State of Lupus Treatment: New Therapeutics

Richard Furie, MDChief, Division of Rheumatology

Professor of MedicineHofstra North Shore-LIJ School of Medicine

New York

Like SnowflakesNo Two Cases Are Alike

• Case 1: 22 y/o Caucasian female with fatigue, photosensitive malar rash, arthralgias, adenopathy,

ANA 1/320 (Sp), SS-A Ab; better with NSAIDs and hydroxychloroquine

• Case 2: 22 y/o African American female with fatigue, alopecia, scarring rash in the scalp and ears, hypertension, arthritis, nephritis, ANA 1/1280 (H), high DNA Ab, low C’, anemia, and thrombocytopenia; refractory to high doses of steroids and MMF; dialysis in the near future

Goals of Therapy: Back to Basics

• Do Good• Control disease activity• Prevent damage from disease • Prevent flares

• Do No Harm• Prevent damage from treatment• Do not treat damage with agents intended for

active disease

Principles of Treatment Design

• Identify disease manifestations• Distinguish activity from chronicity

– Does rash represent active disease or scar?

– Does proteinuria represent active nephritis or previous damage?

• Prioritize active disease manifestations

Principles of Treatment Design

• Disease activity is a continuum• Use the least toxic medicine and lowest

dose to treat the most concerning disease manifestation (and hope the less concerning manifestations come under control)

• Treatment rules would not be an issue if it were not for the toxicities of our most potent agents

Drugs1. Analgesics

2. Topicals

3. NSAID’s

4. Antimalarials

5. Corticosteroids

6. Antimetabolites

7. Chemotherapy

8. Biologics

Pathologic Process (lupus)

Normal Tissues

Specificity and Safety of Therapeutic Interventions

Immunosuppressives Desired Steroids Therapy

Corticosteroids: Toxicities

Hypertension HirsuitismCushingoid appearance OsteoporosisOsteonecrosis Fluid retentionGlucose intolerance Skin fragilityIncreased infection risk Cataracts

• Side effects are related to dose and duration• Use the lowest dose that does the job

Antimetabolites: Toxicities

1. Azathioprine cytopenias, lymphoma

2. Methotrexate hepatotoxicity

3. Mycophenolate mofetil GI symptoms; skin ca.lymphoma

4. Leflunomide hypertension, hepatotoxicity

Cyclophosphamide: Toxicities

1. Cytopenias

2. Infection

3. Hemorrhagic cystitis

4. Sterility (risk related to dose and age)

5. Cancer (bladder cancer; leukemia)

A Case: Rank the Disease Manifestations

• Swollen and painful finger joints (arthritis):• Pain in right hip (osteonecrosis)• Hematuria/proteinuria/high DNA Ab/low C’

(nephritis)• Hair loss (alopecia)• Platelet count low (thrombocytopenia)• Fatigue

A Case: Rank the Disease Manifestations (Patient)

1. Swollen and painful finger joints (arthritis)

2. Hair loss (alopecia)

3. Fatigue

4. Pain in right hip (osteonecrosis)

5. Platelet count low (thrombocytopenia)

6. Hematuria/proteinuria/high DNA Ab/low C’

A Case: Rank the Disease Manifestations (Physician)

1. Platelet count low (thrombocytopenia)

2. Hematuria/proteinuria/high DNA Ab/low C’

3. Swollen and painful finger joints (arthritis)

4. Hair loss (alopecia)

5. Fatigue

6. Pain in right hip (osteonecrosis)

Treating the Disease Manifestations:

1. Thrombocytopenia high dose prednisone

2. Nephritis cyclophosphamide; MMF

3. Arthritis

4. Alopecia

5. Fatigue

6. Osteonecrosis Analgesics

What Does One Follow?:

1. Symptoms (pain, fatigue)

2. Signs (joint swelling, rash)

3. Laboratory values (cell counts, kidney function, DNA Ab, C’)

4. SLEDAI or BILAG (in studies)

Much of this is art and not science

What if Conventional Therapy Fails?:

1. “Pulse” steroids 2. Bone marrow transplantation3. Other chemotherapy/IS (calcineurin inhibitors)4. TNF inhibitors5. Biologics: belimumab6. Off-label biologics: rituximab, abatacept7. Experimental medicine

Survival in SLE

0 20 40 60 80

100

0 1 5 10 Years After Diagnosis

Pro

bab

ilit

y o

f S

urv

ival

Pre-Glucocorticoids

Glucocorticoids

Cytotoxic Agents

Driving Forces Behind SLE Drug Development

• Need for more efficacious therapies– Lupus nephritis– Severe extra-renal lupus– Flare prevention– Remission induction

• Safer therapies– Replace steroids & cyclophosphamide

SLE Clinical Trial Challenges

• Heterogeneity of manifestations– Complicates entry criteria, trial design,

and endpoints

• Confounding by background meds

• Trial endpoints

B Cell

Ab Plasma Cell

T Cell

Sun

pDendritic Cell

C’

IFNα

BLyS/BAFF

APRIL

IL 10

IL 6

IFNγ

DNA

mDC

TLR 9

PMN

CD28 - CD80/86

TCR - MHC

CD40L - CD40

MacrophageDNA

IC

IL 12 CXCL10

Adaptive

Innate

FcR

ICOS - ICOS-L

B Cell-Directed Therapies: Extracellular Targets

Ab

CD 80

CD 86

MHC II

Ag

LFA-3

B

CD40

CD 20

CD 22 Ab

Ab

CD 19

Ab

TACI

BLyS R

BCMA

BLyS

APRIL

TACI

CTLA4 Ig

Ab

Ab

ICOS L

Biologic Rationale for Targeting BLyS

• Crucial to B cells– Maturation– Differentiation– Survival (anti-apoptotic [overrides Bcl-2])

• Murine models– Transgenic mice develop SLE-like disease– TACI-Ig ameliorates murine lupus activity

• Human SLE– Elevated levels (predictive of flare)

Novel Response Endpoint(SLE Responder Index: SRI)

• Index generated from belimumab phase II

• Responder index composed of:

– > 4 point improvement in SS score

– No BILAG worsening (new A or 2 B flares)

– No worsening in PGA (< 0.3 point increase)

Furie RA et al. Arthritis Care and Research. 2009;61:1143-51

BLISS Phase III Summary

Primary endpoint was met in both phase 3 studies– Significant improvement in SRI at wk 52

Belimumab plus current routine therapy was generally well tolerated, with a safety profile comparable to that of placebo plus current routine therapya

BLISS-52 BLISS-76

a Wallace et al. Presented at the American College of Rheumatology Annual Meeting, Nov 9, 2010, Poster 1172.

p = 0.013

Belimumab

– Who should be treated?– What manifestations respond best?– When is a response expected?– When should failure be declared?– If successful, how long should it be used?– How clinically significant is the SRI?

Lessons Learned: SLE Clinical Trials

The recent past– Developing drugs in SLE is humbling– Surprising failures: rituximab– Successful failures: MMF– Sucesses: belimumab– An endpoint that worked

Lessons Learned: SLE Clinical Trials

The future– Unprecedented trials activity now– Challenges

• Not enough patients to fill studies• Trial design challenges remain

Thank you

Move over ACR 20 (and DAS), make room for SLEDAI and BILAG