Rheumatology Drug Updates, Trials, Safety Data

Pipeline & Drug Approvals

Baricitinib (LY3009104), an oral Janus kinase (JAK) 1 and 2 enzyme inhibitor, is currently in Phase 3 clinical trials for treating rheumatoid arthritis (RA).¹ Presented at the 2013 EULAR Annual European Congress of Rheumatology, 52-week baricitinib safety and efficacy data from an open-label, long-term extension of the Phase 2b JADA study in baricitinib-treated patients with active RA (n=201) showed clinical improvements at Week 24, sustained at the end of Week 52.² Through Week 12 of the study, patients received either daily baricitinib 1 mg, 2 mg, 4 mg, or 8 mg, or placebo. During Weeks 12 to 24, patients initially randomized to placebo or baricitinib 1 mg were re-randomized to receive either 2 mg twice daily or 4 mg once daily (for 12 weeks); patients who were initially randomized to receive baricitinib 2 mg, 4 mg or 8 mg continued to receive those doses. In the long-term extension, patients received either once daily 4 mg (n=108) or 8 mg (n=93) baricitinib starting at Week 24 through Week 52.

Treatment-emergent adverse effects (AEs) included infections (n=34) and serious infections (n=2). No tuberculosis or opportunistic infections were observed. One death occurred in the 8 mg group due to a suspected myocardial infarction.

Esomeprazole 20 mg (generic Nexium) will soon be available for over-the-counter (OTC) heartburn treatment.³ This OTC product has three-year market exclusivity.

Tocilizumab (Actemra) is currently in Phase 3 clinical trials for treating polyarticular-course juvenile idiopathic arthritis (pc-JIA).⁴ PC-JIA patients who had active disease greater than or equal to six months with an inadequate methotrexate (MTX) response were treated with open-label tocilizumab every four weeks (8 mg/kg body weight [BW; n=34] or 10 mg/kg for BW <30 kg [n=35] and 8 mg/kg for BW ≥30 kg [n=119]). Patients who at Week 16 had ≥ JIA-ACR30 improvement entered a 24-week, double-blind phase in which they were randomized to receive either tocilizumab (stratified by MTX and steroid background therapy; n=82) or placebo (n=81). The primary endpoint was JIA flare compared to Week 16. Patients who had a disease flare, or completed this second study phase, received open-label tocilizumab. Disease flares occurred in 26% of tocilizumab-treated patients and 48% of placebo-treated patients. At the end of the second phase of the study, 65% of tocilizumab-treated patients had a JIA-ACR70 and 45% of tocilizumab-treated patients had a JIA-ACR90. Patients in this study ranged in age from 6.9 (±3.02) to 13.1 (±2.78) years. Common AEs were pneumonia, bronchitis and cellulitis. No deaths or malignancies were reported.

Five of 22 serious AEs were felt by the investigator to be due to tocilizumab treatment. These were benign intracranial hypertension, cellulitis, pneumonia, urinary calculus and uveitis. Laboratory abnormalities included alanine aminotransferase elevations greater than three times the upper limit of normal (ULN; 4%), aspartate aminotransferase elevations >3× the ULN (0.5%), neutropenia (4%) and thrombocytopenia (1%). Low-density lipoprotein cholesterol levels ≥110 mg/dL were noted in 11% of patients and total cholesterol levels ≥170 mg/dL were noted in 35% of patients. One patient discontinued therapy for lack of efficacy. This patient had a positive anti-tocilizumab antibody result without an anaphylactic reaction.

The European Commission (EC) has approved tocilizumab (RoACTEMRA) for treating moderate-to-severe RA in patients who are either intolerant to, or have failed to respond to, other RA treatments.⁵

Drug Safety

The risk of progressive multifocal leukoencephalopathy (PML) in patients with systemic lupus erythematosus has been added to the Warnings, Precautions and Serious Infections section of the belimumab (Benlysta) package labeling, as well as to the Patient Medication Guide and Patient Advice sections.⁶

Eszopiclone (Lunesta) has been reported to cause next-day impairment of activities requiring mental alertness.⁷ A double-blind study evaluated psychomotor function in healthy adults (ages 25–40 years; n=91) who had received the initially recommended 3 mg eszopiclone dose. Psychomotor coordination included driving impairment, tests of working memory and subjective assessment of coordination and sedation. Compared with placebo-treated patients, subjects who received eszopiclone 3 mg at bedtime had next-morning psychomotor and memory impairment, which was clinically meaningful at 11.5 hours and most severe at 7.5 hours. Additionally, patients were often not aware that they were impaired. The new, lower recommended starting dose is 1 mg at bedtime for both men and women, as they appear equally predisposed. All labeling has been updated by the Food and Drug Administration. Any new information will be reported on this AE when available.

The occurrence of hypocalcemia has been added to the Warnings and Precautions section of the zoledronic acid (Zometa) labeling.6 Cardiac arrhythmias and neurologic AEs including tetany, seizures and numbness have been reported to have occurred secondary to severe hypocalcemia cases. Some of these cases may be life threatening. The labeling recommends that hypocalcemia be corrected prior to initiating zoledronic acid. Patients need to be adequately supplemented with calcium and vitamin D. Additionally, an acute phase reaction consisting of arthritis with subsequent joint swelling has occurred; this has also been added to the Postmarketing AE Experience section of the product labeling.

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.

References

1. Eli Lilly Clinical Pipeline. April 24, 2014. http://www.lilly.com/SiteCollectionDocuments/Pipeline/Clinical%20Development%20Pipeline/index.html. Accessed May 20, 2014.
2. EULAR abstract OP0047: Baricitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: Safety and efficacy in open-label, long-term extension study; Lilly and Incyte announce baricitinib efficacy and safety data from the open-label, long-term extension of the phase 2b JADA study in patients with rheumatoid arthritis—Results from 52-week study presented at EULAR 2013. June 13, 2013. http://lilly.mediaroom.com/index.php?s=9042&item=137205. Accessed May 20, 2014.
3. Johnsen M. Pfizer launches ‘Purple Pill’ Nexium 24HR onto OTC shelves. May 27, 2014. http://www.drugstorenews.com/article/pfizer-launches-purple-pill-nexium-24hr-otc-shelves. Accessed June 25, 2014.
4. Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: Results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis. 2014; May 16. DOI: 10.1136/annrheumdis-2014-205351.
5. Roche receives EU approval for new subcutaneous formulation of RoACTEMRA providing more treatment flexibility for patients with moderate to severe rheumatoid arthritis. April 28, 2014. http://www.firstwordpharma.com/node/1205989#axzz32xnF7G00. Accessed May 27, 2014.
6. FDA. April 2014. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm299628.htm. Accessed May 26, 2014.
7. FDA warns of next-day impairment with sleep aid Lunesta (eszopiclone) and lowers recommended dose. May 15, 2014. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM397277.pdf. Accessed May 27, 2014.