Tozaride (Rhenium 188 P2045)
Rhenium (Re) 188 P2045 is a targeted therapy that combines a high-affinity somatostatin receptor-binding peptide with the high-energy, beta-emitting radionuclide Rhenium-188. Both small cell (~84%), and non-small cell (~87%) lung cancers, as well as neuroendocrine cancers (>90%) are characterized by a high over-expression of the somatostatin receptor (SSTR). SSTR2 is the most widely up-regulated subtype and is the primary mediator of somatostatin effects in cancer cells. P2045 is rapidly internalized by SSTR2 allowing it to be a highly specific targeting agent. In studies with nude mice, Re188 P2045 caused almost complete inhibition of SSTR-bearing pancreatic tumors with no acute damage to any other organ or tissue. In other preclinical studies, Re188 P2045 demonstrated significant growth delay in xenografts of small cell lung and other cancers (Cyr et al, J Med Chem 2007, 50:1354-1364).
Three clinical studies of P2045 have been completed. Initial imaging (Technitium (Tc99)-P2045) and biodistribution (Tc- and Re188-P2045) studies showed that tumor uptake was rapid and substantial, and that the agent was well tolerated and rapidly cleared. In the dose escalation study, conducted in patients who had failed other therapies, four of eight patients presenting with progressive, non-small cell lung cancer achieved stable disease at eight weeks and the median overall survival was 11.5 months, comparable to results seen with erlotinib in previously treated patients (Edelman MJ et al, J Thorac Oncol 2009, 4(12):1550-4).
Re188-P2045 has received Orphan Drug designation for both small cell lung and pancreatic cancers, and is preparing to enter Phase 2 clinical studies.
The key to delivering personalized cancer therapy is selecting the most appropriate patients for a therapy that is targeted to the patient’s specific molecular subtype. Our diagnostic imaging agent is based on Technitium (Tc) 99, a widely used imaging isotope. Tc99 conjugated to P2045 targets tumors expressing high levels of SSTR2. Our Phase 1 clinical trial demonstrated the feasibility of using Tc99-P2045 to image patients in real time to identify the most appropriate patients (those with a high density of the SSTR2 target) for the therapeutic dose with Tozaride.
Peptide targeted radiotherapy (PTRT) is a promising new approach to cancer therapy that has been widely validated in clinical studies and is in routine clinical use in Europe. Our approach systemically delivers a molecularly targeted, radiolabeled peptide which is designed to target with high affinity and specificity the receptors overexpressed on tumors. Guidelines for effectively employing PTRT have been published, further supporting the promise and acceptance of this therapeutic modality (Zaknun JJ et al, Eur J Nucl Med Mol Imaging 2013, 40(5):800-16). Our technology represents the next generation of PTRT, employing superior peptide targeting and a radioisotope with more desirable characteristics than conventional radioisotopes.