New senolytic drugs to clear the accumulation of senescent cells in aged tissues are working their way into clinical trials at the usual slow pace for medical development, slowed even further by the poor biotech investment market of the past three years. Rubedo Life Science's first drug to target GPX4 mechanisms has now made it through a phase 1 trial; the company took the safer path of a topical application in skin conditions where cellular senescence is thought to be an important driver of pathology. That strategy looks promising based on the initial data. The largest challenge for biotech and pharmaceutical companies lies in convincing people to fund the first clinical trials in the first indication for their approach to drug development; given success, matters become easier after that point. So companies tend to initially pursue safer, more certain paths rather than those that may offer greater rewards in terms of addressing the burden of disease in the population.
Rubedo Life Sciences, focused on discovering and rapidly developing selective cellular rejuvenation medicines targeting aging cells, today announced preliminary results from a single-center, ascending-dose, randomized, double-blind, vehicle-controlled trial in patients with plaque psoriasis, atopic dermatitis, and skin aging (photo-aged skin). The recently completed Phase 1 clinical trial, conducted in the European Union, was designed to assess the safety, tolerability, clinical effects, plasma bioavailability, and pharmacodynamics of topical RLS-1496 - the first-ever GPX4 (selective glutathione peroxidase 4) modulator to be studied in human trials, and the first specifically targeting cellular rejuvenation, an area of great interest to the scientific community as a new therapeutic pathway. The study met its primary endpoint, with RLS-1496 also demonstrating early signs of efficacy.
In psoriasis patients an overall reduction in senescent cells seen with RLS-1496 in the mid- and high-dose cohorts. Some subjects treated with RLS-1496 had a reduction of senescent cells, which was associated with a reduction of inflammatory cytokines such as IL-19 and S100A7; this reduction was not seen in the vehicle cohort. An average 20% reduction in epidermal thickness was observed on histology in subjects treated with RLS-1496 for one month. A statistically significant relationship was seen between target engagement and improvement in clinical psoriasis severity.
In atopic dermatitis patients, even higher levels of target engagement and substantial clinical improvement were seen in atopic dermatitis subjects on RLS-1496. After one month of treatment, 25% of subjects on RLS-1496 had a ≥4-point change in pruritus (or itching) on the numeric rating scale (NRS); no vehicle subjects had a 4-point or more change on the NRS.
Early photo-aging data show a dose-dependent target engagement in non-lesional photo-aged skin. Histology, proteomics, and spatial transcriptomics indicate that collagen gene and protein expression increase with treatments over time, in particular, spatial transcriptomics shows an effect in dermal fibroblasts. Spatial transcriptomics show indication that senescence-associated secretory phenotype and inflammatory biomarkers decrease with treatments over time in keratinocytes.
View the full article at FightAging
