope of starting ocrelizumab or siponimod. Add this to reduced MRI capacity, a reduction in neuro-rehab resources, a rising incidence of MS, an ageing workforce with many early retirements, BREXIT, reconfiguration of the NHS and rising expectations from a more informed MS patient population and you begin to realise the task at hand.
Having thought a lot about Tuesday’s meeting I think we need to get the MS Community together to reflect on what has happened over the last 18 months and formulate a plan for what the management of MS is going to look like after the pandemic.
COVID-19 has changed my MS practice for the better and for the worse. What can we learn from our experiences, what should we ditch, what should we improve on and what practices can we take forward into the future? I think we have an opportunity to radically change the MS service model.
If you have any experiences and/or ideas for diagnosing and managing MS in the future please share them with us.
I am asking my colleague Dr Wallace Brownlee, who has taken over from me as director of the MS Academy if he can host a meeting to discuss these issues and what our response should be in the wake of the pandemic. Why the MS Academy? It is an inclusive umbrella organisation that represents many different MS stakeholders, which makes it an ideal platform to bring the relevant people together.
Let’s think, let’s reflect, let’s meet face-2-face, let’s share our experiences and let’s formulate a plan together.
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.
Barts-MS rose-tinted-odometer: ★★★★★ Lime green and purple Thursday, #32cd32 & #6a0dad
If you are on natalizumab and are JC virus seropositive, you are at increased risk of developing PML (progressive multifocal leukoencephalopathy). If you transfer from 4-weekly infusions or standard interval dosing (SID) to 6-weekly or extended interval dosing (EID) you reduce the risk of getting PML by close to 90%.
Does shifting from SID to EID affect the efficacy of natalizumab? In short NO.
The following data was presented at ECTRIMS 2021 and should reassure both patients and HCPs
The NOVA trial was designed to estimate the difference in efficacy between EID and
SID dosing in a population that was clinically stable on SID dosing.
Although a small difference in efficacy between EID and SID dosing was estimated for the primary endpoint (number of new or newly enlarging T2 lesions at week 72) this was driven by two subjects in the EID arm with very high lesion values. The one subject had 30 lesions that occurred 3 months after natalizumab discontinuation, which represents rebound disease activity. The other subject had 25 lesions at week 72 and was subsequently diagnosed with asymptomatic progressive multifocal leukoencephalopathy (PML). The latter could have been PML lesions and not MS lesions.
When you exclude these 2 patients or outliers there is no difference in the primary endpoint between EID and SID. This study shows that patients who are stable on natalizumab SID dosing can switch to EID dosing without a meaningful loss of efficacy.
I hope you now feel confident enough to switch from SID to EID without worrying about rebound or loss of efficacy.
Background: Natalizumab 4-week dosing (Q4W) with 300 mg is approved for treatment of relapsingremitting multiple sclerosis. Dosing frequency of approximately 6 weeks (Q6W) is associated with lower progressive multifocal leukoencephalopathy (PML) risk in retrospective analyses. Real-world data suggest similar effectiveness, but NOVA is the first randomized trial to assess Q6W efficacy.
Objective: Evaluate the efficacy of natalizumab Q6W in patients previously treated with natalizumab Q4W for ≥12 months compared with continuation of Q4W over 72 weeks.
Methods: NOVA is a randomized, contro led, open-label, rater-blinded phase 3b trial. Included patients were treated with natalizumab Q4W without relapse for ≥12 months and had no enhancing lesions at screening. Patients were randomized 1:1 to Q6W or Q4W arms. The primary endpoint was number of new/newly enlarging T2 (N/NET2) hyperintense lesions analysed by negative binomial regression with baseline (BL) weight, prior natalizumab exposure, and region as covariates. Secondary endpoints included relapses and 24week confirmed disability worsening (CDW). Primary estimand used a l observed data; secondary estimand treated post-intercurrent event data as missing. Missing data were imputed by worst value on treatment or multiple imputation depending on discontinuation reason.
Results: 195/248 (79%) Q4W patients and 207/251 (82%) Q6W patients completed NOVA. BL characteristics were wel balanced. Proportions of patients with N/NET2 lesions among observed data were low in both arms (Q4W:4.1%; Q6W:4.3%). Mean N/NET2 lesions in the Q4W and Q6W arms with the primary estimand were 0.05 and 0.20 (P=0.0755) and 0.06 and 0.31 (P=0.0437) with the secondary estimand. The difference was mainly due to 2 Q6W patients with high values: (1) 30 lesions that occurred 3 months after natalizumab discontinuation and (2) 25 lesions that occurred with asymptomatic PML observed at week 72. The sum of a lother N/NET2 lesions in NOVA was 18 with no other patient having >2. Relapse occurred in 2.1% and 2.8% (P=0.64) and CDW occurred in 8% and 10% (P=0.40) of patients in the Q4W and Q6W arms, respectively. Safety data were consistent with the known drug profile and similar between groups.
Conclusions: Despite a sma l difference in efficacy between arms, NOVA data suggest the vast majority of patients stable on Q4W dosing can switch to Q6W dosing with no clinica ly meaningful loss of efficacy. No conclusions on PML risk can be drawn from NOVA.
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.
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.
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.
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.
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.
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:
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?
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?
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.
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.
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:
High-efficacy DMT allowing flipping of the pyramid
Good COVID-19 outcomes
Oral therapy, therefore reduced hospital contacts
No cell lysis syndrome or infusion-type reactions
No pre-dosing with steroids
Innate immunity intact
Only moderate reduction in T-cell counts
Less impact on CD8+ compared to CD4+ T-cells
Antiviral immunity relatively intact
Vaccine immunity intact
Low monitoring requirements
Small risk of lymphocyte count being less than 500/mm3
CNS penetration targeting CNS resident B and T cells
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.
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.
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.
When we interrogated a large number of pwSPMS we discovered that what really determines if you have active vs. inactive SPMS is how frequently you have an MRI scan. The more frequently you get scanned the more likely your team are to find new MRI lesions. If you rely on having a clinical relapse you may wait a long time. For example, after 2 years of no relapse and no MRI activity, disease activity returned in >50% of previously inactive pwSPMS. However, in 4 out of 5 cases this was driven by MRI activity and not by having a relapse.
Based on the observation that many pwSPMS have reduced MRI monitoring this decreases the chances of detecting and potentially treating and preventing disease activity in pwSPMS.
For those of you who have been told you have inactive SPMS and are ineligible for treatment, you need to ask has my MS been looked at in enough detail?
Introduction: Secondary progressive multiple sclerosis (SPMS) is often categorised as active (aSPMS) or non-active (naSPMS) based on the evidence of disease activity (relapses and/or magnetic resonance imaging [MRI] activity).
Objectives: To evaluate the contribution of MRI activity and relapses in defining disease activity in SPMS patients by analysing real-world data from Adelphi real-world MS Disease Specific Programme (Adelphi MS DSP) and to understand whether aSPMS and naSPMS are mutually exclusive groups based on data from the Phase 3 EXPAND study.
Methods: Adelphi MS DSP was a non-interventional, multinational real-world study consisting of 37,318 MS patients that includes 3580 patients with SPMS who were surveyed between 2011–2019. Patients were categorised into aSPMS (≥1 new lesion on the most recent MRI and/or ≥1 relapse in the last 12 months) and naSPMS groups. In the EXPAND study, disease activity (aSPMS) was defined as presence of relapses in the 2 years prior to screening and with/without ≥1 gadolinium-enhancing (Gd+) T1 lesion at baseline. Demographics, MRI and relapse status were analysed descriptively.
Results: Patients with SPMS from the Adelphi MS DSP were categorised as aSPMS (n=1889) and naSPMS (n=665). Disease activity (aSPMS) was defined on the basis of MRI lesions (59.1%), relapse status (12.6%), and both MRI and relapse (28.3%). In the past 12 months, aSPMS (vs naSPMS) patients had a lower mean Expanded Disability Status Scale score (4.6 vs 5.2), a higher proportion of patients undergoing MRI (87.7% vs 58.7%), and more MRIs per patient (1.24 vs 0.87). A greater proportion of naSPMS (vs aSPMS) patients were without treatment (45.1% vs 23.4%). In EXPAND, 52.6% of patients (n/N=866/1645) who had no relapse in the 2 years prior to screening and no Gd+ T1 lesions at baseline were categorised under naSPMS; of these naSPMS patients who were on placebo, 52.7% experienced on-study relapse and/or MRI activity: MRI (41.8%), relapses (4.6%), and both MRI and relapse (9.2%).
Conclusions: In both real-world and clinical studies, MRI activity appears to be a more sensitive measure of disease activity versus relapses. Even after 2 years of no relapse and no MRI activity at baseline, disease activity returned in >50% of previously ‘non-active’ patients on placebo in EXPAND. Further, reduced MRI monitoring in ‘naSPMS’ patients in the real world is a concern, which decreases the chance to detect and treat any new disease activity in these patients.
Some pointed out to me yesterday that they thought it was quite cool that I was P001; I think they were drawing an analogy to 007, but let’s not go there 😉
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.
Barts-MS rose-tinted-odometer: ★★★★★★ (6-stars calls for a bright orange Thursday, #FFA500)
As you are aware by now I am one of the people in the field of MS who thinks EBV is the cause of MS. My position is essentially based on epidemiological evidence and causal inference. At the moment I honestly don’t know how EBV causes MS, but one hypothesis is that ongoing EBV infection in the CNS or in a peripheral compartment drives MS disease activity. EBV resides in memory B-cells and memory B-cell appears to be the main target of all effective MS disease-modifying therapies.
The question is can we simply treat MS by targeting EBV and not using a sledgehammer; i.e. depleting all B-cells (anti-CD20) or taking out the memory B-cell with non-selective immune reconstitution therapies (IRTs), e.g. AHSCT or alemtuzumab? One way to do this is to use anti-EBV drugs or cellular therapies targeting EBV infected cells.
This is why one of my highlights at this meeting is Atara Bio’s phase-1 MRI data on using anti-EBV HLA-matched cytotoxic T-lymphocytes as a treatment for progressive MS. Study subjects who had sustained improvement in the EDSS showed a significant increase or improvement in their brain MTR (magnetization transfer ratio) at 12 months compared to baseline. MTR is an MRI marker of tissue integrity and is thought to represent tissue repair and remyelination. The important point for me is the MTR is an objective measure done using software and is blinded to the clinical information or treatment allocation. Having an objective measure on MRI that correlates with a relatively subjective clinical measure improves my confidence that what we are seeing may be real.
The other remarkable observation in this study is by how much some of the responders in this study improved. EDSS scores improved by well over one EDSS point with one patient improving by as much 2.5 points, i.e. from an EDSS of 5.5 to 3.0. Two other subjects went from EDSS 6.0 to 4.5; from needing a walking stick to walk 100m to be able to walk between 300m and 499m unassisted and without taking a rest. Outside of relapses, these sorts of EDSS improvements don’t happen in people with established progressive MS. This is almost as impressive as the Lazarus effect we see rarely in patients treated with steroids or plasma exchange for a relapse. The Lazarus effect describes those patients who go from EDSS 7.0+ (bed-bound) to getting up and walking within hours to days of being treated.
Note: Lazarus of Bethany, also known as Saint Lazarus, or Lazarus of the Four Days, venerated in the Eastern Orthodox Church as Righteous Lazarus, the Four-Days Dead, is the subject of a prominent sign of Jesus in the Gospel of John, in which Jesus restores him to life four days after his death (source Wikipedia).
The following are heat map tables from the poster in the patients who improved and those who didn’t improve. Green being an improvement and red is no improvement. Even in the so-called non-responders, some study subjects improved.
The good news is Atara’s product is now in phase 2 as part of a blinded study and if it clears this hurdle a large phase 3 programme is planned. Prior to this data emerging my odds of this strategy working in MS would have been way below 50%; actually in the order of 2-5%. Now with objective MTR data correlating with such dramatic clinical improvements, my predictions have soared to now being above 50%, i.e. in the order of 50-67%.
Introduction: Mounting evidence suggests Epstein-Barr virus (EBV) is a necessary risk factor for development of multiple sclerosis (MS) [Abrahamyan et al. JNNP 2020]. Early experience with autologous EBV-specific T-cell therapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018; Ioannides ZA et al. Front Neurol 2021].
Objectives/aims: Evaluate the safety and potential efficacy of ATA188 in adults with progressive MS in an ongoing open-label extension (OLE) study, including an imaging biomarker: magnetization transfer ratio (MTR).
Methods: In part 1 of this 2-part Phase I/II study, 4 cohorts received escalating doses of ATA188. Patients (pts) were followed for 1 year and could participate in a 4-year OLE. Sustained disability improvement (SDI; including expanded disability status scale [EDSS] and timed 25-foot walk), as well as safety, were measured [Pender MP et al. EAN 2020]. As a biomarker of improvement, change from baseline in MTR, an exploratory endpoint, was assessed.
Results: 25 pts received ≥1 dose of ATA188 and were followed for up to 33 mos (m). No grade >3 adverse events (AE), dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion-related reactions were observed. 2 treatment-emergent serious AEs were previously reported (muscle spasticity [grade 2; not treatment related]; MS relapse [grade 3; possibly treatment related]) and, as of April 2021, 1 was reported in the OLE (fall; grade 2; not treatment related). Efficacy was evaluated in 24 pts in the initial 12m period and, as of April 2021, in 18 pts in the OLE followed for up to 33m. 9 pts met SDI criteria either in the initial 12m period (n=7) or in the OLE (n=2); of these, 7 had sustained EDSS improvement. Of the 8 pts that achieved SDI and entered the OLE, 7 maintained SDI at all subsequent timepoints. Pts with sustained EDSS improvement (vs those without) had greater increases in MTR signal (in unenhancing T2 lesions and normal-appearing brain tissue) at 12m.
Conclusions: Preliminary data indicate ATA188 is well tolerated. Sustained EDSS improvement drove SDI in most pts, and in all but 1 pt, SDI was maintained at all subsequent timepoints. As a biomarker associated with disability, pts with sustained EDSS improvement (vs those without) showed greater increases in MTR signal at 12m, which may be suggestive of remyelination. The Phase 2 portion of this study, EMBOLD (NCT03283826), is ongoing and currently enrolling.
The following is Atara’s press release if you want more information.
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.
Barts-MS rose-tinted-odometer: ★★★ (An ECTRIMS red Wednesday #e52330)
I am getting endless questions about when is it the best time to have the 3rd and/or booster dose of the COVID-19 vaccine in relation to ocrelizumab infusions, which is why I did an MS-Selfie Case Study on this topic on the weekend.
Unfortunately, until we have good evidence that shows people on ocrelizumab who seroconvert do better than those who don’t seroconvert after the COVID-19 vaccine there is no right or wrong answer. I think we just need to tell pwMS that they are likely not to seroconvert if they are on an anti-CD20 therapy (ocrelizumab, rituximab & ofatumumab) and still have peripheral B-cell depletion. However, if pwMS on anti-CD20 therapy want to optimise their immunity by seroconverting they will need to delay or miss infusions or injections until they B-cell reconstitute. The latter is more important for older patients and those with comorbidities, who are at higher risk of severe COVID-19 and dying from the infection.
The following vaccine study from Israel in this week’s NEJM tells us why antibodies are important post-vaccination. Breakthrough vaccine infections in healthcare workers who had been double vaccinated with the Pfizer-BionTech mRNA vaccine were much more likely in those with lower antibody titres. In summary breakthrough infections with SARS-CoV-2 is correlated with low neutralizing antibody titers during the peri-infection period. The good news is that most breakthrough infections were mild or asymptomatic, although persistent long-COVID-like symptoms did occur.
Can we extrapolate this to pwMS? Yes, definitely. Why would the biology of neutralizing anti-SARS-CoV-2 antibody protection be different in pwMS compared to people in the general population or in this case healthcare workers? This is why pwMS on anti-CD20 therapy who have not seroconverted after being fully vaccinated with a COVID-19 vaccine must consider themselves at-risk of breakthrough infections, which may be severe, particularly in older age groups and those with comorbidities and not to mention long-COVID.
Background: Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity.
Methods: At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case-control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity.
Results: Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.
Conclusions: Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.
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.
Barts-MS rose-tinted-odometer: ★★ (Dark blue sleepy Friday #00008B)
The study below is another demonstration of how MS affects sleep. Sleepiness, abnormal sleep timing, and poor sleep quality is just the tip of the iceberg. Two-thirds of subjects were in the extreme ranges in at least two sleep domains studied. Worryingly, markers of sleep disruption were associated with more depressive symptoms, fatigue and cognitive function.
The problem is that most routine MS consultations rarely address sleep and sleep quality. How do you diagnose and manage MS fatigue in pwMS without knowing about sleep hygiene and architecture? Isn’t this an example of why we need to transform the management of MS with routine remote home sleep assessments?
Background: Although sleep disturbances are common among people with Multiple Sclerosis (PwMS), understanding of their impact has been stymied by limitations in approaches to sleep measurement within this population. The aim of this study was to comprehensively phenotype sleep patterns in PwMS through application of an emerging seven-domain framework that includes sleep duration, continuity, timing, quality, rhythmicity, regularity, and sleepiness.
Methods: Sleep domains were estimated from wrist-worn accelerometry, Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index responses. Extreme sleep values within each domain were constructed using previously published guidelines. A composite score of extreme values was calculated for each participant. Associations between sleep domains and severity of MS symptoms were explored (pain, fatigue, depressive symptoms, and cognitive dysfunction).
Results: Among n = 49 participants, median total sleep time was 456.3 min. Median time spent awake after sleep onset was 37 min. Sleepiness, abnormal sleep timing, and poor sleep quality affected 33%, 35%, and 45% of participants, respectively. Seventy-six percent had ≥2 sleep domains in extreme ranges. PwMS had longer sleep duration and decreased sleep regularity compared to a non-MS historical cohort of older men. Greater daytime sleepiness, poorer sleep quality, and higher composite sleep health score were associated with more depressive symptoms, and lower sleep rhythmicity was associated with higher fatigue. Associations were observed between measures of cognitive function and sleep fragmentation, duration, quality, rhythmicity, and composite score.
Conclusion: Application of a seven-domain sleep health framework that captures the dynamic and multifaceted aspects of sleep is feasible in PwMS, and offers potential for an improved understanding of the scope and impact of sleep disturbances in PwMS.
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.
Barts-MS rose-tinted-odometer: ★★★ (dollar color Monday hex #6B8068)
Did you know that the effectiveness of high-dose steroids to treat a relapse is small? In reality, there is no difference in outcome at 6 months between relapses treated with steroids and those managed without steroids. In reality, high-dose steroids simply speed up recovery of function by about 2 weeks. So if you are not disabled by your relapse and it has not affected your day-to-day functioning it is better not to have them.
High-dose steroids don’t come without risks, i.e. psychosis, insomnia, depression, avascular necrosis of the hip, hypertension, diabetes, infections, blunted vaccine responses, higher risk of severe COVID-19, etc. So then why do we prescribe them so frequently? Money, money, money!
In many fee-for-service healthcare systems, neurologists and healthcare institutions make money out of admissions and intravenous infusions, which acts as a perverse incentive to prescribe steroids. The good news is that high-dose oral steroids for relapses, taken as an outpatient, work as well.
The French study below shows how much money could be saved from shifting from inpatient intravenous to outpatient oral steroid use (25 million euros per year in France). I doubt this will change behaviour when there is money to be earned. As the saying goes ‘turkeys voting for Christmas’; not on your life.
So the next time you are offered inpatient-intravenous steroids for a relapse you should ask for home-oral steroids instead and see what response you get from your HCP.
Background: Studies have shown that oral high-dose methylprednisolone (MP) is non-inferior to intravenous MP in treating multiple sclerosis relapses in terms of effectiveness and tolerance. In order to assist with resource allocation and decision-making, its cost-effectiveness must also be assessed. Our objective was to evaluate the cost-utility of per os high-dose MP as well as the cost-savings associated with implementing the strategy.
Methods: A cost-utility analysis at 28 days was carried out using data from the French COPOUSEP multicenter, double-blind randomized controlled non-inferiority trial and the statutory health insurance reimbursement database. Costs were calculated using a societal perspective, including both direct and indirect costs. An incremental cost-effectiveness ratio was calculated and bootstrapping methods assessed the uncertainty surrounding the results. An alternative scenario analysis in which MP was administered at home was also carried out. A budgetary impact analysis was carried at five years.
Results: In the conditions of the trial (hospitalized patients), there was no significant difference in utilities and costs at 28 days. The incremental cost-effectiveness ratio was €15,360 per quality-adjusted life-year gained. If multiple sclerosis relapses were treated at home, oral MP would be more effective, less costly and associated with annual savings up to 25 million euros for the French healthcare system.
Conclusions: Oral MP is cost-effective in the treatment of multiple sclerosis relapses and associated with major savings.
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.
