Discovery and development of avotermin (recombinant human transforming growth factor beta 3): a new class of prophylactic therapeutic for the improvement of scarring.

Scarring in the skin following surgery or trauma may be associated with adverse aesthetic, functional, growth and psychological effects, such that both physicians and patients regard it as important to minimize the appearance of scars. The prophylactic improvement of cutaneous scar appearance represents a significant opportunity to improve the well-being of patients. Human recombinant transforming growth factor beta 3 (avotermin) is the first in a new class of therapeutic agents to address this medical need. Herein we describe scar-free healing in early embryonic development, including the identification of the cellular and molecular mechanisms underpinning the scarring process. This understanding has led to the discovery of novel therapeutics such as transforming growth factor beta 3, which can be administered to improve scar appearance in human subjects through pharmacological action. We discuss the pioneering development of transforming growth factor beta 3 in this new therapeutic area showing how it has been possible to translate preclinical concepts into clinical application, namely the improvement of scar appearance following surgery.

Managing the challenge of chemically reactive metabolites in drug development.

The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry.

Effects of avotermin (transforming growth factor ß3) in a clinically relevant pig model of long, full-thickness incisional wounds.

BACKGROUND: The pig is an accepted species for evaluating the safety of molecules in dermal wound healing indications; however, the sizes of wounds assessed have not always been comparable to large incisions encountered clinically. OBJECTIVE: To develop a clinically relevant model of incisional wounding in the Göttingen minipig for assessing the safety and tolerance of compounds in development to improve scarring. METHODS: Intradermal avotermin (recombinant transforming growth factor ß3 [TGFß3]) up to 6,000 ng/100µL was administered twice to 20 cm full-thickness incisions. RESULTS: Incisions were well tolerated in the minipig. Avotermin treatment was not associated with adverse changes in a range of clinical parameters, including wound healing and strength. Plasma TGFß3 levels were transient with ≈0.1% bioavailability. CONCLUSION: A clinically relevant model of long, full-thickness, sutured surgical incisions in the minipig is achievable. Avotermin is well tolerated in this model and does not adversely affect normal wound healing at levels that significantly exceed those doses to be used clinically in humans.

The potential of cytokines as safety biomarkers for drug-induced liver injury.

Drug-induced liver injury (DILI) is an event that has a detrimental impact on drug development and patient safety; therefore the identification of novel biomarkers that are both sensitive and specific to the liver would have great benefit. Inflammation is known to be associated with human cases of DILI, and given the role of cytokines in modulating the inflammatory response, changes in cytokine expression patterns certainly show promise as potential biomarkers of DILI. Cytokines are interesting candidates for novel biomarkers as they are relatively accessible (by blood sampling) and accurately quantifiable. In particular, recent interest has developed in mechanism-specific, rather than tissue-specific, biomarkers. However, without fully understanding the role of inflammation in DILI and the role of cytokines in modulating the inflammatory response, cytokines may be limited in their use, being either diagnostic of the type of injury that has occurred and/or prognostic of outcome (recovery from DILI, cirrhosis, acute liver failure). Intracellular components released by damaged hepatocytes, although inaccessible and currently difficult to quantify, may be better biomarkers for the prognosis of severity of injury. In both cases there is a pressing need for the development and validation of assays sensitive enough and with a sufficient dynamic range to detect changes upon drug treatment. Although promising candidates are appearing in the literature, much remains to be done to understand the role of inflammation in DILI and the role that a given cytokine has in the inflammatory cascade associated with DILI before cytokines are viewed as biomarkers for DILI.

Prevention and reduction of scarring in the skin by Transforming Growth Factor beta 3 (TGFbeta3): from laboratory discovery to clinical pharmaceutical.

Scarring in the skin after trauma, surgery, burn or sports injury is a major medical problem, often resulting in adverse aesthetics, loss of function, restriction of tissue movement and/or growth and adverse psychological effects. Current treatments are empirical and unpredictable, and there are no prescription drugs for the prevention or treatment of dermal scarring. We have investigated the cellular and molecular differences between scar-free healing in embryonic wounds and scar-forming healing in adult wounds. We have identified Transforming Growth Factor beta 3 (TGFbeta3) as a key regulator of the scar-free phenotype in embryonic healing. Exogenous addition of TGFbeta3 to cutaneous wounds in pre-clinical (adult) in vivo models reduces early extracellular matrix deposition and these molecules are deposited with a markedly improved architecture in the neodermis, resembling that of normal skin. This improvement of structural organisation in the healing wound is self-propagating and leads to a reduction of subsequent scarring. TGFbeta3 has completed safety studies and entered human clinical trials. Data from these studies have demonstrated that TGFbeta3 (Juvista) in humans is safe and well tolerated. Acute, local administration of TGFbeta3 (Juvista) significantly reduces dermal scarring in a dose responsive manner resulting in the regeneration of a skin structure that is permanently improved.