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A topical treatment derived from tree bark significantly increased healing of epidermolysis bullosa (EB) lesions versus standard care in an international multicenter clinical trial.

After 45 days of treatment, 41.3% of patients randomized to oleogel-S10 (Filsuvez) had complete wound closure as compared with 28.9% of the control group. A subgroup analysis showed that the beneficial effects were limited to patients with recessive dystrophic, which accounted for almost 80% of the study population.

The wound-healing advantage of oleogel-S10 emerged at about 30 days and persisted out to 90 days, when the proportion of patients with healing became similar in the two treatment groups, reported Dedee Murrell, MD, of the University of New South Wales in Kensington, Australia, during the virtual conference.

"The time to event, which is wound healing over 90 days ... was not statistically significant overall," she said. "The wound healing trajectories demonstrated that oleogel-S10 accelerates wound healing in a subset of the wounds. However, as expected, with good wound care, the control group begins to catch up later by 90 days. The difference in the proportion of healed target wounds had narrowed between treatment groups at 90 days, but the control group never overtook the oleogel arm."

"This is the first time that a phase III trial in EB has met its primary endpoint," she added.

Background of Development

A rare genetic skin-fragility disorder, EB characteristically emerges as a pattern of recurring healing and break-down wounds, along with chronic slow-healing or nonhealing wounds. The condition has no approved therapy, and standard of care consists of nonadhesive bandages, topical antimicrobial agents, topical steroids, and various unapproved therapies that are not specific for EB, Murrell noted.

The primary active ingredient in oleogel-S10 is betulin, a naturally occurring triterpene found in the bark of certain types of birch trees. Dry betulin extract is mixed with sunflower oil to form a gel, which is applied directly to EB lesions and to the contact surface of bandages. The for its use in EB includes evidence that triterpenes help modulate inflammation and are involved in keratinocyte proliferation, migration, and differentiation.

Preliminary clinical research provided in patients with dystrophic EB. The work subsequently led to the international phase III . Investigators at 58 sites in 28 countries enrolled 223 patients, primarily with dystrophic EB but also junctional EB or Kindler syndrome. Eligible patients had a partial thickness wound 10-50 cm² in size, persisting for 21 days to 9 months.

Patients were randomized to oleogel-S10 or control gel, each in addition to standard dressings changed at least once every 4 days. The primary endpoint was the proportion of patients who had a first complete closure of a target wound within 45 days. Secondary endpoints included time to wound healing, proportion of target wounds healed within 90 days, incidence and severity of wound infections, change in total body wound burden, change in itching, and adverse events.

Patients ages 4-12 years accounted for the largest proportion of the study population (38.1%), followed by 18 or older (30%), 12-18 (24.2%), and younger than 4 (7.6%). Murrell said 78.5% of the patients had dystrophic EB, and the median age of the target wound 35.5 days.

Key Findings

The primary results showed that patients randomized to oleogel-S10 had a 44% increase in the likelihood of primary wound healing at 45 days (95% CI 1.01-2.50, P=0.013). The difference represented an odds ratio of 1.84 in favor of oleogel-S10 (95% CI 1.02-3.30).

Subgroup analysis showed 45-day healing rates of 44.0% versus 26.2% among patients with recessive dystrophic EB (P=0.008). In contrast, patients with dominant dystrophic EB (n=20) had identical 50% healing rates in both groups, and patients with junctional EB or Kindler syndrome (n=26) had a numerically higher healing rate with the control therapy (26.7% vs 18.2%, P=0.522). Patients with smaller target dystrophic EB wounds (10-20 cm², n=128) had higher wound-closure rates at 45 days (54.% with oleogel-S10 and 39.4% with control therapy).

The time to wound healing did not differ between groups over the entire 90-day double-blind period (P=0.302). Target wound-closure rates at 90 days were 50.5% with oleogel-S10 and 43.9% with the control gel (P=0.296).

Itch improvement was modest overall and varied by time and age. Among patients ages 4 or older, oleogel-S10 resulted in greater pain reduction, although the difference did not achieve statistical significance (P=0.051). Neither incidence of wound infection (2.8% vs 4.4% with control therapy) nor severity differed significantly between groups.

Presentation moderator Brigitte Dréno, MD, of University Hospital Nantes in France, noted the "important difference" in activity between recessive dystrophic lesions and dominant dystrophic lesions and asked whether investigators had mechanistic explanation for the observation.

Murrell suggested that differences in inflammatory characteristics might account for oleogel-S10's greater effect in recessive dystrophic EB. Regardless of the explanation, investigators were pleased with the results in subgroup with recessive dystrophic EB, who tend to have more severe wounds that are slow to heal.

Dréno also asked about a possible explanation for the strong trend toward more pain reduction with oleogel-S10. Murrell said the betulin molecule is structurally similar to anti-inflammatory cannabinoid molecules that have pain-reducing properties.

"I suspect that is part of the mechanism that is enhancing wound healing in these patients," Murrell added. "We've seen patients with EB using [off-label cannabinoids] from various sources that are not betulin derived and having reductions in pain and improvements in wound healing."

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