On April 2, 2019 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 it has entered into a definitive agreement with certain institutional investors to receive gross proceeds of approximately $3.2 million (Press release, Can-Fite BioPharma, APR 2, 2019, View Source [SID1234534907])

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In connection with the offering, the Company will issue 4,923,078 registered American Depository Shares (ADSs) of Can-Fite at a purchase price of $0.65 per ADS in a registered direct offering. Additionally, for each ADS purchased by investors, the investors will receive an unregistered warrant to purchase one ADS. The warrants will have an exercise price of $0.86 per ADS, will be immediately exercisable and will expire five years from the issuance date. The closing of the offering is expected to take place on or about April 4, 2019, subject to the satisfaction of customary closing conditions.

H.C. Wainwright & Co. is acting as the exclusive placement agent for the offering.

The ADSs described above (but not the warrants or the ADSs underlying the warrants) are being offered pursuant to a shelf registration statement (File No. 333-220644) which became effective on October 11, 2017. Such ADSs may be offered only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement.

The Company will file a prospectus supplement and the accompanying base prospectus with the SEC relating to the offering of such ADSs. When available, copies of the prospectus supplement and the accompanying base prospectus may be obtained at the SEC’s website at View Source, or by contacting H.C. Wainwright & Co., LLC, 430 Park Avenue, 3rd Floor, New York, New York 10022, by telephone: (646) 975-6996 or by email at [email protected].

The warrants described above were offered in a private placement under Section 4(a)(2) of the Securities Act of 1933, as amended (the "Act"), and Regulation D promulgated thereunder and, along with the ADSs issuable upon their exercise, have not been registered under the Act, and may not be offered or sold in the United States absent registration with the SEC or an applicable exemption from such registration requirements.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy any of the securities described herein. There shall not be any offer, solicitation of an offer to buy, or sale of securities in any state or jurisdiction in which such an offering, solicitation, or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On April 2, 2019 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology company with a pipeline of immune-modulating antibodies, cancer vaccines, adjuvants and adoptive cell therapies1, reported that the first patient was dosed in the clinical trial of its next-generation anti-CTLA-4 antibody (AGEN1181) (Press release, Agenus, APR 2, 2019, View Source [SID1234534906]). AGEN1181, a novel ‘Fc engineered’ antibody with potential for enhanced anti-tumor functions, is specifically designed to boost cancer killing immune cells and deplete cells that block the activity of these cancer killing cells.

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The first patient in the trial was dosed by Dr. Steven J. O’Day, M.D., Executive Director of the John Wayne Cancer Institute & Cancer Clinic, and a pioneer in delivering immune therapies to patients with cancer. Dr. O’Day’s pivotal work has led to the approvals of commercial antibodies targeting CTLA-4 and PD-1. "AGEN1181 represents an important next-generation breakthrough with its potential for enhanced immune activation and tumor fighting abilities," said Dr. O’Day. "The pre-clinical data so far suggest that AGEN1181 may bring superior benefit compared to first generation anti-CTLA-4 antibodies and may be an optimal partner for combinations. I am thrilled to be working with this compound."

"AGEN1181 is a product of Agenus’ innovation engine that has been key to rapidly delivering new discoveries to patients," said Garo Armen, Ph.D., Chairman and CEO of Agenus. "AGEN1181 was developed based on a new mechanism of action discovered by our scientists. In addition to this monotherapy trial, we plan to pursue combination studies with AGEN1181 soon. Besides AGEN1181, additional important discoveries from our innovation engine are also advancing towards the clinic this year."

The Phase 1, open-label, multicenter study is designed to assess the maximum tolerated dose of AGEN1181 in subjects with advanced solid tumors. It will also evaluate the safety, tolerability, PK, and PD profiles and immunogenicity of this antibody. The outcome will determine the recommended phase II dose of AGEN1181.

AGEN1181 was developed based on a discovery made by Agenus scientists, that involves modification of a key region of an antibody, known as the "Fc region", to design next-generation, ‘Fc engineered’ antibodies that may significantly enhance functionality and antitumor immunity. To learn more about AGEN1181 and its potential advantages over first-generation anti-CTLA-4 antibodies, please see Agenus’ Newsletter here.

On April 2, 2019 Savara Inc. (NASDAQ:SVRA), an orphan lung disease company, reported that Rob Neville, Chief Executive Officer, will present at the H.C. Wainwright Global Life Sciences conference on Tuesday, April 9, 2019 at 1:50 PM GMT / 8:50 AM EST (Press release, Savara, APR 2, 2019, View Source [SID1234534904]). The conference will be held at the JW Marriott Grosvenor House London.

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Interested parties can access a live audio webcast on the Investors page of the Savara website at www.savarapharma.com/investors/events-presentations/. Please connect to the company’s website at least 15 minutes prior to the start of the presentation to ensure sufficient time for any software download that may be required for the webcast. An archived presentation will be available on Savara’s website for 30 days.

On April 2, 2019 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported that the first patient treated with FT500 successfully completed an initial safety assessment (Press release, Fate Therapeutics, APR 2, 2019, View Source [SID1234534903]). The patient received three once weekly doses of FT500, and the treatment cycle was well-tolerated with no dose-limiting toxicities or serious adverse events reported during the initial 28-day observation period. The universal, off-the-shelf natural killer (NK) cell product candidate is the first-ever cell therapy derived from an induced pluripotent stem cell (iPSC) administered to a patient in the U.S.

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"The ability to effectively and efficiently deliver multiple doses of a cellular immunotherapy ‘on demand’ brings us closer to our goal of transforming the treatment of cancer for more patients. This initial observation of tolerability from the first-ever cancer patient to receive multiple doses of a universal, off-the-shelf cell product derived from a clonal master iPSC line provides early clinical validation of our proprietary iPSC product platform for off-the-shelf cancer immunotherapy," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "In addition to our clinical progress with FT500, our engineered iPSC-derived NK cell product candidates continue to exhibit a highly-differentiated therapeutic profile in preclinical models and we look forward to generating initial clinical data with FT516 and FT596 in 2019."

Two additional patients have also been treated with FT500 as a monotherapy in the first dose cohort of 1×108 cells per dose and are currently within the initial 28-day observation period. The FT500 clinical trial is a two-arm study in up to 64 patients for the treatment of advanced solid tumors. The study is designed to assess the safety and activity of three once weekly doses of FT500 as a monotherapy and in combination with one of three FDA-approved checkpoint inhibitor therapies – nivolumab, pembrolizumab or atezolizumab – in patients that have failed or have confirmed disease progression on checkpoint inhibitor therapy. Patients that are clinically stable following the initial 28-day observation period are eligible to receive a second treatment cycle.

FT516 Novel CD16 Receptor Promotes High-Affinity Engagement with Monoclonal Antibody Therapy
Today the Company presented preclinical data for FT516, its universal, off-the-shelf NK cell product candidate derived from a clonal master iPSC line engineered to express a novel CD16 Fc (hnCD16) receptor, at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) in Atlanta, Georgia. FT516 is the first-ever cell therapy derived from a genetically engineered pluripotent stem cell cleared for clinical testing in the world, and the Company is preparing to initiate clinical investigation of FT516 in the U.S. in patients with certain relapsed/refractory hematologic malignancies, including acute myelogenous leukemia as a monotherapy, non-Hodgkin’s lymphoma in combination with rituximab, and multiple myeloma in combination with elotuzumab.

While CD16 is naturally expressed on NK cells and mediates antibody-dependent cellular cytotoxicity, numerous clinical studies with FDA-approved tumor-targeting antibodies have demonstrated that patients with CD16 high-affinity variant 158V have improved clinical outcomes. However, only about 15% of humans are homozygous for 158V. Additionally, the expression of CD16 on NK cells in cancer patients can undergo considerable down-regulation, which significantly inhibits the cell’s anti-tumor activity. The novel CD16 Fc receptor expressed by FT516 has been designed to overcome these inherent deficiencies: it is comprised of the high-affinity 158V variant and is resistant to down-regulation.

In preclinical studies using a B-cell lymphoma line, the Company showed that approximately 70% of peripheral blood NK cells down-regulated CD16 expression upon co-culture with rituximab, while CD16 expression on FT516 remained resistant to down-regulation. These differences resulted in a significant anti-tumor benefit in vivo where, in a human lymphoma cancer model, mice treated with peripheral blood NK cells and rituximab had a median survival time of 39 days as compared to mice treated with FT516 and rituximab, where the median survival time was not yet reached at 100 days.

FT596 CAR and CD16 Modalities Exert Synergistic Anti-Tumor Activity
The Company also presented today at AACR (Free AACR Whitepaper) new preclinical data for FT596, the Company’s first iPSC-derived chimeric antigen receptor (CAR) NK cell product candidate that is designed to concurrently target multiple tumor-associated antigens. FT596 is derived from a clonal master iPSC line engineered to express a proprietary CAR targeting CD19, a hnCD16 Fc receptor, and a novel IL-15 receptor fusion.

In a mixed co-culture assay, the Company showed that the concurrent activation of the CAR and hnCD16 targeting modalities of FT596 exert synergistic anti-tumor activity. Increased degranulation (CD107a) and cytokine release (interferon-gamma and TNF-alfa) were observed upon concurrent activation of both the CAR and CD16 receptors in CD19+CD20+ Raji cancer cells with rituximab as compared to activation of each receptor alone, suggestive that dual antigen engagement may elicit a deeper and more durable response. Additionally, in a cellular cytotoxicity assay designed to model CD19 antigen escape, FT596 combined with rituximab was able to effectively eliminate leukemia and lymphoma cancer cells that were positive for CD19 antigen expression as well as those that were null for CD19 antigen expression.

About FT500
FT500 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line. FT500 is being investigated in an open-label, repeat-dose Phase 1 clinical trial for the treatment of advanced solid tumors in up to 64 patients, both as a monotherapy and in combination with FDA-approved checkpoint inhibitor therapy. Despite the favorable response rates observed with checkpoint inhibitor therapy, the majority of patients do not respond and many responders relapse. One common mechanism of resistance to checkpoint inhibitor therapy is associated with loss-of-function mutations in genes critical for antigen presentation. A potential strategy to overcome resistance is through the administration of allogeneic NK cells, which have the inherent capability to recognize and directly kill tumor cells with these mutations.

On April 2, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported interim data from the Company’s CD40 agonist program in a late-breaking poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Celldex Therapeutics, APR 2, 2019, View Source [SID1234534902]). CD40, expressed on dendritic cells and other antigen presenting cells, is an important target for immunotherapy, as it plays a critical role in the activation of innate and adaptive immune responses.CDX-1140 is a fully human agonist anti-CD40 monoclonal antibody that was specifically designed to balance good systemic exposure and safety with potent biological activity, a profile which differentiates CDX-1140 from other CD40-activating antibodies.

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CDX-1140 is currently in a Phase 1 dose escalation study. The study includes both monotherapy and combination cohorts with CDX-301, Celldex’s dendritic cell growth factor, designed to increase the number of dendritic cells which are critical to initiating antitumor immunity and are a key target for CDX-1140.

"Preclinical data support that CD40 activation could play an extremely important role in cancer immunotherapy by activating anti-tumor immunity and overcoming resistance to PD-1 blockade," said Rachel Sanborn, MD, Co-director of the Thoracic Oncology Program and Leader of the Phase 1 Trials Program at Providence Cancer Institute and a lead investigator in this study. "The interim results presented today have demonstrated that CDX-1140 is a potent activator of CD40 and can be safely administered at doses that we believe will support good tissue and tumor penetration. We are now reaching dose levels that have the potential for meaningful clinical benefit, especially in combination with drugs that target other key immune pathways, and look forward to initiating tumor specific expansion cohorts to test potential clinical activity."

CDX-1140 has a unique combination of properties relative to other CD40 agonist antibodies: potent agonist activity resulting in dendritic cell and B cell activation is independent of Fc receptor interaction, contributing to more consistent, controlled immune activation; CD40 ligand (CD154) binding is not blocked, allowing potential synergy with the natural CD40 activation pathway; and the antibody promotes strong immune activation without significant adverse events in preclinical toxicology studies.

Presentation Highlights:

Abstract #: LB-194: First in human Phase 1 study of the CD40 agonist monoclonal antibody (mAb) CDX-1140 alone and in combination with CDX-301 (rhFLT3L) in patients with advanced cancers: interim results (Sanborn, et. al)

Overview: 30 patients were enrolled in the study at the time of data analysis (n=22 monotherapy; n=8 combination. Six monotherapy dosing cohorts in both solid tumors and non-Hodgkin lymphoma (NHL) (0.01, 0.03, 0.09, 0.18, 0.36 and 0.72 mg/kg) have been completed. The seventh monotherapy cohort at 1.5 mg/kg is currently being enrolled. Two combination cohorts in solid tumors (0.09 and 0.18 mg/kg) with CDX-301 have been completed and the third cohort at 0.36 mg/kg is currently being enrolled. In general, patients have advanced disease and are heavily pretreated (median number of prior therapies: 4 monotherapy arm; 3.5 combination arm).

Safety: CDX-1140 has been generally well tolerated. A maximum tolerated dose (MTD) has not been reached to date and only three patients have experienced serious treatment related adverse events (pneumonitis and hypoxia; possible cytokine release, fatigue and fever; and, fatigue and nausea). High grade, drug-related (Grade 3 and above) changes in liver function tests or platelet count have not been observed to date, including at CDX-1140 dose levels which exceed the MTDs reported with other CD40 agonists. The addition of CDX-301 has not affected the tolerability of CDX-1140 at dose levels tested to date in the combination cohorts.

Systemic Dosing and Biomarker Analysis: Higher dose levels have achieved circulating antibody concentrations in the range of 20 to 30 micrograms CDX-1140 per milliliter. Transient dose-dependent pharmacodynamic effects have been observed including activation of dendritic cells and B cells, along with increases in pro-inflammatory cytokines and chemokines in the blood, all of which are consistent with CD40-mediated immune activation and the hypothesis that CDX-1140 is achieving dose levels optimal for systemic exposure. The addition of CDX-301 has further enhanced cytokine responses.

Early Clinical Activity: While not anticipated at these lower CDX-1140 dose levels, stable disease has been observed in this heavily pretreated population who have received, at a minimum, all standard of care therapies for their tumor type. Recently enrolled dose levels are still under evaluation.

Future development: Additional patient enrollment (backfill) has been initiated at the 0.72 mg/kg CDX-1140 dose level to characterize the effects of CDX-1140 in the tumor microenvironment and tumor specific expansion cohorts are planned. Future combination opportunities are being considered, including with PD-1 or PD-L1 inhibitors, radiation therapy and Celldex’s potent CD27 agonist monoclonal antibody varlilumab. Several B cell lymphomas (subtypes of NHL) express both CD40 and CD27 and varlilumab has been shown to synergize with CDX-1140 in NHL models.