Elevation Oncology, an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, said it will prioritize key research and development efforts to advance EO-3021 (SYSA1801), its potential best-in-class antibody-drug conjugate (ADC) designed to target Claudin 18.2, and other pipeline programs including those through its existing partnership with Caris Life Sciences.

In July 2022 Elevation Oncology entered into an exclusive license agreement with CSPC Megalith Biopharmaceutical Co., a subsidiary of CSPC Pharmaceutical Group Limited to develop and commercialize EO-3021 (SYSA1801).

Addressing the unmet medical needs
The Claudin 18.2 a transmembrane protein, also known as CLDN18.2, is an isoform of claudin 18, a member of the tight junction protein family. It is a highly selective biomarker with limited expression in normal tissues and often abnormal expression during the occurrence and development of various primary malignant tumors, such as gastric cancer/gastroesophageal junction (GC/GEJ) cancer, breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer.[1]

Claudins are a family of proteins acting to maintain the tight junction that controls the interchange of molecules between cells. The protein is a specific subtype that is expressed only in cancer cells of the gastric epithelia. When the gastric epithelial cells become malignant, the tight junctions become disrupted, exposing the Claudin 18.2 epitopes and allowing them to be targeted by therapeutic antibodies and ADCs.[1]

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Claudin 18.2 has become a unique molecule for targeted therapy in a variety of solid tumors, being investigated by a number of companies. This includes, for example, zolbetuximab (claudiximab, IMAB362), an investigational first-in-class chimeric antibody against Claudin 18.2 being developed by Ganymed Pharmaceuticals (now part of Astellas Pharma), RC118, an antibody-drug conjugate being developed by RemeGen, and CMG901, an ADC developed by Keymed Biosciences.

In addition, various companies are are developing Chimeric antigen receptor T (CAR-T)-cell therapies targeting Claudin 18.2.  Among these investigational agents are BM2L201910 (LCAR-C18S) a CAR T-Cell therapy being developed by Nanjing Legend Biotech Co., LY011 (Shanghai Longyao Biotechnology), third-generation CAR-T-cell product prepared from allogeneic T lymphocytes that have been genetically modified to target the tumor-associated antigen (TAA) CLDN18.2 by using lentivirus vector technology with potential immunostimulating and antineoplastic activities, and CT041, being developed by CARsgen.

Elevation Oncology’s EO-3021, which targets Claudin 18.2, is an ADC containing monomethyl auristatin E (MMAE) payload, a clinically validated and effective anti-tumor payload.  The same payload is used as the cytotoxic component of four other approved and commercially available ADCs.

EO-3021 is currently being evaluated in a Phase 1, dose-escalation study in China. The investigational drug has been granted orphan drug designation and cleared to begin clinical trials in the U.S. by the FDA. The company anticipates initiating a Phase 1 clinical trial in the United States 2023.

“Claudin18.2 is a clinically validated oncology target that has significant potential in multiple gastrointestinal cancers and several other solid tumors, and could be best addressed by utilizing a weaponized antibody like EO-3021,” said David Dornan, PhD, Chief Scientific Officer of Elevation Oncology.

“High Claudin18.2 expression is associated particularly with gastrointestinal cancers, but can also frequently be found in lung, breast and liver cancer, representing an attractive commercial market opportunity. The targeting of Claudin18.2 with EO-3021 could have a transformative role in addressing the unmet medical need in patients whose tumors express Claudin18.2,” Dorman added.

Prioritization and realignment
As part of the prioritization, the company is pausing further investment in the clinical development of seribantumab (MM-121) an anti-HER3-antibody for the treatment of patients diagnosed with solid tumors, and realigning its resources to focus on advancing EO-3021 and other pipeline programs.

Elevation Oncology intends to pursue further development of seribantumab only in collaboration with a partner.

The company also announced that Shawn M. Leland, PharmD, RPh, resigned from his role as Chief Executive Officer and a member of the Board of Directors, effective immediately. The Board of Directors has appointed Joseph J. Ferra as Interim Chief Executive Officer. Mr. Ferra will remain as the Company’s Chief Financial Officer, and lead Elevation Oncology along with Valerie Malyvanh Jansen, MD, PhD, Chief Medical Officer and David Dornan, PhD, Chief Scientific Officer.

“We remain focused on developing innovative cancer therapies to treat patients with significant unmet medical needs, and in EO-3021 we believe we have a potential best-in-class asset that can target solid tumors expressing Claudin18.2 and plan to enter the clinic in the US in the second half of 2023,” said Joseph Ferra, Interim Chief Executive Officer of Elevation Oncology.

“In light of our ongoing evaluation of our pipeline, we are pausing further investment in the development of seribantumab and the CRESTONE study. Additionally, we have made the difficult decision to reduce our workforce which will enable us to realign our resources towards advancing EO-3021 and additional pipeline programs. We would like to extend our deepest gratitude to the patients and their families, the investigators and study teams as well as our employees for their invaluable contributions to the CRESTONE study.”

“Leland’s dedication and leadership were instrumental in the founding and building of Elevation Oncology. On behalf of the Board of Directors, I would like to sincerely thank Shawn for his many contributions and his stewardship of the company,” said Steve Elms, Chairman of the Board of Directors of Elevation Oncology.

“We have the utmost confidence in Joe’s ability to lead Elevation Oncology as Interim CEO during this time of significant transition for the Company in order to realize the full potential of EO-3021, and additional pipeline programs, to benefit patients with significant unmet medical needs,” Elms concluded.

Clinical trials
Study of Seribantumab in Adult Patients With NRG1 Gene Fusion Positive Advanced Solid Tumors – NCT04383210
Study of SYSA1801 in the Treatment of Claudin( CLDN) 18.2 Positive Advanced Malignant Solid Tumor – NCT05009966

Reference
[1] Zhang J, Dong R, Shen L. Evaluation and reflection on claudin 18.2 targeting therapy in advanced gastric cancer. Chin J Cancer Res. 2020 Apr;32(2):263-270. doi: 10.21147/j.issn.1000-9604.2020.02.13. PMID: 32410803; PMCID: PMC7219097.

Featured Image: Pharmaceutical scientific researchers analyzing liquid chromatography data; Pharmaceutical industry manufacturing laboratory Courtesy: © 2016-2023 Fotolia/Adobe. Used with Permission.

 

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