Liposomal steroids: from the bench via pre-clinical research to clinical practice

We developed a stable formulation of PEGylated nano-liposomes (NSSL) remotely loaded with the amphipathic weak acid, steroid prodrug methylprednisolone hemi-succinate (MPS) by trans-membrane calcium acetate gradient. In several animal models of inflammatory diseases including Multiple Sclerosis, Rheumatoid arthritis, Lupus, Duchenne Muscular Dystrophy, local inflammation and Cerebral Malaria [rev. in 1] this steroidal nano-drug was highly efficacious therapeutically. The nano-scale of the liposomes (~80 nm) combined with their PEG corona promote passive targeting and drug accumulation in the diseased tissue (related to the enhanced permeability effect). Where it was, followed by slow, zero-order drug release. These explain NSSL-MPS superior therapeutic efficacy and the improvement in the inflamed tissue pathology and reduced toxicity even in long-term treatment. These advantages seem to be the cause of the unwanted immunogenicity and immunotoxicity (elicitation of anti-PEG antibodies, complement activation, Hypersensitivity Reactions = HSR and accelerated blood clearance = ABC) of systemically administered PEGylated liposomes and proteins. In vitro, NSSL-MPS demonstrated only minimal (much lower than Doxil) ability to activate the complement system (iC3b test). NSSL-MPS was administered under a compassionate approval to a 21y.o patient suffering from intra-cardiac IgG4 sclerosing disease. Steroids are considered the therapy of choice for this condition, however the steroid toxicity limits of steroids as-is was already reached without much therapeutic benefit. Liposomal MPS was administered weekly over 2 courses (5-week and 3-week long) with escalating doses from 50 up to 300mg MPS. The patient received pre-medication aimed to reduce HSR. NSSL-MPS demonstrated efficacy in the mass size reduction and a clear trend toward decrease in IgG levels (IgG1, IgG2, IgG3 and IgG4) with no sign of toxicities, lack of HSR, no elicitation of anti-PEG antibodies, complement activation, and ABC (based on PK studies).

Our results opened the road for the clinical development of this product.

* The authors thank US-NIC-NCL team for for confirming our characterization of NSSL-MPS and with their invaluable knowledge of in vitro testing of complement activation.

[1] Turjeman K, Barenholz Y., Liposomal nano-drugs based on amphipathic weak acid steroid prodrugs for treatment of inflammatory diseases. J Drug Target. 2016 18:1-41.