Aclerastide: Effective Therapy for Diabetic Foot Ulcers

Aclerastide and the Challenge of Diabetic Foot Ulcers

Diabetes mellitus creates a systemic environment that impairs normal tissue repair, making even minor wounds a serious clinical threat. Among the many complications of diabetes, foot ulcers represent a persistent and costly problem. For decades, treatment options have focused on passive wound management, with only one active therapy available. Research into aclerastide, also known as DSC127, offers a different approach rooted in the renin–angiotensin system (RAS). This peptide analog of angiotensin 1–7 targets the Mas receptor, a component of the protective arm of RAS, to promote healing through mechanisms distinct from growth factor therapies.

The Burden of Diabetic Foot Ulcers

Diabetic patients face a lifetime incidence of foot ulcers of approximately 25 percent, according to the source material. These chronic wounds are prone to colonization by bacteria and can progress to deep infections, osteomyelitis, and eventually amputation. The consequences extend beyond individual morbidity, placing a heavy load on healthcare systems worldwide.

Current standard of care for diabetic foot ulcers (DFUs) centers on maintaining a moist wound environment, optimizing bandages, offloading pressure from the affected area, performing regular debridement, and controlling infection. These measures are largely passive; they create conditions permissive for healing but do not actively accelerate tissue repair. The only active topical therapy cleared for DFU treatment, Regranex (becaplermin), is a recombinant platelet-derived growth factor. After a period of market withdrawal, Regranex was reintroduced under close patient monitoring due to safety concerns, including a possible increased risk of malignancy. This limited pharmacologic arsenal highlights the need for new, well tolerated active agents.

What Is Aclerastide?

Aclerastide is the active pharmaceutical ingredient in DSC127, a topical formulation designed specifically for wound healing. Chemically, aclerastide is an analog of the naturally occurring peptide angiotensin 1–7. It acts as an angiotensin receptor agonist. Unlike Regranex, aclerastide is not a growth factor, which may offer a different safety and efficacy profile.

Preclinical studies showed that DSC127 was superior to Regranex in accelerating wound closure in diabetic animal models. This early evidence provided the foundation for moving the compound into human testing.

Evidence from Clinical Development

Phase I studies in patients with DFUs demonstrated that aclerastide was well tolerated and did not produce measurable systemic exposure when applied topically. This limited absorption reduces the risk of off-target effects elsewhere in the body.

Phase II clinical trials provided more detailed efficacy data. After only four weeks of treatment with DSC127, wounds closed more quickly, and a higher proportion of wounds remained fully closed for up to 20 weeks. The pattern of healing observed in people mirrored that seen in animals. First, wound volume decreased, then the wound area shrank, and finally the wound closed completely. This stepwise closure suggests that the peptide promotes regeneration of the underlying tissue matrix before epidermal coverage occurs.

Currently, patients are being recruited for pivotal Phase III trials, which will determine whether DSC127 can be approved for clinical use in DFUs.

How Aclerastide Accelerates Healing

The mechanisms of action of aclerastide involve several coordinated processes. At the tissue level, the compound induces proliferation of progenitor cells, accelerates vascularization (the formation of new blood vessels), stimulates collagen deposition, and promotes re-epithelialization, the process by which new skin cells cover the wound.

Importantly, aclerastide acts through the Mas receptor, part of the protective arm of the renin–angiotensin system. This was confirmed experimentally: when the Mas receptor antagonist A779 was applied, the healing effects of aclerastide were blocked, demonstrating that Mas signaling is required for the peptide’s activity.

Rodgers et al. (2015) described how aclerastide accelerates healing by reducing inflammation and normalizing tissue repair. In diabetic wounds, chronic inflammation and disorganized tissue formation impede closure. Aclerastide appears to shift the wound environment toward a more balanced, less inflammatory state, allowing the extracellular matrix to be deposited in a pattern similar to normal skin. In preclinical studies, the wounds filled with matrix that resembled healthy dermis and then re-epithelialized with minimal scarring, nearly scarless healing.

Preclinical Safety and Tolerability

A series of toxicology studies were performed to support long-term use. Dermatotoxicology tests evaluated local skin reactions. Chronic toxicology after dermal exposure in miniswine, a model chosen for its skin similarity to humans, showed no significant safety concerns. Systemic toxicology studies in dogs and rats also demonstrated tolerability. Reproductive toxicology studies were completed to assess risks during pregnancy. Carcinogenicity studies are ongoing to address long-term safety for a therapy that may be used repeatedly in a chronic disease population.

These safety data, combined with the lack of systemic exposure observed in Phase I, suggest that aclerastide has a favorable safety profile, though final conclusions await Phase III and postmarketing data.

Scientific Context and Promise

The renin–angiotensin system is traditionally associated with blood pressure regulation, but its components include a protective axis mediated by angiotensin 1–7 and the Mas receptor. This pathway counteracts inflammation, fibrosis, and oxidative stress. By designing a stable analog of angiotensin 1–7, researchers created a topical peptide that harnesses these healing signals directly at the wound site.

If Phase III trials confirm the Phase II results, aclerastide would become only the second active topical therapy for DFUs and the first that works through the RAS pathway. This would offer clinicians and patients a new tool that may promote faster, more complete closure of difficult foot wounds, potentially reducing amputation rates and improving quality of life.

Future research will need to clarify the optimal dosing regimen, patient selection criteria, and whether the near-scarless healing observed in animals translates to human skin. The mechanism also raises interesting questions about whether aclerastide could be applied to other types of chronic wounds, such as venous leg ulcers or pressure sores.

Frequently Asked Questions

Q: Is aclerastide the same as the natural peptide angiotensin 1–7?

A: No, aclerastide is an analog of angiotensin 1–7, meaning it has a modified structure to improve stability and activity. It retains the ability to activate the Mas receptor, which is part of the protective arm of the renin–angiotensin system.

Q: How does aclerastide differ from Regranex?

A: Regranex (becaplermin) is a recombinant platelet-derived growth factor that stimulates cell division and migration. Aclerastide is not a growth factor; it works via the Mas receptor to reduce inflammation, promote progenitor cell proliferation, and guide more organized tissue repair. In animal studies, aclerastide was shown to be superior to Regranex in closing diabetic wounds.

Q: Has aclerastide been proven safe for long-term use?

A: Preclinical toxicology studies in multiple species, including miniswine, dogs, and rats, reported safety for long-term topical application. Carcinogenicity studies are still ongoing. Phase I human studies found no systemic exposure after topical application, which reduces the risk of distant side effects.

Q: When might aclerastide become available for diabetic foot ulcers?

A: Patients are currently being recruited for Phase III clinical trials. If these trials show efficacy and safety, the manufacturer can submit for regulatory approval. The timeline depends on trial enrollment, results, and review processes, but aclerastide is still in the development stage and not yet commercially available.