Background

CLARITY, CLARITY Extension, and ORACLE-MS have previously demonstrated the efficacy of cladribine tablets (CT; cumulative dose 3.5 mg/kg over 2 years). CLASSIC-MS (NCT03961204) seeks to explore the long-term efficacy and durability of effect of CT beyond the 2 annual treatment cycles in patients (pts) enrolled to these parent trials, with the aim of informing future treatment approaches.

Objectives

To present interim data on long-term efficacy and durability of effect of CT and real-world treatment patterns in CLASSIC-MS.

Methods

CLASSIC-MS is an exploratory, low-interventional, multicenter, ambispective, Phase IV study of pts with multiple sclerosis (MS), or those with a first clinical demyelinating event, previously enrolled into Phase III parent trials, and who had received ≥1 course of CT or placebo. The primary objective is long-term mobility (no wheelchair use/bedridden; EDSS <7 in the 3 months prior to first visit in CLASSIC-MS). The main secondary objective is long-term disability status (EDSS <6 any time since last parent study dose [LPSD]). Further objectives seek to assess differences in clinical and magnetic resonance imaging characteristics in long-term responders vs non-responders, with long-term responder status defined as: (A) not requiring further disease-modifying drug (DMD) treatment until ≥4 years after LPSD, or (B) no evidence of disease reactivation based on clinical outcomes in the 4 years following LPSD. Analyses are descriptive.

Results

The interim population comprised 147 pts (61% female; 88% exposed to CT in parent studies; mean EDSS 3.3±2.1 at baseline of CLASSIC-MS [vs. 2.6±1.2 at baseline of parent studies]). Median time since LPSD was 10 (range 8–14) years. The proportion of pts not using a wheelchair/bedridden in the 3 months prior to CLASSIC-MS was 94.6% (139/147) and the proportion of pts with no need of ambulatory device at any time since LPSD was 83.7% (EDSS <6; 123/147). Overall, 73.5% of pts (108/147) were long-term responders by definition A and 45.6% by definition B. In addition, 63.3% of pts (93/147) received no subsequent DMD treatment after LPSD, and 59.1% of pts maintained active employment.

Conclusions

Interim data from CLASSIC-MS, with a median of 10 years’ follow-up, suggests sustained efficacy of CT following 2 annual treatment cycles, with a substantial proportion of pts requiring no further treatment with DMDs or assistive ambulatory device.

CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE: NCT00725985

Funding: This study was sponsored by Merck KGaA, Darmstadt, Germany.

Background

In CLARITY and CLARITY Extension (NCT00213135 and NCT00641537, respectively), treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates in patients with relapsing-remitting multiple sclerosis. Moreover, in the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by treatment with placebo for 2 years produced similar clinical benefits to 2 years of cladribine tablets treatment followed by an additional 2 years of treatment, but with a lower risk of higher grade lymphopenia.

Objectives

To assess, post hoc, the temporal occurrence of relapses up to 5 years after treatment initiation with cladribine tablets.

Methods

Patients enrolled into CLARITY treated with CT3.5, and those subsequently receiving CT3.5 (CC7) or placebo (CP3.5) in CLARITY Extension, were included for analysis. The main endpoint was all qualifying relapses reported in CLARITY or CLARITY Extension plus those that occurred during the variable bridging interval (range: 1 day to 118 weeks). A recurrent event analysis was performed to estimate mean cumulative number of relapses over time using a cumulative mean function estimate.

Results

A total of 433 patients from CLARITY treated with CT3.5 were included in this analysis; of these 284 patients entered CLARITY Extension (CP3.5, n=98; CC7, n=186). Recurrent event analysis for the CT3.5 population showed that annual increase in mean cumulative number of relapses was consistently low from Year 2 to Year 5 (range: 0.10–0.15) and was slightly higher in Year 1 (0.17); the 6-month increase in mean cumulative number of relapses was similar in the first 6 months and the second 6 months (0.08 and 0.09, respectively). There were no differences in mean cumulative number of relapses between the CP3.5 and CC7 groups from Year 2 to Year 5. In recurrent event analysis for the CT3.5 population, the yearly increments of mean cumulative function were constant and low from the second treatment to Year 5, supporting the durable efficacy of cladribine tablets (given no increase in relapses following completion of the two courses of cladribine tablets).

Conclusions

Annual increase in mean cumulative number of relapses occurred at a low annualized rate of 0.10 to 0.17 per year to 5 years, almost 4 years after the last dose of cladribine tablets and therefore consistent with durable efficacy. Results also support the early effect of cladribine tablets on relapses, which is apparent in the first year of treatment.

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

Tolerability and adherence to disease-modifying drugs (DMDs) can be influenced by treatment-emergent adverse events (TEAEs) that start shortly after therapy initiation. One potential advantage of cladribine tablets is its short treatment course which may limit TEAEs; patients who receive the approved 3.5 mg/kg dosage only receive doses for two 4 to 5-day periods per treatment year.

Objectives

To identify TEAEs early in the course of treatment in patients enrolled in the Phase 3 CLARITY and ORACLE-MS clinical trials.

Methods

This was a post hoc analysis of safety populations in CLARITY and ORACLE-MS studies. Patients received cladribine tablets 3.5 mg/kg (cumulative dose over 2 years; N=636) or placebo (N=641). The incidence of early adverse events, TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation were summarized based on incidence within 2, 6, and 12 weeks (Wk) after commencement of therapy.

Results

The incidence of TEAEs occurring within the first 2–12Wk of treatment across both trials in both treatment groups was generally low, and the majority of events were mild (placebo: 53.8–68.4%; cladribine tablets: 54.4–68.0%). The most common TEAEs by time epoch after initiating placebo and cladribine tablets 3.5 mg/kg treatment, respectively, were: nausea: 3.3% vs. 4.9% (2Wk), 3.7% vs. 6.4% (6Wk), and 4.5% vs. 8.0% (12Wk); fatigue: 2.0% vs. 1.4% (2Wk), 3.1% vs. 2.5% (6Wk), and 4.4% vs. 3.1% (12Wk); headache: 8.3% vs. 9.0% (2Wk), 11.9% vs. 14.8% (6Wk), and 15.1% vs. 18.4% (12Wk); lymphopenia: 0.0% vs. 2.5% (6Wk) and 0.5% vs. 6.8% (12Wk); leukopenia: 0.0% vs. 1.3% (12Wk). Other endpoints will be shown in the final presentation.

Conclusions

Incidence of TEAEs experienced during the first 12 weeks of treatment with cladribine tablets 3.5 mg/kg in Phase 3 clinical trials was low and mostly mild. Nausea, headache, and lymphopenia were seen more frequently in cladribine tablets-treated patients versus those in the placebo group. These findings suggest that cladribine tablets are generally well tolerated, which may facilitate treatment adherence.

Background

Several integrated analyses have reported on the safety of cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years [CT3.5]) during clinical development for the treatment of patients with relapsing multiple sclerosis (RMS). Additional real-life safety data have accrued since the approval of CT3.5 in many countries worldwide. In recent months the COVID-19 pandemic has become a concern for MS patients and their healthcare providers in terms of the associated safety of their disease-modifying therapy.

Objectives

To update on the post-approval safety profile of CT3.5 in patients with RMS, including COVID-19 and other respiratory viral infections.

Methods

Serious and non-serious adverse events (AEs) from post-approval sources (including spontaneous individual case safety reports, non-interventional post-marketing studies, and reports from other solicited sources) are presented to Jan 2020. AE rates are shown as crude incidences (events/number of patients). Up-to-date COVID-19 findings are summarized.

Results

A total of 2570 AEs were reported for the first 14,813 patients who received CT3.5 post-approval; 303 (12%) events were classified as serious and none represented a new safety signal. Crude incidences for AEs of special interest were as follows: severe lymphopenia, 0.002; herpes zoster, 0.008; tuberculosis, 0.0004; severe infections, 0.009; progressive multifocal leukoencephalopathy, 0; opportunistic infections, 0.001; malignancies, 0.0015; and teratogenicity, 0. The majority of opportunistic infections were superficial dermal and mucosal fungal infections that resolved on standard treatments.

The pattern of respiratory viral infections (typically non-serious) with post-approval use of CT3.5 was also consistent with that from the clinical development program; crude incidences were as follows: influenza, 0.005; viral infection, 0.002; and viral upper respiratory tract infection, 0.0004. As of 29 Jun 2020, the Merck safety database included 18 cases of confirmed COVID-19 in CT3.5-treated patients. An update on latest findings on COVID-19 infections will be presented, including analysis of time of infection since treatment where available.

Conclusions

No new safety signals were identified in the real-world post-approval data of CT3.5, cumulative to Jan 2020. The safety profile of CT3.5, including respiratory viral infections, is consistent with previously published integrated safety analyses of the clinical development data.

Background

Evidence suggests that healthcare providers specializing in MS (HCP-MS) face an evolving treatment and clinical landscape, with a patient population who requires advanced care to manage the many facets of their condition. In this context, the gaps in knowledge, skill and confidence that may impact HCP-MS’ ability to make clinical decisions and optimize patient care need to be assessed.

Objectives

To assess HCP-MS’ clinical practice gaps and challenges, their associated causes, and impact on the care of people with MS.

Methods

In a mixed-methods study, 333 neurologists and 135 advanced practice nurses in Canada, France, Germany, Italy, Spain, the United Kingdom and the United States were interviewed or surveyed. Qualitative data were analysed thematically. Quantitative data were analysed using ANOVA and Chi-squares for comparison by country, years of experience, practice setting and MS certification status. Results were triangulated with data from the literature.

Results

Qualitative data indicate current guidelines are perceived as insufficient to manage the complex needs of people with MS. Tests of cognitive function are perceived as time-consuming, potentially inaccurate, and should preferably be administered by rehabilitation specialists or psychiatrists. Survey data indicate 42% of neurologists and 61% of nurses have no or only basic skills in administering such tests. A further 44% and 67%, respectively, have no/basic skills interpreting these tests. HCP-MS reported additional factors that may impede clinical decision-making for optimal personalized care. Thirty-nine percent of neurologists (higher in the UK, Canada and Italy, p<.05) and 44% of nurses report no/basic skills integrating patient goals into treatment recommendations. No/basic skills to make decisions about disease modifying treatment (DMT) sequencing was reported by 28% of neurologists and 62% of nurses. Some adverse events were considered challenging: HCP-MS reported no/basic skills identifying (51%) and managing (61%) infections, and no/basic skills identifying (47%) and managing (56%) cardiac issues.

Conclusions

HCP-MS face significant challenges trying to provide best care to people with MS. There appears to be a need to improve skills in cognitive testing, DMT decision-making, treatment monitoring, and patient communication. Professional development activities should focus on the heterogeneity of MS presentations and optimize different competencies required.

Disclosure: This project has been supported by educational funds from Merck KGaA, Darmstadt, Germany.

Background

CLARITY, CLARITY Extension, and ORACLE-MS have previously demonstrated the efficacy of cladribine tablets (CT; cumulative dose 3.5 mg/kg over 2 years). CLASSIC-MS (NCT03961204) seeks to explore the long-term efficacy and durability of effect of CT beyond the 2 annual treatment cycles in patients (pts) enrolled to these parent trials, with the aim of informing future treatment approaches.

Objectives

To present interim data on long-term efficacy and durability of effect of CT and real-world treatment patterns in CLASSIC-MS.

Methods

CLASSIC-MS is an exploratory, low-interventional, multicenter, ambispective, Phase IV study of pts with multiple sclerosis (MS), or those with a first clinical demyelinating event, previously enrolled into Phase III parent trials, and who had received ≥1 course of CT or placebo. The primary objective is long-term mobility (no wheelchair use/bedridden; EDSS <7 in the 3 months prior to first visit in CLASSIC-MS). The main secondary objective is long-term disability status (EDSS <6 any time since last parent study dose [LPSD]). Further objectives seek to assess differences in clinical and magnetic resonance imaging characteristics in long-term responders vs non-responders, with long-term responder status defined as: (A) not requiring further disease-modifying drug (DMD) treatment until ≥4 years after LPSD, or (B) no evidence of disease reactivation based on clinical outcomes in the 4 years following LPSD. Analyses are descriptive.

Results

The interim population comprised 147 pts (61% female; 88% exposed to CT in parent studies; mean EDSS 3.3±2.1 at baseline of CLASSIC-MS [vs. 2.6±1.2 at baseline of parent studies]). Median time since LPSD was 10 (range 8–14) years. The proportion of pts not using a wheelchair/bedridden in the 3 months prior to CLASSIC-MS was 94.6% (139/147) and the proportion of pts with no need of ambulatory device at any time since LPSD was 83.7% (EDSS <6; 123/147). Overall, 73.5% of pts (108/147) were long-term responders by definition A and 45.6% by definition B. In addition, 63.3% of pts (93/147) received no subsequent DMD treatment after LPSD, and 59.1% of pts maintained active employment.

Conclusions

Interim data from CLASSIC-MS, with a median of 10 years’ follow-up, suggests sustained efficacy of CT following 2 annual treatment cycles, with a substantial proportion of pts requiring no further treatment with DMDs or assistive ambulatory device.

CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE: NCT00725985

Funding: This study was sponsored by Merck KGaA, Darmstadt, Germany.