On March 19, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) reported its financial results for the fourth quarter and year ended December 31, 2018 as well as provided corporate and operational updates on clinical trials, research and development, recent hires, and intellectual property (Press release, Actinium Pharmaceuticals, MAR 19, 2019, View Source [SID1234534474]).

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Company Highlights:

Presented interim Phase 3 SIERRA trial data at the 2018 ASH (Free ASH Whitepaper) and 2019 TCT Meetings. The SIERRA trial (Study of Iomab-B in Elderly Relapsed or Refractory AML) is a 150-patient pivotal Phase 3 multi-center randomized trial that will compare outcomes of patients who receive Iomab-B and a BMT or Bone Marrow Transplant to those patients receiving physician’s choice of salvage chemotherapy, defined as conventional care, as no standard of care exists for this patient population. Key highlights from the SIERRA Trial presented at ASH (Free ASH Whitepaper) and the TCT Meetings include:
All patients receiving a therapeutic dose of Iomab-B engrafted despite active disease with high blast count (median 30%, or median 45% for crossover patients)
15 of 19 (79%) patients in the control arm failed to achieve a complete response
67% (10/15) of patients eligible for crossover successfully transplanted after Iomab-B treatment
All patients receiving Iomab-B and a BMT (28/28) achieved Donor Chimerism prior to day 100
94% of patients initially randomized to receive Iomab-B and a BMT (17/18) achieved Full Donor Chimerism > 95% prior to day 100 with 1 patient achieving 65% donor chimerism
90% of patients who crossed-over to receive Iomab-B and a BMT (9/10), after salvage chemotherapy in the control arm failed to produce a CR or Complete Response, also achieved Full Donor Chimerism > 95% prior to day 100 with 1 patient achieving 86% donor chimerism
The SIERRA trial is currently enrolling patients at 18 sites in the U.S and Canada including many of the leading BMT sites based on volume. Patients with active, relapsed or refractory AML have dismal prognoses and are typically not offered potentially curative transplant as an option, largely because salvage treatments have a limited ability to produce a complete remission, which is necessary prior to conventional BMT if conventional BMT is to be successful. However, with Iomab-B targeted conditioning, a complete remission prior to starting the Iomab-B conditioning is not necessary for a successful transplant. Iomab-B is an ARC or Antibody Radiation-Conjugate that targets CD45, an antigen expressed on leukemia, lymphoma and immune cells, and delivers Iodine-131 that kills targeted cells via linear energy transfer. Key highlights from the SIERRA Trial presented at ASH (Free ASH Whitepaper) and the TCT Meetings include:

Initiated Actimab-A venetoclax combination trial. This novel Phase 1/2 trial will study Actimab-A in combination with venetoclax for patients with relapsed or refractory AML or Acute Myeloid Leukemia. Venetoclax is a BCL-2 or B-Cell Lymphoma 2 inhibitor, BCL-2 is one of several proteins encoded by the BCL2 gene family, which regulates apoptosis or programmed cell death. Venetoclax is jointly developed and marketed by AbbVie and Genentech and is approved for patients with CLL or Chronic Lymphocytic Leukemia, and SLL or Small Lymphocytic Leukemia and AML with an HMA or hypomethylating agent.
Response rates of relapsed or refractory patients with AML to venetoclax as a single agent have been reported to be 19%. In a recent webinar, Actinium highlighted that one study observed that of 21 relapsed or refractory AML patients that responded to venetoclax and an HMA, 13 (62%) stopped venetoclax treatment with disease progression being the most common reason for discontinuation. The study also observed that no patients with secondary AML responded to treatment with venetoclax and patients with FLT3 mutations had lower response rates.

MCL-1 is another protein encoded by the BCL2 gene family that is also overexpressed in cancers, including relapsed or refractory AML, that prevents apoptosis and promotes resistance to venetoclax, which does not bind to MCL-1. It has been observed that MCL-1 levels can be depleted with radiation, but only external radiation was used in these studies. Actinium is studying the use of targeted internalized radiation from Actimab-A to deplete MCL-1 levels thereby removing the AML cells’ resistance mechanism and rendering them more susceptible to venetoclax. Actimab-A is an ARC that delivers internalized radiation from the alpha-particle emitting isotope Ac-225 or Actinium-225 via the CD33 targeting monoclonal antibody lintuzumab

Actinium is conducting this combination study with the goal of offering a therapy to patients that do not respond or stop responding to venetoclax. In addition to the potential to deplete MCL-1 levels, Actimab-A’s radiation mechanism of action is agnostic to cytogenetic mutations and has shown to produce responses in patients with secondary AML. Actinium is also planning a Phase 1/2 trial that will study Actimab-A in combination with venetoclax and a hypomethylating agent. This triplet trial will also enroll patients with relapsed or refractory AML and is expected to initiate in the first half of 2019.

Advanced to second patient cohort in Actimab-A CLAG-M trial. Actinium is also studying Actimab-A in combination with the salvage chemotherapy regimen CLAG-M (cladribine, cytarabine, filgrastim, and mitoxantrone) in patients with relapsed or refractory AML. Chemotherapy and radiation are routinely used in combination together with a majority of patients receiving external beam radiation. However, patients with AML are not treated with external radiation as the diffuse nature of the disease prohibits therapeutic levels of radiation from being used due to safety and toxicity concerns. Ac-225 is a potent isotope capable of causing lethal double stranded breaks in cell DNA but its energy is limited to a few cell diameters. CD33 is an antigen expressed on the surface of a vast majority of AML cells. This trial is evaluating the effect targeted internalized radiation via Actimab-A will have in combination with CLAG-M on safety and tolerability, response rates, rates of BMT, PFS or progression-free survival, and OS or overall survival.
In the first dose cohort, patients received 0.25 uCi/kg of Actimab-A. This combination trial is designed as a 3+3 dose escalation study. No DLT’s or dose limiting toxicities were reported in the first patient cohort. As a result, and per the study protocol, the Institutional Review Board (IRB) at MCW authorized the initiation of the second dosing cohort, in which patients are receiving 0.50 uCi/kg of Actimab-A. Assuming no DLTs are observed in the second cohort, three patients will be treated and the study will progress to the third and final cohort that will study Actimab-A at a dose of 0.75 uCi/kg.

Advanced to second module of collaborative research program with Astellas Pharma, Inc. (Astellas). The Company’s previously announced research collaboration with Astellas is using its AWE or Antibody Warhead Enabling technology platform to conjugate and label select Astellas targeting agents with the potent Ac-225 payload. In January 2019, Actinium announced that it completed the first module of the collaboration and the second module had been initiated. Since launching its AWE Program in November 2017, Actinium has achieved the following milestones:
Appointed Dr. Dale Ludwig, a leading antibody therapeutics and antibody conjugate expert, as Chief Scientific Officer
Presented positive data at ASH (Free ASH Whitepaper) 2017 demonstrating the superior in vitro cell killing properties of Ac-225 labeled daratumumab or Darzalex, Johnson & Johnson’s blockbuster CD38 targeting therapy for multiple myeloma
Presented additional positive data from in vivo animal studies at AACR (Free AACR Whitepaper) 2018 demonstrating enhanced tumor control and survival with Ac-225 labeled daratumumab
Significantly strengthened senior leadership team in core areas. Appointed Cynthia Pussinen as Executive Vice President of Technical Operations and Supply Chain. Ms. Pussinen brings 25 years of highly relevant experience to Actinium gained at Pfizer and Ipsen Biosciences, Inc. Most recently, she was Head of Strategic Portfolio Management, Worldwide Research & Development. In this role she led efforts to maximize the value of Pfizer’s pre-Proof of Concept portfolio across 6 research units, including driving pipeline decision making, portfolio prioritization and clinical portfolio investment efforts across the R&D organization. Previously, President and General Manager of Ipsen Biosciences, Inc. where she led the operational and strategic directions of this subsidiary company, including maintaining an annual operating budget of more than $100 million, and managing two sites with more than 220 employees.
Appointed Qing Ling, PhD, DABR to newly created position of Vice President, Head of Radiation Sciences. This newly created position will drive innovation in line with Actinium’s strategic vision related to its AWE technology platform. Dr. Liang will collaborate closely with clinical trial sites and their staffs, regulators and other key stakeholders to help advance and optimize Actinium’s clinical ARC programs to deliver the best possible outcomes for patients. Dr. Liang is a Medical Physicist certified by the American Board of Radiology and prior to Actinium was Medical Physicist and Assistant Professor at Fox Chase Cancer Center at Temple University (Philadelphia, PA). Prior to that, she had worked at Mercy Health System (Janesville, WI), Turville Bay MRI & Radiation Oncology (Madison, WI), University of Wisconsin Hospital (Madison, WI), and UW Accredited Dosimetry Calibration Laboratory (Madison, WI).

Appointed Mamata Gokhale, PhD, RAC as Vice President, Global Head of Regulatory Affairs. Dr. Gokhale brings over 20 years of regulatory affairs experience to Actinium that began at the FDA as a reviewer before transitioning to industry where she worked at biotechnology and pharma companies including Amgen, Watson Pharma, Neumedicines Inc. and global Contract Research Organizations including Voisin Consulting Life Sciences and Paraxel International. At Amgen Dr. Gokhale successfully contributed to approvals and expansion of Prolia , Xgeva , Vectibix and Sensipar . Dr. Gokhale’s regulatory experience includes developing regulatory strategies for small molecules, monoclonal antibodies, cell and gene therapies, leading and managing regulatory interactions, requesting orphan drug, breakthrough therapy and fast track designations and pediatric vouchers, resolution of clinical hold issues, developing target product profiles, core data sheets and conducting labeling negotiations.

Significantly expanded patent portfolio. Through rejuvenated R&D activity Actinium’s patent portfolio has increased to a total of 111 issued and pending patents in the U.S. and internationally, which is up from the 75 reported previously. This intellectual property portfolio, contained within 28 patent families, covers key areas of Actinium’s business. The estate covers ARC generation, composition of matter, formulations, and methods of administration for solid and liquid cancers as well as radionuclide production including the manufacturing of Ac-225 or Actinium-225. Actinium’s recent patent filings pertain to its planned pivotal Actimab-MDS targeted conditioning trial, ARC combination trials of Actimab-A with venetoclax and CLAG-M, as well as its next-generation ARC’s resulting from its AWE technology platform. These follow recent patent filings from Actinium related to its Iomab-ACT next generation lymphodepletion program for CAR-T and adoptive cell therapies that includes four pending patents and one provisional patent application for cancer and non-malignant diseases. These new filings are in addition to Actinium’s broad intellectual property and patent portfolio that cover direct labeling, or conjugation and labeling of a biomolecular targeting agent to a radionuclide warhead, and its development and use as a therapeutic regimen for the treatment of diseases such as cancer. Actinium has patents on the use of the "gold standard" chelator DOTA, an organic compound used to attach, or conjugate, the radionuclide Ac-225 to monoclonal antibodies and any conceivable derivative thereof, as well key patents covering the manufacturing of Ac-225 in a cyclotron. In addition, Actinium extensive know-how and trade secrets in the application of its AWE technology platform to support its existing pipeline and potential collaborations.
Research and development expenses for the year ended December 31, 2018 declined by $0.7 million to $17.0 million compared to $17.7 million for the year ended December 31, 2017. The decrease was primarily attributable to the recognition of payments received from Astellas, with such payments accounted for as a reduction in research and development expenses, as well as lower expenses related to Actimab-A and lower non-cash stock-based compensation expense.
General and administrative expenses declined by $2.5 million to $6.7 million for the year ended December 31, 2018 compared to $9.2 million for the year ended December 31, 2017, primarily due to lower compensation expense, resulting from lower non-cash stock-based compensation expense during 2018 and one-time charges paid to certain former employees in 2017.

Actinium reported a cash and cash equivalent balance of $13.6 million as of December 31, 2018. In its Annual Report of Form 10-K which was filed with the Securities and Exchange Commission on March 15, 2018, the Company’s audited financial statements contained a going concern explanatory paragraph in the audit opinion from Marcum LLP, its independent registered public accounting firm.

Net loss decreased by $2.9 million to $23.7 million for the year ended December 31, 2018 compared to $26.6 million for the year ended December 31, 2017. The decrease was primarily due to lower general and administrative expenses and research and development expenses.

Upcoming Conferences
Actinium’s management will present at the Oppenheimer & Co. 29th Annual Healthcare Conference, being held March 19-20. The details of Actinium’s presentation are as follows:

Presentation Details:
Date: Wednesday, March 20, 2019
Time: 1:35 pm Eastern Time
Room: Consulate
Venue: Westin Grand Central Hotel in New York City

In addition, members of Actinium’s executive, clinical, R&D, commercial and CMC teams will be attending the AACR (Free AACR Whitepaper) or American Association of Cancer Research Annual Meeting being held March 29 – April 3 at the Georgia World Congress Center in Atlanta, Georgia and the TAT or 11th International Symposium on Targeted-Alpha-Therapy being held April 1 – 4 at the Fairmont Chateau Laurier in Ottawa, Canada.

On March 19, 2019 I-Mab Biopharma (I-Mab), a China-based clinical stage biopharmaceutical company exclusively focused on the development of innovative biologics in immuno-oncology and autoimmune diseases, and German biopharma company MorphoSys AG (FSE: MOR; Prime Standard Segment, MDAX & TecDAX;NASDAQ: MOR), reported that the first patient dosing (FPD) has been achieved in a phase 2 multi-center clinical study in Taiwan to evaluate an investigational human CD38 antibody TJ202/MOR202 in patients with relapsed or refractory multiple myeloma (Press release, I-Mab Biopharma, MAR 19, 2019, View Source [SID1234534473]). TJ202/MOR202 is an antibody developed by MorphoSys AG. I-Mab owns the exclusive rights for development and commercialization of TJ202/MOR202 in mainland China, Hong Kong, Macao and Taiwan.

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"Advancing TJ202/MOR202 into a late stage phase 2 trial is a significant achievement," said Dr. Joan Shen, M.D., Head of R&D at I-Mab. "We expect that, if approved, TJ202/MOR202 may provide multiple myeloma patients with an important biologics treatment option with its unique benefit that addresses the underlying pathology of the second most common blood cancer worldwide."

The dosing of the first patient triggers a milestone payment of USD 5 million to MorphoSys.

Under I-Mab’s fast-to-market development strategy, the study has been designed as a pivotal trial, which, if successful, could lead to a biologics license application (BLA) in Greater China. The multi-center, single-arm, phase 2 study will be conducted in mainland China and Taiwan to evaluate the efficacy and safety of TJ202/MOR202 in combination with dexamethasone in patients with relapsed or refractory multiple myeloma who have previously received at least two prior lines of treatment. The primary endpoint is to evaluate the objective response rate.

"We are delighted that our partner I-Mab has taken this important step in advancing TJ202/MOR202 into pivotal clinical development in Asia. We see a high medical need for the treatment of patients with multiple myeloma in the Greater China region and look forward to supporting I-Mab in developing this investigational compound for these patients," said Dr. Malte Peters, Chief Development Officer of MorphoSys AG.

With MorphoSys’s support through a licensing agreement in November 2017, I-Mab is currently leading the clinical development of TJ202/MOR202 in Greater China, which includes mainland China, Hong Kong, Macao and Taiwan. In addition to Taiwan, I-Mab has filed an investigational new drug (IND) application to China’s National Medical Products Administration in August 2018.

It should be noted that the recent court decision of the United States (U.S.) District Court of Delaware (1:16-cv-00221-LPS-CJB) has no bearing on the validity and scope of the patents exclusively licensed by I-Mab from MorphoSys AG, whose exclusivity provides protection for I-Mab’s development and commercialization of MOR202 in the Greater China region.

About TJ202/MOR202

TJ202/MOR202 is an investigational human monoclonal antibody derived from MorphoSys’s HuCAL antibody technology. The antibody is directed against CD38 on the surface of multiple myeloma cells, which has been characterized as one of the most strongly and uniformly expressed antigens on the surface of malignant plasma cells. According to its suggested mode of action, the antibody recruits cells of the body’s immune system to kill the tumor through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). The antibody does not involve complement dependent cytotoxicity, or CDC, an additional immune mechanism involved in tumor cell killing. Scientific researches suggest that an anti-CD38 antibody may have therapeutic potential also in other cancers as well as autoimmune diseases. Based on a licensing agreement between MorphoSys and I-Mab signed in November 2017, I-Mab owns the exclusive rights for development and commercialization of TJ202/MOR202 in mainland China, Taiwan, Hong Kong and Macao.

On March 19, 2019 Merck KGaA, Darmstadt, Germany, which operates its biopharmaceutical business as EMD Serono in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported the discontinuation of the ongoing Phase III JAVELIN Ovarian PARP 100 study evaluating the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with talazoparib,* a poly (ADP-ribose) polymerase (PARP) inhibitor, versus an active comparator in treatment-naïve patients with locally advanced or metastatic ovarian cancer (Stage III or Stage IV) (Press release, Merck KGaA, MAR 19, 2019, View Source [SID1234534472]). The alliance has notified health authorities and trial investigators of the decision to discontinue the trial.

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The decision was based on several emerging factors since the trial’s initiation, including the previously announced interim results from JAVELIN Ovarian PARP 100. The alliance determined that the degree of benefit observed with avelumab in frontline ovarian cancer in that study does not support continuation of the JAVELIN Ovarian PARP 100 trial in an unselected patient population and emphasizes the need to better understand the role of immunotherapy in ovarian cancer. Additional factors include the rapidly changing treatment landscape and the approval of a PARP inhibitor in the frontline maintenance setting. The decision to discontinue the JAVELIN Ovarian PARP 100 trial was not made for safety reasons.

The alliance between Merck KGaA, Darmstadt, Germany, and Pfizer was the first to test an immunotherapy in this indication, given the significant unmet need in the treatment of ovarian cancer. Four out of five women with ovarian cancer are diagnosed with disease that has spread to the lymph nodes or to distant organs.1 Most women with advanced ovarian cancer ultimately die within five years due to refractory, resistant or recurrent disease.2,3

JAVELIN Ovarian PARP 100 (B9991030) is an open-label, international, multi-center, randomized study designed to evaluate the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with talazoparib versus an active comparator in treatment-naïve patients with locally advanced or metastatic ovarian cancer (Stage III or Stage IV). The primary endpoint is progression-free survival (PFS) as determined based on blinded independent central review (BICR) assessment per RECIST v1.1.

The decision to discontinue the JAVELIN Ovarian PARP 100 trial does not impact the currently approved indications for avelumab or the remainder of the ongoing JAVELIN clinical development program. The program involves at least 30 clinical programs and more than 9,000 patients evaluated across more than 15 different tumor types, including breast, gastric/gastro-esophageal junction, and head and neck cancers, Merkel cell carcinoma, non-small cell lung cancer, and urothelial carcinoma.

*Avelumab and talazoparib are under clinical investigation for the treatment of advanced ovarian cancer and have not been demonstrated to be safe and effective for this use.

About Avelumab (BAVENCIO)

Avelumab (BAVENCIO) is a human anti-programmed death ligand-1 (PD-L1) antibody. Avelumab has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, avelumab has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.4-6 Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.6-8 In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Approved Indications in the US

In the US, the FDA granted accelerated approval for avelumab (BAVENCIO) for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Avelumab is currently approved for patients with MCC in more than 45 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.

Important Safety Information from the BAVENCIO US FDA-Approved Label

BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis, and permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥ 3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

Please see full US Prescribing Information and Medication Guide available at View Source

Indication for talazoparib (TALZENNA) from the US Prescribing Information

TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA.

Important Safety Information from the TALZENNA US Prescribing Information

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been reported in patients who received TALZENNA. Overall, MDS/AML have been reported in 2 out of 584 (0.3%) solid tumor patients treated with TALZENNA in clinical studies.

Myelosuppression consisting of anemia, leukopenia/neutropenia, and/or thrombocytopenia have been reported in patients treated with TALZENNA. Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 39%, 21%, and 15% of patients receiving TALZENNA. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 0.7%, 0.3%, and 0.3% of patients.

Monitor complete blood counts for cytopenia at baseline and monthly thereafter. Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. If hematological toxicity occurs, dose modifications (dosing interruption with or without dose reduction) are recommended. With respect to MDS/AML, for prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If the levels have not recovered after 4 weeks, refer the patient to a hematologist for further investigations. If MDS/AML is confirmed, discontinue TALZENNA.

TALZENNA can cause fetal harm when administered to pregnant women. Advise women of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose. A pregnancy test is recommended for females of reproductive potential prior to initiating TALZENNA treatment. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with TALZENNA and for at least 4 months after receiving the last dose. Based on animal studies, TALZENNA may impair fertility in males of reproductive potential. Advise women not to breastfeed while taking TALZENNA and for at least 1 month after receiving the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥20%) of any grade for TALZENNA vs chemotherapy were fatigue (62% vs 50%), anemia (53% vs 18%), nausea (49% vs 47%), neutropenia (35% vs 43%), headache (33% vs 22%), thrombocytopenia (27% vs 7%), vomiting (25% vs 23%), alopecia (25% vs 28%), diarrhea (22% vs 26%), and decreased appetite (21% vs 22%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) for TALZENNA vs chemotherapy were anemia (39% vs 5%), neutropenia (21% vs 36%), and thrombocytopenia (15% vs 2%).

The most common lab abnormalities (≥25%) for TALZENNA vs chemotherapy were decreases in hemoglobin (90% vs 77%), leukocytes (84% vs 73%), lymphocytes (76% vs 53%), neutrophils (68% vs 70%), platelets (55% vs 29%), and calcium (28% vs 16%) and increases in glucose (54% vs 51%), aspartate aminotransferase (37% vs 48%), alkaline phosphatase (36% vs 34%), and alanine aminotransferase (33% vs 37%).

Coadministration with P-gp inhibitors or BCRP inhibitors may increase TALZENNA exposure. If coadministering with the P-gp inhibitors amiodarone, carvedilol, clarithromycin, itraconazole, or verapamil is unavoidable, reduce the TALZENNA dose to 0.75 mg once daily. When the P-gp inhibitor is discontinued, increase the TALZENNA dose (after 3–5 half-lives of the P-gp inhibitor) to the dose used prior to the initiation of the P-gp inhibitor. When co-administering TALZENNA with other known P-gp inhibitors or BCRP inhibitors, monitor patients for potential increased adverse reactions.

For patients with moderate renal impairment, the recommended dose of TALZENNA is 0.75 mg once daily. No dose adjustment is required for patients with mild renal impairment. TALZENNA has not been studied in patients with severe renal impairment or in patients requiring hemodialysis.

TALZENNA has not been studied in patients with moderate or severe hepatic impairment. No dose adjustment is required for patients with mild hepatic impairment.

Please see full US Prescribing Information available at View Source

Alliance between Merck KGaA, Darmstadt, Germany, and Pfizer Inc., New York, US

Immuno-oncology is a top priority for Merck KGaA, Darmstadt, Germany, and Pfizer. The global strategic alliance between Merck KGaA, Darmstadt, Germany, and Pfizer enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of BAVENCIO, an anti-PD-L1 antibody initially discovered and developed by Merck KGaA, Darmstadt, Germany. The immuno-oncology alliance is jointly developing and commercializing BAVENCIO. The alliance is focused on developing high-priority international clinical programs to investigate BAVENCIO as a monotherapy as well as combination regimens, and is striving to find new ways to treat cancer.

All Merck KGaA, Darmstadt, Germany, press releases are distributed by e-mail at the same time they become available on the EMD Group Website. In case you are a resident of the USA or Canada please go to www.emdgroup.com/subscribe to register again for your online subscription of this service as our newly introduced geo-targeting requires new links in the email. You may later change your selection or discontinue this service.

On March 19, 2019 SOTIO, a biotechnology company owned by the PPF Group, reported results from SOV02, its Phase II clinical trial evaluating DCVAC/OvCa, an active cellular immunotherapy product, in patients with recurrent ovarian cancer at 2019 SGO’s 50th Annual Meeting on Women’s Cancer today (Press release, SOTIO, MAR 19, 2019, View Source [SID1234534471]). Final analysis of SOV02 shows that DCVAC/OvCa decreased the risk of death significantly compared to patients who did not receive DCVAC/OvCa. Clinical trial results were presented during today’s SGO 2019 Plenary Session by SOV02 principal investigator David Cibula, MD, PhD from General University Hospital in Prague (Czech Republic).

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In the randomized, open label SOV02 clinical trial, patients with recurrent ovarian cancer received DCVAC/OvCa in combination with platinum-based chemotherapy. Compared to patients who did not receive DCVAC, it decreased the risk of death by 62%. The combination of chemotherapy and immunotherapy corresponded with 73% survival at two years, compared to 41% survival when chemotherapy was used alone. Overall survival results are statistically significant with a p-value of 0.0032. Progression Free Survival (PFS) increased from 9.5 to 11.3 months. Treatment with DCVAC/OvCa was very well tolerated and did not lead to any treatment discontinuation.

"Results from final data analysis of SOV02 clinical trial show that patients with recurrent ovarian cancer treated with DCVAC/OvCa are living significantly longer than patients in the control group. This outcome stands out very positively in this highly competitive clinical development landscape," said David Cibula, MD, PhD, General University Hospital (Prague, Czech Republic), Past-President of European Society of Gynaecological Oncology (ESGO), principal investigator of SOV02 study.

Radek Spisek, MD, PhD, Chief Executive Officer of SOTIO commented: "We are very happy that the results of SOV02 study in the second line treatment of ovarian cancer confirm the promising data of SOV01 trial in the first line, reported at ASCO (Free ASCO Whitepaper) 2018. In cooperation with ENGOT, we are now setting up the design of the pivotal trial that will build on the results of the Phase II program. With the development of DCVAC/OvCa and the latest result we are addressing the medical need in this harmful disease."

More information and details about the SOV02 clinical trial results can be found in the slides from the oral presentation at SGO 2019 posted on SOTIO’s webpage.

About SOV02 clinical trial:
SOV02 is a randomized, open-label, parallel-group, multi-center Phase II clinical trial evaluating the effect of adding DCVAC/OvCa to standard chemotherapy (carboplatin and gemcitabine) in women with first relapse of platinum-sensitive epithelial ovarian cancer.

On March 19, 2019 Bristol-Myers Squibb Company (NYSE: BMY) reported that it has filed a new investor presentation with the Securities and Exchange Commission (SEC) in connection with its previously announced definitive merger agreement with Celgene Corporation (NASDAQ: CELG) (Press release, Bristol-Myers Squibb, MAR 19, 2019, View Source [SID1234534470]).

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The investor presentation is available on the SEC’s website at www.SEC.gov and on Bristol-Myers Squibb’s website at View Source Highlights of the presentation include:

The Celgene acquisition is a financially and strategically compelling transaction.
Enhanced product leadership and pipeline: The combined company will be #1 in oncology, #1 in cardiovascular, and top 5 in immunology and inflammation with nine current products over $1 billion in annual sales, six near-term launches, and robust early-stage pipeline and cutting edge technologies and discovery platforms;
Attractive value: Value of approximately $55 billion from marketed products and in excess of $20 billion from synergies implies that the Celgene pipeline was acquired for a highly attractive price when compared to the aggregate purchase price of $90 billion;
Ideal timing: Trading ratio at two-year lows and Celgene P/E near an all-time low when deal was announced;
Sustainable financial strength: Sales and earnings projected to grow every year through 2025; Significant margin improvement of approximately 800 basis points to 36% on a 2018 pro forma basis before the impact of cost synergies compared to 28% on a standalone basis.
Bristol-Myers Squibb has generated a track-record of financial and operational outperformance.
Strong operating performance drives long-term value creation: Five year CAGRs for net revenue and adjusted EPS of 7% and 17%, respectively, both in excess of peer median, with adjusted operating margin up 725 basis points over that time period. Bristol-Myers Squibb has met or exceeded top line and EPS guidance and estimates on an annual basis each year since 2013;
Industry-leading commercialization: Opdivo is one of the most successful commercial oncology launches and has a leadership position in 16 FDA approved indications and delivered $6.7 billion in 2018 sales, up 36% year-over-year. Additionally, Eliquis is the #1 world-wide novel anti-coagulant despite being the third entrant to market and generated $6.4 billion in 2018 sales, up 32% year-over-year;
Portfolio transition success: Transitioned portfolio through multiple Losses of Exclusivity over the last five years, with approximately 60% of 2018 sales coming from new products launched during that period.
The transaction is the result of a robust process characterized by strong oversight, extensive diligence and focused planning.
Comprehensive process: Prioritized more than 20 transformational and ‘string-of-pearls’ opportunities, and Celgene selected as most attractive opportunity;
Thorough Board oversight: Consistent Board involvement throughout process, with eight meetings to discuss Celgene opportunity;
Extensive diligence: Six-month deep-dive analysis and five subsequent weeks of confidential due diligence provided comprehensive view of Celgene’s opportunities and risks;
Focused and committed to a successful integration: Complementary nature of businesses, strong team in place to manage integration and rigorous planning approach.
The Bristol-Myers Squibb Board unanimously recommends that Bristol-Myers Squibb shareholders vote their shares "FOR" the approval of the issuance of shares of the Company’s common stock in connection with our proposed acquisition of Celgene prior to the Special Meeting, which will be held on April 12, 2019. All Bristol-Myers Squibb shareholders of record as of the close of business on March 1, 2019 will be entitled to vote their shares.

Bristol-Myers Squibb urges shareholders to discard any blue proxy cards and disregard any related solicitation materials sent to you by Starboard Value LP, which is soliciting proxies from Bristol-Myers Squibb shareholders against approving the merger. Irrespective of whether shareholders previously submitted a blue proxy card pertaining to the proposals contained in Bristol-Myers Squibb’s definitive proxy statement, the Company urges shareholders to cast their vote on the WHITE proxy card "FOR" the proposal to approve the transaction.