Topical isotretinoin ointment shows ‘reassuring’ efficacy, safety in congenital ichthyosis
Key takeaways:
- Two formulations of novel topical isotretinoin ointment TMB-001 were associated with improvements over vehicle in congenital ichthyosis.
- TMB-001 0.05% showed slightly better clinical response than TMB-001 0.1%.
Two formulations of a novel topical isotretinoin ointment formulation were associated with improvements over vehicle in patients with two types of congenital ichthyosis, according to a study.
“Congenital ichthyosis (CI) is being studied because there are no FDA-approved treatments and there is a significant unmet clinical need for this lifetime challenging condition,” Joyce M. C. Teng, MD, PhD, professor of dermatology and pediatrics and director of pediatric dermatology and fellowship training at Stanford University School of Medicine, told Healio. “Although systemic retinoid therapy is often used off label by CI patients, especially those with severe diseases. But long-term use of systemic retinoids is often associated with side effects including but not limited to bone abnormalities, such as bone spurs, low bone density, hyperlipidemia and liver toxicity, especially at higher doses, among many other problems.”
Teng suggested that effective topical therapy presents an advantage as a long-term management option.
In the current analysis of the randomized phase IIb CONTROL study, Teng and colleagues evaluated the efficacy and safety of TMB-001, which is an isotretinoin ointment formulation that can be applied topically.
Teng noted that there is a variety of CI subtypes that present differently in the clinic. “Certain subtypes of CI, such as Netherton syndrome, may have a significant inflammatory component due to functional impairment of the skin barrier,” she said. “The two cohorts in the CONTROL study, autosomal recessive congenital ichthyosis (ARCI) and X-linked recessive ichthyosis (XLRI), do not usually have much inflammation associated, therefore are feasible for treatment using topical isotretinoin, as topical isotretinoin is well known to modulate keratinocyte proliferation, differentiation and improve skin barrier.”
Patient selection is critical in the success or failure of medications for rare diseases such as CI, Teng added.
Eligible participants were aged 9 years or older and had genetically confirmed XLRI or ARCI-LI. Diagnostic criteria included two or more Visual Index for Ichthyosis Severity (VIIS) assessment areas, along with a scaling score of three or greater.
“The selection of the CI subtypes is thoughtful and somewhat unique,” Teng said, noting that 52% of the cohort had ARCI-LI and 48% had XLRI subtypes. “Dermatologic presentations of ARCI and XLRI are very different even though the body surface involvement associated with both subtypes can be similar, involving 90% to 100% of body surface area sometimes.”
Participants were randomly assigned TMB-001 0.05% (n = 11), TMB-001 0.1% (n = 10) or vehicle (n = 12) in a 1:1:1 ratio. Treatments were administered twice daily for 12 weeks.
Results showed that among patients with ARCI-LI, 33% of patients in the TMB-001 0.05% group, 50% of those in the TMB-001 0.1% group and 17% of those in the vehicle group reached the primary endpoint of VIIS 50. For patients with XLRI, 100% of those in the 0.05% group, 33% of those in the 0.1% group and 75% of those in the vehicle group reached this endpoint.
Turning to the endpoint of improvement in IGA score, for patients with ARCI-LI, 33% of those in the low dose arm, 50% of those in the high-dose arm and 0% of controls reached this endpoint. In the XLRI group, 83% of patients in the 0.05% group reached an improvement of 2 grades or more in IGA score, compared with 33% of those in the 0.1% group and 25% of controls (nominal P = 0.03 for 0.05% vs. vehicle, intention-to-treat population).
“One surprise about the study results is initially we saw a better clinical response with TMB-001 0.05% in comparison to TMB-001 0.1%,” Teng told Healio. “That was a general trend throughout the study. One possible explanation is that TMB-001 0.05% might be better tolerated. The fact that CI patients in this study can use TMB-001 on a very large body surface area and tolerate it very well with 12-week continued twice-daily use is very reassuring.”
Safety data showed that most adverse events were application-site reactions, according to the findings.
Teng further noted that systemic absorption of TMB-001 was “very minimal” overall. “Results from additional sub-analysis showed no concerning laboratory abnormalities associated with the study,” she added. “Overall, this 12-week analysis showed that participants with either ARCI or XLRI have benefited from TMB-001 treatment and the therapy was well tolerated.”