Safety Issues for New RA Biologic | Arthritis Information

Pfizer experienced a shake-up in its stock prices last week on news that four patients had died in a final-phase study of tofacitinib, a new biological drug for rheumatoid arthritis.

Pfizer shares dipped by more than 3% after the company updated the safety profile for tofacitinib, a novel oral inhibitor of the JAK signaling pathway. There has been considerable interest in the drug, which does not require an infusion or injection like most other biologic drugs.

Safety concerns for tofacitinib were first raised two years ago when results of a phase II trial were presented at the annual meeting of the European League Against Rheumatism (EULAR). The most notable concerns then involved elevations in LDL cholesterol. Other adverse events included decreases in neutrophils and hemoglobin levels, and increases in liver enzymes.

The ORAL Sync study was led by Joel Kremer, MD, of Albany Medical College in Albany, N.Y., and included 792 patients with active rheumatoid arthritis who had not responded adequately to one or more disease-modifying anti-rheumatic drug such as methotrexate.

Patients were randomized to receive 5 mg or 10 mg of tofacitinib twice daily or placebo. After three months, nonresponders were switched to active treatment, and after six months all patients were receiving tofacitinib.

Pfizer stressed that three of the four deaths in the phase III trial were determined by Kremer and colleagues to be unrelated to the study drug.

One was the result of a trauma-induced brain injury and one was related to worsening rheumatoid arthritis. These patients had received 5 mg of tofacitinib twice daily.

But there was one instance of death from acute heart failure -- the fourth known case with 10 mg of tofacitinib, said Larry Biegelsen, a senior analyst for Wells Fargo Securities.

The fourth death was attributed to respiratory failure and was related to the study drug, according to Pfizer. This patient was also on the 10 mg dose of tofacitinib.

Whether the higher dose could be directly linked to the patient deaths will require close review by the FDA, according to Biegelsen. "We continue to believe that the 10 mg dose will attract a lot of scrutiny from FDA because we know that the 10 mg works better than the 5 mg," he said.

Answers to the dosing question may be provided when the full results of the phase III study are presented next month at EULAR in a late-breaking abstract session.

In the meantime, the news had investors feeling jittery. Shares of Pfizer were down by 3.6% to .67 in afternoon trading on April 21 on the New York Stock Exchange. In comparison, Pfizer competitor Abbott Laboratories saw a 2% rise in stock prices to .82. Tofacitinib could be a rival to Abbott's Humira (adalimumab).

However, by the afternoon of April 26, Pfizer stock had climbed back to .20 a share.

Pfizer pointed out that four deaths in the 792-patient trial was "within the range of [all-cause mortality] rates reported for biologic therapies for RA. In addition, the company said, "no new safety signals" "emerged in the phase III trial.

The company noted that the primary efficacy endpoints of the phase III study were met, including the American College of Rheumatology 20% improvement (ACR20) criteria at six months; reduction in radiographic damage; and improvements in physical function at three months.