The Wistar Institute
An early stage drug discovery company
Monday, January 16, 2017
Embassy Suites, Chesterbrook, Pennsylvania (directions)
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About
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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
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- 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?
- 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?
- 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:
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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
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 Slides
None available at this time
 Audio
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 Video
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 Webcast
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