Dr. Gadek is a medicinal chemist with a Ph.D. from UC Berkeley and 35 years of experience in the Biotechnology and Pharmaceutical industry. He has co-authored more than fifty peer-reviewed journal articles detailing the identification of novel candidates for clinical trials in cardiovascular, metabolic, inflammatory, and auto-immune diseases. He has developed experience and expertise in both the biotech start-up and large pharmaceutical company spaces, guiding the discovery and development of novel chemical entities as both drug substances and drug products, and defining clinical and regulatory strategies which position molecules for clinical and commercial success based on their mechanism of action (MOA) from concept through approval. Most recently Dr. Gadek has focused his efforts in the ocular arena with the discovery and development of Xiidra, leading to its approval by the FDA in 2016. Xiidra’s MOA targets the adhesion, migration, proliferation and inflammatory cytokine release by T-cells as the source of dry eye’s disease pathophysiology. Thus, preclinical MOA was translated into the first agent to demonstrate dose dependent inhibition of both the symptoms and signs of dry eye.
Development of lifitegrast: a novel T-cell inhibitor for the treatment of dry eye disease.
Clin Ophthalmol. 2016;10:1083-94
Authors: Semba CP, Gadek TR
Dry eye disease (DED) is a multifactorial disorder of the ocular surface characterized by symptoms of discomfort, decreased tear quality, and chronic inflammation that affects an estimated 20 million patients in the US alone. DED is associated with localized inflammation of the ocular surface and periocular tissues leading to homing and activation of T cells, cytokine release, and development of hyperosmolar tears. This inflammatory milieu results in symptoms of eye dryness and discomfort. Homing of T cells to the ocular surface is influenced by the binding of lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18; αLβ2), a cell surface adhesion protein, to its cognate ligand, intercellular adhesion molecule-1 (ICAM-1; CD54), which is expressed on inflamed ocular/periocular epithelium and vascular endothelium. LFA-1/ICAM-1 binding within the immunologic synapse enables both T-cell activation and cytokine release. Lifitegrast is a novel T-cell integrin antagonist that is designed to mimic the binding epitope of ICAM-1. It serves as a molecular decoy to block the binding of LFA-1/ICAM-1 and inhibits the downstream inflammatory process. In vitro studies have demonstrated that lifitegrast inhibits T-cell adhesion to ICAM-1-expressing cells and inhibits secretion of pro-inflammatory cytokines including interferon gamma, tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, interleukin (IL)-1α, IL-1β, IL-2, IL-4, and IL-6, all of which are known to be associated with DED. Lifitegrast has the potential to be the first pharmaceutical product approved in the US indicated for the treatment of both symptoms and signs of DED. Clinical trials involving over 2,500 adult DED patients have demonstrated that topically administered lifitegrast 5.0% ophthalmic solution can rapidly reduce the symptoms of eye dryness and decrease ocular surface staining with an acceptable long-term safety profile. The purpose of this review is to highlight the developmental story - from bench top to bedside - behind the scientific rationale, engineering, and clinical experience of lifitegrast for the treatment of DED.
PMID: 27354762 [PubMed]
Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye.
ACS Med Chem Lett. 2012 Mar 08;3(3):203-6
Authors: Zhong M, Gadek TR, Bui M, Shen W, Burnier J, Barr KJ, Hanan EJ, Oslob JD, Yu CH, Zhu J, Arkin MR, Evanchik MJ, Flanagan WM, Hoch U, Hyde J, Prabhu S, Silverman JA, Wright J
LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.
PMID: 24900456 [PubMed]