A phase 2 trial of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin has shown it reduces articular cartilage loss in knee OA but the magnitude of effect is of uncertain clinical significance.
Published in JAMA, the results from 549 participants in the FORWARD trial showed that six-monthly or 12-monthly intra-articular injections of the recombinant human fibroblast growth factor 18 (rhFGF18) had a statistically significant effect on the primary end point of change in total femorotibial joint cartilage thickness at two years follow up.
In patients given the highest dose (100ug), the changes from baseline in total femorotibial joint cartilage thickness were 0.05 mm with sprifermin administered every 6 months, and 0.04 mm when given every 12 months.
There were no significant differences in cartilage thickness with lower doses of sprifermin (30ug) given at either six or 12 month intervals.
For the secondary end point of changes in total WOMAC scores there were no significant differences seen for any dose of sprifermin compared to placebo, although the study investigators noted that all patients were allowed to use pain medications .
Similarly, no significant differences were observed in mean absolute change from baseline for the WOMAC pain, function, or stiffness subscale scores.
Arthralgia was the most common adverse effect seen in the trial, reported by 40-45% patients in all groups including the placebo group.
The study investigators said the effect of sprifermin to increase cartilage thickness in people with knee osteoarthritis was supported by significant reductions in lateral minimum joint space width narrowing vs placebo.
But they said the clinical significance of the effect remains to be determined, in the context of other studies showing that without treatment the total femorotibial cartilage thickness change in knee OA patients over 2 years was −0.07 mm.
The durability of response also was uncertain, said study lead author Dr Marc Hochberg, of the University of Maryland School of Medicine.
The sponsor of the study, Merck, said in a statement that further results from the FORWARD trial are to be presented at the upcoming 2019 American College of Rheumatology (ACR) Annual Meeting on November 12.
A post-hoc, exploratory analysis evaluated cartilage thickness changes and symptomatic outcomes in a subgroup of OA patients with both greater pain and thinner cartilage, deemed at higher risk of further structural and symptomatic progression.
In this group, WOMAC score improvements increased over the three-year period and were significant at 18 months after last injection in favour of sprifermin compared to placebo (mean difference in WOMAC pain score for sprifermin 100µg every six months versus placebo: -8.75).
“These results support further investigation of sprifermin as a potential OA treatment for higher-risk patient populations,” the company said.
In a recent review article on DMOADs, Professor David Hunter of the Royal North Shore Hospital, Sydney, said other agents in development include gene therapies such as TissueGene-C (TG-C), Wnt/ß-catenin signalling pathway inhibitors, recombinant human PTH teriparatide, the interleukin-1 inhibitor diacerein and the cathepsin K inhibitor MIV-71.