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The Wistar Institute

An early stage drug discovery company

Presenter: Troy Messick, Senior Staff Scientist

 

Monday, January 16, 2017

Embassy Suites, Chesterbrook, Pennsylvania (directions)

 

About

 

Unmet Medical Need

Epstein Barr Virus (EBV) is a human gamma-herpesvirus that infects over 90% of the adult population worldwide. EBV is causative of a number of neoplastic diseases, including nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, gastric carcinoma, and lymphoproliferative disorders in immunocompromised patients (HIV-associated or after solid organ transplant), such as hairy leukoplakia and central nervous system lymphomas.  Increasing evidence provide an association between EBV with a higher risk of certain autoimmune diseases, for example, multiple sclerosis.  200,000 cancer cases per year are attributable to EBV. The World Health Organization has classified EBV as a human class I carcinogen due to its association with 1-2% of all human cancers worldwide.

 

Therapeutic strategy

A consortium of academic and industrial partners has discovered novel inhibitors that are targeted toward therapeutic intervention of EBV-associated diseases. Epstein-Barr Nuclear Antigen 1 (EBNA1) is an ideal target for elimination of latent infection and treatment of EBV-associated disease as it is expressed in all EBV-positive tumors. EBNA1 is required for immortalization of primary B-lymphocytes and for the stable maintenance of the EBV genome in latently infected cells. The structure of EBNA1 contains a unique fold that has no homology to other proteins in the human proteome. By targeting a virally expressed protein with no known human orthologs, we have mitigated the potential risk of dose-limiting toxicity. The three-dimensional structure of EBNA1 bound to the inhibitors has been solved by X-ray crystallography and this has driven the chemical strategy.  We have developed an in depth understanding of the structure-activity relationship with over 70 high-resolution co-crystal structures and more than 1500 compounds synthesized and evaluated during the lead optimization phase of the program.  A portfolio of three non-overlapping patents has been filed to protect these chemically-unique EBNA1 inhibitors.

 

 Preclinical Development to Clinical Development

In conjunction with our clinical partners, we established a target product profile (TPP) to guide our preclinical development program.  Based on the TPP, we set rigorous, industry-accepted attributes that the drug candidate must possess to justify progression to IND-enabling studies. Our clinical candidate meets or exceeds those criteria, which includes standards for potency, selectivity, safety and tolerability.  Our clinical candidate shows excellent efficacy in 4 different EBV-dependent mouse models, including patient-derived xenograft studies with a >16-fold therapeutic window.  And we have performed validation studies to demonstrate in vivo target engagement.  Currently, we are performing solid-state analysis, salt selection, and formulation work.  IND-enabling studies including safety pharmacology and toxicology and GMP manufacturing will commence later this year with a projected First-In-Human clinical trial in H1 2018.  We anticipate that EBV plasma levels will be a useful surrogate biomarker that correlates with disease prognosis and progression.

In summary, our potent EBV-specific clinical candidate:

  • Represents a first-in-class oncology product that addresses an unmet medical need,
  • Possesses potent nanomolar activity, is selective and efficacious in animal models,
  • Should be more effective, better tolerated and safer than the current standard of care, and
  • Meets or exceeds industry-accepted criteria for drug suitability, safety and toxicology.
  • IND-enabling studies will begin later this year with a projected FIH clinical trial in H1 2018.
  • We have assembled a team that includes clinical investigators from Stanford, MSKCC and Chinese University of Hong Kong to conduct a Phase I clinical trial in NPC patients.

 

 

3 Major Issues

 

  1. Regulatory and clinical trial strategy:
    We are currently in the development phase of the program with a potential IND and start of the clinical trial in Q1/Q2 2018.  There are many diseases that are associated with EBV for which our drug could potentially be effective.  Each of these patient populations have advantages and risks.  For example, there is a high incidence of nasopharyngeal carcinoma (NPC) in southeast Asia including Hong Kong and a phase I clinical trial could be carried out there in 2 years in patients with recurrent or metastatic NPC.  An advantage of NPC is that there are plasma biomarkers available to monitor disease progression.  For a Phase II/III studies, one would probably have to involve China, which presents from a regulatory and commercial perspective.  Some have advised us to do a clinical trial in post transplant lymphoproliferative disease (PTLD) or EBV-postive lymphomas.  Because it’s an anti-EBV drug, others have advised us to do a phase I study in healthy volunteers.  Which strategy would you recommend that balances regulatory, clinical and commercial risks and benefits?
  2. Development partner strategy:
    Many potential investors or industrial partners on first pass dismiss this program as not having a large enough market.  Obviously, we disagree.  What can we be doing to bolster their interest?  Which companies should we be targeting?
  3. Funding strategy:
    We have been successful at attracting funding from government sources and the Wellcome Trust.  Current funding will support the program through filing the IND.  We are now, however, entering a new phase that requires funding for a clinical trial.  It presents a particular dilemma because this program has its roots in a non-profit institution and because of our natural inclination to preserve control over the program and the value of the asset.  What should our strategy be to raise funds for a clinical trial?

 

 

Program:

 

6:30 - Cocktails & Dinner (Cash bar and special 2-entree buffet menu)

8:00 - Troy Messick, Senior Staff Scientist, will deliver the Company's "Elevator" Pitch to the Group

8:20 - A Panel will address three major issues crucial to helping the Company reach the next level.

9:00 - Open discussion: members and guests

 

 

Available Media

Please note: All information obtained here is the property of those presenting and should not be copied or duplicated without written consent.

 

Slides

None available at this time

Audio

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Video

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Webcast

None available at this time

 

 

Contact Info:

 

 

Our Sponsors

EisnerAmperGlaxoSmithKlineKEH Insurance Agency
New Jersey Institute of Technology
Science CenterWhite and Williams

 

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Questions or Coments?

Contact: Peter van der Kam,

peter@rxpcci.com | (610) 296-8086

 

 

 

Good Company! Good Drink! Good Food! Good Program! Good Fun!

 

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