A COMBINATION OF A BTK INHIBITOR AND ABATACEPT FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

Abstract

Disclosed is method of treating a patient having rheumatoid arthritis, comprising administering sequentially to said patient, a therapeutically effective dose of branebrutinib for a first period, followed by a therapeutically effect dose of abatacept for a second period.

Claims

1. A method of treating a patient having rheumatoid arthritis, comprising: administering sequentially to said patient, a therapeutically effective dose of a BTK inhibitor for a first period, followed by a therapeutically effect dose of abatacept for a second period.

2. The method according to claim 1 wherein said BTK inhibitor is an irreversible inhibitor.

3. The method according to claim 1, wherein said BTK inhibitor is branebrutinib.

4. The method according to claim 3, wherein said therapeutically effective dose of branebrutinib is from 1 to 10 mg per day.

5. The method according to claim 1, wherein abatacept is administered as a subcutaneous injection.

6. The method according to claim 1, wherein said therapeutically effective dose of abatacept is 125 mg per week.

7. The method according to claim 1, wherein said therapeutically effective dose of branebrutinib is from 1 to 10 mg per day; and said therapeutically effective dose of abatacept is 125 mg per week.

Description

DETAILED DESCRIPTION

[0025] The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[0026] Provided herein are methods of treating a patient having rheumatoid arthritis. The methods comprise administering sequentially to a patient:

[0027] (i) a therapeutically effective dose of branebrutinib for a first period; and

[0028] (ii) a therapeutically effect dose of abatacept for a second period.

The first period and second period are sequential and do not overlap. The second period starts after the completion of the first period.

[0029] In one embodiment the first period is from 1 to 200 days. Included in this embodiment is a first period selected from 1 to 175 days; 1 to 140 days; 1 to 126 days; 1 to 112 days; 1 to 98 days; 1 to 84 days; 1 to 70 days; 1 to 56 days; 1 to 49 days; 1 to 42 days; 1 to 35 days; 1 to 28 days; and 1 to 14 days.

[0030] In one embodiment the first period is from 7 to 200 days. Included in this embodiment is a first period selected from 7 to 175 days; 7 to 140 days; 7 to 126 days; 7 to 112 days; 7 to 98 days; 7 to 84 days; 7 to 70 days; 7 to 56 days; 7 to 49 days; 7 to 42 days; 7 to 35 days; 7 to 28 days; and 7 to 14 days.

[0031] In one embodiment the first period is from 14 to 200 days. Included in this embodiment is a first period selected from 14 to 175 days; 14 to 140 days; 14 to 126 days; 14 to 112 days; 14 to 98 days; 14 to 84 days; 14 to 70 days; 14 to 56 days; 14 to 49 days;

[0032] 14 to 42 days; 14 to 35 days; and 14 to 28 days.

[0033] In one embodiment the first period is from 21 to 200 days. Included in this embodiment is a first period selected from 21 to 175 days; 21 to 140 days; 21 to 126 days; 21 to 112 days; 21 to 98 days; 21 to 84 days; 21 to 70 days; 21 to 56 days; 21 to 49 days; 21 to 42 days; 21 to 35 days; and 21 to 28 days.

[0034] In one embodiment the second period is at least 2 weeks. Included in this embodiment is a second period selected from at least 4 weeks; at least 6 weeks; at least 8 weeks; at least 10 weeks; at least 12 weeks; at least 14 weeks; at least 16 weeks; at least 18 weeks; and at least 20 weeks. The second period can be continued for any period of time provided that the patient responds to treatment. Response to treatment, which can be determined by a qualified medical professional, includes reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with rheumatoid arthritis. The second period can extend as long as the remaining lifetime of the patient.

[0035] In one embodiment, the abatacept therapy in the second period is continued for the period of time that the patient responds to treatment as determined by a qualified medical professional.

[0036] In one embodiment the second period is from at least 2 weeks to 20 years. Included in this embodiment is a second period selected from at least 2 weeks to 15 years; from at least 2 weeks to 10 years; from at least 2 weeks to 5 years; from at least 2 weeks to 3 years; from at least 2 weeks to 2 years; from at least 2 weeks to 1 year; from at least 2 weeks to 40 weeks; from at least 2 weeks to 30 weeks; from at least 2 weeks to 20 weeks; from at least 2 weeks to 12 weeks; and from at least 2 weeks to 10 weeks.

[0037] In one embodiment the second period is at least 4 weeks. Included in this embodiment is a second period selected from at least 4 weeks to 20 years; from at least 4 weeks to 15 years; from at least 4 weeks to 10 years; from at least 4 weeks to 5 years;

[0038] least 4 weeks to 4 years; from at least 4 weeks to 3 years; from at least 4 weeks to 2 years; from at least 4 weeks to 1 year; from at least 4 weeks to 40 weeks; from at least 4 weeks to 30 weeks; from at least 4 weeks to 20 weeks; from at least 4 weeks to 12 weeks; and from at least 4 weeks to 10 weeks.

[0039] In one embodiment the second period is at least 8 weeks. Included in this embodiment is a second period selected from at least 8 weeks to 20 years; from at least 8 weeks to 15 years; from at least 8 weeks to 10 years; from at least 8 weeks to 5 years; from at least 8 weeks to 4 years; from at least 8 weeks to 3 years; from at least 8 weeks to 2 years; from at least 8 weeks; from at least 8 weeks to 1 year; from at least 8 weeks to 40 weeks; from at least 8 weeks to 30 weeks; from at least 8 weeks to 20 weeks; from at least 8 weeks to 12 weeks; and from at least 8 weeks to 10 weeks.

[0040] In one embodiment the second period is at least 12 weeks. Included in this embodiment is a second period selected from at least 12 weeks to 20 years; from at least 12 weeks to 15 years; from at least 12 weeks to 10 years; from at least 12 weeks to 5 years; from at least 12 weeks to 4 years; from at least 12 weeks to 3 years; from at least 12 weeks to 2 years; from at least 12 weeks; from at least 12 weeks to 1 year; from at least 12 weeks to 40 weeks; from at least 12 weeks to 30 weeks; and from at least 12 weeks to 20 weeks.

[0041] In one embodiment the second period is at least 16 weeks. Included in this embodiment is a second period selected from at least 16 weeks to 20 years; from at least 16 weeks to 15 years; from at least 16 weeks to 10 years; from at least 16 weeks to 5 years; from at least 16 weeks to 4 years; from at least 16 weeks to 3 years; from at least 16 weeks to 2 years; from at least 16 weeks; from at least 16 weeks to 1 year; from at least 16 weeks to 40 weeks; from at least 16 weeks to 30 weeks; and from at least 16 weeks to 20 weeks.

[0042] In one embodiment the second period is at least 20 weeks. Included in this embodiment is a second period selected from at least 20 weeks to 20 years; from at least 20 weeks to 15 years; from at least 20 weeks to 10 years; from at least 20 weeks to 5 years; from at least 20 weeks to 4 years; from at least 20 weeks to 3 years; from at least 20 weeks to 2 years; from at least 20 weeks; from at least 20 weeks to 1 year; from at least 20 weeks to 40 weeks; and from at least 20 weeks to 30 weeks.

[0043] In one embodiment, a therapeutically effective dose of branebrutinib is in the range of 0.5 to 10 mg/day. Included in this embodiment is a therapeutically effective dose of branebrutinib selected from the ranges of 1 to 10 mg/day; 2 to 10 mg/day; 3 to 10 mg/day; 4 to 10 mg/day; 5 to 10 mg/day; 6 to 10 mg/day; 7 to 10 mg/day; 8 to 10 mg/day; and 9 to 10 mg/day.

[0044] In one embodiment, a therapeutically effective dose of branebrutinib is 0.5 mg/day.

[0045] In one embodiment, a therapeutically effective dose of branebrutinib is 1 mg/day.

[0046] In one embodiment, a therapeutically effective dose of branebrutinib is 1.5 mg/day.

[0047] In one embodiment, a therapeutically effective dose of branebrutinib is 2 mg/day.

[0048] In one embodiment, a therapeutically effective dose of branebrutinib is 2.5 mg/day.

[0049] In one embodiment, a therapeutically effective dose of branebrutinib is 3 mg/day.

[0050] In one embodiment, a therapeutically effective dose of branebrutinib is 3.5 mg/day.

[0051] In one embodiment, a therapeutically effective dose of branebrutinib is 4 mg/day.

[0052] In one embodiment, a therapeutically effective dose of branebrutinib is 4.5 mg/day.

[0053] In one embodiment, a therapeutically effective dose of branebrutinib is 5 mg/day.

[0054] In one embodiment, a therapeutically effective dose of branebrutinib is 5.5 mg/day.

[0055] In one embodiment, a therapeutically effective dose of branebrutinib is 6 mg/day.

[0056] In one embodiment, a therapeutically effective dose of branebrutinib is 6.5 mg/day.

[0057] In one embodiment, a therapeutically effective dose of branebrutinib is 7 mg/day.

[0058] In one embodiment, a therapeutically effective dose of branebrutinib is 7.5 mg/day.

[0059] In one embodiment, a therapeutically effective dose of branebrutinib is 8 mg/day.

[0060] In one embodiment, a therapeutically effective dose of branebrutinib is 8.5 mg/day.

[0061] In one embodiment, a therapeutically effective dose of branebrutinib is 9 mg/day.

[0062] In one embodiment, a therapeutically effective dose of branebrutinib is 9.5 mg/day.

[0063] In one embodiment, a therapeutically effective dose of branebrutinib is 10 mg/day.

[0064] The therapeutically effective dose of branebrutinib can be administered as a single daily dose (q.d.), divided and administered twice daily (b.i.d.), or divided and administered as three or more doses per day.

[0065] In one embodiment, a therapeutically effective dose of branebrutinib is administered as a single daily dose.

[0066] In one embodiment, a therapeutically effective dose of branebrutinib is administered as a twice daily dose. For example, a therapeutically effective dose of 6 mg/day of branebrutinib can be administered as 3 mg dose administered twice daily (b.i.d).

[0067] Abatacept is available as:

Intravenous Infusion

[0068] For Injection: 250 mg lyophilized powder in a single-use vial for reconstitution and dilution prior to intravenous infusion.

Subcutaneous Injection

[0069] Injection: 50 mg/0.4 mL, 87.5 mg/0.7 mL, 125 mg/mL solution in single-dose prefilled syringes for subcutaneous use. [0070] Injection: 125 mg/mL solution in a single-dose prefilled ClickJect™ autoinjector for subcutaneous use.

[0071] Abatacept Dosage and Administration

TABLE-US-00001 Intravenous Administration for Adult RA and Adult PsA Body Weight of Patient Dose Number of Vials Less than 60 kg  500 mg 2 60 to 100 kg  750 mg 3 More than 100 kg 1000 mg 4

Subcutaneous Administration for Adult RA

[0072] Administer by subcutaneous injection once weekly with or without an intravenous loading dose. For patients initiating therapy with an intravenous loading dose, administer a single intravenous infusion (as per body weight categories above), followed by the first 125 mg subcutaneous injection given within a day of the intravenous infusion. [0073] Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

[0074] In one embodiment, the patient is a human.

[0075] In one embodiment, the abatacept therapy administered during the second period is continued for the period of time that the patient responds to treatment as determined by a qualified medical professional. Response to treatment includes reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with rheumatoid arthritis. The second period can extend as long as the remaining lifetime of the patient.

RA Protocol Duration:

[0076] The total duration of participation in the RA protocol is approximately 32 weeks and will be divided into the following periods: screening (up to 4 weeks), double-blind, PBO-controlled branebrutinib treatment for 12 weeks (Week 0 to Week 12), open-label treatment with abatacept for an additional 12 weeks (Week 12 to Week 24), and follow-up (4 weeks).

RA Sub-Protocol Study Treatment:

[0077] Branebrutinib followed by open-label abatacept therapy: Day 1 to Week 24 [0078] Medication Potency IP/Non-IP [0079] Branebrutinib: dose ranges above QD, PO IP [0080] Branebrutinib PBO: QD, PO IP [0081] Abatacept: 125 mg QW, SC IP [0082] IP=investigational product; PBO=placebo; PO=administered orally; QD=once daily; QW=once weekly; SC=subcutaneous [0083] ACR50 response at Week 24 compared to baseline

[0084] To evaluate the efficacy at Week 24 of branebrutinib or PBO treatment followed by abatacept treatment in subjects with moderate to severe RA on a stable background of methotrexate (MTX) who have had an inadequate response to MTX.

[0085] The ACR50 is a composite measure defined as both improvement of 20% in the number of tender and number of swollen joints, and a 50% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP).

[0086] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.