Model STAR-LLD in MM - Two Continuous Delivery Systems: Subcutaneous and Transdermal
STAR-LLD is in development in two continuous delivery systems: subcutaneous and transdermal. STAR-LLD is in development for new multiple myeloma indications for lenalidomide and achievement of superiority versus oral lenalidomide in maintenance treatment of multiple myeloma. The STAR-LLD delivery system is expected to provide significant reductions in discontinuations and treatment abandonment by reducing area under the curve (AUC) by more than 50%+. Lenalidomide is standard of care in multiple myeloma but can have poor tolerability from dose-dependent side effects. Up to 30% of multiple myeloma maintenance patients do not respond to first-line maintenance treatment with lenalidomide (LLD-intolerant due to myelosuppression, adverse events). Flattening the plasma concentration curve by reducing the Cmax and increasing the Cmin during a dose interval, continuous delivery is expected to improve tolerability.
Immunomodulatory drugs (IMiDs) are the mainstay of early treatment in a number of hematologic malignancies – such as multiple myeloma and lymphomas. The primary first line agent, Revlimid® (lenalidomide), dominates the IMiD market in the US with global revenues expected to reach $ 12 billion in 2020.
STAR-LLD uses a novel treatment modality of continuous delivery of low-dose lenalidomide. The use of continuous delivery of lenalidomide allows for lower peaks and higher troughs which provide therapeutic blood levels for the entirety of the dosing interval whereas once-daily oral dosing is associated with sub-therapeutic blood levels of lenalidomide during each days’ dosing. Importantly, the total daily exposure is 55-70% lower than once-daily oral administration with a resultant AUC which is similarly lower than oral therapy. The expected result of this “flattening of the curve” of the blood levels is better tolerability through lower exposure and improved efficacy through continuous maintenance of the minimum immunomodulatory concentration of the treatment interval.
Starton conducted a proof of concept study in a mouse model, in the study the STAR-LLD continuous infusion displayed superior efficacy versus lenalidomide standard of care: tumor volume increase at day 29 was 483% with standard of care versus an -81% reduction in tumor volume in the STAR-LLD group. Progression-free survival was also significantly increased in the continuous infusion group, STAR-LLD had the longest survival with two animals surviving to 100 days, where all animals treated with lenalidomide standard of care had failed treatment by day 52.
A GLP continuous subcutaneous infusion tolerability study of lenalidomide in mice assessed chronic toxicology of STAR-LLD. Key tolerability and hematology parameters were assessed over a 28 day period. At day 28 the total white blood cell, neutrophil, and lymphocyte counts showed no significant difference between the continuous administration of lenalidomide (STAR-LLD, Group 2 and 3) and vehicle treated mice (group 1). Platelets and all other differentials were not different than those observed in sham-treated animals (Group 1).
These preliminary data support the premise that the administration of a continuous, lower dose of an anti-tumor drug results in better tumor response and no additional toxicity, Starton is advancing two continuous delivery formulations towards the clinic: subcutaneous (SC) and transdermal delivery system (TDS).
STAR-LLD is currently entering a Phase 1 clinical study to assess pharmacokinetics versus the oral formulation. Following the Phase 1, Starton intends to conduct Phase 2 clinical studies in multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). Starton has confirmed with FDA that STAR-LLD will follow a 505(b)2 regulatory path for pre-clinical development of STAR-LLD and intends to conduct a full clinical program in its target indications.