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Author Of 1 Presentation

Biomarkers and Bioinformatics Poster Presentation

P0070 - Effect of evobrutinib, a BTK inhibitor, on immune cell and immunoglobulin levels in relapsing MS: an open-label extension to a phase II study (ID 1683)

Speakers
Presentation Number
P0070
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Evobrutinib (EVO), a highly selective Bruton’s tyrosine kinase (BTK) inhibitor, has a dual mode of action on B cells and myeloid cells involved in multiple sclerosis (MS) pathogenesis. A Phase II randomized study (NCT02975349) investigated the effect of EVO on immune cells and immunoglobulins (Ig). After a 48-week randomized, double-blind period (DBP), relapsing MS (RMS) patients treated with EVO showed no evidence of B cell depletion or clinically relevant changes in memory or mature-naïve B cell subsets. IgG levels remained stable and slight elevations and reductions, respectively, in IgA and IgM levels were observed.

Objectives

To investigate the long-term effects of EVO on B cells (total, mature-naïve and memory subsets), T cells (total, helper and cytotoxic subsets), NK cells, and Ig levels after 48 additional weeks in the ongoing open-label extension (OLE).

Methods

Adults with RMS were randomized double-blind to EVO 25 mg QD, 75 mg QD, 75 mg BID, or placebo (PBO). PBO patients switched to EVO 25mg QD at Week 24. At Week 48, all patients were OLE-eligible, and received EVO 75 mg QD (median ≈48 weeks), then 75 mg BID. Safety of EVO, including assessment of total B cell counts and Ig levels, was a secondary endpoint; effects on B cell subsets, T cells, and NK cells were exploratory. Immune cell counts were assessed at OLE Week 48 relative to DBP baseline, and Ig levels at OLE Weeks 24 and 48.

Results

Of 213 patients receiving EVO during the DBP, 164 (77%) entered the OLE and 148 (90%) completed ≥60 additional treatment weeks. Investigation of total CD19+ B cells and B cell subsets revealed a decrease in CD19+ B cells and in mature-naïve B cells in all groups originally randomized to EVO. The decrease in mature-naïve B cells was consistent with that observed for CD19+ B cell counts, however no evidence of a change in the memory B cell levels was observed. No relevant changes in IgG levels relative to DBP baseline were observed. Mean IgA and IgM levels remained increased and decreased, respectively, but mean values were within normal ranges. Furthermore, there was no evidence of a change in T or NK cell parameters. Overall, EVO treatment was not associated with an increased risk of infections.

Conclusions

Immune cell numbers and Ig levels seen in patients receiving EVO for 48 weeks of the OLE were consistent with those in the DBP. The results suggest a gradual decline of B cells over time with consistent BTK inhibition, however the clinical meaningfulness of these changes remains to be determined. The observed changes in B cells, IgA and IgM levels were not associated with an enhanced risk of infections. These findings suggest that the continuous pharmacological inhibition of BTK over 96 weeks with EVO does not lead to substantial B cell reductions or changes in Ig levels.

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Presenter Of 1 Presentation

Biomarkers and Bioinformatics Poster Presentation

P0070 - Effect of evobrutinib, a BTK inhibitor, on immune cell and immunoglobulin levels in relapsing MS: an open-label extension to a phase II study (ID 1683)

Speakers
Presentation Number
P0070
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Evobrutinib (EVO), a highly selective Bruton’s tyrosine kinase (BTK) inhibitor, has a dual mode of action on B cells and myeloid cells involved in multiple sclerosis (MS) pathogenesis. A Phase II randomized study (NCT02975349) investigated the effect of EVO on immune cells and immunoglobulins (Ig). After a 48-week randomized, double-blind period (DBP), relapsing MS (RMS) patients treated with EVO showed no evidence of B cell depletion or clinically relevant changes in memory or mature-naïve B cell subsets. IgG levels remained stable and slight elevations and reductions, respectively, in IgA and IgM levels were observed.

Objectives

To investigate the long-term effects of EVO on B cells (total, mature-naïve and memory subsets), T cells (total, helper and cytotoxic subsets), NK cells, and Ig levels after 48 additional weeks in the ongoing open-label extension (OLE).

Methods

Adults with RMS were randomized double-blind to EVO 25 mg QD, 75 mg QD, 75 mg BID, or placebo (PBO). PBO patients switched to EVO 25mg QD at Week 24. At Week 48, all patients were OLE-eligible, and received EVO 75 mg QD (median ≈48 weeks), then 75 mg BID. Safety of EVO, including assessment of total B cell counts and Ig levels, was a secondary endpoint; effects on B cell subsets, T cells, and NK cells were exploratory. Immune cell counts were assessed at OLE Week 48 relative to DBP baseline, and Ig levels at OLE Weeks 24 and 48.

Results

Of 213 patients receiving EVO during the DBP, 164 (77%) entered the OLE and 148 (90%) completed ≥60 additional treatment weeks. Investigation of total CD19+ B cells and B cell subsets revealed a decrease in CD19+ B cells and in mature-naïve B cells in all groups originally randomized to EVO. The decrease in mature-naïve B cells was consistent with that observed for CD19+ B cell counts, however no evidence of a change in the memory B cell levels was observed. No relevant changes in IgG levels relative to DBP baseline were observed. Mean IgA and IgM levels remained increased and decreased, respectively, but mean values were within normal ranges. Furthermore, there was no evidence of a change in T or NK cell parameters. Overall, EVO treatment was not associated with an increased risk of infections.

Conclusions

Immune cell numbers and Ig levels seen in patients receiving EVO for 48 weeks of the OLE were consistent with those in the DBP. The results suggest a gradual decline of B cells over time with consistent BTK inhibition, however the clinical meaningfulness of these changes remains to be determined. The observed changes in B cells, IgA and IgM levels were not associated with an enhanced risk of infections. These findings suggest that the continuous pharmacological inhibition of BTK over 96 weeks with EVO does not lead to substantial B cell reductions or changes in Ig levels.

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