The TeGenero Incident and the Duff Report Conclusions: A Series of Unfortunate Events or an Avoidable Event?

Abstract

The administration of the first dose of a novel pharmaceutical compound to humans is the culmination of many years of efforts by many people. There is often a feeling of relief that the compound has made it this far and a feeling of great optimism and anticipation. However, it also can be a time of great trepidation because it is the first opportunity to determine the accuracy of the projections of the compound’s efficacy, ADME (absorption, distribution, metabolism, and elimination) properties, and most important, safety in humans. The administration of the first dose to humans usually results in a celebration by the development project team, although the first few dose levels of the initial clinical trial are usually uneventful and not much can be learned regarding the compound’s efficacy, ADME properties, and safety due to the low doses used in these initial dose cohorts. This is particularly true for nononcology compounds that are typically evaluated first in normal healthy volunteers (NHV) who would be expected to derive no benefit from the compound and thus generally receive a first-in-human (FIH) dose that is not anticipated to have pharmacologic activity. Unfortunately, in some instances, things do not go as anticipated. Sometimes it is learned from these early dose cohorts that the projections of the pharmacokinetics (PK) of the compound are wrong, or that the compound will not be as efficacious in humans as in animals. Sometimes the compound is found to have a side-effect profile in humans that was not predicted from the animal toxicology studies. Usually such side effects are relatively benign, consisting of headaches, nausea, drowsiness and other nuisance events which would have been difficult to appreciate in animal studies. On very rare occasions, the side effects may be more severe and, even more rarely, life-threatening. One such example of the latter was the ‘‘TeGenero Incident’’ (Expert Group on Phase One Clinical Trials 2006; Gambrill 2006). Serious, life-threatening adverse events were observed in all dosed subjects after the administration of TGN1412, a new class of monoclonal antibody (mAb) with a stimulatory mode of action on a subset of T cells known as regulatory T cells (Tregs; Expert Group on Phase One Clinical Trials 2006). This antibody was a humanized IgG4k mAb that was derived from the precursor mouse mAb 5.11A1 by grafting of the complementarity-determining regions (CDR). TGN1412 binds to CD28 and activates T cells without need for T cell receptor (TCR) preactivation, resulting in polyclonal T cell expansion and activation and concentration-dependent IL-2 production. As such, TGN1412 was termed a ‘‘superagonist.’’ The intent was to develop TGN1412 as a treatment for B cell chronic lymphocytic leukemia, in which T cells are deficient, and for autoimmune diseases, such as rheumatoid arthritis, in which Treg cell expansion might be beneficial. The TeGenero incident spurred a subsequent investigation by an expert scientific group (ESG) on Phase 1 Clinical Trials, appointed by the Medicines and Healthcare Products Regulatory Agency (MHRA) and under the leadership of Professor Gordon Duff, which culminated in a report known as ‘‘the Duff Report.’’ The objective of this article is to review the TeGenero incident and the Duff Report and to comment on whether the TeGenero incident was predictable and/or avoidable. Address correspondence to: Christopher Horvath, DVM, MS, DACVP, Vice President, PreClinical Sciences, Taligen Therapeutics, Cambridge, MA 02142; e-mail: chorvath@taligentherapeutics.com. Abbreviations: ABPI, Association of the British Pharmaceutical Industry; ADME, Absorption, Distribution, Metabolism, and Excretion; BBC, British Broadcasting Company; BIA, BioIndustry Association; CBER, FDA Center for Biologics Evaluation and Research; CD, cluster of differentiation; CDER, FDA Center for Drug Evaluation and Research; CDR, complementaritydetermining region; CHM, Commission on Human Medicines; CHMP, Committee for Medicinal Products for Human Use; CPMP, Committee for Proprietary Medicinal Products; CRS, cytokine release syndrome; CTA, clinical trial authorization; DIC, disseminated intravascular coagulation; DLT, doselimiting toxicity; EAG, expert advisory group; Emax, maximum effect; EMEA, European Medicines Agency; ESG, Expert Scientific Group on Phase 1 Clinical Trials; EU, European Union; EUDRA, European Drug Regulatory Authorities; Fc, Fragment, crystallizable; FcR, Fc receptor; FcRn, neonatal Fc receptor; FDA, Food and Drug Administration; FIH, first-in-human; FOI, Freedom of Information; HED, human equivalent dose; HNSTD, highest nonseverely toxic dose; IB, Investigator’s Brochure; IgG, immunoglobulin isotype G; IL2, Interleukin–2; IMPD, Investigational Medicinal Product Dossier; IND, Investigational New Drug; mAb, monoclonal antibody; MABEL, minimum anticipated biological effect (dose) level; MHRA, Medicines and Healthcare Products Regulatory Agency; MOA, mechanism of action; MRSD, maximum recommended starting dose; MTED, minimum toxic effect dose; NHV, normal healthy volunteer; NOAEL, no observed adverse effect (dose) level; NOEL, no observed effect (dose) level; PAD, pharmacologically active dose; PD, pharmacodynamic(s); PK, pharmacokinetic(s); RSS, Royal Statistical Society; Siglecs, Sialic acid binding Ig-like lectins; SUSAR, suspected unexpected serious adverse reaction; TCR, T cell receptor; UK, United Kingdom.