TGFβ3 IMMUNOASSAY STANDARDIZATION: COMPARISON OF NIBSC REFERENCE PREPARATION CODE 98/608 WITH AVOTERMIN LOT 205-0505-005

Abstract

Juvista™ drug product contains human recombinant active transforming growth factor beta 3 (TGFβ3; avotermin). Juvista is being developed for the prevention and reduction of human scarring. Phase II and III clinical and development batches of Juvista were assayed for content by an immunoenzymometric assay (IEMA) using a National Institute for Biological Standards and Control (NIBSC) TGFβ3 reference material (98/608) and avotermin standard (Lot 205-0505-005). Paired Juvista TGFβ3 data were compared directly, pooled, and processed using the statistical analysis described by Bland and Altman. A direct comparison of the two standards was also made. The Bland-Altman result was 1.958, the best estimate of the relationship between Lot 205-0505-005 and reference material 98/608. By IEMA, reference material 98/608 has approximately 50% of the immunoreactivity of Lot 205-0505-005. During clinical development, no change in Juvista TGFβ3 dosage was made, but the standard used for Juvista TGFβ3 assay was changed from 98/608 to 205-0505-005. The stated amount of Juvista TGFβ3 in phase III trials was approximately one-half of that in phase II trials. This article highlights the importance of early adoption of an appropriate and representative standard to achieve accurate quantification of protein drug during clinical development.

Regeneration of Dermis: Scarring and Cells Involved

“…Phase I and II clinical studies of recombinant human TGF-β3 (Avotermin or Juvista) have been successful, where the administration of TGF-β3 reduced scars [82,83]. However, phase III failed and, among other things, the correct system of standardization of the amount of active substance in the sample during the production process was missed [84].…”

The Spectrum of Scarring in Craniofacial Wound Repair

“…Second, although some approaches have been shown to improve scar appearance, to date there is no available therapy that supports true regeneration of skin with secondary dermal elements. Agents targeting the TGFβ signaling pathway and various cellular treatments using autologous adipose- and bone marrow-derived stem cells showed promise in preclinical trials but have not demonstrated clinical efficacy (So et al, 2011; Little et al, 2012). Considering the physiologic and pathologic role that mechanical forces play in wound healing and scar remodeling (Akaishi et al, 2008; Ogawa et al, 2012; Huang et al, 2017).…”

Dynamics of Transforming Growth Factor Beta Signaling in Wound Healing and Scarring

“…162 Unfortunately, avotermin failed to show efficacy in Phase III trials, possibly due to the use of a different TGF-b3 standard, which led to a twofold overestimation of TGF-b3 concentration, and, therefore, a 50% lower dose of TGF-b3 used in the Phase III clinical trial as compared with the Phase I/II clinical trials. 166 Antisense oligonucleotides. Antisense oligonucleotides are single-stranded DNA or RNA that are complementary to a specific mRNA sequence which blocks target gene expression either by inhibiting RNA translation or by promoting enzymatic degradation of the mRNA target.…”