Romosozumab’s Future Is Uncertain
Romosozumab, which has the possible U.S. brand name Evenity, is awaiting approval from the FDA.1 The treatment is an investigational, injectable biologic for treating osteoporosis. It increases bone formation and bone density, reducing a patient’s risk of fractures. The manufacturer no longer expects the FDA to approve the drug this year given the results of a late-stage clinical trial that revealed a higher rate of serious heart-related side effects than anticipated. The nature and severity of these cardiac side effects have not been disclosed.
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During this clinical trial, romosozumab significantly reduced the incidence of new vertebral fractures (primary endpoint) and non-vertebral fractures (key secondary endpoint) in post menopausal women with a high risk of fracture through Month 24 of treatment compared with alendronate-treated patients.2 Serious heart problems were reported in 2.5% of romosozumab-treated patients compared with 1.9% of alendronate-treated patients. All key secondary endpoints were also met. The imbalance in heart-related side effects was not observed in an earlier Phase 3 study, which was submitted to the FDA as a basis for approval.
An FDA decision is expected in July 2017.
Tocilizumab Receives FDA Approval for GCA
In February, a supplemental biologics license application was accepted by the FDA for tocilizumab (Actemra) to treat GCA via a priority review based on results of the Phase 3 study GiACTA.3 GiACTA (NCT01791153) proved the efficacy and safety of tocilizumab in treating GCA at Week 52. More than 251 patients in 14 countries were enrolled.
In GiACTA, when tocilizumab was initially combined with a six-month glucocorticoid regimen, it more effectively sustained disease remission through one year than glucocorticoids. The rates were 56% for patients treated weekly with tocilizumab and 53% for patients treated bi-weekly with tocilizumab compared with patients who received steroid monotherapy tapered over six months (14% remission rate) or 12 months (17.6% remission rate).
Subcutaneous tocilizumab is a humanized interleukin 6 receptor antagonist that is already FDA approved for treating rheumatoid arthritis and polyarticular juvenile idiopathic arthritis (PJIA) or systemic juvenile idiopathic arthritis (sJIA) in patients two years of age and older.4
This FDA approval is the sixth for tocilizumab, which is also the first new treatment for GCA in more than 50 years.
NSAIDs Increase Myocardial Infarction Risk
According to a recent meta-analysis of real-world non-steroidal anti-inflammatory drug (NSAID) use, NSAIDs may increase the risk of acute myocardial infarction (AMI). The analysis used individual patient data meta-analysis of studies from healthcare databases in Canada, Finland and the U.K. to determine the time course for risk of AMI, as well as the effects of dose and duration of continuous NSAID use.5
Researchers found that using NSAIDs for one week or more increases a person’s risk of experiencing an AMI. The NSAIDs in the study include celecoxib, diclofenac, ibuprofen, naproxen and rofecoxib. Low-dose aspirin was not included.
Each NSAID-use category compared the date of AMI for cases and matched the date for controls with NSAID non-use in the prior year, also looking at the posterior probability of AMI. The cohort included 446,763 individuals, of whom 61,460 had an AMI. The corresponding odds ratios were 1.24 for celecoxib, up to 1.53 for naproxen and 1.58 for rofecoxib, which is no longer available in the U.S.
A greater AMI risk was associated with higher NSAID doses and within the first month (Days 8–30) of continued use. Drugs and doses associated with this risk were >200 mg celecoxib, >100 mg diclofenac, >1,200 mg ibuprofen and >750 mg naproxen. The AMI risk with celecoxib did not seem greater than with traditional NSAIDs. Additionally, the AMI risk for using NSAIDs for more than one month did not exceed the risk associated with shorter durations of use.
In the study, the authors note that the absolute risk is very small and varies based on a patient’s baseline risk. They also note that as patients use these agents for longer treatment durations, the risk does not seem to continue to increase. However, they caution that they only studied patients with one AMI, not repeat AMIs. To be prudent, they note, patients should use NSAIDs for as short a time as possible.
Increased Risk of Leg & Foot Amputations with Canagliflozin
On May 16, the FDA confirmed that canagliflozin-treated patients underwent leg and foot amputations about twice as often as placebo-treated patients. This announcement was based on the results of two clinical trials: the Canagliflozin Cardiovascular Assessment Study (CANVAS) and A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus (CANVAS-R). Canagliflozin (Invokana, Invokamet, Invokamet XR) is an oral sodium-glucose cotransporter-2 (SGLT2) inhibitor used to treat Type 2 diabetes.6
The FDA is requiring new warnings, including a boxed warning, be added to the canagliflozin drug labels to describe this risk.
Patients taking canagliflozin are being asked to notify their healthcare professionals if they develop any new pain, tenderness, sores, ulcers or infections in their feet or legs. Healthcare professionals should consider factors that may predispose patients to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and/or diabetic foot ulcers, before starting a patient on canagliflozin. Patients taking canagliflozin should be monitored for signs and symptoms indicative of these predisposing conditions, and canagliflozin should be discontinued if they arise.
Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.
- Hirschler B. Heart safety clouds hopes for Amgen, UCB bone drug. Reuters. 2017 May 23.
- Amgen Inc. News release: Amgen and UCB announce top-line phase 3 data from active-comparator study of Evenity (romosozumab) in postmenopausal women with osteoporosis. 2017 May 21.
- Roche. News release: FDA grants priority review for Roche’s Actemra/RoActemra (tocilizumab) supplemental biologics license application for giant cell arteritis, a form of vasculitis. 2017 Jan 24.
- Genentech Inc. News release: FDA approves Genentech’s Actemra (tocilizumab) for giant cell arteritis. 2017 May 22.
- Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data. BMJ. 2017 May 9;357:j1909.
- U.S. Food and Drug Administration. FDA drug safety communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). 2017 May 16.