An analysis of the long-term safety of certolizumab pegol (Cimzia, UCB [CZP]) treatment in adults with rheumatoid arthritis (RA) was recently conducted by Bykerk et al.1 They evaluated data through Nov. 30, 2011, from 10 completed randomized controlled trials (RCT), one open-label, single-dose pharmacokinetic study and seven open-label extension trials.
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Some of these patients have been receiving CZP for up to seven years. All adverse events that occurred from the first day to 84 days after the last dosing day were noted. Any serious infections, malignancies and deaths were evaluated by external experts and validated by an external committee. Event rates (ERs) and incidence rates (IRs) per 100 patient-years (PYs) were reported. Patients had received either 200 mg CZP every two weeks following a loading dose of 400 mg; CZP 400 mg once every four weeks; or 400 mg every two weeks. The drug was administered as either the reconstituted lyophilized powder for injection or in a prefilled syringe for subcutaneous injection. Overall, 4,049 RA patients who received CZP were included in the safety pooling, with a total exposure of 9,277 PYs, and a mean exposure of 2.1 years (range, 0.04–7.6 years).
The most common serious adverse event was pneumonia, occurring more frequently in CZP-treated (vs. placebo-treated) patients. Serious infectious events were lower in CZP-treated patients.
Tuberculosis (TB) was identified in 44 patients, of whom 39 were from high endemic regions. TB screening was conducted following respective national guidelines of the study center before 2007. Subsequently, any patient with a positive purified protein derivative test received prophylaxis.
Other opportunistic infections were bronchopulmonary aspergillosis (n=6), esophageal or oral candidiasis (n=9) and disseminated herpes zoster (n=3). In addition, 70 malignancies, including five lymphomas, were identified. Non-melanoma skin cancers were excluded. Infections were the most common reason for study withdrawal.
For patients in the open-label extensions, the rate of serious infections did not increase with prolonged exposure to CZP, which is in line with that reported in the literature for other TNF inhibitors.
In the RCT, there were 11 deaths in CZP-treated patients and one death of a placebo-treated patient.
Across all trials, there were 58 CZP-treated patient deaths, mostly related to cardiovascular events, malignancies and infections. There were no cases of optic neuritis, multiple sclerosis or other demyelinating disorders identified. The overall adverse event incidence rate was 335.9 per 100 PYs for CZP-treated patients vs. 362.3 per 100 PYs for placebo-treated patients. Most adverse events were mild to moderate in intensity. The authors noted that for patients in the open-label extensions, the rate of serious infections did not increase with prolonged exposure to CZP, which is in line with that reported in the literature for other TNF inhibitors. In other words, no new or unexpected safety signals.
Clazakizumab (CLZ), a humanized monoclonal antibody, is an interleukin 6 (IL-6) blocker currently undergoing Phase 2b clinical trials for treating moderate to severe active RA and psoriatic arthritis.2 Recently, a randomized, double-blind, placebo-controlled, dose-ranging multicenter safety and efficacy trial evaluated the efficacy of three doses of CLZ in adults with psoriatic arthritis with or without methotrexate (MTX).3
Patients with an inadequate response to nonsteroidal antiinflammatory drugs (NSAIDs) and/or disease-modifying antirheumatic drugs (DMARDs) were randomized to receive CLZ 25 mg, 100 mg, 200 mg or placebo with or without MTX every four weeks for 24 weeks. ACR20 was the primary endpoint measured at Week 16. Secondary endpoints at Week 24 included ACR 20/50/70 and PASI 75 response rates, changes in HAQ-DI and DAS28 (CRP), as well as dactylitis and enthesitis scores. Approximately 75% of patients were receiving MTX, and a total of 165 patients were treated and analyzed. The primary endpoint was met with significantly higher ACR20 response rates in the CLZ 100 mg-treatment arm vs. placebo (52% vs. 29%).
There was a numerically higher response in the CLZ 25 mg and CLZ 200 mg treated groups at Week 16, 46% and 29%, respectively. ACR 20/50/70 response rates were higher than placebo for all CLZ treatment arms at Week 24; however, no clear dose response was identified. PASI 75, HAQ-DI, DAS28 (CRP) and the number of dactylitic digits and enthesitis scores all had mean decreases from baseline to Week 24 compared with placebo-treated patients.
Serious adverse events were similar across most treatment groups (5%), except in the CLZ 200 mg–treated group (10%); CLZ 200 mg was associated with more study discontinuations. Overall, CLZ was well tolerated, and there were no differences from placebo in relation to laboratory safety data. No serious infections, TB, malignancies, gastrointestinal perforations or unusual adverse events were seen during the study.
Hydrocodone bitartrate extended-release capsules (Zohydro ER) will soon be available as a new formulation with BeadTek abuse-deterrent properties.4 The manufacturer has ongoing human abuse liability studies to further characterize the abuse-deterrent properties of the new formulation, which will be submitted to the FDA in the second half of this year. The excipients in BeadTek immediately form a viscous gel when crushed and then dissolved in liquids or solvents.
Transitioning of patients currently on therapy to the new BeadTek formulation is expected to occur in the second quarter of this year without disruption.
Zohydro ER is indicated for managing pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Michele B. Kaufman, PharmD, CGP, RPh, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.
- Bykerk VP, Cush J, Winthrop K, et al. Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials. Ann Rheum Dis. 2015;74(1):96–103.
- Alder Biopharmaceuticals. Pipeline. Feb. 2, 2015. http://www.alderbio.com/therapeutics/pipeline.
- Mease P, Gottlieb AB, Berman A, et al. A Phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, multicenter study to evaluate the efficacy and safety of clazakizumab, an anti-il-6 monoclonal antibody, in adults with active psoriatic arthritis. Arthritis Rheumatol. 2014;66(11):Suppl. Abstract 952.
- Zogenix receives FDA approval of new formulation of Zohydro ER. First Word Pharma. 2015 Feb 1. http://www.firstwordpharma.com/print/1261369?tsid=17.