Breakthroughs in Lupus in Breakthroughs in Lupus in

2015 2015

MEDICINE OF THE HIGHEST ORDER

Jennifer H. Anolik, MD, PhDAssociate Professor of Medicine, Pathology, and

Microbiology/ImmunologyDivision of Allergy, Immunology & Rheumatology

University of Rochester Medical CenterOct 2015 9th Annual Lupus Education Day

Outline

•Basic Review

•Diagnosis

•Pathogenesis (leads to treatment)

•Treatment

Research in Lupus

• The more that is known about clinical outcomes and immune abnormalities associated with lupus, the better equipped we are to fight the disease!

What we’re doing at the U of R:

• NIH funded networks• Autoimmunity Center of Excellence for clinical trials and basic

mechanisms of lupus and clinical trials• Accelerating Medicines Partnership

• Clinical Cohorts: Lupus Clinical Trials Consortium

• 20 centers• Collaborative Longitudinal Lupus Registry

• Clinical Trials

• The AIR unit has an active program in clinical trials in SLE• Investigation of new, targeted biological interventions in SLE

What are the different forms of lupus?

Systemic Lupus ErythematosusSystemic Lupus Erythematosus

Discoid or Cutaneous LupusDiscoid or Cutaneous Lupus

Drug-Induced LupusDrug-Induced Lupus

Neonatal LupusNeonatal Lupus

Systemic Lupus Erythematosus

• Inflammatory multisystem autoimmune disease• 1.5 million cases • Women>Men- 9:1 ratio (90% cases are women)• African Americans>Whites• Onset usually between ages 15 and 45 years, but can occur in

childhood or later in life• Highly variable course and prognosis, ranges from mild to life

threatening• Characterized by flares and remissions• Associated with characteristic autoantibodies

What are the symptoms of lupus?

• Painful swollen joints

• Unexplained fever• Extreme fatigue• Rashes

• Sensitivity to the sun• Mouth Sores • Hair loss • Pale or purple fingers

or toes from cold• Swollen glands• Headache and/or

Depression• Chest pain with deep

breathing• Low blood count

Lupus presenting symptoms

Raynauds

Hair Loss

Photosensitivity

Facial Rash

Pluerisy

Ulcers

Seizures

Clotting

Renal

Anemia

Skin Rashes

Extreme Fatigue

Swollen Joints

Fevers

Painful Joints

0 10 20 30 40 50 60 70 80 90 100

How do we diagnose lupus?

Skin criteria Systemic criteria1. Malar rash 5. Arthritis 2. Discoid Rash 6. Serositis3. Photosensitivity 7. Kidney4. Oral Ulcers 8. Neurologic

Lab criteria9. Anti-nuclear antibody10. Immunologic11. Hematologic

*4 criteria simultaneously or serially for diagnosis

New SLICC criteria

SLE Diagnosis: Autoantibodies

• ANA• Seen in 99% of SLE• Not specific for SLE• Seen in many

inflammatory, infectious, and neoplastic diseases

• Seen in 5% to 15% of normal persons

• Other more specific autoantibodies- antiDNA, antiSmith

The Future of Diagnosis• Identify and detect more lupus specific autoantibodies- Next

generation proteomics• Stanford silicon chip with thousands of histone related

proteins• Rochester collaboration with CDI-19,000 human proteins on a

single microscope slide

• Combine autoantibody panels with other tests• AVISE SLE- diagnostic test for SLE, includes a panel of

autoantibodies+cell-bound complement activation products

geneticsgenetics

hormoneshormonesenvironmentenvironment

Cause/Pathogenesis

New concepts:EpigeneticsMicrobiome

SLE pathogenesis and treatment targetsSLE pathogenesis and treatment targets

IFNIFNCD40

CD40L

B7.1/2

CD28

B7.1/2

TNFIL-1IL-6

IFNIFNmBAFF

sBAFFBR3

TLR9

NN

mDCmDC

BBCTLA4-IgCTLA4-Ig

Abatacept Abatacept

TNF blockadeTNF blockade

IL-6 blockadeIL-6 blockade

Anti-B cell Anti-B cell antibodiesantibodies

BAFFBAFFinhibitorsinhibitors

TLRTLRinhibitorsinhibitors

IFNIFNblockadeblockade

Lymphocyte signaling

small molecule inhibitors

PC

Proteasome inhibitors

AutoantibodiesAutoantibodiesImmune Immune complexcomplex

Sle1, CD22, C1q, BANK, BAFF Sle2 (B), Sle3 (T, DC), PTPN22

FcR, ITGAM

Stages of autoimmunity

Loss of tolerance Innate and adaptive dysregulation End organ targeting

Anolik et al. AR 2007Palanichamy et al. JI 2010

B cells behaving badly

PathogenicB cell functions

ProtectiveB cell functions

SLE Controlled

11 197

IgD

CD

27

SLE Active

R6

739 99

IgD

CD

27

B-cellB-cell Plasma cellPlasma cell(Auto)-antibody

production

• Enzyme that stimulates immune system could hold key to new treatment for lupus• cGAS a cytosolic DNA sensor

• Is the Body’s Clean-up Squad at Fault?• LC3-associated phagocytosis (LAP)

involved in clearance of dying cells; autophagy

• Novel check-point that limits the activity of the immune system• VISTA- a molecule that shuts the

immune system down via inhibition of T cell activation

Recent insights into disease pathogenesis

LRI: Gao…Chen ZJ; PNAS 2015Green and colleaguesNoelle and colleagues

Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases

LRI: Gao…Chen ZJ; PNAS 2015

•Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates interferon•Deletion of cGAS in lupus prone mice decreases disease•cGAS activation increases disease

Treating inflammation or autoimmunity•Anti-inflammatory agents •Antimalarials •Immunosupressive/cytotoxic agents

Other•Prevention: management of cardiovascular risk, immunization •Anti-thrombotic therapy •Dialysis and kidney transplantation

The spectrum of lupus treatment

The The ‘‘traditional treatment traditional treatment armamentariumarmamentarium’’

FDA Approved drugs glucocorticoids hydroxychloroquine low dose ASA

‘Off - label’ but standard of care azathioprine cyclophosphamide NSAIDs

Immunosuppressives developed for other diseases mycophenolate mofetil methotrexate cyclosporin leflunomide tacrolimus fludarabine

Benlysta

Until April 2011 it had been over 50 years since a new drug was approved for lupus!

WHY?WHY?•Lupus is hard to study: Lupus is hard to study:

• Clinical expression is heterogeneousClinical expression is heterogeneous• Pathology is diversePathology is diverse• Disease activity is intermittentDisease activity is intermittent• Lack of agreed upon disease activity measures and Lack of agreed upon disease activity measures and

endpointsendpoints• Small patient populations- rare diseaseSmall patient populations- rare disease

•Development costs: Estimated $1 billion to take a Development costs: Estimated $1 billion to take a drug from the research stage to FDA approvaldrug from the research stage to FDA approval•Lack of a clinical trial infrastructureLack of a clinical trial infrastructure

WE NEED CLINICAL TRIALS TO KNOW WHAT WORKS WE NEED CLINICAL TRIALS TO KNOW WHAT WORKS AND TO GET FDA APPROVAL OF NEW DRUGSAND TO GET FDA APPROVAL OF NEW DRUGS

New Treatments for Lupus

• New venture between lupus and RA scientists, NIH, biopharmaceutical companies and non-profit organizations

• UR is one of the 9 sites• Goal is to transform the current model for

developing new diagnostics and treatments by jointly identifying and validating promising biological targets of disease in TARGET TISSUE

• The ultimate goal is to increase the number of new diagnostics and therapies for patients and reduce the time and cost of developing them

HOW DO WE IDENTIFY NEW TARGETS?Accelerating Medicines Partnership (AMP) Initiative

Accelerating Medicines Partnerships (AMP)

CD3 CD14 CD20

RA synovium

AMP Initiative: Tissue is the Issue!

RNA profiling

CD20

Lupus kidney

•New ALR-LRI collaborationNew ALR-LRI collaboration

•Finding drugs and other treatment Finding drugs and other treatment strategies that may be ripe for repurposing strategies that may be ripe for repurposing in lupusin lupus

•155 candidate drugs have emerged for 155 candidate drugs have emerged for further study in small focused science-rich further study in small focused science-rich clinical trialsclinical trials

•11stst clinical trials of the STAT initiative will clinical trials of the STAT initiative will kick-off soon. Site selection underway.kick-off soon. Site selection underway.

Repurposing drugs:LRxL-STAT

(Lupus Rx List-SLE Treatment Acceleration Trials)

https://www.linkedin.com/in/lrxlstat

SLE Clinical Trials: Summary

www.clinicaltrials.gov

Rituximab= anti-CD20= B cell depletion

• Initial promising studies

• Two large trials of anti-CD20 (rituximab) in SLE failed to meet their primary outcomes

• Advances in the field on how to successfully do lupus clinical trials

• Rituximab is still thought to be effective in lupus and indicated for a subset of refractory patients

Variability in responseVariability in response

Looney, Anolik et al. Arthritis and Rheum 50:2580, 2004Anolik et al. Arthritis and Rheum 48:455, 2003

0.1

1

10

100

0 3 6 9 12

Months

CD

19+

(L

ym

ph

ocyte

s/u

l)

Depleters (11)

Non-depleters (6)

02468

1012141618

0 months 1 month 2 months 3 monthsSLAM

(mea

n an

d 95

% C

.I.)

Non-depleters

Depleters

<0.05

Biomarkers for SLE patients who may do well after ritxumab

New

GC

Transitional

Bone marrowPeripheral lymphoid organs

FO naïve

Post-GC Memory

Pro-B

Pre-B

Immature

FM

MZMZ Memory

ResidualIFN(-)

BAFFBAFF

• B cell biomarkers• IFN

SLESLEGood responderGood responder

TT

NNMM

SLE Poor responder

MM

B cell depletion therapy (BCDT) is rapidly expanding in the treatment of autoimmune diseases

• Rheumatoid Arthritis (Anti-TNF failures)•ANCA-mediated vasculitis

• Sjogren’s • Scleroderma• Myositis• Anti-phospholipid syndrome• ITP• TTP• Transplant rejection• Inflammatory bowel disease• Chronic Graft-versus-host disease• Blistering skin diseases• Idiopathic membranous nephropathy• Pulmonary hypertension• Hepatitis C cryoglobulinemia• IgM-associated polyneuropathy• Uveitis• Autoimmune paraneoplastic syndromes

FDA-approved Others

• RR MS• PP MS•Extra-renal SLE•Renal SLE •Type 1 Diabetes• Early rheumatoid arthritis

Phase 3 RCT

Rituximab/B cell biology paves the way for Belimumab (anti-BAFF)-

Benlysta

• Blocks a B cell survival factor, inducing B cell death

• Recently approved (3/9/2011) for the treatment of SLE

• 1ST DRUG APPROVED FOR LUPUS IN OVER 50 YRS

• 1ST BIOLOGIC APPROVED FOR LUPUS

http://www.youtube.com/watch?v=i24UTvOKK-8

B cell targeted 2015 What’s new?

• Innovative ways to combine rituximab with benlysta

• Other B cell targeted therapies:• Anti-CD22: phase III completed, did not meet

endpoints • Other anti-CD20s-largely halted• Anti-CD19• Proteasome inhibitors

• Cytokine blockade• Benlysta for nephritis, black patients, pediatric, long-

term safety, treatment holiday/restart• Different forms of BAFF blockade in Phase 3-

blisibimod

Interferon and Toll-like receptors

Current Opinion in Rheumatology 2003 Pascual

TLR

IFN and TLR blockade

•Multiple studies on monoclonal antibodies against IFN alpha have been in various stages of development- somewhat disappointing

•Press release that anifrolumab met primary endpoint of reduction in global disease activity score in moderate/severe SLE in Phase 2- AstraZeneca starting Phase 3

•TLRs are key receptors of the innate immune system that can induce strong inflammatory responses- important in production of IFN. Interest in small molecules inhibitors of Toll-like Receptors (TLRs) 7, 8, and/or 9

Proteasome inhibitors

• Targeting autoreactive plasma cells

• Most current therapies do not effectively decrease autoantibodies

• Amgen acquires Onyx: Kyprolis=carlfizomib for myeloma

Ichikawa…Anolik; Arthritis and Rheum 2012

Intracellular signaling pathways

• Mitogen-activated protein kinases (MAPK), tyrosine kinases (TK), Janus kinases (JAK) and nuclear factor κB (NFκB)

• Interesting therapeutic targets

• Experience in RA (tofacitinib=JAK3 inhibitor)

**

**0

1

2

3

0 1 2 3 4 5 6 7 8

Pro

tein

uri

a sc

ore

Weeks of treatment

0

20

40

60

80X 103

dsD

NA

AS

C

UntreatedLowHigh SINEs

Anolik et al.

• Inhibition of intracellular signaling with small molecule oral agents• Inhibitor of ubiquination in Phase II placebo

controlled, multi-center trial by Celgene• We are CURRENTLY enrolling• May have particular efficacy in skin disease

• Cell based therapies• Mesenchymal stem cell transfer

Currently (or soon) enrolling trials at UR

Concluding points

• We are learning how to “borrow” drugs used to treat other diseases

• Some drugs may provide clues about how lupus develops

• Despite barriers, novel mechanism-based therapies are in development for SLE

• Therapy will attempt to target specific pathways in the body

• Eventual treatments may involve combination therapies, i.e., “cocktails” of targeted and semi-targeted therapies

• Patients receive an “individualized” treatment

Learn More

• www.lupusresearch.org/research/research_update.html• LupusTrials.org• www.clinicaltrials.gov • The National Institute of Arthritis and Musculoskeletal and Skin

Diseases (NIAMS) and the Office on Women’s Heath have developed a strategic plan for reducing health disparities. Lupus is included as an area of research focus. Further information on disparities in lupus and educational material at:

• http://thelupusinitiative.org• www.couldihavelupus.gov