Bruton’s tyrosine kinase inhibitors: a promising emerging treatment option for multiple sclerosis

Figures & data

Figure 1. BTK signal transduction pathways. After BCR is activated by phosphorylation, it recruits spleen tyrosine kinase (SYK) to the membrane where it is phosphorylated and subsequently phosphorylates Bruton’s tyrosine kinase (BTK). Phosphorylated BTK is recruited to the plasma membrane via autophosphorylation of Tyr223 in the SRC homology domain, and phosphorylates PLCγ2. Activated PLCγ2 hydrolyzes phosphatidyl inositol 4,5-biphosphate (PIP2), which results in the generation of inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 upregulates calcium levels and DAG mediates activation of protein kinase Cβ (PKCβ). Increased of calcium levels, activation of PLCγ2, and PKCβ in turn promote the activation of the NF-κB-, ERK-, and NFAT-dependent pathways, which control the transcriptional expression of genes involved in proliferation, survival and cytokines secretion. In order to facilitate the understanding of the figure, some intermediate pathways have not been drawn. Ag: antigen; BCAP: B cell adaptor for PI3K; BCR: B cell receptor; BLNK: B cell linker; BTK: Bruton’s tyrosine kinase; DAG: diacylglycerol; ERK: extracellular-signal-regulated kinase; Igα/Igβ: signal transduction moiety (CD79); IKK: IκB kinase; IP3: inositol 1,4,5-triphosphate; NFAT: nuclear factor of activated T cells; NF-κB: nuclear factor κB; PKCβ: protein kinase Cβ; PLCγ2: phospholipase C-γ2. SYK: spleen tyrosine kina

Table 1. Bruton’s Tyrosine Kinase inhibitor emerging drugs for the MS treatment

Compound	Company	Structure	Indication	Stage of development	Mechanism of action
SAR442168 Oral ClinicalTrials.gov Identifier: NCT03889639	Sanofi	•Allocation: Randomized •Control group: placebo •Intervention Model: Crossover Assignment •Masking: Double (Participant, Investigator) •Primary Purpose: Treatment (dose-finding Study) •Primary Objective: new Gd-enhancing lesions on MRI •Secondary Objectives: new T2 lesions and safety	Relapsing MS	Study Type: Interventional Phase: 2b Enrollment: 128 Recruitment Status: completed	Bruton’s Tyrosine Kinase Inhibitor
M2951 Other Name: Evobrutinib Oral ClinicalTrials.gov Identifier: NCT02975349	EMD Serono Collaborator: Merck KGaA,	•Allocation: Randomized •Control group: placebo, dimethyl fumarate •Intervention Model: Parallel Assignment •Masking: Double (Investigator, Outcomes Assessor) •Primary Purpose: Treatment (safety and effectiveness) •Primary Objective: new Gd-enhancing lesions on MRI •Secondary Objectives: ARR, EDSS, new T2 lesions and safety	Relapsing MS	Study Type: Interventional Phase: 2 Enrollment: 267 Recruitment Status: Active, not recruiting	Bruton’s Tyrosine Kinase Inhibitor
SAR442168 Oral ClinicalTrials.gov Identifier: NCT04410991	Sanofi	•Allocation: Randomized •Control group: placebo, teriflunomide •Intervention Model: Parallel Assignment •Masking: Triple (Participant, Investigator, Outcomes Assessor) •Primary Purpose: Treatment (Efficacy and Safety) •Primary Objective: AAR •Secondary Objectives: EDSS, MRI (new or Gd) lesions and safety	Relapsing MS	Study Type: Interventional Phase: 3 Estimated enrollment: 900 Recruitment Status: Active, recruiting	Bruton’s Tyrosine Kinase Inhibitor
SAR442168 Oral ClinicalTrials.gov Identifier: NCT04410978	Sanofi	•Allocation: Randomized •Control group: placebo, teriflunomide •Intervention Model: Parallel Assignment •Masking: Triple (Participant, Investigator, Outcomes Assessor) •Primary Purpose: Treatment (Efficacy and Safety) •Primary Objective: AAR •Secondary Objectives: EDSS, MRI (new or Gd) lesions and safety	Relapsing MS	Study Type: Interventional Phase: 3 Estimated enrollment: 900 Recruitment Status: Active, recruiting	Bruton’s Tyrosine Kinase Inhibitor
SAR442168 Oral ClinicalTrials.gov Identifier: NCT04458051	Sanofi	•Allocation: Randomized •Control group: placebo •Intervention Model: Parallel Assignment •Masking: Triple (Participant, Investigator, Outcomes Assessor) •Primary Purpose: Treatment (Efficacy) •Primary Objective: Confirmed Disability Progression •Secondary Objectives: MRI (new, Gd, brain volume loss) lesions, clinical/cognitive impairment and safety	Primary progressive MS	Study Type: Interventional Phase: 3 Estimated enrollment:990 Recruitment Status: not yet recruiting	Bruton’s Tyrosine Kinase Inhibitor
SAR442168 Oral ClinicalTrials.gov Identifier: NCT04411641	Sanofi	•Allocation: Randomized •Control group: placebo •Intervention Model: Parallel Assignment •Masking: Triple (Participant, Investigator, Outcomes Assessor) •Primary Purpose: Treatment (Efficacy) •Primary Objective: Confirmed Disability Progression •Secondary Objectives: MRI (new, Gd, brain volume loss) lesions, clinical/cognitive impairment and safety	Secondary progressive MS	Study Type: Interventional Phase: 3 Estimated enrollment: 1290 Recruitment Status: recruiting	Bruton’s Tyrosine Kinase Inhibitor
BIIB091 Oral ClinicalTrials.gov Identifier: NCT03943056	Biogen	•Allocation: Randomized •Control group: placebo •Intervention Model: Sequential Assignment •Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) •Primary Purpose: Treatment (Safety, Tolerability, pharmacokinetic and Pharmacodynamic) •Primary Objective: Safety •Secondary Objectives: pharmacokinetic and Pharmacodynamic	Healthy Volunteer	Study Type: Interventional Phase: 1 Enrollment: 64 Recruitment Status: completed	Bruton’s Tyrosine Kinase Inhibitor

AAR: Annualized Relapse Rate, Gd: gadolinium, MRI: magnetic resonance imaging, EDSS: expanded disability status scale, MS: multiple sclerosis.