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Exploring the Role of JAK Inhibitors Across the Spectrum of IMIDs
Vibeke Strand, MD, MACR, FACPBiopharmaceutical Consultant
Adjunct Clinical Professor, Division Immunology/RheumatologyStanford University, Palo Alto CA
Disclosures: Consultant
AbbvieAmgenAsana
InmedixJanssen Kezar
AstraZenecaBayerBMSBoehringer IngelheimCelltrionCORRONACrescendo
KyphaLillyMerckNovartisPfizerRegeneronSamsung
EMDSeronoGenentech/RocheGlenmarkGSKHorizon
SamsungSandozSanofiServierSetpointUCB
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Overview of JAK‐STAT Signaling
KF Baker, and JD Isaacs: Ann Rheum Dis 2018;77:175‐187
Overview of JAK/STAT Signaling
JAKi display different in vitro profiles; they modulate distinct cytokine pathways to different degrees and durations over 24 hoursg
Consistently, JAKi do not potently/continuously inhibit any individual cytokine signaling pathway for 24 hours
It is unclear which cell types and what signaling pathways are affected at any given time
Despite differences, clinical responses appear to be similar
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Rheumatology Indications
Rheumatoid Arthritis
o Tofa: Approved US and EU: 5mg BID; 11mg XR QD
o Bari: Approved EU: 2 and 4mg QD; Approved US: 2 mg QD only in TNF‐IRo Bari: Approved EU: 2 and 4mg QD; Approved US: 2 mg QD only in TNF IR
o Upa: 6 Ph 3 RCTs; 5 completed: SELECT EARLY, NEXT, MONO, BEYOND, COMPARE, CHOICE
o Fil: Ph 3 RCTs; 1 completed: FINCH 1, 2, 3
Psoriatic Arthritis
o Tofa: Ph 3 OPAL and BROADEN RCTs: Approved US: 5mg BID; 11mg XR QD
o Upa: 2 Ph 3 RCTs underway: DMARD‐IR and BIO‐IR
o Fil: Ph 2 EQUATOR RCT positiveo Fil: Ph 2 EQUATOR RCT positive
Spondyloarthropathy
o Tofa: positive Ph 2; now pursuing clinical indication
o Upa: Ph 2 RCT underway
o Fil: Ph 2 TORTUGA RCT positive
Juvenile Inflammatory Arthritis: Tofa: Ph 2/3 recruiting
EQUATOR Phase 2 RCT: Filgotinib (FIL) in csDMARD‐IR PsA
• 131 PsA patients randomized to FIL 200 mg qd (n=65) or PBO (n=66) +/‐csDMARDs for 16 wks
• 1◦ EP: ACR 20/50/70 responses w/ FIL 200mg: 80% v PBO: 33%; p<0∙0001
• PASI 75: 62% w/ involved BSA ≥3%; FIL 200mg: 45.2% v PBO:15%; p=0.0034
• MDA: FIL 200mg: 23.1% v PBO: 9.1%; p=0.0212
• LEI: 58% enthesitis at BL; resolution of enthesitis: FIL 200mg: 50% v PBO: 24%; p=0.0089
• Safety: nasopharyngitis, HA; SAEs: 1 HZ, 1 fatal pneumonia [FIL]
Mease PJ, et al. ACR 2018, Chicago, #1821; Mease P, et al. Lancet 2018; 392: 2367–77
*P<0.05; †P<0.01; ‡P<0.001
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TORTUGA RCT: Filgotinib in AxSpA
• 1◦ EP: Mean △ from BL in ASDAS: FIL: –1∙47 (SD 1∙04) and PBO: –0∙57 (0∙82)Mean diff: –0∙85 (95% CI –1∙17 to –0∙53; p<0 0001p<0∙0001
• Major improvement in ASDAS: FIL:19/38 (33%) vs PBO: 1/58 (2%)Mean diff: 31%, 95% CI 18 to 44; p<0∙0001
• Clinically significant improvement in ASDAS: FIL: 38 (66%) vs PBO: 15 (26%)(Mean diff: 40%, 22 to 54; p<0∙0001)
van der Heijde D et al Lancet http://dx.doi.org/10.1016/S0140‐6736(18)32463‐2
• Inactive disease at wk 12: FIL: 3 (5%) vs PBO: 0(Mean diff: 5%, –2 to 14; p=0∙092)
• FIL effective and well tolerated; Phase 3 RCTs underway
Dermatology Indications
Atopic Dermatitis
o Tofa: Ph 1 positive; (topical): Ph 2 RCT positive; new PFE JAK 1: Ph 3 RCT, breakthrough status
o Bari: Ph 3 RCTs underwayo Bari: Ph 3 RCTs underway
o Upa: Ph 3 RCTs underway
o Ruxo: open label 20mg QD; (topical)
o Asana: combined JAK/Syk inhibitor: Ph 2a positive; well tolerated; Ph 2b RADIANT RCT underway
Canine atopic dermatitis: Oclacitinib approved
Chronic actinic dermatitis: Tofa: RCT
Alopecia Areata:
o Tofa (topical): Ph 2 RCT
o Ruxo (topical): Ph 2 RCT; Bari: positive CR in pt w/ CANDLE
o Aclaris (0.2% topical) JAK 1/3 (ATI‐502): Fast track designation for alopecia areata, totalis and universalis
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Atopic Dermatitis, Alopecia Areata
Atopic Dermatitis: Tofacitinib: Series and Ph 2A RCT
Series: 6 pts w/ mod/severe AD patients failed standard Rx 1
o Improvement in Severity Scoring ADo Improvement in Severity Scoring AD (SCORAD) by 54.8% at 14 wks, maintained to 29 wks
o 69.9% reduction in pruritis, sleep loss
4 week phase 2A RCT: Topical 2% ointment vs vehicle 2
o 69 pts: mild/moderate AD
1. Levy L et al J Am Acad Dermatol 2015;73:395‐9; 2. R Bissonnette et al: Brit J Derm 2016; 175:902–911
p /
o % CFB Eczema Area and Severity Index (EASI) sum score: ‐81.7 vs ‐29.9%; p<0.001
o MDGA, pruritis stat significant wks 1—4
o Safety, tolerability acceptable; more AEs w/ vehicle
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Atopic Dermatitis: Upadacitinib – Phase 2b RCT
• Significant reduction of select symptoms of atopic dermatitis, including pruritis at week 1 and improvement in the extent and severity of skin lesions at week 2
• Significant improvement in extent and severity of atopic dermatitis, as measured by the mean percent change in Eczema Area and Severity Index (EASI) score
Mean % Change from Baseline in EASI ScoreDose Week 2 Week 16 (Primary Endpoint)
30 mg (n=42) 59%* 74%*15 mg (n=42) 56%* 62%*
Guttman‐Yassky E, et al. Presented at: the 2018 American Academy of Dermatology (AAD) Annual Meeting; February 17, 2018; San Diego, CA.
• Granted Breakthrough Therapy Designation from FDA for adult patients with moderate to severe atopic dermatitis who are candidates for systemic therapy
15 mg (n 42) 56% 62%7.5 mg (n=42) 39%* 39%**Placebo (n=39) 9% (n=37) 23% *P<.001; **P<.05
Alopecia Areata: Tofacitinib: 2 Series; Baricitinib and 2 new PFI JAKs in RCTs
Retrospective study of 90 patients w/ alopecia areata,alopecia totalis, alopecia universalis 1
o ≥40% scalp hair loss; ≤10 yrs disease duration
o Primary EP: % change in Severity of Alopecia Tool (SALT)
65 potential responders: 77% achieved clinical response
o 58%: ≥50% improvement in SALT over 4 – 18 mos Rx
o Pts w/ AA (n=13) than AT or AU (n=52) had better SALT responses: 81.9 v 59%
Retrospective study 13 adolescents 2
o Clinically significant hair regrowth: 92%
o SALT: mean 61% improvement at 6.5 mo
Striking improvement w/ Bari in ptw/ CANDLE syndrome and AA 3
All series: Treatment well tolerated 1. Liu LY: J Am Acad Dermatol 2017;76:22‐8; 2. Craiglow BG et al: J Am Acad Dermatol 2017;76:29‐32; 3. Jabbari A et al: EBioMedicine 2015; 2:351–355
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Dermatology Indications
Psoriasis
o Tofa development completed; 10mg BID effective; FDA CRL; (topical: failed)
B i Ph 2B RCT i io Bari: Ph 2B RCT positive
o Ruxo (topical): Ph 2 RCT
o BMS‐986165: Tyk 2 Inhibitor; binds pseudokinase domain that regulates ATP binding site
Vitiligo: Case reports: Tofa, Ruxo (topical); Ruxo: Ph 2A RCT underway
Erythema Multiforme: Tofa
Graft v Host Disease:
o Ruxo: positive survey of use: EU Tx centers; Priority Review at FDA for approval
o Tofa: effective in murine model
Psoriasis
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Psoriasis
Tofa development completed; not approved: effective 10mg dose not considered safe
⎻ 2 Phase 3 OPT RCTs in pts w/ mod/severe Ps; 5 or 10mg BID v PBO; wk 16 PBO rescue 1,2
• PASI75 and PGA 0‐1: at 12 weeks favored 10mg dose; AEs similar between doses
• Phase 3: Tofa 10mg non‐inferior to ETN
– OPT Compare: LTE: mean QD dose mos 7 – 24: 17.9mg 2,3
– Phase 3: Tofa 5 or 10mg Rx x24 wks; if responders then withdrawn and ReRx 5
– PFI now has a Tyk2/JAK 1 inhibitor in clinical development– PFI now has a Tyk2/JAK 1 inhibitor in clinical development
Baricitinib Phase 2 RCT positive, particularly at higher doses of 8 and 10mg
Topical Ruxolitinib effective
BMS‐986165 (oral TYK2 inhibitor) phase 2 RCT positive1. Papp KA et al: Br J Derm. 2015; 173:949‐961; 2. Papp KA et al: J Am Acad Derm 2016; 74:843‐850; 3. Papp KA et al: BMC Dermatol. 2016; 16:15
4. Bachelez H et al: Lancet. 2015; 386:552‐561; 5. Bissonette R et al: Brit J Derm 2015; 172:1395–1406;
Psoriasis: Baricitinib: Phase 2B RCT
Phase 2b RCT in 271 pts w/ mod/severe Ps
o Bari: 2, 4, 8 or 10mg QD x 12 weeks (Part A)
o Dose adjustment Part B for add’l 12 weeks: 8 or 10mgj g
• Rescue PBO
• Increase dose in partial responders
• Non‐responders at 8mg ‐> 10mg; NRs at 10mg D/Ced Rx
Primary EP: PASI75 at 12 weeks in NA patients:
o 8mg: 43%; 10mg: 54% v PBO: 17%; p<0.05
o All but 2mg dose had statistically significant improvements in PAS75 at 12 weeks
o PASI90 responses in 8 and 10mg dose groups
o Responses maintained to 24 weeks; 48% NRs/PRs ‐> PASI75
AEs similar between lower doses; higher w/ 8 and 10mg
o Dose related decreases Hb, pmns; increases CPK, Cr, HDL, LDL
Papp KA et al: Br J Dermatol. (2016) 174, pp1266–1276.
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Psoriasis: Ruxolitinib: Topical Clinical Development
Phase 2A RCT: Topical 1.0 or 1.5% cream applied QD or BID x4 wks to 2 – 20% BSA
o 5 sequential cohorts 5 patients each
o Target lesions scored 0 – 4 for erythema, scaling and thickness and PGA
o Plasma conc; pSTAT3 levels in PBMCs evaluated
o Pre and post skin biopsies
Results: improvement in lesional scores: reduced epidermal hyperplasia and dermal inflammation
fo Low plasma concentrations of drug; no significant inhibition of pSTAT3
o Correlations between clinical improvement and
decreased markers of Th17 and DC activation
o Immunohistochemistry: reduced CD3, CD11c, Ki67 and keratin 16
1. Punwani N et al: Br J Dermatol. 2015; 173; 989–997
BMS‐986165 (oral TYK2 inhibitor): Efficacy and safety Phase 2 RCT
§§
• Unique binding site of BMS‐956165 makes it highly selective for TYK2 1,2
• 267 pts w/ mod‐severely active PsO; 12 wks§
† §§
§
*
267 pts w/ mod severely active PsO; 12 wks3mg qod; 3mg qd, 3 and 6mg bid, 12mg qdvs PBO 3,4
• 1◦ EP: PASI 75; effective TNF naïve and –IR; rapid onset of response at 15 days3mg bid, 6 mg bid, 12 mg QD p<0.0001 v PBO
PASI 90 Si il b fit t hi h d
*P<0.05; †P<0.01; ‡P<0.001; §P<0.0001 vs PBO1. Gillooly K, et al. ACR/ARHP 2016. 11L; 2. Catlett IM, et al. EULAR 2017. SAT0226; 3. Papp KA, et al. ACR 2018, Chicago, #2563; 4. Papp K, et al. NEJM 2018; 379:1313–21
• PASI 90: Similar benefit at high doses
• Safety: low frequency acne at highest doses
• RCTs planned in PsA, IBD, SLETYK2
Activedomain
Regulatory domain
(pseudokinasedomain)
§
§§
‡
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Sarcoidosis
Case Report: Clinical Remission of Chronic Sarcoidosis with Tofacitinib
• A patient with cutaneous sarcoidosis resistant to conventional therapyover many years had clinical improvement w/tofacitinib andimprovement w/tofacitinib and relapsed with withdrawal of the medication
• Before treatment sample obtained from circled area. Skin‐lesion samples during treatment were taken after 10 months of therapy
• RNA sequencing of skin lesion samples• RNA sequencing of skin‐lesion samplesshowed dysregulation of JAK‐STAT thatwas responsive to tofacitinib.
• Change in the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) score for disease activity
• Next panel illustrates remissionDamsky W et al. N Engl J Med 2018; 379:2540‐6
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Case Report: Clinical Remission of Chronic Sarcoidosis with Tofacitinib
Damsky W et al. N Engl J Med 2018;379:2540‐6
Inflammatory Bowel Disease
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Gastroenterology Indications
Crohn’s Disease
o Tofa: Ph 2 RCT: 1, 5, or 15 mg or PBO BID for 4 weeks in 139 pts did not show clinical efficacy
h do Upa: Ph 3 RCTs underway
o Fil: 2 Ph 3 DIVERSITY RCTs: induction and maintenance underway;
⎯ Ph 2 FITZROY RCT: induction and maintenance;
⎯ Ph 2 DIVERGENCE 1: small bowel and DIVERGENCE 2: fistulizing CD
Ulcerative Colitis Ulcerative Colitis
o Tofa development completed; OCTAVE RCTs: induction I and II; SUSTAIN RCT: maintenance FDA approved 5 – 10mg BID dosing based on unanimous vote of GIDAC to approve 5 – 15mg 1
o Upa: Ph 2 induction and maintenance RCTs; Ph 2 symptomatic and endoscopic remission
o Fil: 2 Ph 3 SELECTION RCTs underway
1. https://www.businesswire.com/news/home/20180308006357/en/Pfizer‐Announces‐Favorable‐Outcome‐FDA‐Advisory‐Committee
Crohn’s Disease: Filgotinib: Phase 2 Induction and Maintenance RCT
Ph 2 FITZROY RCT: induction and maintenance
o 174 pts documented ileal, colonic or ileocolonicCD ≥3months; by colonoscopy and histology
• CDAI: 220 –450
o 3:1 randomization: FIL 200mg QDay v PBO x 10 wks; stratified by prior TNFi exposure; CRP, GC use
o 2nd 10 weeks maintenance; assigned Fil 100, 200mg or PBO based on responder status
Primary EP: CDAI remission <150 at week 10
o Fil 200mg: 60/128 (47%) vs 10/44 (23%) PBO achieved remission at week 10, p=0.0077
• Stat sig improvements all IBDQ subscales
Pooled safety 0 – 20 weeks: FIL vs PBO:
o TEAEs: 75 v 67%; SAEs: 9 v 4%; SIEs: 5% vs 0
Vermiere S et al: Lancet 17; 389: 266–75
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Other Autoimmune Disease Indications
Other Autoimmune Disease Indications
Autoinflammatory Ds: Bari: CANDLE, SAVI and STING: compassionate use protocol; case reports
Systemic Lupus Erythematosus
o Tofa: 3 Ph 1 RCTs
o Bari: Ph 2 RCT completed
o Fil: 2 Ph 2 RCT: LOE; Ph 2: membranous nephropathy; Ph 2: active cutaneous SLE
Primary Sjogren’s Syndrome
o Tofa: eyedrops and topical: improved signs and sx in dry eye disease
o Fil: Ph 2: Fil vs GS‐9876 (Syk inhibitor) or Tirabrutinib (BTK inhibitor) 1
Dermatomyositis: case reports in refractory disease with Tofa, Ruxoy p y ,
Giant Cell Arteritis:
o Bari: Ph 1 OLE
o Upa:
Early diffuse SSc: Tofa: Ph 1; Ruxo
Active non‐infectious uveitis: Fil: Ph 2 RCT 1. http://www.whatyousjo.com/2017/04/new‐sjogrens‐syndrome‐clinical‐trial‐filgotinib‐gs‐9876‐and‐tirabrutinib/
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Autoinflammatory Interferonopathies: Baricitinib NIH Expanded Access
• CANDLE: chronic atypical neutrophilic dermatosis w/ lipodystrophy & elevated temperatures: n=10SAVI: stimulator of IFN genes [STING]‐associated vasculopathy with onset in infancy: n=4Other interferonopathies: n=4
– Treated for mean duration 3.0 years
– Median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63); p < 0.0001
– In 14 patients receiving GCs at BL, QD prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09)to to 0.11 mg/kg/day (IQR, 0.02–0.24) p < 0.01
– 5 of 10 patients with CANDLE achieved lasting clinicaremission
– HRQOL, height, BMD sig improvedMontealegre Sanchez G et al: JCI 2018; 128:3041‐52
Systemic Lupus Erythematosus: Baricitinib 24 week Phase 2 RCT
• 314 patients with SLE receiving SOC
– ANA+ or anti‐dsDNA Ab+, SLEDAI‐2K ≥4, arthritis or rash required; mean S2K: 8.8‐9.0
Efficacy at Week 24
– 71‐73% GCs, 43‐46% IS, 68‐73% antimalarials
– Randomized 1:1:1 to PBO, BARI 2 or 4 mg QDay + SOC
– 1◦ EP: Resolution SLEDAI‐2K arthritis or rash
• Positive response in BARI 4 mg
– SLEDAI‐2K arthritis or rash; SRI‐4, SLEDAI Flare Index (SSFI), LLDAS, and TJC
N i ifi t diff EP BARI 2 PBO– No significant differences any EPs: BARI 2 mg vs PBO
– Pred <20mg QD, no increases; tapering BL to wk 16
– 70% IFN high sig BL; BARI 4 sig ↓ wk 12 (‐24%); 24 (‐23%) 2
• AEs: 73 v 71 v 65%; SAEs: 10 v 10 v 5%; SIEs: 6 v 2 v 1%;H zoster: 1 v 0 v 1 BARI 4 v 2 mg v PBO
– 1 SAE of DVT in BARI 4 mg group1. Wallace DJ, et al. EULAR 2018: OP0019: Wallace DJ et al. Lancet 2018: 392:222‐31; 2. Doerner T et al: ACR 2018: #1894
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Refractory Dermatomyositis: Open Label Pilots: Tofacitinib and Ruxolitinib
• 12 wk single center POC in 10 subjects: all failed high dose GCs 1
– 11 mg Tofa QD; ≤20 mg Pred QD; no IS
1◦ EP: IMACS ≥20% improvement in 3/6 core set– 1 EP: IMACS ≥20% improvement in 3/6 core set
measures and ≤2 worsening by ≥25%
– 2◦ EP: Cutaneous Dermatomyositis Disease Area and Severity
Index (CDASI), steroid‐sparing
• 9/9 met 1◦ EP: 5 (56%) moderate; 4 (44%) minimal improvement
– CDASI activity score BL to 12 weeks statistically significant
(28 ± 15 4 (BL) vs 9 5 ± 8 5 (12 wks) p 0 0005(28 ± 15.4 (BL) vs. 9.5 ± 8.5 (12 wks), p=0.0005
– CXCL‐9/10 trend to improvement w/ Rx
– 3/4 (75%) on 20 mg Pred at BL completely tapered off GCs
• Ruxolitinib: 4 refractory pts: rapid improvement rash, weakness 2
– Reverses IFNa induced damage in muscle and endothelial cells
1. Paik JJ et al: ACR 2018: abstract L02; 2. Ladislau L et al: Brain 2018: 141; 1609–21
Safety of the JAK/STAT Inhibitors
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General Overview of the Safety of JAK Inhibitors Across IMIDs
Based primarily on extensive clinical development programs in RA
o Generally similar across agents
o Safety profile similar to TNF inhibitors, with a few notable exceptions:o Safety profile similar to TNF inhibitors, with a few notable exceptions:
• Concerns re SIEs, OIs including TB in endemic regions
• However, incidence H zoster reactivation increased w/ particular risk in Japan and Korea
• Malignancies generally similar, w/ concerns re NMSC and lymphomas, may be disease related
• Despite HDL, LDL increases, these appear related to decreases in inflammation and less ‘atherogenic lipid profile’; incidence of MACEs not apparently increased
• Newly emerging profile of Thromboembolic events/DVTs possibly ‘JAK2 related’?• Newly emerging profile of Thromboembolic events/DVTs, possibly JAK2 related ?
• GI perforations more common than w/ TNFi’s; less common than w/ Tocilizumab
o Laboratory changes require monitoring:
• Hematologic parameters: Hb, lymphocytes, pmns, platelets: variable across agents
• LFT elevations; HDL/LDL increases similar to IL‐6 inhibitors; less atherogenic profile
• CPK and serum creatinine increases: generally idiosyncratic
Comparison of JAK/STAT Inhibitor Safety Profiles: Incidence per 100 Pt Years in RA
Tofacitinib 1,2,3
JAK 3/1/2 Approvedn=6194
Baricitinib 4
JAK 1/2 Ph3/Approvedn=3492
Filgotinib 5
JAK 1 Phase 2n=739
Upadacitinib 6
JAK 1/2 Phase 2n=493
Patient Years 19,406 6,637 1,708 725, , ,
SIEs 2.7 2.9 1.5 2.3
OIs 0.3 √ √ 0.4
Tb 0.2 0.15 0 0
H zoster: non‐serious and serious 3.9 3.2 1.2 3.7
Malignancy (excl NMSC) 0.9 0.8 0.5 0.8
Lymphoma 0 1 0 09 NR NR
1. Mease PJ, et al. ACR2017 #16L; 2. Cohen S et al: ARD 2017: doi:10.1136/annrheumdis‐2016‐210457; 3. Charles‐Schoeman et al. Sem Arth Rheum 2016; 46:261–71; 4. Genovese MC et al. ACR 2017 #511; 5. Genovese MC et al. ACR 2017 #1909; 6. Genovese MC et al ACR 2017 #509
Lymphoma 0.1 0.09 NR NR
NMSC 0.6 0.4 NR 0.7
MACE 0.58 0.5 0.5 0.1
DVT/PE 0.1 0.5 – 0.6 0.12 0.7
GI perforations 0.11 0.05 NR 0.05
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Risk of Thromboembolism Increased in RA Patients
Deep Vein Thrombosis Pulmonary embolism
Patients with RA
Matched controls
Patients with RA
Matched controlsMatched controls
Chung W‐S, et al. Ann Rheum Dis 2014;73:1774–80
• Post approval CV Safety Trial A3921133 fully enrolled in patients ≥50 years age 1
– With ≥1 cardiovascular risk factor
– Tofa 5mg+MTX v Tofa 10mg+MTX v TNFi+MTX
Recent Announcement: Increased Risk for PE and Deaths w/ Tofacitinib 10mg
Tofa 5mg MTX v Tofa 10mg MTX v TNFi MTX
• External DSMB announced Feb 26:
– “Patients treated with tofacitinib 10 mg BID had a statistically and clinically important difference in occurrence of pulmonary embolism compared with patients treated with a TNFi”
– “Also noted an increase in overall mortality in the 10 mg BID treatment group compared to the tofacitinib 5 mg BID and TNFi treatment arms”
• Dose reduced in patients receiving 10mg BID to 5mg BID
• Analyses by FDA and EMA ongoing
• Despite Truven and Medicare data from Tofa new users in US (2012—16); 5.7% of 50,865 RA pts 2
– VTEs (PEs+DVTs) propensity score based fine stratification weighting: 60 confounding variables
– Event rate low: <1/100 pt yrs, numerically higher but statistically not significant risk vs TNFi’s
• As with Bari, VTE mechanism remains poorly understood; treatment or the underlying disease?1. Pfizer Press Release 2/26/2019; 2. Desai RJ, et al. A+R 2019; 71:892–900
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Adjusted Kaplan Meier Plots for VTE Risk: Tofa vs TNFi’s
Desai RJ, et al. A+R 2019; 71:892–900
3‐20‐2019: Increased risk of blood clots in lungs and death with higher dose of Tofacitinib for RA
• Overall incidence of PE 5x higher in Tofa 10mg BID compared with TNFi; approximately 3x higher than other RCTs across development program
EMA Announcements:
approximately 3x higher than other RCTs across development program.
• All cause mortality in 10mg BID statistically exceeded 5mg BID and TNFi treatment arms.
5‐17‐2019: Restrictions in use of Xeljanz while EMA reviews risk of blood clots in lungs
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Risk of Herpes Zoster in RA Patients (retrospective cohort study)
12
s
USAa
10.612
s
UKb
9.8
3.7
2
4
6
8
10
ate per 1000 patient‐years 10.6
4.1
2
4
6
8
10
ate per 1000 patient‐years
aUS PharMetrics claims database;bUK General Practice Research Database Smitten AL, et al. Arthritis Rheum 2007; 57:1431–8
0
RA cohort Non‐RA cohort
Ra
0
RA cohort Non‐RA cohort
Ra
Use of DMARDs and ANY DOSE of oral glucocorticoids was associated with herpes zoster
Real‐World Risk of Herpes Zoster with Tofacitinib and Biologics
Curtis J et al. Ann Rheum Dis 2016; 75:1843–7
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Herpes zoster in RA Patients Treated with Baricitinib
• Methods
– Pooled Ph I, II, III studies and LTE to Jan 2016
– Incidence rate/100 Pt Yrs
HZ by time periods: All BARI RA pts
5
00 pt‐yr 4
3 3.33.9 3.6 3.6
2 4/
• Results
– n=3492, 5141 Pt Yrs; HZ in 170 pts: IR 3.3
– Comparable to ADA
– Most mild‐moderate: 7 multidermatome; 2 facial nerve palsy
Rates higher w/ increasing age but not GC use
Pts with HZ 170 59 46 37 13 15 No. pts 3492 3492 3085 2543 1881 1123
HZ by region: All BARI RA pts
Overall
2
IR/10
0
1
0–24 24–48 48–72 72–96 >96
Weeks
1.92.4
10
8
t‐yr
– Rates higher w/ increasing age, but not GC use nor RA duration;
• HZ 3.3/100 Pt Yrs w/ Bari 4mg
– Rates stable over time;
– Increased in Japan and Korea
Winthrop KL, et al. ACR 2016 #3027
Pts with HZ 170 43 18 52 27 12 18No. pts 3492 514 226 840 783 428 701
Overall
4
0
6
2
Japan Asia (not Japan)
US/ Canada
EU ROW
3.3
6.55.6
4.4
2.1 1.9
C/S America and Mexico
1.7
IR/100 pt
Mean Changes in Laboratory Parameters Associated with JAK Inhibitors
Tofacitinib Baricitinib Filgotinib Upadacitinib
Selectivity JAK1, JAK3, JAK2 JAK1, JAK2 JAK1 JAK1, JAK2
L h t b ↓ N h ↓ ↓Lymphocyte number ↓ No change ↓ ↓
NK cell number ↓ Ini al ↑ then ↓ No change ↓ high doses
Neutrophil number No change ↓ ↓ ↓ high doses
Hemoglobin level ↑ ↓ high doses ↑ ↓ high doses
Platelet count ↓ Ini al ↑↑ then → ↓ then → ↑
Li i ↑ ↑ ↑ ↑Liver transaminases ↑⎯ ↑ ↑⎯ ↑
HDL ↑ ↑ ↑ ↑
LDL ↑ ↑ ↑ ↑
CPK ↑ ↑ ↑ ↑
Creatinine ↑ rare ↑ rare ↑ rare ↑ rare
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JAK Inhibitors: Overall Clinical Conclusions
All studied to date are effective across a broad range of IMIDs
o Early onset of benefit, within 1 – 2 weeks; maximal at 3 months
o Strong benefits on PROs regardless of population with rapid onset of benefito Strong benefits on PROs, regardless of population, with rapid onset of benefit
o In RA: Combo‐Rx superior to ADA+MTX head to head w/ BARI; non‐inferior w/ TOFA
o In PsA: TOFA+MTX comparable to ADA+MTX; in PsO: TOFA 10mg non‐inferior to ETN
Despite differing JAK selectivities, safety similar across JAKi’s
o Thromboembolic AEs and DVTs??: BARI, UPA or is it the underlying disease population?
o Decreased lymphocytes, NK cells w/ TOFA, UPA
o Neutropenia: BARI, FIL, UPA
o ‘JAK2 associated’ Hb decrease: UPA and BARI higher doses; typically not clinically relevant
o LFT elevations w/ monotherapy: FIL, UPA
o Similar effects LDL, HDL – linked to CRP↓; idiosyncra c effects on Cr; no associated renal failure
o H Zoster incidence elevated across all RCTs; higher risk Japan and Korea; vaccination important!
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