Search

Summary Background Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and JAK2, approved for the treatment of patients with active rheumatoid arthritis. Because baricitinib, like other disease-modifying antirheumatic drugs, is used chronically, continuous assessment of its long-term safety profile is important. Here we provide updated data supporting the existing safety profile of baricitinib in this patient population. Methods In this safety analysis, integrated data were included from nine phase 3, phase 2, and phase 1b clinical trials, and one long-term extension study with data up to 360 weeks, ending Feb 13, 2018. We analysed three integrated datasets, the largest of which was the all-bari-RA dataset, which includes patients who received any dose of baricitinib. We compared the safety of baricitinib with placebo on the basis of data from seven studies with baricitinib 4 mg and placebo and four studies with baricitinib 2 mg, including placebo to week 24 (placebo-controlled dataset). We did a dose-response assessment based on four studies with baricitinib 2 mg and 4 mg, including long-term extension data (2–4 mg extended dataset). We did an exploratory analysis of deaths and venous thromboembolic events in a subset of data from the all-bari-RA dataset that included patients who had ever taken baricitinib 2-mg or baricitinib 4-mg. We did an analysis for malignancies (excluding non-melanoma skin cancer) in the as-randomised population (patients not censored at rescue or dose change). Findings We collected data for 3770 patients who were given baricitinib for 10 127 patient-years of exposure in the all-bari-RA dataset (median 1115 days [IQR 426–1441], maximum 2520 days). The placebo-controlled dataset comprised 2836 patients, with 1215 in the placebo group, with 451 patient-years of exposure data; 479 in the baricitinib 2 mg group, with 186 patient-years of exposure data; and 1142 in the baricitinib 4 mg group, with 472 patient-years of exposure data. The 2–4 mg extended dataset comprised 958 patients, with 479 in both the 2 mg and 4 mg groups. No significant differences were seen for baricitinib 4 mg or 2 mg versus placebo, or for 4 mg versus 2 mg in the incidence of death, malignancy, serious infection, or major adverse cardiovascular events. Incidence of herpes zoster per 100 patient-years was higher for baricitinib (4 mg: 4·4 [95% CI 2·7–6·7]; 2 mg: 3·1 [1·1–6·8]) versus total placebo group (1·1 [0·4–2·5]), as were treatment-emergent infections (4 mg: 89·7 [81·3–98·6]; 2 mg: 84·0 [71·3–98·2] vs placebo 75·4 [67·6–83·9]). Consistent with previous reports, incidences in the all-bari-RA dataset for venous thromboembolic events was 0·5 (95% CI 0·4–0·6) per 100 patient-years, deep-vein thrombosis was 0·3 (0·2–0·5) per 100 patient-years, and pulmonary embolism was 0·2 (0·2–0·4) per 100 patient-years. Incidences of malignancy (excluding non-melanoma skin cancer) in the 2–4 mg extended dataset were 0·8 (0·4–1·5) per 100 patient-years for baricitinib 2 mg and 1·0 (0·5–1·7) per 100 patient-years for baricitinib 4 mg, without censoring patients who had dose changes or received rescue treatment. We found no indication of higher incidence of venous thromboembolic events in the baricitinib 4 mg group compared with the 2 mg group in the 2–4 mg extended dataset. Interpretation In this updated integrated analysis of patients with active rheumatoid arthritis exposed to baricitinib for a maximum of almost 7 years, baricitinib 2 mg and 4 mg maintained a similar safety profile to earlier analyses. No new safety signals were identified. Patients in the long-term extension study continue to be followed up to date. Funding Eli Lilly and Company, under license from Incyte Corporation.

Objective To assess the frequency of cardiovascular and venous thromboembolic events in clinical studies of baricitinib, an oral, selective JAK1 and JAK2 inhibitor approved in more than 50 countries for the treatment of moderately‐to‐severely active rheumatoid arthritis (RA). Methods Data were pooled from 9 RA studies. Placebo comparison up to 24 weeks included data from 6 studies. Randomized dose comparison between baricitinib doses of 2 mg and 4 mg used data from 4 studies and from the associated long‐term extension study. The data analysis set designated “All‐bari‐RA” included all baricitinib exposures at any dose. Results Overall, 3,492 RA patients received baricitinib (7,860 patient‐years of exposure). No imbalance compared to the placebo group was seen in the incidence of major adverse cardiovascular events (MACE) (incidence rates [IRs] of 0.5 per 100 patient‐years for placebo and 0.8 per 100 patient‐years for 4 mg baricitinib), arterial thrombotic events (ATE) (IRs of 0.5 per 100 patient‐years for placebo and 0.5 per 100 patient‐years for 4 mg baricitinib), or congestive heart failure (CHF) broad term (IRs of 4.3 per 100 patient‐years for placebo and 2.4 per 100 patient‐years for 4 mg baricitinib). Deep vein thrombosis (DVT)/pulmonary embolism (PE) were reported in 0 of 1,070 patients treated with placebo and 6 of 997 patients treated with 4 mg baricitinib during the placebo‐controlled period; these events were serious in 2 of 6 patients, while all 6 had risk factors and 1 patient developed DVT/PE after discontinuation of the study drug. In the 2 mg–4 mg‐extended data analysis set, IRs of DVT/PE were comparable between the doses across event types (IRs of 0.5 per 100 patient‐years in those receiving 2 mg baricitinib and 0.6 per 100 patient‐years in those receiving 4 mg baricitinib). In the All‐bari‐RA data analysis set, the rates were stable over time, with an IR of DVT/PE of 0.5 per 100 patient‐years. Conclusions In RA clinical trials, no association was found between baricitinib treatment and the incidence of MACE, ATE, or CHF. With regard to incidence of DVT/PE, 6 events occurred in patients treated with 4 mg baricitinib, but no cases of DVT/PE were reported in the placebo group. During longer‐term evaluation, the incidence of DVT/PE was similar between the baricitinib dose groups, with consistent IR values over time, and this was similar to the rates previously reported in patients with RA.

ObjectiveTo characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.MethodsData were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).ResultsMean absolute neutrophil counts decreased (−1.36×109/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30×109/L) within 1 month, then decreased to baseline (weeks 12–24). Mean platelet counts increased at week 2 (+51×109/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (−0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure).ConclusionsModerate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation.

Objectives: Baricitinib is a selective oral inhibitor of JAK1/JAK2 for patients with moderately-to-severely active rheumatoid arthritis (RA). Baricitinib’s safety profile in Japanese patients was evaluated using six studies (five Ph2/Ph3 trials, one long-term extension study through 01 September 2016) from an integrated database (nine RA studies). Methods: Incidence rates (IRs) or exposure-adjusted IRs (EAIRs) of adverse events (AEs) per 100 patient-years (PY) were calculated using data which included RA patients exposed to any baricitinib dose. Results: Five hundred and fourteen Japanese patients received baricitinib for 851.5 total PY of exposure (median 1.7 years, maximum 3.2). The EAIR of treatment-emergent AEs was 57.4/100PY. There were no deaths; 31 patients had serious infections (IR: 3.6/100PY), 55 herpes zoster (6.5), 0 tuberculosis, 10 malignancies (1.1) including two lymphomas, two major cardiovascular AEs (0.3), one gastrointestinal perforation (0.1), and four deep vein thrombosis (0.5). In Japanese patients, herpes zoster was more frequent than that of patients overall in the integrated database, but the events were considered manageable. Conclusion: In this analysis, baricitinib had acceptable safety profile in Japanese RA patients in the context of demonstrated efficacy. Aside from herpes zoster, baricitinib safety was not notably different between Japanese RA patients and those RA patients in the integrated database. Trial registration: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at https://clinicaltrials.gov/

ObjectivesLipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs.MethodsLipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study.ResultsTreatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated.ConclusionsBaricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications.Trial registration numberNCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.

Background Rheumatoid arthritis (RA) is associated with increased neutrophil levels1 and platelet2 counts and decreased lymphocyte levels.1,3 Baricitinib (bari) is a selective and reversible Janus kinase (JAK)1/JAK2 inhibitor in development for patients (pts) with moderate to severe RA.4 Objectives To characterize changes in absolute neutrophil counts (ANC), absolute leukocyte counts (ALC), and platelet counts following once daily oral administration of bari. Methods Data were pooled from 6 placebo-controlled phase 2 and 3 studies of bari (2 and 4 mg). Changes in ANC, ALC, and platelets were evaluated for up to 52 weeks (wks) including data from a long-term extension study. Reversibility was evaluated in a subgroup of pts who discontinued treatment by wk 24. Results Mean ANC decreased within 1 month of administration of bari, followed by stabilization and an increase to baseline after treatment discontinuation (Figure 1). ANC Mean ALC increased within 1 month of bari administration and then decreased to baseline level in wks 12 to 24 (Figure 1). Lymphopenia appeared to be associated with slightly higher rate of overall infections (Table 1). Mean platelet counts increased to peak at wk 2, returned towards baseline, stabilized over time, and returned to baseline after treatment discontinuation (Figure 1). Permanent study drug discontinuations from thrombocytosis occurred in 2 bari-treated pts (0.1%). No clear association between platelet increase and thromboembolic events was observed. Conclusions Treatment with bari was associated with a decrease in ANC and an increase in ALC and platelets, which stabilized over time and returned to baseline with prolonged treatment (ALC) or treatment discontinuation (ANC and platelets). No associations between ANC decrease and infections or between thrombocytosis and thromboembolic events were observed. References Schulze-Koops H et al. Rheumatology. 2017;56(1):46–57. Farr M et al. Ann Rheum Dis. 1983;42(5):545–549. Symmons DP et al. J R Soc Med. 1989;82:462–463. Fridman JS et al. J Immunol. 2010;184:5298–5307. Disclosure of Interest J. Kremer Grant/research support from: Abbvie, Genentech, Eli Lilly and Company, Novartis, Pfizer, Consultant for: Abbvie, Amgen, BMS, Genentech, GSK, Eli Lilly and Company, Novartis, Pfizer, Employee of: Corrona, Speakers bureau: Genentech (non-promotional), T. W. J. Huizinga Grant/research support from: Eli Lilly and Company, Pfizer, Consultant for: Eli Lilly and Company, Pfizer, Speakers bureau: Eli Lilly and Company, Pfizer, L. Chen Employee of: Eli Lilly and Company, C. Saifan Employee of: Eli Lilly and Company, M. Issa Employee of: Eli Lilly and Company, S. Witt Employee of: Eli Lilly and Company, C. Walls Employee of: Eli Lilly and Company, I. de la Torre Employee of: Eli Lilly and Company

Adalimumab is a fully human monoclonal anti-TNF-alpha antibody. Reported adverse effects have raised a number of safety concerns associated with their prolonged use. A case of granulomatous pneumonitis and hemidiaphragm paresis associated with adalimumab therapy for rheumatoid arthritis is described. In May 2012, a 57 year old male presented with dry cough, dyspnea and orthopnea after 4 months of treatment with adalimumab for rheumatoid arthritis. The patient received adalimumab from November 2011 to February 2012. A right hemidiaphragm elevation was shown on chest radiograph. A right hemidiaphragm paresis was shown on chest fluoroscopy. Bilateral lower lobe interstitial disease was shown on the chest HRCT scan. Open lung biopsy of the right lower lobe showed subacute granulomatous pneumonitis. In July 2013, the patient's respiratory symptoms and the previous restrictive pattern on PFTs resolved. In a same patient, a rare association of hemidiaphragm paresis and granulomatous pneumonitis with adalimumab treatment is herein reported.