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LAS VEGAS – The investigational agent FX006 brought improvements in pain and function in patients with knee osteoarthritis that were not only statistically significant but also clinically meaningful by three different yardsticks, according to Scott Kelley, MD.
FX006 (Zilretta) is an extended-release, microsphere-based formulation of triamcinolone acetonide for intra-articular injection now under review for marketing approval by the Food and Drug Administration, which has said it will render a decision in October, Dr. Kelley reported at the World Congress on Osteoarthritis.
He presented a post hoc pooled analysis of the 798 patients with knee OA who participated in two phase II randomized, double-blind clinical trials and in an identically designed pivotal phase III trial of a single 40-mg intra-articular injection of FX006. The three studies included 324 patients who got FX006, 212 who received a single 40-mg intra-articular injection of standard triamcinolone acetonide crystalline suspension, and 262 who got a placebo injection of 5 mL of saline.
All participants had radiographically documented symptomatic knee OA with baseline daily pain scores of 6-9 on a 0-10 scale, corresponding to pain in the moderate-to-severe range. Patients telephoned in their average daily pain scores every day during the studies, one of which lasted 12 weeks while the other two ran for 24 weeks. Patients also visited their clinician every 4 weeks for Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) assessments of pain, stiffness, and physical function.
This secondary analysis was undertaken to demonstrate that FX006 distinguishes itself from current nonsurgical treatments for knee OA, which typically achieve clinical effects that are small, transient, and not clinically relevant, Dr. Kelley said at the congress sponsored by the Osteoarthritis Research Society International.
“What’s different about this product formulation is it maintains a prolonged release of triamcinolone acetonide inside the synovial fluid. The pharmacology has demonstrated prolonged residence time in synovial fluid out to at least 12 weeks after intra-articular administration. In addition, it mitigates the peak plasma level after intra-articular administration, so it blunts the level of corticosteroid in plasma and has a lower systemic exposure over time,” he said.
The clinical relevance of the outcomes achieved in the pooled studies was assessed using three different metrics: the American Academy of Orthopaedic Surgeons (AAOS) criteria for determining whether a result represents a minimal clinically important improvement; the Outcomes Measures in Rheumatology–Osteoarthritis Research Society International (OMERACT-OARSI) “strict responder” definition; and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)–defined proportion of patients achieving substantial improvement in pain.
At the 4- and 8-week follow-up visits post injection, only the FX006 group achieved the AAOS threshold of improvement that’s deemed both statistically and clinically significant. Standard triamcinolone couldn’t reach that bar, even at week 4. This makes FX006 the first intra-articular treatment for knee OA to achieve this stringent standard for a clinically meaningful effect. By week 12, the improvement in pain in the FX006 group had slipped to the level of ‘‘statistically and possibly clinically significant.” At weeks 16-24 following a single injection, the FX006 results were no longer statistically or clinically significant.
A significantly greater percentage of the FX006 group met the OMERACT-OARSI strict responder definition of substantial pain improvement at weeks 4, 8, and 12, compared with the standard triamcinolone and placebo groups. The degree of pain improvement in the FX006 group remained superior to placebo through week 16. The OMERACT-OARSI definition of substantial improvement requires at least a 50% improvement in the WOMAC-A pain score plus an absolute improvement of 20 points or more on the WOMAC-A pain score or WOMAC-C physical function 100-point normalized scale.
Substantial clinical improvement as defined by the IMMPACT criteria requires at least a 50% improvement from baseline in the WOMAC-A pain score. Roughly 60% and 50% of the FX006 group met that standard at weeks 4 and 8, respectively, rates that were significantly higher than for standard triamcinolone. The FX006 group’s IMMPACT substantial improvement rate significantly exceeded that of placebo-treated controls throughout all 24 weeks.
These studies as well as the pooled analysis were funded by Flexion Therapeutics.
FX006 is a type of steroid for joint injection that is formulated to stay in the joint longer than typical steroids through the use of microsphere technology. Typical intra-articular steroid injections tend to provide benefit over the short term, and as described by the Cochrane review, the greatest effect is only moderate at 1-2 weeks and decreases from there, with small effects at 13 weeks and none at 26 weeks (Cochrane Database Syst Rev. 2015;10:CD005328).
As we have previously reported (Semin Arthritis Rheum. 2014;43:701-12), intra-articular corticosteroids are widely recommended by professional societies for the management of knee OA, although a specific formulation is not generally given. This compound may fill an important treatment gap by extending the efficacy of a treatment that is generally accepted as useful and safe for this common painful condition. Also, given the controversy surrounding other intra-articular therapies, it may provide a safe and effective alternative for patients who have not benefited from, or not tolerated, one or more traditional intra-articular steroid injection(s).
Amanda E. Nelson, MD, is with the division of rheumatology, allergy, and immunology and the Thurston Arthritis Research Center at the University of North Carolina, Chapel Hill. She is a consultant to GlaxoSmithKline and has received honoraria for online presentations for MedScape and QuantiaMD regarding OA treatment guidelines.
FX006 is a type of steroid for joint injection that is formulated to stay in the joint longer than typical steroids through the use of microsphere technology. Typical intra-articular steroid injections tend to provide benefit over the short term, and as described by the Cochrane review, the greatest effect is only moderate at 1-2 weeks and decreases from there, with small effects at 13 weeks and none at 26 weeks (Cochrane Database Syst Rev. 2015;10:CD005328).
As we have previously reported (Semin Arthritis Rheum. 2014;43:701-12), intra-articular corticosteroids are widely recommended by professional societies for the management of knee OA, although a specific formulation is not generally given. This compound may fill an important treatment gap by extending the efficacy of a treatment that is generally accepted as useful and safe for this common painful condition. Also, given the controversy surrounding other intra-articular therapies, it may provide a safe and effective alternative for patients who have not benefited from, or not tolerated, one or more traditional intra-articular steroid injection(s).
Amanda E. Nelson, MD, is with the division of rheumatology, allergy, and immunology and the Thurston Arthritis Research Center at the University of North Carolina, Chapel Hill. She is a consultant to GlaxoSmithKline and has received honoraria for online presentations for MedScape and QuantiaMD regarding OA treatment guidelines.
FX006 is a type of steroid for joint injection that is formulated to stay in the joint longer than typical steroids through the use of microsphere technology. Typical intra-articular steroid injections tend to provide benefit over the short term, and as described by the Cochrane review, the greatest effect is only moderate at 1-2 weeks and decreases from there, with small effects at 13 weeks and none at 26 weeks (Cochrane Database Syst Rev. 2015;10:CD005328).
As we have previously reported (Semin Arthritis Rheum. 2014;43:701-12), intra-articular corticosteroids are widely recommended by professional societies for the management of knee OA, although a specific formulation is not generally given. This compound may fill an important treatment gap by extending the efficacy of a treatment that is generally accepted as useful and safe for this common painful condition. Also, given the controversy surrounding other intra-articular therapies, it may provide a safe and effective alternative for patients who have not benefited from, or not tolerated, one or more traditional intra-articular steroid injection(s).
Amanda E. Nelson, MD, is with the division of rheumatology, allergy, and immunology and the Thurston Arthritis Research Center at the University of North Carolina, Chapel Hill. She is a consultant to GlaxoSmithKline and has received honoraria for online presentations for MedScape and QuantiaMD regarding OA treatment guidelines.
LAS VEGAS – The investigational agent FX006 brought improvements in pain and function in patients with knee osteoarthritis that were not only statistically significant but also clinically meaningful by three different yardsticks, according to Scott Kelley, MD.
FX006 (Zilretta) is an extended-release, microsphere-based formulation of triamcinolone acetonide for intra-articular injection now under review for marketing approval by the Food and Drug Administration, which has said it will render a decision in October, Dr. Kelley reported at the World Congress on Osteoarthritis.
He presented a post hoc pooled analysis of the 798 patients with knee OA who participated in two phase II randomized, double-blind clinical trials and in an identically designed pivotal phase III trial of a single 40-mg intra-articular injection of FX006. The three studies included 324 patients who got FX006, 212 who received a single 40-mg intra-articular injection of standard triamcinolone acetonide crystalline suspension, and 262 who got a placebo injection of 5 mL of saline.
All participants had radiographically documented symptomatic knee OA with baseline daily pain scores of 6-9 on a 0-10 scale, corresponding to pain in the moderate-to-severe range. Patients telephoned in their average daily pain scores every day during the studies, one of which lasted 12 weeks while the other two ran for 24 weeks. Patients also visited their clinician every 4 weeks for Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) assessments of pain, stiffness, and physical function.
This secondary analysis was undertaken to demonstrate that FX006 distinguishes itself from current nonsurgical treatments for knee OA, which typically achieve clinical effects that are small, transient, and not clinically relevant, Dr. Kelley said at the congress sponsored by the Osteoarthritis Research Society International.
“What’s different about this product formulation is it maintains a prolonged release of triamcinolone acetonide inside the synovial fluid. The pharmacology has demonstrated prolonged residence time in synovial fluid out to at least 12 weeks after intra-articular administration. In addition, it mitigates the peak plasma level after intra-articular administration, so it blunts the level of corticosteroid in plasma and has a lower systemic exposure over time,” he said.
The clinical relevance of the outcomes achieved in the pooled studies was assessed using three different metrics: the American Academy of Orthopaedic Surgeons (AAOS) criteria for determining whether a result represents a minimal clinically important improvement; the Outcomes Measures in Rheumatology–Osteoarthritis Research Society International (OMERACT-OARSI) “strict responder” definition; and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)–defined proportion of patients achieving substantial improvement in pain.
At the 4- and 8-week follow-up visits post injection, only the FX006 group achieved the AAOS threshold of improvement that’s deemed both statistically and clinically significant. Standard triamcinolone couldn’t reach that bar, even at week 4. This makes FX006 the first intra-articular treatment for knee OA to achieve this stringent standard for a clinically meaningful effect. By week 12, the improvement in pain in the FX006 group had slipped to the level of ‘‘statistically and possibly clinically significant.” At weeks 16-24 following a single injection, the FX006 results were no longer statistically or clinically significant.
A significantly greater percentage of the FX006 group met the OMERACT-OARSI strict responder definition of substantial pain improvement at weeks 4, 8, and 12, compared with the standard triamcinolone and placebo groups. The degree of pain improvement in the FX006 group remained superior to placebo through week 16. The OMERACT-OARSI definition of substantial improvement requires at least a 50% improvement in the WOMAC-A pain score plus an absolute improvement of 20 points or more on the WOMAC-A pain score or WOMAC-C physical function 100-point normalized scale.
Substantial clinical improvement as defined by the IMMPACT criteria requires at least a 50% improvement from baseline in the WOMAC-A pain score. Roughly 60% and 50% of the FX006 group met that standard at weeks 4 and 8, respectively, rates that were significantly higher than for standard triamcinolone. The FX006 group’s IMMPACT substantial improvement rate significantly exceeded that of placebo-treated controls throughout all 24 weeks.
These studies as well as the pooled analysis were funded by Flexion Therapeutics.
LAS VEGAS – The investigational agent FX006 brought improvements in pain and function in patients with knee osteoarthritis that were not only statistically significant but also clinically meaningful by three different yardsticks, according to Scott Kelley, MD.
FX006 (Zilretta) is an extended-release, microsphere-based formulation of triamcinolone acetonide for intra-articular injection now under review for marketing approval by the Food and Drug Administration, which has said it will render a decision in October, Dr. Kelley reported at the World Congress on Osteoarthritis.
He presented a post hoc pooled analysis of the 798 patients with knee OA who participated in two phase II randomized, double-blind clinical trials and in an identically designed pivotal phase III trial of a single 40-mg intra-articular injection of FX006. The three studies included 324 patients who got FX006, 212 who received a single 40-mg intra-articular injection of standard triamcinolone acetonide crystalline suspension, and 262 who got a placebo injection of 5 mL of saline.
All participants had radiographically documented symptomatic knee OA with baseline daily pain scores of 6-9 on a 0-10 scale, corresponding to pain in the moderate-to-severe range. Patients telephoned in their average daily pain scores every day during the studies, one of which lasted 12 weeks while the other two ran for 24 weeks. Patients also visited their clinician every 4 weeks for Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) assessments of pain, stiffness, and physical function.
This secondary analysis was undertaken to demonstrate that FX006 distinguishes itself from current nonsurgical treatments for knee OA, which typically achieve clinical effects that are small, transient, and not clinically relevant, Dr. Kelley said at the congress sponsored by the Osteoarthritis Research Society International.
“What’s different about this product formulation is it maintains a prolonged release of triamcinolone acetonide inside the synovial fluid. The pharmacology has demonstrated prolonged residence time in synovial fluid out to at least 12 weeks after intra-articular administration. In addition, it mitigates the peak plasma level after intra-articular administration, so it blunts the level of corticosteroid in plasma and has a lower systemic exposure over time,” he said.
The clinical relevance of the outcomes achieved in the pooled studies was assessed using three different metrics: the American Academy of Orthopaedic Surgeons (AAOS) criteria for determining whether a result represents a minimal clinically important improvement; the Outcomes Measures in Rheumatology–Osteoarthritis Research Society International (OMERACT-OARSI) “strict responder” definition; and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)–defined proportion of patients achieving substantial improvement in pain.
At the 4- and 8-week follow-up visits post injection, only the FX006 group achieved the AAOS threshold of improvement that’s deemed both statistically and clinically significant. Standard triamcinolone couldn’t reach that bar, even at week 4. This makes FX006 the first intra-articular treatment for knee OA to achieve this stringent standard for a clinically meaningful effect. By week 12, the improvement in pain in the FX006 group had slipped to the level of ‘‘statistically and possibly clinically significant.” At weeks 16-24 following a single injection, the FX006 results were no longer statistically or clinically significant.
A significantly greater percentage of the FX006 group met the OMERACT-OARSI strict responder definition of substantial pain improvement at weeks 4, 8, and 12, compared with the standard triamcinolone and placebo groups. The degree of pain improvement in the FX006 group remained superior to placebo through week 16. The OMERACT-OARSI definition of substantial improvement requires at least a 50% improvement in the WOMAC-A pain score plus an absolute improvement of 20 points or more on the WOMAC-A pain score or WOMAC-C physical function 100-point normalized scale.
Substantial clinical improvement as defined by the IMMPACT criteria requires at least a 50% improvement from baseline in the WOMAC-A pain score. Roughly 60% and 50% of the FX006 group met that standard at weeks 4 and 8, respectively, rates that were significantly higher than for standard triamcinolone. The FX006 group’s IMMPACT substantial improvement rate significantly exceeded that of placebo-treated controls throughout all 24 weeks.
These studies as well as the pooled analysis were funded by Flexion Therapeutics.
AT OARSI 2017
Key clinical point:
Major finding: The investigational extended-release formulation of triamcinolone, known as FX006 (Zilretta), is the first intra-articular treatment for knee OA to meet the American Academy of Orthopaedic Surgeons’ stringent standard for a clinically meaningful, as opposed to merely statistically significant, effect.
Data source: A post hoc pooled analysis of three randomized, double-blind clinical trials involving nearly 800 patients with knee osteoarthritis.
Disclosures: The pooled analysis was funded by Flexion Therapeutics and presented by a company officer.
