As previously disclosed, on January 11, 2021, BeiGene Switzerland GmbH ("BeiGene Switzerland"), a wholly-owned indirect subsidiary of BeiGene, Ltd. (the "Company"), reported to have entered into a Collaboration and License Agreement (the "License Agreement") with Novartis Pharma AG ("Novartis"), pursuant to which BeiGene Switzerland granted Novartis the right to develop, manufacture and commercialize the Company’s anti-PD-1 antibody tislelizumab in the United States, Canada, Mexico, member countries of the European Union, United Kingdom, Norway, Switzerland, Iceland, Liechtenstein, Russia, and Japan (Filing, 8-K, BeiGene, SEP 17, 2023, View Source [SID1234635238]). Under the License Agreement, Novartis was responsible for regulatory submissions and had the right to commercialize in these licensed countries following regulatory approvals.

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On September 17, 2023, BeiGene Switzerland and Novartis entered into a Mutual Termination and Release Agreement (the "Agreement") to mutually terminate the License Agreement, effective immediately. Pursuant to the Agreement, BeiGene Switzerland regained full, global rights to develop, manufacture and commercialize tislelizumab with no royalty payments due to Novartis. Novartis may continue its ongoing clinical trials and has the ability to conduct future combination trials with tislelizumab subject to the Company’s approval. The Company has agreed to provide Novartis with ongoing clinical supply of tislelizumab to support its clinical trials. Pursuant to the Agreement, Novartis will provide transition services to the Company to enable key aspects of the tislelizumab development and commercialization plan to proceed without disruption, including manufacturing, regulatory, safety and clinical support.

The foregoing description of the terms of the Agreement does not purport to be complete and is qualified in its entirety by reference to the full text of the Agreement, which the Company intends to file as an exhibit to a subsequent periodic report or on an amendment to this Current Report on Form 8-K.

On September 17, 2023 Samsung Biologics (KRX: 207940.KS) reported a new agreement with Bristol Myers Squibb (NYSE: BMY) for large-scale manufacturing of a Bristol Myers Squibb commercial antibody cancer drug substance (Press release, Samsung BioLogics, SEP 17, 2023, View Source [SID1234635193]).

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Bristol Myers Squibb and Samsung Biologics have an existing manufacturing agreement for a commercial antibody cancer drug and have expanded the strategic relationship over time. Under the terms of the new agreement, Samsung Biologics will provide drug substance manufacturing for an antibody cancer drug substance at the company’s latest and largest biomanufacturing facility, Plant 4, in Songdo, South Korea.

"Our relationship with Bristol Myers Squibb spans over a decade, and we are proud and excited to help bring important medicines to patients around the world," said John Rim, President and CEO of Samsung Biologics. "This collaboration with Bristol Myers Squibb underscores our commitment to expediting the delivery and ensuring the continuous supply of client pipelines, enabled by our commitment to manufacturing quality, innovation, and capacity."

On September 15, 2023, Ayala Pharmaceuticals, Inc. (the "Company") reported to have entered into a Side Letter Agreement for Conversion (the "Side Letter Agreement") with Israel Biotech Fund I, L.P., Israel Biotech Fund II, L.P. and certain other investors named therein (the "Investors") (Filing, 8-K, Advaxis, SEP 15, 2023, View Source [SID1234635303]). The Side Letter Agreement references (i) the merger contemplated by the Agreement and Plan of Merger and Reorganization, dated as of July 26, 2023, between the Company, Biosight Ltd. ("Biosight") and a wholly owned subsidiary of the Company (the "Merger Agreement"), pursuant to which such subsidiary shall merge with and into Biosight, with Biosight surviving as a wholly owned subsidiary of the Company (the "Merger"), (ii) that certain Senior Secured Convertible Promissory Note entered into between the Company and the investors named therein for an original principal amount of up to $2,000,000 (the "Promissory Note"), which was previously disclosed by the Company in its Quarterly Report on Form 10-Q for the quarter ended June 30, 2023, and (iii) a Simple Agreement for Future Equity by and between Biosight and the Investors, pursuant to which the Investors agreed to invest in Biosight up to $2,500,000, and Biosight agreed to issue equity interests in Biosight to the Investors in certain circumstances (the "SAFE").

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Pursuant to the Side Letter Agreement, the Company and the Investors agreed that should the Merger be consummated prior to the termination of the SAFE, then the Investors shall be entitled to receive, in consideration for amounts actually invested in Biosight up to $2,500,000, shares of the common stock, par value $0.001 per share, of the Company (the "Ayala Common Stock"). The number of shares to be so issued would be equal to the amounts actually invested by the Investors in Biosight, divided by a conversion price equal to sixty-five percent (65%) of either (a) if definitive agreements with respect to private investments in public equity transactions involving shares of the Ayala Common Stock ("PIPE Transaction") are executed prior to the consummation of the Merger and the PIPE Transaction is consummated substantially simultaneous with the closing of the Merger, the lowest effective price per share at which shares of Ayala Common Stock are purchased in the PIPE Transaction, or (b) if the conditions set forth in clause (a) are not satisfied, the average of the closing prices of the Ayala Common Stock on the OTCQB on the five trading days immediately preceding the date on which the closing of the Merger occurs. The Side Letter Agreement also provides that (i) should the Merger be closed prior to the termination of the SAFE, then, following the closing of the Merger, if the Company enters into definitive agreements for the PIPE Transaction, the Investors shall have the right (but not the obligation) to purchase, on the same terms of the PIPE Transaction, a number of shares of Ayala Common Stock equal to up to all of the portion, if any, of the $2,500,000 that they were entitled to invest under the SAFE that was never actually invested by the Investors (the "Uninvested Amount"), except that the price per share shall be equal to sixty-five percent (65%) of the lowest effective price per share at which shares of Ayala Common Stock are purchased in the PIPE Transaction, and (ii) if the PIPE Transaction is not consummated by the date that is six months following the closing of the Merger, then, for a period of 30 days following such date, the Investors shall have the right (but not the obligation) to purchase a number of shares of Ayala Common Stock equal to up to all of the Uninvested Amount at a price per share equal to sixty-five percent (65%) of the average of the closing prices of the Ayala Common Stock on the OTCQB on the five trading days immediately preceding the date on which notice of such purchase is delivered to the Company. The mechanics of conversion, including timing of delivery of the shares of Ayala Common Stock, under the Side Letter Agreement shall be substantially the same as the mechanics of conversion, including timing of delivery of the shares of Ayala Common Stock pursuant to the Promissory Note

The Side Letter Agreement, and the shares of Ayala Common Stock issuable pursuant thereto, are being offered and sold pursuant to the exemption from the registration requirements of the Securities Act of 1933, as amended, afforded by Section 4(a)(2) thereof, for the sale of securities not involving a public offering.

On September 15, 2023 Therapeutic Solutions International, Inc. (TSOI) reported new data and a patent filing from its Subsidiary Company Res Nova Bio which, according to Company scientists, is a potential breakthrough in the field of immunotherapy of cancer (Press release, Therapeutics Solutions International, SEP 15, 2023, View Source [SID1234635189]).

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The conventional dogma, which is supported by numerous well performed studies, is that stem cell administration helps cancer to grow. This is because cancer cells thrive on growth factors generated by stem cells.

To the surprise of Res Nova scientists, administration of multiple types of mesenchymal stem cells increased the efficacy of immunotherapies which act through activation of T cells. Based on preliminary data it is believed that administration of regenerative cells results in altering the tumor environment which makes it easier for T cells to enter the cancer.

"Given that our founding company possesses a wealth of clinical data on mesenchymal stem cells, including FDA Phase III in ARDS, we are currently seeking partners to explore this potentially game-changing discovery," said Famela Ramos, President, and CEO of Res Nova.

"As a practicing physician I see first-hand the urgent need for out of the box approaches to cancer," said Dr. James Veltmeyer, Chief Medical Officer. "To think that in less than a year Res Nova has leveraged technologies ranging from stem cells to the abortion pill to create preclinical and early clinical products is unparallel in my opinion."

"We live in the Golden Age of cancer immunotherapy, and we are at the forefront. Unfortunately, some of the most effective of these therapies cannot enter solid tumors. For example, CAR-T cells have produced miraculous results in leukemias and lymphomas, but they lack efficacy in the majority of cancers," said Timothy Dixon, President, and CEO of Therapeutic Solutions International.

On September 15, 2023 Daiichi Sankyo (TSE: 4568) reported that quizartinib has been recommended for approval in the European Union (EU) in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, followed by quizartinib single-agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3-ITD positive (Press release, Daiichi Sankyo, SEP 15, 2023, View Source [SID1234635188]).

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The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on results from the phase 3 QuANTUM-First trial, which were published in The Lancet. The recommendation will now be reviewed by the European Commission, which has the authority to grant marketing authorizations for medicines in the EU.

In QuANTUM-First, quizartinib combined with standard cytarabine and anthracycline induction and standard cytarabine consolidation, and continued as maintenance monotherapy following consolidation, demonstrated a 22% reduction in the risk of death compared to standard chemotherapy alone (HR = 0.78 [95% CI: 0.62-0.98; p=0.032]) in patients with newly diagnosed FLT3-ITD positive AML. Median overall survival was 31.9 months for patients receiving quizartinib (n=268; 95% CI: 21.0-NE) compared to 15.1 months for patients in the control arm (n=271; 95% CI: 13.2-26.2) at a median follow-up of 39.2 months.

"Today’s positive CHMP opinion for quizartinib is an important step towards translating the clinical benefit observed in QuANTUM-First into an approved treatment option for patients in the EU with the difficult-to-treat FLT3-ITD subtype of acute myeloid leukemia," said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. "If approved, quizartinib would be the first FLT3 inhibitor approved specifically for patients with newly diagnosed FLT3-ITD positive AML."

The safety profile of quizartinib in QuANTUM-First was consistent with previous clinical trials with no new safety signals observed. The most common grade 3 or 4 treatment emergent adverse events (occurring in ≥ 10% of patients) were febrile neutropenia (43%), hypokalemia (19%), neutropenia (18%) and pneumonia (11%). QTcF > 500 ms occurred in 2.3% of patients receiving quizartinib and 0.8% of patients discontinued quizartinib due to QT prolongation. Ventricular arrhythmia events with quizartinib were uncommon. Two (0.8%) patients receiving quizartinib experienced cardiac arrest with recorded ventricular fibrillation on ECG (one with fatal outcome), both in the setting of severe hypokalemia.

About QuANTUM-First
QuANTUM-First is a randomized, double-blind, placebo-controlled, global phase 3 study evaluating quizartinib in combination with standard induction and consolidation therapy, including HSCT, and as maintenance monotherapy, in adult patients aged 18-75 with newly diagnosed FLT3-ITD positive AML. Patients were randomized 1:1 to receive quizartinib or placebo combined with cytarabine and anthracycline induction and cytarabine consolidation chemotherapy followed by up to three years of treatment with single-agent maintenance.

The primary study endpoint was overall survival. Secondary endpoints include event-free survival, post-induction rates of complete remission (CR) and composite complete remission (CRc), and the percentage of patients who achieve CR or CRc with FLT3-ITD measurable residual disease negativity. Safety and pharmacokinetics, along with exploratory efficacy and biomarker endpoints including duration of CR were also evaluated.

QuANTUM-First enrolled 539 patients at 193 study sites in 26 countries across Asia, Europe, North America, Oceania and South America. For more information, visit ClinicalTrials.gov.

About FLT3-ITD Positive Acute Myeloid Leukemia
More than 474,500 new cases of leukemia were reported globally in 2020 with more than 311,500 deaths.1 AML accounts for 23.1% of total leukemia cases worldwide and is most common in adults.2,3 In Europe, approximately 18,000 people are diagnosed with AML each year and the five-year survival rate is reported at 17% for adult patients.4,5

A number of gene mutations have been identified in AML, and FLT3 (FMS-like tyrosine kinase 3) mutations are the most common.6 Approximately 80% of FLT3 mutations are FLT3-ITD mutations, which drive cancer growth and contribute to particularly unfavorable prognosis including increased risk of relapse and shorter overall survival.6,7 FLT3-ITD mutations occur in about 25% of all AML cases, with frequency reported as high as 30%.6,7

About Quizartinib
Quizartinib is an oral, highly potent type II FLT3 inhibitor that selectively targets FLT3-ITD mutations and has been specifically developed for patients with FLT3-ITD positive AML.6

Quizartinib is approved in the U.S. in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed AML that is FLT3-ITD positive as detected by an FDA-approved test. Quizartinib is not indicated as maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (HSCT); improvement in overall survival with quizartinib in this setting has not been demonstrated.

Quizartinib also is approved in Japan for the treatment of AML that is FLT3-ITD mutation positive, including for use in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy and as maintenance monotherapy for adult patients with newly diagnosed FLT3-ITD positive AML, and as a monotherapy for relapsed/refractory AML that is FLT3-ITD positive as detected by an approved test. Quizartinib is an investigational medicine in all countries outside of Japan and the U.S.

About the Quizartinib Clinical Development Program
The quizartinib clinical development program includes a phase 1/2 trial in pediatric and young adult patients with relapsed/refractory FLT3-ITD positive AML in Europe and North America and several phase 1/2 combination studies as part of a strategic collaboration with The University of Texas MD Anderson Cancer Center.