Jamie Geier

Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme

Objectives Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme. Methods Malignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies. Results Of 5671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA. Conclusions The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.

Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist

Cardiovascular (CV) morbidity and mortality are increased in patients with active, untreated rheumatoid arthritis (RA), despite lower levels of total and low-density lipoprotein cholesterol reported in individuals with active RA compared with those without RA. Alterations in non-traditional lipid assessments, such as high-density lipoprotein (HDL) function and HDL-associated proteins, have been described in patients with active RA, including elevated HDL-associated serum amyloid A and decreased paraoxonase-1 activity. We review changes in both traditional lipoprotein concentrations and non-traditional lipoprotein assessments in multiple studies of treatment with disease-modifying antirheumatic drugs (DMARDs), including non-biologic and biologic DMARDs and tofacitinib. In addition, data from a recently published clinical trial with tofacitinib that describe a potential mechanism for suppression of cholesterol levels in active RA patients are reviewed. Finally, CV event data from various studies of DMARDs are presented, and the current management of RA patients with regard to the CV risk is reviewed.

Malignancy rates in a large cohort of patients with systemically treated psoriasis in a managed care population

Background Moderate to severe psoriasis often requires treatment with systemic agents, many of which have immunosuppressive properties and could increase cancer risk, including nonmelanoma skin cancer (NMSC). Objective We sought to estimate the overall malignancy rate (excluding NMSC) and NMSC rate among 5889 patients with systemically treated psoriasis. Methods We identified a cohort of adult Kaiser Permanente Northern California health plan members with psoriasis diagnosed from 1998 to 2011 and treated with at least 1 systemic antipsoriatic agent and categorized them into ever‐biologic or nonbiologic users. Malignancy rates were calculated per 1000 person‐years of follow‐up with 95% confidence intervals (CI). Crude and confounder‐adjusted hazard ratios (aHRs) were calculated using Cox regression. Results Most biologic‐exposed members were treated with TNF‐alfa inhibitors (n = 2214, 97%). Overall incident cancer rates were comparable between ever‐biologic as compared to nonbiologic users (aHR 0.86, 95% CI 0.66‐1.13). NMSC rates were 42% higher among individuals ever exposed to a biologic (aHR 1.42, 95% CI 1.12‐1.80), largely driven by increased cutaneous squamous cell carcinoma risk (aHR 1.81, 95% CI 1.23‐2.67). Limitations No information was available on disease severity. Conclusion We found increased incidence of cutaneous squamous cell carcinoma among patients with systemically treated psoriasis who were ever exposed to biologics, the majority of which were TNF‐alfa inhibitors. Increased skin cancer surveillance in this population may be warranted.

Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor.

OBJECTIVES Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The implications of treatment with tofacitinib on cardiovascular (CV) risk in RA are unknown. Therefore, CV adverse events (AEs), and blood pressure and lipid level changes, in tofacitinib-treated patients with RA were evaluated. METHODS Data were pooled from six Phase (P)3 studies (24 months) and two open-label long-term extension (LTE) studies (60 months) of tofacitinib in patients with RA and inadequate response to DMARDs. Tofacitinib was administered alone or with non-biologic DMARDs. CV events, including major adverse CV events (MACE: CV death and non-fatal CV events) and congestive heart failure (CHF), were assessed by a blinded adjudication committee. RESULTS Overall, 4271 patients from P3 studies and 4827 enrolled from P2/P3 studies into LTE studies were evaluated, representing 3942 and 8699 patient-years of exposure to tofacitinib, respectively. Blood pressure remained stable over time across studies. The number of investigator-reported hypertension-related AEs in tofacitinib-treated patients was low in P3 studies (Months 0-3: 2.8%; Months 3-6: 1.4%; >6 months: 2.8%). Across studies, lipid level increases were generally observed within 1-3 months of treatment and stabilized thereafter. Patients with events (incidence rate [IR]/100 patient-years) for MACE and CHF, respectively, were: 23 (0.58) and 9 (0.23) in P3 studies, and 32 (0.37) and 8 (0.09) in LTE studies; IRs were comparable with placebo (P3) and did not increase over time (LTE). CONCLUSIONS Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.

THU0131 Tofacitinib (CP-690,550), an oral janus kinase inhibitor: Analysis of malignancies across the rheumatoid arthritis clinical programme

Background Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis (RA). Objectives To evaluate the malignancies that occurred in the tofacitinib RA programme from the Phase (P) 2, 3, and long-term extension (LTE) studies up to 29 March 2011. Methods Data were pooled from 6 randomized P2, 5 randomized P3 studies and 2 open-label LTE studies. Patients (pts) in P3 and LTE studies were treated with tofacitinib 5 or 10 mg twice daily. Analyses included malignancy data from 1608 pts in P2, 3315 pts in P3, and 3227 pts in LTE studies (LTE pts rolled over from the P2 and P3 studies). Results A total of 4789 patients (5651 pt-yr) received tofacitinib in the P2, P3 and LTE studies. Fifty pts receiving tofacitinib (all doses) reported malignancies (excluding non-melanoma skin cancer [NMSC]); the most common were lung (12 cases) and breast cancer (9 cases). There were 3 lymphoma cases. The overall incidence rate (IR, events per 100 pt-yr) for all malignancies (excluding NMSC) was 0.89 (95% confidence interval [CI]: 0.67,1.17). The IRs (95% CI) of all malignancies (excluding NMSC) broken down into 0-6, 6-12, 12-18, 18-24 and >24 months based on exposure to study drug were 0.75 (0.46,1.23), 0.73 (0.41,1.28), 0.97 (0.48,1.94), 1.28 (0.53,3.08), and 1.37 (0.71,2.63), respectively. The number of cases in each time interval was small, with resultant wide CIs. The standardised incidence ratio (SIR) (95% CI) (as compared with the Surveillance Epidemiology and End Result database covering the general population) for all malignancies (excluding NMSC), lung, breast cancer and lymphomas in the tofacitinib group were 1.11 (0.82-1.47), 2.16 (1.12,3.77), 0.82 (0.38,1.56) and 1.74 (0.36,5.10), respectively. Twenty-one pts experienced NMSCs, for an IR of 0.37 (95% CI: 0.24,0.57). By comparison, the IR of NMSC in patients treated with anti-TNF was 0.47 (0.37-0.59) in a meta-analysis of randomized controlled trials and ranged from 0.23 to 0.35 in a meta-analysis of registries.1,2 Conclusions The malignancies that occurred in the tofacitinib RA programme are consistent with the type and distribution of malignancies expected for patients with moderate to severe RA. The IRs for all malignancies (excluding NMSC), lung cancer, breast cancer and lymphomas are consistent with published estimates in RA patients treated with biologic and non-biologic DMARDs.3-6 Longer follow-up is necessary to further evaluate the potential risk of malignancies in the CP RA programme. References Askling J, et al. Pharmacoepidemiol Drug Saf 2011;20:119-30. Mariette X, et al. Ann Rheum Dis 2011;70:1895-904. Carmona L, et al. Semin Arthritis Rheum 2011;41:71-80. Pallavicini FB, et al. Autoimmun Rev 2010;9:175-80. Simon TA, et al. Ann Rheum Dis 2009;68:1819-26. Wolfe F, Michaud K. Arthritis Rheum 2007;56:2886-95. Disclosure of Interest X. Mariette Consultant for: Pfizer Inc, J. Curtis Grant/Research support from: Pfizer Inc, Consultant for: Pfizer Inc, E. Lee Consultant for: Pfizer Inc, R. Riese Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. Kaplan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Chew Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Geier Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bradley Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

THU0136 Cardiovascular safety findings in rheumatoid arthritis patients treated with tofacitinib (CP-690,550), a novel, oral jak inhibitor

Background Tofacitinib is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis (RA). Objectives To evaluate the cardiovascular (CV) event rates and changes in blood pressure (BP) in the tofacitinib Phase 3 (P3) and long-term open-label extension (LTE) studies. Methods Five P3 studies in patients (pts) with inadequate response to nonbiologic/biologic disease-modifying anti-rheumatic drugs (DMARDs) and 2 LTE studies were included. Tofacitinib was administered as monotherapy or with background nonbiologic DMARDs, predominantly methotrexate. One P3 study included adalimumab (ADA) as active control. An independent CV Safety Endpoint Adjudication Committee performed blinded adjudication of deaths, potential major adverse CV events (MACE), and events of congestive heart failure (CHF). MACE was defined as CV death and non-fatal CV events. Results: Table 1 All P3 Studies (0-12 Months) LTE Studies PBO *All Dose tofacitinib (5 and 10 mg BID) ADA 40 mg SC q2w All Dose tofacitinib (5 and 10 mg BID) (N=681) (N=3030) (N=204) (N=3227) Exposure 202.6 pt-y 2098.2 pt-y 178.9 pt-y 2622.2 pt-y MACE  Events (n) 2 14 3 5  IR per 100 pt-y (95% CI) 0.99 (0.25, 3.95) 0.57 (0.33, 1.01) 1.68 (0.54, 5.20) 0.19 (0.08, 0.46) CV Mortality  Events (n) 0 2 1 1  IR per 100 pt-y (95% CI) 0 0.10 (0.02, 0.38) 0.56 (0.08, 3.97) 0.04 (0.01, 0.27) Non-fatal myocardial infarction  Events (n) 0 4 2 1  IR per 100 pt-y (95% CI) 0 0.19 (0.07, 0.51) 1.12 (0.28, 4.47) 0.04 (0.01, 0.27) Non-fatal cerebrovascular accidents  Events (n) 2 8 0 3  IR per 100 pt-y (95% CI) 0.99 (0.25, 3.95) 0.33 (0.16, 0.70) 0 0.11 (0.04, 0.36) CHF  Events (n) 0 7 0 3  IR per 100 pt-y (95% CI) 0 0.29 (0.13, 0.64) 0 0.08 (0.02, 0.31) *Pts advanced from PBO to tofacitinib are “PBO” until advanced and only in “All Dose” post-advancement. MACE IRs (per 100 pt-y) in placebo (PBO) and tofacitinib groups in P3 were low. IR in the LTE studies in the tofacitinib All Dose group (0.19) was lower than in P3 (0.57). IRs of CHF in tofacitinib were low. In P3, mean changes from baseline at Month 3 for systolic and diastolic BP, respectively, were -0.1 mmHg and -0.8 mmHg for PBO and -0.2 and 0.3 mmHg for tofacitinib. Mean BP changes at Months 6 and 12 and in the LTE studies remained stable. Conclusions Incidence rates of MACE were similar across groups in P3 with lower rates in LTE, suggesting no increased risk over 3 years of follow up. Tofacitinib was not associated with clinically meaningful increases in BP. Although the number of events have been fewand longer observation periods are warranted, CV risk does not appear to be increased with tofacitinib treatment and rates of CV events are consistent with those observed among patients with RA of similar disease severity.1-3 References Solomon DH et al. Circulation 2003; 107: 1303-1307; Solomon DH et al. Ann Rheum Dis 2006; 65: 1608-1612; 3. Nicola PJ et al. Arthritis Rheum 2006; 54: 60-67. Disclosure of Interest C. Charles-Schoeman Grant/Research support from: Pfizer Inc., Consultant for: Pfizer Inc., P. Wicker Consultant for: Pfizer Inc., U. Sechtem Consultant for: Pfizer Inc., M. Gonzalez-Gay Consultant for: Pfizer Inc., S. Wood Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., M. Boy Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Geier Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., K. Soma Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

Serious infections among a large cohort of subjects with systemically treated psoriasis

Background: Biologic therapy is effective for treatment of moderate‐to‐severe psoriasis but may be associated with an increased risk for serious infection. Objective: To estimate the serious infection rate among patients with psoriasis treated with biologic as compared with nonbiologic systemic agents within a community‐based health care delivery setting. Methods: We identified 5889 adult Kaiser Permanente Northern California health plan members with psoriasis who had ever been treated with systemic therapies and calculated the incidence rates and 95% confidence intervals (CIs) for serious infections over 29,717 person‐years of follow‐up. Adjusted hazard ratios (aHRs) were calculated using Cox regression. Results: Adjusting for age, sex, race or ethnicity, and comorbidities revealed a significantly increased risk for overall serious infection among patients treated with biologics as compared with those treated with nonbiologics (aHR, 1.31; 95% CI, 1.02–1.68). More specifically, there was a significantly elevated risk for skin and soft tissue infection (aHR, 1.75; 95% CI, 1.19–2.56) and meningitis (aHR, 9.22; 95% CI, 1.77–48.10) during periods of active biologic use. Limitations: Risk associated with individual drugs was not examined. Conclusion: We found an increased rate of skin and soft tissue infections among patients with psoriasis treated with biologic agents. There also was a signal suggesting increased risk for meningitis. Clinicians should be aware of these potential adverse events when prescribing biologic agents.

Methodological challenges in the coding and adjudication of sudden deaths in a large simple trial with observational follow-up: the ziprasidone observational study of cardiac outcomes (ZODIAC).

The Ziprasidone Observational study of car DIAC Outcomes (ZODIAC), a large simple trial comparing ziprasidone versus olanzapine in real‐world use, showed no difference in risk of sudden death. Upon the request of the US Food and Drug Administration, 205 fatal events were readjudicated applying ICD‐10 coding rules for sudden death.

THU0173 Pregnancy Outcomes in the Tofacitinib RA Safety Database Through April 2014

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Its effect in pregnant women is of interest, as it has been shown to be foeticidal and teratogenic in both rats and rabbits at exposures 146 times and 13 times, respectively, the maximum recommended human dose. There are no adequate, well-controlled tofacitinib studies in pregnant women; per the RA clinical development programme protocols, all studies exclude pregnant subjects and require use of highly effective contraception by females with child-bearing potential, and study treatment discontinuation if a subject becomes pregnant. Objectives To understand potential effects of tofacitinib, pregnancies in the RA clinical development programme were reviewed. Methods Cases were identified from Pfizers internal safety database up to 30 April 2014, from interventional (one study is ongoing; database not locked) and non-interventional studies, plus cases from post-marketing reporting. Cases were limited to females administered tofacitinib/placebo/blinded therapy at time of conception and/or foetal subjects exposed to tofacitinib/placebo/blinded therapy through maternal exposure. Potential duplicate cases were eliminated. Remaining cases were reviewed for pregnancy-related outcomes and abnormalities; categorised as healthy newborns, spontaneous abortion, medical termination, still-birth, pending or lost to follow-up. Results 35 cases were identified. In tofacitinib RA clinical studies of 6192 subjects with 16839 patient-years exposure, there were 32 cases of maternal exposure. Subject age ranged from 22 to 40 years. Of the 32 cases, 31 received tofacitinib; 13 received 5 mg BID, 17 received 10 mg BID, and 1 received 15 mg BID. 14 of the 31 cases were also taking methotrexate (MTX). 1 subject received placebo/MTX. Pregnancy outcomes with tofacitinib were: 16 healthy newborns (including 1 low birth weight and 1 pre-term birth), 7 spontaneous abortions, 4 medical terminations, 1 congenital malformation of pulmonary valve stenosis reported in a 32-year-old subject with diabetes and hypertension, 1 ongoing pregnancy and 3 lost to follow-up; the placebo-treated subject experienced a spontaneous abortion. The remaining 3 cases receiving tofacitinib were reported from other data sources: 2 from non-interventional studies, 1 from post-marketing reporting. Foetal subjects had maternal exposure to tofacitinib. Of the 3 cases, 1 had a spontaneous abortion; outcomes were still pending for the other 2 cases. Conclusions Most cases with reported outcomes had healthy newborns. Adverse outcomes including spontaneous abortion and congenital malformation were observed in RA subjects who became pregnant during tofacitinib therapy. Pregnancy outcomes in subjects receiving tofacitinib continue to be monitored through routine pharmacovigilance and via a post-approval safety study within the Organization of Teratology Information Specialists (OTIS) registry. Acknowledgements Previously presented (Marren A et al. Arthritis Rheum 2014; 66(11): S5840 abs 1908) and reproduced with permission from Arthritis and Rheumatism. All aspects of this work were funded by Pfizer Inc. Editorial support, under the guidance of the authors, was provided by Amanda Pedder, of Complete Medical Communications, and funded by Pfizer Inc. Disclosure of Interest A. Marren Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer Inc, Y. Chen Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer Inc, D. Frazier Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer, J. Geier Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer

SAT0346 Risk Characterisation Methodology Enabling Safety Comparisons Between Tofacitinib and Tumour Necrosis Factor Inhibitors

Background Tofacitinib is an oral JAK inhibitor for the treatment of RA. For new therapies, it is important to contextualise safety with established therapies such as TNF inhibitors (TNFi). Analyses were conducted based on the projected patient-years (PY) of accrual within the pooled Phase 2, Phase 3 and long-term extension (P2P3LTE) tofacitinib rheumatoid arthritis (RA) studies and external data for TNFi. Objectives To estimate the minimum threshold for detecting risk of specific adverse events (i.e., serious infections, all malignancies [excluding non-melanoma skin cancer (NMSC)], NMSC, major adverse cardiovascular endpoints [MACE], opportunistic infections [OI], lymphoma and gastrointestinal [GI] perforations) based on PY available for tofacitinib. Methods Power calculations were conducted based on a Poisson distribution to estimate the minimum PY of exposure needed to have 90% probability that the lower bound of the confidence interval (CI) for tofacitinib minus TNFi will be >1, for true tofacitinib rates of 1.2×, 1.5× or 2.0× the comparator rates. Rates of events for TNFi were derived from sources (i.e., published clinical trials and observational studies) intended to optimise similarity to the tofacitinib clinical trial database in term of baseline characteristics, study duration and average patient follow-up time. Results Based on projections, approximately 18,000 PY of exposure to tofacitinib will be accrued within the RA BID clinical development programme; the majority of these data will come from patients treated for at least 3 years. Table 1 highlights the PY of exposure needed to detect an increased risk in safety events as compared with published TNFi rates. Conclusions The risk characterisation approach represents an indirect method to contextualise the safety profile of tofacitinib as compared with TNFi. Ongoing and planned prospective active surveillance complement the data generated from clinical trials. References Askling J, Baecklund E, Granath F, et al. Ann Rheum Dis 2009;68(5):648-53. Gout T, Ostör AJ, Nisar MK. Clin Rheumatol 2011;30(11):1471-4. Keystone EC, van der Heijde D, Kavanaugh A, et al. J Rheumatol, 2013. 40(9):1487-97. Mariette X, Matucci-Cerinic M, Pavelka K, et al. Ann Rheum Dis 2011. doi: 10.1136/ard.2010.149419. Winthrop KL. Rheum Dis Clin Am, 2012;38:727-645. Disclosure of Interest J. Curtis Grant/research support from: Pfizer, Inc., L. Klareskog: None declared, R. Zhang Shareholder of: Pfizer, Inc., Employee of: Pfizer, Inc., S. Krishnaswami Shareholder of: Pfizer, Inc., Employee of: Pfizer, Inc., A. Anisfeld Shareholder of: Pfizer, Inc., Employee of: Pfizer, Inc., Y. Chen Shareholder of: Pfizer, Inc., Employee of: Pfizer, Inc., J. Geier Shareholder of: Pfizer, Inc., Employee of: Pfizer, Inc.