Safety of Biological Response Modulators in Rheumatoid Arthritis

Biological Response Modulators
in RA-Safety
Frank R Wellborne, DO, FACR
Co-Director, Rheumatic Innovative
Therapies
Houston Institute for Clinical Research
Clinical Spectrum of RA
Images
courtesy of J. Cush, 2002.
2
Mechanisms That Contribute to Clinically Observed Long-Term Complications
in Patients with Rheumatoid Arthritis.
McInnes IB, Schett G. N Engl J Med 2011;365:2205-2219
Cytokines Signal Through Different
Intracellular Pathways
MAPK
signaling
cascade
NFKB
signaling
cascade
PI3K
signaling
cascade
SYK
signaling
cascade
JAK
signaling
cascade
Lipid
messengers
PI3K
Syk
BTK
signaling
cascade
P13K
P13K
PI3K
Btk
Secondary
messengers
Kinases
JAK
IKK
PKC
Kinases
STAT
STAT
NFκB
JNK
Cytoplasm
CELL
MEMBRANE
CaN
ERK
p38
JAK
NFAT
STAT
STAT
Gene transcription
Nucleus
BTK=Bruton’s tyrosine kinase; ERK=extracellular signal-related kinases; IKK=inhibitor of κB kinase; JNK=c-Jun N-terminal
kinase; MAPK=mitogen-activated protein kinase; NFκB=nuclear factor κ light-chain-enhancer of activated B cells; PKC=protein
kinase C; PI3K=phosphoinositide 3-kinase; Syk=spleen tyrosine kinase.
Figure adapted from Mavers M, et al. Curr Rheum Rep. 2009;11:378-385 and Rommel C, et al. Nat Rev Immunol. 2007;7:
191-201; Btk pathway added based on Mohamed AJ, et al. Immunol Rev. 2009;228:58-73.
7
Disorders Associated with Mutations of JAKs and STATs.
O'Shea JJ et al. N Engl J Med 2013;368:161-170
The Biological Significance of Signaling
Through Different JAK Combinations
Receptors sharing
γ-chain1
IL-2, IL-4, IL-7,
IL-15, IL-21
Type I
IFNR1
IL-10R
family1
IL-10†,
IFNα/β/κ/ω/ε IL-20, IL-22
Receptors sharing
gp130 subunit1,2*
Type II IFNR1
IL-12R family
sharing p40
subunit1
IL-6, IL-11,
IL-27, G-CSF
IFN-γ
IL-6, IL-12,
IL-23
Hormone
receptors1
IL-3R
family1
EPO, TPO, IL-3, IL-5
GH, PRL
TYK2
FUNCTION3
JAK1
JAK3
JAK1
• Growth/ maturation
lymphoid cells
• Differentiation/ homeostasis
T-cells, NK
• B-cell class switching
• Inflammation
TYK2
• Antiviral
• Inflammation
• Antitumor
JAK1
JAK2
• Naïve T-cell
differentiation
• T-cell homeostasis
• Inflammation
• Granulopoiesis
JAK1
JAK2
• Antiviral
• Inflammation
JAK2
TYK2
• Innate immunity
• Differentiation/
proliferation of Th17
• Inflammation
JAK2
JAK2
• Erythropoiesis
• Myelopoiesis
• Megakaryocyte/ platelet
production
• Growth
• Mammary development
*Type II cytokine receptors such as those for IL-10, IL-19, IL-20, and IL-22 as well as gp130 subunit sharing receptors for IL6 and IL-11 mainly signal through JAK1, but also associate with JAK2 and TYK2.2 †IL-10/IL-22 may have pro- or antiinflammatory activities depending on the cellular environment and/or disease state.4
EPO=erythropoietin; G-CSF=granulocyte colony-stimulating factor; GH=growth hormone; IFN=interferon; IL=interleukin;
IRF=interferon regulatory factor; JAK=Janus kinase; PRL=prolactin; TPO=thrombopoietin; TYK=tyrosine kinase.
1. O’Shea JJ, et al. N Engl J Med. 2013;368:161-170; 2. O’Sullivan LA, et al. Mol Immunol. 2007;44(10):2497-506;
3 . Ghoreschi K, et al. Immunol Rev. 2009;228:273-287; 4. Vijayakrishnan L, et al. Trends Pharmacol Sci. 2011;32:25-34.
9
Biologics in Rheumatoid Arthritis
Agent
Biologic Target
Construct
Infliximab
TNF
Chimeric MAb
Etanercept
TNF
IgG-p75 receptor
Adalimumab
TNF
Human MAb
Goliumumab
TNF
Human MAb
Certolizumab
TNF
Peg-Fab’
Abatacept
T-cell costim
IgG-CTLA4 fusion
Rituximab
B-cells
Chimeric MAb
Anakinra
IL-1
IL-1 Recpt antag
Tocilizumab
IL-6
Anti-IL6 Recept MAb
* Tofacitinib is NOT a Biologic
Warnings and Precautions:
Warning: Risk of Serious Infections
• Serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial, invasive
fungal, viral, and other opportunistic infections, have occurred in patients receiving ACTEMRA
• ACTEMRA should not be administered during an active infection, including localized infections
• If a serious infection develops, ACTEMRA should be interrupted until the infection is controlled
• Prior to initiating ACTEMRA, a test for latent TB should be performed
• If the test is positive, treatment for TB should be started prior to starting ACTEMRA
• All patients should be monitored for active TB during treatment, even if initial latent TB test is negative
• The benefits and risks of treatment should be considered prior to initiating ACTEMRA in patients:
– with chronic or recurrent infection
– who have been exposed to TB
– who have a history of serious or opportunistic infections
– who have resided or traveled in areas of endemic TB or mycoses
– with underlying conditions that may predispose them to infection
• Patients should be closely monitored for signs and symptoms of infection during and after treatment
with ACTEMRA
Contraindication
• ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA
Please see full Prescribing Information including Boxed Warning for additional important safety information
1. ACTEMRA Prescribing Information (October 2013). Boxed Warning and Section 5.1 – Serious Infections.
Important Safety Information
SERIOUS INFECTIONS
Patients treated with HUMIRA are at increased risk for developing serious
infections that may lead to hospitalization or death. Most patients who developed
these infections were taking concomitant immunosuppressants such as
methotrexate or corticosteroids.
HUMIRA should be discontinued if a patient develops a serious infection or sepsis.
Reported infections include:
• Active tuberculosis (TB), including reactivation of latent TB. Patients with TB
have frequently presented with disseminated or extrapulmonary disease.
Patients should be tested for latent TB before HUMIRA use and during therapy.
Treatment for latent TB should be initiated prior to HUMIRA use.
• Invasive fungal infections, including histoplasmosis, coccidioidomycosis,
candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients
with histoplasmosis or other invasive fungal infections may present with
disseminated, rather than localized, disease. Antigen and antibody testing for
histoplasmosis may be negative in some patients with active infection. Empiric
anti-fungal therapy should be considered in patients at risk for invasive fungal
infections who develop severe systemic illness.
• Bacterial, viral, and other infections due to opportunistic pathogens, including
Legionella and Listeria.
HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.
Please see accompanying full Prescribing Information.
13
Important Safety Information
SERIOUS INFECTIONS (continued)
The risks and benefits of treatment with HUMIRA should be carefully considered
prior to initiating therapy in patients with chronic or recurrent infection. Patients
should be closely monitored for the development of signs and symptoms of
infection during and after treatment with HUMIRA, including the possible
development of TB in patients who tested negative for latent TB infection prior to
initiating therapy.
•
•
•
•
•
Do not start HUMIRA in patients with an active infection, including localized
infections.
Patients older than 65 years, patients with co-morbid conditions, and/or patients
taking concomitant immunosuppressants may be at greater risk of infection.
Exercise caution in patients with chronic or recurrent infection or with underlying
conditions which may predispose them to infection, patients who have been
exposed to TB, patients with a history of opportunistic infection, or patients who
have resided or traveled in regions where TB or mycoses are endemic.
Patients who develop a new infection should undergo a prompt and complete
diagnostic workup, and appropriate antimicrobial therapy should be initiated.
Drug interactions with biologic products: Concurrent use of anakinra or abatacept
with HUMIRA is not recommended, as the combination of anakinra or abatacept
with TNF blockers has been associated with an increased risk of serious infections.
This risk has also been observed with rheumatoid arthritis patients treated with
rituximab who received subsequent treatment with a TNF blocker.
HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.
Please see accompanying full Prescribing Information.
14
Important Safety Information
MALIGNANCY
Lymphoma and other malignancies, some fatal, have been reported in children
and adolescent patients treated with TNF blockers, of which HUMIRA is a
member. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a
rare
type of T-cell lymphoma, have been reported in patients treated with TNF
blockers including HUMIRA. These cases have had a very aggressive disease
course and have been fatal. The majority of reported TNF blocker cases has
occurred in patients with Crohn’s disease or ulcerative colitis and the majority
were in adolescent and young adult males. Almost all these patients had
received treatment with azathioprine or 6-mercaptopurine concomitantly with a
TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of
HSTCL is related to use of a TNF blocker or a TNF blocker in combination with
these other immunosuppressants.
•
•
The risks and benefits of HUMIRA treatment should be considered prior to
initiating or continuing therapy in a patient with known malignancy.
More cases of malignancies were observed among HUMIRA-treated patients
compared to control patients in clinical trials.
HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.
Please see accompanying full Prescribing Information.
15
Data for Safety
• Randomized clinical trials (RCTs)
• Open-label extension trials (OLE)
• FDA approval…post-market surveillance (FDA
MedWatch & Industry
• Observational studies e.g. claim data bases,
cohorts, bio-registries of different countries
• Clinical practice experience
Output of the Safety Data Collected
• Events per 100 patient-years
– Number of events divided by the total patient-years of exposure and multiplied by
100
– The number of events expected if a single patient was to be on therapy for 100
years
– Or, the number of events expected if 100 patients were to be on therapy for 1 year
each
17
Serious Adverse Events of Interest,
Events/100 Patient-years
RA
PsA
AS
CD
Ps
JIA
Rates displayed as events per 100 patient-years (PY)
As of November 6, 2010
23,942.6 PYa
N=14,109
997.5 PYa
N=837
1985.6 PYa
N=1684
4138.0 PYa
N=3606
5061.8 PYa
N=3010
604.9 PYa
N=212
Serious infections
4.6
2.8
1.4
6.7
1.7
2.0
Active tuberculosis
0.3
0.2
0
<0.1
0.1
0
Opportunistic infections
<0.1
0
0
<0.1
0
0
Malignanciesb
0.9
0.2
0.2
0.5
0.6
0
Lymphoma
0.1
0.2
<0.1
<0.1
<0.1
0
Serious non-melanoma skin cancer
0.2
0.1
0.3
<0.1
0.1
0
Melanoma
<0.1
0
<0.1
0
0.2
0
Demyelinating disorder
<0.1
0
<0.1
0.1
0
0
Lupus-like syndrome
<0.1
0
0.1
<0.1
0
0
Congestive heart failure
0.2
0
0.1
0
<0.1
0
New onset/worsening of psoriasis
<0.1
0.1
<0.1
<0.1
<0.1
0
Any AE leading to death
0.8
0.3
<0.1
0.1
0.2
0
Serious adverse events of interest
18
HUMIRA and Enbrel: Serious Infections
in RA Clinical Trials
Events per 100 PY
6.0
Enbrel†
HUMIRA*
8.0
5.8
4.9
4.8
4.2
4.0
2.0
Rate Reported in Literature
in RA Population1-3
10.0
0
Through August
2002
Through April 2004
DMARD Refractory
EU DMARD
Refractory
Established RA
EU=European Union
1. Singh G, et al. Arthritis Rheum. 1999;42:S242. 2. Doran M, et al. Arthritis Rheum. 2002;46:2287-2293.
3. Moreland L, et al. J Rheumatol. 2001;28:1238-1244.
*Data on file, Abbott Immunology. Data include clinical extension studies.
†Moreland L, et al. Presented at: ACR 2003.
19
Serious Infections (events/100 PY)
Serious Infections in Early RA Clinical Trials
10
9
8
7
6
5
4
3
2
1
0
Exposure (PY)
Adalimumab1
Etanercept2
Infliximab3
5.4
2.9
3
Rate
reported
in the
literature
for the RA
population4-5
0.7
Adalimumab
Alone
Adalimumab
+ MTX
435
482
Etanercept
2383
Infliximab 3 mg/kg
+ MTX
NA
MTX = methotrexate; DMARD = disease-modifying antirheumatic drug.
1. Schiff MH, et al. Presented at: EULAR Annual Meeting; June 8-11, 2005; Vienna, Austria. 2. Lebwohl, et al. Presented at:
63rd Annual Meeting of AAD; February 18-22, 2005; New Orleans, LA; 3. Conservative est. rate assuming 54-wk drug
exposure for all pts (ie, 21 infections in 386 pt-yrs exposure) St Claire E, et al. Arthritis Rheum 2004;50:3432-43; 4. Singh G,
et al. Arthritis Rheum. 1999;42:S242. 5. Doran M, et al. Arthritis Rheum. 2002;46:2287-2293.
20
PREMIER Study
Treatment-Emergent Adverse Events
Adalimumab + Adalimumab
MTX
n=268, PYs=482
MTX
n=274, PYs=435
n=257, PYs=429
Events/100 PY
Events/100 PY
Events/100 PY
Serious AE
18.5
21.1
15.9
Serious Infectious AE*
2.9
0.7
1.6
Infectious AE
123
110
119
Tuberculosis
0.2
0
0
Malignancies
0.4
0.9
0.9
Lymphoma
0
0
0.2
Demyelination
0
0
0
* overall p=NS; p<0.05 adalimumab + MTX vs adalimumab
21
Scope of Infections Associated with Biologic Use
AntiTNF
Rituximab
Tocilizimab
Tofacitinib












*
*
Anakinra Abatacept
Bacterial



TB & Myco

*
*
Fungal &
Opportunistc

*
*
Hepatitis B

*

NSIE
SIE



*
*
*
Hepatitis C
H. Zoster

PML
*
 risk from PI, RCTs & Registries
* Few reports
Low/No Risk
*
*
*


NSIE: nonserious infectious events (URI, etc)
SIE: serious infectious events
PML: progressive multifocal leukoencephalopathy
RhemNow.com
Meta-Analysis of Serious Infections in Approved Biological DMARD
Agents, Randomised Clinical Trial Data
Drug
Number
of Trials
Serious Infections
Rate/100 PYO (95% CI)
Patients
PYO
5635
5752
1920
1287
3516
2473
4577
3546
2213
3103
1384
889
2820
1648
Abatacept
10
Rituximab
6
Tocilizumab
10
Infliximab
10
Etanercept
7
Certolizumab pegol
3
Golimumab
6
Adalimumab
8
4.9
2335
1913
TNF alpha inhibitor
42
4.9
20785
23988
Tofacitinib 5 mg P3All
5
1216
901
Tofacitinib 5 mg LTE
2
1421
3210
Adalimumab (A3921064)
1
204
179
3.1
3.62
6.29
6.08
3.3
6.23
5.31
3.22
2.62
1.68
0
2
4
6
8
10
CI, confidence interval; DMARD, Disease Modifying Antirheumatic Drug; LTE, long term extension studies; P3ALL, tofacitinib
Phase 3 studies; PYO, patient years of observation
Ahadieh et al, 2012; Tofacitinib data as of 19 April 2012; Clinical trial data published between 1999 and 2012.
23
Fig. 2
Copyright © 2012 Elsevier Inc. Martin, RW Rheum Dis Clin N Am 38(2012) 653-662.
Rheumatic Disease Clinics 2012 38, 653-662DOI: (10.1016/j.rdc.2012.08.007)
Fig. 3
Martin,RW Rheum Dis Clin N Am 38 (2012) 653-662
Rheumatic Disease Clinics 2012 38, 653-662DOI: (10.1016/j.rdc.2012.08.007)
Meta-analysis of Malignancies* in Clinical Trials
Published Clinical Trials From 1998 to 2011
Drug
Number
of Trials
Abatacept
6
Rituximab
2
Tocilizumab
8
Infliximab
7
Etanercept
8
Certolizumab
6
Golimumab
5
Adalimumab
12
TNF inhibitor
38
Tofacitinib 5 mg P3All
5
Tofacitinib 5 mg LTE
2
Malignancy
Rate/100 PYO (95% CI)
0.73
1.36
1.06
1.27
1.03
0.59
1.23
1.24
1.1
0.44
1.02
0
0.5
1
1.5
2
2.5
Patients
PYO
3328
3702
1020
738
6825
3222
1742
1908
2574
5472
2367
4065
2227
1284
9228
8410
18993
21502
1216
904
1421
3241
3
Data as of 19 April 2012
*Excluding non-melanoma skin cancers
Ahadieh et al. Arthritis Rheum 2012;64(10 [supplement]): S726
26
Output of Safety Data Collected
Standardized Incidence Rate (SIR)
• Ratio of observed events to expected events in a population
For example:
• If 10 malignancies were observed in drug trials, and
• 20 malignancies were expected in the general population, then
• The SIR (standard incidence rate) for malignancies = 0.5
What does an SIR < 1.0 mean?
• Number of observed events is less than the number of expected events
What does an SIR > 1.0 mean?
• Number of observed events is more than the number of expected events
27
Expected Events ―
Where Do They Come From?
• The expected number of cancers for SIR calculations was based
on two data sources:
– 5-year age-specific cancer incidence rates obtained from the
National Cancer Institute (NCI) Surveillance Epidemiology and
End Results (SEER) database (1993-2001) for all cancers other
than non-melanoma skin cancer (NMSC)
– 10-year age-specific incidence rates for NMSC from an NCI
survey
of 8 locations in the US (1977-1978)
Incidence of Lymphoma in
Patients with Rheumatoid Arthritis
SIR for lymphoma
Study
Country
Number of
RA patients
Years of
follow-up
SIR for
cancer
[OR (Activity level)]
Gridley 1993
Sweden
11,683
20
1.0
2.0
Mellemkjaer 1996
Denmark
20,699
14
1.1
2.5
Isomaki 1978
Finland
46,101
7
1.1
2.7
Adalimumab 2004
Global
10,206#
1.2**
0.92
2.90
(1.0/low)
Baecklund 1998
Matteson 1991
Sweden
Canada
11,683
530
18
7
–
1.5
(5.4/medium)
(25.8/high)
8.0
OR=odds ratio; SIR=standardized incidence ratio (RA population vs general population)
*As of December 31, 2003; #As of June 30, 2004; ** Mean years of follow-up
Gridley, et al. J Natl Cancer Inst 1993;85:307–11; Mellemkjaer, et al. Eur J Cancer 1996;32A:1753–7; Isomaki, et al. J Chronic Dis
24
1978;31:691–6; Baecklund, et al. BMJ 1998;317:180–1; Matteson, et al. J Rheumatology 1991;18:809–14.
Safety of Synthetic and Biological DMARDs: a
systematic literature review (SLR) informing the 2013
update of the EULAR recommendations for
management of RA
• Published with efficacy in RA and the “final”
EULAR recommendations for the management of
RA
• Annals of the Rheumatic Diseases March 2014
Vol 73 (3): 492-535.
• SLR of observational studies & registries
comparing bDMARDs vs. sDMARDs vs. general
population…real world.
• RCTs small #’s and short duration…real world?
Conclusions of EULAR Safety ReviewInfections
• Patients on TNFi vs. sDMARDs had a higher
risk of serious infections (aHR 1.1-1.8)
• Patients on TNFi vs. general pop & one
sDMARD study had a higher risk of TB (SIR 12
& 35)
• Patients on TNFi vs. sDMARDs had a higher,
but NS risk for H. Zoster (aHR 1.0-1.7)
• Other Opportunistic infections “to rare to call”
Conclusions of EULAR Safety ReviewMalignancies
• Distinction between comparator of sDMARDs
or general population
• TNFi vs. sDMARDs no difference in cancer,
lymphoma, NMSC except one study questions
rising trend of melanoma
• TNFi vs. general population cancer no higher
except lymphoma (aHRs 2.3-5.9) and NMSC
may be higher (aHR 1.7)
Conclusions of EULAR Safety ReviewOther Issues
• Five studies found no difference in mortality
between TNFi and sDMARDs
• Other safety outcomes, e.g., CHF,
demyelinating diseases, opportunistic
infections, etc. too few studies to evaluate
• For sDMARDs despite a few exceptions there
are no high-quality studies, but no new signals
• In this analysis not enough data to discuss
non-TNF biologics
Conclusions of EULAR Safety ReviewBottom Line
• “In general, these conclusions, while
stemming mainly from registries, confirm the
findings from RCTs and from what was known
from clinical practice.”
Pearls
ti
2015 ACR Reccommendations
For Use of DMARDs in RA