A first patient has been dosed in a Phase 1 trial of PYX-201, a novel antibody-drug conjugate (ADC) product candidate being developed by Pyxis Oncology and licensed from Pfizer targeting extra-domain-B (EDB) of fibronectin, a non-internalizing antigen, that is an integral component of the extracellular matrix in tumors. It is an alternatively spliced form of fibronectin with high expression in the extracellular matrix of neovascularized tissues and malignant cancer cells and minimally expressed in most normal adult tissues. [1][2][3]

“PYX-201 has the potential to offer a new approach to targeting multiple tumor types via a multi-pronged mechanism of action that may benefit patients with solid tumors. We expect to see preliminary data from this study, including biomarker results and potential early signs of clinical activity, in early 2024,” said Lara S. Sullivan, M.D., President and Chief Executive Officer of Pyxis Oncology.[1]

“I’m proud of the work done by the Pyxis Oncology team to initiate dosing in our first clinical trial. Dosing is a significant achievement and important milestone that marks the transition of Pyxis Oncology to a clinical-stage company.”

Looking for new treatments
“We are always looking for potential new treatments for patients who have limited or no options available,” noted Alexander Spira, M.D., Director NEXT Oncology Virginia, Co-Director, VCS Research Institute, and Director, Thoracic and Phase I Program and Clinical Assistant Professor at Johns Hopkins University,

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“I am particularly excited about PYX-201 because it was designed to offer several important safety and efficacy improvements compared to traditional ADCs, and we look forward to evaluating it in this Phase 1 study,” Sipra added.

Study design
The Phase 1 trial, referred to as PYX-201-101 (NCT05720117), is an open-label, multicenter, dose-escalation trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PYX-201 and identify recommended doses for further study. Patients with relapsed or refractory solid tumors known to have significant expression of EDB of fibronectin, including non-small cell lung cancer (NSCLC), hormone receptor-positive breast cancer, ovarian cancer, thyroid cancer, pancreatic ductal adenocarcinoma, soft tissue sarcoma, hepatocellular carcinoma or kidney cancer are eligible to enroll.

Pyxis Oncology anticipates preliminary data from this trial in early 2024.

New treatment tools
“ADCs are important tools in the cancer treatment armamentarium, and further ADC development may represent a significant opportunity to address several solid tumor types with significant unmet need,” explained Jay Feingold, M.D., Ph.D., Chief Medical Officer of Pyxis Oncology.

“Unlike traditional ADCs, PYX-201 acts via three distinct mechanisms to comprehensively target tumors independent of cell surface marker expression. Once PYX-201 binds to EDB fibronectin in the tumor stroma, a potent auristatin-derived payload is cleaved and diffuses across adjacent tumor cell membranes and surrounding supportive tumor infrastructures, including fibroblasts and tumor vasculature,” said Jan Pinkas, Ph.D., Chief Scientific Officer of Pyxis Oncology.

“PYX-201 also acts via a bystander effect in the tumor microenvironment as aur0101 payload is recycled and re-released, directly killing adjacent tumor cells. Finally, PYX-201 also stimulates anti-tumor immunogenic activity by promoting dendritic cell maturation and inducing immunogenic cell death, which could provide a rationale for the evaluation of combination-based approaches with immuno-oncology products, including checkpoint inhibitors,” Pinkas added.

FACT technology Platform
The Flexible Antibody Conjugation Technology (FACT) technology platform, licensed from Pfizer, in 2021, is designed to facilitate creation of next-generation ADCs like PYX-201 that have the potential for improved anti-tumor activity, safety and tolerability.

Compared to traditional ADC approaches, the FACT platform is based upon technical improvements to allow site-specific payload conjugation, linker stability and payload potency.

In preclinical studies, the FACT platform technology has demonstrated a superior therapeutic index over currently marketed auristatin based ADCs. FACT site-specific conjugation of vc-0101 to engineered cysteine residues exhibits improved therapeutic Index over ado-trastuzumam emtansine (Kadcyla®; Genentech/Roche) and conjugation technology used in brentuximab vedotin (Adcetris®; Seagen) and enfortumab vedotin (Padcev®; Astellas Pharma/Seagen)

Finally, Phase 1 dose-escalation study of a novel anti- HER2 ADC constructed using the FACT platform showed promising efficacy and generally manageable toxicity profile at doses significantly higher than currently approved auristatin ADCs

In addition, the platform technology has demonstrated improvements over currently available auristatin ADCs with clinically validated ADC payloads, novel payloads and improvements on previous payloads, multiple linker chemistries (cleavable and non-cleavable), and site specific stable conjugation.

Clinical trials
Study of PYX-201 in Solid Tumors – NCT05720117

[1] Pyxis Oncology to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of PYX-201 in Phase 1 Study
By ADC Review | Journal of Antibody-drug Conjugates -February 15, 2023 [Article]
[2] Lieverse RIY, Marcus D, van der Wiel AMA, Van Limbergen EJ, Theys J, Yaromina A, Lambin P, Dubois LJ. Human fibronectin extra domain B as a biomarker for targeted therapy in cancer. Mol Oncol. 2020 Jul;14(7):1555-1568. doi: 10.1002/1878-0261.12705. Epub 2020 Jun 15. PMID: 32386436; PMCID: PMC7332215.
[3] Hooper AT, Marquette K, Chang CB, Golas J, Jain S, Lam MH, Guffroy M, Leal M, Falahatpisheh H, Mathur D, Chen T, Kelleher K, Khandke K, Muszynska E, Loganzo F, Rosfjord E, Lucas J, Kan Z, Subramanyam C, O’Donnell C, Neri D, Gerber HP, May C, Sapra P. Anti-Extra Domain B Splice Variant of Fibronectin Antibody-Drug Conjugate Eliminates Tumors with Enhanced Efficacy When Combined with Checkpoint Blockade. Mol Cancer Ther. 2022 Sep 6;21(9):1462-1472. doi: 10.1158/1535-7163.MCT-22-0099. PMID: 35793468; PMCID: PMC9446899.

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