COPENHAGEN — An investigational oral drug showed safety and efficacy as monotherapy in patients with rheumatoid arthritis in a phase II study with 384 patients.
The new drug is CP-690550, a selective inhibitor of Janus kinase (JAK), which is an enzyme involved in cytokine signaling. The agent is “clearly effective,” and so far the adverse effects profile seems manageable, Dr. Roy M. Fleischmann said at the annual European Congress of Rheumatology.
Because CP-690550 is a small molecule and an oral drug, it should be cheaper to make than biologic agents, and it has the potential to be easier and less expensive to use than tumor necrosis factor inhibitors, said Dr. Fleischmann, a rheumatologist at the University of Texas Southwestern Medical Center in Dallas.
“This drug has the potential to be very significant” for treating patients with rheumatoid arthritis (RA), Dr. Fleischmann said.
The study was funded by Pfizer Inc., which is developing CP-690550. Dr. Fleischmann said that he has received research support from and has been a consultant to Pfizer in developing this drug.
The study randomized patients who had active RA despite treatment with a disease-modifying antirheumatic drug either to monotherapy with one of five different dosage regimens of the JAK inhibitor (1, 3, 5, 10, or 15 mg b.i.d.), to the tumor necrosis factor inhibitor adalimumab (Humira) administered at 40 mg subcutaneously once every other week, or to placebo.
About 50 patients formed each treatment group. The primary efficacy end point was ACR 20 response after 12 weeks of treatment using a nonresponder imputation analysis. (Dropouts were considered to be nonresponders.)
ACR 20 response rates in patients who received 3, 5, 10, and 15 mg b.i.d. were all significantly increased over the placebo rate. Response rates were about 25% with placebo, 40% with adalimumab, and 45%-70% in patients on 3-15 mg b.i.d. of CP-690550. Response rates among patients on the JAK inhibitor rose in a dose-dependent way.
Patients who were placed on higher doses of the investigational drug also had significant improvements in their HAQ-DI (Health Assessment Questionnaire-Disability Index) and DAS28 (Disease Activity Score 28).
In the safety analysis, the new drug didn't produce a significant decline in hemoglobin, a significant change in blood pressure, a significant increase in serum creatinine, or any serious or opportunistic infections. The 3- to 15-mg dosages were linked with statistically significant drops in neutrophil counts. Average neutrophil levels did not fall below the normal range, however; average levels in patients on the highest doses were about 4,000/mm
Average levels of LDL cholesterol rose by 25 mg/dL in patients who were given 10-mg or 15-mg b.i.d. dosages. Serum levels of HDL cholesterol also rose by an average of 10 mg/dL in the highest-dosage groups.
Cholesterol levels don't increase in everyone, but everyone should be monitored, and those with elevated levels should be treated, Dr. Fleischmann said in an interview. “Treatment with a statin should control it.” Serum cholesterol levels in all RA patients already need monitoring because cardiovascular disease is such an important comorbidity, he added.
Based on these results and on findings in other phase I and II studies with the drug, Pfizer began a large phase III study last February, according to a company-written statement. The best candidate dosages for phase III testing are 5 mg and 10 mg b.i.d., Dr. Fleischmann said.
A flaw in the study was that the active comparator group was “suboptimal,” using adalimumab monotherapy instead of its usual combination with methotrexate, commented Dr. Ferdinand C. Breedveld, professor of rheumatology at Leiden (the Netherlands) University.
Dr. Fleischmann defended the choice, pointing out that the study was designed to test monotherapy, and that adalimumab is licensed for monotherapy by the Food and Drug Administration. He also noted that a phase III study will likely compare adalimumab plus methotrexate to CP-690550 and methotrexate in RA patients.
But Dr. Breedveld also saw potential for the JAK inhibitor if it can be proved safe and even comparable in efficacy to tumor necrosis factor inhibitors like adalimumab. “It would be easy to use and should save cost. It would be a major step in RA treatment.” Dr. Breedveld has been a consultant to Pfizer and other drug companies.
To watch a video interview with Dr. Fleischmann, go to: www.youtube.com/watch?v=g00XHsjhFS0
CP-690550 is expected to be cheaper and easier to use than TNF inhibitors, with a manageable adverse event profile, according to Dr. Roy M. Fleischmann
Source Mitchel L. Zoler/Elsevier Global Medical News