Topical Treatment of Atopic Dermatitis with a “Small Molecule”

Data from phase 1, 2 and 3 clinical trials have provided preliminary evidence of safety and efficacy of crisaborole topical ointment, 2% in the treatment of Atopic Dermatitis (AD)

How does crisaborole work ?
Crisaborole acts by competitive inhibition of the catalytic domain of phosphodiesterase 4 (PDE4B).
-the tetrahydral boron group from crisaborole occupies a similar spatial position as the phosphate of cyclical AMP (cAMP)
-its inhibion of the catalytic domain of cAMP is proportional (linear way) to the increasingg concentration of cAMP

-in the absence of crisaborole; PDE4 initiates degradation of cAMP, which allows transcription of inflammatory cytokines
-conversely in the presence of crisaborole; PDE4 inhibition increases cAMP, activates protein kinase A (PKA), and inhibits transcription of inflammatory cytokines

What has it shown in treating patients with Atopic Dermatitis ? (AD)
The study was a pooled analysis from previous studies of 82 AD patients Phase 1 and 2:
-It consisted of 4 studies regrouping patients applying topical cisaborole 2% 2 times daily.

• Studies 1 and 2 were evaluated on whole body
  • at day 29 there was an average of 65% of reduction in pruritus
  • baseline pruritus score 2  (2=”constant or intermittent itching with no sleep disturbance) reduced to less than 1 at day 29 (1=  “occasional, slight itching”)
• Studies 3 and 4 evaluated specific areas where lesions were present
  • at day 29, there was an average of 77.3% reduction in pruritus
  • baseline pruritus score of 2 reduced to 0.5 at day 29.

Conclusions
-Crisaborole is a boron-containing, non steroidal, anti-inflammatory compound that exerts its effect by inhibiting PDE4, thereby increasing intracellular cAMP levels and affecting downstream pathways involved in cytokine production
–At day 29 and when compared to baseline, the treatment is quite effective in reducing scratching.

Comments
-Topical treatment is the mainstay treatment for AD – that being said the disease is chronic and can also be widespread.
-Clinical data in this retrospective study shows interesting results. However AD is a chronic condition and prospective studies going beyond 29 days of treatment are needed to evaluate the efficacy and they should be compared to the existing treatments (topical steroids, calcineurin inhibitors…)
-It is also often difficult to keep patients compliant for to long a time. Therefore safe treatments might be a consideration

–Small Molecules, particularly phosphodiesterase inhibitors have shown promising results in terms of efficacy and safety. Case reports exist for apremilast in treating AD as an off-label indication. Other small molecules in development (at time of publication) include LEO 29102* (topical cream) and ponesimod (orally).

-On the other hand dupilumab, an injected biologic might be a consideration in severe AD in the not too distant future (at time of publication).

 
*https://clinicaltrials.gov/ct2/show/NCT01037881
Bibliography
1. Crisaborole topical ointment, 2% (formerly AN2728), an investigational, boron-based topical anti-inflammatory agent, inhibits Phosphodiesterase 4 (PDE4). Freund Y et al
2. Post-hoc analyses of the effect of cisaborole topical ointment 2% on atopic-dermatitis-associated pruritus. Draeleos  ZD
1. and 2. are Posters, EADV Annual Meeting 2015 – Copenhagen, Denmark
Remark. Studies done by Anacor Pharmaceuticals