James Bush

Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies

BACKGROUND Research into mechanisms of skin scarring identified transforming growth factor beta3 (TGFbeta3) as a potential antiscarring therapy. We assessed scar improvement with avotermin (recombinant, active, human TGFbeta3). METHODS In three double-blind, placebo-controlled studies, intradermal avotermin (concentrations ranging from 0.25 to 500 ng/100 microL per linear cm wound margin) was administered to both margins of 1 cm, full-thickness skin incisions, before wounding and 24 h later, in healthy men and women. Treatments (avotermin and placebo or standard wound care) were randomly allocated to wound sites by a computer generated randomisation scheme, and within-participant controls compared avotermin versus placebo or standard wound care alone. Primary endpoints were visual assessment of scar formation at 6 months and 12 months after wounding in two studies, and from week 6 to month 7 after wounding in the third. Investigators, participants, and scar assessors were blinded to treatment. Efficacy analyses were intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00847925, NCT00847795, and NCT00629811. RESULTS In two studies, avotermin 50 ng/100 microL per linear cm significantly improved median score on a 100 mm visual analogue scale (VAS) by 5 mm (range -2 to 14; p=0.001) at month 6 and 8 mm (-29 to 18; p=0.0230) at month 12. In the third, avotermin significantly improved total scar scores at all concentrations versus placebo (mean improvement: from 14.84 mm [95 % CI 5.5-24.2] at 5 ng/100 microL per linear cm to 64.25 mm [49.4-79.1] at 500 ng/100 microL per linear cm). Nine [60%] scars treated with avotermin 50 ng/100 microL per linear cm showed 25% or less abnormal orientation of collagen fibres in the reticular dermis versus five [33%] placebo scars. After only 6 weeks from wounding, avotermin 500 ng/100 microL per linear cm improved VAS score by 16.12 mm (95% CI 10.61-21.63). Adverse events at wound sites were similar for avotermin and controls. Erythema and oedema were more frequent with avotermin than with placebo, but were transient and deemed to be consistent with normal wound healing. INTERPRETATION Avotermin has potential to provide an accelerated and permanent improvement in scarring.

Interleukin-10 reduces scar formation in both animal and human cutaneous wounds: results of two preclinical and phase II randomized control studies.

Cutaneous scarring affects up to 100 million people per annum. There is no effective scar reducing/preventing therapeutic developed to date. Interleukin (IL)‐10 is an anti‐inflammatory and antifibrotic cytokine. In the embryo it is important for scarless wound repair. We investigated the effect on wound healing and scarring of a double deletion of the IL‐10 and IL‐4 genes in a knockout (KO) mouse model, and also the effect of exogenous addition of recombinant human (rh) IL‐10 into rat and human cutaneous incisions. Mouse study: Two incisions were made on the dorsal skin of 20 double IL‐4/IL‐10 KO mice and 20 wild‐type (WT) controls. Rat study: Three concentrations of rhIL‐10 were investigated. Four incisions were made on the dorsal skin of 30 rats. Each rat received two concentrations. Each incision receiving a concentration of rhIL‐10 was matched with a control incision, which received either placebo or standard care. Human study: Eight concentrations of rhIL‐10 were investigated. Four incisions were made on each arm of 175 healthy volunteers. Four incisions received four different concentrations, which were matched with four control incisions that received either standard care or placebo. KO mice healed with poor scar histology and increased inflammation. rhIL‐10–treated rat incisions healed with decreased inflammation, better scar histology, and better macroscopic scar appearance. rhIL‐10–treated human incisions at low concentrations healed with better macroscopic scar appearance and less red scars. IL‐10 is an important cytokine in wound healing and its suppression of inflammation and scarring is demonstrated in mice and rats with a translational effect in humans.

Avotermin for scar improvement following scar revision surgery: a randomized, double-blind, within-patient, placebo-controlled, phase II clinical trial.

Background: Skin scarring is associated with psychosocial distress and has a negative effect on quality of life. The transforming growth factor (TGF)-&bgr; family of cytokines plays a key role in scarring. TGF-&bgr;3 improves scar appearance in a range of mammalian species. This study was performed to assess the efficacy of intradermal avotermin (TGF-&bgr;3) for the improvement of scar appearance following scar revision surgery. Methods: Sixty patients (35 men and 25 women; age, 19 to 78 years; 53 Caucasians; scar length, 5 to 21 cm) received intradermal avotermin (200 ng/100 &mgr;l/linear cm wound margin) and placebo to outer wound segments immediately after, and again 24 hours after, complete (group 1) or staged (group 2) scar revision surgery. A within-patient design was chosen to control for interindividual factors that affect scarring. The primary efficacy variable was a total scar score derived from a visual analogue scale, scored by a lay panel from standardized photographs from months 1 through 7 following treatment. Results: Primary endpoint data from the combined surgical groups showed that avotermin significantly improved scar appearance compared with placebo (total scar score difference, 21.93 mm; p = 0.04). Profilometry showed a greater reduction in scar surface area from baseline with avotermin treatment compared with placebo, significant in group 2 at months 7 and 12 (difference, 41.99 mm and 25.85 mm, respectively; p = 0.03 for both comparisons). Histologic analysis from group 2 showed that, compared with placebo treatment, collagen organization in avotermin-treated scars more closely resembled normal skin in 14 of 19 cases. Avotermin was well tolerated. Conclusion: Avotermin administration following scar revision surgery is well tolerated and significantly improves scar appearance compared with placebo. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I. Figure. No caption available.

Scar-improving efficacy of avotermin administered into the wound margins of skin incisions as evaluated by a randomized, double-blind, placebo-controlled, phase II clinical trial.

Background: The authors report on a prospective, randomized, placebo-controlled phase II trial to investigate avotermin (transforming growth factor beta-3) for reducing scarring resulting from acute incised skin wounds. Methods: Seventy-one healthy male subjects (18 to 45 years) received avotermin at 50 or 200 ng/100 &mgr;l/linear centimeter of wound margin. Subjects received three standardized 1-cm incisional wounds on the inner aspect of each upper arm. Wounds were randomized to receive (into each margin): no injection (standard wound care only), one intradermal injection of avotermin or placebo (immediately before surgery), or two injections of avotermin or placebo (immediately before surgery and 24 hours later). The primary efficacy variable was a 10-cm visual analog scale score, which assessed how closely scars resembled normal skin, administered at month 12 by an independent external scar assessment panel (a panel of lay public individuals). Results: Avotermin at 200 ng/100 &mgr;l/linear centimeter, administered once or twice, achieved significant improvements in scar appearance compared with controls (p < 0.02 for all comparisons). The 50-ng dose, administered twice, achieved significant improvements in scar appearance versus placebo (p = 0.043). Treatment was well tolerated. Conclusion: These results confirm that avotermin is the first of a new class of regenerative medicines that reduce scarring when administered once or twice to the approximated margins of acute skin incisions.

Randomized phase II clinical trial of avotermin versus placebo for scar improvement

Scarring is a major problem following skin injury. In early clinical trials, transforming growth factor β3 (avotermin) improved scar appearance. The aim of this study was to determine whether an injection of avotermin at the time of wound closure is effective in improving scar appearance.

Recommendations on clinical proof of efficacy for potential scar prevention and reduction therapies

Cutaneous scarring is an enormous medical problem with approximately 100 million patients acquiring scars each year. Scar prevention/reduction represents a significant, and largely unmet, clinical need. Research into the prophylactic modulation of scar outcome differs from research into other disease processes as the scar is not present at the start of the study; measurements of changes from baseline are impossible. Final scar morphology is influenced by many variables. A fundamental principle that should be observed in the prospective evaluation of scar prevention/reduction therapies is that, if left untreated, wounds in treatment and control groups should have healed with identical scars. Observation of this principle will allow the detection of true treatment effects. The many variables that influence scar morphology mean that the evaluation of potential pharmaceutical products for this indication favors the use of self‐controlled designs in clinical trials. In this article, we review variables that affect scar morphology and recommend the self‐controlled design for clinical trials aiming to establish proof of efficacy of scar prevention and reduction pharmaceuticals. With no pharmaceutical products currently licensed for this indication, this represents a new therapeutic area. The principles discussed will also have direct relevance to the wider fields of wound healing and regenerative medicine.

Dynamic Skin Tension in the Forearm: Effects of Pronation and Supination

PURPOSE Longitudinal scars on the radial quadrant of the distal forearm skin envelope are typically observed to be wider than those on the ulnar quadrant and have an increased incidence of hypertrophic change. Forearm rotation movements may produce differential skin tensions within the forearm skin envelope, and this may lead to differential scarring patterns. This study was designed to measure skin tension changes in the forearm as a result of rotational position to see if these would be consistent with the hypothesis that greater tension changes are observed on the radial aspect of the forearm. METHODS The effect of forearm position on the magnitude and direction of skin tension was measured on human volunteers. Standardized circles were marked in circumferential fashion at specified intervals on forearm skin, and the angular and dimensional distortion of these circles that occurred with forearm rotation was measured with caliper and goniometer. Data were analyzed for statistical significance using paired t-test. RESULTS Pronation and supination resulted in marked angular rotation of the lines of maximal skin tension at all sites on the forearm. Supination resulted in a greater angular deviation of the lines of maximal skin tension from the longitudinal line of usual surgical incision, particularly on the radial aspect of the forearm. In supination, the magnitude of ellipsoid deformation at the distal forearm was greater on the radial aspect compared with that of the ulnar. Similar significant changes were also demonstrated at the mid-forearm and proximal forearm levels. CONCLUSIONS This study systematically maps the effects of pronation and supination on skin tension within the forearm skin envelope. The significant changes occurring in both the ellipsoid deformation and ellipsoid orientation support our hypothesis that the magnitude of skin tension changes significantly with forearm rotation. The radial aspect of the distal forearm experiences the greatest changes, particularly as the forearm supinates.

A New Approach for the Prophylactic Improvement of Surgical Scarring: Avotermin (TGFβ3)

Patients and physicians are concerned about scarring resulting from surgery, and patients, in particular, value even small improvements in scarring. Translational research into the processes involved in scarring at the molecular, cellular, and tissue levels has facilitated the discovery and development of new biological approaches for improving scarring. This article highlights research concerning avotermin (human recombinant TGF beta 3), the first in a new class of prophylactic medicines that may promote the regeneration of normal skin and improve scar appearance.