Background
Aclerastide, one angiotensin receptor agonist, is the active ingredient of DSC127 and its general structure is shown in Fig. 1. Aclerastide is an analog of the naturally occurring peptide, angiotensin 1-7. The mechanisms of action include induction of progenitor proliferation, accelerated vascularization, collagen deposition, and re-epithelialization. Current modalities for the treatment of DFUs include strict offloading, bandaging, debridement and, on a limited basis, application of Regranex. Novel potent therapies are needed to combat this significant burden to the diabetic patient and the healthcare system. Preclinical and clinical research shows that DSC127 is highly effective in the closure of diabetic wounds and is superior to Regranex in animal studies. Clinical development of DSC127 as a topical agent for the healing of DFU is underway. Further investigation into the mechanisms by which this product accelerates healing is warranted.
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Fig. 1 The General Structure of Aclerastide (Notte, 2014)
Significance
Diabetes is a disorder that is well known to delay wound repair resulting in the formation of colonized chronic wounds. Over their lifetime, diabetic patients have a 25% incidence of foot ulcers, which contributes to an increased risk of morbidity, including osteomyelitis and amputations, and an increased burden to the healthcare system. Currently, the majority of modalities to accelerate the closure of DFU involve maintenance of a moist wound environment, optimization of bandaging, and off-loading, as well as debridement and infection control. The only active therapy for the treatment of DFU, Regranex, has been recently reintroduced into the market with close oversight of the patients receiving this active growth factor. Aclerastide provides insight into a novel, active topical agent for the treatment of DFU, which is not a topical growth factor. Phase I studies in DFU patients showed tolerability and lack of systemic exposure to the active ingredient, aclerastide. Aclerastide was superior to Regranex in preclinical studies and DSC127 accelerated wound closure and increased the proportion of wounds fully closed and remaining closed for up to 20 weeks after 4 weeks of treatment in Phase II clinical studies. Patients are now being recruited to pivotal Phase III trials.
Mechanism of action
The preclinical development and currently known mechanism of action of DSC127 will be reviewed. In the preclinical optimization of the product, it was noted that the wound first filled in with the extracellular matrix that was similar to normal skin and then the wound was re-epithelialized presenting histologically as nearly scarless healing. Similarly, clinical studies showed a reduction in the volume of the wound, followed by the reduction in area, and then closure confirming the translation of preclinical pharmacology studies into clinical benefit. Preclinical studies showed that aclerastide accelerated healing through a receptor of the protective arm of the RAS, Mas, as A779, a Mas antagonist, blocked the effects of aclerastide on wound repair. To further investigate the cellular mechanisms by which aclerastide accelerated healing, Fig. 2 evaluated the quality of tissue repair in the same model in diabetic mice.
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Fig. 2 Mechanisms by which aclerastide accelerates healing. Aclerastide accelerates healing through reduction of inflammation and normalization of tissue healing. (Rodgers et al. 2015) Note: NorLeu3-A(1-7) expressed the aclerastide.
Preclinical safety and tolerability
A series of pharmacology and toxicology studies have been performed with aclerastide and its formulated drug product DSC127. Dermatotoxicology, chronic toxicology after dermal exposure in miniswine, systemic toxicology studies in dogs and rats, and reproductive toxicology studies were performed and demonstrated safety in support of long-term use in clinical populations. Carcinogenicity studies are ongoing.
References:
Notte, T. N. (2014). 'New Chemical Entities Entering Phase III Trials in 2013’, Annual Reports in Medicinal Chemistry, 49, 434-436.
Rodgers, K. E., Bolton, L. L., Verco, S., and diZerega, G. S. (2015). 'NorLeu3-Angiotensin (1-7) [DSC127] as a Therapy for the Healing of Diabetic Foot Ulcers’, Advances in Wound Care, 4(6), 339-345.
