VIENNA — The hypothesis that pivotal clinical trials for osteoarthritis (OA)-modifying therapies are not using appropriate designs or endpoints appears to be consistent with the recent failure of the phase 3 trial of the investigational agent lorecivivint, according to experts tackling this issue.
For the elusive target of disease-modifying OA drugs (DMOADs), “there have been a lot of developments in the last few years but so far a lot of disappointments,” said Francis Berenbaum, MD, PhD, head of the department of rheumatology, Saint-Antoine Hospital, Paris, France.
Disagreement on the target most likely to favorably alter the natural history of disease might be the key issue. Dr. Berenbaum considers it essential to determine which changes in the joint signify a favorable drug effect and will lead to what regulatory agencies consider a clinically meaningful benefit. These include improved function and long-term preservation of the joint, as well as symptom control.
Ted Bosworth/Medscape Medical News
Dr. Francis Berenbaum
Of primary targets to modify the course of OA, cartilage is not one of them, according to Dr. Berenbaum, who spoke in a session on DMOADs and regenerative OA therapies at the annual European Congress of Rheumatology.
OA Is Not a Cartilage-Only Disease
“There is now a big consensus that osteoarthritis is not a cartilage-only disease,” he said. Rather, he addressed the inadequate appreciation of the “whole joint” pathology that underlies OA. He called for a fundamental “paradigm change” to work toward a disease-modifying effect that produces benefit on a hard endpoint.
There are multiple steps needed to work toward this goal after a consensus is reached on a meaningful surrogate endpoint, Dr. Berenbaum said. While symptom reduction is a good start, he called for evidence of disease attenuation or a regenerative effect on an important surrogate such as improved integrity of synovial tissue and improved bone health. Such surrogates are necessary to guide DMOAD development but not sufficient. The proof that a therapy is a DMOAD depends on a favorable effect on a hard endpoint. In the case of the knee, freedom from joint replacement is an example, Dr. Berenbaum said.
Philip G. Conaghan, MBBS, PhD, director of rheumatic and musculoskeletal medicine, University of Leeds, England, agreed with this general premise. Speaking just before Dr. Berenbaum in the same session, Dr. Conaghan traced this history of the effort to create DMOADs and updated those in clinical trials.
Dr. Philip G. Conaghan
In his talk, he listed some of the many disappointments, including those which have targeted cartilage thickness, before updating the numerous ongoing development programs. There are many targets that appear viable, but none are in final stages of testing.
In remarks to this news organization, he said he generally agreed with Dr. Berenbaum about the need for greater rigor for developing drugs to meet regulatory criteria for disease-modifying effects.
Of the drugs he reviewed, Dr. Conaghan identified lorecivivint, an intra-articular CLK/DYRK inhibitor that’s thought to modulate Wnt and inflammatory pathways, as the only drug with DMOAD potential to go to a multicenter phase 3 trial so far. The drug’s negative outcome in phase 3 was particularly disappointing after the substantial promise shown in a phase 2b study published in 2021.
In the phase 3 study, lorecivivint, relative to placebo, did not achieve a significant improvement in the primary endpoint of improved medial joint space width (JSW) in the target knee as assessed at the end of a 48-week, double-blind trial.