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Development of the Cyclin-Dependent Kinase Inhibitor VS2-370 to Target HIV-associated Malignancies and to Purge Viral Reservoir

Periodic Reporting for period 1 - THUNDER (Development of the Cyclin-Dependent Kinase Inhibitor VS2-370 to Target HIV-associated Malignancies and to Purge Viral Reservoir)

Reporting period: 2017-03-01 to 2017-07-31

ViroStatics aims at developing the innovative drug VS2-370 that targets both HIV-associated cancer and its indirect cause, the viral infection. There is no similar drug, as HIV infection and associated malignancies are presently treated independently, without realizing that they are two sides of the same underlying pathogenetic problem. VS2-370 unique anti-CDK4/6/9 profile not only suppresses HIV, but also limits clonal expansion and induces apoptosis of infected cells, therefore bearing the potential to purge the viral reservoir. Unlike with currently available antiretroviral therapy (ART) this could lead to a cure of HIV infection (or functional cure, that is to allow long periods of ART-free remission), mirroring the recent success of Hepatitis C cure, and it would similarly open a multi-billion Euro market opportunity. ViroStatics strategy is to develop VS2-370 through the well established pathway of oncology drugs, then to expand the indication to the HIV cure. VS2-370 has reached an advanced stage of preclinical development and has demonstrated efficacy in CDK4/6/9-dependent tumors in relevant in vitro/in vivo models, showing promising ADME properties, good exposure/tolerability profiles, and it has been produced in a GMP lot. In this project ViroStatics has completed the documentation on VS2-370 intended for meeting Pharmas to select best indications, based on experts opinion and data collected. We have confirmed activity of VS2-370 in a relevant in vivo model of Primary Effusion Lymphoma, a tumor which is relevant in the HIV setting and has very bad prognosis, with mean survival of few months only, and also collected initial evidence of activity in a pancreatic cancer model. These are CDK4/6/9-dependent cancers and are relevant in both HIV and non-HIV setting, they represent the selected indications to move forward. Several pharma companies have been contacted searching for a out-licensing or M&A event and initial feedbacks have been collected. Patent protection has been secured worldwide until 2030 (patent already allowed in US). Based on Pharmas feedback an IND enabling package has been designed, as well as the first-in-man study protocol. These activities will be possibly completed in a future SME Phase II grant application. Data have also been collected showing activity of compounds belonging to the same family of VS2-370 against viruses such as varicella and hepatitis B. We believe this has contributed to raising the enthusiasm of pharmas during the interaction and will play a substantial role in contracting potential deals.
During the project we have completed the documentation on VS2-370 intended for Pharmas and meetings setting to select VS2-370 first indication. Experts have been identified in the field of HIV-associated malignancies in order to select the tumors that could be initially targeted by VS2-370. In vitro experiments performed in house already enabled ViroStatics to select the most relevant tumors susceptible to VS2-370 activity (Non-Hodgkin lymphomas i.e. Primary Effusion Lymphoma, PEL, and pancreatic cancer). In line with the scope of the project, activity of VS2-370 has been confirmed in vivo in established relevant models, one of PEL and on of pancreatic cancer.
Having reached an advanced stage of preclinical development with VS2-370 we have been able to complete a due diligence package suitable for inspection from the potential Pharma Customer. Two sets of presentations have been prepared: a non-confidential and a confidential one illustrating the results achieved so far and elaborating on future plans for first-in-man study (FIM).
The confidential deck can not be disclosed here, here we have only reported the non-confidential set of slides (see technical report for complete slide deck) which has been used for initial contacts with pharmaceutical industries during several international meetings. Aim of ViroStatics is to conclude an out-licensing or M&A event. The outline of the message delivered to the audience was as follows:
ViroStatics is developing novel CDK4/6/9 inhibitors for aggressive cancers and viral diseases, this robust pipeline of compounds distinguish themselves from the competition through their unique selectivity, efficacy and safety profiles. Our lead compound VS2-370:
• Has a distinct anti-CDK4/6/9 profile
• Is active in vitro and in vivo against aggressive cancers (i.e. primary effusion lymphoma, an HIV-related cancer with very poor survival rate)
• Has a good therapeutic window between activity and toxicity
• Is orally bioavailable, has promising ADME and CMC has been completed
Coaching support has been very important during the preparation of this presentation, providing us with very useful suggestions to review and complete the slide deck, as well as indications about value proposition, sales collateral development and investment planning.
Thanks to coaching support a series of interesting meetings for developing international partenerships and sustain corporate development have been set up.
Interaction with potential first customers was one of the main goals in this project. Pharma companies with franchise in HIV and/or oncology have been contacted and involved to identify the preferred initial indication(s) for VS2-370 in oncology. Three leading worldwide Pharmas with franchise both in HIV and Oncology had already expressed initial interest and promptly signed Confidentiality Agreements. During this project we have intensified the process of meeting pharmas and, also thanks to the Investment Bank Stifel’s network, we were able to contact several companies, the main contacts that were created during this project are listed in the final report attached.
Pharmas were met during the following international meetings:
ICTO, The International Congress on Clinical Trials, March 16-17, 2017
Bio-Europe Spring, March 20-22, 2017
AACR Annual Meeting, April 1-5, 2017
ASCO, American Society of Clinical Oncology Annual Meeting, June 2-6, 2017
ViroStatics and Stifel reached out to 34 likely potential future oncology-oriented partners for ViroStatics. Primary goal was to educate these potential partners ahead of a formal process in the Fall after further pre-clinical studies.
Durign this project ViroStatics intended also to improve the IP valorization plan. ViroStatics has developed a robust patent portfolio covering the composition of matter and use of the family of compounds designed to cure HIV infection, with a broad filing and patent protection beyond 2030. Part of the resources have been committed to maintain this broad coverage by paying due annual fees in the numerous countries where we have filed thereby making the project appealing for deal with a Pharma. Two independent analyses from specialized third parties have confirmed ViroStatics’ freedom to operate. A final IND enabling package has been elaborated based on the feedback from big Pharmas and meeting with EMA. According to timelines one year would be necessary to complete the IND-enabling studies, ViroStatics will try to get required funds through the application in SME Instrument Phase II. A FIM study design has also been put together and it is elucidated in the final report.
Developing a drug targeting both the virus and cancer cells would be highly desirable, as up to date no such drug is available. Unlike with currently available ART this could lead to a cure of HIV infection (or functional cure, that is to allow long periods of ART-free remission), mirroring the recent success of Hepatitis C cure. No one has registered a drug to cure HIV so far and HIV-infected individuals treated with ART are comparable to healthy individuals in the mind of regulatory agencies, making the registration pathway of VS2-370 challenging. Also EMA scientific advisors indicated to us the lack of a clear regulatory pathway for HIV eradication and cure. Thus, to accelerate approval of VS2-370 for HIV Cure, ViroStatics is offering a unique alternative and aims at registering VS2-370 as an anti-cancer drug through the well established pathway of oncology drugs, e.g. for PEL, that is common in the HIV setting, evaluating the effects of VS2-370 on HIV reservoir later on, during VS2-370 oncology development, thus expanding indication to HIV cure with a Phase IV trial.
The advantages for the final users (HIV-infected individuals with associated malignancies) will be: tumor- and ART-free remissions, quality of life improvement, decreased side effects associated with ART, cost savings for the patients and the Health Systems. ViroStatics has demonstrated that the compound VS2-370 is active in primary effusion lymphoma, an HIV-associated tumor, and therefore has identified the indication for its lead compound. The goal of ViroStatics program would be to complete the Preclinical Phase of development for VS2-370, performing further in vitro and in vivo characterization of the compound to complete an Investigational New Drug (IND) application package, necessary to run a First-In-Man (FIM) study.