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Background: MM-II is a dispersion of empty large multilamellar liposomes composed of two phosphatidylcholine-based phospholipids, dimyristoyl phosphatidylcholine (DMPC) and dipalmitoyl phosphatidylcholine (DPPC), for intraarticular (IA) injection, under development for treatment of osteoarthritic pain. In a recently completed large global Phase IIb clinical study (NCT04506463), MM-II was shown to reduce knee pain for up to 26 weeks following a single injection and was recently granted a fast-track designation by the US FDA. Previously reported nonclinical studies have demonstrated that MM-II coats cartilage and provides boundary lubrication, as well as reduces cartilage degeneration in-vivo in a rat OA model. A single dose of MM-II in both dogs and rabbits was previously found to be safe and with no adverse events and with a No Observed Adverse Effect Level (NOAEL) of the highest dose employed in the study (66 mg/kg and 59 mg/kg for rabbits and dogs respectively).
Objectives: To support repeat dosing in human subjects, the purpose of this study was to evaluate the repeated dose toxicity of MM-II, when administered via intra-articular (IA) injection into the stifle joint of New Zealand White (NZW) rabbits every three months for a total of 4 injection cycles.
Methods: In this GLP compliant study, NZW rabbits were administered with repeated IA injections of MM-II carrier buffer (placebo), saline, and MM-II at low dose (17.9 mg/kg/dosing cycle), and high dose (35.7 mg/kg/dosing cycle)in 4 dosing cycles, each 3 months apart. Animals were assessed post final dose of the last cycle, at 4 days (Interim), 3 months (Terminal), or 4 months (Recovery). Assessment of toxicity was based on mortality, clinical observations, body weight change, food consumption, urinalysis, ophthalmic observations, and clinical and anatomic pathology. As part of this study, blood samples were collected for toxicokinetic (TK) evaluation and synovial fluid samples were collected for clinical pathology evaluations.
Results: No MM-II-related mortality was identified. No MM-II-related clinical observations were noted including: effects on body weight or qualitative food consumption, findings during ophthalmic examinations, effects on hematology, coagulation, clinical chemistry, urinalysis test results, organ weight effects or macroscopic findings. There were no test article related effects observed among clinical pathology endpoints in any treatment group at any timepoint, even though the high dose employed in the study provided a 39-fold safety margin as compared to the human dose. Administration of MM-II at low and high doses once every three months for a total of 4 dose cycles resulted in non-adverse microscopic findings of infiltration of foamy macrophages in the synovial membrane at the interim necropsy. This finding was not observed at the terminal or recovery necropsy phases and therefore is considered transient.
For the TK assessment, partial AUC0-144h and full cycle 3 months AUC0-2160h for each 90 day cycle was used. After MM-II administration, DPPC exposure, as assessed by mean AUC0-144h and AUC0-2160h, was similar to endogenous baseline levels, as well as to the levels in the placebo and saline control groups. For DMPC, in both the partial AUC0-144h or the AUC0-2160h, exposure was higher than its baseline levels, which were extremely low (Cmax of 3.193 ng/ml). There was no dose proportionality between the low and high dose and no accumulation after subsequent injection cycles.
Conclusion: MM-II related findings were limited to a reversible, non-adverse microscopic finding at the interim necropsy. NOAEL was determined as 35.7 mg/kg/dose cycle, once every three months for a total of 4 dose cycles. Toxicokinetic findings indicated that DMPC exposure appears to be transiently impacted by MM-II administration, with no accumulation between the dosing cycles. DPPC exposure was not impacted by MM-II administration. The increase in DMPC levels post injection are attributed to the remarkably low baseline levels of DMPC in rabbits and this increase was not observed in humans during our Phase IIb trial, where no increase in systemic exposure to DMPC or DPPC was observed following a single injection of up to 6mL MMII. This study found MM-II to be safe for repeated administration every 3 months, with no adverse events and with a NOAEL of highest dose employed in the study and supports clinical studies with a repeat dosing regimen.
REFERENCES: NIL.
Acknowledgements: NIL.
Disclosure of Interests: Gadi Sarfati GS was an employee of Moebius Medical at the time the work was done, Currently a consultant, Roni Wechsler Holds options from Moebius Medical, Current employee of Moebius Medical, Was a consultant of Moebius Medical before becoming an employee, Shahnaz Akhtar An employee of Sun Pharma Advanced Research Company Limited.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (