Diabetic Foot Ulcers: New Treatments Under Study Look Promising

Two Taiwanese companies report on new DFU treatments: one in phase 2, the other completed phase 3 overseas. US phase 3 trials for both are planned.

with David G. Armstrong DPM, MD, PhD and Guang-Huar Young PhD

Bare feet standing in a circle in wet sandDFUs are likely to affect up to a third of people with diabetes in their lifetime.

New treatments for diabetic foot ulcers (DFUs) are greatly needed, and two possibilities may be on the horizon, according to research conducted by two Taiwanese companies. 

In one report presented at the American Diabetes Association's 81st Scientific Sessions, a hydrogel with 0.02% adenine achieved faster wound healing than a comparison treatment in 141 patients with type 2 diabetes and intractable DFUs, according to a team of researchers from Energenesis Biomedical Company in Taipei, Taiwan. 

A different Taiwanese team presented results on their phase 3 study of ON101, a new topical plant-based cream already approved in Taiwan for DFUs. It has a M1-M2 macrophage-regulating mechanism, as macrophages are known to be critical for wound healing. 

As physicians managing the care of patients with diabetes know, foot wounds are a serious and ongoing problem. At least half of all foot amputations are among people with diabetes, and diabetic foot ulcers are a main reason, according to the American Diabetes Association's publication, "Diagnosis and Management of Diabetic Foot Complications." Up to a third of people with diabetes are likely to be affected with a DFU in their lifetime, according to a 2019 update on the management of DFUs.

Management includes offloading, keeping the wound moist and performing debridement (surgical or non-surgical), covering the wound with various dressings and applying topical preparations.

Details: Hydrogel Study 

Yi-Fang Cheng and the team from Energenesis Biomedical Co. evaluated a hydrogel with 0.02% adenine as a treatment for replenishing cellular ATP levels, speeding diabetic wound healing. Wound healing is known to require cellular energy in the form of ATP (adenosine triphosphate); if it is deficient, it negatively impacts every phase of the process.

"As the major energy currency, ATP promotes the hemostatic, immune and local cellular responses required for tissue repair and regeneration," says Guang-Huar Young PhD, director of translational medicine for Energenesis Biomedical Co. and a coauthor on the paper.

The researchers evaluated 141 patients with type 2 diabetes who were age 20 and older. They had A1Cs ranging from 6.5 to 12% and all had intractable DFUs. The DFUs had a Wagner grade of 1-3 without active osteomyelitis. They were randomized 2 to 1 to the hydrogel group, called ENERGI-F703, or the vehicle, or control group (67.4%, 32.6%) for 12 weeks. Ulcers were mainly grade 2 (63.6%), and on the foot, sole or toe.

The primary endpoint was complete ulcer closure rate at the end of treatment. Secondary endpoints were time to complete ulcer closure, accumulated confirmed ulcer closure rate and percent change in ulcer size at each post-treatment visit and adverse event incidence. Those who had complete closure were followed for another 12 weeks; those with incomplete an additional 4 weeks.

For the efficacy analysis, 132 people were included in the intend-to-treat population and 107 in the per-protocol population. 

Among the per-protocol population with a Wagner grade of 1 or 2, there was a higher response rate in the ENERGI-F703 group—48% vs. 20.8%, p=0.0250. Among the intend-to-treat group, the same was found—40.3% response rate versus 20.7%, p=0.0656.  The ENERGI-F703 groups also had quicker time to complete closure.

No unexpected serious adverse reactions were observed.

Dr. Young says, "In the subjects with Wagner grade 1 or 2 target ulcers, the complete ulcer closure rate in the ENERGI-F703 gel group was twice that in the placebo group in 12 weeks." On average, patients got complete closure of the ulcer after treatment with ENERGI-F703 for about 10 weeks, he says. Energenesis Biomedical Co. hopes to launch phase 3 clinical trials in the US in the first quarter of 2022. 

Second Opinion

"This [hydrogel] therapy is definitely intriguing," says David G. Armstrong DPM, MD, PhD, professor of surgery at the University of Southern California and co-director of the USC Limb Preservation Program. He also directs the Southwestern Academic Limb Salvage Alliance (SALSA). 

"The anti-inflammatory and pro-angiogenic characteristics of the gel are plausible," Dr. Armstrong says. "While our group [of researchers] are not presently involved in this research, we have been tracking it." 

Dr. Armstrong says, "I believe that this therapy may very well have potential. If it were to be approved, it would be the first of its category since 1996 to go through such a pathway."

Another Remedy for DFU: ON101

In another ADA 2021 presentation, a different study was presented out of Taiwan. They reported on their phase 3 results of a new topical drug, ON101. This M1-M2-macrophage regulating drug was compared to a hydrocolloid dressing in an international, multicenter, randomized, controlled, evaluated blind phase 3 study conducted at 21 clinical or medical centers in the US, China and Taiwan.

They evaluated 236 eligible patients with post-debridement DFUs between 1 and 25 centimeters in size, present for 4 or more weeks, with a Wagner grade of 1 or 2. They were randomized 1:1 to receive one of the two treatments for up to 16 weeks, followed by a 12-week follow-up.

The primary endpoint, complete healing, was found in 60.7% of the ON101 group and 35.1% of the comparison group during the treatment period (p=0.0001). Time to complete healing, the secondary endpoint, was faster in the ON101 group (p=0.002). The numbers with adverse events were similar in each group; none of the serious events were related to ON101 but one case of osteomyelitis in the comparator treatment was reported.

The Taiwan Food and Drug Administration has approved the drug. According to Oneness Biotech Co. press reports, the company plans to launch phase 3 trials in the US in 2021. 

Comment on ON101

According to Dr. Armstrong, this approach also looks promising. The last data he saw, as he recalls, found a doubling or so of healing with the ON101 compared to standard care. In late March, the FDA granted the company fast track designation to speed the NDA process of the drug in the US, according to Oneness Biotech Company. When the FDA grants fast track status, it enables the company to gain access to FDA's help in facilitating the new drug registration process. 

Continue Reading:
Weekly Debridement Leads to Faster Healing in Diabetic Foot Ulcers
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