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Olumiant® ▼ (baricitinib): Jämförelse mellan Baricitinib och Upadacitinib fas 3 Reumatoid Artrit kliniska utvecklingsprogram

Både baricitinib och upadacitinib genomförde fas 3 reumatoid artrit kliniska utvecklingsprogram.

Phase 3 Rheumatoid Arthritis Clinical Development Program for Baricitinib and Upadacitinib

The phase 3 clinical development programs for BARI and upadacitinib included patients with moderately to severely active RA who had inadequate responses to treatment with MTX, csDMARDs, and bDMARDs or MTX naïve. However, there were differences in the patient populations evaluated and study designs in these clinical development programs.1-9 Therefore, no efficacy and safety comparative conclusions can be drawn from indirectly comparing the results of these programs.

Descriptions of the phase 3 RA clinical development programs for BARI and upadacitinib are provided in

Methotrexate Naïve Patients

The phase 3 RA clinical development programs for both BARI and upadacitinib included studies in MTX naïve patients.2,9

In the BARI program, RA-BEGIN was conducted in patients who were DMARD naïve and compared,

  • MTX monotherapy with

  • BARI monotherapy, and

  • BARI plus MTX.2

The study population of DMARD-naïve patients from the RA-BEGIN study is not included in the approved label. However, the RA-BEGIN study is supportive for the target population of patients with an inadequate response to, or intolerance to, other DMARDs.10

In the upadacitinib program, SELECT-EARLY was conducted in patients who were MTX naïve, but 25.3% of the patient population had been previously treated with nonbiologic DMARDs. SELECT-EARLY compared

  • upadacitinib monotherapy, and

  • dose-titrated MTX monotherapy.9

Thus, the BARI phase 3 RA clinical program evaluated an additional treatment scenario of combination BARI and MTX therapy in patients who were DMARD naïve, not just MTX naïve.

Table 1. Baricitinib and Upadacitinib Phase 3 Clinical Trial Designs in Treatment Naïve Patients2,9

 

Baricitinib
RA-BEGIN

Upadacitinib
SELECT-EARLY

Patient Population

DMARD naïve

MTX naïve

Treatment Arms


BARI 4 mg mono (n=159)

UPA 15 mg mono (n=317)

MTX mono (n=210)

UPA 30 mg mono (n=314)

BARI 4 mg +MTX combination arm (n=215)

MTX mono (n=314)

Background DMARDs

None

None

Duration

52 weeks

24 weeks

Key Efficacy Endpoints

Primary Endpoint(s)

ACR20
(week 24)

ACR50 (week 12),
DAS28-CRP<2.6 (week 24)

Patient-reported Outcomes

HAQ-DI, PtGA

HAQ-DI, SF-36 PCS

Remission

SDAI ≤3.3, CDAI ≤2.8, DAS28-ESR <2.6, DAS28-CRP <2.6

DAS28-CRP<2.6, CDAI ≤2.8

Radiographic outcomes

mTSS

mTSS

Abbreviations: ACR20 = American College of Rheumatology 20% improvement criteria; ACR50 = American College of Rheumatology 50% improvement criteria; BARI = baricitinib; CDAI = Clinical Disease Activity Index; DAS28-CRP = 28-joint Disease Activity Score based on C-reactive protein; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DMARD = disease modifying antirheumatic drug; HAQ-DI = Health Assessment Questionnaire-Disability Index; mono = monotherapy; mTSS = modified total Sharp Score; MTX = methotrexate; PtGA = Patient Global Assessment; SDAI = Simplified Disease Activity Index; SF-36 PCS = short form 36- physical component score; UPA = upadacitinib.

Methotrexate Inadequate Responders

The phase 3 RA clinical development programs for both BARI and upadacitinib included studies in MTX-IR patients.1,8,11

In the BARI program, all patients in RA-BEAM continued on background MTX and were allowed to continue stable doses of hydroxychloroquine or sulfasalazine in each treatment arm,

  • BARI 4 mg

  • ADA 40 mg, or

  • placebo.1,12

In the upadacitinib program, all patients in SELECT-COMPARE continued on background MTX, but discontinued other csDMARDs prior to starting on

  • UPA 15 mg

  • ADA 40 mg, or

  • placebo.11

Table 2. Baricitinib and Upadacitinib Phase 3 Placebo-Controlled Clinical Trial Designs in Patients With an Inadequate Response to Methotrexate1,8,11

 

Baricitinib
RA-BEAM

Upadacitinib
SELECT-COMPARE

Upadacitinib
SELECT-MONOTHERAPY

Patient Population

MTX-IR

MTX-IR

MTX-IR

Treatment Arms





BARI 4 mg (n=487)

UPA 15 mg (n=652)

UPA 15 mg mono (n=217)

ADA 40mg (n=330)

ADA 40 mg (n=327)

UPA 30 mg mono (n=215)

PBO (n=488)

PBO (n=652)

MTX monoa (n=216)

Background DMARDs

MTX

MTX

none

Duration

52 weeks

48 weeks

14 weeks

Key Efficacy Endpoints

Primary Endpoints

ACR20
(week 12)

ACR20, DAS28-CRP <2.6
(week 12)

ACR20, DAS28-CRP <3.2
(week 14)

Patient-reported Outcomes

HAQ-DI, MJS, worst tiredness, worst joint painb, PtGA

HAQ-DI, SF-36 PCS, MJS, FACIT-F, PtGA

HAQ-DI,SF-36 PCS, MJS, FACIT-F, PtGA

Remission

SDAI ≤3.3, CDAI ≤2.8, DAS28-ESR <2.6, DAS28-CRP <2.6

DAS28-CRP <2.6, SDAI ≤3.3, CDAI ≤2.8, ACR/EULAR Boolean

DAS28-CRP <2.6, SDAI ≤3.3, CDAI ≤2.8, ACR/EULAR Boolean

Radiographic outcomes

mTSS

mTSS

NA

Abbreviation: ACR = American College of Rheumatology; ACR20 = American College of Rheumatology 20% improvement criteria; ADA = adalimumab; BARI = baricitinib; CDAI = Clinical Disease Activity Index; DAS28-CRP = 28-joint Disease Activity Score based on C-reactive protein; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DMARD = disease modifying antirheumatic drug; EULAR = European League Against Rheumatism; FACIT-F = Functional Assessment of Chronic Illness Therapy Fatigue scale; HAQ-DI = Health Assessment Questionnaire-Disability Index; IR = inadequate responders; MJS = morning joint stiffness; mono = monotherapy; mTSS = modified total Sharp Score; MTX = methotrexate; NA = not applicable; PtGA = Patient Global Assessment; SDAI = Simplified Disease Activity Index; SF-36 PCS = short form 36- physical component score; UPA = upadacitinib.

a Switched to UPA 15 mg or 30 mg at week 14.

b Daily patient diaries were collected for MJS, severity of worst tiredness and worst joint pain.

Conventional Synthetic DMARD Inadequate Responders

The phase 3 RA clinical development programs for both BARI and upadacitinib included studies in csDMARD-IR patients.3,6

In the BARI RA-BUILD study, most patients received background csDMARDs.3

In the upadacitinib SELECT-NEXT study, all patients received background csDMARDs.6

Table 3. Baricitinib and Upadacitinib Phase 3 Placebo-Controlled Clinical Trial Designs in Patients With an Inadequate Response to csDMARDs3,6

 

Baricitinib
RA-BUILD

Upadacitinib
SELECT-NEXT

Patient Population

csDMARD IR

csDMARD IR

Treatment Arms





BARI 2 mg (n=229)

UPA 15 mg (n=221)

BARI 4 mg (n=227)

UPA 30 mg (n=219)

PBO (n=228)

PBO (n=221)

Background DMARDs

csDMARDs

csDMARDs

Duration

24 weeks

12 weeks

Key Efficacy Endpoints

Primary Efficacy Endpoint(s)

ACR20 (week 12)

ACR20, DAS28-CRP <3.2
(week 12)

Patient-reported Outcomes

HAQ-DI, MJS, worst tiredness, worst joint paina

HAQ-DI, SF-36 PCS, FACIT-F, MJS, PtGA

Remission

SDAI ≤3.3, CDAI ≤2.8, DAS28-ESR <2.6, DAS28-CRP <2.6

DAS28-CRP <2.6, SDAI ≤3.3, CDAI ≤2.8, ACR/EULAR Boolean

Radiographic outcomes

mTSS

NA

Abbreviations: ACR20 = American College of Rheumatology 20% improvement criteria; BARI = baricitinib; bid = twice daily; CDAI = Clinical Disease Activity Index; csDMARD = conventional synthetic disease modifying antirheumatic drug; DAS28-CRP = 28-joint Disease Activity Score based on C-reactive protein; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DMARD = disease modifying antirheumatic drug; FACIT-F = Functional Assessment of Chronic Illness Therapy Fatigue scale; HAQ-DI = Health Assessment Questionnaire-Disability Index; IR = inadequate responders; MJS = morning joint stiffness; mTSS = modified total Sharp Score; PtGA = Patient Global Assessment; SDAI = Simplified Disease Activity Index; SF-36 PCS = short form 36- physical component score; UPA = upadacitinib.

a Daily patient diaries were collected for MJS, severity of worst tiredness and worst joint pain.

Biologic DMARD Inadequate Responders

The phase 3 RA clinical development programs for both BARI and upadacitinib included studies in bDMARD-IR patients.4,5,7

The BARI RA-BEACON study included patients with an inadequate response to at least 1 TNF inhibitor, who may also have had an inadequate response to 1 or more non-TNF inhibitor biologic DMARDs. In the study, about 60% of the patients had previously failed more than 1 bDMARD and about 30% failed 3 or more bDMARDs.4

In the upadacitinib SELECT-BEYOND study, about 50% of the patients had failed more than 1 bDMARD and about 30% failed 3 or more bDMARDs.7

Table 4. Baricitinib and Upadacitinib Phase 3 Clinical Trial Designs in Patients With Inadequate Response to bDMARDs4,5,7

 

Baricitinib
RA-BEACON

Upadacitinib
SELECT-BEYOND

Upadacitinib
SELECT-CHOICE

Patient Population

TNFi-IR

bDMARD-IR

bDMARD-IR

Treatment Arms


 

BARI 2 mg (n=174)

UPA 15 mg (n=165)

UPAa

BARI 4 mg (n=177)

UPA 30 mg (n=165)

Abatacepta

PBO (n=176)

PBOb (n=169)

NA

Background DMARDs

csDMARDs

csDMARDs

csDMARD

Duration

24 weeks

24 weeks

24 weeks

Key Efficacy Endpoints

Primary Endpoints

ACR20 (week 12)

ACR20, DAS28-CRP <3.2
(week 12)

DAS28-CRP change (week 12)

Patient-reported Outcomes

HAQ-DI

HAQ-DI, SF-36 PCS, morning stiffness duration and severity

NA

Remission

SDAI ≤3.3, CDAI ≤2.8, DAS28-ESR <2.6, DAS28-CRP <2.6

NA

DAS28-CRP <2.6

Radiographic outcomes

NA

NA

NA

Abbreviations: ACR20 = American College of Rheumatology 20% improvement criteria; BARI = baricitinib; bDMARD = biologic disease modifying antirheumatic drug; CDAI = Clinical Disease Activity Index; csDMARD = conventional synthetic disease modifying antirheumatic drug; DAS28-CRP = 28-joint Disease Activity Score based on C-reactive protein; DAS28-ESR = 28-joint Disease Activity Score based on erythrocyte sedimentation rate; HAQ-DI = Health Assessment Questionnaire-Disability Index; IR = inadequate response; PBO = placebo; SDAI = Simplified Disease Activity Index; SF-36 PCS = short form 36- physical component score; TNFi = tumor-necrosis factor inhibitor; UPA = upadacitinib.

a Dose not publicly available.

b At 12 weeks, patients were switched to upadacitinib 15 mg or 30 mg.

Information from the label of baricitinib

Baricitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs. Baricitinib may be used as monotherapy or in combination with methotrexate.10

References

1. 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

2. 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

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

5. A phase 3 study to compare upadacitinib to abatacept in subjects with rheumatoid arthritis on stable dose of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) who have an inadequate response or intolerance to biologic DMARDs (SELECT-CHOICE). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03086343. Updated March 22, 2019. Accessed July 22, 2019.

6. Burmester GR, Kremer JM, van den Bosch F, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10139):2503-2512. https://dx.doi.org/10.1016/S0140-6736(18)31115-2

7. Genovese MC, Fleischmann R, Combe B, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet. 2018;391(10139):2513-2524. https://dx.doi.org/10.1016/S0140-6736(18)31116-4

8. Smolen JS, Pangan AL, Emery P, et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet. 2019;393(10188):2303-2311. http://dx.doi.org/10.1016/S0140-6736(19)30419-2

9. van Vollenhoven R, Takeuchi T, Pangan AL, et al. A phase 3, randomized, controlled trial comparing upadacitinib monotherapy to MTX monotherapy in MTX-naive patients with active rheumatoid arthritis [abstract]. Arthritis Rheumatol. 2018;70(suppl 10). https://acrabstracts.org/abstract/a-phase-3-randomized-controlled-trial-comparing-upadacitinib-monotherapy-to-mtx-monotherapy-in-mtx-naive-patients-with-active-rheumatoid-arthritis/

10. Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

11. Fleischmann RM, Pangan AL, Song IH, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase 3, double-blind, randomized controlled trial. Arthritis Rheumatol. 2019 [Epub ahead of print]. https://dx.doi.org/10.1002/art.41032

12. van Vollenhoven R, Helt C, Arora V, et al. Safety and efficacy of baricitinib in patients receiving conventional synthetic disease-modifying antirheumatic drugs or corticosteroids. Rheumatol Ther. 2018;5(2):525-536. https://doi.org/10.1007/s40744-018-0128-0

Glossary

ADA = adalimumab

BARI = baricitinib

bDMARD = biologic disease-modifying antirheumatic drug

bDMARD-IR = inadequate resonse or intolerant to bDMARD treatment

csDMARD = conventional synthetic disease-modifying antirheumatic drug

csDMARD-IR = inadequate response or intolerant to csDMARD treatment

DMARD = disease-modifying antirheumatic drug

IR = inadequate response

MTX = methotrexate

RA = rheumatoid arthritis

TNF = tumor necrosis factor

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn 2019 M07 22


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