Topical RLS-1496 1% cream, an investigational glutathione peroxidase 4 (GPX4) inhibitor, reduced actinic keratosis lesion counts by 43.5% versus 11.3% with untreated control at day 57 in a phase 1b/2a study presented at the European Academy of Dermatology & Venereology (EADV) Congress 2026 in Vienna.¹
RLS-1496 is a first-in-class senotherapeutic designed to induce ferroptosis, a non-apoptotic, iron-dependent form of regulated cell death, in senescent cells accumulating in photodamaged skin.¹ The US Food & Drug Administration (FDA) cleared Rubedo’s investigational new drug application for RLS-1496 in AK in September 2025.2 Current field therapies such as 5-fluorouracil frequently cause intense erythema and crusting, a common reason patients stop treatment early.3
“We were very pleased to see there was really not an indicator the lesions themselves nor the peri-lesional skin became irritated,” said Mary Spellman, MD, chief medical officer, Rubedo Life Sciences. Spellman, the presenting author, discussed the findings with HCPLive during the congress in Vienna.
RLS-1496 Efficacy in Actinic Keratosis of the Forearm
The multicenter, open-label phase 1b/2a study enrolled 24 adult patients with 4 to 12 clinically typical, discrete AK lesions on each forearm.¹ Patients applied RLS-1496 1% cream to a predefined 100 cm² area on the left forearm for 28 consecutive days, with the right forearm serving as an untreated intrapatient control. Follow-up continued for an additional 28 days.
Primary endpoints were the frequency and incidence of adverse events through day 57 and the rate of AK lesion clearance following treatment.¹ At day 29, the mean percent change in total AK lesion count from baseline was -38.3% on treated forearms compared with -5.2% on control forearms. By day 57, the reductions reached -43.5% and -11.3%, respectively.
At least 75% clearance of AK lesions occurred in 25% of treated forearms at day 29 and 34.8% at day 57, compared with 0% of control forearms at both timepoints.¹ According to Spellman, 10 of 24 patients achieved at least a 50% reduction in AK lesions on the treated forearm, compared with none on the control side.
RLS-1496 Safety, Tolerability, and GPX4 Target Engagement
RLS-1496 1% cream was well tolerated, with no application site reactions reported.¹ A single adverse reaction of moderately severe dermatitis occurred adjacent to the application site and resolved within 1 week. All other treatment-emergent adverse events were mild to moderate and considered unrelated to treatment, with no serious adverse events and no discontinuations due to adverse events.
Spellman suggested the adjacent dermatitis may reflect transfer of drug product to nearby skin rather than a direct application adverse event. She noted this tolerability profile is critical for a therapy intended for chronic use.
Pharmacodynamic analysis of lesional biopsies from days 1 and 29 demonstrated 33% GPX4 target engagement.¹ Spatial transcriptomics and multiplex immunostaining confirmed an AK-specific senescent cell signature, along with potential treatment-related changes in senescence and disease markers.
Spellman explained basal keratinocytes in AK express a senescent-like phenotype marked by p16 and p21 expression and pro-inflammatory cytokine release. These cells sustain high levels of lipid peroxidation, leaving them vulnerable to ferroptosis when GPX4 is selectively inhibited.
Next Steps for RLS-1496 in Actinic Keratosis
“We treated the forearms in this study for only a 4-week treatment period,” Spellman said. “The forearms are a notoriously difficult area to treat compared to the face and perhaps even the scalp.”
Spellman said later trials will aim to extend treatment to at least 12 weeks, aligning with endpoints for marketed AK therapies, and will include the face. No data yet address prevention of new lesions or progression to squamous cell carcinoma, and changes in photodamage were modest in some patients after 4 weeks.
References
Spellman M, Lain E, Vitari A, Laslavic A, Quarta M, Beddingfield F. Clinical study of RLS-1496 topical cream: targeting senescence and oxidative stress via GPX4 inhibition in patients with actinic keratosis. Abstract 228. Presented at: EADV Congress 2026; September 30–October 3, 2026; Vienna, Austria.
Rubedo Life Sciences. Rubedo Life Sciences announces US FDA IND clearance for lead drug candidate RLS-1496, a selective GPX4 modulator, for the treatment of actinic keratosis and expands clinical advisory board. Published September 17, 2025. Accessed October 12, 2026. https://www.businesswire.com/news/home/20250917407244/en
Ahmady S, Oyen EMM, Jansen MHE, et al. Patient-reported skin reactions to 5% 5-fluorouracil in treatment of actinic keratosis. Br J Dermatol. 2021;185(5):1050-1052. doi:10.1111/bjd.20570
