EP-104IAR (Long-Acting Intra-Articular Injection of Fluticasone Propionate): Results from a Phase 2 Randomized, Double-blind, Vehicle-Controlled Trial in 318 Subjects with Knee Osteoarthritis

Eupraxia previously presented results from non-clinical studies evaluating PK and local joint safety in beagle dogs (Webb et al, 2018). These data indicated that the prolonged local residence time of EP-104IAR had no impact on cartilage health and supported initiation of clinical development.  Safety and PK data from a Phase 1 trial in 32 OA knee subjects were consistent with nonclinical findings.

Here we report primary and secondary efficacy analysis results as well as safety data from a Phase 2, randomized, double-blind, vehicle-controlled parallel-group trial evaluating the efficacy of EP-104IAR in 318 subjects with knee OA (NCT04120402). We will discuss whether pain severity had an impact on the outcome measures based on responder analyses performed in the sub-set of subjects with moderate OA pain at baseline.

Method:

Subjects were randomized 1:1 to a single IA dose of EP-104IAR 25 mg, or vehicle and followed for 24 weeks. Males and females, ≥40 years, with a diagnosis of primary knee OA, Kellgren-Lawrence Grade 2-3 and symptoms for ≥ 6 months were enrolled.

A 2-week baseline period was used to determine baseline/qualifying pain; defined as weekly WOMAC® Pain scores ≥ 4.0 to ≤9.0 (out of 10) which did not vary by >3 points. Bilateral subjects required Pain to be ≤6.0 in their non-Index knee. Following dosing, subjects recorded weekly WOMAC pain and monthly WOMAC total measurements. Safety assessments included adverse events (AEs), vital signs, laboratory evaluations (including cortisol, ACTH stimulation testing), and knee examinations.

The primary endpoint was the difference in change from baseline between treatments in WOMAC Pain at Week 12. A mixed-effects model for repeated measures (MMRM) was employed.  Key secondary endpoints were analyzed using analogous methods.

Results:

318 subjects were dosed (163 EP104IAR, 155 vehicle), median age = 64, 57.5% female. 68% had moderate OA (definition: baseline WOMAC Pain 3.5-6.5).

EP-104IAR was significantly different to vehicle in WOMAC Pain at Week 12 (least-squares mean change from baseline: -2.89 EP-104IAR -2.23 vehicle; p=0.004). This difference persisted until Week 14 in the full population and until Week 17 in subjects with moderate pain. A similar pattern was observed in other pre-specified analyses in moderate subjects. 

Most AEs were mild/moderate. There were no EP-104IAR-related serious AEs.  No subjects developed adrenal insufficiency (assessed by ACTH stimulation-testing and clinical symptoms).

 

Conclusions: In the overall study population, a single dose of EP-104IAR provided clinically and statistically significant pain relief for 14 weeks compared to vehicle. This is longer than all currently approved immediate- and extended-release corticosteroids.

Furthermore, in subjects with moderate OA pain, the duration of significant pain-relief persisted for 17 weeks. Responder analyses in moderate OA subjects demonstrated that clinically meaningful differences persisted for the majority of the study (the percentage of OMERACT-OARSI strict responders was statistically different until Week 22 and the percentage of subjects who achieved a decrease in WOMAC Pain to ≤1 was statistically different until Week 24). This suggests EP‑104IAR could offer clinically meaningful benefits for substantially longer than any other currently marketed corticosteroids, providing a promising treatment for the currently under-served moderate knee OA patient population.

Regardless of baseline OA pain, EP-104IAR was well-tolerated in all subjects and resulted in low but sustained plasma levels for the entire 24-week study period. These results demonstrate that Eupraxia’s delivery technology offers stable drug delivery over an extended period, with the potential for a reduced systemic side-effect profile compared to other IA corticosteroids.

The safety and efficacy of EP-104IAR will be further evaluated in Phase 3 trials.

References: Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res. 2020 Feb;72(2):149-62.

Juni, P. et al., 2015. Intra-articular corticosteroid for knee osteoarthritis (Review). Cochrane Database of Systematic Reviews, Issue 10.

Webb, M., Price, J., Price, N., Luettgen, S., & Malone, A. 2018. PAINWeek Abstract Book. Postgrad Med. 2018;130(sup1):1–91.