The development of topical Salbutamol to prevent human skin scarring and hyperpigmentation

One hundred and ten million primary surgical incisions occur globally every year, with those made in areas of high tension particularly prone to scarring. Scarring is the result of the natural process of wound repair, generated by excessive cell behaviour in the healing wound. Depending on the body location, wound scars can be emotionally (face) and physically (joint) debilitating. This is especially true for some patients who suffer significant darkening (hyperpigmentation) of the skin at the site of damage, making any injury particularly traumatic. In addition, the care of wound scars places a heavy financial burden on healthcare systems worldwide. An effective scar prevention treatment would benefit the millions of patients with skin injury, enhancing the patient's health and quality of life. There are currently no proven treatments available to prevent wound scarring.
Salbutamol is a safe and well-tolerated pharmaceutical, which has been a mainstay of asthma therapy in the UK since 1968. Research in the Pullar lab and other labs has shown that salbutamol can modulate wound repair processes. Uniquely, when salbutamol is applied to the wound site, it alters the way the wound heals, curbing excessive cell behaviour and moving the healing process away from scarring and towards normal skin regeneration. In a pig wound model, salbutamol reduced scar area and hyperpigmentation by almost 50%, 56 days post-wounding, significantly improving scar appearance.
Here, stable salbutamol and placebo gels will be manufactured for topical use in skin wounds in accordance with good manufacturing practices. Non-clinical studies will be performed in a pig wound model in accordance with good laboratory practices to ensure safety (pharmacokinetic (PK) studies and skin toxicology), to satisfy regulatory requirements and determine the optimum 1x dose for skin scar prevention in the first-in-human clinical trial (CT).
To move towards therapeutic implementation, the phase I CT is designed as a within-volunteer, double-blind, randomised, placebo-controlled dose escalation trial. A robust recruitment plan will recruit 45 healthy volunteers who will be recruited into three groups of 0.5x, 1x (selected from the pre-CT) and 2x salbutamol formulation, starting with the lowest dose. The study, performed in accordance with good clinical practice, will be for 12 months. 2cm linear incisions will be made at the same anatomical location under each arm of volunteers and placebo and salbutamol dose will be randomised between left and right arms. Incisions will be treated daily for 60 days.
The primarily trial objective will be to assess safety and tolerability of topical salbutamol when applied to linear incisions. Blood samples will be collected at day 0/1 after surgery to perform PK analysis to determine if peak salbutamol plasma levels are acceptable. Skin tolerance will be assessed at each site daily. Adverse events will be recorded. Interim analysis of safety will be provided after the 0.5x dose to progress to the higher dose. The secondary objective is to determine the optimal topical salbutamol dose for scar improvement. Wound healing and scar assessments will compare the active dose and placebo in each volunteer's paired, contralateral scars at 6, 9 and 12 months post-wounding, when scars are considered fully mature.
The data will determine whether this study will pave the way for further CTs within patients with surgical procedures prone to scarring. In addition to the benefit to patients, this treatment would also benefit the surgeons and the NHS. Patients would heal better, leave hospital sooner and require less scar revision surgery, which would provide significant cost savings. Demonstrated efficacy in skin scar prevention could pave the way to the use of salbutamol to prevent excessive skin scarring (keloids - raised, progressively enlarging scars at the wound site) and fibrosis in other tissues.

110 million primary surgical incisions occur globally every year. Scars can cause serious cosmetic and functional problems. This is especially true for patients with darker skin tones who often suffer disfiguring hyperpigmentation. Scars place a heavy financial burden on healthcare systems worldwide. No clinically proven treatment is available to reduce wound fibrosis and scarring.

Salbutamol (Sal) is a well-tolerated pharmaceutical, evidenced by its long-standing use for asthma treatment. Previous work by Pullar (12+ papers) details Sal-mediated mechanisms for modulating wound repair. The results from an MRC-funded "proof of concept" grant (G0901844) demonstrated that Sal altered physiological processes during healing, ultimately reducing scar area and hyperpigmentation by almost 50%, significantly improving scar appearance (Le Provost and Pullar, 2014). Two patent families (scar/hyperpigmentation reduction) are under examination in US and Europe.

Sal and placebo gels will be formulated, stability tested (ICH GCP) and manufactured (GMP). A dose-ranging porcine study will be performed to determine the optimum dose for scar prevention. An MHRA suggested non-clinical porcine safety study will be conducted (GLP) to satisfy regulatory requirements for topical Sal registration. A within-volunteer, placebo controlled, double-blinded clinical trial will be conducted (GCP) in healthy volunteers to test Sal safety, tolerability and efficacy to prevent scarring in 2cm linear incisions, under each arm. Scars will be assessed at 6, 9 and 12 months post-wounding.

The ultimate aim is to determine efficacy in patients. Potential Phase II populations are those undergoing cardiothoracic/ abdominal primary surgery. Sal, applied post-surgery, would be highly beneficial to the patient, surgeon and the NHS, reducing the subsequent need to treat scars and improving the patients' health and quality of life. Ultimately we plan to inform novel NICE guidelines on scar prevention

Scarring, following surgery or trauma, is a major cause of discomfort and distress to patients and the most serious or visible scars can cause significant anguish and morbidity from cosmetic and functional problems. This is especially true for patients with darker skin tones who often suffer disfiguring hyperpigmentation making any skin injury especially traumatic. The most severe cases, keloid and severely hypertrophic scars can cause life-changing debilitation and prolonged, expensive and frequently ineffective medical interventions. There are no clinically proven active therapeutics currently available to prevent or reduce scarring, existing solutions being based around moisture control and silicone gels/sheets with only modest effects at best. Emerging "pharmaceutical" products are high value biologics designed for first world post-operative use and have to be injected frequently at the scar margin, restricting efficacy and the high costs limiting utility.

Topical application of Sal provides a unique opportunity to offer an affordable and efficacious scar prevention therapy. Our previous work demonstrates that Salbutamol has all the properties required of an ideal scar prevention therapeutic: 50% reduction in scar area and hyperpigmentation in the closest skin model to humans; low cost of goods; excellent safety profile with a long history of safe use; target product profile compatible with the range of utilities from post-surgical clinical application to over-the-counter and self-administration; high stability at room temperature (including warm climates) and a well-established mode of action.

Patients undergoing surgery will directly benefit from this research. Currently we have identified two potential patient populations to target in the first phase II trials: patients undergoing cardiothoracic surgery requiring chest incisions, such as median sternotomies and patients undergoing abdominal surgery. Both patient populations are prone to hypertrophic scarring due to the extensive tension around the area of the scar. The benefit of a scar reduction agent would be extremely beneficial in improving the patients' quality of life. Current numbers for both surgical procedures are 195,000 procedures per annum in the UK, and 27 million worldwide (www.GlobalData).

In addition, the NHS would see a significant reduction in scar-related costs with patients requiring less interventions and fewer hospital visits. Surgeons would benefit from having to perform less scar revision surgeries and achieving improved patient satisfaction. We plan to engage with NICE early in order to create novel NICE guidelines for wound scar reduction.


The work described herein will complete the non-clinical program and provide the demonstration of safety and some readout on efficacy in a first-in-human trial, that is the major barrier for engaging investors/partners to bring this product to market. This funding is critical to bridge the gap from research to commercialisation, opening the door to the next phase of translational research and facilitating engagement with Industry to develop the product further. We have engaged with the UK Wound Care and Pharmaceutical industry and will re-engage when we have first-in-human data, providing stimulation to the UK economy and upon expansion, the global economy.

We plan to expand our work to all arising primary surgical incisions, healing scars, burns, keloids and fibrosis in other organs/tissues, providing benefit to an expanding number of patients. The first in class nature of our product makes the market for our product challenging to forecast, but, in 2009, there were 175 million wounds globally and 110 million are primary surgical incisions (Driscoll, 2009). The UK market for surgical scar treatment products is approximately £500 million and in the US is approximately $4 billion, while expansion into treating fibrosis would extend the US market to around $16 billion (Frost & Sullivan).