Clazakizumab, a humanized, anti-interleukin (IL) 6 monoclonal antibody directed against the IL-6 cytokine rather than its receptor, is currently undergoing Phase 2b clinical trials. This agent is administered by subcutaneous (SubQ) injection to treat moderate-to-severe rheumatoid arthritis (RA) in patients who have had an inadequate response to methotrexate (MTX).1
In the randomized, dose-ranging, Phase 2b study, the efficacy and safety of clazakizumab injection monotherapy or in combination with MTX was evaluated. Participants were randomized to one of seven treatment arms: clazakizumab 25 mg, 100 mg or 200 mg once monthly (all also receiving MTX background therapy); clazakizumab 100 mg or 200 mg once monthly without MTX; MTX monotherapy; or adalimumab 40 mg twice monthly in combination with MTX. The primary end point was the ACR20 response rate at Week 12. These were: clazakizumab 25 mg plus MTX, 78% (p<0.001); clazakizumab 100 mg plus MTX, 72% (p<0.001); clazakizumab 200 mg plus MTX, 60% (p=0.015); clazakizumab 100 mg monotherapy, 55.0% (p=0.042); clazakizumab 200 mg monotherapy, 61% (p=0.015); MTX monotherapy, 39%; and adalimumab 40 mg plus MTX, 76%. The most common adverse reactions for clazakizumab were dose-related injection site reactions (32–63.3%); most were mild, and none was considered serious. The most common reasons for therapy discontinuation were laboratory abnormalities, mainly transaminase elevations, infections and injection site reactions.
Epratuzumab, a humanized monoclonal antibody targeting CD22 receptors on B lymphocytes, is currently in phase 3 clinical trials to treat systemic lupus erythematosus (SLE).2 This agent has received a Fast Track Product Designation. Two placebo-controlled, randomized, double-blind, multicenter trials are currently ongoing to evaluate the tolerability, safety, efficacy and immunogenicity of epratuzumab in patients with moderate-to-severe SLE (EMBODY 1 & 2). Both trials will enroll more than 700 patients and run for at least one year.
Romosozumab, formerly known as AMG 785/CDP7851, currently is in phase 3 clinical trials for treating postmenopausal osteoporosis.3 This agent is a humanized monoclonal anti-sclerostin antibody. Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. Romosozumab binds to sclerostin and increases bone formation.
In a recently published phase 2 study, 419 women ages 55–85 years old with lumbar spine, femoral neck or total hip low bone mineral density (BMD) were randomized to receive romosozumab, either monthly (dosed at either 70 mg, 140 mg or 210 mg), every three months (140 mg or 210 mg) or a SubQ placebo injection.4 Other patients could also have received open-label active comparator with once weekly alendronate or daily SubQ teriparatide. The primary end point was the percentage change from baseline in BMD at Month 12 in the lumbar spine. Secondary goals were percentage changes in BMD at the femoral neck or total hip. Bone resorption markers were also evaluated. All romosozumab doses were associated with statistically significant increases in BMD at the lumbar spine. The 210 mg monthly dose led to an 11.3% increase in BMD. BMD decreased by 0.1% in the placebo-treated patients, whereas alendronate led to an increased BMD of 4.1% and teriparatide increased BMD by 7.1%. At month 6, the BMD at the lumbar spine and total hip was significantly increased in all romosozumab-treated patients compared with the placebo-treated group. Large increases in bone-formation markers and a decrease in bone-resorption markers were also observed. Injection-site reactions were more common with romosozumab-treated patients than with placebo-treated patients. Reactions were generally mild and did not lead to therapy discontinuation. No serious adverse events were reported by more than one participant in each group, and none of the serious adverse events were deemed by the investigators to be treatment related.
The FDA is investigating heart attack, stroke & death risk in men taking FDA-approved testosterone products.
Drug Safety
As discussed in a prior column, as well as the January 2014 Drug Updates column in this publication, the FDA has once again put out a recommendation for prescribers and dispensers of acetaminophen.5 The recommendation is to discontinue prescribing and dispensing prescription combination drug products containing 325 mg of acetaminophen or more due to a lack of additional benefit. Increasing the dose of acetaminophen to greater than 325 mg increases the risk of liver injury. The FDA is planning to withdraw approval of prescription combinations that contain more than 325 mg acetaminophen per dose. Severe liver toxicity injury has occurred in patients who have taken more than prescribed doses of acetaminophen-containing products within a 24-hour period, who have taken more than one acetaminophen-containing product concomitantly and who have consumed alcohol while taking acetaminophen-containing products.