EDITORIAL
Antiscarring pharmaceuticals: Lost in translation?
Firstly, we congratulate the investigators at Renovo in Manchester, United Kingdom, for the execution of an excellent randomized, double-blind, exploratory trial on the effect of the putative antiscarring cytokine interleukin-10 (rhIL-10; Prevascar).1 The rationale was that IL-10 had shown favorable effects on scarring in preclinical wound-healing models and in light-skinned healthy volunteers. Unexpectedly, these previous results could not be reproduced in a cohort of scarprone dark-skinned individuals in the present study.1 Actually, the scars tended to look better with placebo treatment. What justifies the use of biological medicine in problematic scarring? Cutaneous scars, such as hypertrophic scars or keloids, and fibrotic healing after surgery, burns, or even after minor skin insults, represent a huge medical problem with near to nil treatment options. Cosmetic concerns are important, but pain, redness, pruritus, paresthesia, and functional impairment are all related symptoms with a negative impact on the quality of life.2 Even small scars, especially in visible sites, are often distressing to the patient. In the US only, more than 150,000 scar revisions are carried out yearly but, sadly, with frequent unsatisfactory results from the patients’ perspective. Also, the costs associated with scar revision procedures can be substantial.3 Thus, the therapeutic area of scar prophylaxis represents an unmet medical need. This was realized by Renovo, which was cofounded by professor Mark Ferguson in 1998. To enter this essentially unexplored medical field, well over $US 100 million were raised. This funding enabled Renovo to perform the most ambitious and largest development program in the history to “be first to market with a scar prevention pharmaceutical drug in the US and Europe.” In their pioneering publication in 1992, Ferguson et al. demonstrated that a neutralizing antibody to transforming growth factor (TGF)-β reduced skin scarring in a rat incisional wound-healing model.4 This groundbreaking finding set the sails for a series of studies on pharmaceutical interventions against scarring. rhTGF-β3 (Juvista) was chosen as the lead compound first based on studies in normal animals. In subsequent doubleblind, randomized, phase I/II clinical trials in healthy human volunteers, a range of doses of TGF-β3 were injected intradermally around small skin incisions at the time of wounding.5 Beneficial effects of TGF-β3 were observed on scarring both on a microscopic and macroscopic level, even after 1 year.5 Surprisingly, in 2011, Renovo announced the disappointing results of a phase III trial on scar revision surgery with TGF-β3 where none of the endpoints were met (NCT00742443). This double-blind, within patient placebo-controlled study in over 350 patients assessed the efficacy of two doses of TGF-β3 given at wound closure and 24 hours later. The primary endpoint was photographic-based assessment 1 year postoperatively by an independent panel of experts. Before that, in December 2008, the development of another product in their portfolio 17β-estradiol (Zesteem) had been abandoned. The phase III trial in 296 patients did not achieve Wound Rep Reg (2014) 22 293–294 © 2014 by the Wound Healing Society
the anticipated effect on the closure of split-thickness skin graft donor sites. The fate of mannose-6-phosphate, another antiscarring agent developed by Renovo, is uncertain. The present study on IL-10 represents yet another defeat.1 It is worth mentioning that there were no correlations between the examined biomarkers and the clinical appearance of the scars.1 The authors speculated that this was due to timing and the unexpected large intraindividual variability.1 Another reason could be that other factors determine scar appearance. Collagens are undoubtedly fundamental in fibrotic processes. Admittedly, our knowledge on the exact role of collagens and the quality of scars is incomplete. Certainly, the amount of collagen is a determinant, but also, qualitative properties such as orientation and cross-linking are important. It would have been useful to have data on the different types of collagens and myofibroblasts, the prototypic fibrotic cells. Finally, the discrepancy in response to IL-10 in relation to skin type is striking and indicates some fundamental biological differences in wound-healing mechanisms that are currently unknown. Does history repeat itself? One cannot avoid drawing a parallel with the high expectations placed on growth factor therapy in the 1990s and the beginning of this century. Although the selected cytokines did not produce the desired effects on scarring, Renovo should be acknowledged for their contribution to the wound-healing field. They have invested huge resources into developing and validating wound-healing models as well as assessment tools that can be used in future studies.6 Biological medicine may be a new player in antiscarring, but maybe the selection process of candidate drugs should be different. Pathological scars in the skin are mainly observed in humans, and therefore, we lack a reliable experimental animal model, possibly with the exception of the Red Duroc pig. The urgent and inevitable question arises: Can results from wound-healing experiments in healthy animals and humans be translated into patients? Maybe we should reverse the developmental pathway from bed to bench? There is consensus on this strategy among wound-healing experts.7 Without doubt, the advancement of systems biology as well as genomic, metabolomic, and proteomic techniques will facilitate screening. For example, one novel approach is the determination of the secretome of fibroblasts with a documented nonfibrotic phenotype.8 With reversal of translational medicine, the chance of identifying molecules with antiscarring potential will perhaps increase and encourage the pharmaceutical industry as well as academic researchers to enter this medical field. Nothing ventured, nothing gained!
ACKNOWLEDGEMENT Conflict of Interest: The authors declare no conflicts of interest. 293
Editorial
Magnus S. Ågren, DMSci1,2,3,4; Patricia L. Danielsen, MD, PhD3,5 1. Editorial Board, Wound Repair and Regeneration, 2. Digestive Disease Center, 3. Department of Dermatology and Copenhagen Wound Healing Center, Bispebjerg Hospital, 4. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, and 5. School of Surgery, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, Australia
REFERENCES 1. Kieran I, Taylor C, Bush J, Rance M, So K, Boanas A, et al. Effects of interleukin 10 on cutaneous wounds and scars in humans of African continental ancestral origin. Wound Repair Regen 2014; 22: 325–32. 2. Bock O, Schmid-Ott G, Malewski P, Mrowietz U. Quality of life of patients with keloid and hypertrophic scarring. Arch Dermatol Res 2006; 297: 433–8.
294
3. Mirastschijski U, Sander JT, Weyand B, Rennekampff HO. Rehabilitation of burn patients: an underestimated socio-economic burden. Burns 2012; 39: 262–8. 4. Shah M, Foreman DM, Ferguson MW. Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta. Lancet 1992; 339: 213–14. 5. Ferguson MW, Duncan J, Bond J, Bush J, Durani P, So K, et al. Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies. Lancet 2009; 373: 1264–74. 6. Bush JA, McGrouther DA, Young VL, Herndon DN, Longaker MT, Mustoe TA, et al. Recommendations on clinical proof of efficacy for potential scar prevention and reduction therapies. Wound Repair Regen 2011; 19 (Suppl. 1): s32–7. 7. Gordillo GM, Bernatchez SF, Diegelmann R, Di Pietro LA, Eriksson E, Hinz B, et al. Preclinical models of wound healing: is man the model? proceedings of the wound healing society symposium. Adv Wound Care (New Rochelle) 2013; 2: 1–4. 8. Couty L, Guillaunneau F, Federici C, Leduc C, Lafont M, Coulomb B. Secretome analysis of human gingival fibroblast using mass spectrometry. Wound Repair Regen 2013; 21: A61.
Wound Rep Reg (2014) 22 293–294 © 2014 by the Wound Healing Society
Antiscarring pharmaceuticals: Lost in translation?
Firstly, we congratulate the investigators at Renovo in Manchester, United Kingdom, for the execution of an excellent randomized, double-blind, exploratory trial on the effect of the putative antiscarring cytokine interleukin-10 (rhIL-10; Prevascar).1 The rationale was that IL-10 had shown favorable effects on scarring in preclinical wound-healing models and in light-skinned healthy volunteers. Unexpectedly, these previous results could not be reproduced in a cohort of scarprone dark-skinned individuals in the present study.1 Actually, the scars tended to look better with placebo treatment. What justifies the use of biological medicine in problematic scarring? Cutaneous scars, such as hypertrophic scars or keloids, and fibrotic healing after surgery, burns, or even after minor skin insults, represent a huge medical problem with near to nil treatment options. Cosmetic concerns are important, but pain, redness, pruritus, paresthesia, and functional impairment are all related symptoms with a negative impact on the quality of life.2 Even small scars, especially in visible sites, are often distressing to the patient. In the US only, more than 150,000 scar revisions are carried out yearly but, sadly, with frequent unsatisfactory results from the patients’ perspective. Also, the costs associated with scar revision procedures can be substantial.3 Thus, the therapeutic area of scar prophylaxis represents an unmet medical need. This was realized by Renovo, which was cofounded by professor Mark Ferguson in 1998. To enter this essentially unexplored medical field, well over $US 100 million were raised. This funding enabled Renovo to perform the most ambitious and largest development program in the history to “be first to market with a scar prevention pharmaceutical drug in the US and Europe.” In their pioneering publication in 1992, Ferguson et al. demonstrated that a neutralizing antibody to transforming growth factor (TGF)-β reduced skin scarring in a rat incisional wound-healing model.4 This groundbreaking finding set the sails for a series of studies on pharmaceutical interventions against scarring. rhTGF-β3 (Juvista) was chosen as the lead compound first based on studies in normal animals. In subsequent doubleblind, randomized, phase I/II clinical trials in healthy human volunteers, a range of doses of TGF-β3 were injected intradermally around small skin incisions at the time of wounding.5 Beneficial effects of TGF-β3 were observed on scarring both on a microscopic and macroscopic level, even after 1 year.5 Surprisingly, in 2011, Renovo announced the disappointing results of a phase III trial on scar revision surgery with TGF-β3 where none of the endpoints were met (NCT00742443). This double-blind, within patient placebo-controlled study in over 350 patients assessed the efficacy of two doses of TGF-β3 given at wound closure and 24 hours later. The primary endpoint was photographic-based assessment 1 year postoperatively by an independent panel of experts. Before that, in December 2008, the development of another product in their portfolio 17β-estradiol (Zesteem) had been abandoned. The phase III trial in 296 patients did not achieve Wound Rep Reg (2014) 22 293–294 © 2014 by the Wound Healing Society
the anticipated effect on the closure of split-thickness skin graft donor sites. The fate of mannose-6-phosphate, another antiscarring agent developed by Renovo, is uncertain. The present study on IL-10 represents yet another defeat.1 It is worth mentioning that there were no correlations between the examined biomarkers and the clinical appearance of the scars.1 The authors speculated that this was due to timing and the unexpected large intraindividual variability.1 Another reason could be that other factors determine scar appearance. Collagens are undoubtedly fundamental in fibrotic processes. Admittedly, our knowledge on the exact role of collagens and the quality of scars is incomplete. Certainly, the amount of collagen is a determinant, but also, qualitative properties such as orientation and cross-linking are important. It would have been useful to have data on the different types of collagens and myofibroblasts, the prototypic fibrotic cells. Finally, the discrepancy in response to IL-10 in relation to skin type is striking and indicates some fundamental biological differences in wound-healing mechanisms that are currently unknown. Does history repeat itself? One cannot avoid drawing a parallel with the high expectations placed on growth factor therapy in the 1990s and the beginning of this century. Although the selected cytokines did not produce the desired effects on scarring, Renovo should be acknowledged for their contribution to the wound-healing field. They have invested huge resources into developing and validating wound-healing models as well as assessment tools that can be used in future studies.6 Biological medicine may be a new player in antiscarring, but maybe the selection process of candidate drugs should be different. Pathological scars in the skin are mainly observed in humans, and therefore, we lack a reliable experimental animal model, possibly with the exception of the Red Duroc pig. The urgent and inevitable question arises: Can results from wound-healing experiments in healthy animals and humans be translated into patients? Maybe we should reverse the developmental pathway from bed to bench? There is consensus on this strategy among wound-healing experts.7 Without doubt, the advancement of systems biology as well as genomic, metabolomic, and proteomic techniques will facilitate screening. For example, one novel approach is the determination of the secretome of fibroblasts with a documented nonfibrotic phenotype.8 With reversal of translational medicine, the chance of identifying molecules with antiscarring potential will perhaps increase and encourage the pharmaceutical industry as well as academic researchers to enter this medical field. Nothing ventured, nothing gained!
ACKNOWLEDGEMENT Conflict of Interest: The authors declare no conflicts of interest. 293
Editorial
Magnus S. Ågren, DMSci1,2,3,4; Patricia L. Danielsen, MD, PhD3,5 1. Editorial Board, Wound Repair and Regeneration, 2. Digestive Disease Center, 3. Department of Dermatology and Copenhagen Wound Healing Center, Bispebjerg Hospital, 4. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, and 5. School of Surgery, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth, Australia
REFERENCES 1. Kieran I, Taylor C, Bush J, Rance M, So K, Boanas A, et al. Effects of interleukin 10 on cutaneous wounds and scars in humans of African continental ancestral origin. Wound Repair Regen 2014; 22: 325–32. 2. Bock O, Schmid-Ott G, Malewski P, Mrowietz U. Quality of life of patients with keloid and hypertrophic scarring. Arch Dermatol Res 2006; 297: 433–8.
294
3. Mirastschijski U, Sander JT, Weyand B, Rennekampff HO. Rehabilitation of burn patients: an underestimated socio-economic burden. Burns 2012; 39: 262–8. 4. Shah M, Foreman DM, Ferguson MW. Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta. Lancet 1992; 339: 213–14. 5. Ferguson MW, Duncan J, Bond J, Bush J, Durani P, So K, et al. Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies. Lancet 2009; 373: 1264–74. 6. Bush JA, McGrouther DA, Young VL, Herndon DN, Longaker MT, Mustoe TA, et al. Recommendations on clinical proof of efficacy for potential scar prevention and reduction therapies. Wound Repair Regen 2011; 19 (Suppl. 1): s32–7. 7. Gordillo GM, Bernatchez SF, Diegelmann R, Di Pietro LA, Eriksson E, Hinz B, et al. Preclinical models of wound healing: is man the model? proceedings of the wound healing society symposium. Adv Wound Care (New Rochelle) 2013; 2: 1–4. 8. Couty L, Guillaunneau F, Federici C, Leduc C, Lafont M, Coulomb B. Secretome analysis of human gingival fibroblast using mass spectrometry. Wound Repair Regen 2013; 21: A61.
Wound Rep Reg (2014) 22 293–294 © 2014 by the Wound Healing Society
