BERLIN – Two new Janus kinase inhibitor drugs have shown good safety and efficacy for clinical rheumatoid arthritis, following in the footsteps of the JAK inhibitor tofacitinib, researchers reported at the annual European Congress of Rheumatology.
Baricitinib showed safety and promising efficacy in a multicenter, phase 2 study with 301 rheumatoid arthritis (RA) patients, said Dr. Edward Keystone, professor of medicine at the University of Toronto. And in results from a second study, GLPG0634 showed good safety and efficacy in a placebo-controlled, early phase 2 study with 36 RA patients. In both cases the results should propel these drugs into wider clinical testing.
Mitchel Zoler/IMNG Medical Media
Dr. Edward Keystone
The results also hinted that different JAK inhibitors may produce somewhat different clinical effects depending on exactly which Janus kinases they inhibit. Tofacitinib blocks all four JAKs, but its effect seems strongest on JAK3. Baricitinib specifically inhibits JAK1 and JAK2, while GLPG0634 specifically inhibits only JAK1, said speakers at the meeting.
"JAK selectivity makes a difference," said Dr. Frédéric Vanhoutte, lead investigator of the GLPG0634 study and a staff member at Galapagos, the Belgium drug company developing the agent.
The baricitinib study randomized patients on methotrexate to any of four drug dosages, given as a single, daily oral treatment, or placebo and looked at safety and efficacy after 12 weeks on treatment. At 12 weeks 76% of patients treated with either of the two highest baricitinib dosages (4 mg or 8 mg daily) had an American College of Rheumatology (ACR) 20 response, compared with 41% of the placebo patients, a statistically significant difference for the study’s primary end point, reported Dr. Keystone, who also directs the center for arthritis and autoimmune disease at Mount Sinai Hospital in Toronto. The incidence of remission at 12 weeks, based on a simple disease activity index (SDAI) score of 3.3 or less, occurred in 18% of patients on the 4-mg/day baricitinib plus methotrexate regimen compared with 1% of patients on methotrexate and placebo; 8% of patients who received 8 mg daily also achieved remission.
For safety, baricitinib appeared well tolerated, with an adverse event profile similar to the placebo arm. The results showed dose-dependent reductions in hemoglobin and neutrophils, and an increased level of low density lipoprotein cholesterol, but effects that surpassed the placebo arm primarily occurred in patients who received 8 mg of the drug daily. "The reductions in hemoglobin and neutrophils were of the same order of magnitude as with tofacitinib," Dr. Keystone said in an interview. "Some had thought that baricitinib might be more inhibitory to the hematologic system than tofacitinib, but it wasn’t very."
The study of 36 RA patients on methotrexate who received either of two dosages of the oral JAK 1 inhibitor GLPG0634 or placebo ran for 4 weeks at one center in Europe. The 100-mg b.i.d. dosage led to 92% of patients meeting ACR 20 criteria after 4 weeks, compared with 75% of patients who received 200 mg once daily and 33% among placebo patients, reported Dr. Vanhoutte. Treatment with the JAK1 inhibitor also led to higher remission rates and drops in C-reactive protein.
For safety, the JAK1 inhibitor actually boosted hemoglobin levels, led to no rise in LDL cholesterol or liver enzymes, and produced a "modest" reduction in neutrophils and platelets. Dr. Vanhoutte called the overall safety results "very encouraging."
The baricitinib trial was sponsored by Lilly, the company developing the drug. Dr. Keystone said that he has received research support from Lilly, and that he has received research support and has served as a consultant for several other drug companies. The GLPG0634 study was sponsored by Galapagos. Dr. Vanhoutte said that he is an employee of Galapagos.