Perspective Therapeutics has announced the dosing of the first patient with [212Pb]PSV359 in a Phase 1/2a dose-finding trial. The study aims to evaluate the safety and preliminary anti-tumor activity of this radiopharmaceutical in patients with solid tumors expressing fibroblast activation protein alpha (FAP-α).
The trial employs a theranostic approach, using SPECT imaging with [203Pb]PSV359 to select patients for targeted alpha particle therapy with [212Pb]PSV359. This patient selection strategy helps identify individuals most likely to benefit from the treatment.
"We are excited to explore a new avenue to treat cancers expressing FAP-α with [212Pb]PSV359," said Markus Puhlmann, Chief Medical Officer of Perspective. "FAP-α is expressed directly on certain tumors as well as on cells that form the stroma, a part of the tumor microenvironment, which also plays a role in disease progression and treatment outcome in additional solid tumors."
The Significance of FAP-α in Cancer
FAP-α is a protein abundantly expressed on cancer-associated fibroblasts (CAFs) in the tumor stroma of most epithelial cancers. It is also expressed on certain cancer cells themselves, including sarcomas and mesotheliomas. Higher FAP-α expression correlates with poor prognosis in numerous solid tumors, including colorectal, pancreatic, stomach, head and neck, esophageal, and ovarian cancers.
Importantly, FAP-α expression in healthy tissues is typically low, making it an attractive target for cancer-specific therapies. This differential expression pattern potentially allows for selective targeting of cancer cells while sparing normal tissues.
PSV359: Design and Development
PSV359 was specifically designed to target and deliver the alpha-emitting radioisotope 212Pb to tumor sites expressing FAP-α. The targeting moiety can also be radiolabeled with 203Pb for diagnostic imaging or 68Ga (known as PSV377) to detect FAP-α expression in patients.
"PSV359 showcases the capabilities of our discovery team in creating novel radiopharmaceuticals to provide innovative therapies for cancer patients in need of new treatment options," said Thijs Spoor, Chief Executive Officer of Perspective. "When we selected PSV359 to advance into the clinic, we optimized the construct for preferential uptake and retention in the tumor, in addition to binding affinity to FAP-α and fast clearance from healthy tissues."
Preclinical studies and early human imaging results suggest that Perspective's proprietary targeting ligand demonstrates improved target engagement and tumor uptake, with reduced retention in healthy tissues. These characteristics may result in a favorable therapeutic index, potentially enhancing efficacy while minimizing toxicity.
Trial Design and Objectives
The multi-center, open-label, dose-finding and dose-expansion study (NCT06710756) is enrolling patients with advanced solid tumors that express FAP-α, as determined by [203Pb]PSV359 imaging.
The primary objective of the dose-finding phase is to assess safety and tolerability of various doses of [212Pb]PSV359 to determine the recommended Phase 2 dose. In the subsequent expansion phase, anti-tumor activity will be evaluated as an additional primary outcome measure.
Dr. Puhlmann noted that the study aims to select a dose for [212Pb]PSV359 to advance either as a monotherapy or eventually in combination with other agents for future clinical development.
Perspective's Radiopharmaceutical Platform
Perspective Therapeutics is developing a platform of radiopharmaceuticals that utilize the alpha-emitting isotope 212Pb to deliver targeted radiation to cancer cells via specialized targeting moieties. The company is simultaneously developing complementary imaging diagnostics that incorporate the same targeting molecules.
This theranostic approach enables visualization of specific tumors followed by targeted treatment, potentially improving efficacy while minimizing toxicity to healthy tissues.
In addition to PSV359, Perspective's clinical pipeline includes programs targeting melanoma (VMT01) and neuroendocrine tumors (VMT-α-NET), all currently in Phase 1/2a imaging and therapy trials in the United States.
The company is expanding its regional network of drug product finishing facilities, enabled by its proprietary 212Pb generator, to deliver patient-ready products for clinical trials and potential future commercial operations.
Implications for Cancer Treatment
The development of [212Pb]PSV359 represents a potentially significant advance in targeted radiotherapy for solid tumors. By specifically targeting FAP-α, which is expressed across multiple cancer types and associated with poor prognosis, this approach could address an important unmet need in oncology.
The theranostic strategy employed in this trial—using [203Pb]PSV359 imaging to select patients for [212Pb]PSV359 therapy—exemplifies the growing trend toward precision medicine in cancer treatment, where therapies are matched to patients most likely to benefit based on specific biomarkers.
As the trial progresses, data on safety, tolerability, and preliminary efficacy will help determine the potential of [212Pb]PSV359 as a new treatment option for patients with FAP-α-positive solid tumors.
