Novasep and Exelixis have signed a manufacturing services agreement for the cGMP clinical production of XB002 (previously known as ICON-2), a next-generation tissue factor-targeting antibody-drug conjugate (ADC) for oncology applications.

Exelixis has established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need.

XB002 is a novel ADC composed of a human monoclonal antibody against tissue factor (TF) that is conjugated to a cytotoxic agent and leverages proprietary ZymeLink™ linker-payload platform technology developed by Zymeworks. After binding to tissue factor on tumor cells, XB002 is internalized, and the cytotoxic agent is released, resulting in targeted tumor cell death.

As a next-generation tissue factor-targeting antibody-drug conjugate (ADC), XB002 has the potential for an improved therapeutic index and may provide a favorable safety profile compared with earlier-generation tissue factor-targeting ADCs.

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IND
Following the U.S. Food and Drug Administration’s acceptance of Exelixis’ Investigational New Drug Application (IND) to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity in April 2021, Exelixis initiated a phase 1 clinical trial of XB002 in patients with advanced solid tumors in the second quarter of 2021. The trial is a non-randomized, open-label, multicenter, dose-escalation, and expansion study evaluating the safety, tolerability, PK, pharmacodynamics, and clinical antitumor activity of XB002 administered IV q3w as a monotherapy to subjects with advanced solid tumors, including Non-Small Cell Lung Cancer, Urothelial Cancer, Epithelial Ovarian Cancer, Cervical Cancer, SCCHN and Pancreatic Cancer.

“The acceptance of our Investigational New Drug Application for XB002 gets us one step closer to our first biologic entering the clinic and learning more about its potential to help patients with difficult-to-treat cancers,” said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis.

“Considering XB002’s promising preclinical data and potential differentiation from other tissue factor-targeting antibody-drug conjugates, we look forward to [the results of] our phase 1 trial in patients with advanced solid tumors.”

Preclinical data
Many cancer cells express high levels of both full-length TF and alternatively spliced TF (asTF). The expression of TF in cancer is associated with poor prognosis.[1]

Various unrelated signaling pathways, transcription factors, and micro ribonucleic acids regulate TF gene expression in cancer cells. Research shows that The TF/factor VIIa complex enhances tumor growth by activating protease-activated receptor 2* (PAR2) signaling and by increasing the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF). AsTF further increases tumor growth by enhancing integrin β1 signaling. TF and asTF also contribute to metastasis via multiple thrombin-dependent and independent mechanisms that include protecting tumor cells from natural killer cells.[1][2]

Preclinical data demonstrated that XB002 binds to tissue factor (TF) on both human and non-human primate (NHP) cells with high affinity without affecting the coagulation cascade as measured by FXa conversion and thrombin generation assays, in contrast with prior therapies in this class. The data also demonstrated encouraging the activity of XB002 in multiple solid tumor cancer models and improved tolerability compared with other tissue factor-targeting ADCs.

The investigational drug has shown significant tumor growth inhibition and, in some cases, complete regression. Investigators hypothesize that based on the rational design and preclinical profile of this novel tissue factor-targeting ADC, XB002 could potentially have an improved therapeutic index and favorable safety profile compared with earlier tissue factor-targeting ADCs. The available preclinical data using patient-derived xenograft models derived from several tumor types, also demonstrate the superior tolerability and exposure of XB002 compared with an ADC containing monomethyl auristatin E (MMAE) conjugated to the same anti-tissue factor antibody. Furthermore, XB002 was not found to cause neutropenia.

Process development and cGMP bioconjugation
Novasep performs process development and cGMP bioconjugation of the XB002 ADC at its state-of-the-art ADC manufacturing unit on its Le Mans-site in France. This site, which now has more than 15 years of experience in supporting ADC drug innovators, is utilizing its specialized technologies and expertise to support Exelixis’ XB002 clinical supply needs, where XB002 is manufactured for Exelixis’ ongoing phase 1 clinical trial

“As the first ADC in our growing biologics pipeline to enter clinical development, XB002 is an important program for Exelixis,” said Khalid Shah, Ph.D., Senior Vice President, Pharmaceutical Operations and Supply Chain, Exelixis.

“Novasep’s ADC process development and manufacturing capabilities were integral to our ability to initiate XB002’s first phase 1 study on an aggressive timeline this spring. We look forward to leveraging Novasep’s highly specialized ADC expertise as work on the XB002 clinical development program continues,” Khalid added.

“The Antibody Drug Conjugate clinical pipeline continues to strengthen thanks to innovators such as Exelixis. These therapies have the potential to serve as new treatment options for patients around the world and our aim is to accompany their development,” noted Dr. Michel Spagnol, Chairman and CEO of Novasep.

“We are proud to support Exelixis with our manufacturing services,” he concluded.

Novasep’s bioconjugation facility was successfully inspected by the ANSM (French regulatory drug authorities) earlier in 2021.

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* Protease-activated receptor 2 (PAR2) is also known as coagulation factor II (thrombin) receptor-like 1 (F2RL1) or G-protein coupled receptor 11 (GPR11). PAR2 is associated with many aspects regarding tumor progression, such as the production of pro-tumoral cytokines. [2]

Clinical trials
Study of XB002 in Subjects With Solid Tumors – NCT04925284

Reference
[1] Hisada Y, Mackman N. Tissue Factor and Cancer: Regulation, Tumor Growth, and Metastasis. Semin Thromb Hemost. 2019 Jun;45(4):385-395. doi: 10.1055/s-0039-1687894. Epub 2019 May 16. PMID: 31096306; PMCID: PMC6546519.
[2] Carvalho É, Hugo de Almeida V, Rondon AMR, Possik PA, Viola JPB, Monteiro RQ. Protease-activated receptor 2 (PAR2) upregulates granulocyte colony-stimulating factor (G-CSF) expression in breast cancer cells. Biochem Biophys Res Commun. 2018 Sep 26;504(1):270-276. doi: 10.1016/j.bbrc.2018.08.169. Epub 2018 Aug 30. Erratum in: Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):262. PMID: 30172372.

Feature image: Novasep manufacturing. Photo courtesy: © 2016 – 2021 Novasep. Used with permission.

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