GlaxoSmithKline has missed the primary endpoint in a phase 2 trial of rheumatoid arthritis prospect GSK3196165. The highest dose of the anti-GM-CSF antibody failed to beat the placebo on a disease activity score, but GSK plans to forge ahead with more clinical trials nonetheless.
GM-CSF is linked to the generation of pro-inflammatory cytokines, chemokines and proteases that play a role in the destruction of joints. As levels of GM-CSF are elevated in the joints of rheumatoid arthritis patients, GSK thinks targeting the inflammatory mediator could disrupt the pathways that lead to articular destruction.
The phase 2 study generated some evidence to support that hypothesis. Whether the data paint the antibody as a contender in a fiercely competitive field is another question, though.
Investigators enrolled 222 patients with moderate-to-severe rheumatoid arthritis, whose symptoms persisted despite treatment with methotrexate, and randomized them to receive one of five doses of GSK3196165 or placebo. GSK’s presentation of the top-line data focused on the 37 patients who took the highest, 180mg dose of GSK3196165.
After giving patients weekly injections for five weeks followed by shots every other week up to week 24, GSK looked at how many patients had entered remission, as defined by a DAS28(CRP) score of less than 2.6. GSK3196165 outperformed placebo numerically—16% to 3%—but the difference fell short of statistical significance. The p value came in at 0.134.
The GSK3196165 result compares unfavorably to clinical data on rival drugs, too. Last month, Gilead and Galapagos reported 30.6% of patients in a phase 3 trial of JAK1 inhibitor filgotinib achieved DAS28(CRP) < 2.6 at week 24. AbbVie has generated similar data on its JAK1 inhibitor upadacitinib.
Cross-trial comparisons are confounded by many factors—for example, Gilead gave filgotinib on top of drugs such as methotrexate—but the big difference in the proportion of patients entering clinical remissions implies GSK3196165 may struggle to compete. GSK3196165 is given by injection every other week, while the JAK1 inhibitors are daily, oral medications.
In presenting the data, GSK looked beyond the primary endpoint miss to paint a rosier picture of the outlook for GSK3196165. DAS28(CRP) scores started to fall as early as week one and the decline from baseline hit statistical significance by week 12. The trial also hit secondary endpoints, such as pain scores.
GSK CSO Hal Barron zeroed in on these positives in outlining why GSK thinks further development of GSK3196165 is warranted.
“The rapid onset and marked benefit on clinically meaningful endpoints such as pain and swollen tender joint counts, represents a potentially important advance for patients with rheumatoid arthritis who are in need of new treatment options,” Barron said in a statement.
GSK licensed the asset from MorphoSys in 2013 for €22.5 million ($25.9 million) upfront and up to €423 million in milestones. At that stage, MorphoSys had put the drug through a phase 1/2 trial in mild-to-moderate rheumatoid arthritis.