Many autoimmune and immune-related inflammation disorders are chronic conditions for which the development of orally-delivered therapeutics, usually small-molecule-based, is a sought-after goal because of their convenience of administration and lower cost to the patient, especially for a potentially lifelong therapy. While much progress in the field of immunotherapy has been made with injectable, protein-based therapeutics such as biologics, those therapeutic modalities can only act on cell surface proteins. However, a wealth of new knowledge of immune-related intracellular signaling pathways, partly spurred by the success of biologics, is revealing new intracellular targets against which cell-penetrable therapeutics can be developed. Cambridge Healthtech Institute’s 2nd Annual Autoimmune and Inflammation Drug Targets conference will cover the advancement of promising oral-based drug candidates and emerging intracellular drug targets for combatting autoimmune and inflammatory disease.

Final Agenda

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Wednesday, September 27

11:50 am Conference Registration Open

12:35 pm Plenary Keynote Program

(click here for details)

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

Targeting ROR Nuclear Receptors

2:45 Welcome Remarks

Anjani Shah, Ph.D., Conference Director, Cambridge Healthtech Institute

2:50 Chairperson’s Opening Remarks

Dinesh V. Patel, Ph.D., President & CEO, Protagonist Therapeutics 

2:55 Pharmacology of Targeting ROR in Autoimmunity

Joseph Wahle, Ph.D., Senior Scientist, Immunology and Respiratory Disease Research, Boehringer Ingelheim

The IL-23/Th17 axis is of great importance in the inflammation and autoimmunity field as confirmed by the efficacy of multiple biologics targeting this pathway. A key regulator of this axis is the RORC, and inhibitors of this transcription factor hold great promise in autoimmunity. This presentation will give an overview of the in vitro and in vivo pharmacologic support and rationale for targeting ROR in autoimmunity.

3:25 Pharmacology and Preclinical Safety Studies Related to Pharmacological Inhibition of RORC

Christine Guntermann, Ph.D., Project Team Head, Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research

RORC is a master regulator of Th17 cells and represents a promising target for therapeutic intervention against autoimmune diseases. However, RORC deficiency also leads to metastatic thymic T cell lymphomas in mice. We identified potent and selective RORC inhibitors that impaired Th17 differentiation, IL-17A production, and showed good in vivo efficacy. In a longer-term safety study, we found that RORC inhibition recapitulates the early thymic aberrations found in RORC-deficient mice. While RORC inhibition will likely be an effective therapy for Th17-mediated diseases, T cell lymphoma development with chronic therapy remains an apparent risk.

3:55 Selected Poster Presentations:

Design and Synthesis of a Potent and Selective CBP Inhibitors

Alex Muthengi, Ph.D. Candidate, Department of Chemistry, Laboratory of Wei Zhang, University of Massachusetts Boston

IL6/STAT3 and Multiple Sclerosis

Yuhong Yang, M.D., Research Associate Professor, Department of Neurology, Ohio State University

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

Inflammatory Bowel Disease

5:00 FEATURED PRESENTATION: Emerging Oral Therapies for Inflammatory Bowel Disease: Clinical Programs Targeting SMAD7, S1P1R and PDE4

Kamal Puri, Ph.D., Director, Inflammation & Immunology, Celgene Corporation
Inflammatory bowel disease is a chronic inflammatory disorder of the digestive tract. It is a common disease and the incidence is rising globally. Despite current therapeutics, many patients do not obtain remission and some patients develop fibrotic strictures and require surgery. Celgene has several programs at various stages of clinical development including Mongersen, Ozanimod, and Apremilast. The scientific rationale and emerging clinical data will be discussed.

5:30 Anti-NKG2D Antibody for the Treatment of Crohn’s Disease and Considerations for Small Molecule Approaches

Tatiana Ort, Ph.D., Director, Immunology Research, Janssen Research & Development

NKG2D, an activating receptor expressed by T and innate lymphoid cells, is linked to stress-induced gut inflammation and mucosal damage. JNJ64304500 is a first in class anti-NKG2D antagonizing antibody that showed efficacy signal in a Phase IIa trial in patients with Crohn’s disease. The mechanism of action of JNJ64304500 and considerations for small molecule approaches to target NKG2D pathway will be discussed.

6:00 PTG-100, an Oral Peptide in Development for IBD

David Liu, Ph.D., CSO and Head, R&D Protagonist Therapeutics

PTG-100 is an oral GI-restricted peptide antagonist of α4β7 integrin currently in a global Phase IIb trial with ulcerative colitis patients with active moderate-to-severe disease. As a potent, reversible, and specific inhibitor of α4β7, it blocks T cell trafficking in the gastrointestinal (GI) system where there is rapid local target engagement as demonstrated by the blood pharmacodynamic responses observed in the Phase I trial with normal healthy volunteers.

6:30 Close of Day

6:30 Dinner Short Course Registration

Click here for details on short courses offered.

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Thursday, September 28

7:30 am Registration Open

8:00 Interactive Breakout Discussion Groups with Continental Breakfast

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. Details on the topics and moderators are below. Please click here for full details on all breakouts.

Developing Kinase Inhibitors for Chronic Indications

Moderator: John Robinson, Ph.D., Director, Medicinal Chemistry, Array Biopharma

• Utility of kinase selectivity profiling data
• Safety assessment as an experiment rather than a progression gateway
• Integrating PK/PD to predict safety margins

Drug Development for Inflammatory Bowel Disease

Moderator: Kamal Puri, Ph.D., Director, Inflammation & Immunology, Celgene Corporation

• Why so much activity recently?
• What will the key unmet needs be in 5 years? 
• Biomarkers to predict response and complications; e.g. structuring or fistualizing disease 
• Personalized approach to treatment: how do we use markers to get the right drugs to the right patients?

Targeting IL17 Pathway

Moderator: Joseph Wahle, Ph.D., Senior Scientist, Immunology and Respiratory Disease Research, Boehringer Ingelheim

• Other promising targets in IL17 pathway besides ROR?
• ROR challenges
• Downstream development issues/safety signals
• Animal models

Autoimmune Diseases: New Drug Targets or New Drug Candidates

9:00 Chairperson’s Remarks

John Robinson, Ph.D., Director, Medicinal Chemistry, Array Biopharma

9:05 Report-back from Breakout Discussion Moderators

9:35 BTK Inhibitors for Lupus and Other Autoimmune Diseases

Roland Grenningloh, Ph.D., Director, Preclinical Pharmacology, EMD Serono

10:05 The Cullin Ring Ligase 4-Cereblon (CRL4CRBN) E3 Ubiquitin Ligase Complex and Its Modulation by CC-220 in the Treatment of Systemic Lupus Erythematosus

Garth Ringheim, Ph.D., Director, Translational Development Inflammation and Immunology, Celgene Corporation

CC-220 is a modulator of the CRL4CRBN E3 complex that induces ubiquitination and degradation of the cereblon substrates Aiolos and Ikaros, transcription factors involved in regulating B-cell function and generation of antibody secreting plasma cells. The mechanism of action of CC-220, its impact on B-cell differentiation and function, and results from a Phase IIa dose escalation study in subjects with systemic lupus will be presented.

10:35 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

Autoimmune Diseases: New Drug Targets or New Drug Candidates (Cont.)

11:20 Targeting E2/E3 Ubiquitin Ligase Activity Is a Novel Strategy to Combat Autoimmunity

Kamyar Hadian, Ph.D., Principal Investigator & Head, Assay Development and Screening Platform, Helmholtz Zentrum Muenchen

This lecture will give insights into the discovery of a novel E2/E3 protein-protein interaction small molecule inhibitor that we were able to validate and characterize in a variety of biochemical as well as cell-based assays including primary mouse and human cells. More importantly, we can show that this first-in-class inhibitor is effective in preclinical autoimmune mouse models for psoriasis as well as rheumatoid arthritis.

11:50 Structure-Based Design of IL-17A Antagonists

Shenping Liu, Ph.D., Associate Research Fellow, Discovery Sciences Groton, Pfizer

Monoclonal antibodies targeting pathway of pro-inflammatory cytokine IL-17A have shown significant efficacies in treating psoriasis and psoriatic arthritis. To develop non-antibody IL-17A antagonists, we conducted phage display and X-ray screen to identify peptides and fragment leads. We have determined structures of IL-17A in complex with peptide, fragments and small molecule antagonists. These structures enabled us to understand the structural basis of IL-17A signaling and design IL-17A antagonists with much improved potencies.

12:20 pm Targeting the cGAS-STING Pathway Using a Homogenous HTS Compatible Transcreener cGAS Assay

Robert Lowery, Ph.D., President & CEO, BellBrook Labs

Aberrant activation of the DNA sensor cyclic GAMP synthase (cGAS) by self-DNA drives serious autoimmune diseases such as systemic lupus erythematosus. To accelerate discovery of cGAS inhibitors, we developed Transcreener-based assays for detecting cGAMP, which allow sensitive measurement of cGAS enzymatic activity with FP and TR-FRET signals.

12:50 Enjoy Lunch on Your Own

1:50 Refreshment Break in the Exhibit Hall with Poster Viewing

Intracellular Kinase Targets for Inflammation

2:35 Chairperson’s Remarks

Laura Silvian, Ph.D., Principal Scientist and Head, Physical Biochemistry, Biogen

2:40 RIPK1 - A Kinase at the Intersection of Cell Death and Inflammation

Alexei Degterev, Ph.D., Associate Professor, Developmental, Molecular and Chemical Biology Department, Tufts University

RIPK1 kinase has garnered major interest as a key effector of pathologic necrosis in a variety of settings. Significant evidence, however, points to additional and not yet equally appreciated contributions of this kinase to the cell death-independent regulation of inflammatory responses through the mechanisms that remain largely unknown. My talk will elucidate pathways of cell death-independent regulation of inflammation by RIPK1.

3:10 Targeting RIPK for Autoimmunity

Domagoj Vucic, Ph.D., Senior Scientist, Inflammation, Genentech

Inflammatory form of cell death called necroptosis involves activation of kinases RIP1 and RIP3. We have used genetic (RIP1 Kinase-Dead, RIP3 and MLKL KO mice) and chemical (RIP1 inhibitors) tools to investigate physiological role of necroptosis in inflammatory and ischemia reperfusion injury mediated disease models and find that inhibiting RIP1 kinase activity has a great benefit in a large number of inflammatory diseases.

3:40 Session Break

3:55 ARRY-624: A TYK2-Leaning, JAK Inhibitor: A First-in-Class Small Molecule Selectively Targeting the IL-12/23 Pathways

John Robinson, Ph.D., Director, Medicinal Chemistry, Array Biopharma

Pan JAK inhibitors block signaling of >20 cytokines & growth factors, effect both NK and CD8+ T-cell populations, and exhibit increased risk of infection & malignancy clinically. We hypothesized that a TYK2-targeted kinase inhibitor, such as ARRY-624, which does not engage JAK1/3, may lead to differentiated efficacy and clinical safety vs. currently available treatment options. This profile allows for selective modulation of IL-12 (Th1) and IL-23 (Th17) pathways, while sparing IL-2/IL-7 and IL-15 (g-chain-utilizing cytokines).

4:25 Inhibition of Autoimmune Pathways with Dual Inhibition of JAK1 and TYK2

Andrew Fensome, Ph.D., Associate Research Fellow, Medicinal Chemistry, Pfizer

The Janus (JAK) kinases TYK2 and JAK1 are important signaling molecules in autoimmune diseases such as psoriasis and ulcerative colitis. We will discuss the rationale to pursue dual inhibition of TYK2 and JAK1, our understanding of PK/PD relationships from tofacitinib, property space and insights from structural biology which led to the identification of PF-06700841, which is currently in Phase II clinical trials.

4:55 Close of Conference

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