Osteoarthritis Trial Drug Seeks to Be Analgesic Alternative to Nonsteroidal Anti-inflammatory Drugs

Given the high responder rates and the favorable safety and tolerability profile demonstrated, the findings support moving KF-0210 to phase 3b randomized controlled trials, Yongqi Deng, PhD, founder and CEO of Keythera Pharmaceuticals in Suzhou, China, told attendees.

Deng told Medscape Medical News that phase 2b trials will start in October with a readout hopefully in the third quarter of 2027. Plans are for that trial to test the drug for 6 weeks in 100 patients with a positive control arm, he said.

There’s a substantial unmet medical need for addressing pain in osteoarthritis because nonsteroidal anti-inflammatory drugs (NSAIDs) only improve pain modestly and at the cost of possible gastrointestinal, cardiovascular, and renal side effects from long-term use. Also, existing medication options for managing pain also only provide a slow onset of relief, often taking days to weeks before patients experience meaningful relief, Deng said.

Deng therefore proposed the approach of targeting EP4, a receptor of prostaglandin E2 that drives inflammation and pain sensitization. Since NSAIDs work by inhibiting cyclooxygenase enzymes upstream of prostaglandins, they result in global prostaglandin suppression, the activity that’s associated with the gastrointestinal, cardiovascular, and renal risks of NSAIDs.

KF-0210 overcomes that limitation with its selective EP4 blockade, preserving protective prostaglandins and potentially avoiding the adverse effects seen with global prostaglandin suppression, Deng explained; and its analgesic properties have been shown in rat models.

This study enrolled 16 patients, aged 49-74, who had knee osteoarthritis with Kellgren-Lawrence grades between II and IV. The patients were an average age of 63 years and had an average BMI of 27.5. About a third had Kellgren-Lawrence grade II (31%), a third had grade IV (31%), and the remaining 38% had grade III.

At baseline, their median Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score (scale 0-50) was 29.5, their median stiffness score (scale 0-18) was 12, their physical function score (scale 0-170) was 102.5, and their total WOMAC score (scale 0-240) was 142.5.

Eight participants were randomly assigned to take 150 mg, and eight took 300 mg of KF-0210 once daily for 3 weeks. The study evaluated only patients’ knees that had a baseline WOMAC pain score of at least 20, which included 13 knees in the 150-mg group and 14 knees in the 300-mg group.

The researchers assessed participants’ pain on days 8, 15, and 22. At 22 days, participants’ pain score had improved by 76.6% in the 150-mg group and 86.7% in the 300-mg group. Similarly, the stiffness score improved by 75.5% and 83.6%, the function score improved by 68.9% and 87.3%, and the total score improved by 71.2% and 87.1% in the 150-mg and 300-mg groups, respectively.

These improvements are notably higher than the 30%-40% improvement typically seen in WOMAC scores with published studies of NSAIDs, such as after 4 weeks of celecoxib 200 mg daily, Deng said.

Responder rates were also high, with all patients meeting the response threshold of at least 50% pain score improvement by day 22, and 60%-80% of patients meeting the threshold of at least 70% improvement.

The most commonly reported adverse events were abdominal pain, creatinine increase, and reductions in neutrophils or white blood cell count. No serious or grade 3 treatment-emergent adverse events occurred, no deaths occurred, and no adverse events led to discontinuing treatment.

‘A Really Promising Therapy’

Mick Jurynec, PhD, an associate professor of orthopedic surgery at the University of Utah, Salt Lake City, said in an interview he was impressed with how much more effective this agent was compared to NSAIDs.

“We all know NSAIDs have potentially really bad long-term side effects, and the fact that [KF-0210] had such a dramatic effect was pretty surprising to me when you’re only targeting one of these four receptors,” Jurynec said. During his presentation, Deng explained that, based on genetic evidence in a mouse model, the majority of analgesic effects seen from NSAIDs go through that receptor.

Jurynec also appreciated that the primary focus of this drug was on pain relief. “We often look at structural damage, but we know that there’s a high discordance between having structural or x-ray evidence of osteoarthritis and actually having pain symptoms, so there’s been a real focus over the past several years on trying to find drugs that modulate pain,” Jurynec said.

“We need to deal with the pain because if you can get people moving again, that’s going to be a huge improvement,” he said. “I think this is a really promising therapy, especially if there’s minimal side effects.”