On May 26, 2021 Cleveland Clinic researchers reported that they have identified a promising drug target for treating and preventing aggressive, drug-resistant prostate cancer (Press release, Cleveland Clinic Foundation, MAY 26, 2021, View Source [SID1234583288]).

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Nima Sharifi, M.D.

The team, led by Nima Sharifi, M.D., of Cleveland Clinic’s Lerner Research Institute, demonstrated that inhibiting the protein H6PD led to significantly reduced tumor sizes and improved survival among mouse models with drug-resistant prostate cancer. The H6PD levels also were elevated in biopsied patient tumors, suggesting the protein might be targeted in patients for treatment.

"New treatment approaches for drug-resistant prostate cancer are desperately needed," said Dr. Sharifi, director of Cleveland Clinic’s Genitourinary Malignancies Research Center. "These findings suggest an entirely new strategy for treatment of men with this aggressive form of prostate cancer."

Enzalutamide, a current standard-of-care hormone therapy for metastatic prostate cancer, works by blocking androgen receptors, which are proteins that help drive cancer cells. While initially effective, most patients eventually develop resistance to the treatment. This resistance occurs when androgen receptors are blocked and cancer cells adapt to get their "fuel" from a similar receptor, called the glucocorticoid receptor.

These glucocorticoid receptors bind to and interact with the stress hormone cortisol. In an earlier study published in eLife, Dr. Sharifi and his team linked enzalutamide resistance to increased tumor cortisol levels. They found that tumors typically express a protein called 11β-HSD2, which inactivates cortisol. However, when this protein expression is inhibited in some tumors, cortisol and the glucocorticoid receptor are stimulated and become available for use by cancer cells.

"Taken together, our study findings suggest that pharmacologically inhibiting the H6PD protein can reverse drug resistance in prostate cancer cells," said Dr. Sharifi. "By blocking this protein, we are able to prevent cancer cells from utilizing their backup fuel supply – cortisol and its receptor. When we block this pathway, tumors begin to become responsive to standard treatments again."

In this new study, the researchers demonstrated that, in addition to decreased expression of 11β-HSD2, resistant tumors also have increased H6PD levels.

"With lower levels of 11β-HSD2, which normally functions to cut off the fuel supply to drug-resistant cancer cells, the cells are free to continue to grow and spread unchecked," said Dr. Sharifi. "By inhibiting the H6PD protein, however, we were able to reinstate anti-cortisol effects. This finding is key to better understanding how disruptions in cortisol metabolism contribute to cancer cells’ growth and spread."

Dr. Sharifi’s clinical collaborator Eric Klein, M.D., chair of Cleveland Clinic’s Urology & Kidney Institute and a co-author on the study, said, "We found elevated levels of H6PD in both animal models and patient tissues, particularly after treating tumors with enzalutamide. These findings hold promise for novel precision medicine approaches in the management of men with aggressive prostate cancer."

The researchers targeted H6PD with rucaparib, a drug already approved by the U.S. Food and Drug Administration. Dr. Sharifi collaborated with scientists from Cleveland Clinic’s Center for Therapeutics Discovery to identify what parts of rucaparib are chemically necessary to inhibit the protein.

Researchers administered enzalutamide to mouse models of aggressive prostate cancer that expressed H6PD and those where the protein was blocked with rucaparib. The models where H6PD was blocked had significantly smaller tumors and longer progression-free survival following enzalutamide treatment.

Jianneng Li, PhD, a post-doctoral fellow in Dr. Sharifi’s lab, is first author on the study, which was supported by the National Cancer Institute and the Prostate Cancer Foundation.

"These findings represent an exciting new opportunity to potentially reverse drug resistance in advanced prostate cancer," said Howard R. Soule, PhD, Executive Vice President and Chief Science Officer of the Prostate Cancer Foundation. "PCF commends Dr. Sharifi and the team on their achievement and proudly supports their work to bring us closer to our mission to eliminate death and suffering from prostate cancer."

On May 26, 2021 Ysios Capital, Spain’s largest and leading European venture capital firm specialised in the biotechnology sector, reported that it has closed its third fund, Ysios BioFund 3 (YBF 3) at €216 million ($260 million) (Press release, Ysios Capital, MAY 26, 2021, View Source [SID1234583259]).

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YBF 3 – Ysios’ largest fund to date – provides biotech ventures with the resources to develop novel and disruptive therapies for indications with high-unmet medical need, supporting pioneering businesses striving to make a difference in patients’ lives.

YBF 3 will invest broadly across multiple therapeutic areas and modalities, targeting seed/early stage and development-stage companies at the forefront of the future of medicine. The total investment size per company will typically be of up to €20 million.

Ysios takes lead positions and works closely with entrepreneurial management teams. Emphasis will be placed on building sustainable companies with business models offering dual paths to liquidity. As with previous funds, about 80% of the YBF 3 investments will target Europe, with a special focus on Spain, while the remainder of the fund will target opportunities in North America.

More than 60% of the portfolio has already been constructed, with eight investments made in the last 12 months by blue-chip European and US investors. YBF 3 has participated in the following fund raisings, mostly taking a lead or co-lead role:

Ona Therapeutics (Oncology, Spain) – €30M Series A
SpliceBio (Gene therapy, Spain) – Seed/company build-up
VarmX (Blood clotting, The Netherlands) – €32M Series B
Lava Therapeutics (Oncology, The Netherlands) – €70M Series C/IPO NASDAQ: LVTX $103M
SparingVision (Gene therapy, France) – €44.5M Series A2 round
Synendos (Neuropsychiatry, Switzerland) – CHF 24M Series A
Adcendo (Oncology, Denmark) – €51M Series A
Cytoki (Inflammation, Denmark) – €38M Series A
Commenting on the close, Joël Jean-Mairet, Managing Partner at Ysios Capital, said: "Our latest close is testament to the stellar track record we have built up at Ysios over the last ten years, securing investment beyond our initial target size. The quality of this company portfolio, exemplified by the recent IPO on NASDAQ of Lava Therapeutics shortly after our initial investment demonstrates the role we play in driving forward the future of medicine."

Karen Wagner, Managing Partner at Ysios Capital, added: "We are very proud of the work Ysios has supported over the last decade. With our latest fund, we have expanded the team and advisory board, which is key to our long-term commitment to bring medical products from lab to market."

A proven track record

Since its inception, Ysios has invested in 33 companies – including several of Spain’s biotech success stories – and has brought 14 innovative medical products to market. Currently, over 40 medical products across the portfolio are at the clinical stage for serious diseases and over €1bn has been invested in R&D.

Key liquidity events over the last years include the sale of Tigenix (formerly Cellerix) to Takeda (€450M), the purchase of STAT-Diagnostica by Qiagen (up to €172M), the sale of Endosense to St. Jude Medical ($331M), the investment and purchase option of Pfizer into Vivet (up to €540M), the sale of Biovex to Amgen (up to $1bn), the sale of Prexton to Lundbeck (€100M) and three listings on NASDAQ including Galecto (GLTO), Kala Pharmaceuticals (KALA) and Lava Therapeutics (LVTX).

YBF 3 receives EU backing

Following an initial investment of €30 million, the European Investment Fund (EIF), part of the European Investment Bank Group and a leading player in the European Venture Capital market, mobilised an additional €30 million of participation in the fund. This brings the total EIF related participation to €60 million, representing 27.7% of the total commitments.

Out of this additional €30 million investment, €20 million is backed by the European Guarantee Fund (EGF), part of the European Union’s €540 billion response to the economic fallout caused by COVID-19. The remaining €10 million investment is supported by the Health Compartment of the Sustainable Development Umbrella Fund (SDUF), which aims to crowd-in resources from private investors operating in the pharma and med-tech industry and foster collaboration between the latter and VC firms through the VCoE program, particularly emerging managers addressing markets such as Spain, where the innovation potential is relatively untapped.

Alain Godard, EIF Chief Executive, said: "The science, technology and innovation sectors have been pivotal in helping to address the immediate health challenges of the COVID-19 crisis. I am delighted to see that thanks to the European Guarantee Fund and the Sustainable Development Umbrella Fund we could increase our participation in YBF 3, backing the investment needs and growth of innovative life science companies that develop disruptive therapeutic products."

Jean-Marc Bourez, Managing Director/Head of the Venture Centre of Excellence said: "We are really delighted to welcome Ysios BioFund 3 that will gain access to the VCoE Programme, and brings together an exclusive community of selected venture capital funds and private corporate investors to bolster the flow of co-investment directed towards European life science start-up and small mid-caps."

On May 26, 2021 Lyell Pharmaceuticals reported that it filed for an initial public offering (IPO) with plans to raise $150 million (Press release, Lyell Immunopharma, MAY 26, 2021, View Source [SID1234583252]). The preclinical biotech raked in $493 million in a Series C round on March 12, 2020.

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The company, which isn’t expected to enter the clinic until possibly in 2022, is working to make cell therapies work in solid tumors. So far, cell therapies such as CAR-T have been effective in hematologic cancers but have been far less successful in solid tumors. They are also working to prevent relapses caused by T-cell exhaustion.

In March, the company completed the construction of its $65 million LyFE Manufacturing Center in Bothell, Washington. The facility is 70,000 square feet and holds cell process equipment and manufacturing processes needed to expand and reengineer immune cells obtained from patients.

"This manufacturing center represents crucial infrastructure for our upcoming clinical trials and will be able to scale to meet our cell therapy manufacturing needs as we grow," said Stephen Hill, chief technical operations officer of Lyell.

"Manufacturing is integral to the actual design and performance of new cell therapies, so we have made large investments to build leading edge capabilities in this area. LyFE is a paperless facility that has digital manufacturing integrated into the operation. We believe the ability to capture and analyze data in real time will ultimately lead to better and safer cell therapies for patients."

In September 2020, Lyell inked a research partnership with Orca Bio to combine Orca’s precision purification T-cell technology with Lyell’s T-cell biology expertise to focus on solid tumor cell therapies. Orca has developed T-cell therapies for blood diseases as well as developed an ultra-fast, clinically compatible cell sorter dubbed OrcaSort.

"Lyell Immunopharma is focused on developing curative T-cell therapies for solid tumor cancers by defining starting cell preparations and modulating T-cells, so they are functional in the immunosuppressive tumor microenvironment," said Nick Restifo, executive vice president of Research for Lyell, at the time. "This collaboration with Orca Bio provides the potential to more efficiently define starting cell preparations, which I believe could lead to more effective T-cell therapies."

The company’s lead asset is a CAR (chimeric antigen receptor) that targets ROR-1, a receptor tyrosine kinase present in various cancers with abnormal expression. Lyell and other biotech companies believe that silencing ROR-1 will prevent cancer metastasis. They expect early clinical trials to be on triple-negative breast cancers and non-small cell lung cancer (NSCLC).

They won’t be alone, although their approach appears to be unique. In 2020, Merck acquired VelosBio for an antibody-drug conjugate (ADC) against ROR-1. And the same year, Boehringer Ingelheim bought NBE-Therapeutics to partner on an ADC. ADCs are antibodies directed against a target, in this case ROR-1, linked to a toxic drug, which is more precisely directed to the target.

Lyell’s approach would be to collect T-cells from the patients, engineer them to attack ROR-1, and reinfuse them back into the patient. In its filing, the company wrote, "We are applying our Gen-R and Epi-R technology platforms to our lead CAR program, LYL797, which is expected to be an intravenous (IV) administered CAR-T cell product candidate targeting ROR1. If successful, we anticipate expanding into other ROR1+ cancers with a lower incidence of ROR1 expression, including potentially hormone receptor positive (HR+) breast cancer, ovarian and other solid tumors. We expect to submit an IND for LYL797 in the first quarter of 2022."

GlaxoSmithKline holds 14% of Lyell. According to the filing, GSK is "developing a New York esophageal squamous cell carcinoma 1 (NY-ESO-1) TCR T-cell product candidate, NY-ESO-1C259, currently in pivotal development. We are collaborating with them to potentially enhance this clinical-stage product candidate with Gen-R and Epi-R. Preclinical efforts and IND-enabling studies are underway. We anticipate GSK will conduct initial clinical trials with the enhanced product candidate in synovial sarcoma and multiple other solid tumor indicates. We anticipate an IND submission in the first half of 2022."

In total, the company hopes to submit four Investigational New Drug (IND) applications in 2022.

On May 26, 2021 EVERSANA, the pioneer of next generation commercial services to the global life sciences industry and S3 Connected Health, an award-winning partner in digital health solutions for pharma, reported a strategic partnership to offer end-to-end digital health and commercialization services for pharmaceutical companies (Press release, EVERSANA, MAY 26, 2021, View Source [SID1234583251]).

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S3 Connected Health’s proven experience in design, creation and operation of digital health solutions will complement EVERSANA’s end-to-end commercialization services (including patient support and adherence models), enabling life sciences companies to:

Impact brand planning and optimize performance with digital health solutions, to provide personalized support based on real-world insights.
Improve outcomes through next-generation patient services, and meet the demands of value-based care using digital health solutions and human-based support to deliver integrated therapy and condition management services.
"As we’ve rapidly expanded our services across Europe, we started working with S3 Connected Health and immediately saw the opportunity to blend digital health solutions throughout our commercial support of the product and patient journeys," said Mike Ryan, Executive Vice President, Europe, EVERSANA. "Now more than ever, we can work together to impact brand performance, improve patient experiences, or even deliver and launch life-changing DTX products in market."

Jim O’Donoghue, President of S3 Connected Health said, "Digital health solutions are now vital for delivering better, more sustainable healthcare for patients and clinicians into the future. Through this collaboration with EVERSANA we will be able to offer complete end-to-end solutions and services for digital health from co-creation through to commercialization, providing a unique service to our combined customer base."

On May 26, 2021 Knight Therapeutics Inc. (TSX: GUD) ("Knight") a pan-America (ex-USA) specialty pharmaceutical company, reported that it has completed the acquisition of the exclusive rights to manufacture, market and sell Exelon (rivastigmine Patch, Capsules and Solution) in Canada and Latin America (the "Territory"), as well as an exclusive license to use the intellectual property and the Exelon trademark, from Novartis within the Territory (Press release, Knight Therapeutics, MAY 26, 2021, View Source(TSX%3A%20GUD)%20(%22,as%20well%20as%20an%20exclusive [SID1234580700]).

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Knight has paid USD $168 million in cash and will pay an additional milestone payment of up to USD $12 million upon the achievement of certain conditions.

Knight has entered into a transition service agreement until transfer of marketing authorizations, on a country by country basis during which Knight will receive a net profit transfer. Knight will begin distributing Exelon upon transfer of marketing authorizations, on a country by country basis.