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.

Background

Multiple sclerosis is a chronic disease of the central nervous system, most often with relapsing-remitting (RRMS) course.

Cladribine tablets was tested against placebo in randomized controlled trials (RCT) in RRMS.

As there is lack of head-to-head trials directly comparing CT to other highly active DMTs, an indirect comparison via network meta-analysis (NMA) was performed with placebo as a common comparator.

Objectives

To compare probabilities of sustained disability improvement (SDI) on the EDSS, in patients with relapsing-remitting multiple sclerosis (RRMS), treated with cladribine tablets (CT) or fingolimod (FIN), natalizumab (NAT), alemtuzumab (ALE) and ocrelizumab (OCR).

Methods

In compliance with the Polish HTA guidelines, a systematic review was conducted in Pubmed, Embase and Cochrane to identify clinical trials (RCT or non-RCT) evaluating 6-month SDI. An indirect comparison via network meta-analysis (NMA) was performed. Bayesian inference with Markov chains Monte Carlo methods were applied, using the WinBUGS© software.

Results

Finally, 6 trials presenting SDI results and applicable for NMA were included: 5 non-RCTs, with control groups selected by propensity score matching (Kalincik 2018, Kalincik 2015, Kalincik 2017, Barnocini 2016, Guger 2018) and 1 RCT (CARE MS II), allowing for comparison of CT vs FIN, NAT, ALE. Due to the lack of proper data, comparison with OCR was not possible. Additionally, there were only 37 patients treated with CT with SDI data available (Kalincik 2018). NMA results revealed that Hazard Ratios (95% CrI) for achieving 6-month SDI with CT was statistically significantly higher in comparison with all other high efficacy disease modifying treatments studied in this analysis: CT vs FIN – 5,17 (1,81; 15,01), CT vs NAT – 3,06 (1,06; 8,62), CT vs ALE – 9,45 (2,79; 31,94).

Conclusions

Cladribine tablets treatment was associated with higher probability of sustained recovery from disability compared to fingolimod, natalizumab and alemtuzumab in RRMS patients with highly active disease. The conclusion is based on limited quality of identified clinical data.