EMD Serono
Global Clinical Development Center

Author Of 2 Presentations

Clinical Trials Poster Presentation

P0197 - Clinical relapse rates in relapsing MS patients treated with the BTK inhibitor evobrutinib: results of an open-label extension to a Phase II study (ID 1127)

Speakers
Presentation Number
P0197
Presentation Topic
Clinical Trials

Abstract

Background

Evobrutinib (EVO) is a highly selective Bruton’s tyrosine kinase inhibitor (BTKI) with a dual mode of action targeting both B cells and myeloid cells, which are known to play a key role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Clinical efficacy of EVO in relapsing MS was shown in a Phase II randomized controlled trial (RCT; NCT02975349) with a significant reduction of T1 Gd-enhancing lesions compared to placebo at Week 24 (the primary endpoint of the study) and continued efficacy through Week 48.

Objectives

To report the long-term efficacy of EVO measured as the annualized relapse rate [ARR]), cumulative probability of and time to qualified relapse (QR, change in neurological symptoms or expanded disability status scale score increase attributed to MS lasting ≥24 hours preceded by a stable or improving neurological status ≥30 days).

Methods

In the 48-week double-blind period (DBP), patients received EVO 25mg once daily (QD), 75mg QD, 75mg BID or placebo (PBO) for the first 24 weeks; all arms continued with the original treatment assignment until 48 weeks, except PBO patients who were switched to EVO 25mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75mg QD (for a median of ≈48 weeks) before switching to 75mg BID. Long-term efficacy of EVO was assessed at up to 60 weeks of OLE.

Results

Of 213 patients randomized to EVO or PBO, 164 (77%) entered the OLE; of these 148 (90%) completed 108 weeks of treatment. For patients initially receiving PBO or EVO 25mg QD, 75mg QD or 75mg BID in the DBP, ARR (95% CI) was 0.37 (0.21, 0.59), 0.52 (0.33, 0.78), 0.25 (0.12, 0.44) and 0.11 (0.04, 0.25), respectively, at Week 48, and 0.31 (0.21, 0.45), 0.37 (0.25, 0.52), 0.18 (0.10, 0.29) and 0.12 (0.06, 0.22) at Week 108. The cumulative probability of QR in these groups was 0.26 (0.14, 0.38), 0.24 (0.12, 0.36), 0.15 (0.05, 0.25) and 0.08 (0.00, 0.16) at Week 48, and 0.39 (0.25, 0.53), 0.34 (0.20, 0.48), 0.25 (0.12, 0.38) and 0.20 (0.08, 0.31) at Week 96, respectively. The estimated time from randomization by which 20% of patients had a qualified relapse was almost three times longer for patients initiated in the DBP with EVO 75mg BID (827 days [327, not evaluable]) than for patients initiated in the DBP with PBO (281 days [99, 407]) and longer than for patients initiated in the DBP with EVO 25mg QD (166 days [61, 606]) and 75mg QD (530 days [244, 838]). EVO was generally well tolerated, with the safety profile maintained during the 60-week OLE.

Conclusions

With EVO 75mg BID, the efficacy (ARR, 0.11) at Week 48 was maintained at 108 weeks. Probability of and time to QR highlighted that, despite switching to EVO 75mg QD/BID in OLE, patients initiated in the DBP on EVO 25mg QD, 75mg QD or PBO did not achieve the same level of efficacy of those initiated in the DBP on 75mg BID. The maximum efficacy observed at the 75mg BID dose correlated with optimal BTK occupancy achieved with BID dosing.

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Clinical Trials Poster Presentation

P0235 - Safety of the Bruton’s tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis during an open-label extension to a phase II study (ID 1687)

Speakers
Presentation Number
P0235
Presentation Topic
Clinical Trials

Abstract

Background

In a Phase II randomized study (NCT02975349) in patients with relapsing MS, evobrutinib (EVO) 75 mg twice-daily (BID) reduced total T1 Gd+ lesions (primary endpoint) and annualized relapse rate (ARR) over 24 weeks versus placebo, with efficacy maintained through Week 108. EVO was generally well tolerated.

Objectives

To describe the safety profile of EVO in the long-term treatment of MS by reporting detailed safety data from the study’s open-label extension (OLE) over 60 weeks.

Methods

In the 48-week double-blind period (DBP), patients received EVO 25 mg once-daily (QD) or 75 mg QD, 75 mg BID, or placebo for the first 24 weeks. All arms continued with the original treatment assignment until 48 weeks, except placebo patients who were switched to EVO 25 mg QD. At Week 48, all patients could enter the OLE, where treatment was initially EVO 75 mg QD (for a median of ~48 weeks) before switching to 75 mg BID. Safety was assessed throughout the OLE by the nature, severity, and occurrence of treatment emergent adverse events (TEAEs) by NCI-CTCAE v4.03 criteria, as well as vital signs, ECGs, and clinical laboratory safety parameters.

Results

Of 213 patients who received EVO during the double-blind period, 164 (77%) entered the OLE (safety analysis population) and 148 (90%) completed 60 weeks of treatment. Overall, 107 (65.2%) patients had a treatment emergent adverse event (TEAE), the majority of which were mild (47.6%) or moderate (36.0%), and none led to death. TEAEs were balanced across previous DBP treatment groups; the most frequent TEAEs over the OLE period, including the dose-switch, were nasopharyngitis (7.9%, Grade 2 or less), increased lipase (7.9%, Grade 3 or less), upper respiratory tract infection (6.1%, Grade 2 or less), and urinary tract infection (4.9%, Grade 2 or less); analysis of TEAEs by exposure-adjusted incidence rate showed no evidence of an increase after patients switched to 75 mg BID. Thirteen patients (7.9%) reported a serious TEAE, most frequently related to infections (6 patients, not treatment-related). Five patients (3.0%) had a TEAE during the OLE that led to treatment withdrawal, of which 3 were considered related to treatment (nausea, increased lipase, and increased lipase and amylase). The incidence of overall infections in the OLE was similar to that observed in the DBP. Transient elevated liver aminotransferases reported in the 48-week DBP were not observed in the OLE after prolonged treatment or after the switch to 75 mg BID. No adverse ECG findings were noted across all evobrutinib groups. There was also no apparent effect of EVO dose received in the DBP on safety parameters in the OLE.

Conclusions

In a 60 week OLE period of a Phase II study, the safety of EVO was similar to that seen in the DBP. Overall, long-term EVO treatment was generally well tolerated in patients with relapsing MS.

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