Rapid Transcriptomics Brings Actionable Data to Early-Phase Topical Trials

Early proof-of-concept studies for topical therapies usually involve 30 to 50 patients treated over 8 to 12 weeks. This long timeframe can delay critical insights into a drug’s efficacy and slow down the overall development process. 

A recent exploratory study (NCT05844618), a collaboration between Indero and professor Emma Guttman, chair of dermatology at Mount Sinai, set out to investigate more efficient approaches to study topical drugs for dermatological conditions.

The study focused on participants with atopic dermatitis (AD), a condition characterized by well‑defined inflammatory pathways that are highly responsive to topical intervention. 

Instead of relying solely on clinical endpoints over extended treatment periods, the research examined whether molecular signals, particularly changes in epidermal gene expression, could reveal pharmacodynamic activity within the first few days of treatment. 

The team used short-duration microdosing alongside minimally invasive tape-strip sampling and RNA-sequencing to capture how the skin responds soon after exposure.

Early molecular changes after 72 hours of treatment

The microdosing protocol began by applying a mid-potency corticosteroid to small, defined skin areas of AD patients.

Within the first 24 hours, transcriptomic analysis showed shifts in inflammatory genes associated with AD biology. 

By 72 hours, clear reductions appeared in the specific biomarkers Th2, Th22, and Th17, which play central roles in the condition, demonstrating measurable pharmacodynamic engagement within this short treatment window.

A concise and informative early-phase model

Although the study focused on AD, topical therapies are used across many dermatologic conditions, which means this early-phase model could be applied broadly to evaluate a wide range of drug candidates. 

Pairing microdosing with sensitive molecular assays allows researchers to assess whether a new compound is modulating expected pathways without requiring long treatment periods. 

This approach also supports controlled comparisons within a single participant; different concentrations, formulations, or vehicles can be applied across separate skin sites, and each site sampled for molecular response after a short exposure. 

The resulting data provides a clear picture of relative pharmacodynamic activity, helping researchers identify and select the most promising compounds to advance into later clinical development. 

Furthermore, because microdosing limits the total treated surface area, it reduces participant numbers, overall drug exposure, and study resource requirements in the earliest stages of evaluation.

Implications for early-phase research

The findings from this study highlight several opportunities for improving early clinical development:

• Early molecular signals offer a rapid indication of biological engagement, helping teams identify which candidates warrant further investigation.
• Decisions about optimization or reprioritization can be made sooner, reducing the need for lengthy exploratory studies before confidence is established.
• Microdosing requires less extensive preclinical toxicology than traditional Phase 1 designs, allowing exploratory human evaluation to begin sooner.
• Multiple formulations or concentrations can be compared on the same participant, generating informative data under controlled conditions.
• Sponsors gain clearer insight into mechanisms and target engagement at an earlier stage, supporting more efficient planning for later-phase trials.

A shift toward earlier molecular decision-making

The ability to detect pathway modulation within days illustrates the value of incorporating molecular endpoints into early-phase study designs. 

Transcriptomic analysis provides a detailed view of how the skin responds shortly after treatment begins, offering insights that complement and may precede traditional clinical measures. As these approaches become more widely adopted, early molecular readouts may help reshape expectations for exploratory topical drug development. 

By focusing on the skin’s first biological signals, researchers can guide candidates more confidently through the earliest stages of evaluation and prioritize those with the strongest evidence of meaningful activity.