In the OA pipeline
“There’s a lot of interest in DMOADs – disease-modifying osteoarthritis drugs – but not a lot of success so far,” Dr. Ruderman observed.
Case in point: intra-articular sprifermin, a recombinant human fibroblast growth factor 18. In a 549-patient, multicenter, dose-ranging study, the two highest doses achieved a modest yet statistically significant advantage over placebo in total femorotibial joint cartilage thickness on MRI at 2 years. However, the investigators added that the result was of “uncertain clinical importance,” given the lack of a difference from baseline in total Western Ontario and McMaster Universities OA Index score.
“I’m not sure this is going anywhere,” Dr. Ruderman commented.
Tanezumab, a novel subcutaneously injected monoclonal antibody directed against nerve growth factor, has drawn a lot of attention. In an initial multicenter, phase 3, randomized trial it showed what Dr. Ruderman termed “some modest benefit” on pain and function.
“Very much like everything else in OA, you see a huge placebo effect buried in there,” according to the rheumatologist.
This modest clinical benefit was accompanied by a safety signal at the higher 5-mg dose of tanezumab. Moreover, a second phase 3 trial, this one conducted in nearly 3,000 OA patients and presented at the 2019 annual meeting of the American College of Rheumatology, also raised significant safety concerns at the higher dose. And while the 2.5-mg dose was safer, it was disappointingly no more effective in terms of improvement in pain and function scores than diclofenac at 75 mg twice daily, Dr. Ruderman noted.
Dr. Fleischmann predicted that, given the enormous unmet need for new OA treatments, tanezumab at 2.5 mg will win regulatory approval, but it will be a costly niche drug reserved for the challenging subset of patients who can’t take an NSAID and are poor surgical candidates. (On March 2, 2020, Eli Lilly announced that the Food and Drug Administration had accepted its Biologics License Application for tanezumab for the treatment of chronic pain caused by moderate to severe OA.)
Intra-articular FX006, a microsphere-based, extended-release formulation of triamcinolone, outperformed conventional triamcinolone in a phase 3 clinical trial. However, the placebo-subtracted improvement in pain was modest.
“There’s some marginal benefit here, but over time I’m not sure this adds much to just straight-up triamcinolone,” Dr. Ruderman opined.
Welcome to the wild, wild West
Patients with knee OA ask Dr. Ruderman all the time about the intra-articular injections of platelet-rich plasma (PRP) or mesenchymal stem cells they’ve seen touted on the Internet. As an evidence-based physician, he’s not a fan. A meta-analysis of 14 controlled trials of PRP, none double blind, showed some benefit in terms of pain and function at 3, 6, and 12 months, with little risk of adverse events. However, PRP is being marketed with a hype and claimed efficacy out of all proportion to the actual evidence.
“It’s the wild, wild West out there,” the rheumatologist warned.
He cited a study involving a scripted survey of 179 U.S. clinics offering PRP. The mean price quoted for a unilateral knee injection in a hypothetical 52-year-old man with knee OA was $714, and it’s a cash business, since insurance companies won’t cover PRP. Out of 84 centers that were willing to share their claimed efficacy, 10 quoted 90%-100% rates of good results or symptomatic improvement, 27 claimed 80%-90% efficacy, and 29 quoted figures of 70%-80%, all of which are well above the success rates achieved in the flawed clinical trials.
As for mesenchymal stem cells, “if PRP is the wild, wild West, this is the surface of Mars,” Dr. Ruderman quipped.
These stem cell injections are neither FDA regulated nor approved. There are no barriers to setting up a mesenchymal stem cell injection center, and the number of such centers is skyrocketing. Anybody can set up a center, and there’s essentially no oversight.
“The evidence in this area is really terrible,” the rheumatologist said. He pointed to a meta-analysis of five trials, only two of which were rated by the researchers as having a low risk of bias. The conclusion: There was limited evidence of short-term benefit in pain and function, but no evidence of cartilage repair, which is the chief claimed benefit.
The same group of investigators who queried the PRP clinics also successfully contacted 273 of the proliferating U.S. centers offering direct-to-consumer mesenchymal stem cell therapy. The mean price quoted for a unilateral knee injection was a whopping $5,156, which – like PRP – isn’t covered by insurance. At the 36 clinics responding to a request for their efficacy rates, the mean claim was good results or symptomatic improvement in 82% of treated patients.
Dr. Bugbee didn’t endorse this intervention, which is increasingly popular among his fellow orthopedic surgeons.
“The regulatory pathway drives this. Mesenchymal stem cells are categorized as a minimally manipulated tissue, so the regulatory pathway is easy,” explained Dr. Bugbee. “I talk 9 out of 10 patients out of it because there’s no evidence of disease modification.”