fda arthritis advisory committee meeting fda opening remarks · patients from p2 and p3 studies:...

FDA Arthritis Advisory Committee MeetingFDA Opening Remarks

NDA 207924: Baricitinib for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have

inadequate response to methotrexate

Nikolay P. Nikolov, M.D.Clinical Team Leader

Division of Pulmonary, Allergy, and Rheumatology ProductsU.S. Food and Drug Administration

April 23, 2018

2

Baricitinib

• Applicant: Eli Lilly & Co.• New Molecular Entity (NME)• Second in class for rheumatoid arthritis (RA)• Small molecule, Janus Kinase (JAK) inhibitor for oral

administration

3

Proposed Usage• Indication and Usage

– “Treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or are intolerant to methotrexate (MTX).”

• Dosage and Administration– “The recommended dose is 2 mg once daily. For patients with an inadequate

response or intolerance to more than one disease modifying anti-rheumatic drug (DMARD), a dose of 4 mg once daily is recommended.

– Dose tapering to 2 mg once daily may be considered for patients who have achieved sustained control of disease activity with 4 mg once daily.”

4

Clinical Program: Phase 2 StudiesStudy Patient

population Study design

Treatment arm Patients per arm

Primary endpoint

JADC cDMARD-IR R, DB, PC Baricitinib 4 mgBaricitinib 7 mgBaricitinib 10 mgPBO

32323231

ACR20 at Week 12

JADA cDMARD-IR R, DB, PC Baricitinib 1 mgBaricitinib 2 mgBaricitinib 4 mgBaricitinib 8 mgPBO

4952525098

ACR20 at Week 12

JADN cDMARD-IR R, DB, PC Baricitinib 1 mgBaricitinib 2 mgBaricitinib 4 mgBaricitinib 8 mgPBO

2424242449

ACR20 at Week 12

cDMARD=conventional DMARD; IR=inadequate response; R=randomized; DB=double-blind; PC=placebo controlled; ACR=American College of Rheumatology; PG=parallel group; PBO=placebo

5


populationStudy design Treatment arms Patients

per arm Major endpoints

JADV MTX-IR R, DB, PC and AC52 weeks

Baricitinib 4 mg + MTXAdalimumab 40 mg QOW+ MTXPBO + MTX (→ Baricitinib 4 at Week 24)

Rescue to Bari 4 mg, starting at Week 16

488330487

ACR20, HAQ-DI atWeek 12mTSS at Week 24

JADX cDMARD-IR R, DB, PC24 weeks

Baricitinib 2 mg + cDMARDBaricitinib 4 mg + cDMARDPBO + cDMARD

Rescue to Baricitinib 4 mg, starting at Week 16

229227228

ACR20, HAQ-DI at Week 12

JADW TNF-IR R, DB, PC24 weeks



174177178


JADZ Treatment naïve/early RA

R, DB, ACMTX titrated up to 20 mg weekly52 weeks

MTX Baricitinib 4 mgBaricitinib 4 mg + MTX

Rescue to Baricitinib 4 + MTX mg, starting at Week 24

213160215


JADY Patients from P2 and P3 studies

LTERW

Baricitinib 2 mg (patients from JADX and JADW)Baricitinib 4 mg

2539 SafetyEfficacy

MTX=methotrexate; AC=active controlled; IR=inadequate response; TNF=tumor necrosis factor; QOW=every other week; P2=phase 2; P3=phase 3

6







488330487





229227228





174177178






213160215



LTERW


2539 SafetyEfficacy


7







488330487





229227228





174177178






213160215



LTERW


2539 SafetyEfficacy


8

Efficacy Considerations• Both baricitinib doses, 2 mg and 4 mg once daily, are effective in reducing

signs and symptoms and improving physical function in patients with RA versus placebo– Higher ACR20, 50, 70 response rates versus placebo– Improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI)

compared to placebo– Data not consistent in showing a meaningful benefit of 4 mg over the 2 mg dose

• Radiographic response– The data for 4 mg dose are robust– Some uncertainty about 2 mg dose, studied in only one study as an exploratory

endpoint

9

Safety Considerations• Serious infections, including H. zoster, opportunistic infections and

tuberculosis• Malignancy, including lymphoma and other malignancies• Thrombosis, both venous and arterial• Laboratory Abnormalities (often dose-dependent)

– Decrease in neutrophils and hemoglobin– Platelet elevations– Lipid elevations– Liver test elevations

10

Safety Data Limitations• Limited placebo-controlled data

– Duration of baricitinib versus placebo controlled data pre-escape was limited to 16 weeks

• Overall safety exposure data limited for baricitinib 2 mg vs 4 mg– Four of the seven phase 2 and 3 clinical studies included 2 mg and 4 mg baricitinib dose

arms – Patient escape/cross-overs

• Patients on placebo were switched or escaped to 4 mg of baricitinib• Patients who escaped from 2 mg baricitinib were placed on 4 mg of baricitinib• Patients who were eligible for escape from 4 mg of baricitinib remained on 4 mg of baricitinib

– Patients in study JADY who had a pre-defined response* to 4 mg of baricitinib were eligible to be randomized to 2 mg vs 4 mg of baricitinib

*CDAI≤10 for 3 months in study JADY or CDAI≤2.8 from study JADZ; patients originating from study JADA were not eligible

11

Benefits• Superior efficacy of both baricitinib

doses compared to placebo:– Signs and symptoms – Physical function – No consistent meaningful benefit of 4

mg over 2 mg• Radiographic response:

– Data for 4 mg dose are robust– Some uncertainty about 2 mg dose,

studied in only one study as an exploratory endpoint

Risks

• Serious infections• Herpes zoster, opportunistic

infections and TB• Malignancies• Thrombosis

– Both arterial and venous

• Laboratory abnormalities– Many dose-dependent, including

platelet elevations

Benefit-Risk Considerations

12

Regulatory History: Original Submission• Original NDA was submitted on January 14, 2016

– Indication: “Moderately to severely active rheumatoid arthritis (RA).”– Dosage and Administration: Proposed dose was 4 mg once daily, with an added notation

that “for some patients a dose of 2 mg once daily may be acceptable.”

• Review clock was extended by three months for review of new safety analyses• Complete Response action on April 12, 2017

– An imbalance in thrombotic events in the baricitinib RA program with potential thrombotic risk with use of baricitinib in RA

– Inadequate safety exposure for 2 mg of baricitinib– Not consistent findings to conclude greater efficacy with 4 mg over 2 mg– Lower doses of baricitinib should be considered for use in RA as there was evidence that

lower doses may be effective for treatment of RA– Cases consistent with drug-induced liver injury were observed with baricitinib use and need

to be described

13

Regulatory History: Re-submission• Re-submission on December 04, 2017• A revised proposal

– Indication and Usage: “Moderately to severely active RA who have had an inadequate response or are intolerant to methotrexate (MTX).”

– Warnings and Precautions: Warning about the potential risk of thrombosis– Dosage and Administration: “Proposed dose is 2 mg once daily. For patients with an inadequate

response or intolerance to more than one DMARD, a dose of 4 mg once daily is recommended. Dose tapering to 2 mg once daily may be considered for patients who have achieved sustained control of disease activity with 4 mg once daily.”

• Information provided in the re-submission– Updated analyses of accumulated safety (cut-off date, April 01, 2017 vs. August 01, 2015)– Epidemiological data comparing rates of VTE/PE from retrospective cohorts to those from the

prospective baricitinib studies in RA– Post-hoc efficacy analyses in patients who had failed more than one DMARD to support the new

dosing recommendations

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Discussion Points and Voting Questions1. DISCUSSION: Discuss the efficacy data for baricitinib for the treatment of

adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX). Include a discussion of the 2 mg and 4 mg doses of baricitinib and whether available data support a benefit of one dose over the other.

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Discussion Points and Voting Questions2. VOTE: Do the data provide substantial evidence of the efficacy of baricitinib

2 mg once daily for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

3. VOTE: Do the data provide substantial evidence of the efficacy of baricitinib 4 mg once daily for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

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Discussion Points and Voting Questions4. DISCUSSION: Discuss the safety data for baricitinib for the treatment of

adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX) Include a discussion of the following issues:

a) Adequacy of safety database for the 2 mg dose of baricitinibb) Safety issues of interest and whether data suggest a dose response

– Thromboembolic events– Malignancy– Serious infections, opportunistic infections, herpes zoster, tuberculosis– Abnormal laboratory parameters, specifically platelet count elevations

c) Overall safety profile of the 2 mg dose and the 4 mg dose, and whether the data are more favorable for one dose versus the other.

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Discussion Points and Voting Questions5. VOTE: Are the safety data adequate to support approval of baricitinib 2 mg

once daily for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

6. VOTE: Are the safety data adequate to support approval of baricitinib 4 mg once daily for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

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Discussion Points and Voting Questions7. VOTE: Is the benefit-risk profile adequate to support approval of baricitinib

2 mg once daily for the proposed indication of the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

8. VOTE: Is the benefit-risk profile adequate to support approval of baricitinib 4 mg once daily for the proposed indication of the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

Robert Abugov, Ph.D.Acting Biostatistics Team Leader

Division of Biometrics IIU.S. Food and Drug Administration

April 23, 2018

FDA Arthritis Advisory Committee MeetingEfficacy of Baricitinib



2

Proposed Usage in Re-submission• Indication and Usage:

– “Treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or are intolerant to methotrexate (MTX).”

• Dosage and Administration:– “The recommended dose is 2 mg once daily. For patients with an inadequate

response or intolerance to more than one disease modifying anti-rheumatic drug (DMARD), a dose of 4 mg once daily is recommended.

– Dose tapering to 2 mg once daily may be considered for patients who have achieved sustained control of disease activity with 4 mg once daily.”

3

Presentation Outline• Efficacy Compared to Control

– Clinical Response– Physical Function– Radiographic Response

• Efficacy of Baricitinib 4 mg Compared to 2 mg– Individual Phase 3 Studies– Integrated Analyses of Multiple Studies– Subgroup Analyses

• Efficacy Conclusions

4





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Confirmatory Phase 3 StudiesStudy Patients Design Treatments N Major

EndpointsJADV MTX-IR R, DB, PC and AC

52 weeksB4 + MTXA QOW+ MTXPBO + MTX (→ 4 at Week 24)

Rescue to B4, starting at Week 16

488330487

W12 ACR20, HAQ-DI, DAS28

W24 mTSSJADX cDMARD-IR R, DB, PC

24 weeksB2 + cDMARDB4 + cDMARDPBO + cDMARD


229227228



B2 + cDMARDB4 + cDMARDPBO + cDMARD


174177178




MTX B4B4 + MTX

Rescue to B4 + MTX starting at Week 24

213160215


B4=baricitinib 4 mg PO QD, B2=baricitinib 2 mg PO QD, A=adalimumab 40 mg QOW, MTX=methotrexate, R=randomized, DB=double-blind, PC=placebo-controlled, AC=active-controlled, IR=inadequate response, TNF=tumor necrosis factor, QOW=every other week, W12=week 12, W24=week 24, ACR20=American College of Rheumatology 20% improvement, HAQ-DI=Health Assessment Questionnaire-Disability Index, DAS28=Disease Activity Score 28 Joints, mTSS=modified Total Sharp Score, PO=per orem, QD=each day

6

ACR20 Response in Phase 3 StudiesStudy

% Responders Odds Ratio (p-value)B4 B2 PBO B4:PBO B2:PBO

At Week 12JADV 70% -- 40% 3.6 (<0.001) -JADW 55% 49% 27% 3.4 (<0.001) 2.7 (0.001)JADX 62% 66% 39% 2.5 (<0.001) 3.0 (<0.001)

At Week 24B4+MTX B4 MTX (B4+MTX):MTX B4:MTX

JADZ 78% 77% 62% 2.2 (0.001) 2.0 (0.003)

ACR20=American College of Rheumatology 20% improvement; B2, B4=baricitinib 2 mg, 4 mg; PBO=placebo; MTX=methotrexate

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Change from Baseline in DAS28Study

Mean Change in DAS28 Difference (p-value)B4 B2 PBO B4-PBO B2-PBO

At Week 12JADV -2.19 -0.96 -1.23 (.001) -JADW -1.79 -1.49 -0.83 -0.95 (.001) -0.66 (.001)JADX -1.92 -1.83 -1.08 -0.84 (.001) -0.75 (.001)

At Week 24B4+MTX B4 MTX (B4+MTX)-MTX B4-MTX

JADZ -2.84 -2.75 -2.06 -0.78 (.001) -0.69 (.001)

DAS28=Disease Activity Score for 28 joints; B2, B4=baricitinib 2 mg, 4 mg; PBO=placebo; MTX=methotrexate

8

Change from Baseline in HAQ-DI Study Mean Change in HAQ-DI Score Difference (p-value)

B4 B2 PBO B4-PBO B2-PBOAt Week 12JADV -0.66 -- -0.34 -0.32 (<.001) -JADW -0.41 -0.37 -0.17 -0.24 (<.001) -0.20 (<.001)JADX -0.56 -0.57 -0.36 -0.19 (<.001) -0.21 (<.001)

At Week 24B4+MTX B4 MTX (B4+MTX)-MTX B4-MTX

JADZ -1.03 -1.04 -0.74 -0.29 (<.001) -0.30 (<.001)

HAQ-DI=Health Assessment Questionnaire-Disability Index; B2, B4=baricitinib 2 mg, 4 mg; PBO=placebo; MTX=methotrexate

9





10

Radiographic Response in JADVMean Change in mTSS (n) Difference (p-value)

B4 A PBO B4-PBO A-PBOAt Week 24Linear extrapolation

0.41(470)

0.33(312)

0.90(452)

-0.49 (<.001) -0.56 (<.001)

All observed data 0.36 (424)

0.29 (280)

0.79 (363)

-0.44 (<.001) -0.51 (<.001)

mTSS=modified total sharp score; B4=baricitinib 4 mg; PBO=placebo; A=adalimumab; n=number of values included in analysis

• No radiographic progression• 70% - PBO • 82% - A• 81% - B4

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Radiographic Response in JADXMean Change in mTSS (n) Difference (p-value)

B4 B2 PBO B4-PBO B2-PBOAt Week 24Linear extrapolation

0.15(198)

0.33(208)

0.70(190)

-0.55 (0.003) -0.38 (0.04)

All observed data 0.19(184)

0.34(188)

0.49(167)

-0.30 (0.03) -0.15 (0.3)

mTSS=modified total sharp score; B2, B4=baricitinib 2 mg, 4 mg; PBO=placebo; n=number of values included in analysis

• No radiographic progression• 76% - PBO • 71% - B2 • 80% - B4

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Efficacy of Baricitinib 4 mg versus Adalimumab in JADV

Endpoint Treatment Baricitinib 4 mg vs. Adalimumab

B4 A PBO Odds Ratio (p-value)

Difference (p-value)

ACR20 Response, Week 12

70% 61% 40% 1.5 (.01)

Mean Change inDAS28, Week 12

-2.19 -1.91 -0.96 -0.28 (<.001)

Mean Change in mTSS, Week 24

0.36 0.30 0.80 0.07 (.6)

B4=baricitinib 4 mg; A=adalimumab; PBO=placebo

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Conclusion: Efficacy of Baricitinib

• Clinical Response– Both baricitinib 2 mg and 4 mg are effective

• Physical Function– Both baricitinib 2 mg and 4 mg are effective

• Radiographic Response– 4 mg effective– Some uncertainty about effectiveness of 2 mg

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15

JADW at Week 12: All RandomizedEndpoint B4

N=177B2

N=174PBO

N=176Baricitinib 4 mg vs. 2 mg(95% confidence interval)

ACR20 55% 49% 27% Odds Ratio: 1.3 (0.8, 2.0)ACR50 5% 2% 2% 2.2 (0.7, 7.4)ACR70 28% 20% 8% 1.5 (0.9, 2.5)

∆ DAS28 -1.95 -1.59 -0.85 Difference: -0.36 (-0.64, -0.08)

∆ HAQ-DI -0.41 -0.37 -0.17 -0.03 (-0.14, 0.07)

ACR20, 50, 70=American College of Rheumatology 20%, 50%, 70% improvement; DAS28=disease activity score 28 joints; HAQ-DI=Health Assessment Questionnaire-Disability Index; B2, B4=baricitinib 2 mg, 4 mg; PBO=placebo; ∆=mean change

16

JADX at Week 12: All RandomizedEndpoint B4

N=227B2

N=229PBO



∆ DAS28 -1.92 -1.83 -1.08 Difference: -0.09 (-0.31, 0.13)∆ HAQ-DI -0.56 -0.57 -0.36 0.01 (-0.08, 0.11)

ACR20, 50, 70=American College of Rheumatology 20%, 50%, 70% improvement; DAS28=disease activity score 28 joints; HAQ-DI=Health Assessment Questionnaire-Disability Index; B2, B4=baricitinib 2 mg, 4 mg; PBO=placebo; ∆=mean change

17





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Integrated Analysis* Comparing Doses Endpoint Week B4 B2 Placebo B4-B2 (95% CI)ACR20 2 40% 31% 19% 9% (3%, 15%)

4 54% 45% 28% 8% (2%, 15%)8 59% 53% 34% 7% (0%, 13%)

12 61% 59% 35% 2% (-4%, 8%)

∆ DAS28 2 -1.26 -0.99 -0.60 -0.27 (-0.39, -0.15)4 -1.59 -1.33 -0.75 -0.27 (-0.40, -0.13)8 -1.86 -1.59 -0.95 -0.26 (-0.41, -0.12)

12 -1.97 -1.73 -1.02 -0.24 (-0.40, -0.09)

∆ HAQ-DI 2 -0.30 -0.23 -0.17 -0.06 (-0.11, -0.01)4 -0.37 -0.30 -0.20 -0.06 (-0.12, -0.01)8 -0.44 -0.39 -0.23 -0.05 (-0.11, -0.01)

12 -0.47 -0.43 -0.24 -0.03 (-0.10, -0.03)*Integrated analysis of Studies JADW, JADX, JADA, JADN; CI=confidence interval

19

Conclusion: Comparison of Doses

• Likely some small differences in efficacy between baricitinib 4 mg and 2 mg– May trend downward over time– Estimated differences small

• e.g., 2% difference in ACR20 response at Week 12– Confidence intervals rule out differences as large

as commonly used estimates of minimal clinically important differences for DAS28 and HAQ-DI

20





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JADX at Week 12: At least Two Prior DMARD SubgroupEndpoint B4

N=227B2

N=229PBO



∆ DAS28 -1.92 -1.83 -1.08 Difference: -0.27 (-0.56, 0.03)∆ HAQ-DI -0.56 -0.57 -0.36 0.01 (-0.08, 0.11)ACR20, 50, 70=American College of Rheumatology 20%, 50%, 70% improvement; DAS28=disease activity score 28 joints; HAQ-DI=Health Assessment Questionnaire-Disability Index; B2, B4=baricitinib 2 mg, 4 mg; PBO=placebo; ∆=mean change

22

JADX at Week 12: Less than Two Prior DMARD Subgroup

Endpoint B4N=99

B2N=107

PBON=97

Baricitinib 4 mg vs. 2 mg(95% confidence interval)


∆ DAS28 -1.80 -1.94 -1.01 Difference: 0.14 (-0.20, 0.48)∆ HAQ-DI -0.59 -0.64 -0.37 0.05 (-0.10, 0.19)ACR20, 50, 70=American College of Rheumatology 20%, 50%, 70% improvement; DAS28=disease activity score 28 joints; HAQ-DI=Health Assessment Questionnaire-Disability Index; B2, B4=baricitinib 2 mg, 4 mg; PBO=placebo; ∆=mean change

23

Conclusion: Subgroup Analyses

• Results do not change conclusions about efficacy comparison between doses- Motivated in part by post hoc subgroup analyses- Statistical significance between doses lacking

and differences consistently small- Lack of evidence of interaction- Same methodology in complementary

population suggests implausible conclusions

24



• Efficacy of Baricitinib 4 mg versus 2 mg– Individual Phase 3 Studies– Integrated Analyses of Multiple Studies– Subgroup Analyses


25

Efficacy Conclusions: Baricitinib

• Both doses effective – Clinical response – Improvement in physical function

• Efficacy differences between 4 and 2 mg small• Subgroup analyses do not change conclusions

Raj Nair, M.D.Clinical Reviewer


April 23, 2018

FDA Arthritis Advisory Committee MeetingSafety of Baricitinib



2

Overview of Baricitinib Safety• Immunosuppressive

– Serious infections leading to hospitalization or death – Tuberculosis and bacterial, invasive fungal, viral (herpes zoster), and other

opportunistic infections– Malignancies, including lymphoma and other malignancies

• Laboratory Abnormalities– Decrease in neutrophil counts and hemoglobin– Platelet elevations– Lipids elevations– Liver test elevations

• Thrombosis

3

Focus of Safety PresentationAdverse Events• Deaths • Serious Adverse Events (SAEs)• Adverse events of special interest

– Malignancy– Serious infections– Herpes zoster– Opportunistic infections and TB– MACE– Thrombosis

• Arterial events• DVT/PE

Laboratory Parameters• Hematologic parameters

– Platelet elevations

• Lipid elevations• Liver test elevations

TB=tuberculosis; MACE=major adverse cardiovascular events; DVT=deep vein thrombosis; PE=pulmonary embolism

4

Safety Data Limitations• Limited placebo-controlled data

– Duration of baricitinib versus placebo controlled data pre-escape was limited to 16 weeks

• Overall safety exposure data limited for baricitinib 2 mg vs 4 mg– Four of the seven phase 2 and 3 clinical studies included 2 mg and 4 mg baricitinib dose

arms – Patient escape/cross-overs

• Patients on placebo were escaped to 4 mg of baricitinib• Patients who escaped from 2 mg baricitinib were placed on 4 mg of baricitinib• Patients who met escape criteria on 4 mg of baricitinib remained on 4 mg of baricitinib

– Patients in study JADY who had a pre-defined response* to 4 mg of baricitinib were eligible to be randomized to 2 mg vs. 4 mg of baricitinib

*CDAI≤10 for 3 months in study JADY or CDAI≤2.8 from study JADZ; patients originating from study JADA were not eligible

5

Study Design Limitations

Source: JADX clinical study report, p. 85

6



7



8

Safety Evaluation of Adverse Events

9


10


11


12


13


14

Safety Evaluation: Study Cohorts

• 0-16 weeks– 16-week pooled data from JADC, JADN, JADA/Y, JADV/Y, JADW/Y, JADX/Y– Comparisons: BARI 2 vs BARI 4, BARI 2/4 vs placebo

• 0-52 weeks– Comparisons: BARI 2 vs BARI 4

• >52 weeks– BARI 2 vs BARI 4

15

Presentation of Adverse Events

0-16 weeks: Studies JADA, JADC, JADN, JADV, JADW, and JADX0-52 and >52 weeks: JADA/Y, JADC, JADN, JADV/Y, JADX/Y, JADW/YIRD=incidence rate difference; CI=confidence interval; BARI=baricitinib; N=number of subjects; PYE=patient year exposure; n=number of patients with event; PY=patient year

IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE XX XX XX XX

n (rate/100 PY) n (rate) n (rate) n (rate) n (rate) IRD (95 % CI) IRD (95 % CI)

0-52 weeks

PYE XX XX XX

n (rate/100 PY) n (rate) n (rate) n (rate) IRD (95 % CI)

>52 weeks

PYE XX XX XX

n (rate/100 PY) n (rate) n (rate) n (rate) IRD (95 % CI)

16



IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE XX XX XX XX

n (rate/100 PY) n (rate) n (rate) n (rate) n (rate)

0-52 weeks

PYE

n (rate/100 PY)

>52 weeks

PYE

n (rate/100 PY)

17



IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE

n (rate/100 PY) IRD (95 % CI) IRD (95 % CI)

0-52 weeks

PYE

n (rate/100 PY)

>52 weeks

PYE

n (rate/100 PY)

18



IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE

n (rate/100 PY)

0-52 weeks

PYE XX XX XX

n (rate/100 PY) n (rate) n (rate) n (rate)

>52 weeks

PYE XX XX XX

n (rate/100 PY) n (rate) n (rate) n (rate)

19



IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE

n (rate/100 PY)

0-52 weeks

PYE

n (rate/100 PY) IRD (95 % CI)

>52 weeks

PYE

n (rate/100 PY) IRD (95 % CI)

20

Exposures


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY)

>52 weeks

PYE 155 653 1215

n (rate/100 PY)

21

Death


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 2 (0.6) 0 1 (0.3) 1 (0.2) -0.6 (-1.7, 0.5) 0.7 (-0.7, 2.1)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 0 4 (0.4) 4 (0.3) 0.5 (-0.2, 1.2)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 1 (0.6) 2 (0.3) 4 (0.3) -0.6 (-1.8, 0.6)

22

Serious Adverse Events


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 41 (13) 16 (11.4) 43 (14.4) 59 (13.5) 0 (-5.5, 5.4) 6.1 (-2.8, 15)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 40 (11.9) 113 (12.5) 164 (12.4) 3.2 (-2.2, 8.6)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 12 (7.7) 75 (11.5) 123 (10.1) 6.4 (0.2, 12.6)*

23

Malignancies Excluding NMSC


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 0 1 (0.7) 1 (0.3) 2 (0.5) 0.5 (-0.2, 1.1) 2.8 (-2.4, 7.9)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 2 (0.6) 6 (0.7) 8 (0.6) 0 (-1.1, 1.1)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 0 4 (0.6) 9 (0.7) 1.1 (-0.2, 2.3)

24

Serious Infections


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 13 (4.2) 6 (4.3) 12 (4.1) 18 (4.1) -0.4 (-3.5, 2.7) 1.3 (-3.9, 6.6)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 14 (4.2) 32 (3.5) 50 (3.8) 0.7 (-2.4, 3.7)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 4 (2.6) 20 (3.1) 35 (2.9) 1.3 (-2.2, 4.8)

25

Herpes Zoster

0-16 weeks: Studies JADA, JADC, JADN, JADV, JADW, and JADX0-52 and >52 weeks: JADA/Y, JADC, JADN, JADV/Y, JADX/Y, JADW/Y; >52 week data from resubmissionIRD=incidence rate difference; CI=confidence interval; BARI=baricitinib; N=number of subjects; PYE=patient year exposure; n=number of patients with event; PY=patient year

IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 4 (1.3) 5 (3.6) 15 (5) 20 (4.6) 3 (0.6, 5.3)* 2.8 (-2.4, 7.9)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 11 (3.3) 29 (3.2) 48 (3.6) 0.4 (-2.2, 3)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 6 (2.1) 44 (3.7) 87 (3.7) 0.7 (-1.5, 2.9)

26

Opportunistic Infections


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 2 (0.6) 0 2 (0.7) 2 (0.5) -0.2 (-1.4, 1.0) 0.7 (-0.7, 2.1)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 1 (0.3) 5 (0.6) 6 (0.5) 0 (-0.8, 0.7)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 1 (0.4) 8 (0.7) 13 (0.6) -0.1 (-0.9, 0.7)

27

Tuberculosis


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 0 0 0 0 -- --

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 0 1 (0.1) 1 (0.1) 0.3(-0.2, 0.8)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 0 5 (0.4) 6 (0.3) 1.1 (0.1, 2)*

28

Major Adverse Cardiovascular Events

0-16 weeks: Studies JADV, JADW, and JADX0-52 and >52 weeks: JADV/Y, JADX/Y, JADW/YIRD=incidence rate difference; CI=confidence interval; BARI=baricitinib; N=number of subjects; PYE=patient year exposure; n=number of patients with event; PY=patient year

IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 267 123 273 396

n (rate/100 PY) 2 (0.8) 0 2 (0.7) 2 (0.5) -0 (-1.5, 1.4) 1.6 (-0.6, 3.8)

0-52 weeks

PYE 305 825 1189

n (rate/100 PY) 1 (0.3) 4 (0.5) 5 (0.4) 0.2 (-0.8, 1.2)

>52 weeks

PYE 155 575 1092

n (rate/100 PY) 0 4 (0.7) 7 (0.6) 1 (-0.1, 2.1)

29

Overall Thrombosis


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 1 (0.3) 2 (1.4) 7 (2.4) 9 (2.1) 1.6 (0.1, 3.1)* 1.4 (-2, 4.8)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 5 (1.5) 10 (1.1) 16 (1.2) -0.4 (-2.1, 1.2)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 1 (0.4) 14 (1.2) 21 (0.9) 1.7 (0.3, 3.1)*

30

Arterial Thrombosis


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 1 (0.3) 2 (1.4) 2 (0.7) 4 (0.9) 0.4 (-0.7, 1.4) 0 (-2.8, 2.7)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 3 (0.9) 3 (0.3) 6 (0.5) -0.4 (-1.6, 0.8)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 0 8 (0.7) 11 (0.5) 1.2 (0.3, 2.2)*

31

Venous Thrombosis


IRD (95 % CI)

PlaceboN=1070

BARI 2N=479

BARI 4N=997

BARI 2/4N=1476

BARI 2/4 vs Placebo

BARI 4 vs BARI 2

0-16 weeks

PYE 308 140 298 438

n (rate/100 PY) 0 0 5 (1.7) 5 (1.1) 1.2 (0.1, 2.3)* 1.4 (-0.6, 3.4)

0-52 weeks

PYE 336 904 1318

n (rate/100 PY) 2 (0.6) 7 (0.8) 10 (0.8) 0 (-0.8, 0.3)

>52 weeks

PYE 155 653 1215

n (rate/100 PY) 1 (0.4) 7 (0.6) 11 (0.5) 0.5 (-0.6, 1.5)

32

JADV: 24 Week Safety Summary

TEAE=treatment emergent adverse event

33

JADZ: 24 Week Safety Summary

34

LABORATORY ABNORMALITIES

35

Laboratory Abnormalities

*mean change from baseline in combined phase 3 studies (JADX, JADW, JADV, JADZ)g=gram; dL=deciliter; µL=microliter

0-16 weeks, mean change* Placebo BARI 2 mg BARI 4 mg

Number of patients 892 403 1265

Hematologic Changes

Hemoglobin (g/dL) -0.20 -0.30 -0.26

Neutrophil (thousand cells/µL) 0.10 -0.60 -1.09

Lymphocyte (thousand cells/µL) -0.01 0.11 0.15Platelets (109/L) 2 16 17

36

Platelet Elevations: JADX & JADW

37

Platelet Elevations: JADX & JADW

1Number (%) of patients with platelet counts greater than 600 109/L. Seven (7) patients with their platelet counts greater than 600 109/L at baseline are excluded2Number (%) of patients with platelet counts greater than 450 109/L. Sixty seven (67) patients with their platelet counts greater than 450 109/L at baseline are excludedFrom phase 3 studies that included both 2 mg and 4 mg baricitinib study arms with data to week 24; patient data censored with change in treatment arm

38

Platelet Elevations: Phase 2 Studies

Data up to Week 13

39

Lipid Elevations

*mean change from baseline in combined phase 3 studies (JADX, JADW, JADV, JADZ)LDL=low density lipoprotein; HDL=high density lipoprotein

40

Liver Test Elevations

*mean change from baseline in combined phase 3 studies (JADX, JADW, JADV, JADZ)ALT=alanine aminotransferase; AST=aspartate aminotransferase; IU=international unit; L=liter; mg=milligram

41

Safety Conclusions• Serious infection, including opportunistic infections and tuberculosis• Herpes zoster• Malignancy• Thrombosis, both venous and arterial• Laboratory Abnormalities (often dose-dependent)

– Decreased neutrophil counts and hemoglobin– Platelet count elevations– Lipid elevations– Liver test elevations

Matthew Whittaker, Ph.D.Non-Clinical Reviewer


April 23, 2018

FDA Arthritis Advisory Committee MeetingPotential Biological Mechanisms for Baricitinib-induced Increase in Platelets



2

Janus Kinase (JAK) Enzyme Function

Clark et al. (2014) J. Med. Chem. 57, 5023-5038

3

In Vitro Selectivity of BaricitinibCell-free isolated enzyme assay Cell-based assay (human peripheral blood mononuclear cells)

JAK1 JAK2 JAK3 TYK2 JAK1/2 JAK1/3 JAK1/TYK2 JAK2/JAK2 JAK2/TYK2IC50 (nM) 5.9 5.7 >400 53 IC50 (nM) 32.8 55.4 71.6 NA 69.0

Selectivityvs. JAK3 >68 >70 - >7.5 Selectivity vs.

JAK1/JAK3 1.7 - 0.8 NA 0.8

Apparent selectivity of baricitinib (BARI) for JAK1 & JAK2 over JAK3, TYK2 Decreased inhibitory activity JAK3: intended to limit immune-suppressive effects seen with pan-JAK

inhibitors

Cell-free isolated enzyme assay Cell-based assay (human whole blood)

JAK1 JAK2 JAK3 TYK2JAK1/2 or JAK1/TYK2 JAK1/3 JAK1/TYK2 JAK2/JAK2 JAK2/TYK2 JAK2/TYK2

IC50 (nM) 4.0 6.6 787.0 61.0 IC50 (nM) 21.1 259 28.7 87.8 149 81.9

Selectivityvs. JAK3 197 119 - 13

Selectivityvs.

JAK1/JAK312.3 - 9.0 2.9 1.7 3.2

Clark et al. (2014) J Med Chem. 57, 5023 – 5038

4

Platelet Count: JADX & JADW

5

Kile, B. (2015) Nature Medicine. 21: 11 – 12.

Megakaryopoiesis

Thrombopoietin (TPO): glycoprotein hormone produced in liver

Acts at the TPO receptor (Mpl) to mediate expansion & differentiation of Hematopoietic stem cells (HSCs) → megakaryocyte progenitors (pro-MKs) → MKs → platelets (PLTs)

Mpl expressed on HSCs, pro-MKs, MKs, PLTs Mpl associates with JAK2 Geddis, A. (2010) Seminars in Hematology.

47: 212-219

6

JAK2 and Platelet Homeostasis Based on Meyer et al. Blood (2014); Ng et al. PNAS (2014)

T

T

T

TP

P T

P

T

LIVERT

BONE MARROW

HSC PRO-MK MK

Proliferation & expansion

Mpl MplMpl

TT

T TT

P

TT

PP

P

TPO

JAK2

Internalize & Degrade

TPO

Mpl

JAK2

= TPO= Platelet= JAK2

TP

P

P

P

TT

TT

T

T

P

T

Meyer S et al. (2014) Blood. 124: 2280 – 2284Skoda (2014) Blood. 124: 2168.Ng A. et al. (2014) PNAS. 111, 5884-5889.

T

P

Blood vessels

Blood vesselsHow might BARI increase platelets in RA patients?

7

Baricitinib-Induced Platelet IncreaseT

T

T

TP

P T

P

T

LIVERT

BONE MARROW

HSC PRO-MK MK

Mpl MplMpl

TT

T TT

P

TT

PP

P

TPO

JAK2

Internalize & Degrade

TPO

Mpl

JAK2

= TPO= Platelet= JAK2

TP

P

P

P

TT

TT

T

T

P

T

Meyer S et al. (2014) Blood. 124: 2280 – 2284Skoda (2014) Blood. 124: 2168.Ng A. et al. (2014) PNAS. 111, 5884-5889.

T

P

Blood vessels

BARIT

TTT

TT

T

T

T

TT

TBlood vesselsP

P

P

P

P

P

P

P

P

P

P

Proliferation & expansion

8

Initiation of BARI treatmento At clinical doses, BARI is present at a concentration that is:

• Sufficient to inhibit Mpl-mediated TPO clearance by platelets, BUT• Not sufficient to completely inhibit Mpl-mediated signal transduction in HSC/progenitor cells in

bone marrowo ↑ circulating TPO can stimulate expansion of HSC/progenitor cells that retain Mpl functiono Platelet population reaches maximum at ~ 2 weeks

2 weeks – 8 weeks of dosingo Increased platelet population: sufficient to overcome BARI inhibitory effect on TPO removal–

circulating TPO levels decline o Stimulus for platelet production is attenuated – platelet production is reduced – resetting to a new

equilibrium

Long-term BARI treatmento New equilibrium is achieved: Platelets are chronically elevated vs. placeboo Circulating TPO levels are chronically elevated via BARI inhibition of Mpl-associated JAK2 in platelets –

BARI levels in bone marrow are not sufficient to completely mitigate the effects of elevated TPO on HSC/progenitor cells

Potential Effects on Platelet Homeostasis

9

Evidence from the published literature provides a mechanistic framework for the observed BARI-induced increase in platelet countso Extent of platelet production is defined by TPO activation of Mpl in

HSC/progenitor cells in bone marrowo Circulating TPO levels are controlled by Mpl-mediated removal in mature

plateletso Mpl function is mediated by the activity of JAK2o BARI inhibition of JAK2 alters platelet homeostasis

• Differential inhibition of JAK2 associated with Mpl in platelets vs. stem/progenitor cell population could enhance platelet production

• BARI effects on biological processes associated with platelet removal cannot be ruled out

Conclusions

FDA Arthritis Advisory Committee MeetingEpidemiology Safety Study Review



Veronica V. Sansing-Foster, PhD, MSEpidemiologist

Division of Epidemiology II (DEPI-II)U.S. Food and Drug Administration

April 23, 2018

2

Baricitinib Resubmission

• January 15, 2016: Applicant submitted NDA 207924 for baricitinib – During the 24-week randomized placebo-controlled period of the Phase 2/3 studies, 6

patients with baricitinib 4-mg (n=997) reported venous thromboembolism (VTE) events (deep vein thrombosis [DVT] and pulmonary embolism [PE])

– No events in the baricitinib 2-mg (n=479) and placebo arms (n=1070)

• April 12, 2017: FDA issued a Complete Response letter due to the unfavorable benefit-risk given the potential risk of thrombosis

• December 4, 2017: Applicant resubmitted the application with the pooled incidence rates (IR) for all patients exposed to baricitinib (ALL BARI RA) – VTE IRs for baricitinib from clinical studies were compared to VTE IRs for DMARDs from

applicant’s observational study

3

Observational Safety Study Methods• Design: Retrospective, observational, descriptive study

• Data Sources: IMEDS/Sentinel and Truven Marketscan/Medicare

• Study inclusion criteria: RA, ≥ 18 yrs old, no prior VTE

• Exposure: csDMARDs (including MTX) and bDMARDs

• Outcomes: VTE, including DVT and PE

• Follow-up/Censoring: Outcome, death, plan disenrollment, drug discontinuation, starting another drug, or end of study

• Analysis: Incidence rate (IR) per 100 PY for DMARDs vs. pooled IRs per 100 PY for baricitinibfrom clinical trials; stratified by age, calendar year, and gender

4

Study Groups (Data Source)

VTEIR (95% CI)

Baricitinib (ALL BARI RA)

0.53 (0.38, 0.71)

DMARDs (Truven – Def. 1)

0.68 (0.65, 0.71)


1.05 (1.01, 1.09)


1.63 (1.58, 1.69)

DMARDs (IMEDS)

1.34 (1.24, 1.44)

Results: VTE Incidence Rates per 100 PY by Study Groups

* DEFINITION 1: diagnostic code + anticoagulant w/in 31 days of VTE, DVT, PEDEFINITION 2: inpatient diag. code for venous or PE or phlebitis and thrombophlebitis or DVT or outpatient diagnostic code + anticoagulant w/in 31 ds of VTE DEFINITION 3: diagnostic code for venous embolism or phlebitis and thrombophlebitis or DVT in inpatient, outpatient or emergency department care setting

ǂ The mid-P exact test 95% confidence intervals have been calculated by the DEPI-II reviewer using Open Epi Software.

5


DVTIR (95% CI)


0.38(0.25, 0.54)


0.55 (0.52, 0.58) ǂ


0.84 (0.80, 0.87) ǂ


1.36 (1.31, 1.40) ǂ

DMARDs (IMEDS)

1.97 (1.85, 2.09)

Results: DVT & PE Incidence Rates per 100 PY by Study Groups

* DEFINITION 1: diagnostic code + anticoagulant w/in 31 days of VTE, DVT, PEDEFINITION 2: inpatient diag. code for venous or PE or phlebitis and thrombophlebitis or DVT or outpatient diagnostic code + anticoagulant w/in 31 ds of VTE DEFINITION 3: diag. code for venous embolism or phlebitis and thrombophlebitis or DVT in an inpatient, outpatient or emergency department care setting


6


DVTIR (95% CI)

PEIR (95% CI)


0.38(0.25, 0.54)

0.24(0.14, 0.37)


0.55 (0.52, 0.58) ǂ

0.26 (0.24, 0.28) ǂ


0.84 (0.80, 0.87) ǂ

0.38 (0.36, 0.41) ǂ


1.36 (1.31, 1.40) ǂ

0.46 (0.43, 0.49) ǂ

DMARDs (IMEDS)

1.97 (1.85, 2.09)

0.77 (0.70, 0.84)

Results: DVT & PE Incidence Rates per 100 PY by Study Groups

* DEFINITION 1: diagnostic code + anticoagulant w/in 31 days of VTE, DVT, PEDEFINITION 2: inpatient diag. code for venous or PE or phlebitis and thrombophlebitis or DVT or outpatient diagnostic code + anticoagulant w/in 31 ds of VTE DEFINITION 3: diag. code for venous embolism or phlebitis and thrombophlebitis or DVT in an inpatient, outpatient or emergency department care setting


7

Applicant’s Conclusion

• All rates from the baricitinib patients were lower than or within the lower range of the VTE rates observed in the RA population treated with DMARDs

• The study’s conclusions were not altered by:– Age-stratified rates– bDMARD and csDMARD rates

8

FDA Concerns

• The overall study designs and populations compared by the applicant are fundamentally different and aim to address different objectives

– Clinical studies aim to address efficacy, and sometimes safety, in a clinical setting

– Observational studies aim to address safety in a “real world” setting

9

FDA Concerns

ConcernBaricitinib

Clinical Data Example

DMARDObservational Data Example

Different patient populations US and Non-USpatients

US patients

10

FDA Concerns

ConcernBaricitinib




US patients

Different inclusion and exclusion criteria Past DMARD use Incident DMARD use

11

FDA Concerns

ConcernBaricitinib


DMARD Observational Data Example


US patients


Different collection methods for medical history, RA, and baseline drug exposure

Drug exposure captured at baseline

Drug exposure captured 3 mos. before baseline

12

FDA Concerns

ConcernBaricitinib



Different patient populations US and Non-US patients

US patients


Different collection methods for medical history, RA, and baseline drug exposure

Drug exposure captured at baseline

Drug exposure captured 3 mos. before baseline

Patients with baseline anticoagulant use for prior VTE were included

Stratified rates cannot be compared

13

The VTE rates from the baricitinib clinical trials should not be

compared to those of DMARD users in the IMEDS/Truven data

to conclude that baricitinib

is less safe, as safe as, or safer than DMARDs

FDA Conclusion

14

FDA Acknowledgements

Dr. Efe EworukeDr. Saharat Patanavanich

Nichelle RashidDr. Lockwood Taylor

Dr. Joel WeissfeldDr. Judith Zander

Raj Nair, M.D.Clinical Reviewer


April 23, 2018

FDA Arthritis Advisory Committee MeetingBenefit Risk Considerations



2

Benefits• Both baricitinib 2 mg and 4 mg once daily doses are effective in reducing

signs and symptoms and improving physical function in patients with RA versus placebo

– Higher ACR20, 50, 70 response rates versus placebo – Improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI) compared to

placebo– Data not consistent in showing a meaningful benefit of 4 mg over the 2 mg dose

• Radiographic response– The data for 4 mg dose are robust– Some uncertainty about 2 mg dose, studied in only one study as an exploratory endpoint

3

Risks• Safety consistent with an immunosuppressant and MOA

– Serious and sometimes fatal infections– Opportunistic infections and TB– Herpes zoster– Malignancies – Thrombosis, including arterial and venous thromboses

• Laboratory abnormalities (often dose-dependent)– Decreases in neutrophil counts and hemoglobin– Platelet count elevations– Lipid elevations– Liver test elevations

4

Baricitinib for RABenefits • Superior efficacy of both

baricitinib doses compared to placebo:

– Signs and symptoms – Physical function – No consistent meaningful benefit of 4

mg over 2 mg

• Radiographic response:– Data for 4 mg dose are robust– Some uncertainty about 2 mg dose,


Risks • Serious infections• Herpes zoster, opportunistic




platelet elevations

FDA Arthritis Advisory Committee MeetingCharge to the Committee



Nikolay P. Nikolov, M.D.Clinical Team Leader


April 23, 2018

2

Efficacy Considerations• Both baricitinib 2 mg and 4 mg once daily doses are effective in reducing

signs and symptoms and improving physical function in patients with RA versus placebo– Higher ACR20, 50, 70 response rates versus placebo at week 12 and week 24– Improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI)

compared to placebo– Data not consistent in showing a meaningful benefit of 4 mg over the 2 mg dose

• Radiographic response– The data for 4 mg dose are robust– Some uncertainty about 2 mg dose, studied in only one study as an exploratory

endpoint

3

Safety Considerations• Safety findings

– Serious infection, including H. zoster, opportunistic infections and tuberculosis

– Malignancy– Thrombosis, both venous and arterial– Laboratory abnormalities (often dose-dependent)

• Safety data limitations– Limited controlled comparisons– Overall safety exposure data limited for baricitinib 2 mg vs 4 mg

4

Benefits• Superior efficacy of both

baricitinib doses compared to placebo

– Signs and symptoms – Physical function – No consistent meaningful benefit of 4 mg

over 2 mg

• Radiographic response– Data for 4 mg dose are robust– Some uncertainty about 2 mg dose,


Risks• Serious infections• Herpes zoster, opportunistic




thrombocytosis

Benefit-Risk Considerations

5

• “FDA will approve an application after it determines that the drug meets the statutory standards for safety and effectiveness, manufacturing and controls, and labeling.”

Approval of an Application21 CFR 314.105 (c)

6

• (b)(5) “…substantial evidence consisting of adequate and well-controlled investigations…that the drug product will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling.”

Efficacy Standard21 CFR 314.125

Refusal to Approve an Application

7

(b)(2) “…do not include adequate tests by all methods reasonably applicable to show whether or not the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.”

(b)(3) “The results of the test show that the drug is unsafe for use under the conditions prescribed, recommended, or suggested in its proposed labeling or the results do not show that the drug product is safe for use under those conditions.”

(b)(4) “There is insufficient information about the drug to determine whether the product is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.”

Safety Standard21 CFR 314.125

Refusal to Approve an Application

8

Discussion Points and Voting Questions

1. DISCUSSION: Discuss the efficacy data for baricitinib for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX). Include a discussion of the 2 mg and 4 mg doses of baricitinib and whether available data support a benefit of one dose over the other.

9




10


4. DISCUSSION: Discuss the safety data for baricitinib for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX) Include a discussion of the following issues:

a) Adequacy of safety database for the 2 mg dose of baricitinibb) Safety issues of interest and whether data suggest a dose response

– Thromboembolic events– Malignancy– Serious infections, opportunistic infections, herpes zoster, tuberculosis– Abnormal laboratory parameters, specifically platelet count elevations

c) Overall safety profile of the 2 mg dose and the 4 mg dose, and whether the data are more favorable for one dose versus the other.

11

Discussion Points and Voting Questions5. VOTE: Are the safety data adequate to support approval of baricitinib 2 mg

once daily for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

6. VOTE: Are the safety data adequate to support approval of baricitinib 4 mg once daily for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

12

Discussion Points and Voting Questions7. VOTE: Is the benefit-risk profile adequate to support approval of baricitinib

2 mg once daily for the proposed indication of the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

8. VOTE: Is the benefit-risk profile adequate to support approval of baricitinib 4 mg once daily for the proposed indication of the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate (MTX)?– If no, what data are needed?

fda arthritis advisory committee meeting fda opening remarks · patients from p2 and p3 studies:...

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