On July 2, 2018 Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE:CFBI), a biotechnology company advancing a pipeline of proprietary small molecule drugs that address cancer, liver and inflammatory diseases, reported that U.S. researchers published scientific findings recommending development of anti-Liver Cancer Drugs based on a mechanism of action utilized by Namodenoson (Press release, Can-Fite BioPharma, JUL 2, 2018, View Source [SID1234527537]).

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Can-Fite extensively published that its anti-cancer drug candidate, Namodenoson, inhibits a specific molecular signaling pathway in the liver cancer cells, designated as the Wnt/β-catenin, and is responsible for the development and progression of hepatocellular carcinoma (HCC). The scientific article published on June 28, 2018 by key opinion leaders from the University of Texas MD Anderson Cancer Center, Houston, TX, USA, recommends that targeting and inhibiting the very same Wnt/β-catenin pathway leads to an anti-cancer effect against hepatocellular carcinoma (Role of Wnt/β catenin signaling in hepatocellular carcinoma pathogenesis and clinical significance; Authors: Khalaf AM, Fuentes D, Morshid AI, Burke MR, Kaseb AO, Hassan M, Hazle JD, Elsayes KM. View Source)

"We are very excited to read the MD Anderson group article which we consider as important validation of Can-Fite’s scientific approach to the development of Namodenoson for the treatment of liver cancer. We’re proud to be working in the forefront of research of HCC with our orally available drug Namodenoson with its unique mechanism of action as an anti-cancer agent and its favorable safety profile. We look forward to data release from our ongoing Phase II advanced liver cancer trial," stated Can-Fite CEO Dr. Pnina Fishman.

The currently ongoing global Phase II study is being conducted in the U.S., Europe and Israel. Patients with advanced HCC, Child Pugh B, who failed Nexavar (sorafenib) as a first line treatment are treated twice daily with 25mg of oral Namodenoson or placebo using a 2:1 randomization. The primary endpoint of the Phase II study is Overall Survival (OS). Secondary endpoints include Progression Free Survival (PFS), safety, and the relationship between outcomes and A3AR expression.

Accumulated safety data to date continues to indicate a favorable safety profile, with no clinically significant novel or emerging events attributed to chronic treatment with Namodenoson.

Can-Fite received Orphan Drug Designation for Namodenoson in Europe and the U.S., as well as Fast Track Status in the U.S. as a second line treatment for HCC.

About Namodenoson

Namodenoson is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). Namodenoson is being evaluated in Phase II trials for two indications, as a second line treatment for hepatocellular carcinoma, and as a treatment for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). A3AR is highly expressed in diseased cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug.

On July 2, 2018 AstraZeneca and MedImmune, its global biologics research and development arm, reported that the Japanese Ministry of Health, Labour and Welfare approved Imfinzi (durvalumab) as maintenance therapy after definitive chemoradiation therapy (CRT) in locally-advanced (Stage III), unresectable non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, JUL 2, 2018, View Source [SID1234527536]).

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Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit said: "Non-small cell lung cancer is a leading cause of death in Japan, and we are dedicated to bringing new treatment options to patients as quickly as possible. As the only immunotherapy approved in the curative-intent, Stage III lung cancer setting, Imfinzi has the potential to change the treatment paradigm for patients diagnosed with this disease."

The approval of Imfinzi is based on positive progression-free survival (PFS) data from the Phase III PACIFIC trial in unresectable Stage III NSCLC. In the trial, Imfinzi demonstrated an improvement in median PFS of 11.2 months compared to placebo. Imfinzi improved other meaningful outcomes such as time to distant metastasis or death and overall response rates. Detailed results of the PACIFIC trial were published in the New England Journal of Medicine (NEJM).

1 Blinded Independent Central Review (BICR).

2 Among the ITT population, 7% in the Imfinzi arm and 10% in the placebo arm had non-measurable disease as assessed by BICR according to RECIST v1.1.

3 Stratified by sex, age, and smoking history.

4 Pike estimator.

5 Compared with allocated α of 0.0104 (Lan DeMets spending function approximating O’Brien Fleming boundary) for interim analysis.

The incidence and severity of adverse events were comparable for patients receiving Imfinzi vs. patients receiving placebo. The most frequent adverse reactions were rash which occurred in 73 subjects (15.4%), hypothyroidism which occurred in 50 subjects (10.5%), diarrhoea which occurred in 46 subjects (9.7%) and interstitial lung disease which occurred in 46 subjects (9.7%).

In May 2018, AstraZeneca announced that the PACIFIC trial met its second primary endpoint, showing statistically-significant and clinically-meaningful overall survival (OS) in patients receiving Imfinzi compared to placebo. Full results will be presented at a forthcoming medical meeting.

Imfinzi is also approved in the US, Canada, Switzerland and India based on the Phase III PACIFIC trial. Regulatory reviews in the EU and other jurisdictions are ongoing with an EU decision expected in the second half of 2018.

About Stage III NSCLC

Stage III (locally-advanced) NSCLC is commonly divided into three sub-categories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally and the possibility of surgery. Stage III disease is different from Stage IV disease, when the cancer has spread (metastasised) to distant organs, as Stage III is currently treated with curative intent.

Stage III NSCLC represents approximately one-third of NSCLC incidence and was estimated to affect around 105,000 patients in the top-eight countries (China, France, Germany, Italy, Japan, Spain, UK, US) in 2017. The majority of Stage III NSCLC patients are diagnosed with unresectable tumours. Before the PACIFIC trial, the standard of care was chemotherapy and radiation therapy, followed by active surveillance to monitor for progression.

About PACIFIC

The PACIFIC trial is a randomised, double-blinded, placebo-controlled, multi-centre trial of Imfinzi as treatment in patients with Stage III unresectable NSCLC whose disease has not progressed following platinum-based chemoradiation therapy (CRT).

The trial has been conducted in 235 centres across 26 countries involving 713 patients. The primary endpoints of the trial are PFS and OS, and secondary endpoints include landmark PFS and OS, objective response rate, and duration of response.

About Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with chemotherapy, radiation therapy, small molecules, and tremelimumab, an anti-CTLA4 monoclonal antibody, as a 1st-line treatment for patients with NSCLC, small cell lung cancer, locally-advanced or metastatic urothelial carcinoma, head and neck cancer and other solid tumours.

On July 2, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) reported that Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) has approved Lynparza (olaparib) tablets for use in patients with unresectable or recurrent BRCA-mutated (BRCAm), human epidermal growth factor receptor 2 (HER2) negative breast cancer who have received prior chemotherapy (Press release, AstraZeneca, JUL 2, 2018, View Source [SID1234527535]). Patients are selected for therapy based on an approved companion diagnostic.

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Dave Fredrickson, Executive Vice President, Head of the Oncology Business Unit at AstraZeneca, said: "Earlier this year, Lynparza became the first PARP inhibitor available in Japan for advanced ovarian cancer. Now patients in Japan with BRCA-mutated, metastatic breast cancer will also have the opportunity to benefit from Lynparza. This latest approval underlines our ongoing efforts to make Lynparza available across multiple cancers as quickly as possible to patients around the world."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Metastatic breast cancer is a complex disease with remaining unmet medical need. This approval is significant for breast cancer patients as the evaluation of BRCA mutations, in addition to hormone receptor and HER2 status, now becomes an important step in the management of the disease."

The approval is based on data from the randomised, open-label, Phase III OlympiAD trial, which tested Lynparza vs chemotherapy. Patients were selected for therapy based upon a confirmed BRCA mutation. In the trial, Lynparza significantly prolonged progression-free survival (PFS) compared with chemotherapy, reducing the risk of disease progression or death by 42% (HR 0.58; 95% CI 0.43-0.80; p=0.0009, median PFS was 7.0 months with Lynparza vs 4.2 months with chemotherapy).

Lynparza was generally well tolerated with the majority of adverse events (AEs) reported as mild to moderate with a lower rate of Grade 3 or higher AEs compared with chemotherapy (36.6% vs 50.5%). The most common AEs were nausea (50.2%), anaemia (32.2%) and fatigue (22.4%).

Lynparza is also approved in Japan as maintenance treatment for women with platinum-sensitive relapsed ovarian cancer, regardless of BRCA mutation status. In Japan, the co-promotion of Lynparza by both companies will begin on 1 July 2018.

About OlympiAD

OlympiAD was a randomised, open-label, multicentre Phase III trial assessing the efficacy and safety of Lynparza tablets (300 mg twice daily) compared to physician’s choice of chemotherapy (capecitabine, eribulin, or vinorelbine) in 302 patients with HER2-negative metastatic breast cancer with germline BRCA1 or BRCA2 mutations, which are confirmed or suspected to be deleterious. The international trial was conducted in 19 countries across Europe, Asia, North America and South America.

Patients in the OlympiAD trial had HER2-negative gBRCA1- or gBRCA2-mutated breast cancer, which was hormone-receptor positive (HR+) or triple negative, and received Lynparza for metastatic disease. Approximately half of the patients in the Lynparza and chemotherapy arm of the trial were HR+ (n=152), and approximately half were triple negative (n=150). Among the 205 patients treated with Lynparza, the median age was 44 years (range: 22 to 76). Before enrolment, patients had prior treatment with an anthracycline (unless contraindicated) and a taxane chemotherapy either in the neoadjuvant, adjuvant or metastatic setting and no more than two prior lines of chemotherapy for metastatic disease. HR+ patients had received at least one endocrine medicine or were not eligible for endocrine medicines. Prior treatments with endocrine medicines were not counted as prior lines of chemotherapy.

The primary endpoint of the trial was PFS as measured by a Blinded Independent Central Review. Secondary endpoints included overall survival, time to second progression or death, objective response rate, and effect on health-related quality of life.

About BRCA mutations

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

About breast cancer in Japan

In Japan, breast cancer is the fifth leading cause of death among women.[i] In Japanese women, breast cancer incidence peaks in the late forties, whereas in the US and Europe the peak incidence is in women over 60 years of age.[ii] Despite more treatment options becoming available during the past three decades, there is currently no cure for patients diagnosed with metastatic (Stage IV) breast cancer.[iii] In Japan, 5-year and 10-year relative survival rates for patients with Stage IV breast cancer are as low as 32.6% and 15.6%, respectively.[iv] Therefore, the primary aim of treatment is to slow progression of the disease for as long as possible and improve or maintain a patient’s quality of life.5

About Lynparza

Lynparza (olaparib) is the first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that Lynparza-induced cytotoxicity may involve inhibition of PARP-enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death. Lynparza is being tested in a range of DDR-deficient tumour types.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor and AstraZeneca and MSD are working together to deliver it as quickly as possible to more patients across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

On July 2, 2018 Compugen Ltd. (Nasdaq: CGEN), a clinical-stage cancer immunotherapy company and a leader in predictive target discovery, reported that the U.S. Food and Drug Administration (FDA) has removed the clinical hold on its investigational new drug (IND) application for COM701, a first-in-class immuno-oncology therapeutic antibody targeting PVRIG in patients with advanced solid tumors, and informed the Company it may initiate the clinical study (Press release, Compugen, JUL 2, 2018, View Source [SID1234527529]).

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"Today is a significant milestone for Compugen, having received clearance from the FDA to advance our lead immuno-oncology program into the clinic. COM701 is a first-in-class drug opportunity that was developed by Compugen from discovery of the drug target by computer prediction through preclinical development, to IND clearance," stated Anat Cohen-Dayag, PhD, President and CEO of Compugen. "We believe the COM701 preclinical data suggest that targeting PVRIG may effectively stimulate an anti-tumor immune response in certain cancers such as breast, endometrial, ovarian and lung, and specifically in patient populations that are unresponsive to current checkpoint inhibitors."

"The PVRIG pathway, a new pathway on which we have shed light, is part of a larger complex immuno-oncology biological axis involving the TIGIT and PD-1 pathways. By targeting this pathway, our COM701 program clearly presents a differentiated profile from other drug targets and combination options in the clinic. We are confident we are the only company with an anti-PVRIG candidate available for clinical testing, either as a single agent and in combination with a PD-1 and TIGIT inhibitors, and we are excited to initiate patient dosing with COM701 in a multicenter Phase 1 trial, early in the fall," Dr. Cohen-Dayag added.

"We worked closely with the FDA in connection with this IND application and are eager to evaluate COM701 in a clinical setting," said Henry Adewoye, MD, Chief Medical Officer of Compugen. "We received positive feedback from leading clinical investigators in the field of immuno-oncology who share our excitement for the potential role of the PVRIG pathway in immuno-oncology and our overall clinical program and strategy. We look forward to collaborating with them on this trial."

Under this IND, the Company intends to initiate a first-in-human Phase 1 study in patients with advanced solid tumors and for whom standard of care therapies are currently ineffective. The clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of COM701 as monotherapy and in combination with a PD-1 inhibitor. The Phase 1 trial is planned to be conducted at multiple centers in the United States and site initiation activities are currently underway.

About COM701
COM701 is a humanized hybridoma antibody that binds with high affinity to PVRIG, a novel B7/CD28-like immune checkpoint target candidate discovered by Compugen, blocking its interaction with its ligand, PVRL2. Blockade of PVRIG by COM701 has demonstrated potent, reproducible enhancement of T cell activation, consistent with the desired mechanism of action of activating T cells in the tumor microenvironment to generate anti-tumor immune responses. In addition, COM701 combined with antagonist anti-PD-1 antibodies has demonstrated synergistic effects on human T cell stimulation, indicating the potential of these combinations to further enhance immune response against tumors.

Preclinical data for COM701 suggest that PVRIG may be a dominant checkpoint in diverse patient populations with tumors that express elevated PVRL2 as compared to expression of the TIGIT ligand PVR. This include patients with breast, endometrial, and ovarian cancers. In addition, expression studies show that PVRIG and TIGIT, and their respective ligands, are expressed in a broad variety of tumor types, such as those noted above, as well as lung, kidney, and head & neck cancers. In these tumors the blockade of both TIGIT and PVRIG may be required to sufficiently stimulate an anti-tumor immune response, with or without additional PD-1 pathway blockade.

On July 2, 2018 Celgene Corporation (NASDAQ: CELG) reported that it will host a conference call and live audio webcast on Thursday, July 26, 2018 at 9 a.m. ET to discuss second quarter 2018 financial and operational results (Press release, Celgene, JUL 2, 2018, View Source [SID1234527528]). The webcast can be accessed from the Investor Relations page at www.celgene.com.

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