Background

Since the first report of coronavirus disease (COVID-19) in late 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease quickly became a pandemic with a variety of clinical presentations, including death.

The risk of COVID-19 for patients with multiple sclerosis (MS) receiving interferon beta-1b (IFN β-1b) has been unclear.

In the absence of specific antiviral agents, IFN β has been suggested as a potential therapeutic option for COVID-19 based on its immunomodulatory and antiviral properties. In preclinical studies, IFN β has shown antiviral activities against coronavirus in Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome, but currently there is no clinical data supporting its therapeutic use in COVID-19 patients.

Objectives

The objective of our study is to review the current safety data on IFN β-1b in MS and non-MS patients impacted by COVID-19.

Methods

Retrospective data on IFN β-1b case reports with mention of COVID-19 were extracted from Bayer’s pharmacovigilance (PV) database through July 29, 2020.

Results

A total of 109 cases mentioned COVID-19, which included 75 MS patients (68.8%) and 34 non-MS patients (31.2%) who received IFN β-1b.

Of the 75 MS patients, 23 (30.7%) were diagnosed with COVID-19 (median 49 years; range 27-65 years). No relevant drug-related adverse events (AE) were reported. Two patients (2.7% of 75, 8.7% of 23; ages 42 and 49 years) died due to COVID-19. The 52 patients (69.3%) with no evidence of COVID-19 reported being negatively impacted with depression, anxiety, and difficulty accessing medical care for MS exacerbations and other health conditions.

Of the 34 non-MS patients who received IFN β-1b for experimental COVID-19 treatment, AEs were reported in 19 (55.8%). The most frequently reported AEs were associated with hepatic impairment such as hepatitis, mixed liver injury, hyperbilirubinemia, and increased hepatic enzyme. These events are appropriately reflected in the reference safety information. In almost all cases, IFN β-1b was concomitantly used with other antiviral drugs. Seven patients (20.6%) died due to COVID-19 (median 71 years; range 64-79 years) but IFN β-1b use was not implicated. Five patients (14.7%) reported non-approved route of administration (sublingual), however no AEs were associated with this method.

Conclusions

Our study revealed a small portion of MS patients using IFN β-1b who became infected with SARS-CoV-2 or developed COVID-19.

Although underreporting is a known limitation of PV data, our findings are in accordance with the published low incidence of COVID-19 in IFN β-treated MS population. Future serum anti-SARS-CoV-2 antibody tests may determine the number of asymptomatic COVID-19 IFN-b-1b-treated MS patients.

AEs reported in IFN β-1b-treated COVID-19 patients are consistent with the established safety profile. No new safety concerns were observed in MS or non-MS COVID-19 patients treated with IFN β-1b.

Background

In the pivotal trials of ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis (RRMS; OPERA I, OPERA II), ≈75% of participants had no previous disease-modifying therapy (DMT).

Objectives

To report 2-year findings from the Phase IIIb CHORDS study (NCT02637856) investigating OCR in patients with RRMS who had a suboptimal response with previous DMT.

Methods

CHORDS enrolled patients who had a suboptimal response (≥1 relapse, ≥1 T1 gadolinium [Gd]-enhancing lesion or ≥2 new/enlarging T2 lesions) after ≥6 months of treatment with 1 to 3 previous DMTs. All participants received OCR 600 mg every 24 weeks for 96 weeks and were included in the intention-to-treat (ITT) population. Annualized relapse rate (ARR), changes in Expanded Disability Status Scale (EDSS) and safety were assessed in the ITT population. The primary endpoint was the proportion of patients free of any protocol-defined event (i.e. relapse, T1 Gd-enhancing lesion, new/enlarging T2 lesion, 24-week confirmed disability progression [CDP] on the EDSS) and was evaluated using a modified ITT (mITT) population, which imputed as having an event those patients who terminated early for lack of efficacy or death and excluded patients who discontinued for reasons other than an event.

Results

The ITT population included 608 patients with a mean (SD) time since diagnosis of 4.2 (3.03) years. The most frequently used DMTs prior to enrollment included glatiramer acetate (49.3%), dimethyl fumarate (35.4%) and fingolimod (20.1%). In the mITT population (576 [94.7%]), 48.1% of patients were free of all protocol-defined events, and most experienced freedom from individual events (relapse, 89.6%; T1 Gd-enhancing lesions, 95.5%; new/enlarging T2 lesions, 59.5%; 24-week CDP, 89.6%) over 96 weeks. Similar results were observed for the primary endpoint in those who received 1 vs >1 prior DMT (50.9% vs 44.5%) as well as for individual events (relapse, 90.0% vs 89.2%; T1 Gd-enhancing lesion, 95.8% vs 95.1%; new/enlarging T2 lesion, 61.4% vs 57.1%; 24-week CDP, 90.9% vs 87.9%). The adjusted ARR over 96 weeks was 0.046. Most patients had stable (<1-point change; 61.5%) or improved (≥1-point decrease; 22.7%) EDSS scores. There were no deaths or new safety signals.

Conclusions

This analysis demonstrates the potential benefits of ocrelizumab treatment over 2 years in patients with RRMS who are relatively early in the disease course and have experienced suboptimal response on prior DMTs.

Background

Minority patients with multiple sclerosis (MS), including those of African ancestry (AA) and Hispanic and Latino ethnicity (HA), have greater disease severity and faster progression than Whites. Minorities are vastly underrepresented in clinical trials, owing to poor access and cultural, economic and other participation barriers. Ocrelizumab (OCR), an anti-CD20 therapy targeting B cells, reduced the rates of disease activity and progression in patients with relapsing MS (RMS) and primary progressive MS in pivotal studies; however, minority participation was <10%.

Objectives

To investigate the efficacy and safety of OCR in AA and HA patients with RMS (2017 McDonald criteria) who meet the US prescribing information criteria in a single-arm Phase IV clinical study designed exclusively to meet the needs of these specific demographic groups.

Methods

An industry-sponsored collaborative approach rooted in minority needs and known knowledge gaps was used.

Results

Key differences between CHIMES (NCT04377555) and other MS trials are as follows:

1. CHIMES was developed in collaboration with patients with MS, patient advocacy groups and investigators.

2. Inclusion criteria allow for ≈150–200 participants with specific, well-controlled, pre-existing comorbidities and baseline creatinine levels within race-specific limits; these factors may disproportionately limit minority patient qualification in other trials.

3. OCR was chosen because of the indications that AA patients with MS may have greater B-cell–mediated pathology, such as a higher CSF IgG index.

4. Written materials will be available in English and Spanish and will be reviewed by a minority patient panel to ensure that they are easy to understand.

5. To enable early results, the primary endpoint is disease activity, defined by the proportion of patients free of protocol-defined events (clinical relapses, CDP or MRI activity) at the end of year 1.

6. All patients may participate in the second-year extension to study disease progression and various biomarker endpoints.

7. One-third of patients will participate in a substudy to assess CSF-specific biomarkers at two time points.

Conclusions

Findings from CHIMES are expected to improve current understanding of MS disease biology, treatment response and clinical trial participation among AA and HA patients with MS, with the ultimate goals of increasing high-quality standard of care to traditionally underserved populations and enhancing equality through clinical research.

Background

Since the first report of coronavirus disease (COVID-19) in late 2019 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease quickly became a pandemic with a variety of clinical presentations, including death.

The risk of COVID-19 for patients with multiple sclerosis (MS) receiving interferon beta-1b (IFN β-1b) has been unclear.

In the absence of specific antiviral agents, IFN β has been suggested as a potential therapeutic option for COVID-19 based on its immunomodulatory and antiviral properties. In preclinical studies, IFN β has shown antiviral activities against coronavirus in Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome, but currently there is no clinical data supporting its therapeutic use in COVID-19 patients.

Objectives

The objective of our study is to review the current safety data on IFN β-1b in MS and non-MS patients impacted by COVID-19.

Methods

Retrospective data on IFN β-1b case reports with mention of COVID-19 were extracted from Bayer’s pharmacovigilance (PV) database through July 29, 2020.

Results

A total of 109 cases mentioned COVID-19, which included 75 MS patients (68.8%) and 34 non-MS patients (31.2%) who received IFN β-1b.

Of the 75 MS patients, 23 (30.7%) were diagnosed with COVID-19 (median 49 years; range 27-65 years). No relevant drug-related adverse events (AE) were reported. Two patients (2.7% of 75, 8.7% of 23; ages 42 and 49 years) died due to COVID-19. The 52 patients (69.3%) with no evidence of COVID-19 reported being negatively impacted with depression, anxiety, and difficulty accessing medical care for MS exacerbations and other health conditions.

Of the 34 non-MS patients who received IFN β-1b for experimental COVID-19 treatment, AEs were reported in 19 (55.8%). The most frequently reported AEs were associated with hepatic impairment such as hepatitis, mixed liver injury, hyperbilirubinemia, and increased hepatic enzyme. These events are appropriately reflected in the reference safety information. In almost all cases, IFN β-1b was concomitantly used with other antiviral drugs. Seven patients (20.6%) died due to COVID-19 (median 71 years; range 64-79 years) but IFN β-1b use was not implicated. Five patients (14.7%) reported non-approved route of administration (sublingual), however no AEs were associated with this method.

Conclusions

Our study revealed a small portion of MS patients using IFN β-1b who became infected with SARS-CoV-2 or developed COVID-19.

Although underreporting is a known limitation of PV data, our findings are in accordance with the published low incidence of COVID-19 in IFN β-treated MS population. Future serum anti-SARS-CoV-2 antibody tests may determine the number of asymptomatic COVID-19 IFN-b-1b-treated MS patients.

AEs reported in IFN β-1b-treated COVID-19 patients are consistent with the established safety profile. No new safety concerns were observed in MS or non-MS COVID-19 patients treated with IFN β-1b.

Background

Background: Adrenocorticotropic hormone (ACTH) is an alternative to corticosteroid therapy to treat relapses in Multiple Sclerosis. ACTH stimulate low levels of corticosteroid release from the adrenal glands, but it also works through the melanocortin system to induce anti-inflammatory, neuroprotective, osteoprotective, and analgesic effects specific to ACTH by binding to melanocortin receptors (MCR). Although cortisol and cortisol receptor levels have been examined extensively in MS, ACTH effects on MCR expression and on regulatory immune cells have not been examined, particularly in patients undergoing MRI-confirmed MS relapses.

Objectives

Objectives: To elucidate if ACTHAR administration causes changes in MRI scans, modifies expression of MCR acutely and long-term in MS, or changes regulatory subsets, acutely or long-term.

Methods

Methods: Six MS patients with acute clinical exacerbations and active contrast-enhancing lesions were given a 10-day course of subcutaneous ACTHAR (80 units/day). Blood was drawn from patients at baseline, 10 days, and 1, 3, 6, and 12 months post ACTHAR injections. MRIs were performed at baseline and months 3, 6, and 12. Mononuclear cells (MNCs) were isolated from the blood using Lympholyte FICOL gradient separation and frozen. MNC were stained for MCRs 1,3, and 5 with newly-developed assays, and for CD8+CD28- and CD4+FOXP3+ regulatory T cells (Tregs) for flow cytometry with a Fortessa 4-15 analyzer.

Results

Results: MCRs, 3>1>5 (%) and 1>3>5 (expression) on MNC at baseline, were highly variable after depot ACTH. CD8 Tregs as % of lymphocytes did not change acutely or long-term. However, CD8+CD28+ cytolytic cells (CTL) decreased at 1 month (8.15%) compared to baseline (14.6%; p=0.046, paired t-test, n = 5). 3/6 patients also had a new T2 and/or contrast-enhancing MRI lesions at month 1.

Conclusions

Conclusions: ACTHAR may decrease potentially MS-toxic CD8 CTLs at 1 month post-administration, due to direct effects or to induction of corticosteroids. There were no clear changes in MCRs and T regulatory populations. A 10-day course of ACTHAR was not enough to completely suppress MRI activity in some of patients at month 1. A longer duration of ACTHAR treatment is probably required for further suppression of MRI activity and greater control of immune cell activity.