Targeting Fibrosis

 

The incidence of fibrosis, a normal part of wound healing, but also, under persistent inflammation or injury, a disease process that contributes to organ damage, has been steadily increasing over the past decade. This could be partly due to the percentage of elderly and thus chronic disease and inflammation rising in the population. Activity in the drug development arena for fibrosis has also grown. Much of the progress has been spurred by the fields of autoimmunity and inflammation which are revealing common mechanisms for fibrosis across the organs where fibrosis is most frequently observed: lung, liver, heart, kidney and skin. The approval of two drugs for a form of lung fibrosis, idiopathic fibrosis (IPF), has also accelerated progress in the field. However it is likely that multiple therapeutic approaches for treating fibrosis will be necessary because of the many contributors to the condition. For this reason, CHI’s Inaugural Targeting Fibrosis conference aims to convene the leading fibrosis researchers from academics and industry working across organ types, as well as immunology and inflammation investigators to share progress and shape future directions in this burgeoning field of new drug discovery.

Final Agenda

Wednesday, September 18

11:20 am Conference Registration Open


PLENARY KEYNOTE PROGRAM
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12:20 pm Event Chairperson’s Opening Remarks

An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute

 

12:30 Plenary Keynote Introduction

12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells

David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University

 

 

1:20 PROTACs: Past, Present, and Future

Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University

 

 

2:00 Close of Plenary Keynote Program

2:00 Dessert Break in the Exhibit Hall with Poster Viewing

Integrins As Fibrosis Targets

2:45 Organizer's Welcome Remarks

2:50 Chairperson’s Opening Remarks

Carolyn Cuff, PhD, Senior Director, Translational Immunology, Immunology Discovery, AbbVie Bioresearch Center

2:55 FEATURED PRESENTATION: An Overview of Fibrosis and the Hope of Pharmacologic Treatments

Bryan Fuchs, PhD, Senior Director, Research TA Head for GI & Liver Disease, Ferring Research Institute

 

3:25 Targeting Integrins for Fibrotic Diseases

Liangsu Wang, PhD, Vice President, Head of Biology, Morphic Therapeutic

Integrins lie at the heart of many biological processes and are involved in the pathophysiology of a variety of human diseases. This talk will discuss the roles of integrins in fibrotic diseases, highlight some key data on pharmacological effects of Morphic small molecule inhibitors against selected integrin targets, and share our insights of molecular modes of action of different inhibitors and the implications of integrin conformations in disease microenvironment.

3:55 Sponsored Presentation (Opportunity Available)

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

5:00 Targeting Integrins for Fibrosis

Ji Zhang, PhD, Scientist, Cardiorenal Metabolic & Ophthalmologic Drug Discovery, Merck Research Labs

Fibrosis is an evolutionarily conserved mechanism developed by an organism to survive chronic injury. Excessive fibrosis, however, leads to disruption of organ function and is a common feature of many chronic diseases. We are developing new medicines for multiple indications and this presentation will describe some of our efforts to target integrins for fibrosis.

5:30 IDL-2965: A Selective, Highly Potent, Clinical-Stage, Oral Integrin Antagonist for Treatment of Chronic Fibrosis

Karl Kossen, PhD, Senior Vice President, Translational Science, Indalo Therapeutics

IDL-2965 is an oral small-molecule integrin antagonist that potently inhibits αvβ1, αvβ3, and αvβ6. These integrins play central roles in TGF-β activation and the ability of stiff extracellular matrix to promote fibro-blast activation and survival. Once-daily, oral, therapeutic dosing reduces fibrosis in multiple animal models across organ systems with minimal effective doses ranging from 0.4 to 3 mg/kg. 28-day GLP safety studies suggest a large therapeutic index. IDL-2965 entered clinical studies in April 2019.

6:00 Established and Emerging Integrin Targets and Treatments for Fibrosis

Scott Turner, PhD, Vice President, Translational Sciences, Pliant Therapeutics

Fibrosis is a common pathway for progression of many debilitating diseases associated with loss of organ function. Integrins play a key role in regulating TGF-β activation and cell-matrix interactions, and thus represent attractive antifibrotic targets. We evaluated small molecule integrin inhibitors with different selectivity profiles in lung, liver and kidney models of injury and fibrosis, in tissue slices from patients with lung and liver fibrosis, as well as assessed non-invasive in vivo biomarkers of target engagement.

6:30 Dinner Short Course Registration
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9:30 Close of Day

Thursday, September 19

7:00 am Registration Open

7:30 Interactive Breakfast Breakout Discussion Groups

Grab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Visit the conference website for discussion topics and moderators.

8:30 Transition to Sessions

Challenges In Anti-Fibrotic Drug Development

8:40 Chairperson’s Remarks

Cory M. Hogaboam, PhD, Professor, Department of Medicine, Cedars-Sinai Medical Center

8:45 FEATURED PRESENTATION: Cell Senescence and Senolytic Strategies in IPF

Cory M. Hogaboam, PhD, Professor, Department of Medicine, Cedars-Sinai Medical Center

Cellular senescence is a state of permanent growth arrest combined with stereotyped phenotypic changes and it has an important role in maintaining physiological homeostasis. While cellular senescence may be a protective mechanism in modulating proliferative capacity, the accumulation of senescent fibroblasts and epithelial cells is now recognized as a key pathogenic mechanism in idiopathic fibrosis (IPF), a form of lung fibrosis. This presentation will cover therapeutic interventions that target and reduce the burden of senescent cells, which are promising for modulating the progression of IPF and other age-related lung disease.

9:15 Novel in vitro Models for IPF

Lisa Hazelwood, PhD, Principal Research Scientist, Liver Disease and Fibrosis, AbbVie

9:45 Developing Translational Tools for the Development of Anti-Fibrotic Therapies

Melanie Ruzek, PhD, Principal Scientist, Translational Immunology, AbbVie

Assessment of anti-fibrotic drug activities and/or fibrosis endpoints within target tissues can be difficult due to accessibility or limited frequency of collections. Thus, novel methodologies are needed for non-invasive or peripheral biomarkers that will reflect tissue fibrosis and local anti-fibrotic drug activities. Case studies of some of these approaches will be discussed.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

Emerging Fibrosis Targets (Non-Integrins)

10:55 Targeting ROS-Generating NADPH Oxidases in Aging and Fibrosis

Victor J. Thannickal, MD, Professor & Director, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham

Fibrosis may be viewed as a physiological, evolutionarily-conserved response to tissue injury, even at the cost of a loss in organ structure/function. This “trade-off” may result in progressive/pathological fibrosis when certain genes associated with tissue repair manifest antagonistically pleiotropic effects with aging. In this seminar, we provide evidence for the reactive oxygen species (ROS)-generating enzyme, NADPH oxidase 4 (Nox4), in age-related lung fibrosis and pre-clinical studies to support its therapeutic targeting.

11:25 CXCR4: A Novel i-body for the Treatment of Fibrosis

Sam Cobb, CEO and Managing Director, AdAlta Limited

AdAlta has used its unique human single domain protein platform to identify a novel i-body, AD-214, that specifically antagonizes the GPCR CXCR4 and shows both anti-inflammatory and anti-fibrotic in several animal models of fibrosis.

11:55 Sponsored Presentation (Opportunity Available)

12:25 pm Session Break

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:25 Refreshment Break in the Exhibit Hall with Poster Viewing

Emerging Fibrosis Targets (Non-Integrins)

2:05 Chairperson’s Remarks

Brian Murphy, PhD, Senior Principal Scientist, CV and Fibrosis Drug Discovery, Disease Sciences and Biologics, R&D, Bristol-Myers Squibb

2:10 RIPK1 as a Liver Fibrosis Target

Allison Beal, PhD, Associate Fellow, Innate Immunity Research Unit, GSK

RIPK1 (receptor-interacting protein kinase-1) is a key homeostatic regulator of cell survival and cell death signaling pathways, particularly downstream of TNF signaling. RIPK1 is ubiquitously expressed and has complex, cellular context-dependent actions mediated by a combination of scaffold activity (survival) and kinase activity (cell death). I will discuss the role of RIPK1 in tissue injury and discuss why it is a promising target for modulating fibrosis.

2:40 Lysyl Oxidase and Lysyl Oxidase-Like Inhibitors for the Direct Treatment of Fibrosis

Jonathan Foot, PhD, Senior Research Scientist, Drug Discovery, Pharmaxis Ltd.

The lysyl oxidase (LOX/LOXL1-4) family are proteins involved in the cross-linking of elastin and collagen fibrils in the extracellular matrix. Up-regulation of one or more of the LOX family can lead to aberrant cross-linking, excessive local collagen deposition and propagation of pro-fibrotic signaling. This can lead to tissue scarring, fibrosis and ultimately organ failure. We will present strategies to directly target lysyl oxidases using small molecule inhibitors, and their effectiveness in treating fibrosis.

3:10 Discovery and Development of NTZ as an Anti-Fibrotic Agent in NASH

Suneil Hosmane, PhD, Executive Vice President, Strategic Development, Genfit

Nitazoxanide, or NTZ, is an approved anti-parasitic agent that has shown promising activity against fibrosis in preclinical disease models. We are currently evaluating NTZ in an investigator-initiated Phase 2 proof-of-concept clinical trial for the treatment of NASH-induced significant or severe fibrosis.

3:40 Targeting ROCK in Fibrotic Disease

Masha Poyurovsky, PhD, Vice President, Discovery Biology, Kadmon Corporation, LLC

Rho-associated coiled-coil kinase (ROCK) is central to the control of cell movement and shape. This presentation will cover the role of ROCK in the regulation of the bio-mechanical and biochemical signaling pathways in fibrotic disease. We discuss re-sults of Kadmon’s ROCK inhibitor discovery program which integrated lessons from earlier ROCK inhibitors, SBDD and medicinal chemistry. Our compounds are currently progressing toward early stage clinical development and Phase II clinical trials for IPF.

4:10 Close of Conference
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