On March 18, 2019 Alligator Bioscience (Nasdaq Stockholm: ATORX), reported that they will present preclinical data for the drug candidate ATOR-1017 at the 4th Annual Immuno-oncology Summit Europe, to be held in London on March 18-22, 2019 (Press release, Alligator Bioscience, MAR 18, 2019, View Source [SID1234538668]).

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ATOR-1017 is a monoclonal antibody in development for the treatment of metastasizing cancer. It activates the costimulatory receptor 4-1BB and its immunostimulatory function is dependent on cross-linking to Fc-gamma receptors on immune cells.

The new data show that ATOR-1017, in an experimental model for colon cancer (MC38), displays potent anti-tumor effects. Furthermore, ATOR-1017 induces a dose-dependent effect on tumor growth inhibition and survival. Existing preclinical data have already shown that ATOR-1017 stimulates both NK (Natural Killer) and T cells, both of which contribute to an effective immune-mediated killing of tumor cells.

"ATOR-1017 is designed to have a superior safety and efficacy profile through its tumor-directed properties and these latest data support the positioning of ATOR-1017 as a best-in-class 4-1BB antibody with the potential to reduce side effects, but also to generate a potent and long-lasting immune response. This provide us with a strong preclinical package to move into the next phase of development. We expect to start clinical trials in cancer patients later this year," said Christina Furebring, SVP Preclinical Development, at Alligator Bioscience.

Dr Karin Enell Smith, Senior Scientist Immuno-oncology at Alligator, will hold an oral presentation with the title: "ATOR-1017 – A Tumor Directed Fcγ-Receptor Cross Linking Dependent 4-1BB Agonistic Antibody" on Monday, March 18, 5:45 p.m GMT (6:45 p.m. CET).

For further information, please contact:
Cecilia Hofvander, Director Investor Relations & Communications
Phone +46 46 540 82 06
E-mail: [email protected]

This information is such information as Alligator Bioscience AB (publ) is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact person set out above, at 1:30 p.m. CET on March 18, 2019.

About ATOR-1017
ATOR-1017 is an immunostimulatory antibody (IgG4) that binds to the costimulatory receptor 4-1BB (also known as CD137) expressed on tumor-specific T cells and NK cells.
4-1BB has the capacity to support the immune cells involved in tumor control, making 4-1BB a particularly attractive target for cancer immunotherapy.

ATOR-1017 is differentiated from other 4-1BB antibodies, partly because of its unique binding profile, but also because its immunostimulatory function is dependent on cross-linking to Fc-gamma receptors on immune cells. The aim is to achieve effective tumor-targeted immune stimulation with minimum side effects. ATOR-1017 is planned to enter clinical studies 2019.

On March 18, 2019 Stemline Therapeutics, Inc. (Nasdaq: STML), a commercial-stage biopharmaceutical company focused on the development and commercialization of novel oncology therapeutics, reported that Ivan Bergstein, M.D., Stemline’s CEO, was selected to participate as a panelist on "The Brave New World of Myeloid Tumors (Press release, Stemline Therapeutics, MAR 18, 2019, View Source [SID1234534420])." The panel will take place on Monday, March 18 at 3 PM PT during the 31st Annual ROTH conference at the Ritz-Carlton Laguna Niguel, CA.

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About CD123
CD123 is a cell surface target expressed on a wide range of myeloid tumors including blastic plasmacytoid dendritic cell neoplasm (BPDCN), certain myeloproliferative neoplasms (MPNs) including chronic myelomonocytic leukemia (CMML) and myelofibrosis (MF), acute myeloid leukemia (AML) (and potentially enriched in certain AML subsets), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML). CD123 has also been reported on certain lymphoid malignancies including multiple myeloma (MM), acute lymphoid leukemia (ALL), hairy cell leukemia (HCL), Hodgkin’s lymphoma (HL), and certain Non-Hodgkin’s lymphomas (NHL). In addition, CD123 has been detected on some solid tumors as well as autoimmune disorders including cutaneous lupus and scleroderma.

About ELZONRIS
ELZONRIS (tagraxofusp), a CD123-directed cytotoxin, was approved by the Food and Drug Administration (FDA) on December 21, 2018 for the treatment of adult and pediatric patients, two years and older, with blastic plasmacytoid dendritic cell neoplasm (BPDCN). For full prescribing information in the U.S., visit www.ELZONRIS.com. In November 2018, the European Medicines Agency (EMA) granted ELZONRIS accelerated assessment to the marketing authorization application (MAA), which was submitted to, and validated by, the EMA in January 2019. ELZONRIS is also being evaluated in additional clinical trials in other indications including chronic myelomonocytic leukemia (CMML), myelofibrosis (MF) and acute myeloid leukemia (AML).

About BPDCN
BPDCN is an aggressive hematologic malignancy with historically poor outcomes and an area of unmet medical need. BPDCN typically presents in the bone marrow and/or skin and may also involve lymph nodes and viscera. The BPDCN cell of origin is the plasmacytoid dendritic cell (pDC) precursor. The diagnosis of BPDCN is based on the immunophenotypic diagnostic triad of CD123, CD4, and CD56, and other markers. For more information, please visit the BPDCN disease awareness website at www.bpdcninfo.com.

On March 18, 2019 Protalix BioTherapeutics, Inc. (NYSE American:PLX) (TASE:PLX), a biopharmaceutical company focused on the development and commercialization of recombinant therapeutic proteins expressed through its proprietary plant cell-based expression system, ProCellEx, reported its financial results for the full-year ended December 31, 2018 and provided a corporate update (Press release, Protalix, MAR 18, 2019, View Source [SID1234534453]).

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"Throughout 2018 and into early 2019, we significantly advanced our clinical development program for PRX-102 and, as of today, have enrolled 127 Fabry disease patients across all of our PRX-102 clinical trials. Most recently, we had a very productive meeting with the U.S. Food and Drug Administration (FDA) to discuss the potential filing of an application for accelerated approval and, at the FDA’s request, we intend to hold a follow up meeting by the end of the second quarter of 2019 to discuss the data and content of the potential filing for accelerated approval. We are very pleased with the collaborative manner our engagement with the FDA has been to date and cautiously optimistic about the prospects of our discussions with the agency," said Mr. Moshe Manor, Protalix’s President and Chief Executive Officer. "We are very excited as we move forward into 2019 which could be a transformational year for us, including the read outs from our Fabry trials and the potential for establishing the path for accelerated approval for PRX-102 with the FDA."

2018 Clinical and Corporate Highlights

Pegunigalsidase alfa (PRX-102) for the treatment of Fabry Disease

·Recently the Company held a very productive meeting with the FDA regarding the potential path for accelerated BLA approval for PRX-102.
·The FDA confirmed that the Company’s PRX-102 program could rely on surrogate endpoints as part of the basis for a potential accelerated BLA approval.
·The FDA urged the Company to apply for a follow up Type C meeting as soon as possible to review with the agency the data and content of such potential accelerated filing application.
·The discussion with the FDA revolved around the data the Company has generated from all of its PRX-102 clinical trials to date, primarily the kidney biopsy results and the eGFR data, that could be included in the potential application for accelerated approval.
·In January 2018, the Company received fast track designation from the FDA for PRX-102.
·In May 2018, the Company reported on the baseline characteristics for its BALANCE phase III clinical trial for the treatment of Fabry disease highlighting that PRX-102 is less inhibited by preexisting neutralizing antibodies compared to Fabrazyme, and, therefore, has the potential to attenuate renal decline and/or stabilize renal function in patients who have not had an optimal clinical response to Fabrazyme.
·In July 2018, the Company expanded its partnership with Chiesi Farmaceutici S.p.A., or Chiesi, to include exclusive U.S. rights for the development and commercialization of PRX-102. The terms of the agreement include an up-front payment of $25 million, up to $20 million in development costs, up to $760 million, in the aggregate, in regulatory and commercial milestone payments and tiered royalties ranging from 15 to 40%.

·In October 2018, the Company presented positive preliminary data from its BRIDGE phase III clinical trial for the treatment of Fabry disease indicating a significant improvement in kidney function in patients switched from agalsidase alfa (Replagal) to PRX-102 at the 1st Canadian Symposium on Lysosomal Diseases.
·In December 2018, the enrollment for the BRIDGE phase III clinical trial for the treatment of Fabry disease was completed.
·As of today, the BALANCE trial is over 80% enrolled and the BRIGHT trial is over 90% enrolled.
·Based on the FDA discussion during our recent meeting we believe that the potential filing for accelerated approval might be based on data the Company has already generated in its clinical trials of PRX-102.
·Currently, substantially all patients treated in the BRIGHT trial have remained on the once-monthly 2mg/kg dosing regimen. All of the 13 patients that have completed the 12-month study have opted, together with their treating physician’s advice, to continue with once-monthly dosing in an extension study rather than switching back to the 1mg/kg every two weeks regimen.

Oral antiTNF (OPRX-106) for Ulcerative Colitis

·Throughout 2018, the Company reported positive results from its phase II clinical trial of OPRX-106 for the treatment of ulcerative colitis. Final results demonstrated as follows:
oclinical response in 67% of patients and clinical remission in 28% of patients;
omucosal improvement in 61% of patients, with 33% achieving mucosal healing; and
o89% of the patients experienced a reduction in Mayo Score, and 61% of the patients experienced a reduction in endoscopic sub score.
·The Company is evaluating the best path forward which could include initiating next-stage development internally or collaborate with potential parties.

Alidornase alfa (PRX-110) for the treatment of Cystic Fibrosis

·In 2018, the Company received valuable feedback on PRX-110 from potential partners. While the data generated to date is very encouraging, further analysis will likely be required to maximize the potential value of this asset. Given the Company’s focused cash utilization, it does not plan to conduct further development of PRX-110 at this time.

Full-Year 2018 Financial Results

·During the preparation of the 2018 annual report, the Company reevaluated its revenue recognition policies and determined that certain revenues generated under the Company’s license agreements should be recognized for accounting purposes. Previously, the Company did not recognize those revenues.

·The Company recognized revenues from license and R&D services equal to $2.2 million, $2.8 million and $11.7 million over the first, second and third quarters of 2018, respectively. The restatement is expected to decrease the Company’s loss for each of those periods.

·The Company recorded total revenues of $34.2 million during the year ended December 31, 2018, which was comprised of $9.0 million from selling goods and $25.2 million from license revenues, compared to $19.2 million from selling goods, and $1.8 million from license and R&D services for the same period of 2017.

·Research and development expenses for the year ended December 31, 2018, were $33.3 million, compared to $28.8 million for the same period of 2017. Selling, general and administrative expenses for the year ended December 31, 2018 were $10.9 million, compared to $11.5 million incurred during the same period of 2017.

·Operating loss for the year ended December 31, 2018 was $19.3 million compared to $34.5 million for the year ended December 31, 2017.

·For the year ended December 31, 2018, the Company reported a net loss of $26.5 million, or $0.18 per share, basic and diluted, compared to $45.4 million, excluding a one-time, non-cash net charge of $38.1 million in connection with the remeasurement of a derivative, or $0.35 per share, basic and diluted, for the same period of 2017.

·On December 31, 2018, the Company had $37.8 million of cash and cash equivalents, compared to $51.2 million on December 31, 2017, which is currently projected to fund operations into mid-2020. As of December 31, 2018, a total of $57.9 million aggregate principal amount of the Company’s 7.5% convertible notes due November 2021 was outstanding.

Conference Call and Webcast Information

The Company will host a conference call on Monday, March 18, 2019, at 8:30 am ET to review the clinical, corporate and financial highlights.

To participate in the conference call, please dial the following numbers prior to the start of the call: United States: +1-844-358-6760; International: +1-478-219-0004. Conference ID number 9583103.

The conference call will also be broadcast live and available for replay for two weeks on the Company’s website, www.protalix.com, in the Events Calendar of the Investors section. Please access the Company’s website at least 15 minutes ahead of the conference to register, download, and install any necessary audio software.

On March 18, 2019 Fortress Biotech, Inc. (NASDAQ: FBIO) ("Fortress"), an innovative biopharmaceutical company focused on identifying, in-licensing and developing high-potential marketed and development-stage drugs and drug candidates, reported financial results and recent corporate highlights for the fourth quarter and full year ended December 31, 2018 (Press release, Fortress Biotech, MAR 18, 2019, View Source [SID1234534421]).

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Lindsay A. Rosenwald, M.D., Fortress’ Chairman, President and Chief Executive Officer, said, "Fortress achieved significant milestones in 2018 and early 2019, closing numerous business development transactions and developing high-quality partnerships with Alexion Pharmaceuticals and InvaGen Therapeutics (a subsidiary of Cipla Limited), which could provide our shareholders with long-term revenue streams. These contingent sale agreements have the potential for combined aggregate proceeds to shareholders of up to $680 million (excluding potential contingent value right ("CVR") amounts based on drug sales). Also in 2018, our seven marketed specialty dermatology products generated net revenue of $23.4 million and $3.8 million in net income. Additionally, Fortress and our development partners, continued to efficiently advance more than 25 development-stage programs across seven therapeutic categories within a streamlined operating structure, allowing us to create value while mitigating risk for our shareholders."

Dr. Rosenwald continued, "2019 is positioned to be a successful year on the business development and partnership fronts. Our world-class business development team continues to identify and in-license high-potential marketed and development-stage assets to further expand our portfolio of product opportunities. We look forward to several important data readouts and the potential for our first New Drug Application ("NDA") filing later this year."

Financial Results1:

·As of December 31, 2018, Fortress’ consolidated cash, cash equivalents, short-term investments (certificates of deposit) and restricted cash totaled $99.2 million, compared to $114.4 million as of September 30, 2018, and $147.0 million as of December 31, 2017, a decrease of $15.2 million for the fourth quarter and a decrease of $47.8 million year-to-date.
·Fortress’ net revenue totaled $26.9 million as of December 31, 2018, compared to $17.2 million as of December 31, 2017, an increase of $9.7 million year-to-date.
·Research and development expenses were $83.3 million for the year ended December 31, 2018, of which $78.5 million was related to partner companies. This compares to $48.3 million for 2017, of which $40.6 million was related to partner companies. Non-cash, stock-based compensation expenses included in research and development were $5.3 million for the year ended December 31, 2018, compared to $4.0 million for 2017.

·Research and development expenses from license acquisitions totaled $4.1 million for the year ended December 31, 2018, compared to $4.2 million for 2017.
·General and administrative expenses were $53.4 million for the year ended December 31, 2018, of which $33.0 million was related to partner companies. This compares to $50.9 million for 2017, of which $31.4 million was related to partner companies. Non-cash, stock-based compensation expenses included in general and administrative expenses were $9.7 million for the year ended December 31, 2018, compared to $9.4 million for 2017.
·Net loss attributable to common stockholders was $84.1 million, or $1.94 per share, for the year ended December 31, 2018, compared to a net loss attributable to common stockholders of $66.9 million, or $1.61 per share, for 2017.

2018 and Recent Corporate Highlights2:

Marketed Dermatology Products

·In 2018, our seven marketed products generated net revenue of $23.4 million and $3.8 million in net income.
·In the fourth quarter of 2018, we launched Exelderm, a cream and solution for fungal infections.
·Also in 2018, we signed a co-promotion agreement with Crown Laboratories to promote Triderm, a topical corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses; Ala-quin, a cream for mixed infections; and Ala-scalp, a hydrocortisone lotion for corticosteroid-responsive dermatoses.
·Additionally, we anticipate launching at least one or two new prescription drugs in 2019.

IV Tramadol

·In May 2018, we announced that the first pivotal Phase 3 trial of IV tramadol achieved the primary endpoint of a statistically significant improvement in Sum of Pain Intensity Difference over 48 hours compared to placebo in patients with moderate to moderately severe postoperative pain following bunionectomy surgery. In addition, the trial met its key secondary endpoints and demonstrated a clear dose response.
·In November 2018, we announced definitive agreements regarding an equity investment and contingent acquisition by InvaGen, a subsidiary of Cipla Limited, a leading pharmaceutical company. The first stage of the transaction closed in February 2019, and InvaGen acquired 5,833,333 shares of Avenue Therapeutics’ common stock at $6.00 per share for total gross consideration of $35.0 million, representing a 33.3% stake in Avenue’s capital stock on a fully diluted basis.
·In December 2018, we announced that the first patient has been dosed in a pivotal Phase 3 clinical trial of IV tramadol for the management of moderate to moderately severe pain in patients following abdominoplasty surgery. Topline data is expected to be available in mid-2019.
·IV Tramadol is currently in development at our partner, Avenue Therapeutics, Inc.

CAEL-101

·In January 2019, Caelum Biosciences, Inc. ("Caelum") signed a collaboration agreement with Alexion Pharmaceuticals, Inc. ("Alexion") to advance the development of CAEL-101. Under the terms of the agreement, Alexion acquired a minority equity interest in Caelum and an exclusive option to acquire the remaining equity in the company based on Phase 2 data for pre-negotiated economics. Alexion will make payments to Caelum totaling $60 million, including the purchase price for the equity and milestone-dependent development funding payments. The collaboration also provides for potential additional payments of up to $500 million, including the upfront, regulatory and commercial milestone payments, in the event Alexion exercises the acquisition option.

·In March 2018, a new analysis of data from the Phase 1b trial of CAEL-101 (mAb 11-1F4), a light chain fibril-reactive monoclonal antibody ("mAb") 11-1F4, for the treatment of relapsed or refractory amyloid light chain ("AL") amyloidosis was presented at the 16th International Symposium on Amyloidosis. The data demonstrated a correlation between a sustained decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and an improvement in global longitudinal strain ("GLS") following CAEL-101 treatment in patients with cardiac AL amyloidosis.
·In June 2018, Caelum announced a complete analysis of cardiac data from a Phase 1b trial of CAEL-101 (mAb 11-1F4) for the treatment of relapsed or refractory AL amyloidosis demonstrating CAEL-101’s potential to improve myocardial function as assessed by GLS and generate a sustained decrease in N-terminal pro-brain natriuretic peptide levels in AL amyloidosis patients experiencing cardiac involvement. Columbia University presented the data at the American Society of Echocardiography’s 29th Annual Scientific Sessions.
·In December 2018, Caelum announced additional GLS data from the Phase 1b study of CAEL-101 in patients with cardiac AL amyloidosis, which further confirmed CAEL-101’s efficiency improving GLS and NT-proBNP. The Company also announced imaging data from a preclinical study that demonstrate the potential of using radiolabeled CAEL-101 for real-time imaging of human amyloidosis in vivo. The data were presented during two oral sessions at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") Annual Meeting.

Triplex

·The multicenter Phase 2 study of Triplex for cytomegalovirus ("CMV") control in allogeneic stem cell transplant recipients has concluded, and its primary endpoint was met. We anticipate the full dataset will be presented at the 45th Annual Meeting of the European Society for Blood and Marrow Transplantation ("EBMT") being held in Frankfurt, Germany March 24-27, 2019.

MB-107 (XSCID Gene Therapy)

·In August 2018, we announced that we entered into an exclusive worldwide license agreement with St. Jude Children’s Research Hospital for the development of a potentially first-in-class ex vivo lentiviral gene therapy for the treatment of X-linked severe combined immunodeficiency (XSCID), also known as bubble boy disease. The therapy is currently being evaluated in a Phase 1/2 multicenter trial in infants under the age of two. This study is the world’s first lentiviral gene therapy trial for infants with XSCID. The therapy is also being investigated in patients over the age of two in a second Phase 1/2 trial at the National Institutes of Health ("NIH"). We believe these may be registration trials.
·MB-107 (XSCID Gene Therapy) is currently in development at our partner, Mustang Bio, Inc.

CK-301 (anti-PD-L1 antibody)

·In March 2018, we completed the dose escalation portion of the ongoing Phase 1 trial of CK-301, a fully human anti-PD-L1 antibody, in selected recurrent or metastatic cancers, and initiated the first dose expansion cohort, which is evaluating an 800 mg dose of CK-301 administered every two weeks.
·In January 2019, we announced that the ongoing multi-center clinical trial of anti-PD-L1 antibody CK-301 was expanded to enroll patients in three endometrial and colorectal cohorts intended to support requests for accelerated approval and Biologics License Application ("BLA") submissions to the FDA. The ongoing trial is also enrolling cohorts of patients with NSCLC and cutaneous squamous cell carcinoma.
·CK-301 (anti-PD-L1 antibody) is currently in development at our partner, Checkpoint Therapeutics, Inc.

CK-101 (third-generation EGFR inhibitor)

·In September 2018, we announced interim safety and efficacy data from our Phase 1/2 clinical trial of CK-101, a third-generation EGFR tyrosine kinase inhibitor ("TKI") being evaluated in advanced non-small cell lung cancer ("NSCLC"). The data were disclosed in an oral presentation at the International Association for the Study of Lung Cancer ("IASLC") 19th World Conference on Lung Cancer in Toronto. CK-101 was well tolerated across multiple dose groups. Durable anti-tumor activity was observed, particularly in treatment-naïve EGFR mutation-positive NSCLC patients.
·In March 2019, we announced two new patent issuances by the U.S. Patent and Trademark Office and the European Patent Office for CK-101. The patents cover CK-101 in the U.S. and Europe through at least August 2034, not including any potential patent term extensions.

·CK-101 (third-generation EGFR inhibitor) is currently in development at our partner, Checkpoint Therapeutics, Inc.

CUTX-101 and AAV-based gene therapy

·In July 2018, we announced that the FDA granted Fast Track Designation to CUTX-101 ("Copper Histidinate"), a product candidate for patients diagnosed with classic Menkes disease who have not demonstrated significant clinical progression. CUTX-101 is currently in a Phase 3 clinical trial.
·In September 2018, we announced the publication of preclinical data on adeno-associated virus (AAV)-based gene therapy combined with subcutaneous CUTX-101 for Menkes disease in Molecular Therapy: Methods & Clinical Development.

MB-102 (CD123 CAR T)

·In July 2018, we completed a pre-Investigational New Drug ("pre-IND") meeting with the U.S. Food and Drug Administration ("FDA") for MB-102 ("CD123 CAR T"). Based on the meeting, we expect to initiate a multicenter Phase 1/2 trial of MB-102 in acute myeloid leukemia ("AML"), blastic plasmacytoid dendritic cell neoplasm ("BPDCN") and high-risk myelodysplastic syndrome in the second half of 2019.
·In November 2018, we announced that additional safety and efficacy Phase 1 data evaluating MB-102 (CD123 CAR) in relapsed or refractory AML and BPDCN were presented in an oral session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Special Conference on Tumor Immunology and Immunotherapy.
·In December 2018, the FDA granted Orphan Drug Designation to MB-102 (CD123 CAR T) for the treatment of BPDCN, a rare and incurable blood cancer. Historically the median survival for BPDCN has been less than 18 months.
·MB-102 (CD123 CAR T) is currently in development at our partner, Mustang Bio, Inc.

MB-101 (IL13Rα2-specific CAR T)

·In May 2018, we announced the publication of preclinical data in JCI Insight demonstrating that glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity over CD8+ CAR T cells. The data, published by research partner City of Hope, will be applied in the ongoing Phase 1 trial of IL13Rα2-specific CAR T MB-101 in glioblastoma.
·MB-101 (IL13Rα2-specific CAR T) is currently in development at our partner, Mustang Bio, Inc.

Oncolytic Virus (C134)

·In February 2019, we announced that we partnered and entered into an exclusive worldwide license agreement with Nationwide Children’s Hospital to develop an oncolytic virus (C134) for the treatment of glioblastoma multiforme. We intend to combine the oncolytic virus with MB-101 (IL13Rα2-specific CAR) to potentially enhance efficacy in treating glioblastoma multiforme.

·C134 (oncolytic virus) is currently in development at our partner, Mustang, Bio, Inc.

MB-103 (HER2-specific CAR T)

·In October 2018, we announced that a first-of-its-kind Phase 1 clinical trial evaluating the safety and effectiveness of intraventricular delivery of CAR T cells to the brains of patients with HER2-positive breast cancer with brain metastases was initiated at City of Hope; the first patient was dosed in December 2018. In addition, we announced that City of Hope dosed the first patient in a Phase 1 clinical trial of HER2-specific CAR T cells in treating recurrent or refractory grade III-IV glioma. The trial is evaluating the side effects and best dose of HER2-specific CAR T cells in treating patients with grade III-IV glioma that has come back or does not respond to treatment.
·MB-103 (HER2-specific CAR T) is currently in development at our partner, Mustang, Bio, Inc.

CK-103 (BET Inhibitor)

·In April 2018, preclinical data was presented on our BET inhibitor, CK-103, at the AACR (Free AACR Whitepaper) Annual Meeting. CK-103 demonstrated combinatorial effects in an in vivo model with anti-PD-1 antibodies, which may support the development of CK-103 as an anti-cancer agent alone and in combination with CK-301.
·CK-103 (BET Inhibitor) is currently in development at our partner, Checkpoint Therapeutics, Inc.

CNDO-109

·In June 2018, data from a Phase 1 trial evaluating CNDO-109-activated allogeneic natural killer ("NK") cells in AML patients were published in the journal Biology of Blood and Marrow Transplantation. The data demonstrated that CNDO-109-activated NK cells are safe, well tolerated and may be capable of extending complete remissions in high-risk AML patients.

AVTS-001 (AAV Gene Therapy)

In January 2018, we entered into a sponsored research agreement with the laboratory of Guangping Gao, Ph.D., at the University of Massachusetts Medical School to evaluate construct optimization for our AAV gene therapy treatment for complement-mediated diseases, including dry age-related macular degeneration, paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.
·In August 2018, we announced that we entered into a sponsored research agreement with the laboratory of Wenchao Song, Ph.D., at the University of Pennsylvania to evaluate our AAV gene therapy technology in the university’s proprietary animal models of complement-mediated diseases.

On March 18, 2019 Array BioPharma Inc. (NASDAQ: ARRY) reported that the National Comprehensive Cancer Network (NCCN) has updated their Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer to include BRAFTOVI in combination with MEKTOVI and an anti-EGFR antibody as a Category 2a treatment for patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), after failure of one or two prior lines of therapy for metastatic disease (Press release, Array BioPharma, MAR 18, 2019, View Source [SID1234534454]). The BRAFV600E mutation is associated with a poor prognosis compared to patients with CRC who do not carry the BRAF mutation, and currently there are no FDA-approved therapies specifically for this high unmet need population. [1-5]

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"With no current FDA-approved therapies for BRAF CRC, this combination represents an important treatment option for this patient population," said Scott Kopetz, M.D., Ph.D., FACP, Associate Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Historical published benchmarks in BRAFV600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy, are an overall response generally between 4% to 8%, a median progression-free survival of 2 to 3 months and median overall survival of 4 to 6 months. The NCCN recommendation underscores the potential for this triplet combination to benefit these patients in critical need."

The NCCN based their recommendation on data from the safety lead-in of the BEACON CRC trial evaluating the triplet combination of BRAFTOVI in combination with MEKTOVI and ERBITUX (cetuximab), in 29 patients with BRAFV600E-mutant mCRC. As presented at the ASCO (Free ASCO Whitepaper) 2019 Gastrointestinal Cancers Symposium (ASCO GI), confirmed overall response rate (ORR) and median progression-free survival (mPFS) results for patients treated with the triplet in the safety lead-in demonstrated 48% ORR (95% CI, 29.4–67.5) and 8 months mPFS (95% CI, 5.6-9.3). ORR by central assessment, 41% (95% CI 24%–61%), was consistent with local assessment. Mature median overall survival (OS) was 15.3 months (95% CI, 9.6–not reached) for patients with BRAF-mutant mCRC treated with the triplet.

"Patients with BRAFV600E-mutant mCRC are in great need of effective treatment options," said Ron Squarer, Chief Executive Officer. "Based on data from the safety lead-in portion of the BEACON CRC Phase 3 trial, the FDA granted Breakthrough Therapy Designation in August 2018 for BRAFTOVI, in combination with MEKTOVI and cetuximab for the treatment of patients with BRAFV600E-mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease. We look forward to the interim analysis of the randomized portion of the trial in the first half of this year."

As presented at ASCO (Free ASCO Whitepaper) GI, the triplet combination was generally well-tolerated with no unexpected toxicities. The most common grade 3 or 4 adverse events seen in at least 10% of patients were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate aminotransferase (10%) and urinary tract infections (10%). The rate of grade 3 or 4 skin toxicities was lower than generally observed with ERBITUX in mCRC.

About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. [6] In the U.S. alone, an estimated 140,250 patients were diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease each year. [7] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and represent a poor prognosis for these patients. [4,8-11] The V600 mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. [4-5] Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established observed historical published benchmarks in BRAFV600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy. These benchmarks include ORR of 4% to 8%, mPFS of 2 to 3 months and median OS of 4 to 6 months. [9-16] BRAFV600E-mutant mCRC is an area of high unmet need as there are currently no FDA-approved therapies specifically indicated for patients with BRAF-mutant mCRC, and these patients derive limited benefit from available chemotherapy regimens. [1-3] For more information about BRAFV600E-mutant mCRC visit www.brafmcrc.com.

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and ERBITUX in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAFV600E-mutant mCRC. Thirty patients were treated in the safety lead-in and received the triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and ERBITUX per label). Of the 30 patients, 29 had a BRAFV600 mutation. Microsatellite instability high, resulting from defective DNA mismatch repair, was detected in only 1 patient. As previously announced, the triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial. The randomized portion of the BEACON CRC trial is designed to assess the efficacy of BRAFTOVI in combination with ERBITUX with or without MEKTOVI compared to ERBITUX and irinotecan-based therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet combination, doublet combination (BRAFTOVI and ERBITUX) or the control arm (irinotecan-based therapy and ERBITUX). The study has been amended to include an interim analysis of endpoints including ORR. The primary overall survival endpoint is a comparison of the triplet combination to the control arm. Secondary endpoints address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include PFS, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial is being conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. The BEACON CRC trial is being conducted with support from Ono Pharmaceutical Co. Ltd., Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC is investigational and not approved by the FDA.

About BRAFTOVI + MEKTOVI
BRAFTOVI is an oral small molecule BRAF kinase inhibitor and MEKTOVI is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer and others. In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. In Europe, the combination is approved for adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation, as detected by a validated test. In Japan, the combination is approved for unresectable melanoma with a BRAF mutation.

Array has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and Canada. Array has granted Ono Pharmaceutical Co. Ltd., exclusive rights to commercialize both products in Japan and South Korea, Medison exclusive rights to commercialize both products in Israel and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Latin American and Asia (excluding Japan and South Korea).

BRAFTOVI + MEKTOVI have received regulatory approval in the United States, European Union, Australia and Japan. The Swiss Medicines Agency (Swissmedic) is currently reviewing the Marketing Authorization Applications for BRAFTOVI and MEKTOVI submitted by Pierre Fabre.

Indications and Usage
BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma.

BRAFTOVI + MEKTOVI Important Safety Information
The information below applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

Warnings and Precautions
New Primary Malignancies: Cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or V600K mutation prior to initiating BRAFTOVI.

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. Cardiomyopathy resolved in 87% of patients. Assess left ventricular ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. Safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal. Patients with cardiovascular risk factors should be monitored closely.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥ Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients. Assess for visual symptoms at each visit. Perform ophthalmological evaluation at regular intervals and for any visual disturbances, and to follow new or persistent ophthalmologic findings.

Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT) and 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. Monitor liver laboratory tests before and during treatment and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum creatine phosphokinase (CPK) occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated.

QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms.

Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.

Adverse Reactions
The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial): were fatigue, nausea, diarrhea, vomiting, abdominal pain, arthralgia, myopathy, hyperkeratosis, rash, headache, constipation, visual impairment, serous retinopathy.

In the COLUMBUS trial, the most common laboratory abnormalities (≥20%, all Grades): included increased creatinine, increased CPK, increased gamma glutamyl transferase, anemia, increased ALT, hyperglycemia, increased AST, and increased alkaline phosphatase.

Drug Interactions
Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided. Avoid co-administration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information. [17-18] You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Array at 1-844-Rx-Array (1-844-792-7729).