Breakthroughs in Lupus in 2014 - University of Rochester Medical

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Breakthroughs in Lupus in 2014
Jennifer H. Anolik, MD, PhD
Associate Professor of Medicine, Pathology, and
Microbiology/Immunology
Division of Allergy, Immunology & Rheumatology
University of Rochester Medical Center
Oct 2014 8th Annual Lupus Education Day
MEDICINE OF THE HIGHEST ORDER
Outline
•
Basics
•
Diagnosis and Biomakers
•
Pathogenesis (leads to treatment)
•
New Treatments
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
Systemic Lupus Erythematosus
•
•
•
•
•
Inflammatory multisystem 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
Lupus history
•Lupus is the Latin word for wolf
•1st used medically in the 10th century
•Described clinically in the 19th century
•Butterfly rash in 1845
•Arthritis in 1892
•Nephritis in 1895 by Osler
•Serologic tests become available in the 20th century
•LE cell in 1948
•Lupus anticoagulant in 1952
•ANA in 1954
From Dubois
What are the different forms of lupus?
Systemic Lupus Erythematosus
Discoid or Cutaneous Lupus
Drug-Induced Lupus
Neonatal Lupus
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
Other problems
• Repeated Miscarriages
• Disease in organs
–
–
–
–
Kidney
Heart
Lungs
Brain and nerves
Lupus presenting symptoms
Painful Joints
Fevers
Swollen Joints
Extreme Fatigue
Skin Rashes
Anemia
Renal
Pluerisy
Facial Rash
Photosensitivity
Hair Loss
Clotting
Raynauds
Seizures
Ulcers
0
10
20
30
40
50
60
70
80
90
100
Who gets lupus?
•World-wide prevalence : 10-100/100,000
•Estimated frequency:
•1 per 700 white women
More people have
•1 per 245 black women
Lupusestimates
than
•The Lupus Foundation
that 1.5
Cerebral
Palsy,
million Americans
have some
form of the
disease
Multiple Sclerosis,
•African-Americans
> Caucasians
Sickle Cell
Anemia (3x)
•Asian-American
and Hispanics
> Caucasians
and Cystic
Fibrosis
•Age at diagnosis:
combined.
•16-55 years of age: 65% of cases
•< 16: 20%
•> 65: 15%
•9/10 lupus patients are women
How do we diagnose lupus?
Skin criteria
1. Malar rash
2. Discoid Rash
3. Photosensitivity
4. Oral Ulcers
Systemic criteria
5. Arthritis
6. Serositis
7. Kidney
8. Neurologic
Lab criteria
9. Anti-nuclear antibody
10. Immunologic
11. Hematologic
*4 criteria simultaneously or serially for diagnosis
SLE Diagnosis: The ANA
• 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
New Diagnostics
• AVISE SLE- diagnostic test to help rule-in and
rule-out RA, SLE, and other autoimmune diseasesincludes a panel of autoantibodies + cell-bound
complement activation products
• A team at Stanford engineered a silicon computer
chip containing thousands of subtly different protein
segments derived from a single protein (known as a
histone 2B), which is a common target of
autoantibodies in lupus
Nature Medicine 2012
PJ Utz group
Cause
genetics
hormones
environment
Triggers
Ultraviolet light
Stress
Medications
Infections
Hormonal Changes
New thoughts on causes and triggers
• Human Microbiome Project (HMP) an NIH initiative
started in 2008 to identify the microorganisms
which are found in association with both healthy
and diseased humans (the human microbiome)
• Can contribute to development of a variety of
autoimmune diseases including multiple sclerosis,
rheumatoid arthritis, and possibly lupus
Identifying Novel Lupus Targets
• Hallmark of Lupus is an overactive immune system
• Recently identified that lupus patients have
abnormally low levels of a switch that puts the
bad-acting autoantibody-secreting B cells to
sleep called PTEN
• Lupus patients with a low level of PTEN exhibit a
more severe disease
Science Translational Medicine 2014
Identifying Novel Lupus Targets through
genetics
• TREX1-helps the body break down unnecessary DNA
molecules or fragments that may be generated during the
copying of cells genetic material
• A small % of lupus patients have mutations in the TREX1
gene
• Methods to limit TREX1 stimulation of the immune
response are in early stages of study
• Another example- MDA5
‘shutting off the immune response based on new molecular
knowledge’
Immunity 2014
How is lupus treated?
Treating inflammation or autoimmunity
•Anti-inflammatory agents
•Antimalarials
•Immunosupressive/cytotoxic agents
Other
•Prevention: management of cardiovascular
risk, immunization, etc.
•Anti-thrombotic therapy
•Treating seizures
•Dialysis and kidney transplantation
The ‘traditional treatment
armamentarium’
FDA Approved drugs
 glucocorticoids
Benlysta
 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
New Treatments for Lupus
Until April 2011 it had been over 50 years
since a new drug was approved for lupus!
WHY?
•Lupus is hard to study:
•
•
•
•
•
Clinical expression is heterogeneous
Pathology is diverse
Disease activity is intermittent
Lack of agreed upon disease activity measures and endpoints
Small patient populations- rare disease
•Development costs: Estimated $1 billion to take a drug from
the research stage to FDA approval
•Lack of a clinical trial infrastructure
Clinical Trials
What are they?
• Very carefully controlled human studies
of drugs that are not yet approved by
the US Food and Drug Administration
(FDA) for use in a particular disease
• The FDA will approve a drug once it has
been proven that the benefits outweigh
the risks
Why do we need clinical trials?

We need to know what works

We need better medications for lupus

Many lupus patients have progressive damage to vital
organs
Many lupus patients have ongoing symptoms that limit
function
Many lupus patients suffer toxicity from medications

We need FDA approval



We need to get insurance companies to pay for
medications
Steps for drug approval


Pre-clinical studies – Non-Human
Phase I studies – 1st time in humans <100
people
–

Phase II studies – 100+ people
–

What are the side effects and what dose should
be given?
Does the drug work and are there other side
effects?
Phase III studies – 1000+ people
–
Does the drug work and is it safe long term?
SLE pathogenesis and treatment targets
Stages of autoimmunity
Loss of tolerance
End organ targeting
Innate and adaptive dysregulation
FcR, ITGAM
Sle1, CD22, C1q, BANK, BAFF
Sle2 (B), Sle3 (T, DC), PTPN22
Autoantibodies
Immune
BAFF
complex
inhibitors
Proteasome
inhibitors
mBAFF
PC
Anti-B cell
antibodies
TLR
inhibitors
TLR9
IFN
blockade
pDC
sBAFF
BR3
IFN
B
mDC
B7.1/2
B7.1/2
CD28
CD40
CD40L
T
N
Lymphocyte
signaling
small molecule
inhibitors
IFN
TNF blockade
IL-6 blockade
CTLA4-Ig
Abatacept
Repurposing drugs:
LRxL-STAT
(Lupus Rx List-SLE Treatment Acceleration Trials)
•New ALR-LRI collaboration
•Finding drugs and other treatment strategies that
may be ripe for repurposing in lupus
•155 candidate drugs have emerged for further
study in small focused science-rich clinical trials
•1st clinical trials of the STAT initiative will kickoff in early 2015
https://www.linkedin.com/in/lrxlstat
Mycophenolate mofetil (CellCept®) Use for
Kidney Inflammation in Lupus
• Generally well tolerated
• “Turns down” the immune system
• FDA-approved for use in patients receiving organ
transplants
• May have fewer side effects than older
medications
Accelerating Medicines Partnership (AMP)
Initiative
• New venture between the NIH, 10
biopharmaceutical companies and non-profit
organizations to transform the current model for
developing new diagnostics and treatments by
jointly identifying and validating promising
biological targets of disease
• The ultimate goal is to increase the number of
new diagnostics and therapies for patients and
reduce the time and cost of developing them
• Lupus and Rheumatoid Arthritis: Define shared
and disease specific biological pathways
• $41 million dollars; 11 sites recently awarded
including UR!
SLE Clinical Trials: Summary
www.clinicaltrials.gov
B cell targeted 2014 What’s new?
• Targeting B cells with anti-CD20
– Initial studies
– Rituximab in general lupus (Genentech; phase II/III):
completed; Rituximab in proliferative lupus nephritis (LN)
(Genentech; phase II/III): completed
– ?Induction therapy
• Cytokine blockade: BAFF blockade- LN, black
patients, pediatric, long-term safety, SQ
• Other B cell targeted therapies:
•
•
•
•
Anti-CD22: phase III underway
Other anti-CD20s-largely halted
Anti-CD19
Proteasome inhibitors
Belimumab (anti-BAFF)- Benlysta
for Treatment of SLE
• 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
Rituximab= anti-CD20=
B cell depletion
• 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
• Innovative ways to combine rituximab with benlysta
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
SLE Clinical Trials:
Cytokines
Targeting cytokines of pathogenic importance
• Targeting Interferon α
• Targeting IL6
Interferon and Toll-like receptors
TLR
Current Opinion in Rheumatology 2003 Pascual
IFN as a common denominator in
trigger of flares
•Sun exposure
•Drug reactions, e.g. sulfa drugs
•Infections
Some of our current drugs are
now believed to target IFN
pathways: e.g. anti-malarials
IFN blockade
•Multiple studies on monoclonal antibodies
against IFN alpha in various stages of
development
•Recent press release that sifalimumab
(Medi-545) met primary endpoint of
reduction in global disease activity score in
moderate/severe SLE
TLR antagonists
• TLRs are key receptors of the innate immune system
that can induce strong inflammatory responsesimportant in production of IFN
• Small molecules inhibitors of Toll-like Receptors (TLRs)
7, 8, and/or 9 are under development
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)
80
3
2
**
1
**
0
0 1 2 3 4 5 6 7 8
Weeks of treatment
dsDNA ASC
Proteinuria score
X 103
60
40
20
0
Untreated
Low
High
SINEs
Anolik et al.
Things to Remember Tomorrow
• SLE is a heterogeneous autoimmune disease
• SLE can be mild and is almost always treatable
• Although lupus can affect almost any part of
the body, most people experience symptoms in
only a few organs.
• Treatment must be directed at the whole
person not just the disease.
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
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