Horvath, Christopher, Maclachlan, Timothy and Milton, Mark (2012) Letter to the Editor - Response to Hunig Commentary in Nat Rev Immunol. Nature Reviews Immunology.

Abstract

There is no "abstract" in this letter, however below are the first two paragraphs -

Dear Editor:
This letter is in response to the COMMENT published in Nature Reviews Immunology by Thomas Hünig (The storm has cleared: lessons from the CD28 superagonist TGN1412 trial. Nat Rev Immunol 2012; 12: 317-8.). In his commentary, Dr. Hünig attempts to explain “why the three sets of preclinical data (from rodents, primates and human cells) used to support [the] Phase I clinical trial [of the superagonist IgG4 anti-human CD28 monoclonal antibody (mAb), TGN1412] had failed to predict the cytokine storm” in healthy volunteers. He describes in detail some of the more recent findings in these three preclinical test systems and concludes that they “all failed to provide evidence for the toxic potential of the antibody for distinct and unrelated reasons”. He further claims that “the disastrous outcome…may have made a positive contribution to the future development of immunomodulatory drugs”, primarily by “teaching us the superiority of the MABEL [minimum anticipated biological effect level]-based approach over the NOAEL [no observed adverse effect level]-based approach”.

In sharp contrast to Dr. Hunig’s opinions, we believe that the TeGenero incident happened, not because the preclinical testing systems were not predictive, but because of inadequate expertise in the design, implementation, interpretation and review of the TGN1412 preclinical safety program. The purpose of a preclinical safety assessment program is to identify potential safety risks and to qualify and quantify these risks by the translational use of mechanism-based knowledge of the intended pathway modulation, in vitro human data, and in vitro and in vivo animal data to “predict” in vivo human responses. These criteria were not met for TGN1412. Specifically, the publically-available information in the Investigational Medicinal Product Dossier (IMPD) and/or Investigator’s Brochure (IB) demonstrates deficiencies in four major areas: 1) failure to identify risk based upon the intended target, mechanism of action and previous experiences with comparator products, 2) failure to reconcile discordant preclinical data sets, 3) failure to identify a pharmacologically-relevant species and/or data set for determination of the first-in-human dose (FIHD), and 4) failure to translate the preclinical data to estimate the anticipated pharmacologic activity of the FIHD dose. We shall discuss these topics, and the decision to use a NOAEL approach in order.

Item Type:	Article
Additional Information:	This letter is a cross-company response to the article by Hunig T - The  storm  has  cleared:  lessons  from  the  CD28  superagonist  TGN1412  trial.    Nat  Rev  Immunol  2012;  12:   317-­‐8. I have abbreviated the list of authors as there are 18 of them. These authors are on the leadership committee of "Biosafe", a cross company expert working subgroup of the industry organization "BIO" that specialize in the preclinical safety evaluation of biopharmaceuticals.
Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/8204