Cambridge Healthtech Institute’s 4th Annual

Targeting NASH

Drug Development for the Fatty and Fibrotic Liver

September 16 - 17, 2020 ALL TIMES EDT

Non-alcoholic steatohepatitis (NASH) is a disease of the liver that starts with a build-up of fat in the organ and if inflammation is also present, results in fibrosis and dysfunction of the liver which can sometimes lead to cirrhosis, a type of liver cancer. No medical treatments for NASH yet exist, but drug discovery efforts against the disease are growing. There are a few drug candidates progressing in clinical trials, but there have also been a few recent failures. CHI’s Targeting NASH conference convenes leading drug discovery and development researchers and industry experts to share the latest publicly available results and discuss important questions in the field, such as which target classes still have potential, what are promising drug combinations, and best practices for clinical trial design.

Wednesday, September 16

CLINICAL-STAGE DRUG CANDIDATES FOR NASH

9:30 am

NASH Drug Development Landscape in NASH Patients

Peter G. Traber, MD, Partner, Alacrita Consulting
Rebecca A. Taub, MD, CMO and President of R&D, Madrigal Pharmaceuticals

I will present data from clinical studies of resmetirom (MGL-3196). MGL-3196 is an orally administered, small-molecule, liver-directed compound that is currently in Phase III development for NASH.


10:30 am Session Break
10:50 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Jamie G. Bates, PhD, Senior Research Scientist II, NASH, Gilead Sciences Inc.
Panelists:
Peter G. Traber, MD, Partner, Alacrita Consulting
Rebecca A. Taub, MD, CMO and President of R&D, Madrigal Pharmaceuticals
11:10 am Coffee Break - View Our Virtual Exhibit Hall

CLINICAL-STAGE DRUG CANDIDATES FOR NASH (CONT.)

11:25 am

A Novel Fatty Acid Bile Acid Conjugate, Aramchol, in Clinical Development for NASH

Liat Hayardeny, PhD, CSO, Galmed Pharmaceuticals
11:45 am

Aldafermin: Latest Clinical Results from a FGF-19 Agonist for the Treatment of NASH

Hsiao D. Lieu, MD, Senior Vice President & CMO, NGM Biopharmaceuticals, Inc.

24-weeks aldafermin treatment showed significant reduction in absolute LFC compared to placebo (-7.7% vs. -2.7%; P=0.002) in NASH patients.  Aldafermin had greater efficacy compared to placebo in histological endpoints: fibrosis improvement (38% vs. 18%) and NASH resolution (24% vs. 9%).  On combined endpoint of both fibrosis improvement and NASH resolution, aldafermin was superior to placebo (22% vs. 0%; P=0.015).  Discontinuations due to AE were 0% (aldafermin) vs. 4% (placebo).

12:05 pm Session Break
12:25 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
William Esler, PhD, Senior Director, Internal Medicine Research Unit, Pfizer Inc.
Panelists:
Liat Hayardeny, PhD, CSO, Galmed Pharmaceuticals
Hsiao D. Lieu, MD, Senior Vice President & CMO, NGM Biopharmaceuticals, Inc.
Alison MacKinnon, PhD, Preclinical Research Consultant, Galecto Biotech AB
12:45 pm Lunch Break - View Our Virtual Exhibit Hall

NASH TARGETS

1:15 pm

Targeting Galectin-3 in NASH

Alison MacKinnon, PhD, Preclinical Research Consultant, Galecto Biotech AB

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are major health problems without approved therapies. The prevalence of NASH fibrosis leading to cirrhosis is growing and it is at present, the second leading cause for liver transplantation. Galectin-3, a beta-galactoside-binding lectin, is a key regulator of fibrosis and inflammation in multiple organs, including the liver. Mice deficient in galectin-3 are protected from CCl4-induced fibrosis and exhibit reduced scarring in response to injury. Galectin-3 regulates myofibroblast differentiation (the major source of collagens during tissue fibrosis) and also has profound effects on profibrotic macrophage polarization. An inhaled galectin-3 inhibitor - TD139 - is currently undergoing phase IIa clinical development for idiopathic pulmonary fibrosis. However, the identification of systemically active galectin-3 inhibitors will be required for the development of effective therapies for NASH. GB1107 significantly reduced fibrotic collagen deposition in the hepatic parenchyma as assessed by PSR staining at 10, but not 2 mg/kg. This was accompanied by a reduction in LgalS3, alpha-SMA, Col1A2, and Col1A3 transcripts. At 2h, post-dose plasma levels of GB1107 were 1670 ± 310 nM in the 10 mg/kg group, and 213 ± 24 nM in the 2 mg/kg group. GB1211 also reduced fibrosis when administered twice daily during the last 3 weeks of a 6-week CCl4 regimen. Both GB1107 and GB1211 inhibited TGF-beta induced transcription of Col1A2, alpha-SMA, LgalS3 and TIMP1 in human liver fibroblasts in vitro.

These inhibitors show promise as potential new oral anti-fibrotic agents for the treatment of NASH. GB1211 is undergoing clinical development for NASH. Results from a first-time, in-human study indicate that GB1211 is both safe and well-tolerated in man with PK that supports twice daily dosing. A phase IIb study is planned in NASH patients.

1:35 pm

Optimized FXR Agonist with Best-in-Class Potential for NASH Treatment

Hubert C. Chen, MD, CMO, Metacrine

FXR agonists have been validated as a treatment for NASH, although improvements in therapeutic index for the class remain elusive. MET409, a sustained agonist with a novel non-bile acid structure, has demonstrated a promising profile – including significant reductions in liver fat content, improvements in liver enzymes, and differentiated pruritus and LDL-cholesterol profiles – after 12 weeks of treatment. These findings support the best-in-class potential of MET409 and structurally related agonists.

1:55 pm Sponsored Presentation (Opportunity Available)
3:00 pm Interactive Breakout Discussions - View Our Virtual Exhibit Hall

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. Discussion topics and moderators will be listed on the website.

BREAKOUT: Drug Development Challenges for NASH Therapies

Bryan C Fuchs, PhD, Senior Director & Research Therapeutic Area Head, GI & Liver Disease, Ferring Research Institute
  • Animal models for NASH
  • Surrogate markers for NASH
  • Predicting the medical landscape (combination therapies?)

3:35 pm Close of Day

Thursday, September 17

NASH DRUG CANDIDATE COMBINATIONS

10:15 am

A Novel NASH Combination: ACC and DGAT2 Inhibitors

William Esler, PhD, Senior Director, Internal Medicine Research Unit, Pfizer Inc.

Acetyl-CoA carboxylase (ACC) inhibitors robustly reduce steatosis and ALT in NAFLD patients but also markedly increase circulating triglycerides, potentially limiting the clinical utility of the class.  However, co-administration of an ACC inhibitor with a diacylglycerol acyltransferase 2 (DGAT2) inhibitor may block ACCi-mediated increases in circulating triglycerides and may have potential for greater efficacy than either monotherapy.  Data from nonclinical and clinical studies aimed at testing these hypotheses will be presented.

10:35 am

Evaluating Combinations of PPAR Agonists with ACC Inhibitor for NASH

Archana Vijayakumar, PhD, Senior Research Scientist I, Fibrosis Biology, Gilead Sciences, Inc.

Firsocostat, an acetyl-CoA carboxylase inhibitor (ACCi), improves hepatic steatosis and liver biochemistry, but may increase plasma TGs in NASH patients with pre-existing hypertriglyceridemia. This is mitigated by fenofibrate, a PPARα agonist, (pre)clinically. We evaluated the effects of clinical PPAR agonists on plasma and liver TGs in combination with ACCi in diet-induced obese rats. All PPAR agonists effectively reduce ACCi-induced hypertriglyceridemia similar to fenofibrate with minimal combination effects on liver TGs.

10:55 am Session Break
11:35 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Kevin Hart, PhD, Principal Scientist, Inflammation, Pfizer Inc.
Panelists:
Hubert C. Chen, MD, CMO, Metacrine
William Esler, PhD, Senior Director, Internal Medicine Research Unit, Pfizer Inc.
Archana Vijayakumar, PhD, Senior Research Scientist I, Fibrosis Biology, Gilead Sciences, Inc.
11:55 am Coffee Break - View Our Virtual Exhibit Hall

PLENARY KEYNOTE PROGRAM

12:20 pm

PLENARY KEYNOTE: Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics

VHL tumor suppressor protein (pVHL) inactivation is common in kidney cancer and upregulates the HIF2 transcription factor. PT2977/MK-6482 is an allosteric HIF2 inhibitor now in Phase 3 testing. Thalidomide-like drugs (IMiDs) bind to cereblon which, like pVHL, is the substrate-binding unit of a ubiquitin ligase. IMiDs redirect cereblon to destroy the myeloma oncoproteins, IKZF1 and IKZF3. We have developed new assays for identifying drugs that can destabilize oncoproteins of interest.

12:45 pm LIVE Q&A:

Plenary Keynote Discussion

Panel Moderator:
Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.
Panelist:
William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics
12:55 pm LIVE PANEL AND Q&A:

Plenary Keynote Discussion: De-Risking Early Drug Discovery

Panel Moderator:
Nadeem Sarwar, PhD, Founder & President, Eisai Center for Genetics Guided Dementia Discovery, Eisai, Inc.
  • Data Sciences
  • ​Novel Chemical Modalities
  • Investment and Partnering Models
  • COVID-19 Progress as Examples of Successful Partnerships
Panelist:
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
1:35 pm Lunch Break - View Our Virtual Exhibit Hall
2:05 pm Close of Targeting NASH Conference

Please click here to continue to the agenda for Targeting Fibrosis






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