Safety of Biological Response Modulators in Rheumatoid Arthritis
Transcription
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