An injection of the investigational osteoarthritis drug sprifermin (Merck KgaA) into the knee joint every 6 or 12 months resulted in statistically significant improvement in cartilage thickness after 2 years compared with placebo, new research indicates.
However, the authors say, both the clinical importance and the question of whether the 2-year improvement will last 5 years are uncertain. These results are from the phase 2 FORWARD trial (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses), a dose-finding, 10-site, randomized clinical trial involving patients with symptomatic knee osteoarthritis.
"That won't be answered until the entire 5-year dataset is locked and analyzed," lead author Marc C. Hochberg, MD, MPH, the University of Maryland School of Medicine in Baltimore, told Medscape Medical News.
Findings from the original investigation by Hochberg and colleagues were published online October 8 in JAMA.
"I was very pleased with the findings," Hochberg said. "I think they are exceedingly promising."
Sprifermin, a recombinant human fibroblast growth factor 18, met the primary endpoint. Over a 2-year period, patients who received sprifermin at the higher doses experienced statistically significant thickening of the cartilage compared with patients who received saline placebo; the patients who received placebo experienced a reduction in cartilage thickness.
However, the secondary endpoint ― improvement in symptoms ― was not met.
Richard Loeser, MD, director of the University of North Carolina Thurston Arthritis Research Center in Chapel Hill, told Medscape Medical News he was excited by the fact that the drug can thicken cartilage but was disappointed that "it didn't result in any differences in terms of pain and function."
He noted that it is the first study to document a "benefit for structure in a really well-done clinical trial. That's a breakthrough."
He said the osteoarthritis community has been waiting to see whether symptoms improve following a strengthening of cartilage.
"No one knows that," he said, "because most of the pain doesn't come from cartilage. More work needs to be done to see if this treatment would benefit the other joint tissues in addition to cartilage."
Preventing cartilage loss, or increasing cartilage thickness, is among the criteria for an agent to qualify as a disease-modifying osteoarthritis drug. Current therapies mostly treat symptoms, the authors point out, not the underlying cause.
No disease-modifying osteoarthritis drugs have been approved in the United States or Europe.
No Benefit at Lower Doses
The study randomly assigned participants evenly to one of five groups. Only two groups ― those who received 100 μg every 6 months or every 12 months ― showed statistically significant improvement.
There was no significant difference for 30 μg of sprifermina recombinant human fibroblast growth factor 18 at 6 and 12 months compared with placebo.
Among 549 participants (average age, 65 years; 69% women), 474 (86.3%) completed the 2-year follow-up.
Table. Change in Femorotibial Joint Cartilage Thickness at 2 Years
| Sprifermin Dose | Change vs Placebo | Confidence Interval |
|---|---|---|
| 100 μg every 6 months | 0.05 mm | 0.03 – 0.07 mm |
| 100 μg every 12 months | 0.04 mm | 0.02 – 0.06 mm |
| 30 μg every 6 months | 0.02 mm | −0.01 to 0.04 mm |
| 30 μg every 12 months. | 0.01 mm | −0.01 to 0.03 mm |
| Placebo | (−0.02 mm) |
The secondary endpoints included 2-year improvement in symptoms such as pain, stiffness, and trouble walking, as determined on the basis of total Western Ontario and McMaster Universities Osteoarthritis Index scores. On these endpoints, the higher-dose groups did not improve significantly over the lower-dose groups or those who received placebo.
Cartilage loss in knee joints is a sign of osteoarthritis progression. It is measured by MRI or indirectly by x-ray through evidence of a reduction in joint space.
Adverse Events
Treatment-emergent adverse events were reported by more than 90% in all five groups, but Hochberg pointed out that there was no significant difference in side effects in the treatment and placebo groups.
"The only adverse event associated with the treatment are some local inflammatory responses, which were infrequent. The safety data suggest that this is well tolerated," he said.
Site investigators said no serious adverse events were considered to be related to treatment.
Post Hoc Analysis Shows Promise
Hochberg said results of a post hoc exploratory analysis, presented this year at the European League of Associations of Rheumatology, of a subgroup that had joint space narrowing of 2.5 mm to 4.5 mm in the medial compartment and moderate to severe knee pain showed a significant improvement in symptoms over 3 years compared with patients who received placebo.
He said the fact that patients were allowed to continue pain medications during this study may have made it hard to see improvement in symptoms attributable to the treatment.
Additionally, the authors write, "It is possible that using intraarticular saline injections as a control may act as an active placebo, masking symptomatic improvements associated with sprifermin in this study."
The phase 2 results leave important questions unanswered regarding benefit to patients.
"It is unknown whether increased articular cartilage thickness with sprifermin will lead to reduced risk of knee replacement, delayed time to knee replacement, or both," the authors conclude.
Hochberg said, "I'm not disappointed by the lack of so-called clinical differences."
He said the hope is that the trial will move to phase 3 on the basis of these data as well as the positive safety data of phase 1 and that those questions can be further explored.
Loeser said, "This would be far better than going and having things like platelet-rich plasma injected into your knee or stem cells injected into your knee, which lots of people are doing without any evidence that they benefit the joint tissues at all.
"At least this is evidence of something that really could benefit at least the articular cartilage," Loeser said.
The study was funded by Merck KGaA of Darmstadt, Germany, and EMD Serono Research Institute Inc (a business of Merck KGaA). Hochberg is president of Rheumcon Inc and has received consulting fees from Bioiberica SA, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Galapagos, IBSA Biotechniq SA, Novartis Pharma AG, Pfizer, Plexxikon, Samumed LLC, Theralogix LLC, and TissueGene Inc. A full listing of the authors' relevant financial relationships is included in the original article. Loeser has disclosed no relevant financial relationships.
JAMA. Published online October 8, 2019. Abstract
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Cite this: Investigational Osteoarthritis Drug Results Mixed - Medscape - Oct 10, 2019.
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