Wednesday, May 17, 2017

Fulranumab in Knee or Hip Osteoarthritis

I have been quite surprised to read this morning about fulranumab in knee and hip osteoarthritis. Rheumatology Network referred to a study on fulranomab in osteoarthritis pain [1]. Fulranomab is a monoclonal antibody that selectively targets nerve growth factor (NGF). It targets NGF like tanezumab [2], on which we didn’t hear much after the US FDA had imposed a partial clinical hold on studies due to unexpected adverse events. The point had been osteonecrosis [ON], but later this serious adverse event had been “downgraded” to rapid progression osteoarthritis [3]: “Despite initial reports, tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA [rapid progression osteoarthritis].”

But let’s come to the study by P. Sanga and colleagues [4]: “Long-Term Safety and Efficacy of Fulranumab in Patients With Moderate-to-Severe Osteoarthritis Pain: A Phase II Randomized, Double-Blind, Placebo-Controlled Extension Study”. The authors concluded: “Long-term treatment with fulranumab was generally well-tolerated and efficacious. RPOA was observed as a safety signal. Future studies are warranted to demonstrate whether the risk of RPOA can be reduced in patients taking fulranumab.” We talk about a phase II double-blind, placebo-controlled extension study of 401 patients. “Overall, 81 joint replacements were performed in 71 patients (8 [11%] receiving placebo and 63 [89%] receiving fulranumab); 15 patients (21%) had rapid progression of OA (RPOA).” I don’t read this as “long-term treatment with fulranumab was generally well-tolerated and efficacious.” I read the results as if you receive fulranumab you have a higher chance for joint replacement. Maybe one of the authors could clarify this discrepancy.

I have a problem with MABs like tanezumab, fasinumab or fulranumab in osteoarthritis as pain and not reversing the course of osteoarthritis is addressed.

Adisinsight noted as most recent event: “24 Jun 2016 Takeda terminates its licence for fulranumab in Japan” (25 Mar 2017) [5].
John Carroll had written an article last year: “That blockbuster anti-NGF pain drug fulranumab? J&J doesn't want it anymore” [6]. Last year J&J had decided to hand back fulranumab to Amgen. The reason given: “This decision was based on strategic portfolio prioritization and was not based on any emerging safety concerns from the Phase 3 clinical studies with fulranumab”. I can understand this very well.

If we look at fulranumab, we should also look at tanezumab and fasinumab. A metaanalysis for tanezumab has been punblished by Shun-Li Kan and colleagues last year [7]. Conclusion: “Tanezumab can alleviate pain and improve function for patients with OA of the knee. However, considering the limited number of studies, this conclusion should be interpreted cautiously and more clinical randomized controlled trials are needed to verify the efficacy and safety of tanezumab for OA of the knee.” Last year “the FDA (U.S. Food and Drug Administration) had placed the Phase 2 study for fasinumab for the indication of osteoarthritis pain and chronic back pain on clinical hold” [8].

One unmet need for the treatment of osteoarthritis is a safe and effective pain medication. I don’t see this need being met by anti-NGF-MABs like furanumab, tanezumab or fasinumab. Moreover these drugs do not seem to lead to a better course of osteoarthritis degenerating joints.



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