On July 6, 2022 Portage Biotech Inc. (NASDAQ: PRTG), a clinical-stage immuno-oncology company developing therapies to improve patient lives and increase survival by avoiding and overcoming cancer treatment resistance, reported that it has signed an agreement to acquire Tarus Therapeutics, a private company developing adenosine receptor antagonists (Press release, Portage Biotech, JUL 6, 2022, View Source [SID1234616528]). Under the terms of the agreement, Portage will acquire Tarus in exchange for 2,425,999 PRTG shares along with the assumption of $3 million of liabilities. Additionally, payments of up to $32M in Portage shares or cash would be triggered upon achievement of future development and sales milestones. As a result of the transaction, Portage acquires four best-in-class assets targeting different aspects of the adenosine pathway, and is now in a unique position to evaluate the role of adenosine in cancer and other diseases.

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"Portage’s development strategy relies on our ability to identify and efficiently develop novel opportunities to improve the landscape of immuno-oncology treatment for patients with cancer. Based on the extensive scientific literature and promising clinical data supporting the role of adenosine in immunosuppression, we expect that these new products represent such an opportunity," said Dr. Ian Walters, Chief Executive Officer of Portage Biotech. "Coupled with the ongoing progress of our invariant natural killer T cell (iNKT) agonists, PORT-2 and PORT-3, which are currently in Phase 1/2 clinical trials, Portage is well-positioned to make important strides over the next year within our expanded portfolio and numerous milestones on the horizon."

"Historical evidence has proven that adenosine is an important target in cancer research, with multiple approaches in development from biotech and big pharma companies," added David Epstein, independent Director of Tarus Therapeutics and former CEO & Division Head of Pharmaceuticals at Novartis. "Furthermore, the potential promise of the adenosine assets, coupled with Portage’s highly experienced development team, underscores the rationale to partner these best-in-class assets with Portage."

The new assets acquired from Tarus Therapeutics include:

TT-10 (now PORT-6): an adenosine receptor type 2A (A2A) inhibitor to treat solid tumors. PORT-6 has received IND clearance and Portage expects to move into a Phase 1/2 clinical trial by the end of 2022 in an enriched patient population.
TT-4 (now PORT-7): an adenosine receptor type 2B (A2B) inhibitor to treat solid tumors, which has received IND clearance and which Portage plans to initiate clinical development in 2023.
TT-53 (now PORT-8): a dual inhibitor of adenosine receptors 2A and 2B (A2A/A2B) to address solid tumors. Portage plans to submit an IND in the near future.
TT-3 (now PORT-9): a gut selective A2B inhibitor to address gastrointestinal cancers, which is currently in preclinical studies.
Portage believes that having the ability to evaluate all four compounds alone or in combination will unlock the best patient populations and best disease settings (oncology and non-oncology) to leverage the adenosine pathway.

Portage also announced that Robert Glassman, M.D., Ph.D., current EVP of Search and Evaluation at Enavate Sciences, and former independent director of Tarus Therapeutics, will join the Portage Board of Directors. Dr. Glassman brings more than 25 years of healthcare banking, venture investing and advisory experience, including as vice chair of Credit Suisse, Global Healthcare Banking and Venture Partner of Public Equity at OrbiMed. He previously served as clinical assistant professor at Weill Cornell Medicine and has also held academic positions at the Hospital University of Pennsylvania, Cornell and Rockefeller University. Dr. Glassman holds an M.D. from Harvard Medical School and is a Board-certified hematologist-oncologist.

"Portage’s team has a long history of successfully identifying promising therapeutic assets and advancing them toward clinical trials for ultimate commercialization," said Dr. Glassman. "I am thrilled to join the Board of Directors and look forward to working closely with Ian and the team to advance these newly acquired adenosine treatments along with Portage’s broader portfolio of immuno-oncology therapies."

Concurrent with the acquisition, Portage has entered into a committed share purchase agreement for up to $30 million with Lincoln Park Capital Fund, LLC ("LPC"), a Chicago-based institutional investor, providing financing flexibility to Portage. Under the terms of the purchase agreement, Portage will have the right at its sole discretion, but not the obligation, to sell to LPC up to $30 million worth of its ordinary shares over the 36-month term of the agreement based on the market prices prevailing at the time of each sale to LPC, subject to certain conditions. In consideration for entering into the agreement, LPC received 94,508 ordinary shares. This commitment helps support the incremental development costs for the adenosine programs, and also provides significant financial flexibility for advancement of Portage’s existing pipeline of novel immunotherapy treatments, potentially extending Portage’s total cash runway into 2024.

The Portage team wishes to thank the founders and leadership of Tarus: Sushant Kumar, Ph.D., Peter Molloy, and Kasim Mookhtiar, Ph.D., for their efforts to progress the adenosine programs to this point, and looks forward to continuing to collaborate with them to advance the assets through the clinic.

Conference Call and Webcast Details
The Company has scheduled a conference call for Thursday, July 7 at 8:30am Eastern Time to discuss its adenosine programs and combined pipeline in greater detail. There will be a question-and-answer session following management’s prepared remarks.

Access to the live conference call will be available five minutes prior to the start of the call by dialing 1-877-704-4453 (U.S.) or 1-201-389-0920 (International). For all callers, please refer to Conference ID: 13731382. The conference call will be webcast live and will be accessible from the Portage Biotech website at www.portagebiotech.com or through this link: View Source;tp_key=8ef53cb012

This press release does not constitute an offer to sell or a solicitation of an offer to buy securities, nor shall there be any sale of securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.

About Adenosine
A critical mechanism of cancer immune evasion is the generation of high levels of immunosuppressive adenosine within the tumor microenvironment (TME). Research suggests that the TME has significantly elevated concentrations (100-500 fold) of extracellular adenosine. Engagement with adenosine receptors A2A and A2B triggers a dampening effect on the immune response, suppressing effector cell function and stabilizing immunosuppressive regulatory cells. Over-expression of the A2A and A2B receptors leads to poor prognosis in multiple cancers, including prostate cancer, colorectal cancer and lung adenocarcinoma, driven by a reduced ability to generate an immune response against the tumor. These findings have made A2A and A2B high-priority targets for immunotherapeutic intervention. Portage is advancing four first-in-class adenosine inhibitors which together represent the full suite of adenosine-targeting approaches and will enable a comprehensive exploration of how targeting the adenosine pathway could improve response in multiple cancer and non-cancer indications.

On July 6, 2022 Sequoia Sciences reported that New investments in China life science may have declined over the last year, but large investment companies continue to raise large sums to invest, apparently convinced the current slowdown won’t last for long (Press release, Sequoia Sciences, JUL 6, 2022, View Source [SID1234616523]). According to unofficial sources, Sequoia China has raised about $9 billion to make investments in China’s healthcare and tech companies, above its $8 billion target. Investors would have raised the total by 50%, but Sequoia allowed only a $1 billion increase over their goals. So far, Sequoia has declined to comment on the news, which was unofficially leaked to The Information.

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On July 6, 2022 Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage, precision-oncology biopharmaceutical company, reported that it has enrolled the first patient in a phase 2 clinical trial of sapanisertib (CB-228) in patients with relapsed/refractory NRF2 (NFE2L2)-mutated squamous non-small cell lung cancer (sqNSCLC) (Press release, Calithera Biosciences, JUL 6, 2022, View Source [SID1234616522]).

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NRF2 mutations are found in a considerable sub-population of patients across multiple solid tumor types. Sapanisertib is a potent and selective, dual mTORC 1/2 inhibitor that targets a key survival mechanism in tumors harboring these mutations. The compound previously demonstrated single-agent clinical activity in patients with relapsed/refractory NRF2-mutated sqNSCLC. Approximately 50,000 to 60,000 individuals are diagnosed with sqNSCLC in the United States alone each year, and about 15% of all sqNSCLC tumors harbor the NRF2 mutation.

"Our experience enrolling biomarker-driven clinical trials has allowed us to quickly advance sapanisertib since acquiring it from Takeda in the fourth quarter of last year. Enrollment of the first patient in this phase 2 study marks an important milestone for the program," said Susan Molineaux, PhD, president and chief executive officer of Calithera. "Sapanisertib has the potential to be a first-in-class treatment for patients with NRF2-mutated squamous lung cancer, a patient population with poor prognosis and high unmet need. This study is designed to further validate the NRF2 mutation as a selection biomarker, and we plan to share data from the trial by the first quarter of 2023."

The phase 2 trial (NCT05275673) is a multicenter, open-label study of sapanisertib monotherapy in patients with NRF2-mutated sqNSCLC whose disease has progressed on or after platinum-doublet chemotherapy and immune checkpoint inhibitor therapy (anti-PD-L1) with or without anti-CTLA-4, administered as separate lines of therapy or in combination. The study will evaluate sapanisertib 2 mg twice a day or 3 mg once a day in patients with sqNSCLC harboring either wild-type (WT) or mutated NRF2, as detected by next-generation sequencing.

The study is designed to confirm the selective activity of sapanisertib in NRF2-mutated tumors compared to WT tumors, and to refine dose in this biomarker-defined population. The primary endpoints of the study are investigator-assessed overall response rate (ORR) per RECIST v1.1, and safety. Secondary endpoints include duration of response, progression-free survival and overall survival.

Data from this study could position Calithera to initiate a study with registrational intent in biomarker-specific sqNSCLC populations.

On July 6, 2022 Mnemo Therapeutics, a biotechnology company developing transformational immunotherapies, reported a publication in Nature Communications demonstrating that the histone lysine methyltransferase enzyme Suv39h1 plays not only a key role in T cell persistence, but also in T cell activation and exhaustion (Press release, Mnemo Therapeutics, JUL 6, 2022, View Source [SID1234616521]). This research was conducted at Institut Curie between the lab of Sebastian Amigorena, Ph.D., CNRS research director, head of the Immune Responses and Cancer Team (Immunity and Cancer Unit – Institut Curie/Inserm) and scientific co-founder of Mnemo, and the lab of Eliane Piaggio, Ph.D., Inserm research director and head of the Translational Immunotherapy Team (Immunity and Cancer Unit, Institut Curie/Inserm).

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"T cell exhaustion and lack of persistence are two key challenges that hinder effective and durable immunotherapy treatments for tumors," said Mnemo Chief Executive Officer, Robert LaCaze. "Through Suv39h1 inactivation, Mnemo aims to create therapies with increased durability and activity."

Previous research, exclusively licensed to Mnemo from the lab of Dr. Amigorena, demonstrated that Suv39h1 is a key enzyme involved in the epigenetic regulation of immune cell memory, and that deletion of Suv39h1 results in increased immune cell memory and more durable therapeutic responses. The research demonstrated in the Nature publication goes on to show that this enzyme is a key factor in regulating T cell exhaustion.

"As is known, the potency of current treatments such as immune checkpoint inhibitors (i.e. anti-PD-1) is limited by repeated stimulation of T cells in a tumor rich environment, resulting in T cell exhaustion," said Dr. Amigorena. "The current study showcases that Suv39h1 acts as an epigenetic checkpoint inhibitor that, when coupled with anti-PD-1 treatment, results in increased T cell activity and decreased T cell exhaustion."

Key takeaways from the study include:

Suv39h1 KO CD8+ T cells are more responsive to T-cell receptor (TCR) activation and become highly cytolytic following PD-1 blockade, resulting in increased tumor killing potency.
Deletion of Suv39h1 resulted in higher CD8+ T cell tumor infiltration when coupled with anti-PD-1 treatment.
CD8+ T cells in Suv39h1 KO mice treated with anti-PD-1 displayed the highest level of a protease (GZMb) responsible for T cell induced apoptosis of tumor cells, despite displaying elevated levels of biomarkers associated with exhaustion.
Suv39h1 deletion resulted in increased chromatin accessibility in regions responsible for immune cell signaling and cytotoxicity during anti-PD-1 treatment, compared to WT with anti-PD-1 treatment.
Inhibition of Suv39h1 via small molecules mimicked Suv39h1 deletion in mouse models, reinforcing that this enzyme is playing a direct role in T cell activity.
"Limited potency, durability, and cancer-specific targets impede the efficacy of current immunotherapies, leading to off-target side effects and patient relapse," said Mnemo Co-Founder and Chief Operating Officer, Alain Maiore. "Alongside our EnfiniT Discovery Engine that identifies novel cancer targets, this research demonstrates Mnemo’s commitment to addressing multiple bottlenecks in the efficacy of immunotherapy, as well as bringing solutions to patients."

References: CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas. Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, Pamela Caudana, Jordan Denizeau, Ludovic Colombeau, Raphaël Rodriguez, Christel Goudot, Jean-Michel Luccarini, Anne Soudé, Bruno Bournique, Pierre Broqua, Luigia Pace, Sylvain Baulande, Christine Sedlik, Jean-Pierre Quivy, Geneviève Almouzni, José L. Cohen, Elina Zueva, Joshua J. Waterfall, Sebastian Amigorena & Eliane Piaggio.

On July 6, 2022 RefleXion Medical, a therapeutic oncology company pioneering the use of biology-guided radiotherapy (BgRT)* for all stages of cancer, reported the closing of a $125M debt facility, of which $55M is available immediately to repay the company’s existing $50M of debt (Press release, RefleXion Medical, JUL 6, 2022, View Source [SID1234616520]). The remaining $70M of the new facility will be made available upon reaching certain regulatory and commercial milestones. The funds will support the continued commercialization of the RefleXion X1 platform and the introduction of RefleXion’s novel BgRT technology.

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"We have again partnered with Oxford Finance to refinance our existing credit facility to lower our effective interest rate, increase access to additional funding and provide greater financial freedom as we approach the launch of our novel BgRT," said Martyn Webster, chief financial officer at RefleXion Medical. "Among other things, these funds will allow us to expand our installation capacity and build a robust radiopharmaceutical program that will one day expand the clinical indications for BgRT to include advanced prostate and kidney cancers."

"We are pleased to expand our commitment and continue supporting the RefleXion team through development and commercialization of RefleXion’s X1 radiotherapy platform and the introduction of its novel BgRT technology, which we believe has transformative potential for treating metastatic disease," said Christopher A. Herr, senior managing director at Oxford Finance.

Recently RefleXion announced a co-development agreement with Telix Pharmaceuticals to develop a new indication for Telix’s novel prostate surface membrane antigen (PSMA) targeted diagnostic PET radiotracer to include use with BgRT. Earlier this month, the company also hosted its first cancer symposium that included clinicians from 30 of the top cancer care programs in the United States.