Abstract
Simple SummaryNon-clinical safety, toxicology, and pharmacokinetic studies according to ICH guidelines with a new fusion protein tTF-NGR consisting of human truncated tissue factor (TF) and a small targeting peptide are reported. Results are compared with those of a phase I clinical dose escalation trial with tTF-NGR in cancer patients. Most of the non-clinical results were not predictive for human tolerability. Thus, animal sparing alternative pathways for translation of such a bio-pharmaceutical compound from preclinical studies on efficacy and mode of action into the clinic are discussed.Background: CD-13 targeted tissue factor tTF-NGR is a fusion protein selectively inducing occlusion of tumor vasculature with resulting tumor infarction. Mechanistic and pharmacodynamic studies have shown broad anti-tumor therapeutic effects in xenograft models. Methods: After successful Good Manufacturing Practice (GMP) production and before translation into clinical phase I, ICH S9 (S6) guideline-conforming animal safety, toxicology, and pharmacokinetic (PK) studies were requested by the federal drug authority in accordance with European and US regulations. Results: These studies were performed in mice, rats, guinea pigs, and beagle dogs. Results of the recently completed clinical phase I trial in end-stage cancer patients showed only limited predictive value of these non-clinical studies for patient tolerability and safety in phase I. Conclusions: Although this experience cannot be generalized, alternative pathways with seamless clinical phase 0 microdosing—phase I dose escalation studies are endorsed for anticancer drug development and translation into the clinic.
Highlights
The high selectivity of vascular occlusion by truncated TF (tTF)-NGR for tumor blood vessels was demonstrated by the fact that no visible thrombosis occurred in the vasculature of normal tissues such as heart, kidney, liver, and lung at therapeutic doses [1,5]
As exemplified here with a new targeted fusion-protein, results of formal preclinical animal safety and toxicity studies according to European Medicines Agencies (EMA) guidelines M3, S6 and S9 are not generally predictive for subsequent human trials and do not necessarily contribute to patient safety
As the necessity for further toxicology studies probably varies between different drug candidates and on the basis of these orienting safety studies, the necessity for additional non-clinical safety and toxicology should be discussed and planned within the scientific advice by investigators and federal regulatory drug authorities individually for each investigational compound with the objective to considerably reduce non-clinical toxicology testing
Summary
Cancers 2020, 12, 3536 selective tumor vascular occlusion and infarction [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21] To this end the non-specific membrane anchor of TF was replaced by peptides such as the CD13-binding NGR motif GNGRAHA. CD-13 targeted tissue factor tTF-NGR is a fusion protein selectively inducing occlusion of tumor vasculature with resulting tumor infarction. I, ICH S9 (S6) guideline-conforming animal safety, toxicology, and pharmacokinetic (PK) studies were requested by the federal drug authority in accordance with European and US regulations
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