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Lupus Therapies and Pipeline in 2019 Learning Objectives

• Describe the current prognosis of lupus patients treated with available therapies. • List preventative measures necessary for good patient outcomes. • Review the concepts of T2T to achieve remission or low disease activity with current . • Discuss why lupus studies fail. • Define the novel targets for potential new lupus therapies and the rationale for each.

PROGNOSIS:

Morbidity (damage) vs. Mortality Prognosis

• Overall mortality • Hospitalizations – 5YS: 95% – 20-25% hospitalized annually – 10YS: 89-93% • Causes of death – 15YS: 76-82% – Infection: 25% – 2-3x ↑ over age-matched – Active SLE (first 1-5 yrs): 35% population – Cardiovascular Dz (after 5 yrs): • Poor prognostic factors 30-40% – AA race, males – Malignancy: 5-10% – Age of onset < 20 or > 50yo – Dz manifestations • Renal/ESRD, CNS, GI • Vasculitis, cardiopulmonary

Fors Nieves CR, et al. Curr Rheumatol Rep 18: 21, 2016; Tektonidou MG, et al. Ann Rheum Dis, 2017 Garris C, et al. J Med Econ 16: 667, 2013 Comorbidities

• Overall: , depression, underemployment • Premature atherosclerosis: overall CV events 12x RR compared to general population – SLE CV risk is 2x calculated Framingham risk score – MI: 2.5x RR; CHF: 3.24x RR – Stroke: 2.53x RR – PAD: 9.0x RR • Renal: ESRD in up to 30% (HR 44x) who develop lupus nephritis. • Neurologic deficits – Strokes – Dementia: especially in pts with aPLabs and prior NPSLE • Disfiguring skin lesions • side effects: AVN, osteoporotic fxs, infection, malignancy, infertility • Malignancy – Viral (HPV)-related malignancy (SIR 5). Hematologic malignancies (SIR 2.75). Lymphoma increased 5x (SIR 3.64). • Pregnancy comorbidities: 20% have adverse outcomes (fetal death, IUGR, prematurity)

Dregan A, et al. Heart, 2017; O’Sullivan M, et al. Best Prac Res Clin Rheumatol 30: 81, 2016 Lin Y-R, et al. Arthritis Care Res 68: 1774, 2016; Buyon JP, et al. Ann Int Med 163: 153, 2015 Diagnosis

Classification vs. Diagnostic SLE Classification Criteria: Diagnosis

SLICC-2012 ACR-1982/97 • Meet 4 of 17 criteria: must • Meet 4 of 11 criteria have at least one clinical and one immunologic criteria • Lupus nephritis proven by biopsy plus one immunologic criteria (ANA or anti-dsDNA).

Sensitivity: 97% Sensitivity: 83% Specificity: 84% Specificity: 96%

Aringer M, et al. Lupus 25: 805-811, 2016 Common Mimickers of SLE

• Rheumatologic • Infections – UCTD – Viral: EBV, CMV, parvo, HIV – Other CTD (early dz) – Syphilis, Lyme – Fibromyalgia – Parasitic: toxoplasmosis, – Sarcoidosis leishmania • Other autoimmune diseases • Neoplasms – Autoimmune hepatitis – Lymphoma – ITP – Myelodysplastic syndrome – AIHA • Medications – TTP – DILE – MAS – Uncommon (e.g. minocycline)

Calixto OJ, et al. Autoimmun Rev 13: 865, 2014 Iaccarino L, et al. Autoimmun Rev 12: 363, 2013 Treatment

Evidence-based vs. Eminence-based General pPrinciples

• Avoid: sun (UVA and UVB protection), high estrogen BCPs, sulfa, echinacea • Encourage exercise: 30 minutes/day • Counsel on contraception and potential teratogenic risk of meds • Immunizations: prevnar/pneumovax, annual influenza, HPV, zoster(?) • Control CV and MetSyn risk factors: smoking, BP < 130/80, DM, BMI (< 25 kg/m2; men waist < 40 in, women < 35 in), lipids, homocysteine • Cancer screens: skin, cervical, breast, anal, colon, bladder, lymphoma, lung, heme • Prior to glucocorticoids/immunosuppressives: hep B, hep C, and TB status; HIV if risk factors • Measure disease activity index and HQoL each visit; SLICC-DI annually

Yazdany J, et al. BMJ Qual Saf 23: 659, 2014 SLEDAI-2K

• Components – Clinical: 16 – Laboratory: 8 • Scores – Score range: 0-105 – Activity • Score ≥ 6 = active needing Rx • Score ≥ 12 = highly active • Score ≥ 20 is rare – MCID • Increase ≥ 8 is significant • Decrease ≥ 6 is significant

Gladman DD, et al. J Rheum 29: 288, 2002 A&R 40:809,1997 Max score =49 General Medicine

• Calcium and vitamin D (especially if on prednisone) – Measure height yearly • Vitamin D to achieve 25OHVitD level > 40mg/dl (controversial) • Hypertension – ACE or ARB to achieve BP < 130/80 esp if GFR < 60cc/min and/or proteinuria • Steroid-induced diabetes mellitus – Metformin: also acts as an anti-oxidant and may reduce SLE flares • Hyperlipidemia – Lifestyle changes if LDL 100-130mg/dL to achieve < 100mg/dL. If not use a statin. – Statin (water-soluble) if LDL > 130mg/dL to achieve < 100mg/dL • Thrombosis prevention (if aPLab positive) – ASA: unclear benefit. 15% of pts are ASA-resistant. Pair with hydroxychloroquine. – Postoperative and postpartum prophylactic anticoagulation for 1 wk or 6 wks (high risk) – Contraception: IUD instead of OCPs.

Azrielant S, et al. Lupus 25: 563, 2016 Rule #1: R/O non-SLE Cause for sxs

• Damage (nonreversible) from prior active disease or treatment • Fibromyalgia, sleep apnea, thyroid dz, vitamin D deficiency, etc • Medication side effect (e.g. SCLE and buproprion) • Infection (↑ procalcitonin, CRP > 6x ULN) • Thrombosis (PE, cardiac embolus, etc) • TTP/HUS (↓ platelets, schistocytes, LDH > 800-1000) • MAS/HLH [fever, splenomegaly, cytopenias (2/3 cell lines), ↓fibrinogen (? nl ESR), ↑ ferritin, ↑TG, ↑CD25 (IL-2 receptor), R/O EBV/CMV infection] • Malignancy Goals of Treatment: T2T with the Least

Remission Low disease activity (LLDAS) • Can be on antimalarials • Can be on antimalarials • SLEDAI-2K = 0 on no prednisone • Clinical SLEDAI-2K ≤ 4 with no or immunosuppressive (7%) major organ involvement, +/- • Clinical SLEDAI-2K = 0, +/- active active serology on prednisone ≤ serology on prednisone (1-5 mg/d) 7.5 mg/d and and immunosuppressives (30%) immunosuppressives. • If remission maintained for 2 years, damage accrual reduced • If LLDAS maintained 50% of time, damage accrual reduced 50%. • Median time of most remissions: 3 months • If LLDAS maintained for 2 yrs, damage accrual reduced > 70%. Ann Rheum Dis 76: 547, 2017 Ann Rheum Dis 76: 562, 2017 2017 Ann Rheum Dis 75:1615, 2015 Ann Rheum Dis 76 :562, 2017 FDA Approved Drugs for the Treatment of SLE

• Low dose acetylsalicylic acid • Glucocorticoids • Hydroxychloroquine •

www.fda.gov Medications

• Glucocorticoids – Dosing: pulse (1 gram qd), high-dose (> 30mg/d), lower doses (for non-life threatening dz) – Dose > 5-7.5mg/d associated with organ damage (HR 1.7); >10mg/d with CVD – Avascular necrosis increased (10-40%) in SLE pts: active dz, aPLabs, Cushingoid appearance, mean daily steroid dose/cumulative dose are risk factors – Osteoporotic fractures can occur with relatively normal T scores – PJP prophylaxis if on prednisone > 15-20mg/d: SMX-TMP, dapsone, atovaquone, inhaled pentamidine

Tsang-A-Sjoe MWP, et al. Exp Opin Pharma 16: 18, 2015 Pneumocystis jiroveci pneumonia (PJP) Prophylaxis Pneumocystis occurs in ~10% of vasculitis/SLE patients on prednisone + another immunosuppressive and prophylaxis should be given • Prophylaxis if use prednisone > • Additional risk factors: 15-20 mg/d for ≥ 4 wks – Elderly • Recommendations for stopping – Underlying lung dz (esp GPA, MPA, prophylaxis DM/antisynthetase syndrome, DAH) – If no additional risk factors, stop PJP – Initial prednisone dose > 60mg/d, prophylaxis after 3 weeks on – Lymphopenia (< 1000/uL) prednisone 15mg/d or less. – Low CD4 count (< 250/uL), – If ≥ 2 additional risk factors continue – Cyclophosphamide use, anti-TNF PJP prophylaxis even on prednisone use, or use. What about < 15mg/d esp if have underlying MTX/MMF/AZA/ inhib? lung injury.

Winthrop KL, et al. Ann Rheum Dis 2018 Medications

• Hydroxychloroquine (HCQ) – Anchor drug for all SLE pts. – Effects: reduces flares, reduces lipids, improves glucose tolerance, reduces thrombosis, improves survival, decreases renal damage, decreases neonatal lupus/cardiomyopathy – Dose: 5mg/kg/d up to 400mg/d. Can measure drug levels (therapeutic > 500 ng/ml). – Risk of retinopathy: 0.5-1.0% at 5 yrs. Increased risk if age > 60 yo, hx of renal dz, concomitant retinal dz, tamoxifen, or on HCQ for > 5 yrs – Other side effects: dizziness, headaches, nausea. Split dose or use brand name. Risk of cardiomyopathy and myopathy (esp if renal insufficiency) – Can combine HCQ with quinacrine for refractory skin dz without increased risk of retinopathy

Tsang-A-Sjoe MWP, et al. Exp Opin Pharma 16: 18, 2015 AAO 2016 Guidelines for HCQ

• Keep dose below 5 mg/kg real weight up to 400mg/d • Risk for toxicity <1% for 5 years of use, <2% for 10 years of use, 20% for 20 years (after 20 years, pt without toxicity has 4% risk in subsequent years) • Asian patients can show initial damage outside of the parafovea (central macula) • Renal disease, maculopathy, age > 60, and tamoxifen are risk factors • Screen: baseline then yearly after five yrs if no risk factors • Retinopathy can progress even after cessation of drug • Retinopathy is not reversible and there is no therapy

www.aao.org March 2016 guidelines Belimumab

• Approved by the FDA 3/8/11 to reduce disease activity in adult SLE patients with autoAb positive active SLE on standard therapy • Human IgG1 Ab binds to soluble B-lymphocyte stimulator (BLyS) important in B cell survival • Most effective for mucocutaneous, arthritis, serositis, and fatigue manifestations in serologically active SLE pts. • Reduces SLE flares and steroid-sparing • Monitor for depression

Lancet 2011, 377(9767):721-731 Arthritis Rheum 2009, 61(9):1168-1178 Phase 3 Trials for Belimumab in SLE

1o endpoints SRI response: • met at 52 wks (not 76 wks) 70 P= 0.013 1mg/kg 2o endpoints met: P=0.0006 10mg/kg • reduced risk for severe flare 60 58 • reduced steroid use 51 P=NS 1 mg/kg P=NS 1 mg/kg • improved HR-QoL

50 P=0.021 10 mg/kg P=NS 10 mg/kg 44 43.2 40.6 39.6 40 38.5 33.5 32.4 30

20 SRI response (%) response SRI PBO 10 Belimumab 1 mg/kg 0 BLISS-52 BLISS-76 at Wk 52 BLISS-76 at Wk 76 Belimumab 10 Lancet 2011, 377(9767):721-731 mg/kg Arthritis Rheum 2009, 61(9):1168-1178 Belimumab

• Subgroup analysis: African Americans had lower response • Subsequent studies did not confirm this (Lupus Sci Med 3:e000118, 2016) • No increase SAEs compared to PBO • Rx: Belimumab 10 mg/kg IV weeks 0, 2, 4, then q4weeks • Avg price for therapy : $42,000/yr • Pregnancy category C • The studies used for FDA approval did not include severe active lupus nephritis or CNS lupus • 2 cases of PML • Subcutaneous belimumab 200 mg q/week equally effective

Lancet 2011, 377(9767):721-731; Arthritis Rheum 2009, 61(9):1168-1178 Arthritis Rheumatol. 2017, 69: 1016-1027 Belimumab and Lupus Nephritis

• Meta-analysis of belimumab on renal outcomes • 11 studies: 234 patients • 55% had some renal response • In pts with any proteinuria, average reduction 38% • In pts with proteinuria > 1 gm/24h, 71% had some improvement • Renal flare rate 1.7% • Concomitant MMF with belimumab gave the most favorable outcome

S. Sciascia et al. / Autoimmunity Reviews 16 (2017) 287– 293 Non-Approved Drugs/Biologics Used “Off Label” in the Treatment of SLE

• Cyclophosphamide • Mycophenolate mofetil • • • • Rituximab • Other Medications

• Cyclophosphamide – Regimens used for severe disease (usually nephritis) • IV monthly (0.5-1.0gm/m2) with mesna x 6 months then q3 months x 12-18mos • Euro-lupus: 500mg IV q 2wks x 6 doses then switch to maintenance (AZA or MMF) – Other non-renal manifestations: CNS, vasculitis, pneumonitis, heme – Side effects: worse with IV monthly. Hemorrhagic cystitis (R/O BK virus), ovarian failure (check anti-Mullerian hormone; Lupron prophylaxis), testicular failure, malignancy, infection, other

Tsang-A-Sjoe MWP, et al. Exp Opin Pharma 16: 18, 2015 EuroLupus Nephritis: Low vs. High Dose CYP

LD = 500 mg CYP q2wk X 6 Houssiau, et all. Arthritis Rheum. 2002; 46(8):2121-31 HD = 500-1000 mg/m2 qmo X 6 Medications

• Mycophenolate mofetil – MOA: inhibits de novo pathway for purine synthesis (activated lymphs) and lymphocyte migration to areas of inflammation – MMF 1-1.5gm BID. Use lower dose in Asians. Used for induction Rx for nephritis and maintenance (esp AA, Hispanics). Can follow blood levels. – Other non-renal manifestations: CNS, cutaneous (esp SCLE), arthritis – Side effects: GI (use ), infection, teratogenic, lymphoma. – Med interactions: interferes with BCPs, less absorption on PPI

Tsang-A-Sjoe MWP, et al. Exp Opin Pharma 16: 18, 2015 Mycophenolate Mofetil vs Cyclophosphamide

• Is MMF effective in induction therapy for lupus nephritis? Yes • Is MMF effective in maintenance therapy for lupus nephritis? Yes

• Is MMF effective in non-renal manifestations of lupus? Yes • Is MMF better than CYC? No • Is MMF safer than CYC ? Yes

ALMS study group. J Am Soc Nephrol. 2009; 20(5):1103-12 MAINTAIN Nephritis Trial. Ann Rheum Dis. 2010;69(12):2083-9 2012 ACR Lupus Nephritis Guidelines

ISN/RPS Classification of LN Class I Minimal mesangial LN Don’t TREAT Class II Mesangial proliferative LN Don’t TREAT Class III Focal LN (<50% glomeruli) TREAT A= active C= chronic A/C = active/chronic Class IV Diffuse LN (>50% glomeruli) TREAT S= segmental, D=diffuse A= active C= chronic A/C = active/chronic Class V Membranous TREAT Class VI Advanced sclerosis LN (>90% globally) Don’t TREAT

Bertsias GK, et al. Ann Rheum Dis 71:1771, 2012 Hahn BA, et al. Arth Care Res 64:797, 2012 2012 ACR Lupus Nephritis Guidelines

Class III/IV INDUCTION Poor prognostic indicators - ↓ GFR > 50% GC pulse IV X 3 - Crescents MMF 2-3 g/day X 6 mo* days, then CYC - Fibrinoid necrosis prednisone 0.5-1 - Poor compliance mg/kg Hi CYC Lo CYC** 500-1000 500 mg IV mg/m2 IV q2weeks X 6 qmonth X 6 IMPROVED? IMPROVED? MAINTENANCE Y N N Y MAINTENANCE •MMF 1-2 g/d CYC: Lo/Hi MMF 2-3 g/d •MMF 1-2 g/d •AZA 2mg/kg/d + GC pulse + GC pulse •AZA 2 mg/kg/d +/- GC +/- GC Not improved? RTX or Calcineurin inhibitors *Preferable in Blacks/Hispanics + GC Bertsias GK, et al. Ann Rheum Dis 71:1771, 2012 ** Studied in European Whites Hahn BA, et al. Arth Care Res 64:797, 2012 2012 ACR Lupus Nephritis Guidelines

Class V LN MMF 2-3 g/day X 6 mo + prednisone 0.5 mg/kg/day X 6 mo*

IMPROVED? Y N •MMF 1-2 g/d Hi CYC 500-1000 mg/m2 + GC •AZA 2 mg/kg/d pulse followed by prednisone 0.5-1 mg/kg/d

Bertsias GK, et al. Ann Rheum Dis 71:1771, 2012 Hahn BA, et al. Arth Care Res 64:797, 2012 Goals for Treatment by 6-12 Months: Lupus Nephritis Complete remission Partial remission • CrCl to normal or within 10% of • CrCl to normal or within 10% of normal baseline normal baseline (< 1.4mg/dL) • Proteinuria < 0.5 grams/24hrs • Improvement of proteinuria by • No RBCs or cellular casts > 50% to non-nephrotic range. • No RBCs or cellular casts

Can predict good renal outcome (< 10% ESRD) if achieve proteinuria < 0.8 grams/24hrs with no RBCs or cellular casts and a normal C3 level by 6-12 months.

Bertsias GK, et al. Ann Rheum Dis 71:1771, 2012 Hahn BA, et al. Arth Care Res 64:797, 2012 Dall’Era M, et al. Arth Rheumatol 67: 1305, 2015 Medications

• Methotrexate – Used for arthritis and skin disease. Can follow blood levels. – Side effects: photosensitizing, teratogenic, liver, leukopenia, other • Leflunomide – Alternative therapy in pts with arthritis who can’t tolerate MTX – Side effects: hair loss, diarrhea, HBP, rash, teratogenic, liver, neuropathy, other • Azathioprine – Most commonly used as maintenance therapy for nephritis. Caucasians may respond better. Can follow drug levels. – Less data on use in non-renal manifestations but does decrease lupus flares – Side effects: GI sxs (use 6-MP), pancreatitis, hepatitis, aseptic meningitis, leukopenia, infections especially zoster. – Med interactions (allopurinol, warfarin, ampicillin)

Tsang-A-Sjoe MWP, et al. Exp Opin Pharma 16: 18, 2015 Medications

• Calcineurin inhibitors – easier to use than cyclosporine. Can follow levels. – Tacrolimus (4mg/d) used in combination with MMF for nephritis. ↓ proteinuria (Liu Z, et al. Ann Int Med 162, 18: 2015) – Side effects: tremor, HBP, increased creatinine, diabetes, bone pain • Biologics – Rituximab (anti-CD20) • Effective in the clinic but failed to meet primary endpoint in trials • Clinical considerations: SLE pts more likely to get infusion reactions and may not deplete B cells completely

Tsang-A-Sjoe MWP, et al. Exp Opin Pharma 16: 18, 2015 Rituximab

• 257 pts with mod to severe lupus • 52 week RDBPCT RTX vs. PCB • All pts received 0.5-1 mg/kg prednisone • Failed to meet primary endpoints • Failed to meet secondary endpoints

Is Rituximab effective for non-renal SLE? NO EXPLORER Trial – failed to meet endpoints

Arthritis Rheum. 2010 Jan;62(1):222-33 Rituximab

• 144 pts Class III/IV nephritis (protein:Cr 60 57 ratio > 1) 46 p=NS • 52 weeks RDBPCT • All pts received MMF 1.5-3 g/d + pred 40 0.75 mg/kg/d tapered to 10mg/d by week 16 20

• All patients received methylprednisolone % Responders 1 g X 2 0 • Primary endpoint: % pts with complete RTX PCB or partial response at week 52

• Is Rituximab effective for lupus nephritis? NO LUNAR Trial (SLE nephritis III/IV)- failed to meet endpoints

Ann Rheum Dis 69(Suppl 3):549, 2010a. Arthritis Rheum. 2010 Jan;62(1):222-33 Niche Therapies

• Fatigue – Fish oil: antioxidant effect – DHEA (prasterone) 200mg qd – Modafinil (200mg qd) and armodafinil (150-250mg qd) • Fibromyalgia – Naltrexone (4.5mg qd) • AIHA or ITP (especially if fails RTX and splenectomy) – Danazol 50mg/d – 800mg/d • Refractory skin disease – Anti-leprosy drugs: dapsone (measure G6PD level), (beware neuropathy) • Antiphospholipid syndrome – NOACs: limited data; RAPS trial showed rivaroxaban non-inferior to warfarin • Pericarditis – Colchicine • Stem cell transplantation

Arriens C, et al. Nutr J 14: 82, 2015.; Younger J, et al. Clin Rheumatol 33: 451, 2014 Cohen H, et al. Lancet Hematol 3: e426, 2016; Morel N, et al. Lupus 24: 1479, 2015 Therapy Withdrawal

• Glucocorticoids – Taper to < 5mg/d successful in 50% who are in remission or LLDA – Less successful if have MSK or cutaneous sxs – Less successful if not on antimalarials • Antimalarials – Flares are 2.5x more common when tapered off antimalarials – Try to decrease to HCQ 200mg/d if in remission • Immunosuppressives – If prednisone taper fails then can’t taper off immunosuppressives – Do not try to taper off immunosuppressives if disease was hard to get under initial control, the patient has had previous disease relapses, or patient not in remission(clinical/serologic) for > 1 yr off prednisone

Gatto M, et al. Nat Rev Rheum 15: 30, 2019; Zahr Z, et al. Lupus 22: 697, 2013 Tsakonas E,et al. Lupus 7: 80, 1998; Steiman AJ, et al. Arthritis Care Res 64: 511, 2012 Future Therapies

The Pipeline Why Do Lupus Trials Fail?

• Inadequate understanding of disease pathogenesis • SLE has genetic and phenotypic heterogeneity • Fluctuating disease activity makes it difficult to capture a response • Poor study design (e.g. let ANA negative patients into studies) • No biomarkers • Outcome tools capture multiple organ manifestations – difficult to capture organ specific response • Background meds are variable, gauging treatment response is difficult Genetics and pathogenesis of SLE

Neutrophil -↑ NETosis Dendritic cells -↑IFNα production -↑BTK activity Abnormal -↑ presentation self apoptosis Ag - DNA damage - ↓ DNA damage repair

T cells B cell -↓IL-2/Treg function -↑mTOR activity - ↑ activation -↑ Ras activity - ↑ autoAb -↑IL-17 - costim -↑IFNγ production -↓cholesterol efflux -

Liu Z. Nat Med 18: 871, 2012 Lo M. Curr Opin Rheum 30: 222, 2018 Microarray Technology

IFN-inducible genes Use of microarray data to: 219426_at (FLJ12765) 202446_s_at (PLS CR1) 200815_s_at (LIS1, MDCR, PAFA H) • Diagnose SLE patients 210337_s_at (ATPCL, CLATP) 203119_at (FLJ22321) 214453_s_at (MTAP44) • Identify genes assc w/ 201554_x_at (GYG) 38158_at (KIAA0165) 203353_s_at (PCM1) severe disease 202418_at (54TM) 219356_s_at (CGI-34) 208436_s_at (IRF7) • Find potential targets 218400_at (OA S3) 201609_x_at (ICMT) 201649_at (RIG-B, UBCH8) • Individualize treatment 213523_at (CCNE1) 201013_s_at (ADE2H1) 202411_at (IFI27) • Gene therapy 209276_s_at (GLRX) 209231_s_at (MGC3248) 202767_at (A CP2) 202939_at (STE24, FACE-1, STE24P, FLJ14968) 218482_at (DC6) 202912_at (A DM) 205644_s_at (SNRPG) 213797_at (Homo sapiens cig5 mRNA, partial sequence) 218357_s_at (TIMM8B) 202430_s_at (MMTRA1B) 218143_s_at (SCAMP2) 206181_at (S LAM) 218321_x_at (MK -STYX) 202086_at (MX, MXA, IFI78, IFI-78K) 212809_at (FLJ14639) 218999_at (FLJ11000) 201786_s_at (ADAR) 219352_at (FLJ20637) 221502_at (KPNA3) 222154_s_at (DKFZP564A2416) 218986_s_at (FLJ20035) 219841_at (A ID, HIGM2) 219863_at (LOC51191) 2013 http://dx.plos.org/10.1371/journal.pone.0067003 Disease severity: Healthy Mild Moderate Severe

Selected Gene Tree: 100803 CD19 gene tree stats sig genes Colored by: 100803 SLE CD19, Disease severity in log Gene List: all genes (22283) Targets FailedAgents T cells CTLA-4Ig () Anti-CD28 (lulizumab, theralizumab) therapeuticsAnti-CD40L (BG9588, IDEC-131) Anti-CD11 () ICOS inhibitor (AMG-557, MEDI-570) hCDR1/anti-DNA as tolerogen (edratide) B cells Anti-CD20 (RTX, OCZ, OFT, TRU-15) Anti-CD22 (epratuzumab) Anti-CD30 (brentuximab) Anti-BAFF (tabalumab) Anti-BAFF/APRIL (atacicept) BAFFR-Ig () BR3-Ig (briobacept) DNA tolerogen (LJP394, ) Proteasome inhibitor (bortezomib) Complement Anti-C5a () Cytokines Anti-TNF (IFN, ETN) Anti-IL-1 () Anti-IL-6 (sirukumab) Anti-IL-6R (, vobarilizumab) Anti-IFN alpha (sifalizumab, rontalizumab, AGS-009) Anti-IFNAR1 (anifrolumab) Anti-IFN gamma (AMG 811) Anti-MIF (imalumab) Other Anti-TLR-7/9 S1p receptor 1 agonist (cenerimod, KRP203) AhR activator (laquinimod) Syk inhibitor (fostamatinib) Felten R, et al. Autoimmun Rev 17: 781, 2018 Target Agent T cells TherapeuticsAnti-CD40L Fab-PEG in(dapirolizumab ) Rigerimod (P140 peptide) (lupuzor) (orelvo) Low dose IL-2 (NKTR-358, AMG-592) phase 2/3Autologous trials TREGs B cells BTK inhibitors (evobrutinib, AC0058TA, M2951, GDC0853) Anti-CD19/FcγRIIb (obexelimab) Anti-CD20 (SBI-087, ) Anti-CD38 on plasma cells (TAK-079) Anti-CD40 (BI 655064) Anti-BAFF/April (RC18, ? atacicept) pDC Anti-BDCA2 (BIIB059) Complement Anti-MASP-2 (OMS721) Cytokines Anti-IL-6 (MRA 003, PF-04236921) Anti-IL-10 (BT063) Anti-IL-21 (BOS-161721) Anti-IL-12/23 () Anti-TWEAK (BIIB023) JAK-STAT Jak 1,3 (tofacitinib) Jak 1,2 (baricitinib) Jak 1 () Tyk-2 (BMS-986165) Other CB2 agonist (lenabasum) PDE-4 inhibitor () Cereblon modulator (iberdomide) Human RNAase (RSLV-132) Mesenchymal stem cell infusion Chemokine inhibitor (PF-06835375) Proteasome-LMP2/7 unit (KZR-616) alpha kinoid vaccine Felten R, et al. Autoimmun Rev 17: 781, 2018 Efficacy and safety of baricitinib in SLE: 24-week, Phase 2 RDBPCT • 314 patients with SLE receiving SOC – ANA+ or anti-dsDNA antibody, SLEDAI-2K ≥4, arthritis or rash required Efficacy at Week 24 – Randomized 1:1:1 to PBO, or BARI 2 or 4 mg qd PBO • Positive response in BARI 4 mg – 1° endpoint: resolution of SLEDAI-2K arthritis or rash, Week 24 1° endpoint 2° endpoint S TJC SJC CLASI 100 BL ↓ from BL ↓ from BL ↓ from BL, * * 80 67.3 64.4 BL, Week BL, Week Week 24 58.1 24 24 60 53.3 51.4 47.6 PBO 7.7 ‒5.6 5.3 ‒4.6 4.9 ‒2.8 40 2 mg 8.7 ‒6.5 5.2 ‒4.1 3.8 ‒1.7

Patients (%) Patients 20 4 mg 8.5 ‒6.9 ⃰ 5.5 ‒4.8 4.0 ‒2.3 0 – 2° endpoints: SRI-4, SFI, LLDAS Resolved SLEDAI-2K SRI-4 response • No significant differences in AEs among the groups arthritis or rash – One SAE of DVT in BARI 4 mg group *P≤0.05 vs PBO

Significant clinical improvements with BARI 4 mg vs PBO in SLE patients receiving SOC CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; SFI, SELENA-SLEDAI Flare Index; LLDAS, Lupus Low Disease Activity State Wallace DJ, et al. EULAR 2018, Amsterdam, OP0019 Summary

• Prognosis is guarded • Morbidity and mortality are high • New SLE classification criteria allows for earlier identification of SLE • General medicine and principles of care • Approved and off-label medications to treat SLE • Guidelines: PJP prophylaxis, HCQ eye monitoring • Therapy withdrawal • SLE nephritis management guidelines • Lupus trials are hard to conduct/even harder to interpret • Hope for the future with new targets (????better study designs????)

QUESTIONS ???