Uudet reumalääkkeet, JAK-kinaasin estäjät

Esitys aiheesta: "Uudet reumalääkkeet, JAK-kinaasin estäjät"— Esityksen transkriptio:

1 Uudet reumalääkkeet, JAK-kinaasin estäjät
dos Heikki Valleala oyl HYKS, reumaklinkka

2 Tyypin I ja II sytokiinit
Nivelreumassa keskeisistä sytokiineistä mm. interferonit, GM-CSF, IL-6, IL-7, IL-10, IL-12, IL- 15 ja IL-23 vaikuttavat kohdesoluihin aktivoimalla JAK- STAT –signalointireitin . Kaikki nivelreumassa keskeiset pro-inflammatoriset sytokiinit, kuten TNF, IL-1 ja IL-17, eivät aktivoi JAK-STAT - signalointireittiä. Schwartz Nat Rev Rheumatol 2016

3 JAK-STAT-signaalivälitystie aktivoituu useiden (tyypin I ja II) sytokiinien toimesta
Januskinaaseja (JAK) tunnetaan neljä (JAK1, JAK2, JAK3 ja TYK2) STAT-transkriptiotekijöitä seitsemän (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6). Tietty sytokiini aktivoi tietyt JAK-kinaasit (tyypillisimmin kaksi eri JAK kinaasia) ja tietyt STAT transkriptiotekijät Kuitenkaan JAK-kinaasit ja STAT transkriptiotekijät eivät ole spesifisiä tietylle sytokiinille vaan useat sytokiinit aktivoivat samoja JAK-STAT-signalointireittejä STAT= signal transducer and activator of transcription Tanaka J Biochem 2015 JAK-kinaaseilla on keskeinen asema immuunijärjestelmässä sekä hematopoieesissa JAK3 ilmenee vain lymfoidisen solulinjan soluissa, JAK1, JAK2 ja Tyk2 laajalti eri solutyypeissä JAK1- ja JAK2-poistogeeniset hiiret menehtyvätkin joko sikiökaudella tai pian syntymän jälkeen. JAK3- sekä TYK2-poistogeeniset hiiret ovat puolestaan immuunipuutteisia ja alttiita infektioille.

4 Gadina Arthritis Rheum 2016

5 Oral-Start - MTX-naïve patient population
Figure 1 Clinical Responses over Time. An American College of Rheumatology (ACR) 70 response is defined as at least a 70% reduction from baseline in the number of both tender and swollen joints, as well as at least a 70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician. The coprimary end point (the ACR 70 response at month 6) was derived from the prespecified interim (year 1) data set; the ACR 70 response over time was derived from the final (year 2) data set. Missing data were imputed with the use of nonresponse imputation. I bars indicate standard errors. Asterisks denote P<0.001 for the comparison with methotrexate. Lee EB et al. N Engl J Med 2014;370:

6

7 ORAL Strategy Fleischmann et al. Lancet. 2017

8 ACR Responses Baricitinib in MTX-IR RA pts Week 12 Week 24 Week 52
9/15/2018 ACR Responses Baricitinib in MTX-IR RA pts Week 12 Week 24 Week 52 vs. placebo ***p≤.001 **p≤.01 *p≤.05 vs. adalimumab ++p≤.01 +p≤.05 % Patients (NRI) Abbreviations: ACR20 = American College of Rheumatology 20% improvement criteria; ACR50 = American College of Rheumatology 50% improvement criteria; ACR70 = American College of Rheumatology 70% improvement criteria; csDMARDs, IR, inadequate responder; MTX, methotrexate; NRI, non-responder imputation; RA, rheumatoid arthritis ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 Placebo Baricitinib 4 mg Adalimumab Primary endpoint = ACR20 for baricitinib 4 mg vs. placebo at Week 12 Patients who were rescued or permanently discontinued were imputed thereafter as non-responders

9 Electronic Daily Diary PROs
9/15/2018 Electronic Daily Diary PROs Baricitinib in MTX-IR RA pts Duration of Morning Joint Stiffness Severity of Morning Joint Stiffness vs. placebo ***p≤.001 **p≤.01 *p≤.05 vs. adalimumab +++p≤.001 ++p≤.01 +p≤.05 Median, minutes LS Mean, NRS 0-10 Week Week Worst Joint Pain Worst Tiredness Abbreviations: IR, inadequate responder; LS, least squares; MTX, methotrexate; NRS, numeric rating scale; PRO, patient-reported outcome; Pts, patients; RA, rheumatoid arthritis; LS Mean, NRS 0-10 LS Mean, NRS 0-10 Week Week

10 Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis
Mease et al. NJEM 2017

11 JAK-estäjien turvallisuudesta

12 Incidence rates for serious infection events over time
ISS 2015 data cut IR (patients with events/ 100 patient-years (95% CI) Time (months) Total pt exposure (N) 6,194 5,293 4,823 4,420 4,106 3,645 3,372 2,996 2,605 1,979 Patient with SIE (N) 71 86 67 61 51 49 36 38 22 46 In data pooled from Phase 1, 2, 3 and LTE studies in patients with active RA, the IRs for serious infections was 2.7(2.5–3.0).[Cohen2017/p1/abstract/objectives/ln3-5;results/ln4] The most common types were pneumonia, HZ, UTI and cellulitis. IRs did not increase with longer treatment.[Cohen2017/p3/col2/para5/ln1-2] There was no increase in serious infections over time. [Cohen2017/p4/fig1] To assess whether IRs increased over time, rates were examined within 6-month intervals of tofacitinib exposure. IRs are reflective of the number of patients with events during each time period and not accumulative over time Cohen S, et al. Ann Rheum Dis. 2017;0:1–10. The most common serious infection events were: pneumonia, HZ, urinary tract infection and cellulitis Serious infection rates are stable over time 1. Cohen S, et al. Ann Rheum Dis. 2017;0:1–10. CI, confidence interval. Bars indicate 95% confidence limits; incidence rate of patients per 100 patient-years; Phase 2, Phase 3 and LTE data as of 31 March 2015

13 Herpes zoster rates compared with published rates for bDMARD
Incidence rate /100 PY (95% CI) Health plan data from 2010 to 2014, including patients with RA initiating tofacitinib or biologics with no history of HZ or HSV, was assessed (n=2,526).[Curtis2016/p1843/abstracts/methods/ln1-3;results/ln1] The IRs per 100 py of HZ among tofacitinib and biologic-treated patients with RA are shown in the slide.[Curtis2016/p1845/fig1; p1845/col2/para2/ln2-10] HZ rates ranged from 1.95 (95% CI 1.65, 2.31) for adalimumab to 3.87 (2.82, 5.32) for tofacitinib. After multivariable adjustment for a variety of potentially confounding factors*, the risk for HZ associated with tofacitinib was 2.01 (1.40, 2.88) compared with abatacept. No biologics were significantly different compared with this same referent, and all of them were numerically close to 1.00 (no excess risk vs abatacept). *Adjusted for age, gender, glucocorticoid use, MTX, number of biologics used, prior hospitalised infection, prior hospitalisation for other reasons, prior outpatient infection (other than varicella) and zoster vaccination. Curtis JR, et al. Ann Rheum Dis. 2016; Apr 25: doi: /annrheumdis Incidence rates and adjusted* HRs of herpes zoster among tofacitinib and biologic-treated patients with RA. *Adjusted for age, gender, glucocorticoid use, methotrexate, number of biologics used, prior hospitalised infection, prior hospitalisation for other reasons, prior outpatient infection (other than varicella) and zoster vaccination Curtis JR, et al. Ann Rheum Dis. 2016; Apr 25: . doi: / annrheumdis 13

14 Incidence Rate per 100 PY (95% CI)
Incidence rates of herpes zoster on tofacitinib based on concomitant treatment April 2014 data cut Pooled Phase 3 Studies Tofacitinib 5 mg BID Incidence Rate per 100 PY (95% CI) Safety data was pooled from Phase 3 studies of patients with RA receiving tofacitinib as monotherapy or in combination with glucocorticoids. The IRs for HZ were higher in patients receiving glucocorticoids in combination with tofacitinib compared with the IRs in patients receiving tofacitinib monotherapy. The lowest rate was in the patients receiving 5 mg tofacitinib monotherapy The highest IR was in patients who received DMARDs plus glucocorticoids in combination with tofacitinib. REFERENCE Winthrop et al. Poster 559. ACR 2015. Patients 579 384 320 296 Total PY 603 412 367 361 Events Winthrop et al. Poster 559. ACR 2015. Bars indicate 95% Confidence Limits; Incidence rate of patients per 100 patient-years. Monotherapy and Combination therapy (+DMARDs) was defined by index study. BID=twice-daily; CI=confidence interval; DMARD=disease-modifying antirheumatic drug; GC=glucocorticoid; PY=patient-year.

15 Vyöruusu Kliininen kuva ja patogeneesi Vyöruusu (zoster), varicellaviruksen aiheuttama 1–3 spinaali- tai aivohermon hermottamalla ihoalueella (dermatomilla) vyömäisesti esiintyvä rakkulainen ihottuma, rajoittuu keskiviivaan. Kiertävät vasta-aineet eivät yksin suojaa yksilöä vyöruusun puhkeamiselta. Kun soluvälitteinen immuniteetti heikkenee riittävästi iän tai immunosuppressiivisen lääkityksen vuoksi, pääsee virus lisääntymään ganglion lähisoluissa ja aiheuttamaan tulehdusreaktion Vyöruusu voi uusia, usein saman dermatomin alueella. Jopa 3–4 zosteruusiutumaa on kuvattu samalla potilaalla

16 Komplikaatiot ns. postherpeettinen neuralgia on vyöruusun tavallisin komplikaatio. Yli 50-vuotiaista potilaista lähes puolelle kehittyy hermokipua, ja yli 60-vuotiailla kivun kesto voi olla kuukausia. pään alueen vyöruusuun liittyy useita komplikaatioita. meningoenkefaliitti keratiitti, vaikea iridosykliitti, makuaistin häviäminen kasvohermon halvaus. noin 2–4 %:ssa vyöruusutapauksista ihottuma yleistyy ja muistuttaa tällöin vesirokkoa (herpes zoster generalisata). Tällainen on uhkaamassa, kun potilaalla on vaikea perussairaus.

17 Epidemiologia Vyöruusun ilmaantuvuuden on arvioitu olevan 2–5 tapausta/1 000 asukasta/vuosi. Taudilla on selvä ikäjakauma Aikuisiässä frekvenssi alkaa suurentua ja on suurimmillaan 60–80-vuotiailla. Yli 2/3 tapauksista todetaan yli 45-vuotiailla. Eroja sukupuolijakaumassa ei ole. Yhteinen syytekijä on elimistön immunologisen puolustusmekanismin huonontuminen Viime vuosian vyöruusun insidenssi lisääntynyt kaikissa ikäryhmissä Syynä mahdollisesti lasten roikottaminen vesirikkoa vastaan - VZV immuniteetin boostaus, mikä aiheutuu kontaktista vesirikkoa sairastavaan lapseen, jää pois.

18 vyöruusun ehkäisy Prof. Timo Vesikari Tampereen yliopisto Rokotetutkimuskeskus

19 Prof. Timo Vesikari Tampereen yliopisto Rokotetutkimuskeskus

20 Prof. Timo Vesikari Tampereen yliopisto Rokotetutkimuskeskus

21 Prof. Timo Vesikari Tampereen yliopisto Rokotetutkimuskeskus

22 Prof. Timo Vesikari Tampereen yliopisto Rokotetutkimuskeskus

23 Changes in lymphocyte counts over time in patients on tofacitinib
April 2014 data cut Month 6 12 18 24 30 36 42 48 54 60 66 1.0 0.8 0.6 0.4 0.2 Mean change from baseline in lymphocyte count (103/mm3) ± SE 0.0 –0.2 –0.4 –0.6 –0.8 Tofacitinib 5 mg BID An analysis of haematological changes in tofacitinib-treated patients with RA across Phase 3 and LTE studies was performed.[Schulze-Koops2017/p46/title] At 3 months of treatment with tofacitinib 5 mg, there was an initial small increase in mean lymphocyte counts, followed by a progressive decrease in mean counts.[Schulze-Koops2017/p48/col2/para4/ln1-4] In Phase 3 studies, mean lymphocyte counts showed continual gradual reductions for up to 48 months for 5 mg tofacitinib bd.[Schulze-Koops2017/p48/col2/para5;p49/col2/para1/ln1-2] Beyond month 48, the mean lymphocyte count stabilised for the 5 mg tofacitinib bd group. [Schulze-Koops2017/p49/col2/para1/ln4-6] Schulze-Koops H, et al. Rheumatology (Oxford) Jan;56(1):46–57. –1.0 Baseline was that of the phase 2 or phase 3 index study for patients who enrolled within 7 (Study A ) or 14 (Study A ) days of index study finalization; for the other patients, baseline values were derived from the final pre-drug visit on entry into the long-term extension studies Decreases in lymphocyte counts were observed that generally stabilised beyond Month 48 1. Schulze-Koops H, et al. Rheumatology (Oxford) Jan;56(1):46-57. BID, twice daily; DMARD, disease-modifying antirheaumatic drug; SE, standard error.

24 Lymphopenia and infection rate in patients on tofacitinib
ISS 2011 data cut Treated infection rate Serious infection rate Opportunistic infection rate % of patients % of patients % of patients VanVollenhoven2013/posterTHU0252/tables 2 & 3 VanVollenhoven2013/posterTHU0252/tables 2 & 3 The incidence of treated and serious infections in the LTE studies by confirmed lymphopenia are illustrated on this slide. For patients with ALC ≥0.5, there was no increase in the frequency of treated or serious infections.[VanVollenhoven2013/posterTHU0252/table2/row5] Confirmed lymphopenia with ALC <0.5 x 1000cells/mm3 was infrequent: 5/2430 patients (0.2%) in Phase 3 and 17/4088 patients (0.4%) in the LTE.[VanVollenhoven2013/posterTHU0252/column3/bullet3] There was an increase in the frequency of infections with confirmed lymphopenia (ALC <0.5).[VanVollenhoven2013/posterTHU0252/column3/bullet3] Additional information Absolute lymphocyte count and adverse event data of treated (requiring antimicrobial therapy or surgical intervention; TI), serious (SI), and opportunistic (OI) infections were analysed from all studies in the tofacitinib clinical development programme. The objective of the current analysis was to characterise changes in absolute lymphocyte counts (ALC) and lymphocyte subsets following tofacitinib treatment and evaluate the relationship between ALC and rates of infections of interest. van Vollenhoven RF, et al. Presented at EULAR (Poster #THU0252). Confirmed ALC (x103 cells/mm3) Tofacitinib 5 mg BID Confirmed ALC <0.5 x 1000cells/mm3 occurred rarely and may be the optimum threshold for defining increased risk of serious, treated and opportunistic infections 1. van Vollenhoven RF, et al. Poster #THU0252 EULAR 2013. ALC, absolute leukocyte count.

25 Incidence of opportunistic infections (excluding TB)
70 OIs were recorded in 68 patients (IR: 0.32 [0.25, 0.41]) c As of January 2016, data pooled from Phase 1, 2, 3 and LTE studies shows that 71 opportunistic infections (OIs) were recorded in 68 patients. The incident rate for OIs was 0.32 (0.25, 0.14) per 100 patient-years. The most common OIs were HZ, oesophageal/invasive Candidiasis, and cytomegalovirus. Listing of Patients with Adjudicated Events of Opportunistic Infections Excluding Tuberculosis - All Patients (Average Dosing) Adhoc Table (CII_Adhoc1150_P123LTE_05JULY2016(Average Dosing)) Listings_SCS1159_List of OI excl TB_Adhoc1150.xls. Data as of January 2016. n=number of subjects experiencing OIs excluding TB. a 1 subject experienced 2 events of esophageal candidiasis. Subjects are counted once in each category of OI. b One case of candidiasis was invasive. c Cases of HZ assessed by the OIRC as involving only 2 adjacent dermatomes are not included. There were 4 cases of disseminated HZ. Winthrop Ann Reum Dis 2016 HZ, herpes zoster; OI, opportunistic infection; OIRC, opportunistic infections review committee; TB, tuberculosis.

26 Incidence rate for tuberculosis in patients on tofacitinib by background incidence
ISS 2015 data cut bDMARD 0–2.56 (Rangea) Asia Pacific Europe US/Canada Tofa 0.62 n=28 bDMARD 0.05–0.45 (Rangea) bDMARD 0.04–0.13 (Rangea) Tofa 0.10 n=7 Tofa 0.01 n=1 The IR of TB in patients receiving tofacitinib or a bDMARD is classified as low, intermediate and high. The IR for the bDMARDs is shown as a range rather than a single point estimate. The IR of TB reported during tofacitinib treatment is within the range of bDMARDs. Table Low Background Incidence 1) Wolfe, 2004; Adult RA Inflix; US; IR=0.05; 2) Brassard, 2006; bDMARD; Canada; IR=0.257; 3) Burmester, 2007; ADA; Germany; IR=0.5; 4) Askling, 2005; TNFi RA patients during treatment; Sweden; IR=0.118; 5) Askling, 2005; RA patients ever been treated with a TNFi; Sweden; IR=0.105; 6) Askling, 2005; IFX; Sweden; IR=0.145; 7) Askling, 2005; ETN; Sweden; IR=0.08; 8) Sichletidis 2006; Adult RA; Greece; IR=0.449. Intermediate Background Incidence 1) Carmona 2003; Adult RA; Spain; IR=0.134; 2) Yamada 2006; Adult RA; Japan; IR= High Background Incidence 1) Seong, 2007; Inflix; Korea; IR=2.558; 2) Seong, 2007; Etan; Korea; IR=0; 3) Jung, 2015; TNFi; Korea; IR=1.14; 4) Ke, 2013; TNFi total; Taiwan; IR=0.96; 5) Ke, 2013; ETN; Taiwan; IR=0.68; 6) Chiu, 2014; bDMARD; Taiwan; IR=1.46. All countries included in categorizations: Low: US, Czech Republic, Germany, Slovakia, Australia, Canada, Austria, Italy, Sweden, Finland, Greece, Belgium, France, Denmark, New Zealand, Ireland. Intermediate: Japan, Brazil, Mexico, Poland, Chile, Bulgaria, Spain, Colombia, Argentina, Croatia, Hungary, UK, Costa Rica, Venezuela, Bosnia-Herzegovina, Turkey. High: Korea, Ukraine, China, India, Russia, Thailand, Philippines, Malaysia, Taiwan, Dominican-Republic, Peru, Romania. Low (<0.01) Intermediate (≥0.01 and ≤0.05) High (>0.05) a Low background incidence (observational): Wolfe, 2004; Brassard, 2006; Burmester, 2007; Askling, 2005; Sichletidis, Intermediate background incidence: (observational) Carmona, 2003; Yamada, High background incidence (observational): Seong, 2007; Jung, 2015; Ke, 2013; Chiu, 2014 Data as of March IRs are patients with events per 100 patient-years. Bars indicate 95% confidence limits TB background country incidence rate categories from World Health Organization, 2011 report for year 2010 bDMARD=biologic disease-modifying antirheumatic drug; IR=incidence rate; P123LTE=Phase 1, 2, 3, and long-term extension; PY=patient-years; TB=tuberculosis

27 Syöpä ja lymfoproliferatiiviset sairaudet
kuten TNF-salpaajien tullessa käyttöön, JAK-estäjien kohdalla on pohdittu lääkkeitten mahdollista vaikututusta pahalaatuisten kasvainten ilmaantumiseen. maliginteettieriskin kannalta merkitystä saattaa olla JAK-estäjien vaikutuksella NK-soluihin sekä IFN γ:n solunsisäiseen signalointiin toistaiseksi ei signaalia, että malignisoitumisriksi tofasitinibia ja barisitinibia poikkeaisi reumapotilailla yleensäkin todetusta IR (patients with events/ 100 patient-years (95% CI) Total pt exposure (N) 6,194 5,306 4,852 4,450 4,143 3,681 3,407 3,030 2,640 1,999 Patient with malignancies (N) 18 15 23 19 17 12 16 14 20 Cohen ARD 2017

28 Natural killer cells after short- and long-term tofacitinib treatment
Baseline, Month 1.5 and Month 6 data are from Phase 2 studies. Month 22 data predominantly represent Phase 3 patients who participated in LTE study, with a median of 22 months’ tofacitinib exposure Hodge Clin Exp Rheumatol 2015

29 Laboratoriotutkimukset - Xeljanz
Suositukset Lähtötilanteessa 4-8 vkon kohdalla 3 kk välein Lymfosyytit (B-Lymf)  Neutrofiilit (B-Neut) Hemoglobiini Lipidit a Maksaentsyymitb Suositellaan säännöllistä seurantaa. Hoidon aloittamista ei suositella, jos: B-Lymf < 0,75 x 109/l B-Neut < 1,0 x 109/l Hb <90 g/l aSuositus mitata 8 vkon kohdalla. bVirushepatiitin seulonta ennen hoidon aloitusta kliinisten ohjeistusten mukaan. Lähde: Xeljanz-valmisteyhteenveto PP-XEL-FIN

30 Lymfosyytit alussa ja 3 kk välein
Lähde: Xeljanz-valmisteyhteenveto ; kuvat MS Office Clipart PP-XEL-FIN

31 Neutrofiilit alussa ja 4-8 vk kuluttua + 3 kk välein
Lähde: Xeljanz-valmisteyhteenveto ; kuvat MS Office Clipart PP-XEL-FIN

32 Lähde: Xeljanz-valmisteyhteenveto 30.5.2017; kuvat MS Office Clipart
Munuaiset Xeljanz Vaikea munuaisten vjt (kreatiniinipuhdistuma < 30 ml/min)-> pienennä annos 5 mg x 1 annosta 5 mg x1 voidaan jatkaa myös hemodialyysin aikana Olumiant Suositeltu annos on 2 mg kerran vuorokaudessa, jos potilaan kreatiniinipuhdistuma on 30–60 ml/min. Olumiant-valmistetta ei suositella potilaille, joiden kreatiniinipuhdistuma on < 30 ml/min Lähde: Xeljanz-valmisteyhteenveto ; kuvat MS Office Clipart PP-XEL-FIN