POS0106 INTRA-ARTICULAR MM-II, A NOVEL SUSPENSION OF LARGE EMPTY MULTILAMELLAR LIPOSOMES, IN PAINFUL KNEE OSTEOARTHRITIS: A 26 WEEK PHASE 2B RANDOMIZED TRIAL

Background

MM-II, a novel suspension of empty large multilamellar liposomes composed of dimyristoylphosphatidylcholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC), has demonstrated beneficial effects in OA animal models. In a prior first-in-man study, MM-II demonstrated the ability to lower pain in knee OA patients for up to 3 months.

Objectives

The aims of this phase 2b study were to determine an effective dose, the durability of response, and the safety of MM-II in patients with symptomatic knee OA.

Methods

Consented participants were enrolled in a 6-arm randomized, double-blind, placebo-controlled 26-week trial evaluating a single IA injection of MM-II at doses of 1ml, 3ml and 6ml (150mM concentration of lipids) and placebo of matching volumes. Key inclusion criteria: age ≥ 40 years, KL grades 2 or 3, ACR OA criteria, WOMAC A pain ≥2 (0-4 Likert scale), VAS ≥50 and ≤90 (100mm scale), and intolerance/inadequate response to NSAIDs or acetaminophen. Primary endpoint was change in WOMAC A pain score at week (Wk) 12; secondary endpoints included weekly average daily pain score (ADP, e-diary) at Wks 12 & 26, WOMAC A pain at 26 wks, Patient Global Assessment (PGA) and WOMAC B and C at Wks 12 & 26, and use of rescue medication. Randomization was stratified by BMI (< 30, 30 ≤BMI<35, and BMI ≥ 35) and baseline knee pain (VAS≤74, VAS≥ 75). Statistical analysis for the primary endpoint was analyzed based on FAS using a mixed model repeated measures (MMRM) with fixed effects for treatment group, visit (Wk 1-12), and treatment-by-visit interaction and covariates of site, baseline WOMAC pain, BMI and VAS groups. Subjects were included as random effects. Treatment differences were estimated using least square means (LSM) with 95% CIs. Step-down Dunnett's hierarchical testing procedure compared the active doses to 3 mL placebo to adjust for multiplicity. Confidence intervals were unadjusted.

Results

397 participants were randomized with no significant differences in baseline demographics or clinical characteristics across all treatment groups. Mean age was 62.7 (SD 8.1) years; participants were predominantly female (65.0%) and white (67.0%) with mean BMI 30.8 (SD 6.1) kg/m2. Overall, 6.8% of participants discontinued the study. The primary endpoint of WOMAC A change from baseline to Wk 12 showed LSM difference of -0.24, 95% confidence interval (CI) -0.476, -0.004, p = 0.085 for the 3ml group and -0.02, 95% CI -0.269, 0.222, p = 0.85 for the 6ml group, both vs 3ml placebo, adjusted for multiplicity. The results of the 3ml group were sustained to Wk 26. Nominal significance was seen at some time points. When comparing 3ml MM-II to the pooled placebo groups, the LSM difference in change from baseline of the WOMAC A at Wk 12 was -0.28, 95% confidence interval (CI) -0.484, -0.068, p = 0.018 adjusted for multiplicity. The LSM differences in weekly ADP scores were nominally significant at Wks 12 and 26 for the MM-II 3ml group vs 3 ml placebo: -10.9, 95% CI (-18.88, -2.83), p = 0.008 and -11.8, 95% CI (-20.19, -3.34), p =0.006, though the 6ml group was not significant (Figure 1). The changes in use of rescue medication corresponded to changes in symptoms during the trial. Treatment was well tolerated with TEAEs reported in 2.6% of MM-II and 2.9% of control participants. Injection site reactions were similar in the treatment and control groups, 1.9% and 2.9%, respectively.

Conclusion

Differences between MM-II and placebo in WOMAC A were not statistically significant at Wk 12, though WOMAC reductions were nominally significant at some time points, and when comparing 3ml MM-II to the pooled placebo groups, results were nominally significant at Wk 12. MM-II at 3ml dose demonstrated consistent and durable reduction in weekly knee ADP scores, nominally significant compared to placebo, as early as Wk 6, with efficacy maintained through Wk 26. Treatment with MM-II was well tolerated with low levels of adverse events. MMI-II may have the ability to provide durable and relevant pain relief, warranting confirmation in further clinical studies.

REFERENCES:

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Acknowledgements:

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Disclosure of Interests

Philip G Conaghan Speakers bureau: AbbVie, Novartis, Consultant of: AbbVie, AstraZeneca, Biosplice, BMS, Eli Lilly, Galapagos, Genascence, GSK, Janssen, Merck, Moebius Medical, Novartis, Pfizer, Regeneron, Stryker, and UCB, Helene Rovsing: None declared, Edith Lau: None declared, Sidsel Lyngaard Boll: None declared, Ballari Brahmachari Employee of: Sun Pharmaceutical Industries, Inc., Richard C Chou Employee of: Sun Pharmaceutical Industries, Inc., Tarini Joshi Employee of: Sun Pharmaceutical Industries, Inc., Roni Wechsler Employee of: Moebius Medical Ltd., Siu Long Yao Employee of: Sun Pharmaceutical Industries, Inc., Sveta Weiner Employee of: Sun Pharmaceutical Industries, Inc., Asger Reinstrup Bihlet Shareholder of: NBCD A/S, Employee of: NBCD A/S, Thomas Schnitzer Consultant of: AstraZeneca, Biosplice, BMS, Galapagos, Genascence, GSK, IBSA, Lilly, Merck, Moebius Medical, Paradigm, Pfizer, Regeneron, Techfields, Xalud, Grant/research support from: None personally; to my institution: Anika, KolonTissueGene, Lilly, Paradigm, Pfizer, Regeneron, Techfields, TLC.