On May 18, 2021 Almac Discovery, the independent research driven drug discovery company dedicated to the development of novel and innovative therapeutics, reported that it is delighted to share ground-breaking new research which has identified nearly thousands of gene pairs that represent ‘Achilles Heels’ or cancer vulnerabilities in analysis of more than 700 different cancer models (Press release, Almac, MAY 18, 2021, View Source [SID1234580179]). In the future, this could lead to new ways to stop cancer cells in their tracks by using existing drugs, as well as proposing new targets for drug development. These drugs could even be used to combat cancers that do not respond to the current standard treatments.

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The research was led by Mark Wappett, Head of Bioinformatics at Almac Discovery and Honorary Lecturer at Queen’s University Belfast, in collaboration with the Overton and McDade groups in the Patrick G Johnston Centre for Cancer Research (PGJCCR) at Queen’s University Belfast and the Department of Biochemistry at Vanderbilt University, USA.

Pivotal to the research is a completely new computational method for discovering cancer synthetic lethality from clustered regularly interspaced short palindromic repeats (CRISPR) and gene expression data using a website called ‘SynLeGG’. This site analyses large and complex datasets to identify changes in genes that occur in certain cancers that may make them more addicted to other similar genes and therefore susceptible to treatments targeting these partners. It was published today (17 May) in the journal Nucleic Acids Research and can be accessed here.

Study lead Mark Wappett, Almac Discovery, commented "Synthetic Lethality with Genetics and Genomics, or SynLeGG for short, provides the wider scientific community access to key datasets generated by cutting edge molecular biology technologies, such as CRISPR, and a toolkit with which to analyse this data. Ultimately we hope that by increasing the reach of this data we can expedite more targeted and effective cancer treatments."

Dr Ian Overton, Senior Lecturer at the PGJCCR explains: "Understanding the molecular fingerprints of cancer can pinpoint ways to target drugs precisely to those patients where they will be most effective. Our work makes a step towards more effective and personalised cancer treatments, ultimately saving lives.

"We make our results available on the SynLeGG web server, opening a window to share these rich resources with researchers across the scientific community – in order to accelerate progress in cancer research."

Dr Simon McDade, Senior Lecturer from the PGJCCR said: "We anticipate that this resource will seed detailed investigation of a number of specific vulnerabilities we have identified, ultimately identifying novel treatment strategies that will translate into significant benefits for cancer patients in the long term."

On May 18, 2021 CNS Pharmaceuticals presented the corporate Presentation (Presentation, CNS Pharmaceuticals, MAY 18, 2021, View Source [SID1234580199]).

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On May 18, 2021 Mustang Bio, Inc. ("Mustang") (NASDAQ: MBIO), a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, and City of Hope, a world-renowned independent cancer research and treatment center, reported that the first patient has been dosed in a clinical trial to establish the safety and feasibility of administering MB-101 (autologous IL13Rα2-CAR T cells) to patients with leptomeningeal brain tumors (e.g., glioblastoma, ependymoma or medulloblastoma) (Press release, Mustang Bio, MAY 18, 2021, View Source [SID1234580215]). The trial will enroll up to 30 patients and is taking place at City of Hope, where this chimeric antigen receptor T ("CAR T") cell therapy was initially developed. Even though it is a single center clinical trial, Mustang and City of Hope will facilitate patient transfers from other centers, as needed.

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All subjects enrolled in the Phase 1 single-center, two-arm clinical trial will undergo surgery for the placement of an intraventricular (ICV) Rickham catheter for CAR T cell delivery. The Phase 1 trial will determine the safety and feasibility of administering MB-101 through the ICV Rickham catheter over four weekly cycles in patients with glioblastoma (Arm 1) and ependymoma or medulloblastoma (Arm 2). The primary endpoints that will be evaluated are toxicity and survival at three months. Secondary endpoints include overall survival, CAR T and endogenous T cell levels, cytokine levels and phenotype detection in peripheral blood, tumor cyst fluid and cerebrospinal fluid.

Lisa Feldman, M.D., Ph.D., a neurosurgeon and assistant clinical professor in the Division of Neurosurgery at City of Hope and principal investigator of the clinical trial, commented, "Based on our research to date, including a previous clinical trial at City of Hope, further evaluation is warranted for this CAR T cell therapy. The prior clinical trial demonstrated encouraging potential of administering autologous IL13Rα2-CAR T cells intraventricularly to help treat patients with leptomeningeal brain tumors, a form of metastatic brain cancer that is difficult to treat. We continue to work closely with the Mustang team to potentially bring a safe, effective treatment option to patients suffering with this life-threatening disease."

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, "The successful dosing of the first patient in this clinical trial of MB-101 is an important milestone in Mustang’s development program. We are pleased to support City of Hope to further study MB-101 in leptomeningeal brain tumors to potentially bring hope to patients suffering from this devastating and fatal disease. MB-101 has already demonstrated therapeutic potential when infused into the ventricular system, including delivering a complete response in a patient with leptomeningeal glioblastoma that was published in the New England Journal of Medicine. We aim to generate additional data that supports the advancement of this program."

Additional information about the trial can be found on clinicaltrials.gov using the identifier NCT04661384.

About MB‐101 (IL13Rα2‐specific CAR T cells)
IL13Rα2 is an attractive target for CAR T therapy as it has limited expression in normal tissue but is overexpressed on the surface of the majority of malignant glioma cells, including glioblastoma multiforme, ependymoma and medulloblastoma. CAR T cells are designed to express a membrane‐tethered IL‐13 receptor ligand (IL‐13) incorporating a single‐point mutation that provides high affinity for IL13Rα2 and reduces binding to IL13Rα1 in order to reduce healthy tissue targeting. Mustang is developing MB‐101 as an optimized CAR T product incorporating enhancements in CAR design and T cell engineering to improve antitumor potency and T cell persistence. MB‐101 includes a second‐generation hinge optimized CAR containing mutations in the IgG4 linker to reduce off‐target Fc interactions, the 4-1BB (CD137) co‐stimulatory signaling domain for improved persistence of CAR T cells and the extracellular domain of CD19 as a selection/safety marker. To further improve persistence, central memory T cells are enriched and genetically engineered using a manufacturing process that limits ex vivo expansion to reduce T cell exhaustion and maintain a memory T cell phenotype.

On May 18, 2021 Innovent Biologics, Inc. (HKEX: 01801) and Eli Lilly and Company (NYSE: LLY) reported that the U.S. Food and Drug Administration (FDA) accepted for review a Biologics License Application (BLA) for sintilimab injection in combination with pemetrexed and platinum chemotherapy for the first-line treatment of people with nonsquamous non-small cell lung cancer (NSCLC) (Press release, Innovent Biologics, MAY 18, 2021, View Source [SID1234580231]). This is the first U.S. regulatory submission of sintilimab, a PD-1 inhibitor being developed and commercialized under a global collaboration agreement between Innovent and Lilly.

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"The acceptance of this application – the first for sintilimab in the U.S. and outside of China – is an important milestone in Innovent’s global commercialization strategy and in our collaboration with Lilly," said Dr. Yongjun Liu, president of Innovent. "We look forward to working closely with the FDA to potentially bring this sintilimab-pemetrexed-platinum chemotherapy combination as a treatment option in the U.S., following the regimen’s regulatory approval in China earlier this year."

Sintilimab is currently being evaluated in a wide variety of cancer types under a broad clinical development program. To date, sintilimab has two indications approved in China, three regulatory submissions under review in China, and this regulatory application under review in U.S.. This regulatory application was submitted to the FDA in March 2021, primarily based on the results of the Phase 3 ORIENT-11 trial. The Prescription Drug User Fee Act (PDUFA) goal date for the FDA to make a decision on the sintilimab application is in March 2022. The FDA stated that it did not identify any potential review issues in its acceptance letter. It is currently planning to hold an Advisory Committee meeting to discuss this application.

"We are pleased the sintilimab submission is progressing. Our pursuit of this proposed indication in the U.S. reinforces Lilly’s and Innovent’s joint commitment to offer additional therapeutic options for people living with lung cancer and the healthcare providers who treat them," said Anne White, president, Lilly Oncology. "This is an encouraging start for our collaborative efforts to make sintilimab available in countries beyond China, as we continue to pursue opportunities globally for this immuno-oncology medicine across various tumor types."

About the ORIENT-11 Trial

ORIENT-11 is a randomized, double-blind, Phase 3 clinical trial assessing the efficacy and safety of sintilimab in combination with pemetrexed and platinum chemotherapy compared to placebo in combination with pemetrexed and platinum chemotherapy as a first-line treatment for patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC), with no sensitizing EGFR mutations or ALK rearrangements. The primary endpoint is progression-free survival (PFS) as assessed by Independent Radiographic Review Committee (IRRC) based on RECIST v1.1., and secondary endpoints include overall survival (OS) and safety profile.

A total of 397 patients were enrolled and randomized 2:1 to receive either sintilimab 200mg or placebo in combination with pemetrexed and platinum chemotherapy every three weeks for up to four cycles, followed by either sintilimab or placebo plus pemetrexed maintenance therapy. Patients received treatment until radiographic disease progression, unacceptable toxicity or any other conditions that required treatment discontinuation. Conditional crossover was permitted. The results of the ORIENT-11 study were published in 2020.1

About Lung Cancer

Globally, lung cancer is the leading cause of cancer death, killing nearly 1.8 million people worldwide each year. In the U.S., lung cancer is the second most common cancer (not counting skin cancer) and the leading cause of cancer death, responsible for nearly 25 percent of all cancer deaths – more than those from colorectal, breast and prostate cancers combined. Non-small cell lung cancer (NSCLC) accounts for approximately 85 percent of all lung cancers, and about 70 percent of those with NSCLC have the nonsquamous subtype. Fifty percent of NSCLC patients present with advanced or metastatic disease at diagnosis.

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is an innovative PD-1 inhibitor with global quality standards jointly developed by Innovent and Lilly. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved for:

The treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy
In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of nonsquamous non-small cell lung cancer
Additionally, Innovent currently has regulatory submissions under review in China for sintilimab:

In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer
In combination with BYVASDA (bevacizumab injection) for the first-line treatment of hepatocellular carcinoma
The second-line treatment of squamous non-small cell lung cancer
In May 2021, the U.S. FDA accepted for review the Biologics License Application (BLA) for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of nonsquamous non-small cell lung cancer.

Sintilimab was included in China’s National Reimbursement Drug List (NRDL) in 2019 as the first PD-1 inhibitor and the only PD-1 included in the list in that year.

On May 18, 2021 Sibylla Biotech reported a research collaboration with Takeda Pharmaceutical Company Limited to discover novel small molecules that modulate the activity of selected pharmacological targets (Press release, Sibylla Biotech, MAY 18, 2021, View Source [SID1234641500]).

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Sibylla Biotech is the sole licensee of PPI-FIT (Pharmacological Protein Inactivation by Folding Intermediate Targeting), a novel technology that can predict the existence of druggable pockets in the folding intermediates of proteins. PPI-FIT has been invented by Sibylla‚ academic founders and is a striking example of technology transfer. PPI-FIT can be applied to any therapeutic area.

Many previously‚ undruggable‚ pharmacological targets can be newly analyzed and druggable pockets may be found, which disappear in the native state. Small molecules capable of binding these pockets can be developed into new drugs to solve long-lasting and unmet medical needs. The technology has been validated by generating small molecules that impair the folding process of the prion protein, thus inactivating it. The prion protein, when misfolded, is responsible for the Creutzfeld-Jakob disease and other lethal neurodegenerative diseases.

Under the terms of the agreement, Sibylla will use the PPI-FIT technology to identify druggable binding pockets in the folding intermediates of proteins of interest to Takeda. Once these pockets have been identified, Sibylla will also generate small molecules that can bind such pockets and will test the biological effects of those novel molecules.

"We are very excited to collaborate with Takeda where we have the opportunity to discover novel pharmacological targets with the potential to open the door to new treatments for neurological and neurodegenerative diseases with significant need. This is just a first step, yet a big one" said Dr. Lidia Pieri, CEO and co-founder of Sibylla Biotech.

The financial terms and the scientific details of the agreement remain undisclosed.