Welcome and Overview
Advances in the Treatment of Psoriasis
Neil Korman, MD, PhDDirector, Clinical Trials Unit
Clinical Director, Murdough Family Center for Psoriasis
Professor, DermatologyUniversity Hospitals Cleveland
Medical CenterCase Western Reserve University
School of MedicineCleveland, Ohio
Disclosure: Neil Korman, MD, PhD
Dr. Korman is an investigator, advisor, speaker, and or consultant for AbbVie, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Prothena, Regeneron, Sun Pharma, Valeant Pharmaceuticals International, and Regeneron
Trends in Biologic Use in Psoriasis in the United States
AAD=American Academy of Dermatology. NPF=National Psoriasis Foundation. Menter A, et al. J Am Acad Dermatol. 2008;58:826-850. Hsu S, et al. Arch Dermatol. 2012;148(1):95-102.
Step therapy Phototherapy
Then oral systemics
Then biologics
Phototherapy or oral systemics
or biologics
Both the AAD and the NPF support the use of biologics as a first-line agent for patients with moderate to severe psoriasis
Considerations Prior to Initiating Systemic Therapy in Patients With Psoriasis
TB=tuberculosis. CHF=congestive heart failure. TNF=tumor necrosis factor.
Assess for TB
Screen for hepatitis B and C
viral infections
Assess underlying cancer risk
Use caution in patients with
active CHF when considering
medications with TNF inhibitors
Verify absence of demyelinating
disease
Use caution in patients with CD/UC when considering
medications with IL-17 inhibitors
Verify absence of current infection
Consider completing
all age-appropriate
immunizations
FDA-Approved Biologics
PsA=psoriatic arthritis. IL=interleukin. FDA=US Food and Drug Administration.
Drug Class Agent
TNF antagonistsEtanerceptInfliximab
Adalimumab
Psoriasis, PsAPsoriasis, PsAPsoriasis, PsA
p40 IL-12/23 antagonist Ustekinumab Psoriasis, PsA
IL-17 antagonistsSecukinumabIxekizumab
Psoriasis, PsAPsoriasis
Indication
Brodalumab Psoriasis
IL-23 Blockers: Biologics on the Horizon
3 different IL-23 agents in development
Guselkumab Tildrakizumab Risankizumab
Phase 2 efficacy and safety data as well as some phase 3 data are very promising
IL-17 Inhibitors
IgG=immunoglobulin G.Gaspari AA, et al. Dermatol Ther. 2015;28(4):179-193.
Secukinumab Ixekizumab Brodalumab
Fully human IgG1 monoclonal
antibody
Neutralizes IL-17A
Approved for psoriasis and PsA
Humanized IgG4 monoclonal
antibody
Neutralizes IL-17A
Approved for psoriasis
Human anti–IL-17A
receptor monoclonal
antibody
Approved for psoriasis
Ustekinumab
Secukinumab
Secukinumab
Ixekizumab
Guselkumab
Superior Agent
Short-Term Head-to-Head Clinical Trials Among Biologics Used for Psoriasis
*All doses used are FDA-approved doses. Etanercept dose is the high-dose 50 mg twice weekly for the first 3 months.Blauvelt A et al. J Am Acad Dermatol. 2017;76:60-69. Gordon KB et al. N Engl J Med. 2015; 373:136-144. Griffiths CE at el. N Engl J Med. 2010:362:118-128. Griffiths CEM et al. Lancet. 2015;386:541-551. Langley RG et al. N Engl J Med. 2014;371: 326-338. Lebwohl M et al. N Engl J Med. 2015;373:1318-1328. New head-to-head data. 2017. https://investor.lilly.com/releasedetail.cfm?ReleaseID=1015859.
Ustekinumab vs etanercept
Secukinumab vs etanercept
Secukinumab vs ustekinumab
Ixekizumab vs etanercept
Guselkumab vs adalimumab
BrodalumabBrodalumab vs ustekinumab
IxekizumabIxekizumab vs ustekinumab
Treat to Target: The National Psoriasis Foundation Consensus
BSA=body surface area.Armstrong AW et al. J Am Acad Dermatol. 2017;76(2):290-298.
Preferred Assessment Tool in Clinical Practice BSA
Time at initial evaluation after treatment initiationAt 3 months
after initiation
Acceptable response at 12 weeks after treatment initiationEither BSA 3% orBSA improvement 75% from baseline
Target response at 12 weeks after treatment initiation BSA 1%
Time interval for evaluation during maintenance therapy Every 6 months
Target response during maintenance therapy BSA 1%
Unmet Needs in Psoriasis Still Exist
Lebwohl et al. Am J Clin Derm. 2016;17:87-97.
Patients report that itching is the most important factor in disease severity, while physicians report that size and severity of lesions are most important in disease severity
Patients with psoriasis must be regularly screened for PsA, and tools are needed to separate PsA from other rheumatic diseases
Ongoing communication between patients and physicians is needed for better understanding of choice of therapies
Summary: Treatment of Moderate to Severe Psoriasis
Options are increasing with inhibitors to TNF,
IL12/23, or IL17; among the currently
approved biologics at the currently approved doses, IL-17-blocking agents appear to be
most efficacious
Comparative effectiveness studies and consideration of
comorbidities are critical in determining
optimal therapy for individual patients
New biologics targeting IL-23 are
in development
Psoriasis Therapeutics From the 1950s to the Present:
Enter the Renaissance
Bruce E. Strober, MD, PhDProfessor and Chair,
Department of DermatologyUniversity of Connecticut Health Center
Farmington, Connecticut
Disclosure: Bruce E. Strober, MD, PhD
Dr. Strober is a consultant and or advisor for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, Cutanea-Maruho, Dermira, Lilly, Janssen, Leo Pharma, Medac Pharma, Novartis, Pfizer, Sun Pharma, UCB, and Valeant Pharmaceuticals International, and is the Scientific Director for the Corrona/NPF Psoriasis Patient Registry
Game Rules
Your knowledge of psoriasis therapeutics and disease pathogenesis will be tested through a series of 10 questions
• Each question starts out worth 10 points, but the point value decreases with time so think fast!
• The score for each question is calculated by taking the total team points and dividing by the number of team members
• At halftime, you’ll be able to see how you are stacking up against your competition
• The team with the most points at the end wins bragging rights
• There will also be a Team MVP for each team—the individual with the highest overall score
Methotrexate
Molecular weight454.45 g/mol
Methotrexate (cont.)
Therapeutic Suppression of Tissue Activity II. Effect of Aminopterin (4-aminopteroylglutamic acid) in Rheumatoid Arthritis and Psoriasis
Gubner R, August S, Ginsberg V
Gubner R, August S, Ginsberg V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci. 1951;221(2):176-182.
1951
Methotrexate
Structurally similar to folic acid
Irreversible inhibition Reversible inhibition
Dihydrofolate reductase
Thymidylate synthetase
Folic acid tetrahydrofolate DNA
Methotrexate: Adenosine Metabolism
• Methotrexate is metabolized to polyglutamate derivatives potent inhibitors of AICAR transformylase
• Accumulation of AICAR inhibits adenosine deaminase and AMP deaminase increased concentrations of adenosine
• Adenosine binds to 1 or more of 4 known receptors (A1, A2a, A2b, and A3) that have anti-inflammatory effects
AICAR=5-aminoimidazole-4-carboxamide ribonucleotide. AMP=adenosine monophosphate.Chan ES, Cronstein B. Arthritis Res. 2002;4:266-273. Montesinos MC et al. Arthritis Rheum. 2003;48:240-247. Morgan SL et al. Arthritis Rheum. 2004;50:3104-3111. Whittle SL, Hughes RA. Rheumatology. 2004;43:267-271.
Methotrexate: Adenosine Metabolism
• Methotrexate is metabolized to polyglutamate derivatives potent inhibitors of AICAR transformylase
• Accumulation of AICAR inhibits adenosine deaminase and AMP deaminase increased concentrations of adenosine
• Adenosine binds to 1 or more of 4 known receptors (A1, A2a, A2b, and A3) that have anti-inflammatory effects
• Methotrexate increases the amount of adenosine, an endogenous anti-inflammatory compound
AICAR=5-aminoimidazole-4-carboxamide ribonucleotide. AMP=adenosine monophosphate.Chan ES, Cronstein B. Arthritis Res. 2002;4:266-273. Montesinos MC et al. Arthritis Rheum. 2003;48:240-247. Morgan SL et al. Arthritis Rheum. 2004;50:3104-3111. Whittle SL, Hughes RA. Rheumatology. 2004;43:267-271.
Etretinate and Acitretin
EtretinateMolecular weight
354.48 g/mol
AcitretinMolecular weight
326.43 g/mol
Etretinate and Acitretin (cont.)
A Double-Blind Comparison of Acitretin and Etretinate in the Treatment of Severe Psoriasis
Results of a Nordic Multicentre Study
Kragballe K, Jansén CT, Geiger JM, Bjerke JR, Falk ES, Gip L, Hjorth N, Lauharanta J, Mork NJ, Reunala T, et al.
Kragballe K, Jansen CT, Geiger JM, et al. A double-blind comparison of acitretin and etretinate in the treatment of severe psoriasis. Results of a Nordic multicentre study. Acta Derm Venereol. 1989;69(1):35-40.
1989
Etretinate and Acitretin
Induce differentiation and inhibit
proliferation of keratinocytes
Have no immunosuppressive
activity
Have low efficacy as monotherapy and at tolerable (lower) doses
Cyclosporine
Molecular weight1202.61 g/mol
Cyclosporine (cont.)
Cyclosporine for Plaque-Type Psoriasis
Results of a Multidose, Double-Blind Trial
Ellis C, Fradin M, Messana J, Brown M, Siegel M, Howland Hartley A, Rocher L, Wheeler S, Hamilton T, Parish T, Ellis-Madu M, Duell E, Annesley T, Cooper K, Voorhees J
Ellis CN, Fradin MS, Messana JM, et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med. 1991;324(5):277-284.
1991
Cyclosporine: Mechanism of Action
IL=interleukin.
Selectively inhibits production of IL-2 and other
proinflammatorycytokines
Prevents T-cell activation
Is broadly acting immunosuppressant
TNF-α Inhibitors
Molecular weight=144 kDa
Antigen (TNF)binding sites
TNF receptors(TNF binding sites)
Anti-TNFmonoclonal antibody
Soluble TNF receptor:Fc fusion protein
Fc fragment Fc fragment
Infliximab and adalimumab Etanercept
Molecular weight=51 kDa
TNF=tumor necrosis factor.
Infliximab
Efficacy and Safety of Infliximab Monotherapy for Plaque-Type Psoriasis: A Randomized Trial
Early Report
Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB
Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet. 2001;357(9271):1842-1847.
2001
Etanercept
A Randomized Trial of Etanercept as Monotherapy for Psoriasis
Gottlieb AB, Matheson RT, Lowe N, Krueger GG, Kang S, Goffe BS, Gaspari AA, Ling M, Weinstein GD, Nayak A, Gordon KB, Zitnik R
Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol. 2003;139(12):1627-1632; discussion 1632.
2003
Adalimumab
Adalimumab Therapy for Moderate to Severe Psoriasis: A Randomized, Controlled Phase III Trial
Menter A, Tyring SK, Gordon K, Kimball AB, Leonardi CL, Langley RG, Strober BE, Kaul M, Gu Y, Okun M, Papp K
Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106-115.
2008
Current Model of Psoriasis Immunopathogenesis
GM-CSF=granulocyte/macrophage-colony stimulating factor.Keijsers RR et al. Br J Dermatol. 2013;168:1294-1302. Lin AM et al. J Immunol. 2011;187:490-500. Res PCM et al. PloS ONE. 2010;5:e14108. Taylor PR et al. Nat Immunol. 2014;15:143-151.
Stressed keratinocytes
Myeloid dendritic cell
Activation
T cells
Keratinocytes
TNF-α
IL-1BIL-6
TNF-α
IL-17A/FIL-22
GM-CSF
IL-23IL-12
TNF-α Inhibitors
Leads to the induction of an inflammatory milieu that accelerates
keratinocyte proliferation epidermal hyperplasia
Angiogenic tissue reaction leading to increased skin vascularization
An inflammatory cellular infiltrate
IFN=interferon. Th1=Type 1 T helper.
Inhibits the activity of TNF-α
Autoreactive Th1 cells
produce IFN-and TNF-α
TNF-α inhibitors reverse all of
the above
Demonstrate a dose-response
effect in clearing psoriasis
TNF-α
T-Cell Inhibitors
A Randomized, Double-Blind, Placebo-Controlled Phase III Study Evaluating Efficacy and Tolerability of 2 Courses of Alefacept in Patients With Chronic Plaque Psoriasis
Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN;Alefacept Clinical Study Group
Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol. 2002;47(6):821-833.
2002
T-Cell Inhibitors (cont.)
Efalizumab for Patients With Moderate to Severe Plaque Psoriasis
A Randomized Controlled Trial
Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, Bresnahan BW, Menter A; Efalizumab Study Group
Gordon KB, Papp KA, Hamilton TK, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA. 2003;290(23):3073-3080.
2003
T-Cell Inhibitors
Low efficacy drugs with variable safety concerns
and monitoring requirements
No longer available
IL-12/23 (p40) Inhibitors
Efficacy and Safety of Ustekinumab, a Human Interleukin-12/23 Monoclonal Antibody, in Patients With Psoriasis: 76-Week Results From a Randomized, Double-Blind, Placebo-Controlled Trial (PHOENIX 1)Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB; PHOENIX 1 study investigators
Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665-1674.Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675-1684.
Efficacy and Safety of Ustekinumab, a Human Interleukin-12/23 Monoclonal Antibody, in Patients With Psoriasis: 52-Week Results From a Randomized, Double-Blind, Placebo-Controlled Trial (PHOENIX 2)Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, Guzzo C, Hsu MC, Wang Y, Li S, Dooley LT, Reich K; PHOENIX 2 study investigators
2008
IL-12/23 (p40) Inhibitors (cont.)
Comparison of Ustekinumab and Etanercept for Moderate to Severe Psoriasis
Griffiths CE, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, Guzzo C, Xia Y, Zhou B, Li S, Dooley LT, Goldstein NH, Menter A; ACCEPT Study Group
Griffiths CE, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010;362(2):118-128.
2010
IL-12/23 (p40) Inhibitors (cont.)
Efficacy and Safety Results From a Phase III, Randomized Controlled Trial Comparing the Safety and Efficacy of Briakinumab With Etanercept and Placebo in Patients With Moderate to Severe Chronic Plaque Psoriasis
Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA
Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA. Efficacy and safety results from a phase III, randomized controlled trial comparing the safety and efficacy of briakinumab with etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol. 2011;165(3):661-668.
2011
Current Model of Psoriasis Immunopathogenesis
GM-CSF=granulocyte/macrophage-colony stimulating factor.Keijsers RR et al. Br J Dermatol. 2013;168:1294-1302. Lin AM et al. J Immunol. 2011;187:490-500. Res PCM et al. PloS ONE. 2010;5:e14108. Taylor PR et al. Nat Immunol. 2014;15:143-151.
Stressed keratinocytes
Myeloid dendritic cell
Activation
T cells
Keratinocytes
TNF-α
IL-1BIL-6
TNF-α
IL-17A/FIL-22
GM-CSF
IL-23IL-12
Molecular Weight = 460.5
Apremilast
Molecular weight460.50 g/mol
Apremilast
Apremilast, an Oral Phosphodiesterase 4 (PDE4) Inhibitor, in Patients With Moderate to Severe Plaque Psoriasis: Results of a Phase III Randomized Controlled Trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM 1])
Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, Hu C, Stevens RM, Day RM, Gordon KB, Korman NJ, Griffiths CE
Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37-49.
2015
Apremilast (cont.)
Efficacy and Safety of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients With Moderate to Severe Plaque Psoriasis: Over 52 Weeks: A Phase III Randomized Controlled Trial (ESTEEM 2)
Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz U, Ferrandiz C, Crowley J, Hu C, Stevens RM, Shah K, Day RM, Girolomoni G, Gottlieb AB
Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol. 2015;173(6):1387-1399.
2015
Apremilast: Mode of Action
cAMP=cyclic adenosine monophosphate.
Proinflammatory
mediators
(ie, TNF-α,
IL-23, IFN-γ)
Anti-inflammatory
mediators
(ie, IL-10)
cAMP
AMP
AMP
AMP
PDE4
Apremilast: Mode of Action (cont.)
Proinflammatory
mediators
(ie, TNF-α,
IL-23, IFN-γ)
Anti-inflammatory
mediators
(ie, IL-10)
Apremilast
cAMP
AMP
PDE4
cAMP
cAMP
IL-17 Inhibitors
Secukinumab in Plaque Psoriasis: Results of 2 Phase III Trials
Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, Puig L, Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai TF, Wasel N, Tyring S, Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C; ERASURE Study Group; FIXTURE Study Group
Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 2014;371(4):326-338.
2014
IL-17A/FIL-22
GM-CSF
IL-17 Inhibitors (cont.)
Phase III Trials of Ixekizumab in Moderate to Severe Plaque Psoriasis
Gordon KB, Blauvelt A, Papp KA, Langley RG, Luger T, Ohtsuki, K Reich,Amato D, Ball SG, Braun DK, Cameron GS, Erickson J, Konrad RJ, Muram TM, Nickoloff, Osuntokun OO, Secrest RJ, Zhao F, Mallbris L, Leonardi CL; UNCOVER-1, UNCOVER-2; UNCOVER-3 Study Groups
Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis. N Engl J Med. 2016;375(4):345-356.
2016
IL-17 Inhibitors (cont.)
Phase 3 Studies Comparing Brodalumab With Ustekinumab in Psoriasis
Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, Papp K, Spelman L, Toth D, Kerdel F, Armstrong AW, Stingl G, Kimball AB, Bachelez H, Wu JJ, Crowley J, Langley, Blicharski T, Paul C, Lacour JP, Tyring S, Kircik L, Chimenti S, Duffin KC, Bagel J, Koo J, Aras G, Li J, Song W, MIlmont CE, Shi Y, Erondu N, Klelotka P, Kotzin B, Nirula A
Lebwohl M, Strober B, Menter A, et al. Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis. N Engl J Med. 2015;373(14):1318-1328.
2015
Current Model of Psoriasis Immunopathogenesis
GM-CSF=granulocyte/macrophage-colony stimulating factor.Keijsers RR et al. Br J Dermatol. 2013;168:1294-1302. Lin AM et al. J Immunol. 2011;187:490-500. Res PCM et al. PloS ONE. 2010;5:e14108. Taylor PR et al. Nat Immunol. 2014;15:143-151.
Stressed keratinocytes
Myeloid dendritic cell
Activation
T cells
Keratinocytes
TNF-α
IL-1BIL-6
TNF-α
IL-17A/FIL-22
GM-CSF
IL-23IL-12
IL-23 (p19) Inhibitors
A Phase II Trial of Guselkumab vs Adalimumab for Plaque Psoriasis
Gordon KB, Duffin KC, Bissonnette R, Prinz JC, Wasfi Y, Li S, Shen YK, Szapary P, Randazzo B, Reich K
Gordon KB, Duffin KC, Bissonnette R, et al. A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med. 2015;373(2):136-144.
2015
IL-23IL-12
Tildrakizumab (MK-3222), an Anti-Interleukin-3p19 Monoclonal Antibody, Improves Psoriasis in a Phase IIbRandomized Placebo-Controlled TrialPapp K, Thaçi D, Reich K, Riedl E, Langley RG, Krueger JG, Gottlieb AB, Nakagawa H, Bowman EP, Mehta A, Li Q, Zhou Y, Shames R
Papp K, Thaci D, Reich K, et al. Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol. 2015;173(4):930-939. Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2015;136(1):116-124 e117.
Anti-IL-23A mAB BI 655066 for Treatment of Moderate to Severe Psoriasis: Safety, Efficacy, Pharmacokinetics, and Biomarker Results of a Single-Rising-Dose, Randomized, Double-Blind, Placebo-Controlled TrialKrueger JG, Ferris LK, Menter A, Wagner F, White A, Visvanathan S, Lalovic B, Aslanyan S, Wang EE, Hall D, Solinger A, Padula S, Scholl P (Pulled from NCBI)
2015
IL-23 (p19) Inhibitors (cont.)
Clinical Case Roundtable
Linda Stein Gold, MDDirector of Dermatology Clinical Research,
Division Head, DermatologyHenry Ford Health System
Detroit and West Bloomfield, Michigan
Disclosure: Linda Stein Gold, MD
Dr. Stein Gold is an investigator, advisor, and or consultant for Celgene, GSK, Leo Pharma, Novartis, Taro, and Valeant Pharmaceuticals International
10-year history of psoriasis
and PsA
Was started on etanercept in 2011; did well for 2 years but flared
in 2013
This photo is not the actual patient.
CASE 1: Mr. Melfor, 48-Year-Old White Man
PMH: HTN,
BMI=35
The patient stopped adalimumab himself and
was subsequently admitted to psoriasis day hospital
with 90% TBSA
Images: Courtesy of Dr. Linda Stein Gold.PsA=psoriatic arthritis. PMH=past medical history. HTN=hypertension. BMI=body mass index. TBSA=total body surface area.
The patient was switched to adalimumab; after 6 weeks, his joints improved but his
skin was still flaring
Comparison of Ustekinumab and Etanercept for Moderate to Severe Psoriasis
Griffiths CE et a. N Engl J Med. 2010;362:118-128.
0
20
40
60
80
100
0 2 4 6 8 10 12
*P<0.001†P=0.01
†*
**
Week
% o
f P
atie
nts
At Least 75% Improvement in PASI Score
0
20
40
60
80
100
0 16 20 24 28 32
Week
% o
f P
atie
nts
At Least 75% Improvement in PASI Score
Crossover to ustekinumab 90 mg after no response to etanercept
Among patients who did not have a response to etanercept:
48.9%had at least 75% improvement in the PASI score and 23.4%
had at least 90% improvement after crossing over to ustekinumab 90 mg for 12 weeks
Ustekinumab 90 mg (N=347)
Ustekinumab 45 mg (N=209)
Etanercept (N=347)
TNFi Primary Failure Predicts Decreased Ustekinumab Efficacy in Patients With Psoriasis
TNFi=tumor necrosis factor inhibitor. Sorensen EP et al. J Drugs Dermatol. 2015;14(8):893-898.
Retrospective study: 44 patients with psoriasis treated with ustekinumab who had 1 previous TNFi exposure
Result: Among patients with psoriasis previously exposed to TNFi, a history of a previous TNFi primary failure predicts a decreased response to ustekinumab independent of patient demographics and medical comorbidities
Success After Anti-TNF Failure
58.150.7
55.2
42.044.6
29.4 30.827.5
21.217.8 20.7
12.5
1.3 0.7 0.0 1.80
20
40
60
80
100
No Previous Biologic(n=1889)
Previous Biologic(n=498)
Biologic Without Failure(n=307)
Biologic With Failure(n=191)
Secukinumab 300 mg Secukinumab 150 mg Etanercept Placebo
% o
f S
ubje
cts
With R
esponse
PASI 90 Response
*P<0.0001 vs placebo. †P=0.0001 vs placebo. ‡P<0.0001 vs etanercept. §P=0.0001 vs etanercept. ||P<0.01 vs etanercept. ¶P<0.05 vs etanercept.Missing data were imputed as nonresponse. n=number of evaluable subjects.PASI= Psoriasis Area and Severity Index. PASI 90=90% improvement from baseline PASI score.Griffiths C et al. J Am Acad Dermatol. 2015;72(5):AB251.
*‡
*‡
*
*§
*
*
*||
*
†
*¶
*
SCULPTURE: Secukinumab Treatment—Adverse EventsSafety Remains Consistent Through 4 Years
AEs=adverse events. TB=tuberculosis. MACE=major adverse cardiac event. NMSC=nonmelanoma skin cancer.*1 case was an exacerbation of previously existing ulcerative colitis. †1 case of cholangiocarcinoma, 1 case of invasive ductal breast carcinoma .Bissonnette R, et al. 25th Congress of EADV, 28 September–2 October 2016, Vienna, Austria. Oral Presentation.Mrowietz U, et al; SCULPTURE Study Group. J Am Acad Dermatol. 2015;73(1):27-36.
Treatment Emergent AEsYear 1 n=168n (%)
Year 2n=168n (%)
Year 3n=157n (%)
Year 4n=142n (%)
Selected Less Frequent AEs
Opportunistic infections (other than TB and candidiasis) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Tuberculosis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Candida infections
Vulvovaginal candidiasis 3 (1.8) 3 (1.8) 1 (0.6) 0 (0.0)
Oral candidiasis 0 (0.0) 1 (0.6) 0 (0.0) 1 (0.7)
Neutropenia 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
MACE 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Crohn’s disease 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Ulcerative colitis 0 (0.0) 2 (1.2)* 1 (0.6) 0 (0.0)
Malignant or unspecified tumors (excluding NMSC) 0 (0.0) 2 (1.2)† 0 (0.0) 0 (0.0)
Ixekizumab (IXE) vs Etanercept (ETN) by Prior Biologic Exposure
50.7
24.3
7.0
34.6
13.2
3.7
82.2
64.4
34.9
76.2
55.2
25.2
87.7
67.7
37.0
91.5
76.1
47.2
0
20
40
60
80
100
PASI 75 PASI 90 PASI 100
% o
f P
atients
PASI Response Rates (NRI)
N=total number of patients. NRI=nonresponder imputation. Q4W=every 4 weeks. Q2W=every 2 weeks.Gottlieb AB et al. 2016 Fall Clinical Dermatology Conference.
ETN biologic naïve (N=604)ETN biologic experienced (N=136)
IXE Q4W biologic naïve (N=590)IXE Q4W biologic experienced (N=136)
IXE Q2W biologic naïve (N=594)IXE Q2W biologic experienced (N=142)
Both doses of ixekizumab provided higher efficacy compared to etanercept regardless of previous biologic use
P<0.001 for all comparisons between IXE and ETN
Safety Summary: Selected AEs of Special Interest
TEAE=treatment-emergent adverse event. SAE=serious adverse event. MI=myocardial infarction.*No deaths were observed. †This case was adjudicated as “probable” but classified as a diagnosis per EPIMAD criteria. ‡These cases were adjudicated as “definitive.”Gottlieb AB et al. 2016 Fall Clinical Dermatology Conference.
Placebo ETN IXE Q4W IXE Q2W
Biologic naïven (%)
Biologic experienced
n (%)
Biologic naïven (%)
Biologic experienced
n (%)
Biologic naïven (%)
Biologic experienced
n (%)
Biologic naïven (%)
Biologic experienced
n (%)
1 TEAE 126 (44.4) 34 (44.7) 324 (53.6) 75 (55.6) 341 (58.2) 78 (54.5) 346 (58.4) 78 (54.9)
1 SAE* 6 (2.1) 1 (1.3) 12 (2.0) 2 (1.5%) 12 (2.0) 2 (1.4) 12 (2.0) 2 (1.4)
Infections 31 (20.5) 5 (14.3) 67 (22.9) 17 (28.8) 66 (24.1) 12 (23.5) 76 (25.9) 14 (25.9)
Oral candidiasis 0 (0.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.7) 1 (1.9)
Vulvovaginal candidiasis 0 (0.0) 0 (0.0) 0 (0.0) 1 (4.0) 1 (1.2) 0 (0.0) 0 (0.0) 0 (0.0)
Skin candida 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.3) 0 (0.0)
MACE: Acute MI 1 (0.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Crohn’s disease 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.2)† 0 (0.0)
Ulcerative colitis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.4)‡ 0 (0.0)
CASE 1: Mr. Melfor, 48-Year-Old White Man
Patient started on ustekinumab 90 mg
After 4 weeks, PASI 50
After 12 weeks, PASI 90
Case 2: Mr. Rodder, 22-Year-Old White Man
He is heading out of state for graduate school and would like to discuss other options for psoriasis
History of extensive psoriasis
Has been on phototherapy and methotrexate in
the past
This photo is not the actual patient.
Has Crohn’s disease; well
controlled with sulfasalazine
TNFi and IBD
TNF plays a central role in the pathogenesis of CD and UC
High levels of TNF-α are found in the stool, lamina propria, and blood of patients with active disease
Inhibition of TNF-α with neutralizing monoclonal antibodies reduces disease activity in both CD and UC
FDA approved treatments for IBD include:
• Infliximab• CD (pediatric and adult)
• UC (pediatric and adult)
• Adalimumab• CD (pediatric and adult)
• UC (adult)
• Ustekinumab• CD (adult)
IBD=inflammatory bowel disease. CD=Crohn’s disease. UC=ulcerative colitis.Fréling E et al. Am J Gastroenterol. 2015;110(8):1186-1196. Singh S et al. Clin Gastroenterol Hepatol. 2016;14(8):1120-1129.
Secukinumab Long-Term Safety Experience: A Pooled Analysis of 10 Phase II and III Clinical Studies in Patients With Moderate to Severe Plaque Psoriasis
van de Kerkhof PC, Griffiths CE, Reich K, Leonardi CL, Blauvelt A, Tsai TF, Gong Y, Huang J, Papavassilis C, Fox T
van de Kerkhof PC, Griffiths CE, Reich K, et al. J Am Acad Dermatol. 2016;75(1):83-98.
Secukinumab and IBD: Background and Objectives
• Patients with psoriasis are up to 4 times more likely than the general population to have CD1
• The role of IL-17A in IBD is unclear2,3
• Secukinumab has been shown to be ineffective in treating patients with CD4
• IBD, including CD and UC, was analyzed in a set of pooled safety data from 10 clinical studies of secukinumab in subjects with moderate to severe plaque psoriasisand in the subgroup with a prior history of IBD
1. Li WQ et al. Ann Rheum Dis. 2013;72:1200-1205. 2. Skroza N et al. Biomed Res Int. 2013;2013:983902.3. O‘Connor W Jr et al. Nat Immunol. 2009;10:603-609. 4. Hueber W et al. Gut. 2012;61:1693-1700.
Methodology Relevant for IBD Analysis
Subjects: Subjects with prior or ongoing CD were allowed to participate in secukinumab psoriasis studies
Analysis: A broad search using IBD narrow NMQ consisting of 32 relevant preferred terms was performed to ensure all suspected cases of CD and UC were retrieved
NMQ=Novartis MedDRA Query.van de Kerkhof PC et al. J Am Acad Dermatol. 2016;75(1):83-98.
Incidence of IBD (CD and UC) Across Treatments in First 12 Weeks
Secukinumab 300 mg*(n=1173)
Secukinumab150 mg*(n=1174)
Secukinumab 300 mg, 150 mg, or Other Doses†
(n=2877)Etanercept‡
(n=323)Placebo(n=793)
Incidence Overall, n (%) (95% CI)
IBD1 (0.09)
(0, 0.55)
1 (0.09)
(0, 0.55)
2 (0.07)
(0.01, 0.28)
1 (0.3)
(0, 2.0)
0
(0, 0.6)
CD0
(0, 0.41)
1 (0.09)
(0, 0.55)
1 (0.03)
(0, 0.23)
0
(0, 1.5)
0
(0, 0.6)
UC1 (0.09)
(0, 0.55)
0
(0, 0.41)
1 (0.03)
(0, 0.23)
1 (0.3)
(0, 2.0)
0
(0, 0.6)
*Includes subjects from phase 3 studies only who were randomized to the specified secukinumab dose at the study start. †Includes subjects from phase 2 and 3 studies who were randomized to any dose of secukinumab at the study start. ‡Etanercept data are from 1 pivotal phase 3 study, FIXTURE.van de Kerkhof PC et al. J Am Acad Dermatol. 2016;75(1):83-98.
Exposure-Adjusted IR of IBD (CD and UC) Across Treatments for 52 Weeks
Any Secukinumab 300 mg*(n=1410)
Any Secukinumab 150 mg*(n=1395)
Secukinumab 300 mg, 150 mg, or Other Doses†
(n=3430)Etanercept‡
(n=323)
Exposure-Adjusted Incidence Overall, n (IR) (95% CI)
IBD§ 3 (0.26)
(0.05, 0.75)
4 (0.35)
(0.10, 0.90)
9 (0.33)
(0.15, 0.63)
1 (0.34)
(0.01, 1.90)
CD0
(0, 0.31)
2 (0.18)
(0.02, 0.63)
3|| (0.11)
(0.02, 0.32)
0
(0, 1.26)
UC2 (0.17)
(0.02, 0.61)
2 (0.18)
(0.02, 0.63)
4|| (0.15)
(0.04, 0.38)
1 (0.34)
(0.01, 1.90)
IR=incidence rate per 100 subject-years. *Includes subjects from phase 3 studies only who were randomized to the specified secukinumab dose at the study start and subjects on placebo who were rerandomized to secukinumab at Week 12. †Includes subjects from phase 2 and 3 studies who were randomized to any dose of secukinumab at the study start and subjects on placebo who were re-randomized to secukinumab at Week 12. ‡Etanercept data are from 1 pivotal phase 3 trial, FIXTURE. §“Anal fistula” and “sclerosing cholangitis,” although not true IBDs, were also retrieved because of the broad search criteria applied. ||2 of the 3 cases of CD had a prior history of CD, and the third case was in a subject who had gastrointestinal symptoms at baseline suggestive of undiagnosed active CD–the event resolved with therapy and did not cause study treatment discontinuation; 2 of the 4 UC cases had a prior history of UC. van de Kerkhof PC et al. J Am Acad Dermatol. 2016;75(1):83-98.
IBD Reported During Entire 52 Weeks
3 cases of CD (2 flares and 1 new event, all on secukinumab 150 mg) were identified over 52 weeks of treatment1
• 1 flare occurred during the first 12 weeks in a subject with long-standing CD; the event resolved with therapy
• Another flare was ongoing at the time of reporting; both flare cases led to study treatment discontinuation
• 1 new event was reported in a subject with gastrointestinal symptoms at baseline, suggestive of an undiagnosed active CD; the event resolved with therapy and did not cause study treatment discontinuation
2 cases of exacerbation of UC and 2 cases of new-onset UCwere reported over 52 weeks of secukinumab treatment2
1. van de Kerkhof PC et al. J Am Acad Dermatol. 2016;75(1):83-98. 2. Cosentyx [US package insert] 2015.
Integrated Safety of Ixekizumab in Patients With Moderate to Severe Psoriasis: Results From a Pooled Analysis of 7 Clinical Trials
This study was supported by Eli Lilly and Company.Presented at 2016 Fall Clinical Dermatology Conference; Las Vegas, Nevada; October 20-23, 2016.
Strober B, Papp KA, Leonardi CL, Bissonette R, Ferris L, Mrowietz U, Lebwohl M, Braun DK, Acharya N, Reich K
Crohn’s Disease
Incidence of reported CD was low and rates remained stable over time
Placebo Etanercept Ixekizumab Q4W
Ixekizumab Q2W
Ixekizumab Q12W
Ixekizumab Q4W
All Patients on Ixekizumab
0
2
4
6
IR9
5%
CI
n (%)N
0 (0.0)791
0 (0.0)739
1 (0.1)1161
1 (0.1)1167
0 (0.0)408
1 (0.2)416
9 (0.2)4209
IR (Patients With Event/100 PYs)
0.4 0.4 0.0 0.3 0.1
Fall Clinical Dermatology Conference; Las Vegas, Nevada; October 20-23, 2016.
0.0 0.0
12 Weeks(Phase 3 RCT)
12-60 Weeks(Phase 3 RCT)
Integrated Safety
Population (7 Trials)
Ulcerative Colitis
Incidence of UC was low and rates remained stable over time
Placebo Etanercept Ixekizumab Q4W
Ixekizumab Q2W
Ixekizumab Q12W
Ixekizumab Q4W
All Patients on Ixekizumab
0
2
4
6
IR9
5%
CI
12 Weeks(Phase 3 RCT)
12-60 Weeks(Phase 3 RCT)
Integrated Safety
Population (7 Trials)
n (%)N
0 (0.0)791
0 (0.0)739
0 (0.-)1161
2 (0.2)1167
2 (0.5)408
1 (0.2)416
10 (0.2)4209
IR (Patients With Event/100 PYs)
0.0 0.0 0.00.7 0.7
0.3 0.2
Fall Clinical Dermatology Conference; Las Vegas, Nevada; October 20-23, 2016.
The patient was diagnosed and treated for breast cancer
After S/P chemo and radiation, in remission for the past
12 months
CASE 3: Ms. Morgan,56-Year-Old White Woman
15-year history of psoriasis
No arthritis
Psoriasis has gotten progressively worse; currently at 25% BSA
This photo is not the actual patient.S/P=status post. BSA=body surface area. Image source: https://en.wikipedia.org/wiki/Psoriasis.
Safety Surveillance for Ustekinumab and Other Psoriasis Treatments From PSOLAR
PSOLAR=Psoriasis Longitudinal Assessment and Registry. F/U=follow-up.Papp K et al. J Drugs Dermatol. 2015;14(7):706-714.
DiscontinuedPresumed lost to F/U
Patient choice Lost to F/U Other Death Site closed
No longer met criteria
4364received ustekinumab
1394received infliximab
4251received other biologics
2084received nonbiologics
Continuing in registry
Disposition of Patients Enrolled in PSOLAR (12,093 Patients Enrolled)
Ustekinumab*(N=4364)
12,472 PYs
Infliximab(N=1394)5176 PYs
Other Biologics(N=4251)
15,991 PYs
Nonbiologics(N=2084)6749 PYs
Total(N=12,093)40,388 PYs
nRate/
100 PYs nRate/
100 PYs nRate/
100 PYs nRate/
100 PYs nRate/
100 PYs
Malignancy† (excluding NMSC) 60 0.48 41 0.79 116 0.73 57 0.84 274 0.68
MACE† 40 0.32 17 0.33 45 0.28 32 0.47 134 0.33
Cardiovascular death 15 0.12 5 0.10 14 0.09 14 0.21 48 0.12
Nonfatal CVA 9 0.07 4 0.08 13 0.08 7 0.10 33 0.08
Nonfatal MI 16 0.13 8 0.15 21 0.13 13 0.19 58 0.14
Serious infections‡ 74 0.93 96 2.91 245 1.91 233 1.43 648 1.60
All-cause mortality† 51 0.41 21 0.41 67 0.42 46 0.68 185 0.46
Cardiovascular 15 0.12 5 0.10 14 0.09 14 0.21 48 0.12
Other 25 0.20 12 0.23 35 0.22 20 0.30 92 0.23
Unexplained death 11 0.09 4 0.08 18 0.11 12 0.18 45 0.11
Safety Surveillance for Ustekinumab and Other Psoriasis Treatments From PSOLAR (cont.)
PYs=patient-years. CVA=cerebrovascular accident.*Attribution rules for this analysis dictated that, after a patient was exposted to ustekinumab, subsequent adverse events of special interest were attributed to ustekinumab, regardless of past of future exposures and duration of other therapies. †‡Incidences for malignancy, MACE, and mortality were based on patients who were ever exposed to a given biologic therapy. ‡Incidences for serious infections were based on patients who were exposed to a given biologic therapy within 91 days of the event (40,389 total patient-years: 7944 for ustekinumab, 3301 for infliximab, 12,833 for other biologics, and 16,322 for nonbiologics.)Papp K et al. J Drugs Dermatol. 2015;14(7):706-714.
Number of Events and Cumulative Incidence Rates per 100 PYs of AEs of Special Interest
Secukinumab Malignancy Rates During the First 12 Weeks
During the first 12 weeks, the incidence of malignant or unspecified tumors was comparable in the secukinumab 300 mg, 150 mg, and placebo groups
• No event was reported in the etanercept group
n (%)
(95% CI)
Secukinumab300 mg*(n=1173)
Secukinumab150 mg*(n=1174)
Secukinumab 300 mg,150 mg, or Other Doses†
(n=2877)Etanercept‡
(n=323)Placebo(n=793)
Malignant or
unspecified tumors§
2 (0.17)
(0.03, 0.69)
4 (0.34)
(0.11, 0.93)
6 (0.21)
(0.08, 0.48)
0
(0, 1.5)
3 (0.4)
(0.1, 1.2)
NMSC|| 1 (0.09)
(0, 0.55)
2 (0.17)
(0.03, 0.68)
3 (0.10)
(0.03, 0.33)
0
(0, 1.5)
3 (0.4)
(0.1, 1.2)
Other malignancies§
(excluding NMSC||)
1 (0.09)
(0, 0.55)
2 (0.17)
(0.03, 0.68)
3 (0.10)
(0.03, 0.33)
0
(0, 1.5)
0
(0, 0.6)
CI=confidence interval. MedDRA=Medical Dictionary for Regulatory Activities. *Includes subjects from phase 3 studies only who were randomized to the specified secukinumab dose at the study. †Includes subjects from phase 2 and 3 studies who were randomized to any dose of secukinumab at the study start. ‡Etanercept data are from 1 pivotal phase 3 trial, FIXTURE. §Based on standardized MedDRA query. ||Based on narrow Novartis MedDRA query.van de Kerkhof PC et al. J Am Acad Dermatol. 2016;75(1):83-98.
Initial 12-Week Treatment Period (Baseline to Week 12)
Secukinumab Exposure-Adjusted IRof Malignancy
Over 52 weeks, the exposure-adjusted IR of malignant or unspecified tumors was comparable in the secukinumab 300 mg, 150 mg, and etanercept groups
• For malignant or unspecified skin tumors, the exposure-adjusted IR (per 100 subject-years) was also comparable in the secukinumab 300 mg (0.60), 150 mg (0.70), and etanercept (0.34) treatment groups
The exposure-adjusted IR of NMSC was comparable in the secukinumab 300 mg and 150 mg groups
With NMSC cases excluded, the exposure-adjusted IR of malignant or unspecified tumors was comparable in the secukinumab 300 mg and 150 mg groups and lower than that in the etanercept group
n (IR per 100 Subject-Years)
(95% CI)
Any Secukinumab 300 mg*(n=1410)
Any Secukinumab 150 mg*(n=1395)
Secukinumab 300 mg, 150 mg,or Other Doses†
(n=3430)Etanercept‡
(n=323)
Malignant or unspecified tumor§ 9 (0.77)
(0.35, 1.46)
11 (0.97)
(0.48, 1.73)
26 (0.96)
(0.63, 1.40)
2 (0.68)
(0.08, 2.47)
NMSC|| 5 (0.43)
(0.14, 0.99)
7 (0.61)
(0.25, 1.27)
13 (0.48)
(0.25, 0.82)
0
(0, 1.26)
Other malignanciesd (excluding NMSC||)4 (0.34)
(0.09, 0.87)
4 (0.35)
(0.10, 0.90)
13 (0.48)
(0.25, 0.82)
2 (0.68)
(0.08, 2.47)
Entire Treatment Period (Baseline to Week 52)
*Includes subjects from phase 3 studies only who were randomized to the specified secukinumab dose at the study start and subjects on placebo who were rerandomizedto secukinumab at Week 12. †Includes subjects from phase 2 and 3 studies who were randomized to any dose of secukinumab at the study start and subjects on placebo who were rerandomized to secukinumab at Week 12. ‡Etanercept data are from 1 pivotal phase 3 trial, FIXTURE. §Based on standardized MedDRA query. ||Based on narrow Novartis MedDRA query. van de Kerkhof PC et al. J Am Acad Dermatol. 2016;75(1):83-98.
Integrated Safety of Ixekizumab in Patients With Moderate to Severe Psoriasis: Results From a Pooled Analysis of 7 Clinical Trials
This study was supported by Eli Lilly and Company.Presented at 2016 Fall Clinical Dermatology Conference; Las Vegas, Nevada; October 20-23, 2016.
Strober B, Papp KA, Leonardi CL, Bissonette R, Ferris L, Mrowietz U, Lebwohl M, Braun DK, Acharya N, Reich K.
Integrated Safety of Ixekizumab in Patients With Moderate to Severe Psoriasis, Pooled Analysis of 7 Clinical Trials: Malignancies Excluding NMSC
Malignancies excluding NMSC were uncommon and balanced between ixekizumab and placebo
Placebo Etanercept Ixekizumab Q4W
Ixekizumab Q2W
Ixekizumab Q12W
Ixekizumab Q4W
All Patients on Ixekizumab
0
2
4
6
IR9
5%
CI
12 Weeks(Phase 3 RCT)
12-60 Weeks(Phase 3 RCT)
Integrated Safety
Population (7 Trials)
n (%)N
1 (0.1)791
1 (0.1)739
2 (0.2)1161
1 (0.1)1167
2 (0.5)408
0 (0.0)416
33 (0.8)4209
IR (Patients With Event/100 PYs)
IR=incidence rate (exposure-adjusted) per 100 PYs. Q2W=80 mg ixekizumab every 2 weeks. IXE Q4W=80 mg ixekizumab every 4 weeks. Q12W=80 mg ixekizumab every 12 weeks. RCT=randomized controlled trial.Fall Clinical Dermatology Conference; Las Vegas, Nevada; October 20-23, 2016.
0.6 0.60.8
0.40.7
0.0 0.5
Influence of Anti-TNF Therapy on CI in Patients With RA Who Have Had a Prior Malignancy
• Results from the British Society for Rheumatology Biologics Register
• Study evaluated patients with RA and malignancy treated with either a biologic agent or a nonbiologic control
• 177 patients treated with biologics vs 117 treated with nonbiologics, all with a history of malignancy
• Results demonstrated no increased risk of new primary, recurrent, or metastatic malignancies in the biologic arm (IR ratio 0.58; 95% CI 0.23-1.43)
RA=rheumatoid arthritis. DMARD=disease-modifying antirheumatic drugs.Dixon WG et al. Arthritis Care Res (Hoboken). 2010;62(6):755-763.
Influence of Anti-TNF Therapy on CI in Patients With RA Who Have Had a Prior Malignancy (cont.)
% C
um
ula
tive Incid
ence
Cumulative Incidence of Malignancy in Patients With Prior Malignancy by Nelson-Aalen Plot
0 1 2 3
0
12
14
16
4
6
8
10
2
4
Years Since Registration
Results From the British Society for Rheumatology Biologics Register.Dixon WG et al. Arthritis Care Res (Hoboken). 2010;62(6):755-763.
DMARD
Anti-TNF
Risk of Incident or Recurrent Malignancies Among Patients With RA Exposed to Biologic Therapy in the German Biologics Register
• Results from the German Rheumatoid Arthritis Observation of Biologic Therapy Register (RABBIT)
• The study analyzed whether biologic use causes increased risk of new or recurrent malignancies
• This study found no significant increase in the risk of recurrence in patients with a previous history of cancer exposed to biologics compared to nonbiologics (1.4; 95% CI 0.5-5.5)
Strangfeld A et al. Arthritis Res Ther. 2010;12(1):R5.
Observed Numbers of Cancers and Expected Numbers From the General Population, Standardized by Age and Sex
Total number of malignancies
60 0 6040 20 20 40
15 0 1510 5 5 10
58.7 29.444.0 30.0
Reproductive organs—males
Reproductive organs—females3.0 3.0
6.0 3.0
3.0 1.04.9 2.4
Pancreatic cancer1.0 5.0
1.5 0.8
Non-Hodgkin’s lymphoma 1.05.01.9 0.9
Malignant melanoma
Lung cancer
Breast cancer
3.0 0.02.1 1.0
7.05.7 2.8
6.0
8.013.9 6.8
3.0 Expected
Observed
Strangfeld A et al. Arthritis Res Ther. 2010;12(1):R5.
Risk of Incident or Recurrent Malignancies Among Patients With RA Exposed to Biologic Therapy in the German Biologics Register (cont.)
Anti-TNFα Controls
Question and Answer Session