First clinical evaluation of the safety and efficacy of tarumase for the debridement of venous leg ulcers.

We report the first clinical evaluation of a new enzymatic wound debridement product containing tarumase in venous leg ulcer patients. As a first-in-human study, this was a prospective, open-label, multi-centre, dose escalation study across five dose cohorts and involving a total of 43 patients treated three times weekly for up to 4 weeks (12 applications). The primary and secondary endpoints of the study were to assess the systemic safety, local tolerability, and early proof of concept both for wound debridement and healing. Results indicated that the tarumase enzyme was well tolerated when applied topically to wounds, with no indications of systemic absorption, no evidence of antibody generation, and no systemic effects on coagulation pathways. Locally, there was no evidence of pain on application, no local itching, no increases in erythema, oedema, exudate or bleeding and only a few treatment emergent adverse events were reported. As the concentration of tarumase was escalated, trends towards faster and improved effectiveness of wound debridement were observed, especially in patients with significant slough at baseline. Trends towards faster rates of healing were also noted based on observations of increased granulation tissue, increased linear healing and reduction in surface area over the 4-week treatment period.

Preliminary evidence supporting a new enzymatic debridement product for use in chronic wounds.

A new recombinant proteolytic enzyme, isolated from maggot saliva, with fibrinolytic action has been investigated through a series of non-clinical toxicology and in-vitro/in-vivo pharmacology studies to explore its potential safety and efficacy as an enzymatic debridement agent for use in chronic wounds. Studies indicate that the enzyme has a good safety profile. When locally administered, it is not detrimental to wound healing, is non-sensitising and is rapidly inactivated in the systemic circulation. Adverse effects are limited, at very high concentrations, to transient erythema at the site of application. In-vitro testing indicates that the enzyme, whilst selective for fibrin, has additional proteolytic action against collagen and elastin, with enzymatic action for all three substrates being dose dependent. In-vivo, we used an established MRSA biofilm model, in which microbiological counts were used as a surrogate for debridement efficacy. Here, we showed that higher concentrations of the enzyme in a formulated proprietary gel, significantly reduced MRSA counts over a period of 2 to 14 days, and significantly improved the vascularity of the wound at 14 days. Together, these data support the potential for this maggot-derived proteolytic enzyme as a clinically effective debriding agent.

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.

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.

Avotermin for the improvement of scar appearance: a new pharmaceutical in a new therapeutic area.

Disfiguring scarring in the skin is an area of high medical need. Current treatments for scarring have variable or limited effectiveness and have typically not been evaluated in randomized, controlled, double-blind clinical trials. The prophylactic improvement in scar appearance, through administration of agents around the time of injury, represents a new therapeutic approach for which there are currently no registered pharmaceuticals. Extensive research into the mechanisms of scar-free and scar-forming healing has provided a robust scientific rationale for the development of avotermin (human recombinant TGF-beta3) as a potential therapeutic for the improvement of scar appearance in humans. The pioneering approach used for the clinical development of avotermin in this new indication has explained the efficacy and safety profile of avotermin in several, prospectively randomized, double-blind clinical studies in human volunteers and patients. These studies, which show a clear translation from preclinical efficacy models to the clinical environment, have shown that prophylactic scar improvement is pharmaceutically achievable. It is anticipated that therapeutics such as avotermin, with a sound mechanistic basis and proof of effectiveness in suitably robust clinical trials, will be available to meet the needs of patients in the foreseeable future.

A randomised comparison of radical radiotherapy with or without chemotherapy for patients with non-small lung cancer: results from the Big Lung Trial.

BACKGROUND: A meta-analysis of trials comparing primary treatment with or without chemotherapy for patients with non-small cell lung cancer published in 1995 suggested a survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings studied, but it included many small trials, and trials with differing eligibility criteria and chemotherapy regimens. METHODS: The Big Lung Trial was a large pragmatic trial designed to confirm the survival benefits seen in the meta-analysis, and this paper reports the findings in the radical radiotherapy setting. The trial closed before the required sample size was achieved due to slow accrual, with a total of 288 patients randomised to receive radical radiotherapy alone (146 patients) or sequential radical radiotherapy and cisplatin-based chemotherapy (142 patients). RESULTS: There was no evidence that patients allocated sequential chemotherapy and radical radiotherapy had a better survival than those allocated radical radiotherapy alone, HR 1.07 (95% CI 0.84-1.38, P=0.57), median survival 13.0 months for the sequential group and 13.2 for the radical radiotherapy alone group. In addition, exploratory analyses could not identify any subgroup that might benefit more or less from chemotherapy. CONCLUSIONS: Despite not suggesting a survival benefit for the sequential addition of chemotherapy to radical radiotherapy, possibly because of the relatively small sample size and consequently wide confidence intervals, the results can still be regarded as consistent with the meta-analysis, and other similarly designed recently published large trials. Combining all these results suggests there may be a small median survival benefit with chemotherapy of between 2 and 8 weeks.