Many drugs that target transforming growth factor-β (TGFβ) signalling have been developed, some of which have reached Phase III clinical trials for a number of disease applications. Preclinical and clinical studies indicate the utility of these agents in fibrosis and oncology, particularly in augmentation of existing cancer therapies, such as radiation and chemotherapy, as well as in tumour vaccines. There are also reports of specialized applications, such as the reduction of vascular symptoms of Marfan syndrome. Here, we consider why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGFβ inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens.

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Targeting the TGFβ signalling pathway in disease.

The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases.

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Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis

Over the past decade, immune therapy has become a standard treatment for a variety of cancers. Monoclonal antibodies, immune adjuvants, and vaccines against oncogenic viruses are now well-established cancer therapies. Immune modulation is a principal element of supportive care for many high-dose chemotherapy regimens. In addition, immune activation is now appreciated as central to the therapeutic mechanism of bone marrow transplantation for hematologic malignancies. Advances in our understanding of the molecular interactions between tumors and the immune system have led to many novel investigational therapies and continue to inform efforts for devising more potent therapeutics. Novel approaches to immune-based cancer treatment strive to augment antitumor immune responses by expanding tumor-reactive T cells, providing exogenous immune-activating stimuli, and antagonizing regulatory pathways that induce immune tolerance. The future of immune therapy for cancer is likely to combine many of these approaches to generate more effective treatments.

Immune therapy for cancer.

https://hal.archives-ouvertes.fr/hal-00506515/document

TGF-β and fibrosis in different organs — molecular pathway imprints

The extracellular matrix (ECM) consists of numerous macromolecules classified traditionally into collagens, elastin, and microfibrillar proteins, proteoglycans including hyaluronan, and noncollagenous glycoproteins. In addition to being necessary structural components, ECM molecules exhibit important functional roles in the control of key cellular events such as adhesion, migration, proliferation, differentiation, and survival. Any structural inherited or acquired defect and/or metabolic disturbance in the ECM may cause cellular and tissue alterations that can lead to the development or progression of disease. Consequently, ECM molecules are important targets for pharmacotherapy. Specific agents that prevent theexcess accumulation of ECM molecules in the vascular system, liver, kidney, skin, and lung; alternatively, agents that inhibit the degradation of the ECM in degenerative diseases such as osteoarthritis would be clinically beneficial. Unfortunately, until recently, the ECM in drug discovery has been largely ignored. However, several of today's drugs that act on various primary targets affect the ECM as a byproduct of the drugs' actions, and this activity may in part be beneficial to the drugs' disease-modifying properties. In the future, agents and compounds targeting directly the ECM will significantly advance the treatment of various human diseases, even those for which efficient therapies are not yet available.

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Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy

Objective. To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth factor beta 1 (TGF beta 1), in the treatment of early-stage diffuse cutaneous systemic sclerosis (dcSSc). Methods. Patients with SSc duration of < 18 months were randomly assigned to the placebo group or to 1 of 3 CAT-192 treatment groups: 10 mg/kg, 5 mglkg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT-192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGF beta 1 and TGF beta 2. Results. Forty-five patients were enrolled. There was significant morbidity and mortality, including I death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r = -0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). Conclusion. We report the first evaluation of a systemically administered and repeatedly dosed anti-TGF beta 1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed. (Less)

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Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192

Human safety issues arise throughout the life cycle of pharmaceutical products and relevant information comes from a multitude of sources. Assessment and management of risks to humans requires a problem-based analysis to bring together relevant information regardless of source. The Safety Evaluation Plan (SEP) is a tool to support problem-oriented safety analysis. Safety issues are specified and the evaluation and management of each problem is based on a status summary that integrates the most current information from all relevant sources. The status summary is updated regularly during the course of clinical development to reflect the results of new studies and new clinical trials. In the postmarketing period, relevant postmarketing data is incorporated. Recent regulatory initiatives emphasise early identification of product safety risks so that appropriate risk-management measures can be instituted at the time of approval. A problem-oriented approach supports growing regulatory expectations regarding risk assessment and risk management. The problem-oriented approach facilitates early identification of safety issues and an evidence-based approach to their evaluation. Proactive management of safety problems leads to prompt assessment of risks and timely and appropriate steps aimed at risk reduction. The SEP provides a single global assessment for each safety issue. Regulatory submissions for pharmaceutical and biological products are organised by type of information. International Conference of Harmonisation documents covering clinical safety issues structure and analyse information separately by type, for example, adverse events, serious adverse events, laboratory data, vital signs, etc. A problem-oriented analysis would need to find a place in the regulatory process. A problem-oriented approach to safety cuts across typical structures in the pharmaceutical industry where different groups handle preclinical, clinical and postmarketing safety information. The SEP can improve communication within the company and externally. Nonetheless, supporting structures need to be adapted to support such an interdisciplinary process. Overall, the problem-oriented approach, supported by a SEP, contributes to realistic expectations and sustained credibility when dealing with safety issues.

A Problem-Oriented Approach to Safety Issues in Drug Development and Beyond

Joanna F. Haas joined Genzyme in 2000 after spending 15 years working in clinical development and pharmacovigilance for leading pharmaceutical companies in France, Germany, Austria and the US. She is a recognized leader in the management of human safety risks and has participated in industry and government collaborations in the US and Europe to optimize pharmacovigilance regulations and standards. For products that will be on the market you need to use methods that are available and will be accepted in medical practice.

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Joanna F. Haas

Papers

Recombinant human anti-transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo-controlled phase I/II trial of CAT-192

A Problem-Oriented Approach to Safety Issues in Drug Development and Beyond

An audience with... Joanna F. Haas.