Recombinant Growth Factor Reduced Cartilage Loss in Knee OA

Janis C. Kelly

May 07, 2014

Recombinant human fibroblast growth factor 18 (rhFGF18) (Sprifermin, Merck Serono SA) slowed cartilage loss in some parts of the arthritic knee, according to a study published online April 16 in Arthritis & Rheumatology.

L. Stefan Lohmander, MD, PhD, senior professor of orthopedics, Lund University Hospital, Sweden; professor, Research Unit for Musculoskeletal Function and Physiotherapy and Department of Orthopedics and Traumatology, University of Southern Denmark, Odense; and editor-in-chief of Osteoarthritis and Cartilage, and colleagues conducted the company-sponsored study.

Recombinant human fibroblast growth factor 18 binds to and activates fibroblast growth factor receptor 3 (FGFR3) receptors in cartilage, which might stimulate chondrogenesis and cartilage repair, slowing the natural course of osteoarthritis (OA).

However, at 12 months, there was no significant difference in central medial femorotibial compartment (cMFTC) cartilage loss between patients with knee OA treated with placebo and those treated with any of 3 doses of rhFGF18, which was the primary endpoint of the trial.

Patients treated with rhFGF18 lost significantly less cartilage in the total MFTC and in the lateral MFTC than those who received placebo. Treatment was also associated with significant, dose-dependent reductions in loss of joint space width in the lateral MFTC.

Dr. Lohmander told Medscape Medical News, "In [OA] development, there is an interaction between 'systemic' factors and the local biomechanical environment. In some patients, the local biomechanical environment may 'overpower' the body's inherent repair mechanisms, as well as any pharmacological attempts to enhance repair, such as [rhFGF18]."

Multiple Dosing Regimens Tested

The proof-of-concept double-blind placebo-controlled randomized, multicenter trial enrolled 192 patients with symptomatic knee OA. Of these, 180 completed the trial and 168 were evaluated for the primary efficacy endpoint (change in cartilage thickness in the cMFTC at 6 and 12 months, measured by quantitative magnetic resonance imaging [MRI]).

Eligibility criteria included age 40 years or older, 6 months or more of established primary femorotibial knee OA by American College of Rheumatology criteria, stage 2 or 3 radiographic disease by Kellgren-Lawrence grading, need for ongoing analgesics, and total Western Ontario McMaster Universities (WOMAC) OA index score of 24 to 72 (mild to severe symptoms). Exclusion criteria included treatment with intra-articular steroids or a hyaluronic acid derivative within 3 months of baseline.

Researchers evaluated rhFGF18 first as a single injection and then in a multiple-dosing regimen, and reviewed safety at each new single-dose level before progression to the next level. Patients in the multidose regimen were randomly assigned 3:1 in 6 cohorts to receive rhFGF18 (10, 30, or 100 μg) or placebo intra-articular injections, using the lateral patellar route. Patients received 3 weekly injections in weeks 0 to 2 and 3 more injections during weeks 13 to 15, and then were followed up to week 52.

The primary safety endpoints were local and systemic treatment-emergent adverse events, acute inflammatory reactions, and changes in blood chemistry. There were no local or systemic safety concerns in any treatment group.

The study was powered to detect a 75% reduction in loss of cMFTC cartilage thickness per year, reducing cartilage loss from an expected 0.1 mm to less than 0.025 mm/year.

Secondary efficacy endpoints included changes in cartilage thickness and volume in the total femorotibial compartment and in the medial and lateral compartments. Other secondary endpoints were changes in joint space width and changes in bone marrow lesions, cartilage, menisci, effusion, and synovitis assessed by semiquantitative MRI (modified Whole-Organ Magnetic Resonance Imaging Score [WORMS]).

The study was not designed to assess symptom efficacy, but this was routinely monitored using WOMAC scores and a 0 to 100 visual analog scale for knee pain. Patients were allowed to continue taking pain medication as needed during the trial.

Secondary Endpoints, but Not Primary Endpoint, Met

Mean cartilage thickness in the cMFTC, the primary endpoint, decreased steadily in the placebo group and was not significantly affected by any dose of rhFGF18.

At 6 months, changes from baseline in the mean cartilage thickness in the cMFTC were −0.06 mm (95% confidence interval [CI], −0.14 to 0.02 mm) in the placebo group, 0.03 mm (95% CI, −0.18 to 0.24 mm) in the 10-μg group, −0.09 mm (95% CI, −0.16 to −0.03) in the 30-μg group, and −0.01 mm (95% CI, −0.06 to 0.03) in the 100-μg group.

At 12 months, the changes found were −0.11 mm (95% CI, −0.20 to −0.02) in the placebo group, 0.02 mm (95% CI, −0.18 to 0.23) in the 10-μg group, −0.11 mm (95% CI, −0.18 to −0.03) in the 30-μg group, and −0.03 mm (95% CI, −0.11 to 0.04) in the 100-μg group.

Among the prespecified MRI secondary endpoints, treatment was associated with significantly less loss of total femorotibial and lateral femorotibial cartilage, as well as with better preservation of joint space width.

Patients showed a statistically significant dose-dependent effect on cartilage thickness change in the lateral femorotibial compartment in the overall analysis (P = .0311) and at 12 months (placebo, −0.04 mm [95% CI, −0.10 to 0.02 mm]; 10 μg, −0.02 mm [95% CI, −0.19 to 0.15 mm]; 30 μg, 0.02 mm [95% CI, −0.02 to 0.05 mm]; 100 μg: 0.04 mm [95% CI, 0.01 - 0.07 mm]; P = .0072).

The researchers found no statistically significant changes in semiquantitative MRI (WORMS) parameters in the placebo or sprifermin groups and emphasized that the study was not designed to assess symptom outcomes.

"All study groups improved in symptoms over the course of the study. The difference between the 100-μg group and control at 12 months (but not other time points), albeit statistically significant, was less than what is commonly regarded as clinically important," Dr. Lohmander said.

The primary safety endpoints were local and systemic treatment-emergent adverse events, acute inflammatory reactions, and changes in blood chemistry. The researchers found no local or systemic safety concerns in any treatment group.

"The study was well-designed, given current technology and assessment methods, and very rigorously done," Garry E. Gold, MD, professor of radiology and orthopaedic surgery, Stanford School of Medicine, California, told Medscape Medical News. "The overall positive effect and positive effect in the lateral compartment are promising. Lack of an effect in the central MFTC is not surprising because OA is a regional and heterogenous disease and effects may not be confined to one small region in the knee. The global effect, in my opinion, is more powerful than the lack of change in the central MFTC." Dr. Gold was not involved in the study.

"One of the things we have learned through this study is that it is feasible to use quantitative MRI assessment of cartilage as an outcome to assess changes in joint subregions. This is important for the planning of future studies. The secondary endpoint changes were important for our improved understanding and interpretation of study results. However, at this time, the clinical importance of such structural changes cannot be assessed with certainty. The results of the study suggest that structure modification of the osteoarthritic knee may be possible, but further studies are needed to confirm and extend the present results," Dr. Lohmander said. Further rhFGF18 studies are underway in the Study to Investigate the Safety and Effectiveness of Different Doses of Sprifermin (AS902330) in Patients With Osteoarthritis of the Knee (FORWARD) phase 2 clinical trial.

The clinical trial was sponsored by Merck Serono SA. The study sponsor was involved in the study design; collection, analysis, and interpretation of data; manuscript preparation, and decision to publish. Dr. Lohmander has received consulting fees from Merck Serono, Flexion, and Ossur. Other study authors are employees or former employees of Merck Serono, have provided consulting services to Merck Serono, or have received consulting fees from Merck Serono, sanofi-aventis, or Tissue Gene. Dr. Eckstein is co-owner and chief executive officer of Chondrometrics GmbH, a company providing quantitative image analysis service to other academic researchers and the pharmaceutical industry. He has received consulting fees from Merck Serono, sanofi-aventis, and AbbVie; speaking honoraria from Medtronic and Synthes; and research grants from Merck Serono, Novartis, Stryker, Pfizer, GlaxoSmithKline, Eli Lilly, Wyeth, Centocor, Kolon, and Synarc. Dr. Gold has disclosed no relevant financial relationships.

Arthritis Rheumatol. Published online April 16, 2014. Abstract

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