On December 1, 2021 The National University Cancer Institute, Singapore ("NCIS") and MiNA Therapeutics Limited ("MiNA" or the "Company"), the pioneer in small activating RNA therapeutics, reported that the first patient has been dosed in an investigator-sponsored Phase 1 study of MiNA’s small activating RNA oligonucleotide, MTL-CEBPA, in combination with first-line standard of care, atezolizumab and bevacizumab, in patients with previously untreated, advanced hepatocellular carcinoma (HCC) (Press release, MiNA Therapeutics, DEC 1, 2021, View Source [SID1234596349]). Atezolizumab and bevacizumab are being provided by F. Hoffmann-La Roche, Ltd ("Roche") who is also supporting the study.

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The study has been designed by Principal Investigator Dr. Cheng Ean Chee, Senior Consultant at the Department of Haematology-Oncology, NCIS and supported by the Singapore Ministry of Health’s National Medical Research Council under its Centre Grant programme (CG; NMRC/CG/M005/2017_NCIS). The study will be conducted at NCIS’s clinical trial facility with the Haematology-Oncology Research Group (HORG) at the National University Hospital, Singapore.

This is a single-center, Phase 1, open label dose-escalation and dose expansion study of MTL-CEBPA, co-administered with atezolizumab and bevacizumab, in approximately 30 patients with unresectable or advanced HCC who have not previously received systemic therapy. The primary endpoint for the dose escalation phase will be determination of any dose-limiting toxicity, and the primary endpoint of the dose expansion phase will be objective response rate (ORR). The study is expected to read out top-line data in 2023.

Dr Cheng Ean Chee, Senior Consultant at the Department of Haematology-Oncology, NCIS, commented:

"Despite the recent progress of immunotherapies, advanced liver cancer remains a significant unmet medical need. With only 30% of patients benefiting from objective responses to first-line standard of care, new treatment combinations are needed in order to improve patient outcomes. We are excited to evaluate investigational agent MTL-CEBPA in combination with the current standard of care and we are glad to collaborate with MiNA Therapeutics and Roche."

Nagy Habib, Head of R&D at MiNA Therapeutics, commented:

"We are delighted to collaborate with the National University Cancer Institute, Singapore, and Roche to evaluate this new immunotherapy combination. In preclinical and clinical studies, MTL-CEBPA has been reported to improve the anti-tumour activity of leading oncology drugs by counteracting a new cancer immune evasion pathway which causes resistance to those drugs. Based on this data, we believe that MTL-CEBPA combinations have the potential to improve the standard of care significantly in patients with advanced HCC."

Dr Sivabalan Sivanesan, Medical Director at Roche Singapore, commented:

"Roche is both proud and excited to join this investigation of a new treatment combination in advanced HCC. Having established a role in metastatic HCC and other cancers, atezolizumab is currently being investigated in many different cancers including early HCC. With more than 70% of the global liver cancers being diagnosed in Asia, this is an amazing opportunity to study the role of a new combination with atezolizumab in HCC."

About MTL-CEBPA

MTL-CEBPA is the first therapy that specifically up-regulates CCAAT/enhancer binding protein alpha (C/EBP-α), a transcription factor that acts as a master regulator of myeloid cell lineage determination and differentiation. Dysregulated myeloid cells have been implicated in several diseases and in solid tumour cancers have been identified as a critical barrier for many therapies to induce clinical responses. In pre-clinical studies MTL-CEBPA has been shown to improve the anti-tumour activity of cancer therapies by targeting dysregulated myeloid cells and reducing their suppressive effect in the tumour micro-environment. MTL-CEBPA is currently in clinical development as a combination therapy for the treatment of advanced liver cancer and advanced solid tumour malignancies.

About atezolizumab and bevacizumab

Atezolizumab is a human monoclonal antibody IgG1 classified as a PD-L1 inhibitor, and functions by binding to PD-L1 and blocking the PD-1/PD-L1 interaction, thus restoring T-cell activation and antitumour responses.4 Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). 4 The immunomodulatory effect of bevacizumab is expected to increase CD8-positive T-cell recruitment and relieve intratumoral immunosuppression, thereby boosting the effects of atezolizumab.

The results of the phase 3 study of atezolizumab plus bevacizumab vs sorafenib in untreated, advanced HCC patients has been published and an overall survival (OS) benefit was observed with the combination compared to sorafenib.4 The median OS in the atezolizumab plus bevacizumab group compared to those in sorafenib group was 19.2 mo vs 13.4 mo (HR 0.66, 95% CI: 0.52-0.85; P=0.0009).7 The trial also reported an updated objective response rate (ORR) of 29.8% with atezolizumab plus bevacizumab vs 11.3 % in sorafenib (per RECIST 1.1).7 The combination provides the longest survival seen in a front-line phase 3 study in advanced HCC, confirming atezolizumab plus bevacizumab as a standard of care for first line therapy in untreated, advanced HCC.

About hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the seventh most common cancer diagnosed and second most common cause of cancer deaths worldwide.1 It has an annual incidence of at least 840 000 patients1,2 with rising incidence in the developed world. HCC is an aggressive tumour that often occurs in the setting of chronic liver disease and cirrhosis and is often diagnosed late in its course, as there are no biomarkers to detect it when it is incipient and potentially curable. Treatment options are divided into surgical therapies and nonsurgical therapies. Curative therapies such as resection, transplantation, or percutaneous therapies benefit only 25% of patients. The majority of patients are not eligible for such therapies because of the extent of their tumour or underlying liver dysfunction. Improving treatment outcomes in patients with advanced stage hepatocellular carcinoma (HCC) requires the development of agents with tolerable safety profiles and the identification of biomarkers capable of predicting tumour response or resistance to treatment. The underlying aetiology for HCC development is often chronic viral infection and inflammation. Recently, the combination of atezolizumab (anti-PDL1) and bevacizumab (anti-VEGF) was approved by the FDA in 2020 for frontline therapy in advanced HCC based on an overall survival benefit compared to sorafenib.4 This has established atezolizumab and bevacizumab as a standard of care for first line therapy in untreated, unresectable or metastatic HCC. Sorafenib, a multikinase inhibitor, was approved by the FDA and globally in 2007 for treatment of advanced-stage HCC. In the past 4 years, additional systemic therapies have been approved for treatment of advanced HCC including other tyrosine kinase inhibitors such as lenvatinib, regorafenib, and cabozantinib; antibodies against VEGFR2 eg. ramucirumab; and anti-PD1 immunotherapy such as nivolumab. Overall response and survival benefit of all of these agents have been modest and highlight a need for better treatment in this disease.

On December 1, 2021 Halozyme Therapeutics, Inc. (NASDAQ: HALO) reported Janssen Biotech, Inc. (Janssen) received U.S. Food and Drug Administration (FDA) approval of DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) in combination with Kyprolis (carfilzomib) and dexamethasone (Kd) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy (Press release, Halozyme, DEC 1, 2021, View Source [SID1234596366]). This approval follows Janssen’s regulatory submission to the FDA in February 2021.

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"We are pleased that Janssen received U.S. FDA approval for the ninth indication for DARZALEX FASPRO in multiple myeloma, this time in combination with Kyprolis (carfilzomib) and dexamethasone," said Helen Torley, president and chief executive officer at Halozyme. "With its three-to-five-minute subcutaneous administration, DARZALEX FASPRO is now a treatment option for a broader range of patients suffering from multiple myeloma."

The FDA approval for DARZALEX FASPRO is based on data from Janssen’s PLEIADES Study, which met its primary endpoint of overall response rate. For more information about the PLEIADES study and its findings, please view Janssen’s press release issued today.

DARZALEX FASPRO is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

On November 30, 2021 Mereo BioPharma Group plc (NASDAQ: MREO) ("Mereo" or the "Company"), a clinical stage biopharmaceutical company focused on oncology and rare diseases, reported promising interim efficacy, safety, and biomarker data on patients from ACTIVATE, a Phase 1b/2 study of its anti-TIGIT antibody, etigilimab, in combination with nivolumab in select recurrent advanced / metastatic solid tumors (Press release, Mereo BioPharma, NOV 30, 2021, View Source [SID1234596277]).

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"These early results from the ACTIVATE study are highly encouraging and support the further study of etigilimab in combination with an anti-PD-1 antibody in solid tumor types, especially in gynecologic malignancies," said Dr. Denise Scots-Knight, Chief Executive Officer of Mereo. "We are particularly excited by the complete response in the cervical cancer cohort and the partial response in one of the ovarian cancer patients treated to-date. In the efficacy analysis set, biomarker analysis showed a positive trend between baseline PVR expression and clinical benefit including in the absence of PD-L1 expression in the efficacy analysis population. Clinical benefit also occurred in tumor types with historically low response rates to anti-PD-1/PDL-1 antibodies. We look forward to providing additional updates on the study in 2022."

The ACTIVATE study aims to enroll approximately 125 patients across seven parallel cohorts. At the time of the data cut-off, 22 patients were included in the safety analysis set, 20 patients were evaluable with a minimum of at least one scan (as of November 8, 2021) and 15 patients were included in the efficacy analysis population.

As of the cut-off date, there are one complete response in cervical cancer, one partial response in ovarian cancer and four instances of stable disease in ovarian cancer, cervical cancer, and uveal melanoma. The ovarian cohort in ACTIVATE has now crossed futility for expansion into the second stage of the study (IDMC review pending). These results add to the earlier Phase 1b data of etigilimab in combination with nivolumab, with a partial response in the single ovarian cancer patient of the 8 patients evaluable and support the continued development of this dual checkpoint combination regimen.

The combination of etigilimab and nivolumab has been safe and well tolerated, with no new safety signals. The most common treatment-related adverse events were skin reactions, observed in seven patients. None of these reactions required treatment with systemic steroids. There was one case of immune diabetes mellitus.

Conference Call and Webcast

Mereo BioPharma will hold a conference call today, November 30, 2021, at 8:30am ET. To participate by telephone, please dial (866) 688-2942 (Domestic) or (561) 569-9224 (International). The conference ID number is 6585106. To view the slideshow please use the live webcast which can be accessed through the Investors section of the Company’s website at www.Mereobiopharma.com/investors. An archived replay of the webcast will be available on the Company’s website for two weeks following the live presentation.

On November 30, 2021 Navrogen, Inc., a biopharmaceutical company specialized in developing therapies for cancer and immune-related disorders, reported the publication of preclinical data regarding application of its proprietary Block–Removed Immunoglobulin Technology (BRITE) to enhance the efficacy of the CD20-targeting rituximab antibody in the presence of the immunosuppressive CA125 protein (Press release, Navrogen, NOV 30, 2021, View Source [SID1234596296]). The peer-reviewed study was published in Oncology Letters (www.spandidos-publications.com/10.3892/ol.2021.13120).

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The study results showed that CA125 can directly bind rituximab and suppress its immune-effector complement–dependent cytotoxicity (CDC) and antibody–dependent cellular cytotoxicity (ADCC) mechanisms of action. Recent clinical evidence suggests that high serum levels of CA125 reduce the effectiveness of rituximab’s clinical activity in patients with follicular lymphoma. In an attempt to overcome CA125-mediated suppression, BRITE was applied to generate antibody variants that were refractory to CA125 binding and retained efficient CDC and ADCC activity in the presence of CA125. BRITE is an engineering platform that generates and selects for proteins that are refractory to immunosuppressive factors. The application of BRITE resulted in the discovery of an antibody (NAV-006) with a single amino acid change that was refractory to CA125 immunosuppression while retaining similar antigen binding and immune-effector activities as the parental rituximab.

Dr. Luigi Grasso, Chief Scientific Officer of Navrogen said, "the findings here are another demonstration of the humoral immunosuppressive effects that proteins such as CA125 can have on antibody-mediated therapies and the opportunities that BRITE technology can bring to overcome their impact. Our BRITE-optimized rituximab NAV-006 will offer a new opportunity to treat CA125-positive follicular lymphoma patients in our efforts to combat this disease."

Navrogen is actively applying BRITE to improve other therapeutic antibodies affected by immunosuppressive factors for internal pipeline candidates and 3rd party collaborators.

On November 30, 2021 AstraZeneca reported its supplemental New Drug Application (sNDA) for Lynparza (olaparib) has been accepted and granted Priority Review in the US for the adjuvant treatment of patients with BRCA-mutated (BRCAm) HER2-negative high-risk early breast cancer who have already been treated with chemotherapy either before or after surgery (Press release, AstraZeneca, NOV 30, 2021, View Source [SID1234596240]).

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Lynparza is being jointly developed and commercialised by AstraZeneca and MSD.

The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that offer significant advantages over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance.1 The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is during the first quarter of 2022.

Breast cancer is now the most diagnosed cancer worldwide with an estimated 2.3 million patients diagnosed in 2020.2 Nearly 91% of all breast cancer patients are diagnosed at an early stage of disease and BRCA mutations are found in approximately 5% of patients.3,4,5

The sNDA was based on results from the OlympiA Phase III trial presented during the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and simultaneously published in The New England Journal of Medicine.

These results showed Lynparza demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS), reducing the risk of invasive breast cancer recurrence, second cancers or death by 42% versus placebo (based on a hazard ratio of 0.58; 99.5% confidence interval 0.41-0.82; p<0.0001). The safety and tolerability profile of Lynparza in this trial was in line with that observed in prior clinical trials.

Lynparza is approved in the US, EU, Japan and several other countries for the treatment of patients with germline BRCAm, HER2-negative, metastatic breast cancer previously treated with chemotherapy based on results from the OlympiAD Phase III trial. In the EU, this indication also includes patients with locally advanced breast cancer.

Notes

Early breast cancer
Early breast cancer is defined as disease confined to the breast with or without regional lymph node involvement, and the absence of distant metastatic disease.6 The 5-year survival rate is 99% for localised breast cancer (only found in the breast area) and 86% for regional breast cancer (cancer that has spread outside the breast to nearby structures or lymph nodes).3 Despite advancements in the treatment of early breast cancer, up to 30% of patients with high-risk clinical and/or pathologic features, such as BRCA mutations, recur within the first few years.7,8

Breast cancer is one of the most biologically diverse tumour types with various factors fuelling its development and progression.9 The discovery of biomarkers in the development of breast cancer has greatly impacted scientific understanding of the disease.10

OlympiA
OlympiA is a Phase III, double-blind, parallel group, placebo-controlled, multicentre trial testing the efficacy and safety of Lynparza tablets versus placebo as adjuvant treatment in patients with germline BRCAm high-risk HER2-negative early breast cancer, who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy.11

The primary endpoint of the trial is iDFS defined as time from randomisation to date of first loco-regional or distant recurrence or new cancer or death from any cause.11

The OlympiA Phase III trial is led by the Breast International Group (BIG) in partnership with the Frontier Science & Technology Research Foundation (FSTRF), NRG Oncology, AstraZeneca and MSD.11

BRCA
BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells.11

When either of these genes is mutated or altered such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer and confer sensitivity to PARP inhibitors including Lynparza.12-15

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as new hormonal agents).

Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy.

It is also approved in the US, EU and Japan as a 1st-line maintenance treatment with bevacizumab for patients with HRD-positive advanced ovarian cancer (BRCAm and/or genomic instability).

Lynparza is approved in the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer.

It is also approved in the US, the EU, Japan and several other countries for the treatment of germline BRCAm metastatic pancreatic cancer.

Lynparza is approved in the US for HRR gene-mutated metastatic castration-resistant prostate cancer (BRCAm and other HRR gene mutations) and in the EU and Japan for BRCAm metastatic castration-resistant prostate cancer.

Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers. Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 40,000 patients worldwide.

Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types.

Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US (known as MSD outside the US and Canada) announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types.

Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumour environment.

AstraZeneca aims to continue to transform outcomes for HR-positive breast cancer with foundational medicines Faslodex (fulvestrant) and Zoladex (goserelin) and the next-generation selective estrogen receptor degraders (SERD) and potential new medicine camizestrant (formerly known as AZD9833).

Lynparza is a targeted treatment option for metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD continue to research Lynparza in early and metastatic breast cancer patients with a BRCA mutation.

Building on the first approval of Enhertu (trastuzumab deruxtecan), a HER2-directed antibody-drug conjugate (ADC), in previously treated HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are exploring its potential in earlier lines of treatment and in new breast cancer settings. Results from the DESTINY-Breast03 Phase III trial showed that Enhertu significantly improved progression-free survival in patients with HER2-positive metastatic breast cancer.

To bring much needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is testing immunotherapy Imfinzi (durvalumab) in combination with other oncology medicines, including Lynparza and Enhertu, assessing the potential of AKT kinase inhibitor, capivasertib, in combination with chemotherapy, and collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.