The US Food and Drug Administration’s (FDA’s) decision earlier this year to delay approval of baricitinib (Olumiant, Lilly) for the treatment of rheumatoid arthritis (RA) because of concerns about thromboembolic events raises questions about two related drugs already on the US market: tofacitinib (Xeljanz, Pfizer) and ruxolitinib (Jakafi, Incyte). Neither carries warnings about thromboembolic risk, but all three drugs are Janus kinase (JAK) inhibitors.
The three agents act by suppressing one or more of the JAK enzymes (JAK1, JAK2, JAK3, and TYK2) and downregulating the JAK-STAT pathway. This inhibition reduces transcription and expression of genes involved in a wide variety of processes, including immunity, cell proliferation and differentiation, apoptosis, and oncogenesis.
Tofacitinib is approved in the United States for treatment of moderate to severe RA. Ruxolitinib is approved in the United States for the treatment of intermediate- or high-risk myelofibrosis and polycythemia vera. Baricitinib was approved earlier this year in Japan and Europe for use in moderate to severe RA, but carries warnings about possible venous thromboembolism (VTE) risk.
Given the warning for baricitinib, Abril Verden and colleagues from Advera Health Analytics in Santa Rosa, California, examined whether the VTE signals seen in baricitinib clinical trials data might point to a class effect that extends to other JAK inhibitors.
The researchers screened data from the FDA Adverse Event Reporting System (FAERS) database of voluntarily reported AEs, medication errors, and product quality complaints. Their results were published online December 2 in Drug Safety.
Brian M. Overstreet, chief executive officer and president of Advera Health Analytics (formerly AdverseEvents Inc) told Medscape Medical News that their analysis was designed to produce a statistical calculation of numbers of reports for a particular drug–AE pair relative to reports of that AE with other drugs in the FAERS data set.
The FAERS data set included 190 patients treated with ruxolitinib, 115 patients treated with tofacitinib, and 12 patients treated with tofacitinib extended-release (XR). The AEs examined included pulmonary thrombosis (tofacitinib, 16; ruxolitinib, 9; tofacitinib XR, 3), pulmonary embolism (PE) (tofacitinib, 36; ruxolitinib, 55; tofacitinib XR, 3), portal vein thrombosis (tofacitinib, 0; ruxolitinib, 11; tofacitinib XR, 0), deep vein thrombosis (DVT; tofacitinib, 18; ruxolitinib, 40; tofacitinib XR, 1), and thrombosis (tofacitinib, 43; ruxolitinib, 75; tofacitinib, 5).
The team’s methodology, however, does not take into account factors such as number of patients taking the drug, disease state, comorbidities, or how long the drug has been on the market, and thus cannot be used to calculate event rates (number of events per 1000 patient-years). Instead, the analysis used the reporting odds ratio and the empirical Bayesian geometric mean to identify AEs with higher-than-expected reporting rates within FAERS.
Overstreet said, “What this all means is that certain AEs are being reported to FDA about certain drugs at a higher-than-expected rate relative to other drugs, which signals that there may be something going wrong with the drug that needs further study.”
“Our safety review of postmarketing FAERS reports associated with three FDA-approved JAK inhibitors did not find elevated reporting rates for DVT and PE specifically. However, the FAERS data indicated that pulmonary thrombosis may potentially be a class-wide issue for JAK inhibitors. Portal vein thrombosis may also be a potential risk for ruxolitinib,” the authors write.
However, Philip J. Mease, MD, chief of rheumatology research at Swedish Hospital Medical Center and clinical professor of Medicine at University of Washington in Seattle, told Medscape Medical News that he has several problems with the analysis.
“First, this analysis was based on very few patients. Second, the FAERS reporting system for [AEs] is not necessarily accurate or representative of what is truly going on in the population of all treated patients. It does not take into account the natural increased background rate in an inflammatory disease population, and this report offers no comparison with analysis of biologic agents (eg, anti-[tumor necrosis factors]) or conventional synthetic [disease-modifying antirheumatic drugs] (methotrexate).”
He continued, “I certainly don’t dismiss the question or potential concern, especially since the FDA highlighted the imbalance between placebo and treatment arms in the baricitinib database, but to lump agents together as a class effect, especially since there may be real biological differences between the various JAK inhibitors, is too sweeping and potentially inaccurate. It is reminiscent of how celecoxib got stained when the rofecoxib myocardial infarction data came out, only to be exonerated years later by the PRECISION trial.”
Dr Mease recently reviewed thromboembolic events in clinical trials of tofacitinib for treatment of RA, psoriasis, psoriatic arthritis, and ulcerative colitis, and presented the data as a late-breaking abstract at the American College of Rheumatology (ACR) 2017 Annual Meeting. His group included all patients treated with tofacitinib in the clinical trials and compared those data with the Corrona registry database, which includes more than 100,000 patient-years of data on patients with RA being treated with conventional disease-modifying antirheumatic drugs, biologics, and tofacitinib.
Dr Mease told Medscape Medical News, “This very in-depth and population-representative analysis showed no thromboembolic signal, either DVT or PE, due to tofacitinib. Both the tofacitinib study database and the Corrona registry data involved many more patients than the Verden et al report and, as such, should be more reliable. Before I could make a judgment about baricitinib, I would want to see much more of this kind of large database and real-world evidence.”
With regard to ruxolitinib, Jenifer Antonacci, director, US Public Affairs for Incyte Pharmaceuticals, Wilmington, Delaware, told Medscape Medical News that the company is evaluating the report from Advera.
She said, “When evaluating safety information such as that referenced by Advera, it is important to note that myelofibrosis and polycythemia vera are inherently associated with increased risk of thromboembolic complications…. Consequently, the reporting rates of thromboembolic events seen in patients with [polycythemia vera] are likely related to the natural history of the disease rather than to treatment with a JAK inhibitor.”
Verden and colleagues say they initiated their analysis of ruxolitinib and tofacitinib after the FDA delayed the launch of baricitinib in the United States and requested an additional clinical trial to deal with a concern about thromboembolic events. Safety warnings were added to baricitinib labeling in Europe and Japan, where the drug was already approved.
Interestingly, the warning added to the baricitinib label in Europe is for DVT and PE, neither of which was identified as a concern with either of the other JAK inhibitors in the new analysis by Verden and colleagues.
A spokesperson for Lilly/Incyte told Medscape Medical News that the event rates over time for patients with RA treated with baricitinib are similar to those for patients with RA treated with other drugs. According to a statement from the company, “We continue to believe in the benefit/risk profile of baricitinib, which has been approved in the [European Union], Japan, Switzerland and Kuwait. The safety and efficacy of baricitinib has been evaluated in more than 3,000 adults with [RA] in a clinical trial program with four Phase 3 studies worldwide. Events of [VTE] have been reported in patients receiving baricitinib. In an internal review of all available safety information for baricitinib, Lilly observed an imbalance between baricitinib and placebo in the number of patients with reports of [DVT and PE] in the randomized controlled studies. However, based on their review of the clinical trial data, the [European Medicines Agency], Japan, and Lilly/Incyte have not concluded that baricitinib causes thrombotic events.”
Lilly plans to resubmit a new drug application to the FDA for baricitinib as a treatment for adult patients with RA before the end of January 2018.
Meanwhile, researchers reported at the ACR meeting that there was a potential safety signal seen in a phase 3 trial with the experimental JAK inhibitor, upadacitinib (ABT-494, AbbVie). In the first 24 weeks of therapy, there were six venous thrombotic events (PE or DVT) among 329 patients treated with the drug. That said, the company recently released top-line data from a separate phase 3 trial in which there were two reported venous thrombotic events among 433 patients treated. The company said this was within the expected baseline rate for patients with RA.
Verden and coauthors are employees and equity owners (through stock and/or stock options) of Advera Health Analytics, Inc. One coauthor is a member of the Scientific Advisory Board and an equity owner (through stock and/or stock options) of Advera Health Analytics. No outside sources of funding were used to assist in the preparation of this study. Dr Mease has received research funding or other support from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, Sun Pharmaceutical, and UCB.
Drug Safety. Published online December 2, 2017. Abstract
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