Actionable insights into drug mode of action

In a landmark MOA study of over 1100 heart failure patients from the EMPEROR program, Professor Faiez Zannad and colleagues used Olink^® Explore 1536 to measure ~1500 plasma proteins longitudinally over the course of a 52-week trial of the SGLT2 inhibitor, empagliflozin. Comparing empagliflozin and placebo-treated patients, 32 proteins were differentially expressed (>10% change at an FDR of <1%). The 9 proteins showing the largest treatment effect (>15% change at an FDR of <1%) were IGFBP1, TfR1, CA2, EPO, TGM2, TMSB10, uMtCK, IGFBP4 & AFABP4. The functions of these proteins were most commonly related to the promotion of autophagic flux in the heart, kidney or endothelium (6 proteins), along with others linked to important biological processes in the heart and kidney. These findings in the clinical setting are consistent with those from previous experimental studies on the effects of SGLT2 inhibitors.

Zannad F, Ferreira JP, Butler J, et al. Effect of Empagliflozin on Circulating Proteomics in Heart Failure: Mechanistic Insights from the EMPEROR Program. (2022) European Heart  Journal, DOI: 10.1093/eurheartj/ehac495

Protein biomarker analysis is increasingly used in the clinical trials setting to generate invaluable additional data beyond primary clinical endpoints, providing unique insights into the deeper biology of the therapeutics under investigation, including a better understanding of drug MOA. One example of this approach came from a successful phase I clinical trial for the oral dual inhibitor of Janus kinase and spleen tyrosine kinase, ASN002, for atopic dermatitis (AD) patients.

When plasma samples taken longitudinally over the course of treatment from patients treated with ASN002 were compared to those from placebo subjects in the trial using Olink, significant reduction was seen in serum levels of individual markers of general inflammation, T-cell/B-cell markers, T-cell activation, innate immunity and T helper cell regulation. Further pathway enrichment analysis indicated that cytokine–cytokine-receptor interaction, cytokine, Th1–Th2, inflammatory, chemokine-receptor binding, chemokine signaling, JAK-STAT signaling and IL-23 signaling were the primary pathways affected by ASN002. One particularly interesting finding was that the drug significantly reduced the level of the known atherosclerosis marker, E-selectin. This raises the possibility that ASN002 could help protect against CVD risk, which is a known comorbidity in patients with AD.

Reduction of serum proteins in AD patients treated with ASN002 (Bissonnette et al., 2019)

Bissonnette R, Maai C, Forman S, Bhatia N, Lee M, Fowler J, Tyring S, Pariser D, Sofen H, Dhawn S, Zook M, Zammit D, Usansky H, Denis L, Rao N, Song T, Pavel A and Guttman-Yassky E. (2019) The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate‐to‐severe atopic dermatitis: results from a randomized double‐blind placebo‐controlled study. British Journal of Dermatology, Doi: 10.1111/bjd.17932

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🔗Dörner T, Tanaka Y, Dow ER, et al. Mechanism of action of baricitinib and identification of biomarkers and key immune pathways in patients with active systemic lupus erythematosus (2022) Annals of the Rheumatic Diseases, DOI: 10.1136/annrheumdis-2022-222335

🔗Paramel GV, Lindkvist M, Idosa BA,  et al. Novel purine analogues regulate IL-1β release via inhibition of JAK activity in human aortic smooth muscle cells. (2022) European Journal of Pharmacology, DOI: 10.1016/j.ejphar.2022.175128

🔗Simats A, Ramiro L, Valls R, et al.  Ceruletide and Alpha-1 Antitrypsin as a Novel Combination Therapy for Ischemic Stroke. (2022) Neurotherapeutics, DOI: 10.1007/s13311-022-01203-0