Preclinical pharmacology, toxicology, biodistribution and dosimetry, and radionuclide production CMC validation for Pb-212 receptor targeted alpha-particle therapy for neuroendocrine tumors.

Neuroendocrine tumors (NET) are enigmatic malignancies, with an increasing incidence and poor outcomes (5-yr survival andlt;30%). Recently, peptide-receptor radionuclide therapy (PRRT) using [177Lu]DOTATATE beta(b)-particle treatment (LutatheraÔ) improved survival vs standard of care and was FDA approved. However, objective tumor responses were low (18%) in the Phase 3 trial. Nonetheless, Lutathera developer AAA, Inc. was subsequently acquired by Novartis for $3.9 Bln demonstrating the commercial potential and significance of PRRT products. Viewpoint’s next-generation PRRT employs alpha(a)-particle therapy, an emergent form of PRRT that is producing objective (and even complete) responses. Viewpoint and the University of Iowa have secured an NIH R01 (CA243014-01; Viewpoint CSO Michael Schultz is Co-PI) that supports a Phase 1 trial of Viewpoint’s [203/212Pb]VMT-a-NET for NET in human subjects (a-therapy to begin Oct., 2021). VMT-a-NET (patent now pending) is innovative because rationally-designed molecular modifications (patents now pending) significantly improve radiolabeling, in vitro cell/internalization binding (20-fold) Kd (up to 6-fold) and in vivo PK properties that significantly improve tumor accumulation/retention and reduce other organ retention (e.g., tumor:kidney ratio increased 8-fold) compared to competing agents. Thus, this research is significant because new predicate biomarker and efficacy data demonstrate a therapeutic window that can significantly improve outcomes for NET patients. This research is further significant because Viewpoint’s proprietary 212Pb production device (VMT-a-GEN) establishes control of on-demand supply of 212Pb for commercialization. In this revised Direct to Phase II SBIR project, Viewpoint will (i) procure GMP VMT-a-NET and conduct IND-enabling toxicology prior to the therapy trial; and (ii) validate formulations and automate manufacturing of VMT-a-GEN. PREDICATE MILESTONES: Secured $1.2Mln seed financing; signed terms for Series A investment; validated SST2R target; secured R01 for [203/212Pb]VMT-a-NET Phase 1 therapy trial; GMP kits for production; exclusive licenses; secured 203Pb supply (Lantheus); working prototype of therapeutic isotope (212Pb) production device (VMT-a-GEN); VMT-a-GEN mfg. facilities established. Completing two Specific Aims readies Viewpoint for trials: AIM 1. Manufacture and validate GMP VMT-a-NET peptide and conduct FDA-required toxicology in non- human primates prior to a funded (R01) Phase 1 clinical therapy trial. AIM 2. Automate, validate, and document manufacturing of 212Pb production device (VMT-a-GEN). IMPACT: With success, we expect to have validated GMP VMT-a-NET and completed required toxicology studies in non-human primates for CMC/IND submission/approval. We further expect to have automated manufacturing of our 212Pb radioisotope generator (VMT-a-GEN). Thus, Viewpoint will be prepared to enter the funded Phase 1 trial and have the competitive advantage of on-demand control of the supply of therapeutic radionuclide 212Pb for expanded trials and commercialization of VMT-a-NET.This project will conduct text article toxicology, produce GMP test article, validate formulation and automate radioisotope production for alpha-particle therapy for NET. Other agents are not available for these aims.