Olumiant® (Baricitinib)

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Baricitinib: Eficacia en artritis reumatoide de los estudios clínicos fase 3

En cada uno de los 4 estudios fase 3, baricitinib demostró eficacia en AR moderada a severa con un perfil de seguridad aceptable.

Overview of Phase 3 Clinical Trials

Each of the 4 phase 3 studies in the clinical program evaluated a distinct treatment population of patients with moderate-to-severe RA.

  • RA-BEGIN compared BARI 4 mg monotherapy, BARI 4 mg plus MTX, and MTX monotherapy in patients who had limited or no prior treatment with MTX and were naïve to other DMARDs.1

  • RA-BEAM compared BARI 4 mg vs placebo or adalimumab, with background MTX, in patients with inadequate response to MTX.2 

  • RA-BUILD compared BARI 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with inadequate response to csDMARDs.3

  • RA-BEACON compared BARI 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with an inadequate response to at least one TNF inhibitor, who may also have had an inadequate response to one or more non-TNF inhibitor biologic DMARDs.4

Efficacy Summary

Within the phase 3 development program, BARI demonstrated improvements across relevant domains of efficacy at pre-specified endpoints, including patient-reported outcomes and radiographic progression of joint damage, compared with placebo and established standards of care in RA such as approved oral conventional and injectable biologic DMARDs.1-4

For details on efficacy endpoints, see

Table 1. Summary of Key Efficacy Assessments at Pre-Specified Endpoints in RA-BEGIN1

Primary Endpoint at Week 24

BARI 4-mg MONO
(N=159)

BARI 4-mg + MTX
(N=215)

MTX MONO
(N=210)

ACR20a

77b

78c

62

ACR50a

60b

63c

43

ACR70a

42c

40c

21

DAS28-hsCRPa ≤3.2

DAS28-hsCRPa ˂2.6

57b

40b

60c

40c

38

24

DAS28-ESRa ≤3.2

DAS28-ESRa ˂2.6

36b

21d

39c

25c

23

12

CDAIa ≤10

CDAIa ≤2.8

60c

21b

59c

22b

39

11

SDAIa ≤11

SDAIa ≤3.3

62c

22b

61c

23c

40

10

HAQ-DI MCIDa

81d

79d

70

mTSS, LSM change

0.39

0.29d

0.61

Abbreviations: ACR = American College of Rheumatology; ACR20 = ACR 20% response criteria; ACR50 = ACR 50% response criteria; ACR70 = ACR 70% response criteria; BARI = baricitinib; CDAI = Clinical Disease Activity Index; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DAS28-hsCRP = 28-joint Disease Activity Score based on high-sensitivity C-reactive protein; HAQ-DI = Health Assessment Questionnaire-Disability Index; LSM = least squares mean; MCID = minimum clinically important difference; MONO = monotherapy; mTSS = modified Total Sharp Score; MTX = methotrexate; SDAI = Simplified Disease Activity Index.

a Data are percentage of patients (non-responder imputation). Low Disease Activity criterion: DAS28-ESR ≤3.2, CDAI≤10, SDAI≤11. Remission criterion: DAS28-ESR <2.6, CDAI ≤2.8, SDAI ≤3.3.

b p≤.01 vs active comparator.

c p≤.001 vs active comparator.

d p≤.05 vs active comparator.

Table 2. Summary of Key Efficacy Assessments at Pre-Specified Endpoints in RA-BEAM2

Primary Endpoint at Week 12

BARI 4-mg + Background csDMARDs
(N=487)

ADA Q2W + MTX (N=330)

PBO + Background csDMARDs
(N=488)

ACR20a

70bc

61c

40

ACR50a

45dc

35c

17

ACR70a

19bc

13c

5

DAS28-hsCRP ≤3.2a

44dc

35c

14

DAS28-hsCRP <2.6 a

24c

19c

4

DAS28-ESR ≤3.2a

24c

21c

7

DAS28-ESR ˂2.6a

10c

12c

2

CDAI ≤10a

40bc

33c

17

CDAI ≤2.8a

8c

7e

2

SDAI  ≤11a

42bc

35c

16

SDAI ≤3.3a

8c

7c

2

HAQ-DI MCIDa

75c

71c

58

mTSS, LSM change

0.41c

0.33c

0.90

Abbreviations: ACR = American College of Rheumatology; ACR20 = ACR 20% response criteria; ACR50 = ACR 50% response criteria; ACR70 = ACR 70% response criteria; ADA = adalimumab; BARI = baricitinib; CDAI = Clinical Disease Activity Index; csDMARD = conventional synthetic disease modifying anti-rheumatic drug; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DAS28-hsCRP = 28-joint Disease Activity Score based on high-sensitivity C-reactive protein; HAQ-DI = Health Assessment Questionnaire-Disability Index; LSM = least squares mean; MCID = minimum clinically important difference; mTSS = modified Total Sharp Score; MTX = methotrexate; PBO = placebo; Q2W = once every 2 weeks; SDAI = Simplified Disease Activity Index.

a Data are percentage of patients (non-responder imputation). Low Disease Activity criterion: DAS28-ESR ≤3.2, CDAI≤10, SDAI≤11. Remission criterion: DAS28-ESR <2.6, CDAI ≤2.8, SDAI ≤3.3.

b p≤.05 vs active comparator.

c p≤.001 vs PBO.

d p≤.01 vs active comparator.

e p≤.01 vs PBO.

Table 3. Summary of Key Efficacy Assessments at Pre-Specified Endpoints in RA-BUILD3

Primary Endpoint at Week 12

BARI 2 mg + Background csDMARDs
(N=229)

BARI 4 mg + Background csDMARDs
(N=227)

PBO + background csDMARDs
(N=228)

ACR20a

66b

62b

39

ACR50a

34b

34b

13

ACR70a

18b

18b

3

DAS28-hsCRP ≤3.2a

DAS28-hsCRP ˂2.6a

36b

26b

39b

26b

17

9

DAS28-ESR ≤3.2a

DAS28-ESR ˂2.6a

21b

11b

22b

9b

7

2

CDAI ≤10a

CDAI ≤2.8a

34c

10b

35b

9b

21

2

SDAI ≤11a

SDAI ≤3.3a

33c

9b

35b

9b

20

1

HAQ-DI MCIDa

69c

64c

54

mTSS, LSM change

NA

NA

NA

Abbreviations: ACR = American College of Rheumatology; ACR20 = ACR 20% response criteria; ACR50 = ACR 50% response criteria; ACR70 = ACR 70% response criteria; ADA = adalimumab; BARI = baricitinib; CDAI = Clinical Disease Activity Index; csDMARD = conventional synthetic disease modifying anti-rheumatic drug; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DAS28-hsCRP = 28-joint Disease Activity Score based on high-sensitivity C-reactive protein; HAQ-DI = Health Assessment Questionnaire-Disability Index; LSM = least squares mean; MCID = minimum clinically important difference; mTSS = modified Total Sharp Score; NA = not applicable; PBO = placebo; SDAI = Simplified Disease Activity Index.

a Data are percentage of patients (non-responder imputation). Low Disease Activity criterion: DAS28-ESR ≤3.2, CDAI≤10, SDAI≤11. Remission criterion: DAS28-ESR <2.6, CDAI ≤2.8, SDAI ≤3.3.

b p≤.001 vs PBO.

c p≤.01 vs PBO.

Table 4. Summary of Key Efficacy Assessments at Pre-Specified Endpoints in RA-BEACON4

Primary Endpoint at Week 12

BARI 2 mg + Background csDMARDs
(N=174)

BARI 4 mg + Background csDMARDs
(N=177)

PBO + Background csDMARDs
(N=176)

ACR20a

49b

55b

27

ACR50a

20c

28b

8

ACR70a

13b

11c

2

DAS28-hsCRP ≤3.2a

DAS28-hsCRP ˂2.6a

24b

11d

31b

16b

9

4

DAS28-ESR ≤3.2a

DAS28-ESR ˂2.6a

13c

6c

12c

6d

4

1

CDAI ≤10a

CDAI ≤2.8a

24c

3

28b

6

11

2

SDAI ≤11a

SDAI ≤3.3a

22b

2

28b

5

9

2

HAQ-DI MCIDa

59c

67b

43

mTSS, LSM change

NA

NA

NA

Abbreviations: ACR = American College of Rheumatology; ACR20 = ACR 20% response criteria; ACR50 = ACR 50% response criteria; ACR70 = ACR 70% response criteria; BARI = baricitinib; CDAI = Clinical Disease Activity Index; csDMARD = conventional synthetic disease modifying anti-rheumatic drug; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DAS28-hsCRP = 28-joint Disease Activity Score based on high-sensitivity C-reactive protein; HAQ-DI = Health Assessment Questionnaire-Disability Index; LSM = least squares mean; MCID = minimum clinically important difference; mTSS = modified Total Sharp Score; NA = not applicable; PBO = placebo; SDAI = Simplified Disease Activity Index.

a Data are percentage of patients (non-responder imputation). Low Disease Activity criterion: DAS28-ESR ≤3.2, CDAI≤10, SDAI≤11. Remission criterion: DAS28-ESR <2.6, CDAI ≤2.8, SDAI ≤3.3.

b p≤.001 vs PBO.

c p≤.01 vs PBO.

d p≤.05 vs PBO.

Safety Summary

No clinically relevant increases in important measures of safety including event rates across treatment groups for malignancy, MACE, and serious infections were observed for the BARI 4-mg group compared to the active comparator or placebo. Clinically relevant measures of tolerability and adverse events leading to discontinuation of study treatment occurred in similar frequency in patients receiving BARI and the active comparator DMARD (MTX or adalimumab).1-4

The proportions of patients in each study who reported a TEAE or SAE are shown in Table 5.

Table 5. Proportion of Patients Reporting a TEAE or SAE in the Phase 3 Clinical Trials1-4

Phase 3 Study

Patients Reporting a TEAE (%)

Patients Reporting a SAE (%)

RA-BEGINa

MTX monotherapy

72

10

BARI monotherapy

71

8

BARI plus MTX

78

8

RA-BEAMb

Placebo

60

5

Adalimumab

68

2

BARI

71

5

RA-BUILDb

Placebo

71

5

BARI 2 mg

67

3

BARI 4 mg

71

5

RA-BEACONb

Placebo

64

7

BARI 2 mg

71

4

BARI 4 mg

77

10

Abbreviations: BARI = baricitinib; MTX = methtrexate; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

a Data through 52 weeks.

b Data through 24 weeks.

References

1. Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 2017;69(3):506-517. http://dx.doi.org/10.1002/art.39953

2. Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652-662. http://dx.doi.org/10.1056/NEJMoa1608345

3. Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study [published correction appears in Ann Rheum Dis. 2017;76(9):1634. http://dx.doi.org/10.1136/annrheumdis-2016-210094corr1 ]. Ann Rheum Dis. 2017;76(1):88-95. http://dx.doi.org/10.1136/annrheumdis-2016-210094

4. Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243-1252. http://dx.doi.org/10.1056/NEJMoa1507247

Glossary

BARI = baricitinib

csDMARD = conventional synthetic disease-modifying antirheumatic drug

DMARD = disease-modifying antirheumatic drug

MACE = major adverse cardiovascular event

MTX = methotrexate

RA = rheumatoid arthritis

SAE = serious adverse event

TEAE = treatment-emergent adverse event

TNF = tumor necrosis factor

Fecha de la última revisión: 2019 M04 10


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