Faster Way To Spot Skin Drug Success Without Long Trials

There are many aspects to it. Traditional Phase 1 studies that evaluate the efficacy of topical agents typically require many patients (30–50). They also require treatment for a prolonged period of time, often 8–12 weeks. These proof-of-concept trials are very extensive; they're long, costly and resource-intensive.

For these reasons, we wanted to explore an alternative approach. We know that topical corticosteroids are very effective for the treatment of AD. We wanted to use this as a treatment to explore an alternative technique, which is to treat for a very short period of time, three days only, and couple this with clinical outcomes and transcriptomics to see if there would be an early signal detected by gene expression.

This was done with the intent to eventually use this technique to explore the efficacy of new topical treatments in this condition and potentially other dermatology conditions.

In this study, we measured gene expression by performing tape strip sampling coupled with RNA sequencing. Tape stripping is a technique that involves the collection of skin cells by applying small tapes sequentially to the skin of patients. The RNA from these multiple layers of skin cells is then extracted and processed. We ensure the quality of the RNA is good and there is no degradation before it is analyzed by RNA sequencing, a technique that allows us to look at the expression of any gene from the transcriptome. This was done in collaboration with Prof. Emma Gutman from Mount Sinai, a world-leading expert in the field.

The analysis compared lesions treated with triamcinolone vs vehicle. Skin tape strip collection can induce irritation or stress responses; however, any transcriptional changes triggered by tape stripping should occur in both samples and not lead to differential gene expression between them. Consequently, the measured signal reflects the isolated effect of triamcinolone treatment on gene expression.

It is also important to note that tape strip samples collected at 24, 48, and 72 hours were taken from adjacent sites within the treated lesional area rather than the exact same location. This approach ensured that a similar depth of skin cells was obtained across all samples, allowing for proper comparison.

As mentioned previously, we profiled the entire transcriptome of lesions treated with triamcinolone vs vehicle; however, the expression of genes associated with AD and immune dysregulation were examined specifically. The analysis revealed that many genes related to immunity and pruritus were differentially expressed, which makes sense because AD is a chronic inflammatory and highly pruritic skin condition.

To our knowledge, there was one study that investigated the efficacy and the molecular changes observed following treatment of AD lesions with triamcinolone acetonide, but the concentration was lower (0.025% vs 0.5% in our study) and the disease severity differed. In Brunner et al., patients had moderate-to-severe AD, while in our study, all treated and analyzed AD lesions were of moderate severity based on lesional IGA (5-point scale).

It's not possible to really compare our data with what's been published previously because, at least to our knowledge, no previous study has explored the impact on transcription of longer-term treatment with triamcinolone, at the same strength and application frequency as in our study, on AD lesions of moderate severity. However, the results of Brunner et al. show that treatment for 16 weeks improves AD genomic signature and causes significant downregulation of inflammatory genes, both of which have also been observed in our study, as early as 24 hours after the first treatment application.

I believe this will make a huge difference — the advantages are numerous compared to traditional proof-of-concept trials.

First, this intra-patient minizone study design model meets the regulatory requirements of early Phase 1 trials, which require less toxicity data in order to be initiated. Therefore, new topical drugs can enter clinical development faster.

Then, patients become their own control; two treatments or more can be applied on the same patient and multiple samplings can be performed at once, which could reduce interpatient variability and the number of patients required for the study. This study design model further presents the advantage of allowing a comparison with an active comparator, which is normally only possible in later phase trials.

Topical agents are not typically associated with multiple side effects, but when they are investigational, you don't want to expose patients unnecessarily. With this microdosing approach, patient exposure to potentially harmful drugs is limited, reducing the risk of side effects.

Ultimately, using this three-day treatment duration study design model could potentially reduce cost by identifying the most promising candidate products faster and with less patients than traditional proof-of-concept trials.

As you can appreciate, there are multiple advantages to this approach, but most importantly, there is applicability to almost any cutaneous condition.

Due to the intraindividual nature of this design, it may not be applicable to investigate the efficacy of systemic treatments. However, this framework, which involves microdosing coupled with gene expression could be expanded to pretty much any dermatology indication.

It could definitely be used as a screening tool because you can test different formulations to identify the most promising candidate. It could be used similarly to a dose-ranging study to explore which is most efficient or holds the greatest potential.

Based on these findings, companies can make informed decisions as to whether it's appropriate to move forward with that candidate into a more formal proof of concept study with a placebo-controlled, parallel group design.

Usually, topical treatments are the first-line treatment for AD. They are generally highly efficient, and when patients are unresponsive or become more severe, they receive oral drugs or injections of biologics. Atopic dermatitis is not considered a life-threatening condition, but it significantly raises the risk of serious, potentially fatal complications.

Transcriptomics is one of the key omics approaches frequently integrated to advance personalized medicine. It's possible that some analysis of this type may be performed in the future to explore if a patient is likely to respond to treatment by looking, for example, at the expression of certain genes within the skin. However, this approach may evolve to have clinical applications more specifically for AD patients who have been refractory to multiple lines of treatment, and to guide future lines of treatment rather than be used globally for individualized healthcare of AD patients.