Fleximers are modified purines with the imidazole and pyrimidine rings separated by a single carbon-carbon bond. Fleximer technology uniquely combines biodegradability with biological stealth properties, lacking interactions with biologic recognition elements including phagocytes and immune cells, making Fleximer materials and their conjugates long circulating and non-immunotoxic. Fleximer molecules are characterized by solubility in water, stability in common manufacturing procedures and in normal physiological conditions, and non-enzymatic biodegradability upon uptake by cells. Fleximer is non-toxic at large doses in rodents.

MER-1001 is a polymer-directed prodrug of camptothecin (CPT). MER-1001 is a macromolecular (60-70 kDa) conjugate of CPT with the hydrophilic polymer PHF [poly-(1-hydroxymethylethylene hydroxyl-methyl formal)]. Release of CPT from MER-1001 involves a dual-phase, non-enzymatic release mechanism, in which CPT is first released in plasma as lipophilic prodrugs CPT-SI (a succinimidoglycinate derivative) and CPT-SA (a succinamidoyl glycinate derivative), which are then hydrolyzed in tissues to release the lactone form of CPT (Schwertschlag U, AACR07, Abs. 4723).

MER-1001 is a polymeric prodrug derivative of camptothecin in which the drug is chemically tethered to a hydrophilic, biodegradable 60-70-kDa polymer, Fleximer (poly[1-hydroxymethylene hydroxymethyl formal], PHF). When administered IV, MER-1001 releases camptothecin-20-(N-succinimido-glycinate) (CPT-SI), CPT, and camptothecin-20-(N-succinamidoyl-glycinate) (CPT-SA) over an extended time period. Because of the biologically inert nature of Fleximer, MER-1001 distributes throughout the vascular space and slowly releases the prodrug CPT-SI, and to a lesser extent, CPT, over time. Initial PK measurements in animals confirm the release-limited PK of CPT and CPT-SI. Thus, in contrast to the known PK profile of CPT alone, MER-1001 (CPT+linker+PHF) releases CPT slowly and is not expected to be excreted at potentially toxic levels into the gallbladder, intestine, and urinary bladder. In addition, the dual-phase release mechanism affords a more sustained exposure to the active lactone form of CPT because the lactone ring is stabilized in prodrug CPT-SI. Both distribution and extended release are hypothesized to improve safety and efficacy over existing drugs of the same class (Yurkovetskiy A, etal, AACR07, Abs. 781).