Study Comparing Pharmacokinetics of Different Formulations of Evobrutinib in Healthy Participants

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety and tolerability of evobrutinib after oral administration of immediate release (IR) and modified release (MR) formulations in healthy participants.

Official Title
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A Phase I, Single-site, Open-label, Partially Randomized Study to Evaluate the Relative Bioavailability and Pharmacokinetics of Evobrutinib Following Administration of Different Formulations in Healthy Participants

Conditions
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Healthy

Intervention / Treatment
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* Drug: Ref (TF2)
* Drug: Evobrutinib MR-T1
* Drug: Evobrutinib MR-T2
* Drug: Evobrutinib MR-T3
* Drug: Evobrutinib MR-T4
* Drug: Evobrutinib MUPS-C1
* Drug: Evobrutinib MUPS-C2
* Drug: Evobrutinib MUPS-C3
* Drug: Evobrutinib MUPS-C4
* Drug: Evobrutinib MR-T adapated


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are overtly healthy as determined by medical evaluation, including comprehensive clinical assessment (detailed medical history and a complete physical examination), ECG, and laboratory investigations (hematology and biochemistry) Participants have a body weight within 50.0 to 100.0 kilogram (kg) and body mass index (BMI) within the range 19 to 32 kilogram per meter square (kg/m^2) (inclusive) Other protocol defined inclusion criteria could apply Exclusion Criteria: Participants with history or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, metabolic, hematological, lymphatic, neurological (including epilepsy), cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders, as determined by medical evaluation Participants with history of any malignancy Administration of live vaccines or live-attenuated virus vaccines within 3 months prior to Screening. Administration of other types of vaccines (e.g. SARS-CoV-2 vaccines) is allowed until 2 weeks before the admission to the CRU Medical history and physical examination results that include any ongoing clinically relevant findings as judged by the Investigator Moderate or strong inhibitors or inducers of CYP3A4/5 or Pgp within 4 weeks prior to the first administration of study intervention Other protocol-defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part A, B and C, periods 1 to 3 will be an incomplete cross-over; Part A, B and C, periods 4 and 5 are sequential. Part D, periods 1 and 2 will be 2-sequence cross-over design with 2 treatment sequences; Part D, period 3 is optional.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Evobrutinib: Treatment Sequence 1<br>Participants will receive single oral dose of modified release evobrutinib tablet-1 (MR-T1) on Day 1 in treatment period 1, followed by single oral dose of modified release tablet-2 (MR-T2) on Day 1 in treatment period 2, followed by two single oral doses of immediate release (IR) oral tablet [Ref (TF2)] on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or multiparticulate system capsules (MUPS-C) formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MR-T1<br>* Participants will receive single oral dose of MR-T1 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;Drug: Evobrutinib MR-T2<br>* Participants will receive single oral dose of MR-T2 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;|
| Experimental: Part A: Evobrutinib: Treatment Sequence 2<br>Participants will receive single oral dose of MR-T2 on Day 1 in treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by single oral dose of MR-T1 on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MR-T1<br>* Participants will receive single oral dose of MR-T1 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;Drug: Evobrutinib MR-T2<br>* Participants will receive single oral dose of MR-T2 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;|
| Experimental: Part A: Evobrutinib: Treatment Sequence 3<br>Participants will receive two single oral doses of Ref (TF2) on Day 1 in treatment period 1, followed by single oral dose of MR-T1 on Day 1 in treatment period 2, followed by single oral dose of MR-T2 on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MR-T1<br>* Participants will receive single oral dose of MR-T1 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;Drug: Evobrutinib MR-T2<br>* Participants will receive single oral dose of MR-T2 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;|
| Experimental: Part A: Evobrutinib: Treatment Sequence 4<br>Participants will receive single oral dose of modified release evobrutinib tablet-3 (MR-T3) on Day 1 in treatment period 1, followed by single oral dose of modified release tablet-4 (MR-T4) on Day 1 in treatment period 2, followed by two single oral doses of immediate release (IR) oral tablet [Ref (TF2)] on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or multiparticulate system capsules (MUPS-C) formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MR-T3<br>* Participants will receive single oral dose of MR-T3 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;Drug: Evobrutinib MR-T4<br>* Participants will receive single oral dose of MR-T4 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;|
| Experimental: Part A: Evobrutinib: Treatment Sequence 5<br>Participants will receive single oral dose of MR-T4 on Day 1 in treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by single oral dose of MR-T3 on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MR-T3<br>* Participants will receive single oral dose of MR-T3 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;Drug: Evobrutinib MR-T4<br>* Participants will receive single oral dose of MR-T4 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;|
| Experimental: Part A: Evobrutinib: Treatment Sequence 6<br>Participants will receive two single oral doses of Ref (TF2) on Day 1 in treatment period 1, followed by single oral dose of MR-T3 on Day 1 in treatment period 2, followed by single oral dose of MR-T4 on Day 1 in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MR-T3<br>* Participants will receive single oral dose of MR-T3 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;Drug: Evobrutinib MR-T4<br>* Participants will receive single oral dose of MR-T4 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;|
| Experimental: Part B: Evobrutinib: Treatment Sequence 1<br>Participants will receive single oral dose of MUPS-C1 evobrutinib on Day 1 in treatment period 1, followed by single oral dose of MUPS-C2 on Day 1 in treatment period 2, followed by two single oral doses of Ref (TF2) on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C1<br>* Participants will receive single oral dose of MUPS-C1 on Day 1 in treatment period 1, 2, and 3 of Part B.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C2<br>* Participants will receive single oral dose of MUPS-C2 on Day 1 in treatment period 1, 2, and 3 of Part B.<br>* Other names: M2951;|
| Experimental: Part B: Evobrutinib: Treatment Sequence 2<br>Participants will receive single oral dose of MUPS-C2 evobrutinib on Day 1 in treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by single oral dose of MUPS-C2 on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C1<br>* Participants will receive single oral dose of MUPS-C1 on Day 1 in treatment period 1, 2, and 3 of Part B.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C2<br>* Participants will receive single oral dose of MUPS-C2 on Day 1 in treatment period 1, 2, and 3 of Part B.<br>* Other names: M2951;|
| Experimental: Part B: Evobrutinib: Treatment Sequence 3<br>Participants will receive two single oral doses of Ref (TF2) evobrutinib on Day 1 in treatment period 1, followed by single oral dose of MUPS-C1 on Day 1 in treatment period 2, followed by single oral dose of MUPS-C2 on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C1<br>* Participants will receive single oral dose of MUPS-C1 on Day 1 in treatment period 1, 2, and 3 of Part B.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C2<br>* Participants will receive single oral dose of MUPS-C2 on Day 1 in treatment period 1, 2, and 3 of Part B.<br>* Other names: M2951;|
| Experimental: Part C: Evobrutinib: Treatment Sequence 4<br>Participants will receive single oral dose of MUPS-C3 evobrutinib on Day 1 in treatment period 1, followed by single oral dose of MUPS-C4 on Day 1 in treatment period 2, followed by two single oral doses of Ref (TF2) on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C3<br>* Participants will receive single oral dose of MUPS-C3 on Day 1 in treatment period 1, 2, and 3 of Part C.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C4<br>* Participants will receive single oral dose of MUPS-C4 on Day 1 in treatment period 1, 2, and 3 of Part C.<br>* Other names: M2951;|
| Experimental: Part C: Evobrutinib: Treatment Sequence 5<br>Participants will receive single oral dose of MUPS-C4 evobrutinib on Day 1 in treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by single oral dose of MUPS-C3 on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C3<br>* Participants will receive single oral dose of MUPS-C3 on Day 1 in treatment period 1, 2, and 3 of Part C.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C4<br>* Participants will receive single oral dose of MUPS-C4 on Day 1 in treatment period 1, 2, and 3 of Part C.<br>* Other names: M2951;|
| Experimental: Part C: Evobrutinib: Treatment Sequence 6<br>Participants will receive two single oral doses of Ref (TF2) evobrutinib on Day 1 in treatment period 1, followed by single oral dose of MUPS-C3 on Day 1 in treatment period 2, followed by single oral dose of MUPS-C4 on Day 1 of in treatment period 3, followed by 2 sequential periods 4 and 5. The best MR-T and /or MUPS-C formulation from period 1, 2, and 3 will be tested with additional optimization to choose the best overall formulation in treatment period 4. The best overall formulation from Period 4 may be further tested in treatment period 5 under fed or fasted conditions. There will be 72 hours washout period between Periods 1 to 3 and 28 days between Period 3 and 4 and Period 4 and 5. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C3<br>* Participants will receive single oral dose of MUPS-C3 on Day 1 in treatment period 1, 2, and 3 of Part C.<br>* Other names: M2951;Drug: Evobrutinib MUPS-C4<br>* Participants will receive single oral dose of MUPS-C4 on Day 1 in treatment period 1, 2, and 3 of Part C.<br>* Other names: M2951;|
| Experimental: Part D: Evobrutinib: Treatment Sequence 1<br>Participants will receive single oral dose of MR-T adapted on Day 1 of treatment period 1, followed by two single oral doses of Ref (TF2) on Day 1 in treatment period 2, followed by 1 sequential period 3. There will be 72 hours washout period between Periods 1 and 2 and 28 days between Period 2 and 3. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MR-T1<br>* Participants will receive single oral dose of MR-T1 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;Drug: Evobrutinib MR-T adapated<br>* Participants will receive single oral dose of MR-T adapted on Day 1 in treatment period 1, 2, and 3 of Part D.<br>* Other names: M2951;|
| Experimental: Part D: Evobrutinib: Treatment Sequence 2<br>Participants will receive two single oral doses of Ref (TF2) on Day 1 of treatment period 1, followed by single oral dose of MR-T adapted on Day 1 in treatment period 2, followed by 1 sequential period 3. There will be 72 hours washout period between Periods 1 and 2 and 28 days between Period 2 and 3. | Drug: Ref (TF2)<br>* Participants will receive 2 single oral doses of Ref (TF2) on Day 1 in treatment period 1, 2, or 3 of Part A, B, C and D.<br>* Other names: M2951;Drug: Evobrutinib MR-T1<br>* Participants will receive single oral dose of MR-T1 on Day 1 in treatment period 1, 2, and 3 of Part A.<br>* Other names: M2951;Drug: Evobrutinib MR-T adapated<br>* Participants will receive single oral dose of MR-T adapted on Day 1 in treatment period 1, 2, and 3 of Part D.<br>* Other names: M2951;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero to 24 Hours Post Dose [Frel(AUC0-24)] of Evobrutinib Modified-Release Formulation Compared to Immediate-Release Evobrutinib Reference Formulation |  | Pre-dose up to 72 hours post-dose on Day 4 | 
| Relative Bioavailability Based on Area Under the Plasma Concentration Curve From Time Zero to Infinity [Frel(AUC0-inf)] of Evobrutinib Modified-Release Formulation Compared to Immediate-Release Evobrutinib Reference Formulation |  | Pre-dose up to 72 hours post-dose on Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), Abnormal Laboratory Test Results, Abnormal Vital Signs and Abnormal Electrocardiogram (ECG) Measurements |  | Up to Day 123 | 
| Pharmacokinetic Plasma Concentration of Evobrutinib Formulations |  | Pre-dose up to 72 hours post-dose on Day 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bruton's tyrosine kinase, delayed release, multiparticulate