Sharon O'kane

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.

Visual analogue scale scoring and ranking: a suitable and sensitive method for assessing scar quality?

Background: The field of scar assessment lacks a standard methodology. Previous methods have focused on a wide range of scar types, resulting in poorer sensitivity and diminishing their discriminatory effectiveness. Methods: As part of a clinical trial investigating the scar-improving efficacy of transforming growth factor-&bgr;3, the authors investigated the use of a visual analogue scale and scar ranking as scar assessment tools. Scar photographic images were assessed using a newly developed computerized scar assessment system by an external lay panel. Results: A total of 4296 scar images were collected for visual analogue scale assessment and 2148 scar pairs were collected for scar ranking. Intrarater consistency was 100 percent for the ranking data, with differences very close to zero for the visual analogue scale consistency data. Reducing the number of assessors in the external panel significantly improved intraclass correlation coefficients. From month 1 to month 12, the correlation coefficients for the difference in visual analogue scale score showed that the assessors reliably noted the changes in the maturing scars. Combining logistic regression with an area under the curve of 0.72 in a receiver operating characteristic curve analysis, the visual analogue scale score was shown to be a highly statistically significant predictor of a good scar. Conclusions: The authors have shown the visual analogue scale scar scoring and scar ranking methods to be consistent, reliable, valid, and feasible. These methods for scar assessment are highly sensitive and capable of reliably measuring differences in scar quality, making them valuable techniques, reaching an unmet clinical need, and enabling investigation of changes in scar quality (e.g., with time or after therapeutic intervention).

Prevention and reduction of scarring in the skin by Transforming Growth Factor beta 3 (TGFβ3): 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 (TGFβ3) as a key regulator of the scar-free phenotype in embryonic healing. Exogenous addition of TGFβ3 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. TGFβ3 has completed safety studies and entered human clinical trials. Data from these studies have demonstrated that TGFβ3 (Juvista™) in humans is safe and well tolerated. Acute, local administration of TGFβ3 (Juvista™) significantly reduces dermal scarring in a dose responsive manner resulting in the regeneration of a skin structure that is permanently improved.

Maturation of the human scar: an observational study.

Background: The natural history of scar maturation in humans has never been formally described from either a clinical or a histologic standpoint. Methods: The maturation of incisional scars was observed in 58 healthy male volunteers who each had 2 × 1-cm incisional wounds created on the inner aspect of both upper arms. The resulting scars were photographed digitally at monthly intervals for 12 months and excised for histologic analysis at specific time points. All histologic specimens were stained using Massons trichrome and reviewed together with the corresponding digital clinical scar images to produce macroscopic and microscopic descriptions of the maturation process. Results: Three distinct groups, each displaying a different rate of longitudinal progression of scar maturation, were identified from within the study group. The majority of volunteers belonged to a “representative” subset but distinct “poor” and “excellent” subsets were also identified. The poor subset invariably contained volunteers younger than 30 years of age, whereas the majority of the excellent subset comprised subjects older than 55 years of age. Conclusions: Scar maturation occurs as a series of defined macroscopic and microscopic stages over the course of 1 year. The rate of scar maturation varied within the study group, with older subjects (>55 years) displaying accelerated maturation, whereas a prolonged high turnover state and a retarded rate of maturation were observed in younger subjects (<30 years).

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.

Transforming Growth Factor beta levels during second intention healing are related to the different course of wound contraction in horses and ponies

Wound healing in horses is often complicated by wound infection, exuberant granulation tissue, and hypertrophic scars, especially when wounds are located on the limbs. Wound healing in ponies is less problematic, characterized by a greater degree of wound contraction and a more intense initial inflammatory response. Because both processes are influenced by transforming growth factor‐β (TGF‐β), it was hypothesized that the better wound healing in ponies was associated with different TGF‐β profiles. A series of small wounds was created on the distal limbs and hindquarters of ponies and horses. Tissue samples were harvested on alternate days until day 13 postwounding, and levels of total and active TGF‐β were determined. Levels of TGF‐β were significantly higher in pony wounds than in those of horses. The TGF‐β profile differed between limb and body wounds, with levels in body wounds decreasing at the end of the experiment and persisting in limb wounds. In ponies, the higher TGF‐β levels can, to a large extent, explain the more intense inflammatory response and may explain the greater degree of wound contraction. Apparently adequate levels in the limbs fail to result in greater wound contraction, probably because of a stronger fixation of the skin. The persistence of elevated levels of TGF‐β may result in the production of exuberant granulation tissue. Further research on the temporal patterns of the different TGF‐β isoforms seems indicated, because manipulation of TGF‐β levels appears to be a promising option for intervention in problematic wound healing in horses. (WOUND REP REG 2002;10:)

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.

Scar redness in humans: how long does it persist after incisional and excisional wounding?

Background: The natural history of scar redness in humans has never been formally described, and the point at which normal scar redness fades is unknown. Methods: As part of a randomized, placebo-controlled, clinical trial investigating the effects of various doses of transforming growth factor-&bgr;3 on scar quality, the authors observed the process of scar redness and maturation in non-drug-treated incisional and excisional wounds made on the upper inner arms of 103 volunteers. Scar photographic images were assessed by a review panel to ascertain the month during which redness faded for a particular scar. Scar histology documented the level of inflammation and angiogenesis. Results: Scar redness faded at an average of 7 months. Scar redness for incisions faded significantly faster than excisions (p = 0.0001, Kruskal-Wallis test), and significant differences were also seen between anteriorly and posteriorly placed scars for incisions (p = 0.0008) and excisions (p = 0.0035), respectively. Month 12 histologic examination revealed the absence of any ongoing inflammatory processes in all scars. Conclusions: Scar redness fades on average at 7 months. This is influenced by the wound type and position. The authors advocate the use of the term “rubor perseverans” to describe the physiologic redness of a normal scar as it matures beyond the first month, a process that does not involve inflammation.

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.