Neurofilament Light Chain Levels and Disease Activity During Long-Term Treatment of Relapsing Multiple Sclerosis with the Bruton’s Tyrosine Kinase Inhibitor Evobrutinib (P1-3.011)

Field: Medicine (Health Sciences)

Objective:

To evaluate neurofilament light chain (NfL) levels, a biomarker of neuroaxonal damage, as a prognostic and a potential surrogate marker of evobrutinib treatment response (MRI and relapse outcomes) in patients with relapsing multiple sclerosis (PwRMS).

Background:

Evobrutinib is a highly selective, CNS-penetrant Bruton's tyrosine kinase inhibitor, currently in Phase III for RMS. The efficacy of evobrutinib (MRI and clinical outcomes) observed in double blind phase (DBP) of a Phase II trial (NCT02975349) in PwRMS was maintained in the open-label extension (OLE; beginning at Week [W] 48 from DBP baseline). Previous analyses of the Phase II trial showed sustained reductions in NfL levels with evobrutinib up to W144.

Design/Methods:

NfL levels were measured over time in the pooled OLE safety population and reported as control-adjusted NfL Z-scores (expression of standard deviations [SDs] away from mean NfL level in a control population [participants without evidence of CNS disease]). The number of T1 Gd+ and new/emerging T2 lesions at W96 and W144 and qualified relapses over W96–144 were assessed, stratified by W96 NfL Z-scores (<1; ≥1 [Z-score 1 being one SD above the control mean]). MRI outcomes at W48 and W96 and relapses over W48–96 were also assessed using stratified W48 NfL Z-scores [<1; ≥1].

Results:

Stratified by W96 Z-scores (<1[N=66]; ≥1[N=34]), the proportion of patients with no T1 Gd+ lesions, no new/enlarging T2 lesions (both at W144) and no relapse between W96–144 were 84.5% (n=49/58) vs 57.1% (n=16/28), 65.5% (n=38/58) vs 28.6% (n=8/28) and 95.4% (n=62/65) vs 94.1% (n=32/34), respectively. Similar findings were observed in patients stratified by W48 Z-scores (<1[N=84]; ≥1[N=40]).

Conclusions:

Evobrutinib reduced NfL levels in a sustained manner (up to W144). Low NfL levels were associated with improved MRI and relapse outcomes, supporting the role of NfL as a prognostic marker of disease activity and a potential surrogate marker for evobrutinib's treatment effect. Disclosure: Dr. Kuhle has nothing to disclose. The institution of Dr. Kappos has received research support from Bayer. The institution of Dr. Kappos has received research support from Biogen. The institution of Dr. Kappos has received research support from Genentech. The institution of Dr. Kappos has received research support from Genzyme. The institution of Dr. Kappos has received research support from Janssen. The institution of Dr. Kappos has received research support from Merck Serono. The institution of Dr. Kappos has received research support from Minoryx. The institution of Dr. Kappos has received research support from Novartis. The institution of Dr. Kappos has received research support from Roche. The institution of Dr. Kappos has received research support from Sanofi. The institution of Dr. Kappos has received research support from Santhera. The institution of Dr. Kappos has received research support from Swiss MS Society, Swiss National Research Foundation, European Union, Roche Research Foundation, Innosuisse. The institution of Dr. Kappos has received research support from Shionogi. The institution of Dr. Kappos has received research support from Japan Tobacco. The institution of Dr. Kappos has received research support from Auriga Vision AG. The institution of Dr. Kappos has received research support from EMD Serono. The institution of Dr. Kappos has received research support from Glaxo Smith Kline. The institution of Dr. Kappos has received research support from Wellmera AG. The institution of Dr. Kappos has received research support from Eli Lilly (Suisse) SA. The institution of Dr. Kappos has received research support from Bristol Myers Squibb. The institution of Dr. Kappos has received research support from Celltrion Inc. Dr. Kappos has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck/ EMD Serono. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Hoffmann-La Roche. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion/ Janssen. The institution of Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for BMS/ Celgene. The institution of Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi/ Genzyme. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion/ Janssen. Dr. Montalban has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS/ Celgene. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/ EMD Serono. Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann-La Roche. Dr. Montalban has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi-Genzyme. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic Therapeutics. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viatris/ Mylan. The institution of Dr. Montalban has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. The institution of Dr. Montalban has received research support from Biogen. The institution of Dr. Montalban has received research support from Hoffmann-La Roche. The institution of Dr. Montalban has received research support from Sanofi/ Genzyme. The institution of Dr. Montalban has received research support from Merck/ EMD Serono. The institution of Dr. Montalban has received research support from Novartis. The institution of Dr. Montalban has received research support from Teva Pharmaceuticals. The institution of Dr. Montalban has received research support from Actelion/ Janssen. The institution of Dr. Montalban has received research support from BMS/ Celgene. Pascal Benkert has nothing to disclose. Ying Li has received personal compensation for serving as an employee of EMD Serono. Karthinathan Thangavelu has received personal compensation for serving as an employee of Sanofi Genzyme. Karthinathan Thangavelu has received personal compensation for serving as an employee of EMD Serono . Dr. Hyvert has received personal compensation for serving as an employee of The healthcare business of Merck KGaA, Darmstadt, Germany. An immediate family member of Dr. Hyvert has received personal compensation for serving as an employee of The healthcare business of Merck KGaA, Darmstadt, Germany. Davorka Tomic has nothing to disclose.