皮膚專科朱芃年醫師的醫學美容部落格

Intradermal Avotermin Improves Appearance of Scars in Early Clinical Trials

April 10, 2009 — Intradermal injection of avotermin, a clinical application of transforming growth-factor beta 3 (TGFβ3), has the potential to provide accelerated improvement in scarring, according to results of 3 phase 1/2 randomized trials reported in the April 10 issue of The Lancet.

"Skin is the most frequently injured tissue, and millions of people worldwide acquire scars every year," write Mark W. J. Ferguson, PhD, BDS, FDS, FFD, from the Faculty of Life Sciences at the University of Manchester, United Kingdom, and chief executive officer of Renovo, the manufacturer of avotermin, and colleagues. "Some therapies aim to improve existing scars; however, these treatments are empirically based and do not have evidence of efficacy from [randomized] controlled trials."

The authors write that 20 years of research into skin scarring has identified TGFβ3, a skin morphogenic factor synthesized predominantly by keratinocytes and fibroblasts, as a potential antiscarring therapy. So in their 3 double-blind, placebo-controlled studies, the investigators compared the preventive administration of avotermin (recombinant, active, human TGFβ3) with placebo or standard wound care in healthy volunteers aged 18 to 85 years. All studies excluded women of childbearing potential to avoid pregnancy during the trial.

The participants in all studies received 1-cm incisions on each arm. Intradermal avotermin was then administered in concentrations ranging from 0.25 to 500 ng/100 µL per linear centimeter wound margin. Treatments were randomly allocated to wound sites by a computer-generated randomization scheme. Primary endpoints were visual assessment of scar formation at 6 months and 12 months in the first 2 studies, and from week 6 to month 7 in the third. Efficacy analyses were intention to treat.

An independent scar assessment panel, made up of lay volunteers blinded to treatment, scored standardized and calibrated digital images of scars from all studies with a 100-mm visual analog scale (VAS). In study 0036, a panel consisting of 6 US board-certified clinical experts (3 dermatologists, 2 facial plastic surgeons, and 1 oculofacial plastic surgeon) also scored digital images of scars taken at 7 months using a 100-mm VAS. Both panels also reviewed paired photographs of treated scars and ranked which, if any, appeared better. A clinical investigator also scored scars with a VAS at every study visit.

Phase 1/2 Study (1002)

The first trial, completed in September 2003 and named study 1002 by the investigators, was a phase 1/2 study consisting of 103 healthy men (96% white) aged 18 to 45 years with a body mass index (BMI) of 15 to 55 kg/m2. A total of 76 participants (74%) completed the study.

Each man received 2 full-thickness incisions 1 cm in length on the inner aspect of each upper arm (1 posterior and 1 anterior incision, separated by 3 cm) and then was randomly allocated to receive 1 of 7 doses of avotermin: 0.25, 1, 5, 20, 50, 100, or 500 ng/100 µL. On the first arm, the participants received avotermin at 1 incised site and either placebo or standard care at the other. On the second arm, the treatment pattern was switched, with avotermin applied to the incision location (posterior or anterior) not used in the first arm and placebo or standard care applied to the other.

On arm 1, the incisions were dosed on day 0 (before surgery), day 1, and day 3 (before excision). After an elliptical excision was performed on day 3, the patients were redosed on day 4. Arm 2 incisions were used for scar improvement assessment and were dosed on day 0 and on the day after surgery (day 1). They were not excised.

In addition, 1 punch biopsy sample 3 mm in diameter was taken from the inner aspect of each upper arm (4 cm from the incision sites) to test for adverse effects. These samples were then randomly allocated to treatment with 100 µL/3 mm of avotermin or a control, and with dosing schedules similar to those for incisions.

Phase 2 Study (1005)

The second trial was a phase 2 study completed in June 2003 and named study 1005. It consisted of 33 men and 9 postmenopausal women (by at least 2 years) who were 60 years or older with a BMI of 15 to 35 kg/m2. Each participant in this study received a single 1-cm full-thickness incision on the inner aspect of each upper arm (anterior to the long axis of the arm), and participants were then randomly allocated to receive 1 of 3 doses of avotermin: 5, 50, or 100 ng/100 µL. On the first arm, the participants received either avotermin or placebo, with the second arm receiving the other treatment. All dosings were given immediately before incision and 24 hours later.

Two 3-mm punch biopsy samples were also taken in this study from each inner upper arm. These samples were then randomly allocated to treatment with 100 µL/3 mm of avotermin or a control, with dosing schedules similar to those for incisions.

Results

In both of these studies, results showed significant improvements from the 50 ng/100 µL dose of avotermin. In study 1002, the median VAS score improved by 8 mm (range, -29 to 18; P = .0230) compared with control subject scores at month 12. Also at month 12, a total of 12 avotermin-treated scars (60%) showed at least a 10% improvement, and 5 avotermin-treated scars (25%) showed improvement of at least 25%.

Scar redness was also assessed as fading faster in wounds receiving avotermin vs control wounds (P < .01 for all avotermin doses except 500 ng/100 µL).

In study 1005, the median VAS score improved by 5 mm (range, -2 to 14; P = .001) for the 50 ng/100 µL avotermin dose compared with placebo at month 6, with 10 avotermin-treated scars (67%) showing 10% or more improvement and 6 avotermin-treated scars (40%) showing improvement of 25% or more.

Scar redness in this trial faded significantly faster after treatment with both 5 ng/100 µL and 50 ng/100 µL doses of avotermin vs placebo (P < .01).

Second Phase 2 Study (0036)

Study 0036 was a phase 2 trial completed in August 2007 consisting of 78 healthy men and women aged 18 to 85 years, with a BMI of 15 to 35 kg/m2. All participants received 4 incision wounds 1 cm in length on the inner aspect of each upper arm, giving 4 pairs of anatomically matched wound sites per person. They then received 4 concentrations of avotermin (5, 50, 200, and 500 ng/100 µL), with each dose administered to 1 wound site per anatomically matched pair of wounds. The second wound site from each matched pair received the placebo.

For this article, the authors reported results from the 39 participants randomly assigned to the subgroup that received avotermin or placebo 10 to 30 minutes before wounding, with a second treatment given 24 hours (range, 20 – 28 hours) later.

These results showed that avotermin significantly improved total scar scores at all concentrations vs placebo (mean improvement, from 14.84 mm [95% confidence interval (CI), 5.5 – 24.2 mm] at 5 ng/100 µL to 64.25 mm [95% CI, 49.4 – 79.1 mm] at 500 ng/100 µL).

In addition, avotermin 500 ng/100 µL significantly improved VAS scores vs placebo at all time points, including by 16.12 mm (95% CI, 10.61 – 21.63 mm) after only 6 weeks from wounding.

For all 3 trials, there were no treatment-related serious adverse events, whereas adverse events at wound sites were similar for both participants receiving avotermin and control treatment. Although erythema and edema were more frequent with avotermin than with placebo, they were transient and deemed consistent with normal wound healing.

The study authors write that limitations include the predominantly male study populations and that studies 1002 and 1005 "were exploratory and not sufficiently powered to establish a definitive dose-response curve." However, they say that the results of these studies were confirmed and extended in study 0036, which was powered to show treatment effects.

"Our series of three [randomized], within-participant controlled clinical trials have shown that intradermal administration of avotermin to incisions reduces subsequent skin scarring compared with control treatment," the study authors conclude. "[The results] show that avotermin (TGFβ3) is a new class of prophylactic medicine promoting the regeneration of healthy skin and improving scar appearance."

In an accompanying editorial, Edward E. Tredget, MD, from the Department of Critical Care Medicine, and Jie Ding, from the Division of Plastic Surgery in the Department of Surgery, University of Alberta, Edmonton, Canada, write, "The investigators are to be congratulated for successful completion of a well-designed and carefully controlled study that used a previously validated outcome measure of clinical significance to a broad range of both patients and observers."

The editorialists continue, "Although the investigators have acknowledged their commercial interests in TGFβ3, adherence to established standards in this translational investigation and the rigorous nature of the statistical analysis in a well powered series of studies provide strong evidence for the benefits of avotermin in this setting."

They go on to list the 2-dimensional nature of scar assessment in standardized photographs and the need to apply treatment before skin wounding as study limitations. In addition, "The use of total scar score in primary efficacy analysis in the final study...might be less preferable to [analysis of variance] for repeated measurements over time."

However, the editorial authors conclude, "With these investigations, Ferguson and colleagues provide substantial optimism for new solutions to difficult fibrotic disorders in the future."

This study was supported by Renovo. All authors of the article are or were formerly employees of Renovo, with several owning shares in the company. Dr. Ferguson is a cofounder of the company. Dr. Tredget disclosed a joint patent application for keratinocyte-derived antifibrogenic factor. The Canadian Institutes for Health Research and the Firefighters' Burn Trust of the University of Alberta supported for the editorial.

http://www.medscape.com/viewarticle/590916?src=rss