Association of Ustekinumab and Briakinumab with Major Adverse

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320 27 ustekinumab, (26 of 53 atotal MACEs with along patients, placebo-treated in events zero with compared studies III and II of phase phase placebo-controlled the during patients treated actively- in recorded been have 5briakinumab) (5 ustekinumab, Ten (CPP). MACEs plaquepsoriasis of chronic treatment for the briakinumab) (ustekinumab, biologic agents of anti-IL-12/23 use the with (MACEs) events cardiovascular oftion major adverse associa possible the regarding raised been have concerns Safety Dermato- http://dx.doi.org/10.4161/derm.23100 11/28/12;Submitted: Accepted: 11/28/12 Email: [email protected] Zouboulis; C. to: Christos *Correspondence of these patients. these of initiating anti- initiating before factors risk cardiovascular manageable for patients CPP screen should Clinicians denied. be cannot class effect a and excluded be cannot morbidity cardiovascular increase Potential anti- of analyses. 1:5 from to ranging 1:1ratios meta- these in case as is the 1% of event rates randomization baseline and with less or studies of meta-analyses for suitable is more that Peto method (p = 0.11). significance achieve not reports theory Statistical did but measure, effect as differences risk absolute with model fixed-effects Mantel-Haenszel utilized other the = 0.04), while (p riskmethod using Peto cardiovascular in increase significant ( 53 of atotal with MAC along patients, placebo-treated in phase of phase placebo-controlled the during patients actively-treated in (CPP). psoriasis plaque chronic Ten MAC trials calculated risk for MAC for risk calculated trials randomized, placebo-controlled, double-blind, monotherapy of meta-analyses Two studies. these industry-independent of phases all across (1deaths 4briakinumab) ustekinumab, with use of anti- of use with (MAC events cardiovascular adverse major of association possible regarding raised have concerns been Safety 26 ustekinumab, 27 briakinumab) and five cardiovascular cardiovascular five 27 and 26 briakinumab) ustekinumab,

An appraisal of meta-analyses and industry sponsored An appraisalofmeta-analysesandindustry 1 Association of ustekinumab and briakinumab Association andbriakinumab ofustekinumab review Division of of Division E Keywords: ndocrinology 4:3,320–323;July–Decemberndocrinology 2012;©2012LandesBioscience with majoradverse cardiovascular events E v I idence Based Dermatology; Departments of Dermatology, Dermatology, of Departments Dermatology; Based idence L -12/23 intensive monitoring with along agents Thrasivoulos Tzellos,Thrasivoulos II I L briakinumab, ustekinumab, chronic plaque psoriasis, major adverse cardiovascular events, meta-analysis events, cardiovascular major adverse plaquepsoriasis, chronic ustekinumab, briakinumab, and and -12/23 biologic agents for the treatment of of -12/23 treatment the for agents biologic III studies compared with zero events events zero with compared studies I L -12/23 biologic agents to further -12/23 to further agents biologic E s . One detected statistically statistically detected . One pooled analysesto date 1,2 E Athanassios Kyrgidis, s h 2 Hospital for Skin and and Skin for Hospital ave been recorded recorded ave been D ermato- V E E e s V s nereal Diseases; Thessaloniki, Greece Thessaloniki, Diseases; nereal ) e nereology, Allergology and and Allergology nereology, E - ndocrinology 1 Anastasia Trigoni Anastasia the use of the risk difference method in the first study. first the in method difference risk of the use the to attributable be may meta-analyses two these between results in divergence The data. same the use essentially which analyses meta- two these between results divergent be could how there of MACEs with anti-IL-12/23 agents. anti-IL-12/23 with of MACEs association possible the to examine conducted recently been have method less suitable for meta-analysis of rare events. of rare for meta-analysis suitable less method this make may power. This low statistical in resulting potentially rare, are events when coverage interval confidence conservative avery but yields corrections, zero-cell using studies, event zero including studies, for all estimates provides method difference risk for MACEs in the treatment arm compared with placebo. with compared arm treatment the in for MACEs risk higher apossible to itexclude more is suitable method powerful Peto amore is as considered; methods meta-analytical all among performance best the has of Peto 1% rate event or method less, ized, double-blind, placebo-controlled, monotherapy trials monotherapy placebo-controlled, double-blind, ized, studies. of these phases all across briakinumab) 4 ustekinumab, (1 deaths cardiovascular five and briakinumab) trial results, with weights reflecting the amount of information amountinformation of the reflecting weights with results, trial of average aweighted practically is ameta-analysis Since groups. two the between of events or risks odds relative the about tion no informa conveys trial that atrial, in atall occur no events However, if ameta-analysis. from studies any to exclude wrong it is that feel One might meta-analysis. second the in included of 5out of 9studies data the not necessitated did ratio odds Peto of the Calculation risks. to relative approximations close very fact in are ratios odds rare, are events when Additionally, agents respectively. both and briakinumab 0.35% 0.31% and for ustekinumab, were 0.28%, rates event MACEs by zero. to divide attempting when occur that errors to avoid computational correction cal numeri arbitrary of an use involve the also methods Haenszel events. zero with studies excluded which =0.04), (p Peto the method using risk cardiovascular in increase significant astatistically detected Tzellos al. et contrast, although their findings approached significance (p= 0.11). significance approached findings their although measure, effect an as differences absolute risk with model effects fixed- Mantel-Haenszel the using increase significant a statistical Two industry-independent meta-analyses of these 9random of these Two meta-analyses industry-independent

2 I and Christos Zouboulis C. m munology; Dessau Medical Center; Dessau, Germany; Germany; Dessau, Center; Medical Dessau munology; 2 It has been demonstrated that at a baseline atabaseline that demonstrated been It has 2 An astute reader may wonder may reader astute An 1,2 Ryan et al. did not detect not detect did al. et Ryan 1, * 1,2 V olume 4 12-14 12-14 1 The risk risk The Mantel- I ssue 3 1 In In 3-11 12 12 - - -

©2012 Landes Bioscience. Do not distribute. 20 weeks. lasting phase acontrolled one, with except 12, up to week phase acontrolled had studies All factors. risk cardiovascular baseline to report failed of them many characteristics, to demographic respect with groups treatment across balanced were well patients that reported studies all Although of MACEs. rate the in ence differ significant astatistically to detect were underpowered meta-analyses RCTs these in included individual all note that 4 y of follow-up) of 4 RCTs (3 and phases uncontrolled the in ustekinumab with treated patients in of MACEs rate the calculating published, been effect. treatment’s of the pragmatic underestimation an and bias tion selec to possible leading criterion, also exclusion as accidents” cerebrovascular recent failure, heart congestive disease, heart documented history of recurrent infections, unstable ischemic with diabetes uncontrolled as condition,such medical trolled of “a presence con poorly the used study briakinumab excluded One MACEs. capture for and to screen method aclear to report fail also excluded studies briakinumab three All MACEs. ture cap for and to screen method aclear to report fail meta-analysis Study (FHS) after adjustment for baseline CV risk factors, factors, risk CV for baseline adjustment after (FHS) Study Heart US Framingham the from developed One was models. predictive discrete two using population general the in rates in estimates of balanced large treatment effects are negligible. are effects treatment large of balanced estimates in biases whereas arm), treatment anti-IL-12/23 experimental the case this (in arm larger the in rate event of the underestimation to an lead may Peto of the method application arms, treatment or higher, or 8:1 are arms compared the in numbers patient between ances imbal when bias considerable to demonstrate reported been has Peto the method While rate. MACEs true the underestimated still have may by Tzellos al., et conducted meta-analysis the Thus, populations. Caucasian primarily in were conducted studies other all whereas www.landesbioscience.com 3179 (aggregate 1474). vs. arm placebo to the than arm interventional to the were randomized more patients trials, clinical most in case the is As risk. the populations, Asian in were conducted meta-analysis second the in excluded were that trials Two evaluation. ustekinumab under oflation the poputhe as changes it to recognize important be may trials five observed. of 0.5 are addition no when events events arbitrary for the need the avoiding while trials across comparisons within-trial gates aggre Peto the method Furthermore, bias. notmay introduce appropriate be and may weight azero no information with trial a allocating statistic, summary the about contains study each meta-analyses had randomization ratios ranging from 1:5 from to 1:1. ranging ratios randomization had meta-analyses separating low from high risk patients. risk low high from separating point of 50 yold, time akey with by age vary may therapies systemic with treated patients psoriasis in infarction myocardial for risk the that suggested been note, 50 yold.it Of has than There is also a possibility that these methods underestimated underestimated methods these that apossibility also is There of these exclusion that exists notion also the hand, other On the In parallel, two industry sponsored pooled analyses pooled sponsored industry two parallel, In review 6 All patients included in the studies had a mean age less less age a mean had studies the in included patients All 7 16 all studies of anti-IL-12/23, agents included in the the in included agents of anti-IL-12/23, studies all 5,11 3,4,6-10 which generally have lower cardiovascular risk, risk, lower have cardiovascular generally which The three ustekinumab trials included in both both in included trials ustekinumab three The

7-9,19 and comparing it with expected expected it with comparing and 1,2 Where there is imbalance in in imbalance is there Where 15 It is also important to important It also is Dermato- 17,18 have have E 12 ------ndocrinology

of those experiencing MACE had such a history. such had MACE experiencing of those 69.2% while study parent respective of their atbaseline history aCV-related medical had of patients 36.9% population, analysis pooled this In were recorded. patients) 26 (in 27 MACEs of time, period of follow-up. this 4,704 In years patient contributing OLE, received Caucasian and Asiatic populations. Asiatic and Caucasian European in risk MACEs to overestimate documented been has FHS the to note that But it important is populations. nal but not mater relevant from rates incident MACEs comparing by issue this to overcome attempted The authors son difficult. compari makes phase placebo-controlled week 12–20 initial the beyond of acontrolcohort absence Furthermore, biases. potential to susceptible less been have may analysis A stratified tion and stroke. and tion infarc for myocardial were performed Comparisons trials. all across data safety the by pooling for ustekinumab observed of MACEs rate the summarized analyses pooled These (GRPD). Database Research Practice General UK the from developed was model predictive second The status. smoking and mellitus diabetes gender, hyperlipidemia, age, hypertension, including briakinumab in 5RCTs in briakinumab with treated patients in of MACEs rate the calculating lished, general. in population riasis pso to the results of these extrapolation and interpretation the in exercised be should caution appropriately acknowledge, also authors the as Therefore, bias. of sampling possibility the and misclassification for diagnostic potential to considerable leading codes, on billing heavily relies database, aclaims GRPD, as The results. final the impact which exist may covariates and ables vari confounding unrecognized other FHS, to the comparing when comorbidities or characteristics confounding possible for analyses modeled to adjust made was attempt an although Furthermore, MACEs. and ustekinumab between association across studies, they also report that variability was observed. was variability that report also they studies, across comparable were generally characteristics baseline that report authors although and settings, different from derived included RCTs the problematic as group. is However, this this in included of patients number total by the results the dividing and trials the across group treatment a given in observed of events bers num the of adding consists Simple pooling trial. asingle from came data the if as trials all from data of the simple pooling performed authors The studies. both across committee same least two of these factors were present. Based on their results, they they results, on their Based were present. factors of these two least at when for MACEs eight-fold risk an relative calculated authors Moreover, ≥30. BMI and the of CVD, history of diabetes, tory ≥140 BP (SBP his or DBP baseline ≥90), elevated for MACE: risk increased with associated factors cardiovascular four report (OLE) study. (OLE) detected. be can toxicity no cumulative that and events cardiovascular serious on effect nor abeneficial neither adetrimental exhibits cal trials clini multinational in patients ustekinumab-treated selected carefully- in reported of lower MACEs rate the that concluded An industry sponsored pooled analysis has been recently pub recently been has analysis pooled sponsored industry An

17,18 1 dose of briakinumab in a parent study and/or the the and/or study aparent in of briakinumab ≥ 1dose 17,18 compared with FHS rates translates into a lack of into alack translates rates FHS with compared All MACEs were retrospectively evaluated by the by the evaluated were retrospectively MACEs All 30 Two thousand five hundred twenty patients patients twenty Two five hundred thousand 17,18 Both analyses concluded that ustekinumab ustekinumab that concluded analyses Both 3,4,6,10,29 and an Open Label Extension Extension Label Open an and 20-28 Therefore, it cannot be be it cannot Therefore, 30 The authors authors The REVIEW 17,18 321 ------

©2012 Landes Bioscience. Do not distribute. 322 to establish than evidence of benefit. While the truthful answer answer truthful the While of benefit. evidence than to establish 32. at week levels baseline to above decrease agradual with treatment of the weeks 12 first 13-fold the in paradoxically of IL-12unit were increased sub p40 of the levels serum of ustekinumab, 2study aphase In phase. treatment-induction initial the in particularly excluded, be cannot briakinumab and of ustekinumab use with MACEs of MACE. risk low and athigh patients briakinumab-treated between guishing distin for possibly method meaningful and relevant a medically in results factors 0or 1risk by ≥2vs. categorizing conclude that with increased risk of MACEs. risk increased with sub-groups possible of identification also and analyses to-event time- robust for more statistically to allow data level sive patient comprehen use ideally would RCTs which conducted, be must of the meta-analysis data patient individual an objectively fully mentioned above hypothesis the order In to test available. are hypertension, obesity, hyperlipidemia, mellitus 2 diabetes type status, smoking previous like factors risk dent cardiovascular indepen and important However, known elucidated. to be other remains of MACEs rate the in agents biological these with treated tis. arthri psoriatic in morbidity playarolecardiovascular may in disease joint inflammatory that suggests evidence Recent plaque. atherogenic on human briakinumab and of ustekinumab effect possible the evaluate to are required, profiling factor risk vascular cardio comprehensivebaseline and duration of sufficient phases RCTs powered placebo-controlled- adequately with hypothesis, a such order In to test tested. to be ought and formulated be can plausible, is factors risk cardiovascular pre-existing baseline with morbidity to cardiovascular predisposed CPP patients in especially place, takes effect probable agonistic the where phase, initial the in atleast of MACEs, risk the increases anti-IL-12/23 with treatment that hypothesis The no MACEs. exhibited cebo pla in populations randomized the that fact due to the ranted war is caution anyway, MACEs developed have would patients these that to theorize tempting Although factors. risk vascular cardio baseline three at least had MACEs with patients All tors. fac risk cardiovascular due to baseline to MACEs predisposed patients in especially plaque, of atherogenic to instability ing lead increase paradoxical to this related be could groups treated anti-IL-12/23 the in Development of MACEs proatherogenic. IL-12 is that indicates evidence Preliminary phase. induction the in atleast vivo, in antagonists, than rather agonists, as tion func might antibodies monoclonal anti-cytokine many that ity 32 Evidence of harm from a clinical intervention is more difficult more is difficult intervention aclinical from of harm Evidence of risk increased an evidence, current of the On review

The potential role of psoriatic arthritis in patients with CPP with patients in arthritis role of psoriatic potential The 30 31 This concept suggests the troubling possibil troubling the suggests concept This 33 D ermato- E ------ndocrinology moderate to severe CPP. to severe moderate with of patients biologic therapy and systemic the in goal utmost the remains safety that to ensure and biologic agents IL-12/23 of anti- safety long-term cardiovascular and monitor short the to necessary also are biologic registries of appropriately designed use the and studies Post-marketing patients. ofmonitoring these intensive with along agents anti-IL-12/23 tors prior to initiating fac risk cardiovascular for manageable patients psoriasis screen should clinicians are available, data more definitive Ideally, until produces adalimumab (Humira adalimumab produces which of Abbott, suppurativa for hidradenitis Board Advisory the at lecturing and for participating ahonorary received have and hotel accommodation and expenses for travel reimbursed been medicine is applied to individuals. applied is medicine produces infliximab (Remicade infliximab produces Cilag, which produces ustekinumab (Stelara ustekinumab produces which Cilag, by Janssen- Congresses Dermatological to attend modation hotel accom T.T. and expenses for travel reimbursed been has interest. of conflict no declares andMSD. A.K. Pfizer Janssen-Cilag, by Abbott, sponsored plaquepsoriasis for chronic trials clinical in A.T. participated adalimumab. has with suppurativa hidradenitis of treatment on the studies atclinical to participate continues efit outweighs the risk of harm for every patient within the trial. the within patient every for harm of risk the efit outweighs of ben of probability RCTs the not results imply that does mary sum in a a benefit challenging: be can effects group average from patients. of their care the guiding in evidence available best the use cians pharmacodynamics. similar strate demon both They indication. same for the were used included RCTs the in and class drug same to the belong IL-23, IL-12 and of (p40) sub-unit shared same the targeting antibodies clonal mono human both are ustekinumab and Briakinumab available. is evidence more conclusive and substantial until not denied, be can effect aclass and excluded be cannot morbidity diovascular car increase to further biologic agents of anti-IL-12/23 potential morbidity. The cardiovascular in increase possible due tois the component, it alife-threatening it If has disease. life-threatening not CPP in a that context clinical the in to date pret evidence inter must Clinicians available. readily are trials of such results the before decisions therapeutic make must clinicians points, end primary as events cardiovascular serious to detect powered adequately are which trials controlled randomized designed well of results the we have until not known may be question to this Contemporary evidenced-based medicine demands clini demands medicine evidenced-based Contemporary

34 Notably, evidence is derived from groups, whereas whereas groups, from derived Notably, is evidence Disclosure of Potential Conflicts of Interest of Conflicts ofPotential Disclosure ® ® ) and by Novartis. C.C.Z. has has C.C.Z. by Novartis. ) and ). He has also participated and and participated also He has ). 35 Inferring individual effects effects individual Inferring ® ), by MSD, ), which V olume 4 I ssue 3 35 ------

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