Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of plaque psoriasis.

BACKGROUND: There is a significant need for novel, safe, and efficacious topical treatments for psoriasis. OBJECTIVE: We assessed the safety and efficacy of tapinarof in a new cream formulation at 2 concentrations and with 2 application frequencies in adults with psoriasis. METHODS: Double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in adults, with psoriasis with body surface involvement ≥1% and ≤15% and Physician Global Assessment (PGA) score ≥2 at baseline. Primary endpoint included PGA of 0 or 1 at week 12 and a 2-grade improvement from baseline. Additional analyses included assessment of ≥75% improvement of Psoriasis Area and Severity Index and mean percent change in Psoriasis Area and Severity Index and body surface area involvement. RESULTS: Treatment success defined by PGA 0 or 1 and a 2-grade improvement at week 12 was statistically significantly higher (at a .05 significance level) in the tapinarof groups (65% [1% twice daily], 56% [1% once daily], 46% [0.5% twice daily], and 36% [0.5% once daily]) than in the vehicle groups (11% [twice daily] and 5% [once daily]) and was maintained for 4 weeks posttreatment. Treatment-emergent adverse events were more frequent in patients treated with tapinarof (85/152, 56%) than vehicle (19/75, 25%) and mild-to-moderate in intensity. Severe treatment-emergent adverse events were reported in all tapinarof groups except the 0.5% once daily group. LIMITATIONS: Large confirmation trials are needed. CONCLUSIONS: Tapinarof cream is efficacious and well tolerated in adult patients with psoriasis.

A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis.

BACKGROUND: Safe and efficacious topical treatments are needed for atopic dermatitis (AD). OBJECTIVE: We assessed the safety and efficacy of tapinarof cream (2 concentrations and 2 application frequencies) in patients with AD. METHODS: A double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in patients age 12 to 65 years, with body surface area involvement of at least 5% to 35% and an Investigator's Global Assessment score of 3 or higher (moderate to severe) at baseline. Primary end points included an Investigator's Global Assessment score of clear or almost clear (0 or 1) and a minimum 2-grade improvement (treatment success) at week 12. Secondary analyses included a 75% or greater improvement in Eczema Area and Severity Index score, reduction of numeric rating scale (NRS) score for itch from baseline, and other prespecified end points. RESULTS: The rates of treatment success with tapinarof cream at week 12 were 53% (a concentration of 1% twice daily), 46% (a concentration of 1% once daily), 37% (a concentration of 0.5% twice daily), 34% (0.5% once daily), 24% (vehicle twice daily), and 28% (vehicle once daily). The rate with a concentration of 1% twice daily (53%) was statistically significantly higher than the rate with vehicle twice daily (24%). Treatment success was maintained for 4 weeks after the end of tapinarof treatment. The rate of treatment-emergent adverse events was higher with tapinarof (93 of 165 [56%]) than with vehicle (34 of 82 [41%]), and the events were mild to moderate in intensity. LIMITATIONS: Large confirmation trials are needed. CONCLUSIONS: Tapinarof cream is efficacious and well tolerated in adolescent and adult patients with AD.

Chemical genetic transcriptional fingerprinting for selectivity profiling of kinase inhibitors.

The importance of protein kinases as a major class of drug targets across multiple diseases has generated a critical need for technologies that enable the identification of potent and selective kinase inhibitors. Bruton's tyrosine kinase (Btk) is a compelling drug target in multiple therapeutic areas, including systemic lupus erythematosus, asthma, rheumatoid arthritis, and B cell malignancies. We have combined potent, selective kinase inhibition through chemical genetics with gene expression profiling to identify a "fingerprint" of transcriptional changes associated with selective Btk kinase inhibition. The Btk transcriptional fingerprint shows remarkable relevance for Btk's biological roles and was used for functional selectivity profiling of two kinase inhibitor compounds. The fingerprint was able to rank the compounds by relative selectivity for Btk, and revealed broader off-target effects than observed in a broad panel of biochemical kinase cross screens. In addition to being useful for functional selectivity profiling, the fingerprint genes are themselves potential preclinical and clinical biomarkers for developing Btk-directed therapies.

Comparison of mRNA gene expression by RT-PCR and DNA microarray.

Few studies have compared the quantification of mRNA by DNA microarray to the results obtained by reverse transcription PCR (RT-PCR). In this study, mRNA was collected from the healing femoral fracture callus of adult and juvenile rats at various times after fracture. Ten samples were measured by both methods for 26 genes. For RT-PCR, mRNA was reverse transcribed, amplified, electrophoresed, blotted, and probed with 32P-labeled internal oligonucleotides, which were quantified. For DNA microarray, the mRNA was processed to biotin-labeled cRNA, hybridized to 10 Affymetrix Rat U34A microarrays, and quantified. Correlation coefficients (r) for each gene for the agreement between RT-PCR and microarray ranged from -0.48 to +0.93. This variation made the interpretation gene-specific. Genes with moderate expression levels gave the highest r values. Increased numbers of absent calls by the microarray software and increased separation between the location of the PCR primers and the microarray probes both led to reduced agreement. Microarray analysis suggested a floor effect in expression levels measured by RT-PCR for two genes. In conclusion, moderate mRNA expression levels with overlap in the location of PCR primers and microarray probes can yield good agreement between these two methods.