On June 17, 2021 Cullgen Inc., a leading biotechnology company developing small molecule therapeutics based on its proprietary uSMITE platform of targeted protein degradation technology, reported that Drs. Jian Jin and Yue Xiong, co-founders of Cullgen, have published a review of targeted protein degradation technology as well as a comprehensive summary of degraders in development for the treatment of cancer in the prestigious journal, Nature Reviews Cancer (Press release, Cullgen, JUN 17, 2021, View Source [SID1234584161]). The article reviews the history and mechanism of targeted protein degradation, the ubiquitin-proteasome system, and the key principles required for design of heterobifunctional small-molecule degraders. The publication also contains an in-depth review of the current state and challenges associated with the use of common E3 ligands. The article is entitled "Advancing targeted protein degradation for cancer therapy". The complete publication can be found on-line here: View Source

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"The use of targeted protein degradation principles by pharmaceutical companies has now become ubiquitous in drug development strategies", said Dr. Jin. "We are thrilled to see that forty years of research on the ubiquitin-proteasome system has made such a significant contribution to drug discovery", added Dr. Xiong, Cullgen’s Chief Scientific Officer. "We look forward to witnessing more targeted protein degraders entering human clinical trials in the near future".

"As pioneers in ubiquitin ligase and protein degradation field, the contributions of Drs. Jin and Xiong have positioned Cullgen as one of the leading companies in this revolution of drug discovery. Since the founding of Cullgen about three years ago, we have built an extensive therapeutic pipeline utilizing conventional and novel E3 ligands developed in house", said Ying Luo, Chairman and President of Cullgen. "Our co-founders’ visionary insights into the complicated ubiquitin-proteasome system provide Cullgen with a clear advantage in the development of the next generation of targeted therapies."

On June 17, 2021 CytoReason, an AI company developing a computational disease model of the human body for clinical drug development, reported the initiation of a project with French global biopharmaceutical company Sanofi, which will utilize its cell-centered models and deconvolution techniques to suggest mechanistic insights for each asthma endotype (Press release, CytoReason, JUN 17, 2021, View Source [SID1234597888]).

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The focus of this project is to gain clarity on the heterogeneity of asthma patients, with the goal of identifying stable and reproducible asthma endotypes, as well as associated diagnostic features, using minimal invasive procedures. For this project, CytoReason’s AI platform will use one of the most comprehensive datasets in moderate to severe asthma, covering samples from both adults and children.

Asthma is a complex disease with genetic and environmental factors that lead to airway inflammation, resulting in excess mucus in a patient’s airway, which causes coughing, wheezing and shortness of breath. It can appear in several degrees of severity, ranging from mild to severe, and can be classified as either Type 2 asthma, which includes allergic and eosinophilic asthma, or non-Type 2 asthma, which is associated with low eosinophil counts often presented with altered innate immune response and activation of Th17 cells. Though symptoms of the disease can often be controlled, asthma, which is a key area of research for Sanofi, cannot be completely cured. One of the main challenges in the disease is classification of patients to find the most suitable treatment.

"We are very excited to be launching our collaboration with Sanofi," said David Harel, CEO and Co-founder of CytoReason. "It represents a chance to make a real difference in driving better understanding of the heterogeneous and complex nature of asthma and its diversified manifestation in patients. Additionally, the work we do with Sanofi could enhance future research in this field and could inform precision medicine strategies for improved patient benefit."

On June 17, 2021 Artios Pharma Limited (Artios), a leading DNA Damage Response (DDR) company exploiting a broad DDR-based platform and small molecule drug design capabilities to develop a diverse pipeline of product candidates for the treatment of cancer, reported the publication of a peer reviewed article titled, "Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance" in Nature Communications(Press release, Artios Pharma, JUN 17, 2021, View Source [SID1234584104]). Using novel small molecule tool compounds, the preclinical data generated in collaboration with researchers at the Institute for Cancer Research, London, and Cancer Research U.K., validates the Company’s approach to developing a potential first-in-class Polθ inhibitor, which demonstrated potent, selective Polθ inhibition, BRCA-gene synthetic lethality in a potentially PARP-resistant setting, and PARP inhibitor synergy.

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Professor Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, London and study co-leader, said: "Polθ is an ideal DNA damage response drug target as it is tumor specific, overexpressed in many tumors and found at low levels in healthy tissues. These results show that Polθ inhibitors exhibited exquisite selectivity and on-target activity, affecting only Polθ-Mediated End Joining and not other forms of DNA repair. This specificity, combined with demonstrated synthetic lethality with BRCA mutations, as well as synergy with a PARP inhibitor, suggest small molecule Polθ inhibition has broad utility for targeted clinical development in genetic backgrounds that are reliant on Polθ activity. I look forward to seeing how Polθ inhibitors perform in clinical trials and hope they will be able to benefit patients by opening up a new way of overcoming drug resistance."

Dr. Graeme Smith, Chief Scientific Officer of Artios Pharma, said: "This preclinical dataset further strengthens the scientific foundation of our Polθ inhibitor program. This publication is a testament to the deep scientific heritage and expertise in DNA damage response that drives the Artios discovery platform and pipeline. The extensive efforts of our team have delivered insights into the genetics and mechanisms that underlie the activity of Polθ inhibitors, leaving us well positioned to pursue a strategic development plan in the clinic across a wide range of opportunities."

Dr. Niall Martin, Chief Executive Officer at Artios Pharma, said: "These published results provide a clear rationale for three high-value opportunities for Polθ inhibitors: in the monotherapy setting to treat Polθ dependent cancers; in combination with PARP inhibitors to expand the utility of this important drug class; and in combination with DNA damaging therapies such as ionizing radiation to provide effective and widespread use of these agents. We are on track to launch our Polθ clinical program before year end, building upon our strong execution which includes strategic partnerships with Merck KGaA and Novartis, and our ongoing Phase 1 study of ART0380, a potential best-in-class ATR inhibitor."

Publication highlights include:

• Artios’ small molecule Polθ inhibitors provided nanomolar potent, selective, allosteric inhibition of the polymerase function of DNA polymerase Polθ, selectively inhibiting Theta-Mediated End Joining DNA repair without targeting Non-Homologous End Joining or Homologous Recombination.
• Inhibiting Polθ elicited DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumor cells and enhanced the effects of a PARP inhibitor.
• Genetic screening revealed defects in the Shieldin complex causing both PARP inhibitor resistance and synthetic lethality with Polθ inhibition, thus identifying a subset of PARP inhibitor resistant disease with the potential to be specifically targeted with Polθ inhibitors.
• Sensitivity of BRCA1, Shieldin-defective tumours to Polθ inhibition was confirmed in vivo laying the foundations for preclinical and clinical development.

On June 17, 2021 Amneal Pharmaceuticals, Inc. (NYSE: AMRX) ("Amneal" or the "Company") reported the U.S. Food and Drug Administration (FDA) has accepted for review the Biologics License Application (BLA) for Bevacizumab, pursuant to Section 351(k) pathway of the Public Health Service Act, and with a standard review goal date in the second quarter of 2022 according to the BsUFA (Biosimilar User Fee Act) (Press release, Amneal Pharmaceuticals, JUN 17, 2021, View Source [SID1234584162]).

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The biosimilar was developed in collaboration with mAbxience, a Spain-based biotechnology company. Bevacizumab is the biosimilar version of Avastin and when approved will be marketed under the proprietary name AlymsysTM. Alymsys was approved by the European Medicines Agency (EMA) in February 2021. Amneal and mAbxience believe that the data supports the biosimilarity of its AlymsysTM product to Avastin.

"The FDA’s acceptance of our BLA for Bevacizumab is a significant milestone in our journey to become an important player in biosimilars," stated Chirag and Chintu Patel, Co-Chief Executive Officers. As previously announced, the Company expects its initial biosimilar portfolio will include Filgrastim (biosimilar for Neupogen), Pegfilgrastim (biosimilar for Neulasta) and Bevacizumab (biosimilar for Avastin).

Bevacizumab is a vascular endothelial growth factor inhibitor. Amneal is seeking approval for Bevacizumab for the treatment of metastatic colorectal cancer, in combination with intravenous fluorouracil-based chemotherapy for first- or second-line treatment and metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first line Alymsys-containing regimen. Amneal also intends to seek approval for the remainder of the indications from the reference product label as soon as possible, subject to patent and regulatory exclusivities, by the biosimilarity pathway pursuant to Section 351(k).

According to IQVIA, a leading healthcare data and analytics provider, U.S. annual sales for Bevacizumab for the 12 months ended April 2021 were approximately $2.8 billion.

On June 17, 2021 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a global biotechnology company focused on developing and commercializing innovative medicines worldwide, reported that the first patient was dosed in the global Phase 3 AdvanTIG-302 trial of BeiGene’s investigational anti-TIGIT antibody ociperlimab (BGB-A1217) in combination with its anti-PD-1 antibody tislelizumab, for the first-line treatment of patients with locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC) whose tumors exhibit high PD-L1 expression and do not harbor EGFR-sensitizing mutations or ALK translocations(Press release, BeiGene, JUN 17, 2021, View Source [SID1234584106]). This marks the initiation of the first Phase 3 clinical trial in the planned global pivotal program for ociperlimab.

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"Ociperlimab is a potent anti-TIGIT antibody with intact Fc function, which we believe to be critical for the anti-tumor activities of TIGIT antibodies. Ociperlimab is our fourth internally discovered molecule entering the pivotal stage of clinical development, and now one of the most advanced anti-TIGIT antibodies in development globally. We intend to explore the potential use of ociperlimab in additional settings and indications in our late-stage development program," commented Yong (Ben) Ben, M.D., Chief Medical Officer, Immuno-Oncology, at BeiGene. "We hope that the AdvanTIG-302 trial will support a new and improved chemotherapy-free regimen for a significant portion of first-line patients with NSCLC and potentially other cancer patients with unmet needs."

AdvanTIG-302 Trial of Ociperlimab in Combination with Tislelizumab in NSCLC

AdvanTIG-302 is a randomized, double-blind, multicenter, global Phase 3 clinical trial (NCT04746924), expected to enroll approximately 605 treatment-naïve patients with locally advanced, unresectable, or metastatic NSCLC whose tumors exhibit high PD-L1 expression and do not harbor EGFR-sensitizing mutations or ALK translocations in the United States, Australia and other countries and regions across the globe. Patients will be randomized to receive ociperlimab and tislelizumab combination treatment, pembrolizumab, or tislelizumab alone. The primary endpoints of the trial are progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population; secondary endpoints include safety and other efficacy endpoints.

For more information about the trial, patients and physicians should email BeiGene at [email protected].

About Ociperlimab (BGB-A1217)

Ociperlimab (BGB-A1217) is an investigational humanized IgG 1 monoclonal antibody discovered and being developed globally by BeiGene. An immune checkpoint molecule, BGB-A1217 is one of the most advanced anti-TIGIT antibodies in development with intact Fc function.

Targeting TIGIT provides a potential mechanism to rescue immune cells (e.g., T cells, NK cells, and dendritic cells) from the immunosuppressive tumor microenvironment, to induce an efficient antitumor immune response. The TIGIT pathway has been understood to cooperate with PD-1 to maximize the suppression of effector tumor infiltrating immune cells as well as to promote resistance to anti-PD-1 therapy. TIGIT represents a promising target with the potential to significantly improve and/or extend the therapeutic benefit of anti-PD-1 therapy to a greater number of patients.

Ociperlimab is currently being investigated in combination with tislelizumab in multiple ongoing trials, including:

AdvanTIG-302: Phase 3 trial in untreated non-small cell lung cancer (NCT04746924);
AdvanTIG-202: Phase 2 trial in metastatic cervical cancer (NCT04693234);
AdvanTIG-203: Phase 2 trial in advanced esophageal squamous cell carcinoma (NCT04732494); and
Phase 1b trial in advanced solid tumors (NCT04047862).
About Tislelizumab

Tislelizumab (BGB-A317) is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug from BeiGene’s immuno-oncology biologics program and is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

The China National Medical Products Administration (NMPA) has granted tislelizumab approval in three indications, including full approval for first-line treatment of patients with advanced squamous non-small cell lung cancer (NSCLC) in combination with chemotherapy; and conditional approval for the treatment of patients with classical Hodgkin’s lymphoma (cHL) who received at least two prior therapies and for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) with PD-L1 high expression whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Full approval for these indications is contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

In addition, four supplemental Biologics License Applications for tislelizumab have been accepted by the Center for Drug Evaluation (CDE) of the NMPA and are under review for first-line treatment of patients with advanced non-squamous NSCLC in combination with chemotherapy, for second- or third-line treatment of patients with locally advanced or metastatic NSCLC who progressed on prior platinum-based chemotherapy, for patients with previously treated unresectable hepatocellular carcinoma, and for the treatment of patients with previously treated, locally advanced unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors.

BeiGene has initiated or completed 17 potentially registration-enabling clinical trials in China and globally, including 13 Phase 3 trials and four pivotal Phase 2 trials.

In January 2021, BeiGene and Novartis entered into a collaboration and license agreement granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

Tislelizumab is not approved for use outside of China.

About the Tislelizumab Clinical Program

Clinical trials of tislelizumab include:

Phase 3 trial comparing tislelizumab with docetaxel in the second- or third-line setting in patients with NSCLC (NCT03358875);
Phase 3 trial comparing tislelizumab to salvage chemotherapy in patients with relapsed or refractory classical Hodgkin Lymphoma (cHL; NCT04486391);
Phase 3 trial in patients with locally advanced or metastatic urothelial carcinoma (NCT03967977);
Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced squamous NSCLC (NCT03594747);
Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced non-squamous NSCLC (NCT03663205);
Phase 3 trial of tislelizumab in combination with platinum-based doublet chemotherapy as neoadjuvant treatment for patients with NSCLC (NCT04379635);
Phase 3 trial of tislelizumab combined with platinum and etoposide versus placebo combined with platinum and etoposide in patients with extensive-stage small cell lung cancer (NCT04005716);
Phase 3 trial comparing tislelizumab with sorafenib as first-line treatment for patients with hepatocellular carcinoma (HCC; NCT03412773);
Phase 2 trial in patients with previously treated unresectable HCC (NCT03419897);
Phase 2 trial in patients with locally advanced or metastatic urothelial bladder cancer (NCT04004221);
Phase 3 trial comparing tislelizumab with chemotherapy as second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC; NCT03430843);
Phase 3 trial of tislelizumab in combination with chemotherapy as first-line treatment for patients with ESCC (NCT03783442);
Phase 3 trial of tislelizumab versus placebo in combination with chemoradiotherapy in patients with localized ESCC (NCT03957590);
Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment for patients with gastric cancer (NCT03777657);
Phase 2 trial of tislelizumab in patients with relapsed or refractory cHL (NCT03209973);
Phase 2 trial in patients with MSI-H/dMMR solid tumors (NCT03736889); and
Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment in patients with nasopharyngeal cancer (NCT03924986).