On July 27, 2020 AstraZeneca reported that it has entered into a new global development and commercialisation agreement with Daiichi Sankyo Company, Limited (Daiichi Sankyo) for DS-1062, Daiichi Sankyo’s proprietary trophoblast cell-surface antigen 2 (TROP2)-directed antibody drug conjugate (ADC) and potential new medicine for the treatment of multiple tumour types (Press release, AstraZeneca, JUL 27, 2020, https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-daiichi-sankyo-enter-collaboration-to-develop-and-commercialise-new-antibody-drug-conjugate.html [SID1234562368]).

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DS-1062 is currently in development for the treatment of multiple tumours that commonly express the cell-surface glycoprotein TROP2. Among them, TROP2 is overexpressed in the majority of non-small cell lung cancers1 and breast cancers,2,3 tumour types that have long been a strategic focus for AstraZeneca. This collaboration reflects AstraZeneca’s strategy to invest in antibody drug conjugates as a class, the innovative nature of the technology and the successful existing collaboration with Daiichi Sankyo.

Pascal Soriot, Chief Executive Officer, said: "We see significant potential in this antibody drug conjugate in lung as well as in breast and other cancers that commonly express TROP2. We are delighted to enter this new collaboration with Daiichi Sankyo and to build on the successful launch of Enhertu to further expand our pipeline and leadership in Oncology. We now have six potential blockbusters in Oncology with more to come in our early and late pipelines."

Sunao Manabe, Representative Director, President and CEO of Daiichi Sankyo, said: "DS-1062, one of our lead DXd ADCs that will form a pillar of our next mid-term business plan, has the potential to become a best-in-class TROP2 ADC in multiple tumours, including lung and breast cancers. This new strategic collaboration with AstraZeneca, a company with extensive experience and significant expertise in the global oncology business, will enable us to deliver DS-1062 to more patients around the world as quickly as possible. As we have done with Enhertu, we will jointly design and implement strategies to maximise the value of DS-1062."

Using Daiichi Sankyo’s proprietary DXd ADC technology, DS-1062 is designed to deliver chemotherapy selectively to cancer cells and to reduce systemic exposure. A comprehensive development programme with DS-1062 is planned globally.

Financial considerations

AstraZeneca will pay Daiichi Sankyo an upfront payment of $1bn in staged payments: $350m is due upon completion, with $325m after 12 months and $325m after 24 months from the effective date of the agreement.

AstraZeneca will pay additional conditional amounts of up to $1bn for the successful achievement of regulatory approvals and up to $4bn for sales-related milestones.

The transaction will be accounted for as an intangible asset acquisition, recognised initially at the present value of non-contingent consideration, with any potential future milestone payments capitalised into the intangible asset as they are recognised.

The companies will jointly develop and commercialise DS-1062 worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights. AstraZeneca and Daiichi Sankyo will share equally development and commercialisation expenses as well as profits relating to DS-1062 worldwide, except for Japan where Daiichi Sankyo will be responsible for such costs and will pay AstraZeneca mid single-digit royalties. Daiichi Sankyo will record sales in the US, certain countries in Europe and certain other countries where Daiichi Sankyo has affiliates. Profits shared with AstraZeneca from those countries will be recorded as Collaboration Revenue by AstraZeneca. AstraZeneca will record Product Sales in other countries worldwide, for which profits shared with Daiichi Sankyo will be recorded within Cost of Sales. Daiichi Sankyo will manufacture and supply DS-1062.

There are no closing conditions to the transaction. The collaboration agreement became effective on 27 July 2020. The transaction does not impact the Company’s financial guidance for 2020.

TROP2

TROP2 is a transmembrane glycoprotein that is overexpressed in many cancers including up to 80% of patients with triple-negative breast cancer.2,3 High TROP2 expression also has been identified in a majority of non-small cell lung cancers.1 Research indicates that high TROP2 expression is associated with cancer cell growth and proliferation.4 TROP2 is recognised as a promising molecular target for therapeutic development in various cancers.4

DS-1062

DS-1062 is a TROP2-directed ADC. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (‘payload’) via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, DS-1062 is comprised of a humanised anti-TROP2 monoclonal antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker. DS-1062 is a potential new medicine that has not been approved for any indication in any country. Safety and efficacy have not been established.

Collaboration between AstraZeneca and Daiichi Sankyo in Oncology

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu (HER2-directed ADC) worldwide, except in Japan, where Daiichi Sankyo maintains exclusive rights.

AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On July 26, 2020 TCR2 Therapeutics Inc. (Nasdaq: TCRR), a clinical-stage immunotherapy company with a pipeline of novel T cell therapies for patients suffering from cancer, reported positive interim data from the first five patients treated in the Phase 1 portion of the TC-210 Phase 1/2 clinical trial for mesothelin-expressing solid tumors (Press release, TCR2 Therapeutics, JUL 26, 2020, View Source [SID1234562396]). All five patients showed tumor regression including two RECIST unconfirmed partial responses (one of which remains subject to independent central review) and two patients with stable disease through six months. Translational data further demonstrated TRuC-T cell expansion and activation. A manageable toxicity profile was observed with only one patient exhibiting TC-210-related non-hematologic grade >2 toxicity and no evidence of neurotoxicity or on-target, off-tumor toxicity.

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"We are delighted that our very first dose of TC-210 induced consistent tumor regression and clinical benefit in heavily pre-treated cancer patients," said Garry Menzel, Ph.D., President and Chief Executive Officer of TCR2 Therapeutics. "There are very few options for patients with solid tumors and those expressing mesothelin represent a significant frontier of unmet medical need. While these are early data requiring further study, we are encouraged by the potential of our TRuC-T cells as we continue to enroll and treat patients with the goal of quickly finding a recommended Phase 2 dose for TC-210."

"Based on my prior experience working with both TCR-T and CAR-T cells, including the FDA approval of Kymriah, observing consistent clinical benefit in patients at presumably suboptimal T cell doses is quite meaningful," said Alfonso Quintás-Cardama, M.D., Chief Medical Officer of TCR2 Therapeutics. "These early TC-210 data suggest our approach may overcome the challenges faced by many T cell therapies in the hostile solid tumor microenvironment. Our enrolled patients have failed multiple lines of therapy, including standard chemotherapy, checkpoint inhibitors and in some cases other mesothelin-directed approaches, in indications where survival has been historically shorter than six months."

The primary objectives of the Phase 1 portion of the study are to define the safety profile of TC-210 in patients whose tumors overexpress mesothelin and to determine the recommended Phase 2 dose (RP2D). Secondary objectives include overall response rate (ORR) and disease control rate (DCR). Exploratory objectives include the assessment of expansion, tumor infiltration, and persistence of TC-210 T cells.

Summary of trial conduct, baseline characteristics and TC-210 dose:

Screening: Forty-eight percent of patients met the mesothelin expression cut-off as defined per protocol.

Manufacturing: TC-210 T cell products meeting protocol defined specifications have been manufactured successfully for each patient enrolled in the clinical trial.

Patient Characteristics: TC-210 treated patients included four with mesothelioma and one with ovarian cancer with a median age of 61 years (range, 36-74 years). The median number of prior therapies was five (range, 3-9), including immune checkpoint inhibitor therapy (n=3) and the anti-mesothelin ADC anetumab ravtansine (n=1).

TC-210 Dose: All patients received the same TC-210 dose either with or without lymphodepletion. One patient with mesothelioma was enrolled to dose level (DL) 0 (5×107 TC-210 T cells/m2 without lymphodepletion) whereas four patients (three with mesothelioma and one with ovarian cancer) were enrolled to DL1 (5×107 TC-210 T cells/m2 following lymphodepletion with fludarabine 30 mg/m2/day x4 and cyclophosphamide 600 mg/m2/day x3).

Key clinical findings from the first five patients treated with TRuC-T cells include:

Safety: TC-210 was generally well tolerated, with no patients experiencing neurotoxicity or on-target, off-tumor toxicities. Three (60%) patients experienced Cytokine Release Syndrome (CRS), which was Grade 1 in two patients and Grade 3 in one patient. The patient experiencing Grade 3 CRS also developed Grade 3 pneumonitis during the first week post infusion that responded to tocilizumab and steroid therapy. This patient died 34 days post treatment due to fungal sepsis, which was deemed unrelated to TC-210. Because of the earlier pneumonitis event, however, the Safety Review Team recommended the expansion of the cohort from three to six patients. None of the subsequent three patients treated at DL1 developed pneumonitis or CRS above Grade 1.

Clinical Activity: All five patients treated with TC-210 T cells have had at least one disease response assessment. The DCR was 100%, with all patients experiencing tumor regression. The median change in the sum of diameters of target lesions was -42% (range, -17% to -67%). The ORR was 40% (2 unconfirmed PRs) according to RECIST v1.1. TC-210 therapy induced a significant reduction in FDG uptake by PET imaging in two evaluable patients, including one patient who achieved a complete metabolic response (PR by RECIST v1.1).

Translational Data: Peak TC-210 expansion (Cmax) occurred between days 7 and 22. The median peak TC-210 expansion was 821 copies/µg of genomic DNA (range, 520 to 5,901 copies/µg). Cmax increased when TC-210 was administered following lymphodepletion. Cytokine induction post-TC-210 infusion was observed in all evaluable patients suggesting target engagement.

About the Phase 1/2 Clinical Trial in Advanced Mesothelin-Expressing Solid Tumors

The Phase 1/2 clinical trial (NCT03907852) is evaluating the safety and efficacy of TC-210, TCR2’s T-cell receptor fusion construct directed against mesothelin. The trial is enrolling patients with mesothelin expressing NSCLC, ovarian cancer, cholangiocarcinoma, and malignant pleural/peritoneal mesothelioma. The Phase 1 dose escalation portion of the clinical trial utilizes a modified 3+3 design with four increasing TC-210 T cell doses. At each dose, TC-210 will be tested in two separate dose levels: first without lymphodepletion and then following lymphodepleting chemotherapy. The Phase 1 portion of the clinical trial is ongoing.

In the Phase 2 portion of the clinical trial, approximately 50 patients are planned to receive TC-210 at the RP2D in four distinct cohorts according to their cancer diagnosis: NSCLC, ovarian cancer, malignant pleural/peritoneal mesothelioma and cholangiocarcinoma. Each cohort will include ten patients, except the NSCLC cohort which will include 20 patients with eight patients to receive TC-210 as single agent and 12 patients to receive TC-210 in combination with a programmed cell death 1 (PD-1) blocking antibody.

About Mesothelin-Expressing Solid Tumors

Mesothelin is a cell-surface glycoprotein highly expressed in a wide range of solid tumors, including malignant pleural/peritoneal mesothelioma, ovarian cancer, cholangiocarcinoma, breast cancer, pancreatic cancer and others. Overexpression of mesothelin is associated with poorer prognosis in some cancers due to its active role in both malignant transformation and tumor aggressiveness by promoting cancer cell proliferation, invasion, and metastasis. Of the wide range of solid tumors expressing mesothelin, non-small cell lung cancer, ovarian cancer, mesothelioma and cholangiocarcinoma represent a significant patient population up to 80,000 in the United States alone.

TCR2 Therapeutics Conference Call and Webcast

TCR2 Therapeutics will host a conference call and webcast on Monday, July 27th at 8:00am E.T. The webcast and presentation will be made available on the TCR2 Therapeutics website in the Investors section under Eventsat View Source Following the live audio webcast, a replay will be available on the Company’s website for approximately 30 days.

On July 24, 2020 Researchers at Children’s Hospital of Philadelphia (CHOP) reported that have developed a new computational algorithm that has, for the first time, identified a spectrum of mutations in the noncoding portion of the human genome across five major pediatric cancers (Press release, Children’s Hospital of Philadelphia, JUL 24, 2020, View Source [SID1234562375]). The study, which was published today in Science Advances, used the algorithm to analyze more than 500 pediatric cancer patients’ mutations and gene expression profiles to develop a comprehensive list of potentially cancer-causing mutations.

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"Noncoding mutations are very important because the noncoding portion of the genome typically regulates how genes are turned on and off, much like a control switch, which has implications for the uncontrolled growth that occurs in cancer," said Kai Tan, PhD, Professor of Pediatrics at CHOP and senior author of the study. "However, these regions are also challenging to study, and our knowledge about them not as developed as that of coding regions. Our computational model has identified a set of targets in pediatric cancers that we hope to study further and eventually move to clinical practice."

The researchers developed a computation tool called PANGEA (predictive analysis of noncoding genomic enhancer/promoter alterations) to analyze noncoding mutations and their impact on gene expression in more than 500 pediatric cancer patients who had five major types of pediatric cancer: B cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), neuroblastoma, Wilms tumor, and osteosarcoma. PANGEA identified all types of mutations that are associated with gene expression changes, including single nucleotide variants, small indels, copy number variations, and structural variants.

Previous studies on noncoding mutations have focused on single nucleotide variants and small indels, which are insertions or deletions of bases in the genome that are relatively short in length. However, structural variants are regions of DNA much larger in size – 1 kilobase or larger – a quality that makes them more difficult to identify but also more likely to contribute to changes in gene regulation that lead to cancer.

Using PANGEA, the researchers found that structural variants are indeed the most frequent cause of potentially cancer-causing mutations and identified 1,137 structural variants that affect the expression of more than 2,000 genes across the five pediatric cancer types.

In analyzing the data, the researchers found that coding and noncoding mutations affect distinct sets of genes and pathways, which is likely due to the different genomic locations of these two types of genes. The researchers found that genes involved in metabolism – the rewiring of which is a hallmark of cancer – are more frequently affected by noncoding mutations. However, it is unclear to what degree noncoding mutations facilitate metabolism rewiring in the five cancer types the researchers studied.

"Our results highlight the need for comparative analysis of both coding and noncoding mutations, which might reveal novel cancer-related genes and pathways," said Tan. "Identifying putative mutations is a starting point that will facilitate experimental work to validates these predictions."

This work was supported by grants from the National Institutes of Health, including the National Cancer Institute and the National Institute of General Medical Sciences.

B. He et al. "Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers," Science Advances, July 24, 2020. DOI: 10.1126/sciadv.aba3064

On July 24, 2020 Tvardi Therapeutics Inc. ("Tvardi"), a privately held, clinical-stage biopharmaceutical company focused on the development of STAT3 inhibitors, reported over $5 million in non-dilutive grants to support the ongoing validation and clinical development of Tvardi’s lead compound, TTI-101 (Press release, Tvardi Therapeutics, JUL 24, 2020, View Source [SID1234562350]). The three National Cancer Institute (NCI) funding awards are two Specialized Programs of Research Excellence (SPORE) grants to support clinical trials of TTI-101 in hepatocellular carcinoma (HCC) and gastrointestinal cancer as well as funding from the PREVENT program to support translational work of TTI-101 in HCC prevention.

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The new funding brings the total non-dilutive support of TTI-101 to approximately $20 million from multiple sources including the National Institutes of Health (NIH), V Foundation and the Cancer Prevention & Research Institute of Texas (CPRIT).

"These grants are rigorously peer-reviewed and validate the scientific foundation of Tvardi’s STAT3 inhibitor program. Our ability to serve our patients’ needs has been greatly enhanced by strong collaborations with the academic community and private sector. TTI-101 has the potential to help millions of patients suffering from STAT3-related diseases," said Ronald DePinho, M.D., Tvardi’s Co-Founder and Director.

"Our success to date stems from a strong team effort of dedicated, innovative scientists coming together to solve a major unmet need. To date, TTI-101 has demonstrated an excellent safety profile and, importantly, the ability to shrink tumors in patients who have no other options," shared Imran Alibhai, Ph.D., CEO of Tvardi.

On July 24, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a Positive Opinion recommending marketing authorisation for IMBRUVICA (ibrutinib) to include the combination with rituximab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (Press release, Janssen Pharmaceuticals, JUL 24, 2020, View Source [SID1234562349]).

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The Positive Opinion is based on data from the Phase 3 E1912 study, designed and conducted in the United States (U.S.) by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), which is part of the U.S. National Institutes of Health. The study evaluated 529 patients with previously untreated CLL aged 70 years or younger (median age 58) who were randomly assigned in a 2:1 ratio to receive ibrutinib plus rituximab (n=354) or the standard of care chemo-immunotherapy fludarabine, cyclophosphamide and rituximab (FCR) (n=175). The primary study results were published in The New England Journal of Medicine, and the extended four-year median follow-up results were presented at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.1,2

"Ibrutinib in combination with rituximab represents an important new targeted and non-chemotherapy option for patients with CLL," said John Gribben, MD DSc, Professor of Medical Oncology at St Bartholomew’s Hospital, Barts Cancer Institute, Queen Mary, University of London. "For people living with CLL, relapse is often inevitable. Using this combination in the frontline setting has the potential to not only extend life, but also offer a tolerability profile with less of the known chemotherapy-related events."

The CHMP Positive Opinion comes after the U.S. Food and Drug Administration’s (FDA) approval of this expanded indication for ibrutinib in April 2020. The application will now be reviewed by the European Commission (EC).

"Ibrutinib has been used to treat more than 200,000 people globally, and this latest milestone further highlights its potential for patients diagnosed with CLL," said Dr Patrick Laroche, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag. "We look forward to working with the European Commission to bring this new, ibrutinib-based, non-chemotherapy frontline treatment option to adult patients with CLL."

"This landmark head-to-head study, conducted by the ECOG-ACRIN Cancer Research Group and the National Cancer Institute has generated important, practice changing results which challenge FCR, the gold standard of chemotherapy-based treatment regimens for younger, fit patients with previously untreated CLL for over a decade," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Oncology, Janssen Research & Development. "We are pleased to build upon the robust body of data supporting the most widely studied BTK inhibitor as we continue to study further ibrutinib-based regimens in our mission to improve the lives of patients with complex blood cancers, like CLL."

About ibrutinib
Ibrutinib is a once-a-day, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally.3 Ibrutinib blocks the BTK protein; the BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.4 By blocking BTK, ibrutinib may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.5

Ibrutinib is currently approved in Europe for:3

Chronic lymphocytic leukaemia (CLL): As a single agent or in combination with obinutuzumab for the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult patients with CLL who have received at least one prior therapy
Mantle cell lymphoma (MCL): As a single agent for the treatment of adult patients with relapsed or refractory MCL
Waldenström’s macroglobulinemia (WM): As a single agent for the treatment of adult patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemo-immunotherapy, and in combination with rituximab for the treatment of adult patients
Ibrutinib is approved in more than 99 countries for at least one indication, and to date, has been used to treat more than 200,000 patients worldwide across its approved indications.6

The most common adverse reactions seen with ibrutinib include diarrhoea, neutropenia, haemorrhage (e.g., bruising), musculoskeletal pain, nausea, rash, and pyrexia.3

For a full list of side effects and information on dosage and administration, contraindications and other precautions when using ibrutinib please refer to the Summary of Product Characteristics for further information.

About chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) is typically a slow-growing blood cancer of the white blood cells.7 The overall incidence of CLL in Europe is approximately 4.92 cases per 100,000 persons per year and is about 1.5 times more common in men than in women.8 CLL is predominantly a disease of the elderly, with a median age of 72 years at diagnosis.9

The disease eventually progresses in the majority of patients, and they are faced with fewer treatment options with each relapse. Patients are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.