ESMO 2019: Target Engagement in Phase I Clinical Trial with First-in-Class TGF-beta 1 + 3 Inhibitor

General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.
General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 - October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission.

Clinical-stage protein engineering company Forbius, focusing on developing biotherapeutics to treat fibrosis and cancer, reported results from its non-clinical GLP toxicology program with first-in-class, rationally designed, selective transforming growth factor-beta (TGF-beta) inhibitor AVID200 and evidence of TGF-beta target engagement in patients treated with this novel immuno-oncology agent at the European Society of Medical Oncology (ESMO) 2019 Congress, being held September 27 – October 1, 2019 in Barcelona, Spain.

Forbius’ team of TGF-beta biology experts designed a proprietary platform of TGF-beta inhibitors with best-in-class potency and selectivity against the principal disease-driving isoforms 1 & 3.

This novel class of TGF-beta inhibitors has proven highly active in preclinical models of fibrosis and cancer and was well-tolerated in long-term toxicology studies. The company’s lead TGF-beta 1 & 3 inhibitor, AVID200, is undergoing Phase I clinical trials in two fibrotic indications as well as in solid tumors.

During the ESMO 2019 Congress Forbius, for the first time, presented data confirming that AVID200, administered at doses of ≥1 mg/kg, sequestered its target TGF-beta in patient blood over the entire dosing period.

TGF-beta 1 & 3 are the main oncogenic TGF-beta isoforms expressed by many solid tumors. They are believed to play a major role in T-cell suppression, fibrosis, and resistance to anti-PD-(L)1 therapies such as nivolumab (Opdivo®) and pembrolizumab (Keytruda®) [1]

Key highlights of the presentation included that AVID200:

  • Selectively neutralizes TGF-beta 1 & 3 with pM potency in vitro, and increases T-cell-mediated cytotoxicity as well as immune checkpoint inhibitor efficacy in syngeneic mouse tumor models
  • Was well tolerated in 1- and 6-month GLP toxicology studies in non-human primates
  • In patient blood sequestered peripheral TGF-beta over the entire dosing period

Antibody-drug Conjugates
Forbius’ lead program, AVID100, is a rationally designed anti-EGFR antibody-drug conjugate or ADC with a novel tumor-selective mode of action. Conjugating the antibody MAB100 to the microtubule inhibitor DM1, the drug exhibits high potency, an increase in apoptosis, against cancer cells relative to unconjugated MAB100-treated tumor cells, while not exhibiting increased toxicity on normal cells. AVID100 is undergoing Phase IIa clinical trials in epidermal growth factor receptor (EGFR-) overexpressing solid tumors. [2]

The investigational agent specifically targets EGFR which is highly expressed on a variety of cancers making it a promising target for ADCs. However, due to the presence of EGFR on normal, healthy, skin cells, on-target off-tumor toxicity has been noted and is a concern.

In preclinical research, AVID100 was very effective on tumor cell lines derived from breast, head and neck, and lung cancers with the cytotoxic IC50 values generally correlating with the number of EGFR molecules on the cell surface.

Finally, in multiple mouse xenograft studies, AVID100 demonstrated significantly reduced tumor growth and caused tumor regressions in some of the mice, even when administered as a single dose.

Clinical trials
A Trial of AVID200, a Transforming Growth Factor β (TGFβ) Inhibitor, in Patients Malignancies – NCT03834662
AVID100 in Advanced Epithelial Carcinomas – NCT03094169

References
[1] Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE III, Koeppen H, er al.TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018 Feb 22;554(7693):544-548. doi: 10.1038/nature25501. Epub 2018 Feb 14.
[2] Thwaites MJ, Figueredo R, Tremblay G, Koropatnick J, Goldmacher V, O’Connor-McCourt M. AVID100 is an anti-EGFR ADC that promotes DM1-meditated cytotoxicity on cancer cells but not on normal cells. AACR 2019 Abstract 218. DOI: 10.1158/1538-7445.AM2019-218 Published July 2019