"If a medicine is not going into your blood or your brain, but rather is just sitting in your stomach, then it is as good as you not taking it.”

, September 12–16, 2020, by Rajesh Pahwa, MD, revealed that patients with Parkinson disease (PD) who were treated with levodopa-carbidopa intestinal gel (LCIG) experienced a faster time to ON without troublesome dyskinesia (ON-woTD) compared with immediate-release levodopa-carbidopa oral capsules (LCIR). Within 30 minutes of waking up, 11.3% of patients on LCIG had ON-woTD compared to 20% of those on LCIR.

Pahwa, the Laverne and Joyce Rider Professor of Neurology; chief of the Parkinson’s and Movement Disorder Division; and director of the Parkinson's Foundation Center for Excellence at University of Kansas Medical Center, feels as though the advantages clear enough to where LCIG should be more normalized into clinical care. The major difference between the 2 options is that LCIG is administered through a port, whereas LCIR is taken orally.

, Pahwa explained the concepts behind how LCIG is administered, and why its mechanism of action allows for faster ON-woTD in patients with PD.

Videos

The director of the Parkinson’s Foundation Center for Excellence at University of Kansas Medical Center detailed the pros and cons of levodopa-carbidopa intestinal gel. 

Rajesh Pahwa, MD: Advantages of Levodopa-Carbidopa Intestinal Gel

This is the second of a 2-part interview. For part 1, 

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, a number of posters representing datasets from both clinical development programs and independent analyses were presented on 2 major therapies developed by Genentech: the multiple sclerosis (MS) agent ocrelizumab (Ocrevus) and the neuromyelitis optica spectrum disorder (NMOSD) therapy satralizumab (Enspryng).

Satralizumab recently won FDA approval for the treatment of NMOSD, making it just the third option for patients, and the first to offer at-home administration. Its approval was based on robust data from the phase 3 SAkuraStar (NCT02073279) and SAkuraSky (NCT02028884) clinical trials, which combined included more than 170 patients who were randomly assigned to receive satralizumab 120 mg or placebo. In SAkuraSky, patients added treatment to baseline immunosuppressive therapy.

Notably, at MS Virtual, data from the open-label extension and a substudy of the SAkuraSky and SAkuraStar trials revealed that patients with NMOSD—regardless of treatment status—had a reduced risk of relapse with treatment with satralizumab.

 spoke with Kathleen Hawker, MD, Medical Director Manager, Neuroscience, Genentech.

: Could you offer a high-level view of some of the data presented at MS Virtual on satralizumab?

 Obviously, we were going to be collecting data long-term, but I was very excited about it. Anytime you get out into longer-term data and show no changes in the safety and the efficacy maintained, that's really what everybody wants to see. So, the data between Ocrevus and satralizumab are very similar. We don't have as much long-term data with satralizumab, but they're both showing the same thing: that patients are still continuing to do well.

I think what's exciting about our data as well, too, is that these were patients who were on other immunosuppressants and we were not seeing an uptick in safety issues in them, despite the fact that they were on a variety of other medications. So not only the drug is safe by itself, but we can see that safety is as good when you combine it with drugs with no safety profile concerns and the relapse rate is staying down. The other big and exciting part, too, is the patients are feeling better according to the patient-related outcomes. We always talk about MRIs and about a lot of different things, but the biggest thing when you get in the clinic is you say, “How are you doing?” Patients are very good about that. Those patient-related outcomes, the fact they are really improved and staying that way, is also great given the longevity of the drug and the great benefit without the safety issues.

How important is it for you that satralizumab is offered as an at-home, subcutaneous injection, particularly in these times?

Even beside COVID, when you take a look at a subcutaneous injection, patients with NMOSD can be much more disabled in terms of their vision when it comes to trying to get around, and also their walking ability. More so than patients with MS. The fact they can do it at home is a huge boon to them, even besides the times of COVID-19. If you can't see it's very hard to get to appointments—really, to get places—and it raises the burden upon families, caregivers, and patients. This at-home administration, I think, is really tremendous. Long-term as well, and during COVID, even though nobody likes COVID, it's been a boon for them as well.

Was there anything you’d to add about the data on ocrelizumab or satralizumab?

As I said, I'm really excited that there are some options for patients that’re on other drugs that satralizumab—it's got a very unique mode of action, so I think that's really important that we're not doing the same old, same old that we’ve done before. That's really crucial.

I've always been excited about ocrelizumab. I've been in the development program for a long period of time, and I think it's one of the drugs that is high efficacy without some of the safety issues that a lot of the other high efficacy therapies that we developed. And the fact that we're hearing from patients, too. Again, coming back to the patients, when we talk to them about them, they're feeling better, they're doing better, they're getting on with their lives. I'm really proud of a lot of stuff based on what's been going on.

We've got some new studies that are probably going to be planned, in trying to push the envelope even further to treat even earlier in the CHIMES study. That's crucial because it’s very under-represented In most of our studies. So, to try to understand what we can do to help in these cases is important. There’s more to come.

Transcript edited for clarity. For more coverage of MS Virtual 2020, 

REFERENCES
1. Greenberg B, Bennett J, De Seze J, et al. Efficacy of satralizumab in neuromyelitis optica spectrum disorder (NMOSD): results from open-label extension periods of SAkuraSky and SAkuraStar. Presented at MDS Virtual Congress; September 12–16, 2020. Abstract P0711
2. Palace J, Bennett J, Stokmaier D, Von Budingen H, Klingelschmitt G, Traboulsee A. Satralizumab in first incident treatment-naïve AQP4-IgG seropositive NMOSD patients enrolled to SAkuraStar: a case series. Presented at MDS Virtual Congress; September 12–16, 2020. Abstract P0754.

Articles

ECTRIMS

The medical director manager of neuroscience at Genentech offered her perspective on the mountain of data presented at MS Virtual 2020 on the recently approved NMOSD treatment.

Satralizumab Benefits Relapse Risk Across NMOSD Treatment Spectrum

An evaluation of the cardiac safety profile of ponesimod (Janssen Pharmaceutical) showed that treatment with the agent was not associated with an increased risk for major cardiovascular (CV) events such as myocardial infarction (MI), stroke, or CV death when compared to teriflunomide (Aubagio; Sanofi).

The dataset was from the phase 3 OPTIMUM study (NCT02425644) and was presented at 

, the 8th Joint ECTIMS-ACTRIMS meeting, September 11–13, 2020, by Till Sprenger, MD, neurologist, DKD Helios Klinik Wiesbaden.

Researchers found no major CV events (MACE)—defined as CV death, non-fatal MI, and non-fatal stroke—in patients who were treated with ponesimod. In comparison, 3 instances of MACE occurred in the teriflunomide group.

Among a cohort of 1131 patients who received treatment with either ponesimod (n = 565) or teriflunomide (566), cardiac treatment-emergent adverse events (TEAEs) that led to discontinuation occurred in 1 patient (0.2%) on ponesimod (cardiomyopathy) and 2 patients (0.4%) on teriflunomide (1 atrial fibrillation, 1 coronary artery insufficiency).

Patients within the study were between the ages of 18 and 55 years were randomized 1:1 to ponesimod 20 mg or teriflunomide 14 mg for 108 weeks. Those on ponesimod underwent a gradual 14-day titration starting with 2 mg implemented to address first-dose cardia effects. Blood pressure (BP) and 12-lead electrocardiogram (ECG) measurements were used to assess cardiac safety.

Sprenger and colleagues noted that there was no association between clinically significant bradyarrhythmia events and patients who had dosage uptitrated. Additionally, none of those evens were serious or led to discontinuation. No 2nd degree or higher atrioventricular (AV) blocks were reported.

READ MORE: Low-Dose Rituximab Safe, as Effective as High Dose in MS

Hazard risks (HRs) and rhythm TEAEs of special interest (AESIs) were reported in 29 patients (5.1%) on ponesimod compared to 24 patients (4.2%) in the teriflunomide group. On Day 1, the incidence of HR and rhythm AESIs was 2.1% in the ponesimod group and included bradycardia (HR, <50 bpm) in 0.7% and 1st degree AV block in 0.5%. First degree AV block was found in 0.4% of teriflunomide patients.

On Day 1, the max mean reduction in HR from pre- to post-dose at 2 hours was –8.7 bpm for ponesimod and –1.7 bpm for teriflunomide.

A total of 3 patients in the ponesimod group had post-dose asymptomatic HR ≤40 bpm on Day 1, and all had pre-treatment HR <55 bpm. Furthermore, new electrocardiogram (ECG) findings of sinus bradycardia was 20% in patients at risk for symptomatic bradyarrhythmia, compared to 3.0%, all of which were asymptomatic, in patients who were not at-risk.

 at ECTRIMS 2019. Results showed that ponesimod, an orally active, selective modulator of the sphingosine-1-phosphate receptor 1 (S1P) had a statistically significant 30.5% greater reduction in annualized relapse rate (ARR) compared to teriflunomide. At week 108, the respective ARRs for the ponesimod and teriflunomide groups were 0.202 and 0.290 (

Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS)

—an MS-specific, 20-item patient-reported outcome measure—scores at week 108 suggested statistically significant effects on fatigue symptoms with ponesimod in comparison to teriflunomide, with a mean difference of —3.57 (

Additionally, the cumulative number of combined unique active lesions (CUALs), measured with MRI, showed a 56% reduction (

 <.0001) with ponesimod. Although 12-week confirmed disability accumulation was observed in 10.1% and 12.4% of patients in the ponesimod and teriflunomide arms, respectively, the results were not statistically significant.

The results from this study led Janssen to 

 (NDA) for ponesimod for the treatment of adults with relapsing MS in March. The company did not announce a prescription user drug fee act (PDUFA) date or when they would hear back from the FDA on the NDA.

1. Vaclavkova A, Burcklen M, Freedman M, et al. Cardiac safety of ponesimod in relapsing multiple sclerosis in the randomized, active-controlled, double-blind, parallel-group phase 3 OPTIMUM study. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0194

2. New Head-to-Head Phase 3 Study Data Show Ponesimod Superiority Versus Aubagio® (teriflunomide) 14 mg in Adults with Relapsing Multiple Sclerosis (MS) [press release]. Stockholm, Sweden: Janssen Pharmaceuticals; Published September 11, 2019. Accessed September 25, 2020. prnewswire.com/news-releases/new-head-to-head-phase-3-study-data-show-ponesimod-superiority-versus-aubagio-teriflunomide-14-mg-in-adults-with-relapsing-multiple-sclerosis-ms-300916102.html.

3. Janssen Submits Ponesimod New Drug Application to the U.S. FDA for Treatment of Adults with Relapsing Multiple Sclerosis. News release. Titusville, NJ. The Janssen Pharmaceutical Companies of Johnson & Johnson. Published March 18, 2020. Accessed September 25, 2020. prnewswire.com/news-releases/janssen-submits-ponesimod-new-drug-application-to-the-us-fda-for-treatment-of-adults-with-relapsing-multiple-sclerosis-301026319.html

Researchers concluded that uptitration of ponesimod was not associated with clinically significant bradyarrhythmia events; none were serious or lead to discontinuation.

Ponesimod Shows Safe Cardiac Profile in MS

“The rubber meets the road when our ideas are tested in the clinical area, and one would never have expected a primacy of B cells in the MS pathway were it not for the B-cell therapeutics.”

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, a presentation was given that detailed the upcoming phase 3 assessment of fenebrutinib, an investigational Bruton Tyrosine Kinase (BTK) inhibitor, in both relapsing and primary progressive multiple sclerosis (MS). There will be 2 trials in relapsing disease and 1 in progressive, with 1:1 randomization and estimated enrollment of 734 patients in each of the relapsing MS trials and 946 in the primary progressive MS trial.

All 3 trials aim to assess the agent’s impact on disease progression, and thus will feature 12-week composite Confirmed Disability Progression (cCDP12) as a primary end point—the relapsing trials will also include annualized relapse rate as a co-primary end point. Assessment with cCDP12 requires at least an increase in Expanded Disability Status Score (EDSS) score of ≥1.0 point from a baseline score of ≤5.5 points, or a ≥0.5 point increase from a baseline score of >5.5 points; a 20% increase from baseline in time to complete the 9-Hole Peg Test; or a 20% increase from baseline in the Timed 25-Foot Walk Test.

, Stephen L. Hauser, MD, professor of neurology, and director, UCSF Weill Institute for Neurosciences, who presented the details of these trials, spoke to the driving theory behind BTK inhibition in MS, and how fenebrutinib may play a role as a particularly specific inhibitor, unlike other agents in its class.

REFERENCE
Hauser SL, Bar-Or A, Francis G, et al. Examination of fenebrutinib, a highly selective BTKi, on disease progression of multiple sclerosis. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0211.

The director of the UCSF Weill Institute for Neuroscience spoke to the advantages of having agents that can be used across the spectrum of MS, and the role disease progression plays early on.

Stephen L. Hauser, MD: Fenebrutinib and BTK Inhibiton in Progressive MS

Results from a 2-center ambispective study presented at 

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, demonstrated that low doses of rituximab (Rituxan; Genentech/Biogen) seem to offer similar effectiveness with better safety profile than high doses when treating multiple sclerosis (MS).

Presented by Luciana Midaglia, MD, neurologist, Vall Hebron University Hospital, and the Multiple Sclerosis Centre of Catalonia, the study compared patients in the Barcelona center (BC; n = 249) who were administered 2 g of rituximab intravenously (IV) during at least 3 cycles, followed by 1 g every 6 months to those in the Girona center (GC; n = 54). In that cohort, 2 g rituximab was administered for at least the first cycle, followed by 500 mg every 6 months.

At baseline, mean annualized relapse rate (ARR) was 0.37 (±0.6) for those in the BC and 0.33 (±0.5) in the GC. At Year 1, ARR decreased to 0.05 (87.5%; 

Remaining stable or improvements on the Expanded Disability Status Scale (EDSS) score was found in 79.4% and 71.4% of progressive MS phenotypes in BC and GC, respectively. Median EDSS at baseline was 5.5 (BC: range, 1–9.0) versus 6.0 (GC: range, 1–8.0).

At Year 1, 2.7% of the BC population had contrast-enhancing lesions (CELs) and 19% reported with new T2 lesions. In comparison, 8% of those in the GC had CELs while 16% had new T2 lesions. At third year, 0% of the GC population documented CELs or new T2 lesions, whereas 12% of the BC reported CELs. Notably, there were 0 cases of CELs reported in the BC at third year.

In the BC, adverse events (AEs) occurred in 14.8% of patients during the first year compared to 4.1% at third year. Researchers noted that there was no difference in the dynamics of CD19% lymphocytes, while immunoglobulin (IgG) values in serum decreased significantly in the BC cohort throughout the first 3 years.

Rituximab, an anit-CD20 monoclonal antibody, has been widely used as an off-label treatment for MS, but has not received FDA approval for this indication. It was first approved in November 1997 and has been indicated for the treatment of chronic lymphocytic leukemia, rheumatoid arthritis, Non-Hodgkin’s lymphoma, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus.

The agent has been often linked in use to treat other MS phenotypes such as myasthenia gravis and neuromyelitis optica spectrum disorder (NMOSD). A study published in May showed that treatment with 

rituximab performs better if initiated earlier

 after the onset of generalized symptoms in those with myasthenia gravis.

 Results from another study of patients with NMOSD suggest that first-line treatment with 

rituximab is more effective in suppressing clinical activity

, independent of the antibody status, compared with mycophenolate mofetil (MMF) and other first-line immunosuppressants.

1. Midaglia L, Alvarez GB, Cedeno RR, et al. Rituximab treatment for MS: an observational multicentric dose comparison. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract PS01.05

2. Stewart J. Rituxan FDA approval history. Drugs.com. drugs.com/history/rituxan.html. Updated September 30, 2019. Accessed Thursday September 24, 2020.

3. Brauner S, Eriksson-Dufva A, Hietala MA, Frisell T, Press R, Piehl F. Comparison Between Rituximab Treatment for New-Onset Generalized Myasthenia Gravis and Refractory Generalized Myasthenia Gravis. 

Published online May 4, 2020. doi: 10.1001/jamaneurol.2020.0851

4. Poupart J, Gioivannelli J, Deschamps R, et al. Evaluation of efficacy and tolerability of first-line therapies in NMOSD. Neurology. 2020;94:1-12. doi:10.1212/WNL.0000000000009245.

In the third year of treatment, both dose cohorts did not experience any contrast-enhancing lesions, and only a small population in the Barcelona center showed new T2 lesions.

Low-Dose Rituximab Safe, as Effective as High Dose in MS

This is the first of a 2-part interview. For part 2, 

A number of data sets examining the efficacy and safety of ocrelizumab (Ocrevus; Genentech) in real-world and long-term populations of patients with multiple sclerosis (MS) were presented at 

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020.

All told, the data included findings from a number of studies focused on patients who were exposed to prior disease-modifying therapy (DMT) as well as those who were initially treated with the humanized anti-CD20 monoclonal antibody. Ultimately, the range of posters showed the agent held benefit for those with a prior suboptimal response, and improved symptoms and rates of no evidence of disease activity (NEDA), among other conclusions.

To find out more about the swath of data presented on the agent at MS Virtual, 

: Could you offer a high-level view of some of the data presented at MS Virtual on ocrelizumab?

 In the newer data, we have 7 years of safety data, and there have been no changes, which is great news. No increase in infections, malignancies, or any other new safety signals. That's been excellent. We have some really interesting data some coming from a rework of the relapsing-remitting MS and also the primary progressive MS data looking at 2 things: thalamic volume, and neurofilament light.

What was really interesting about that is thalamic volume is 1 of the biggest predictors of what a patient's going to do. What it did show is that patients with more thalamic volume loss did worse and that patients treated with Ocrevus did better than patients who have either been on the interferon in 1 and placebo in the other. And again, this is what we've seen over and over again, that when patients start early, they never get caught up, so that atrophy continued in patients who had started on Ocrevus early.

The other one that they looked at was neurofilament light, which was very interesting, too. It's a biomarker that can also predict disability, so you can take a look at it in the beginning and you can say, “This patient is going to do worse than others.” There was a correlation between thalamic volume, and Ocrevus actually brought the NfL levels back down to normal with treatments. That was very exciting to see that we could also alter not only shorter-term MRI data and relapses, but also long-term. And there were correlations with disability data, too. That's really important that we could see differences with the 25-Foot Walk Test and EDSS and also the 9-Hole Peg Test. So that was exciting.

There were a number of presentations on patients who switched to ocrelizumab from other agents, what were your thoughts on those findings?

The transition from natalizumab was also very interesting, and I think the biggest message on that is that we have not seen increases in any PML with the transition from natalizumab. We have seen very few cases, period. None reported—that hasn't been different—and the only cases we've had have been either from fingolimod or from natalizumab. But the numbers are still very, very small, and they haven't been increasing as opposed to some of the other drugs. So that's been very good. The other part of a note is there was no increase in safety issues with that transition, as well. A lot of our patients come from either fingolimod or natalizumab, so that's been good that the safety has persisted.

We had 3 studies: 1 from Europe, 1 from the US, and some substudies from 1 of our global studies, the CHORDS and CASTING studies, looked at patients that had suboptimal responses to other drugs. I think that’s important because these patients typically are more difficult to treat the longer that they've been on other drugs, and across all 3 studies, what we found is that the 24-week confirmed disability was down significantly—89% in one study. Those rates were in the high 80s and all 3 studies showed that the MRI activity went down by over 90%. They looked at what we called NEDA when they re-baselined it after 8 weeks, and the NEDA rate was 75% to over 80% decreased, and there was a slight difference between patients who had been on 1 drug versus more than 1 drug. But there wasn't a big difference. I think that's really exciting news that patients who have failed other drugs and are further along in their course are still doing really, really well on Ocrevus. 

They also had long-term efficacy data, looking at both EDSS and relapse rate, and again, the same thing that we've seen before—the patients who had been on interferon or on placebo never caught up, but it was wonderful to see that not only the safety has remained the same, but the relapse rate has actually gone down over a period of 7 years, and also the EDSS has stayed low, too. So again, that long-term persistence on efficacy.

Where there any other data that are worth highlighting?

We have another trial called OBOE, which is still ongoing, and some really exciting data came out of that. There have been changes in B cells, in what they do in the cerebral spinal fluid, which I've never seen, even after 20 years of working in this. We saw some decreases in oligoclonal bands in patients, which is the first time that’s been reported. That was very exciting.

Then we have the 3 new studies, with fenebrutinib which is getting underway and is a BTK inhibitor. That's in PPMS, as well as 2 RMS studies, and we’re just starting up our CHIME study, which is in minorities. It has started to recruit, which is very exciting, and that's going to be 150 patients who are Hispanic and African American. We're going to be looking at some special testing to find out why these 2 minority groups do worse than Caucasians. There's going to be special MRIs as well as a lot of special blood testing to try to find out what we need to do to help these populations. That's underway as well.

How important is it to you, and particularly to physicians, to be aware that this appears to be not only an effective first option but an effective second option as well?

I think it's crucial. It's one of the biggest things we used to struggle with when we were in clinical practice, because, your phase 3 data don't give you that information, obviously, very well because of washouts and things like that. In the real world, we see not only the efficacy—and that's why the CHORDS, CASTING, and the ENSEMBLE data are saying, even after multiple drugs, that the drug is still very, very effective against, relapse, MRI, and disability—but also the safety, too. We always worry about, when people have been on multiple different drugs, what's happened to the immune system, and we haven't seen an uptick in safety signals. We typically know, generally, that when people are a little bit older, safety can change, but we haven't seen that in any age group either. So they're doing better, they're stabilizing, and we're not seeing an uptick in safety concerns, which we've seen with other drugs in some switches.

This is also important, too, because, in our regular studies, there's always a washout. But you don't want to do that in the real world because you want the patient on therapy very quickly. So, I think we've got quite a bit of data from a lot of different drugs that people go on before Ocrevus without a problem in safety at this point, so that was great news.

We saw this in the satralizumab longer-term data too. We haven't seen an uptick in safety, and people who are relapse-free have also stayed very, very low too. That's 2 of the biggest things when you're treating MS. Two years in a clinical study is very different than the real world. We've got 170,000 patients on Ocrevus right now for that period of time, so a lot of powerful data. There was a lot of data about immunoglobulins, and it was the same type of thing—followed for a long period of time and seeing no increase in infections. The good news is we're very boring, and it's exciting that we've seen this across multiple different trials and now in independent studies as well.

How important is it to have that collection of real-world data across the spectrum of disease?

It's a very, very good point. We've been trying to push that boundary of treating very early to prevent, but sometimes you get patients that haven't had that opportunity. So, it is wonderful that you have a drug that can also make a huge difference in their lives from multiple different aspects. And we're still gathering more data. Again, we have trials looking at earlier and earlier patients to see if we can even push that. Can we actually even prevent disease from going on if we start early enough? Those are very big points, and I think, that one of the biggest things people worry about, obviously, is safety. But with this long-term safety, I think this is giving a very good idea that you can use this drug, you can use it for a long time, and you can use it in a variety of patients in a variety of different types of MS very early, before any drug, after one drug, after several drugs, and at different ages, and still maintain that same improvement without making anything worse.

I'm very excited about the data, and we've been presenting it to a lot of neurologists, and they are also very excited that we haven't seen anything new from safety and that the efficacy data is remaining as good as it was in the original trials.

REFERENCES
1. Weinstock-Guttman B, Bermel R, Cutter G, et al. Ocrelizumab treatment in patients with RRMS who had suboptimal response with one or more prior disease-modifying therapies: CHORDS 2-year results. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0221.
2. Wiendl H, Comi G, Oreja-Guevara C, et al. Ocrelizumab Phase IIIb efficacy from CASTING: 2-year NEDA (MRI re-baselined) subgroup rates in RRMS patients with a suboptimal response to prior DMTs. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0219.
3. Wiendl H, Comi G, Oreja-Guevara C, et al. Ocrelizumab Phase IIIb efficacy from CASTING: 2-year NEDA (MRI re-baselined) subgroup rates in RRMS patients with a suboptimal response to prior DMTs. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0219.
4. Kister I, Cutter G, Buffels R, Clinch S, Kuenzel T, Vermersch P. Improvements in patient-reported SymptoMScreen scores among ocrelizumab-treated patients with RRMS: 2-year results from the CASTING clinical trial. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P1039.

The medical director manager of neuroscience at Genentech discussed the swath of data presented on the humanized anti-CD20 monoclonal antibody at MS Virtual.

Ocrelizumab Shows Range of Benefits for Spectrum of Patients With Multiple Sclerosis

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, suggest that early intensive treatment in patients with relapsing multiple sclerosis (MS) is more effective at controlling disability progression, with an increasing effect over time, compared with an escalation therapy approach.

Notably, this increasing effect was observed even in light of patients utilizing an escalation approach when switching to higher-efficacy disease-modifying therapy (DMT).

The data were presented by Pietro Iaffaldano, MD, assistant professor of neurology, University of Bari Aldo Moro, who, along with his colleagues, hinted at the importance of these findings due to the fact that “no consensus exists on how to aggressively and timely treat relapsing-remitting multiple sclerosis patients.”

The total study cohort consisted of 2652 patients with relapsing MS from 62 Italian MS centers, with a 1:1 propensity score-matched cohort of 365 pairs. The median follow-up after the initiation of first DMT was 8.5 years (interquartile range [IQR], 6.5–11.7). Those in the escalation group continued to a higher-efficacy DMT after a median time of 5.1 years (3.1–8.4).

Disability trajectories were evaluated by applying a longitudinal model for repeated measures with an autoregressive variance-covariance structure, and the effect of early versus late start of high-efficacy DMT was evaluated via mean annual Expanded Disability Status Scale (EDSS) score changes compared to baseline values in both groups.

Fatigue Plays A Factor in Multiple Sclerosis Daily Functioning

The early intensive group included individuals who received either fingolimod (Gilenya; Novartis), natalizumab (Tysabri; Biogen), mitoxantrone (Novantrone; EMD Serono), alemtuzumab (Lemtrada; Sanofi), ocrelizumab (Ocrevus; Genentech), or cladribine (Mavenclad; EMD Serono) as first DMT. The escalation group consisted of those individuals who received a high efficacy DMT after ≥1 year of glatiramer acetate, interferon, azathioprine, teriflunomide, or dimethyl fumarate treatment.

Baseline EDSS values were estimated as 2.52 (95% CI, 2.33–2.71) in the escalation group compared to 2.45 (95% CI, 2.26–2.64) in the early intensive group.

Iaffaldano and colleagues observed that mean delta-EDSS score at each 12-month period was significantly higher in the escalation group compared to the early intensive group (

 <.02). Particularly, the mean delta-EDSS differences between the 2 groups tended to increase from 0.1 (95% CI, 0.01–0.19; 

 = .03) at 1 year to 0.30 (95% CI, 0.07–0.53; 

 = .009) at 5 years, and to 0.67 (95% CI, 0.31–1.03; 

These data are not the first to explore the differences in treatment approach for MS, as the conversation around induction versus escalation therapy has been ongoing. In 2019, 

data from a cohort study of 592 patients with MS

 suggested that real-world escalation approaches may be inadequate to prevent unfavorable long-term outcomes.

That trial, conducted by Katharine Harding, PhD, of the Institute of Psychological Medicine and Clinical Neuroscience at the School of Medicine at Cardiff University, and colleagues, ultimately found that those in the early intensive treatment group (n = 104) had a mean 5-year change in EDSS score of 0.3 (standard deviation [SD], 1.5) compared to the moderate-efficacy DMT escalation group (n = 488), which had an EDSS score of 1.2 (SD, 1.5) that remained significant after adjustment (95% CI, –1.38 to –0.32; 

 = .002). The median time to sustained accumulation of disability for the early intensive group was 6.0 years (95% CI, 3.17 to 9.16) compared to 3.4 years (95% CI, 2.77 to 4.00) for the escalation group (

Individuals who underwent early intensive therapy were more likely to receive alemtuzumab (n = 70; 67%) than natalizumab (n = 34; 33%), while those who received high-efficacy therapy as second-line treatment (part of an escalation algorithm) were more likely to receive natalizumab (n = 43; 74%) than alemtuzumab (n = 15; 26%). In the overall cohort, 61 patients received fingolimod, and in the sensitivity analysis, 2 were reclassified to the intensive group and 59 were classified as escalated from moderate- to high-efficacy DMT. For those in the escalation group who escalated to a high-efficacy DMT as second-line treatment, the median time to sustained accumulation of disability was 3.3 years (95% CI, 1.8–5.6; comparison to the intensive group, 

REFERENCES
1. Iaffaldano P, Lucisano G, Caputo F, et al. Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract PS01.04.
2. Harding K, Williams O, Willis M, et al. Clinical outcomes of escalation vs early intensive disease-modifying therapy in patients with multiple sclerosis. 

Published online February 18, 2019. doi: 10.1001/jamaneurol.2018.4905.

Early intensive treatment was more effective in controlling disability progression over time compared with an escalation therapy approach.

Early Intensive MS Treatment Yields Better Outcomes Than Escalation Approach

“This new idea that progression in MS is present across the continuum [of disease], and is also more easily controlled earlier on, means that highly effective therapy as early as possible is a very reasonable clinical approach to patients.”

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, a number of presentations were given highlighting agents that are approved for use in patients at a variety of disease stages, ranging from clinically isolated syndrome (CIS) to secondary progressive multiple sclerosis (MS). Although MS is a field that is well-equipped with therapeutic options, the advantages of having high-efficacy therapies that can be used at almost any point in disease are somewhat obvious.

One such agent is ofatumumab (Kesimpta; Novartis), which Stephen L. Hauser, MD, professor of neurology, and director, UCSF Weill Institute for Neurosciences, and colleagues presented data on. Those findings suggest that ofatumumab is superior to teriflunomide (Aubagio; Sanofi) in newly diagnosed, treatment-naïve patients with multiple sclerosis (MS) who have low absolute relapse rates, very low MRI lesion activity, and prolonged time to disability worsening.

These findings also bring up the ongoing debate around whether early intensive (or induction) therapy or escalation therapy strategies should be utilized for patients with MS. As Hauser pointed out to 

 in this interview, the improved understanding of the role disease progression plays in the process of disease has given hints that initial or early treatment with therapies such as ofatumumab may provide better benefit.

REFERENCE
Gartner J, Hauser S, Bar-Or A, et al. Benefit-risk of ofatumumab in treatment-naïve early relapsing multiple sclerosis patients. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0192

Stephen L. Hauser, MD: Increasing Understanding of Disease Progression in MS

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, suggest that fatigue occurs in most patients with relapsing multiple sclerosis (MS) and influences daily functioning.

Presented by Lindsey L. Lair, MD, FAAN, senior Global Medical Affairs Leader-Neuroscience, Janssen Pharmaceuticals, the research aimed to measure MS fatigue and its impact on daily life in a real-world population using a survey that included that relapsing MS (RMS)-specific Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS).

On a score range from 0 to 100, higher scores indicated greater severity. Findings from the cohort of 142 patients with RMS revealed that fatigue levels are severe, with a mean FSIQ-RMS symptom domain score of 59.5 during a 7-day period.

Demographic and clinical questionnaires that included disease history and status, sleep, and social and emotional function were completed by the participants along with the FSIQ-RMS, which was administered daily for 7 days. Physical, cognitive/emotional, and coping subdomain scores were 45.1, 44.9, and 50.6, respectively, following the 7-day period.

Walking difficulties and fatigue were recorded as the 2 most impactful symptoms on daily functioning. Notably, 56% of the patient population experienced fatigue prior to MS diagnosis.

In total, 72% of patients were not currently relapsing and had a mean fatigue symptom domain score of 56.2, compared to 68 who had an active relapse. Lair and colleagues also noted that fatigue was rated the most impactful symptom on daily life by those with lower disability.

Patients without depression, which represented 56% of the population, still reported mean fatigue symptom domain scores of 53.7 compared to 67 in those with depression. Among those who reported a sleep disorder, a mean fatigue symptom domain score of 58.1 was recorded in 72% of the population. In contrast, those without a sleep disorder recorded a 63.3 mean fatigue symptom domain score.

The most common triggering factor for fatigue was heat exposure, which occurred in 82% of patients.

Disability and economic burden have both been associated with higher levels of fatigue in patients with MS. 

Another study presented at MS Virtual 2020

 revealed that patients with relapsing-remitting MS who were stratified by high levels of fatigue had greater comorbidity and economic burdens compared to those with MS who had low levels of fatigue.

The data from that study showed that the annualized number of outpatient visits, emergency room visits, and hospitalizations were greater for those with relapsing-remitting MS with high levels of fatigue compared to those with relapsing-remitting MS with low levels of fatigue.

Amy B. Sullivan, PsyD, ABPP, director of Behavioral Medicine at the Mellen Center for MS Treatment and Research at Cleveland Clinic, recently sat down with 

and discussed how she approaches fatigue in MS from a behavioral standpoint. Watch the interview below.

1. Azoulai M, Levy-Heidmann T, Morisseau V, et al. A real-world study characterizing symptoms and impacts of fatigue in US adults with relapsing multiple sclerosis using a novel disease specific scale. Presented at: MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P1004.

2. Le H, Ken-Opurum J, Maculaitis M, Sheehan J. Comorbidity and economic burdens of fatigue among patients with relapsing-remitting multiple sclerosis in the United States. Presented at: MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0857.

Patients with lower levels of disability tended to report fatigue as the most impactful symptom in daily life.

Fatigue Plays a Key Factor in Multiple Sclerosis Daily Functioning

"In the S1P class, the effects are that it starts rapidly, but they also stop rapidly. Within 1 week, lymphocytes are back to normal.”

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11-13, 2020, revealed that 

 20 mg resulted in consistently low levels of disease activity across relevant clinical and magnetic resonance imaging (MRI) outcomes in patients with relapsing-remitting multiple sclerosis (MS). The results of the study add to the already robust profile of ponesimod, which has shown efficacy against FDA-approved teriflunomide (Aubagio; Sanofi) in previous phase 3 studies.

Ponesimod, a selective sphingosine 1-phosphate receptor-1 (S1P) modulator, is designed to inhibit S1P protein activity, and in doing so, is believed to reduce the number of circulating lymphocytes that can cross the blood-brain barrier. Luc Truyen, MD, PhD, global head, Development and External Affairs-Neuroscience, Janssen Pharmaceutical, feels as though ponesimod’s design stands out among other MS treatments.

The MS treatment landscape has undergone a number of additions in the past decade and ponesimod could be the next one with its new drug application which was filed in March 2020. Truyen sat down with 

 to discuss the positives of a robust MS treatment landscape and why ponesimod stands above the rest.

The global head of Development and External Affairs-Neuroscience at Janssen Pharmaceutical detailed what makes ponesimod different from other currently FDA-approved treatments. 

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