Biosimilar for Infliximab Launched in Europe

The first biosimilar for infliximab has been launched in 12 new European markets, including the United Kingdom.¹ Abroad, Remsima (infliximab) developed by Celltrion Inc., is indicated for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis, psoriasis, psoriatic arthritis and Crohn’s disease. Remsima has shown comparability in efficacy, safety and quality to its reference product Remicade. Marketing authorization was obtained in September 2013 from the European Medicines Agency for marketing abroad.

Biosimilar infliximab is currently being reviewed by the FDA. Most recently, FDA postponed a meeting of the Arthritis Advisory Committee scheduled for mid-March, which was to discuss the infliximab biosimilar CT-P13.²

Hospira has exclusive rights to market biosimilar infliximab in the U.S., if and when it garners approval.

Arhalofenate is currently in Phase 2b studies for reducing gout flares.³ Arhalofenate appears to lower serum uric acid (sUA) levels by blocking its reabsorption in the proximal tubules, inhibiting a renal uric acid transporter (URAT1), causing a uricosuric effect. It also has antiinflammatory activities. Recent study results indicate a reduction in gout flares in patients without co-administered colchicine. The 12-week, randomized, placebo- and active-controlled, double-blind, Phase 2b study treated gout patients with hyperuricemia with at least three flares in the prior year. The primary endpoint was met. There was a 46% reduction in flare rate for patients who received 800 mg daily arhalofenate compared with 300 mg allopurinol daily. A secondary analysis showed a lower flare rate of 41% compared with placebo-treated patients. Reductions in sUA were statistically significant for arhalofenate 600 mg and 800 mg, but did not lead to a statistically significant number of patients reaching the goal sUA of <6 mg/dL.

Phase 3 studies are planned for 2016 for this potential new gout therapy class, known as ULAFT (urate-lowering anti-flare therapy).

ALO-02 (oxycodone and naltrexone) extended-release capsules are an abuse-deterrent, combination formulation for managing pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.⁴ The Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for this product, which had been designed to reduce abuse via the intranasal, intravenous and oral routes when crushed.

The formulation consists of sequestered naltrexone surrounded by extended-release oxycodone pellets. When administered as directed, patients receive oxycodone as an extended-release preparation. If pellets are crushed for abuse or misuse, naloxone is released and inhibits the oxycodone effect. ALO-02 was studied in two Phase 3 trials in patients with moderate to severe, nonmalignant pain.

Baricitinib is an oral, once-daily, selective janus kinase inhibitor (JAK) for JAK1 and JAK2. In a Phase 3 trial, it showed statistically significant improvements in patients with moderate to severe active RA compared with placebo.⁵ Patients in this study, known as RA-BUILD (n=684), had RA and did not tolerate or had an inadequate response to at least one nonbiologic disease-

modifying antirheumatic drug (DMARD) and had not received any biologic DMARDs. Patients received either one or two doses of once-daily baricitinib or placebo in addition to their background therapy. The primary endpoint, ACR20 response, was met at Week 12 of treatment. There were no serious adverse events or treatment-emergent adverse events. There was one case of tuberculosis in a baricitinib-treated patient.

Results of an earlier Phase 3 study, RA-BEACON, also met the primary endpoint of ACR20 response, compared with placebo at Week 12 in patients with moderate to severe RA (n=527) who had previously failed at least one tumor necrosis factor inhibitor and were on stable doses of DMARDs.⁶ Adverse events, including serious events and infections, were similar to placebo-treated patients. Nasopharyngitis, headache and upper respiratory tract infection were the most common nonserious reactions. Discontinuation rates due to adverse events were similar between treatment groups.

Decernotinib, an oral selective JAK-3 inhibitor, recently showed significant symptom improvement in RA patients (n=204) in a multicenter Phase 2a, dose-ranging study.⁷ Patients enrolled in this trial had previously had an inadequate response to at least one DMARD and could have received one prior biologic agent. Stable doses of nonsteroidal antiinflammatory agents and low-dose prednisone were allowed. Twenty-five mg, 50 mg, 100 mg or 150 mg doses of decernotinib or placebo were evaluated. Mean disease duration was 7.7 years. Most patients were white women with a mean age of 56 years. Mean disease activity score in 28 joints (DAS28) was 6.1 at baseline. At Month 3, a 61% improvement in ACR20 was seen in patients who received 50 mg decernotinib compared with 29% of placebo-treated patients. At Month 3, a 65% improvement in ACR20 was obtained in patients who received 100 mg decernotinib daily and a 66% improvement in ACR20 was noted in patients who received 150 mg decernotinib daily. Mean DAS28 score changes from baseline and ACR50 responses were statistically significant for all doses except for 50 mg, compared with placebo.

Although the efficacy data were impressive, the safety data showed more serious infections and lipid and hepatic enzyme elevations in patients who received higher doses of decernotinib. Eight of nine patients who received decernotinib developed pneumonia compared with one placebo-treated patient. Three cases of herpes zoster occurred, as well as cases of erysipelas and osteomyelitis. One patient treated with 100 mg decernotinib died. Due to these serious adverse events, the manufacturer has decided not to continue developing decernotinib for RA.

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. Celltrion launches world’s first biosimilar monoclonal antibody Remsima in 12 new European markets. First Word Pharma. 2015 Feb 24.
2. FDA delays meeting to evaluate infliximab biosimilar. GABI Online. 2015 Feb. 27.
3. CymaBay Therapeutics announces positive results from its Phase 2b clinical study demonstrating that arhalofenate met the primary endpoint of reduction in gout flares. CymaBay Therapeutics. 2015 Feb 24.
4. Pfizer announces FDA acceptance for review of a new drug application for ALO-02 (oxycodone hydrochloride and naltrexone hydrochloride). Pfizer. 2015 Feb 13.
5. Baricitinib superior to placebo in reducing rheumatoid arthritis disease activity in second Phase 3 study. Eli Lilly & Co. 2015 Feb 23.
6. Arthritis drug baricitinib meets primary endpoint in Phase 3 RA_BEACON study. News Medical. 2014 Dec 9.
7. Walsh N. JAK-3 drug effective in RA, but safe? MedPageToday. 2015 Feb 12.