Scientific Journal Articles
AACR Virtual Journal Club:
Molecular Cancer Therapeutics with Dr. Louis Denis - August 2021
Watch the recording of the AACR Journal Club session featuring Dr. Louis Denis discussing his First Disclosure article published in Molecular Cancer Therapeutics, "ASN004, a 5T4-targeting scFv-Fc antibody-drug conjugate with high drug-to-antibody ratio, induces complete and durable tumor regressions in preclinical models." In the paper, Dr. Denis and colleagues present the preclinical development and profile of ASN004, a 5T4-targeted antibody drug conjugate (ADC) that incorporates a novel single-chain scFv-Fc antibody and Dolaflexin drug-linker technology, with an Auristatin F Hydroxypropylamide payload drug-to-antibody ratio of ca. 10-12. The pharmacology, toxicology and pharmacokinetic properties of ASN004 and its components were investigated in vitro and in vivo and clinical development is planned in patients with advanced solid tumors.
“Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis”, Journal of Allergy and Clinical Immunology (2019); available online July 26, 2019.
Authors: Ana B. Pavel, Teresa Song, Hyun-Je Kim, Ester Del Duca, James G. Krueger, Celina Dubin, Xiangyu Peng, Hui Xu, Ning Zhang, Yeriel D. Estrada, Louis Denis, Niranjan Rao, Sandeep Gupta, David J. Zammit, Robert Bissonnette, Emma Guttman-Yassky
Summary: In this study, the Janus kinase/spleen tyrosine kinase inhibitor ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including TH2, TH17/TH22, and TH1 axes and barrier-related measures. Significant improvements in AD gene signatures were observed predominantly in the 40- and 80-mg dose groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups. In summary, ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. This supports the potential for ASN002 as a novel therapeutic agent for moderate-to-severe AD.
"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 (2019), available online March 28, 2019.
Authors: R. Bissonnette, C. Maari, S. Forman, N. Bhatia, M. Lee, J. Fowler, S. Tyring, D. Pariser, H. Sofen, S. Dhawan, M. Zook, D.J. Zammit, H. Usansky, L. Denis, N. Rao, T. Song, A.B. Pavel, E. Guttman-Yassky
Summary: ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways. The objectives of this study were to evaluate the efﬁcacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28‑day period (20 mg, 40 mg and 80 mg once daily). ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50, EASI 75 and in change from baseline in pruritus. Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, signiﬁcantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE. In summary, in patients with moderate-to-severe AD, ASN002 showed strong efﬁcacy with rapid onset of action and associated improvements in systemic inﬂammation.
Selected Scientific Presentations
“A Phase 1 PK/PD Study of ASN003, a Novel Highly Selective BRAF and PI3K Inhibitor, in Patients with Advanced Solid Tumors", AACR-NCI-EORTC Philadelphia, PA, October 26-30, 2017.
“Clinical Activity, Safety and Tolerability of ASN001, a Selective CYP17 Lyase Inhibitor, Administered without Prednisone in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC)", ASCO Annual Meeting, Chicago, IL, June 2-6, 2017.
“Clinical Activity, Safety and Tolerability of ASN002, a Dual SYK/JAK Inhibitor, in Patients with Non-Hodgkin Lymphoma (NHL) and Solid Tumors", ASCO Annual Meeting, Chicago, IL, June 2-6, 2017.
“ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity in both hematological and solid tumor xenograft models", AACR Annual Meeting, Washington, D.C. April 1-5, 2017.
“ASN003: a highly selective inhibitor of B-RAF and PI3 kinases, shows strong antitumor activity in a B-RAF inhibitor resistant patient-derived xenograft model", AACR Annual Meeting, Washington, D.C. April 1-5, 2017.
“ASN004: a Novel 5T4-targeted Dolaflexin™ ADC achieves complete regressions and tumor-free survivors in a broad variety of solid tumor models", AACR Annual Meeting, Washington, D.C. April 1-5, 2017.
“ASN003, a highly selective inhibitor of BRAF and PI3K kinases, shows strong antitumor activity in melanoma and colon cancer xenograft models", 14th International Congress on Targeted Anticancer Therapies (TAT) , Washington, D.C. March 21-23, 2016.
“ASN002: a potent dual SYK/JAK inhibitor currently in a phase I/II study shows strong antitumor activity in preclinical studies”, American Society of Hematology (ASH) Annual Meeting, Orlando, FL. December 5-8, 2015.
"ASN003, a unique B-RAF inhibitor with additional selective activity against PI3K and mTOR kinases, shows strong antitumor activity in multiple xenograft models”, AACR-NCI-EORTC International Conference, Boston, MA. November 5-9, 2015.
“ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity”, AACR Annual Meeting, Philadelphia, PA, April 18-22, 2015.
“ASN004, a Novel 5T4-Targeted Dolaflexin™ ADC for the Treatment of Various Cancers”; World ADC Summit, San Diego, CA. October 26-29, 2014.
“ASN004, a novel 5T4-targeted Dolaflexin™ antibody drug conjugate, causes complete regression in multiple solid tumor models”; AACR Annual Meeting, Philadelphia, PA, April 18-22, 2015.