OP0247 EFFICACY OF A NOVEL LONG-ACTING FLUTICASONE PROPIONATE INTRA ARTICULAR INJECTION (EP-104IAR) IN KNEE OSTEOARTHRITIS: PER-PROTOCOL ANALYSIS OF A RANDOMISED, DOUBLE-BLIND, PHASE 2 TRIAL OF EP-104IAR VS VEHICLE PLACEBO (SPRINGBOARD)

Background:

Global prevalence of knee osteoarthritis (KOA) was estimated at 365 million in 2019. Treatment with available IA corticosteroids has limited duration of effect and risk of side effects. EP-104IAR is a long-acting fluticasone propionate (FP) IA injection employing novel controlled-release technology designed to maximize IA residence time and efficacy while limiting systemic exposure.

Objectives:

Here we present per-protocol (PP) efficacy analyses of the SPRINGBOARD study (NCT04120402).

Methods:

318 subjects with KOA pain were randomized 1:1 to receive a single IA dose of EP-104IAR 25mg (n=163), or vehicle (n=155) in one index knee and were followed for 24 weeks. The study enrolled males and females, ≥40 years, diagnosed with primary KOA with a Kellgren-Lawrence Grade 2 or 3, OA symptoms for ≥6 months and weekly WOMAC® Pain scores ≥4.0 to ≤9.0 (out of 10) which did not vary by >3 points within the screening period. 256 subjects (132 EP-104IAR, 124 vehicle) were included in the PP population (PPP) described here. Of the 62 subjects excluded from the PPP, 25 were due to prohibited pain medications such as paracetamol dose >3,000mg/day, any NSAIDs or opioids. Other reasons for exclusion included missed/out-of-window assessments, eligibility deviations, and dosing deviations. WOMAC Pain, Stiffness and Function (0-10 scales) were collected for the index knee weekly (pain) and monthly (stiffness/function) via e-diary. Baseline was the average of 3 pain scores during the 2-week baseline period or a single pre-dose score for stiffness and function. A mixed-effects model for repeated measures (MMRM) was fit to the change from baseline. From this model, mean efficacy curves were estimated for each treatment and sidedness combination; and treatment contrasts estimated for each week. The small amount of missing data was accounted for by the MMRM model; as such, no additional imputation was performed. FP was quantified in peripheral blood collected pre-dose, 2 hours post-dose and during study weeks 1, 2, 4, 8, 12, 18 and 24.

Results:

Least-squares mean (LSM) change from baseline for WOMAC total score and subscales are shown in Figure 1. LSM change from baseline to Week 12 was significantly better for EP-104IAR vs vehicle for each of the WOMAC subscales: pain (-2.97 vs -2.24; p=0.003), function (-2.64 vs -1.99; p=0.005) and stiffness (-2.85 vs -2.05; p=0.001). Stiffness and function maintained p<0.05 to the Week 20 assessment and pain to Week 15. Total WOMAC score at Week 12 was significantly better for EP-104IAR vs vehicle (-2.79 vs -2.07; p=0.002) and this difference persisted with p<0.05 to the Week 20 assessment. The proportion of OMERACT-OARSI strict pain responders, defined as ≥50% decrease from baseline with absolute decrease ≥2 on the 10-point WOMAC pain scale was calculated for each week. The proportion of strict pain responders at Week 12 was 55.3% for EP-104IAR vs 39.5% for vehicle (p=0.013). This difference persisted with p<0.05 to the Week 15 assessment. The proportion of subjects with 70% reduction in pain score at Week 12 was 34.4% for EP-104IAR vs 14.6% for vehicle (p<0.001). This difference persisted with p<0.05 to the Week 21 assessment at all but one timepoint. The observed C_max of FP in the full study population (n=163) was 90pg/mL with a terminal phase half-life of 18-20 weeks.

Conclusion:

In this PP analysis, a single dose of EP-104IAR provided statistically and clinically meaningful improvement in WOMAC scores for up to 20 weeks compared to vehicle, with greater separation between treatment arms than in preliminary intent-to-treat analyses¹. The PP analysis demonstrated duration of effect is longer than the currently approved immediate- and extended-release corticosteroids. This analysis and previously reported safety data reinforces that EP-104IAR has potential for sustained clinically meaningful benefit in KOA, addressing a significant unmet need. Phase 3 trials are now planned.

REFERENCES:

[1] Arthritis Rheumatol 2023;75,S9:5200.

Acknowledgements:

NIL.

Disclosure of Interests:

Amanda Malone Eupraxia Pharmaceuticals minor shareholder, Eupraxia Pharmaceuticals full-time employee, James Helliwell Eupraxia Pharmaceuticals minor shareholder, Eupraxia Pharmaceuticals full-time employee, Mark Kowalski Eupraxia Pharmaceuticals full-time employee, Helene Rovsing Full time employee at Sanos Clinic, Sidsel Lyngaard Boll Full time employee at Sanos Clinic, Kathrine Moriat Full time employee at Sanos Clinic, Asger R. Bihlet NBCD A/S minor shareholder, NBCD A/S Full-time employee, Claire Prener Miller NBCD A/S Full-time employee, Alejandro Castillo Mondragon NBCD A/S Full-time employee, Yanqi Li NBCD A/S minor shareholder, NBCD A/S Full-time employee, Christine Dobek Eupraxia Pharmaceuticals minor shareholder, Eupraxia Pharmaceuticals full-time employee, Vik Peck Eupraxia Pharmaceuticals minor shareholder, Eupraxia Pharmaceuticals full time employee, Michael Wilmink Eupraxia Pharmaceuticals minor shareholder and member of Board of Directors, Lee Simon Paid consultant for Pharmaceutical drug development, Philip G. Conaghan AbbVie, Eli Lilly, Novartis, AbbVie, BMS, Eli Lilly, Galapagos, Genascence, GSK, Grunenthal, Janssen, Levicept, Novartis, Stryker, Takeda, TrialSpark.