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A new treatment is on its way providing superior results for the patients suffering from diabetic foot ulcers.

Chronic diabetic foot ulcers (DFUs) account for around 80% of lower limb amputations, resulting in effective medical treatment and cost burdens. Currently, the treatment for DFUs concentrates mainly on local wound care, which consists of debridement, offloading, controlling infection, and preserving a moist setting with dressings. Adjunctive therapies are also utilized, such as growth factors, hyperbaric oxygen, tissue engineering agents, and negative pressure wound treatments if DFUs worsen. Most treatments may be beneficial in controlling the advancement of DFUs however, they lack substantial support by clinical evidence or are not advised for standard treatment by the International Working Group on the Diabetic Foot (IWDF). The rise in yearly amputations is indicative of the need for improved treatment strategies. Furthermore, the pathology of DFUs is perplexed because the ulcers coexist with several risk factors, including inadequate patient compliance to therapy, ulcer severity, ulcer duration and location, vascular health, HbA1c regulation, nicotine use, and renal dysfunction. The risks, as mentioned above, dictate the need for new and efficacious strategies to address DFUs, a debilitative and life-threatening condition.

The data aggregation has demonstrated that focusing on macrophage phenotypes may be a promising treatment for DFUs because the ratio of proinflammatory M1 to pro regenerative M2 macrophages is increased by hyperglycemia, an underlying cause of DFUs. ON101 cream is a novel agent developed to treat DFUs consisting of two ingredients, PA-F4 from Plectranthus amboinicus extract and S1 from extract, two medicinal plants with essential pharmacological actions in healing wounds. There are 48 in vitro and in vivo studies documenting these two ingredients provide a synergistic effect on regulating the M1:M2 macrophage ratio. Furthermore, PA-F4 considerably mitigates M1 macrophages, and C Asiatica has been described to trigger M2 macrophages. The study by Huang et al. aims to compare the novel ON101 cream with an absorbent dressing when treating chronic DFUs. The study was a phase III randomized clinical trial carried out in twenty-one medical and clinical centers in China, Taiwan, and the United States. Patients were randomized to either ON101 cream or absorbent dressing (control), where ON101 cream was applied twice daily, and the absorbent dressing was changed daily or two to three times a week for 16 weeks. The eligibility criteria included individuals 20 to 80 years old, type 1 or type 2 diabetes, and baseline HbA1c <12%. The target ulcer categorized as grade 1 or 2 needed to measure from 1 to 25cm2 according to the Wagner system on foot, after debridement, no active infection, and a duration for a minimum of 4 weeks before randomization. Before randomization, participants with ankle-brachial, purulence, necrosis, sinus tracts in the ulcer, or persons with acute Charcot neuroarthropathy were excluded. The primary outcome was complete healing compared between the two arms after the sixteen-week treatment period. Secondary ulcer-related outcomes included the incidence of infection of the ulcer, percentage of individuals with a decrease of surface area by 50%, percentage of alteration in surface area of the ulcer from baseline, and time to complete healing of the ulcer. The safety outcomes evaluated occurrences of adverse events, vital signs, and clinical lab values.

There were 236 participants included in the study, where 74% were men. The mean age of participants was 57 years old, mean HbA1c was 8.1%, with DFUs categorized as Wagner grade one or two. One hundred twenty-two participants were randomized to receive ON101 cream, and 114 received absorbent dressing. The occurrence of complete healing in the full analysis set 60.7% (n=74 participants) in the ON101 cream arm and 35.1% (n=40 participants) in the absorbent group during the 16 weeks (25.6 percentage points difference; OR 2.84; p<0.001). 5.7% (n=7) treatment-emergent adverse events occurred in the ON101 cream arm compared to the absorbent arm at 4.4% (n=5). No treatment-related major adverse events occurred in the ON101 cream arm, and 0.9% (n=1) occurred in the absorbent arm. Thus, ON101 cream proved to be a superior agent in the complete healing of DFUs. An underlying cause of chronic DFUs is hyperglycemia resulting in delayed M1:M2 transition and prolonged inflammation stage. Patients with high-risk factors show strong efficacy that ON101 cream may offer preemptive and numerous ways to enhance healing wounds by supporting M1:M2 transition. Moreover, this M1:M2 transition accelerates ulcer healing, including early formation, high-risk factors such as HbA1c level, not less than 9%, ulcer size greater than 5 cm2, and ulcer continuance of at least six months. This study is a primary global phase III RCT examining an investigational drug that regulates M1:M2 macrophage actions in persons with DFUs.

Practical Pearls

• ON101 cream is being developed to treat DFUs and consists of 2 pharmacological extracts, Plectranthus amboinicus, and Centella Asiatica, which have important actions in healing wounds.
• ON101 cream was demonstrated to be superior regarding absolute would healing rate and the time to complete healing compared to absorbent dressing.
• DFUs are perplexing because the ulcers coexist with several risk factors, including inadequate patient compliance to therapy, ulcer severity, ulcer duration and location, vascular health, HbA1c regulation, nicotine use, and renal dysfunction.

Huang, Yu-Yao, et al. “Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients with Diabetic Foot Ulcers.” JAMA Network Open, vol. 4, no. 9, 3 Sept. 2021, p. e2122607, 10.1001/jamanetworkopen.2021.22607. https://jamanetwork.com/journals/jamanetworkopen/article-abstract/2783718

Hingorani, Anil et al. “The management of diabetic foot: A clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine.” Journal of vascular surgery vol. 63,2 Suppl (2016): 3S-21S. doi:10.1016/j.jvs.2015.10.003.

https://www.jvascsurg.org/article/S0741-5214(15)02025-X/pdf

Kuo, Yuan-Sung et al. “Plectranthus amboinicus and Centella asiatica Cream for the Treatment of Diabetic Foot Ulcers.” Evidence-based complementary and alternative medicine : eCAM vol. 2012 (2012): 418679. doi:10.1155/2012/418679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369464/

Trina Maglalang RPh, 2022 PharmD Candidate University of Colorado

This article is reposted from Diabetes in control. Read the full article here: Click to view.