On February 23, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US (known as MSD outside the US and Canada) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion, recommending a marketing authorisation of Lynparza (olaparib) tablets (300mg twice daily) for use as a maintenance therapy for patients with platinum-sensitive relapsed high grade, epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response or partial response to platinum-based chemotherapy (Press release, AstraZeneca, FEB 23, 2018, View Source [SID1234524132]). Lynparza is recommended for treatment in this setting regardless of patients’ BRCA mutation status.

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Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "The data show that Lynparza provides long-term disease control, delaying the need for further chemotherapy for this broader group of women with platinum-sensitive relapsed ovarian cancer, irrespective of their BRCA status. It also offers a well-characterised safety and tolerability profile, which is critical to help enable patients to stay on treatment."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "We welcome this positive opinion based upon data which indicate the potential impact for Lynparza as maintenance therapy for women with platinum-sensitive relapsed ovarian cancer. We look forward to our continued work with AstraZeneca to bring Lynparza to patients in the EU."

The CHMP recommendation is based on two randomised trials, SOLO-2 and Study 19, which showed Lynparza reduced the risk of disease progression or death for platinum-sensitive relapsed patients compared to placebo.

Summary of key efficacy results from randomised trials:

Analysis

SOLO-2

[germline BRCA-mutated]

n=295

Study 19

[platinum-sensitive relapsed]

n=265

Lynparza

Placebo

Lynparza

Placebo

Reduction in the risk of disease progression or death (PFS)

70%

(HR 0.30 [95% CI, 0.22-0.41], P<0.0001; median 19.1 vs 5.5 months)*

65%

(HR 0.35 [95% CI, 0.25-0.49], P<0.0001; median 8.4 vs 4.8 months)*

Reduction in the risk of death (OS)

Data not yet mature

27%

(HR 0.73 [95% CI, 0.55-0.95], P=0.02138**;

median 29.8 vs 27.8 months)***

PFS = progression-free survival; OS = overall survival

* By investigator-assessed analysis
** P-value considered nominal as criterion for statistical significance (P<0.0095) not met
*** Not adjusted for treatment crossover

The most frequently observed adverse reactions across clinical trials in patients receiving Lynparza monotherapy (≥ 10%) were nausea, vomiting, diarrhoea, dyspepsia, fatigue, headache, dysgeusia, decreased appetite, dizziness and anaemia.

Lynparza, the first poly ADP-ribose polymerase (PARP) inhibitor approved, was initially licensed as a capsule formulation. The new tablet formulation will reduce dosing from 8 capsules twice daily to 2 tablets twice daily.

Lynparza is available in nearly 60 countries and has treated more than 20,000 patients globally. It has the broadest clinical development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to bring Lynparza to more patients across multiple cancers. In January 2018, Lynparza was approved by the US FDA for use in metastatic breast cancer, becoming the first PARP inhibitor licensed beyond ovarian cancer.

NOTES TO EDITORS
About Ovarian Cancer in Europe

Among women in Europe, ovarian cancer is the fifth most common cancer and the sixth leading cause of cancer death. The five-year survival rate for ovarian cancer in Europe is 38%. In 2012, there were nearly 65,000 new cases diagnosed and around 42,700 deaths. As there is no cure for relapsed ovarian cancer, the primary aim of treatment is to slow progression of the disease for as long as possible and improve or maintain the patient’s quality of life.

About SOLO-2

SOLO-2 was a Phase III, randomised, double-blinded, multicentre trial designed to determine the efficacy of Lynparza tablets compared to placebo as maintenance monotherapy in patients with platinum-sensitive relapsed or recurrent germline BRCA-mutated ovarian, fallopian tube and primary peritoneal cancer. The trial, conducted in collaboration with the European Network for Gynaecological Oncological Trial Groups (ENGOT) and Groupe d’Investigateurs National pour l’Etude des Cancers de l’Ovaire et du sein (GINECO), randomised 295 patients with documented germline BRCA1 or BRCA2 mutations who had received at least two prior lines of platinum-based chemotherapy and were in complete or partial response. Eligible patients were randomised to receive 300mg Lynparza tablets twice daily or placebo tablets twice daily.

About Study 19

Study 19 was a Phase II, randomised, double-blinded, placebo-controlled, multicentre trial, which evaluated the efficacy and safety of Lynparza capsules compared with placebo in relapsed, high-grade serous ovarian cancer patients. The trial randomised 265 patients regardless of BRCA mutation status and who had completed at least two courses of platinum-based chemotherapy and their most recent treatment regimen. Eligible patients were randomised to receive Lynparza maintenance monotherapy at a dose of 400mg per day or matching placebo.

About Lynparza (olaparib)

Lynparza is a first-in-class poly ADP-ribose polymerase (PARP) inhibitor and the first targeted treatment to potentially exploit tumour DNA damage response (DDR)-pathway deficiencies to preferentially kill cancer cells. Specifically, in vitro studies have shown that Lynparza-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

Lynparza is being investigated in a range of DDR-deficient tumour types and is the foundation of AstraZeneca’s industry-leading portfolio of compounds targeting DDR mechanisms in cancer cells.

About the AstraZeneca and MSD Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. The collaboration is based on increasing evidence that PARP and MEK inhibitors can be combined with PD-L1/PD-1 inhibitors for a range of tumour types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as a monotherapy. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology
AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance New Oncology as one of AstraZeneca’s five Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody-Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On February 23, 2018 Bellicum Pharmaceuticals, Inc. (NASDAQ:BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers and orphan inherited blood disorders, reported that it has received notification from the U.S. Food and Drug Administration (FDA) outlining the criteria required for lifting the clinical hold on U.S. studies of BPX-501 (Press release, Bellicum Pharmaceuticals, FEB 23, 2018, View Source [SID1234524133]). To address the FDA requirements, the Company plans to implement revisions to the U.S. study protocols, including the addition of more comprehensive monitoring and management of neurotoxicity. In addition, the Company will revise the Investigator Brochure and Informed Consent Documents to inform healthcare providers, patients and caregivers of the changes. The Company expects to provide a full response to the FDA within a few weeks.

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The clinical hold does not affect the Company’s BP-004 registration trial in Europe.

About BPX-501
BPX-501 is an adjunct T cell therapy administered after allogeneic hematopoietic stem cell transplant (HSCT) to improve outcomes in patients who lack a matched donor. It is comprised of genetically modified donor T cells incorporating Bellicum’s CaspaCIDe safety switch. BPX-501 is designed to provide a safety net to eliminate alloreactive BPX-501 T cells (via administration of activator agent rimiducid) should uncontrollable GvHD occur. This enables physicians to more safely perform stem cell transplants by administering BPX-501 engineered T cells to speed immune reconstitution, provide control over viral infections and enhance Graft-versus-leukemic effect without unacceptable GvHD risk.

On February 23, 2018 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported that the first patient has been enrolled in a Phase 2 clinical trial evaluating the efficacy and safety of defibrotide for the prevention of acute Graft-versus-Host-Disease (aGvHD) in adult and pediatric patients after allogeneic hematopoietic stem cell transplant (HSCT) (Press release, Jazz Pharmaceuticals, FEB 23, 2018, View Source;p=RssLanding&cat=news&id=2334320 [SID1234524137]). The defibrotide clinical trial will be conducted across approximately 60 medical centers in the United States (U.S.), Canada and European Union.

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"Potential complications of hematopoietic stem cell transplant such as acute Graft-versus-Host Disease can be life threatening and even fatal," said Karen Smith, M.D., Ph.D., executive vice president, research and development and chief medical officer at Jazz Pharmaceuticals. "Despite the use of current immunoprophylaxis strategies, Graft-versus-Host Disease remains a leading cause of non-relapse mortality after allogeneic stem cell transplant. Jazz is committed to advancing our understanding of how defibrotide may address this unmet need."

The Phase 2 clinical trial is a prospective, randomized, open-label study of the efficacy and safety of defibrotide added to standard of care immunoprophylaxis for the prevention of aGvHD, compared to the standard of care alone. Jazz expects to enroll approximately 150 adult and pediatric patients who have undergone allogeneic HSCT from an unrelated donor. The primary endpoint is cumulative incidence of Grade B-D aGvHD by day +100 post-allogeneic HSCT. Additional information about the trial, including eligibility criteria and a list of clinical trial sites can be found at: View Source (ClinicalTrials.gov Identifier: NCT03339297).

This Phase 2 trial complements the company’s ongoing Phase 3 clinical trial evaluating defibrotide for prevention of hepatic veno-occlusive disease (VOD) in high-risk adult and pediatric patients undergoing hematopoietic stem cell transplant.

About GvHD
Graft-versus-Host-Disease (GvHD) is a life-threatening complication of HSCT, a potentially curative option for several malignant and non-malignant disorders, and occurs when immune cells from a non-identical donor (graft) recognize the transplant recipient (host) as foreign. GvHD is the most frequent cause of morbidity and non-relapse mortality following allogeneic HSCT.1 One in five patients receiving a transplant from an unrelated donor dies from GvHD. Approximately 24,000 allogeneic patients in the United States and Europe are at risk for acute GvHD (aGvHD), which usually occurs within the first 100 days following HSCT and typically involves damage to the skin, gastrointestinal tract and/or liver.1,2,3,4 The International Bone Marrow Transplant Registry (IBMTR) Severity Index grades aGvHD as follows: Grade A includes patients with stage 1 skin aGvHD only; B includes those with stage 2 skin and no visceral aGvHD or stage 0-2 skin with stage 1 or 2 visceral aGvHD; C includes patients with stage 3 skin, liver and/or gut aGvHD; D includes those with stage 4 skin, liver and/or gut aGvHD.5

About Defitelio (defibrotide sodium)
In the U.S., Defitelio (defibrotide sodium) injection 80mg/mL received U.S. FDA marketing approval on March 30, 2016 for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT) and is the first and only FDA-approved therapy for patients with this rare, potentially fatal complication. Defitelio is not approved for the treatment of prevention of GvHD or prevention of VOD.

Defitelio is contraindicated in patients currently taking anticoagulants or fibrinolytics and in patients who are allergic to Defitelio or any of its ingredients. Defitelio may increase the risk of bleeding and should be withheld or stopped if significant bleeding occurs. Patients should be monitored for allergic reactions, especially if there is a history of previous exposure to Defitelio. The most common side effects of Defitelio are decreased blood pressure, diarrhea, vomiting, nausea and nose bleeds.

Please see full Prescribing Information for Defitelio.

In Europe, defibrotide is marketed under the name Defitelio▼(defibrotide). In October 2013, the European Commission granted marketing authorization to Defitelio under exceptional circumstances for the treatment of severe VOD in patients undergoing HSCT therapy. It is the first and only approved treatment in Europe for severe VOD. In Europe, Defitelio is indicated in patients over one month of age. It is not indicated in patients with hypersensitivity to defibrotide or any of its excipients or with concomitant use of thrombolytic therapy.

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system found under section 4.8 of the SmPC. (View Source)

About VOD
HSCT is an aggressive, potentially curative procedure to treat patients with malignant and non-cancerous hematologic disorders such as leukemia, lymphoma and aplastic anemia, and congenital immunodeficiency and autoimmune disorders.6 VOD is a rare complication of HSCT that occurs in approximately 9-14% of HSCT patients.7,8 Hepatic VOD, also known as SOS, is an early and life-threatening complication affecting the sinusoidal endothelial cells of the liver, which can typically occur within the first 21 days following HSCT.8,9 Hepatic VOD progresses to become life-threatening in approximately 30-50% of cases.9 VOD with multi-organ dysfunction (MOD), when left untreated, can be associated with an overall mortality (death) rate of 84%.7 MOD is characterized by the presence of renal or pulmonary dysfunction.10,11 VOD is often characterized by sudden weight gain, hepatomegaly (abnormally enlarged liver), and elevated bilirubin.10,11

On February 23, 2018 Pfizer Inc. (NYSE:PFE) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted positive opinions recommending that two Pfizer hematology medicines be granted marketing authorizations in the European Union (EU) (Press release, Pfizer, FEB 23, 2018, View Source [SID1234524144]). MYLOTARG (gemtuzumab ozogamicin) in combination with daunorubicin and cytarabine has been granted a positive opinion for the treatment of patients age 15 years and above with previously untreated, de novo, CD33-positive acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL). BOSULIF (bosutinib) has been granted a positive opinion for the treatment of adults with newly diagnosed chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML). The CHMP’s opinions for both medicines will now be reviewed separately by the European Commission (EC).

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"There is an urgent need to improve outcomes for leukemia patients in Europe," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "If approved, the addition of MYLOTARG to standard chemotherapy will provide an important new treatment option for patients with acute myeloid leukemia who would typically be treated with chemotherapy alone. Additionally, the potential expansion of the approved use of BOSULIF to include first-line therapy expands the treatment options for adult patients with newly diagnosed chronic myelogenous leukemia."

The Marketing Authorization Application (MAA) for MYLOTARG was based on data from an investigator-led, Phase 3, randomized, open-label study (ALFA-0701) in previously untreated, de novo patients.

BOSULIF currently has conditional marketing authorization in Europe related to the initial marketing authorization. The Type II Variation application for BOSULIF for adults with newly diagnosed chronic phase Ph+ CML was based on results from BFORE (Bosutinib trial in First line chrOnic myelogenous leukemia tREatment), a randomized multicenter, multinational, open-label, Phase 3, head-to-head study of BOSULIF 400 mg versus imatinib 400 mg, a current standard of care.

Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial. Under the terms of the agreement, Avillion provided funding for the trial to generate the clinical data used to support this application and other potential regulatory filings for marketing authorization for BOSULIF as first-line treatment for patients with chronic phase Ph+ CML. Pfizer retains all rights to commercialize BOSULIF globally.

IMPORTANT MYLOTARG (gemtuzumab ozogamicin) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

WARNING: Hepatotoxicity, including severe or fatal hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), has been reported in association with the use of MYLOTARG as a single agent, and as part of a combination chemotherapy regimen. Monitor frequently for signs and symptoms of VOD after treatment with MYLOTARG.

Hepatotoxicity, Including Veno-occlusive Liver Disease (VOD): An increased risk of VOD was observed in patients with moderate/severe hepatic impairment and patients who received MYLOTARG either before or after HSCT. Assess ALT, AST, total bilirubin, and alkaline phosphatase prior to each dose of MYLOTARG. After treatment with MYLOTARG, monitor frequently for signs and symptoms of VOD; these may include elevations in ALT, AST, and total bilirubin, hepatomegaly, rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, monitor liver tests frequently during the post-HSCT period, as appropriate. Manage signs or symptoms of hepatic toxicity by dose interruption or discontinuation of MYLOTARG. In patients who experience VOD, discontinue MYLOTARG and treat according to standard medical practice.

Infusion-Related Reactions (Including Anaphylaxis): Life-threatening or fatal infusion-related reactions can occur during or within 24 hours following infusion of MYLOTARG. Signs and symptoms of infusion-related reactions may include fever, chills, hypotension, tachycardia, hypoxia, and respiratory failure. Premedicate prior to MYLOTARG infusion. Monitor vital signs frequently during infusion. Interrupt infusion immediately for patients who develop evidence of infusion reaction, especially dyspnea, bronchospasm, or hypotension. Monitor patients during and for at least 1 hour after the end of the infusion or until signs and symptoms completely resolve. Discontinue use of MYLOTARG in patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension.

Hemorrhage: MYLOTARG is myelosuppressive and can cause fatal or life-threatening hemorrhage due to prolonged thrombocytopenia. Assess blood counts prior to each dose of MYLOTARG and monitor blood counts frequently after treatment with MYLOTARG until resolution of cytopenias. Monitor patients for signs and symptoms of bleeding during treatment with MYLOTARG. Manage severe bleeding, hemorrhage, or persistent thrombocytopenia using dose delay or permanent discontinuation of MYLOTARG, and provide supportive care per standard practice.

QT Interval Prolongation: QT interval prolongation has been observed in patients treated with other drugs containing calicheamicin. When administering MYLOTARG to patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients with electrolyte disturbances, obtain electrocardiograms and electrolytes prior to the start of treatment and as needed during administration.

Adverse Cytogenetics: In a subgroup analysis in ALFA-0701, the addition of MYLOTARG to standard combination chemotherapy did not improve event-free survival in the subgroup of patients having adverse-risk cytogenetics. For patients being treated with MYLOTARG in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, when cytogenetics testing results become available consider whether the potential benefit of continuing treatment with MYLOTARG outweighs the risks for the individual patient.

Embryo-Fetal Toxicity: MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman. Advise patients of reproductive potential to use effective contraception during and for 3 and 6 months following treatment for males and females, respectively. Apprise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with MYLOTARG.

Adverse Reactions: The most common adverse reactions (greater than 15%) were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, and mucositis.

Contraindications: Hypersensitivity to MYLOTARG or any of its components. Reactions have included anaphylaxis.

The full U.S. prescribing information, including BOXED WARNING, for MYLOTARG can be found here.

IMPORTANT BOSULIF (bosutinib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Contraindication: History of hypersensitivity to BOSULIF. Reactions have included anaphylaxis. Anaphylactic shock occurred in less than 0.2% of treated patients in single-agent cancer studies with BOSULIF.

Gastrointestinal Toxicity: Diarrhea, nausea, vomiting, and abdominal pain can occur. In the randomized clinical trial of patients with newly diagnosed Ph+ CML, the median time to onset for diarrhea (all grades) among patients in the BOSULIF treatment group (n=268) was 3 days and the median duration per event was 3 days. Among 546 patients in a single-arm study of patients with CML who were resistant or intolerant to prior therapy, median time to onset of diarrhea (all grades) was 2 days, median duration was 2 days, and the median number of episodes per patient was 3 (range 1-268). Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and/or fluid replacement. Withhold, dose reduce, or discontinue BOSULIF as necessary.

Myelosuppression: Thrombocytopenia, anemia, and neutropenia can occur. Perform complete blood counts weekly for the first month and monthly thereafter, or as clinically indicated. Withhold, dose reduce, or discontinue BOSULIF as necessary.

Hepatic Toxicity: Elevations in serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) can occur. Perform hepatic enzyme tests at least monthly for the first 3 months and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. One case consistent with drug-induced liver injury occurred without alternative causes in a trial of BOSULIF in combination with letrozole. Withhold, dose reduce, or discontinue BOSULIF as necessary. In patients with mild, moderate, or severe hepatic impairment, the recommended starting dose is 200 mg daily.

Renal Toxicity: An on-treatment decline in estimated glomerular filtration rate has occurred in patients treated with BOSULIF. Monitor renal function at baseline and during therapy, with particular attention to patients with preexisting renal impairment or risk factors for renal dysfunction. Consider dose adjustment in patients with baseline and treatment-emergent renal impairment.

Reduce the BOSULIF starting dose in patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min) or severe (CLcr less than 30 mL/min) renal impairment at baseline. For patients who have declining renal function while on BOSULIF who cannot tolerate the starting dose, follow dose adjustment recommendations for toxicity.

Fluid Retention: Fluid retention can occur with BOSULIF and may cause pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. Among 546 patients in a single-arm study of patients with Ph+ CML who were resistant or intolerant to prior therapy, Grade 3/4 fluid retention was reported in 26 patients (5%). Monitor and manage patients using standards of care. Interrupt, dose reduce, or discontinue BOSULIF as necessary.

Embryofetal Toxicity: BOSULIF can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraceptive measures to prevent pregnancy while being treated with BOSULIF and for at least 1 month after the final dose.

Adverse Reactions: The most common adverse reactions observed in greater than or equal to 20% of patients with newly diagnosed CML were diarrhea, nausea, thrombocytopenia, rash, increased ALT, abdominal pain, and increased AST. The most common Grade 3/4 adverse reactions and laboratory abnormalities observed in greater than 10% of newly diagnosed CML patients were thrombocytopenia and increased ALT.

The most common adverse reactions observed in greater than or equal to 20% of patients with CML who were resistant or intolerant to prior therapy were diarrhea, nausea, abdominal pain, rash, thrombocytopenia, vomiting, anemia, fatigue, pyrexia, cough, headache, ALT, and edema. The most common Grade 3/4 adverse reactions and laboratory abnormalities observed in greater than 10% of patients who were resistant or intolerant to prior therapy were thrombocytopenia, neutropenia, and anemia.

CYP3A Inhibitors and Inducers: Avoid concurrent use with strong or moderate CYP3A inhibitors or strong CYP3A inducers.

Proton Pump Inhibitors: Use short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in BOSULIF exposure. Separate antacid or H2 blocker dosing and BOSULIF dosing by more than 2 hours.

Lactation: Because of the potential for serious adverse reactions in a nursing child, breastfeeding is not recommended during treatment with BOSULIF and for at least 1 month after the last dose.

Please see full U.S. Prescribing Information for BOSULIF here.

ABOUT ACUTE MYELOID LEUKEMIA (AML)

Acute myeloid leukemia is a rapidly progressing, life-threatening blood and bone marrow cancer. 1 If left untreated, patients with AML will die within months, if not weeks, of their disease. AML is the most common type of acute leukemia in adults and accounts for approximately 80% of all cases of acute leukemia.2 About 1/33,000-1/25,000 people are expected to be newly diagnosed with AML in Europe annually.2

ABOUT CHRONIC MYELOGENOUS LEUKEMIA (CML)

Chronic myelogenous leukemia (CML) is a rare blood cancer, which begins in the bone marrow, but often moves into the blood.3 Researchers estimate that by 2020, more than 412,000 people worldwide will be diagnosed with leukemia (all types).4 Across Europe, CML constitutes about 15% of all leukemia and occurs with an incidence of about 1-1.5/100,000.5

About MYLOTARG (gemtuzumab ozogamicin)

MYLOTARG is an antibody-drug conjugate (ADC) composed of the cytotoxic agent calicheamicin, attached to a monoclonal antibody (mAB) targeting CD33, an antigen expressed on the surface of myeloblasts in up to 90 percent of AML patients.6,7,8 When MYLOTARG binds to the CD33 antigen on the cell surface it is absorbed into the cell and calicheamicin is released causing cell death.7,8

MYLOTARG was approved by the U.S. Food and Drug Administration in September 2017 for adults with newly diagnosed CD33-positive AML, and adults and children 2 years and older with relapsed or refractory CD33-positive AML. MYLOTARG was originally approved in 2000 at a higher dose under the FDA’s accelerated approval program for use as a single agent in patients with CD33-positive AML who had experienced their first relapse and were 60 years or older and who were not considered candidates for other cytotoxic chemotherapy. In 2010, Pfizer voluntarily withdrew MYLOTARG in the U.S. after a confirmatory trial failed to show clinical benefit and there was a higher rate of fatal toxicity compared to chemotherapy. MYLOTARG has been available to individual patients through Pfizer’s compassionate use programs.

In addition, MYLOTARG is commercially available in Japan where it has been approved since 2005 for the treatment of patients with relapsed or refractory CD33-positive AML who are not considered candidates for other cytotoxic chemotherapy.

MYLOTARG originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development and commercialization activities for this molecule.

Pfizer also collaborated with SFJ Pharmaceuticals Group on the registrational program for MYLOTARG.

ABOUT BOSULIF (bosutinib)

BOSULIF (bosutinib) is an oral, once-daily, tyrosine kinase inhibitor (TKI), which inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases. In the U.S., BOSULIF (bosutinib) is indicated for the treatment of adult patients with newly-diagnosed chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML). Continued approval for this indication may be contingent upon verification and confirmation of clinical benefit in an ongoing long-term follow up trial. BOSULIF is also indicated in the U.S for the treatment of adult patients with chronic, accelerated or blast phase Ph+ CML with resistance or intolerance to prior therapy (first approved in September 2012).

In Europe, BOSULIF was granted conditional marketing authorization in March 2013 for the treatment of adult patients with Ph+ CML previously treated with one or more TKIs and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.

On February 22, 2018 RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company primarily focused on late clinical-stage development and commercialization of proprietary drugs for gastrointestinal diseases and cancer, reported an investor update on its fourth quarter and full-year 2017 financial results (Press release, RedHill Biopharma, FEB 22, 2018, View Source [SID1234524154]).

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The Company will host a conference call today, February 22, 2018 at 9:00 am EST to review the financial results and business highlights. Dial-in details are included below.

Micha Ben Chorin, RedHill’s CFO, said: "Following a highly productive 2017, we enter 2018 with confidence and are committed to pursue top-line growth with financial discipline, including gradual reduction in cash to be used in operating activities to a quarterly average of approximately $8.5 million during the year. Our cash position was approximately $46 million at the end of 2017 and net revenues in the fourth quarter of 2017 were $2 million, up 31% over the prior quarter. We are looking forward to top-line results from the first Phase III study with RHB-104 for Crohn’s disease, expected in mid-2018, and from the confirmatory Phase III study with TALICIA for H. pylori infection, expected in the second half of 2018."

Fourth Quarter 2017 Results1

Net Revenues for the fourth quarter of 2017 were $2.0 million, an increase of 31% from the third quarter of 2017. Net Revenues for the fourth quarter of 2016 were $0.1 million. The increase from the fourth quarter of 2016 was due to the initiation of U.S. commercial operations in mid-2017.

Cost of Revenues for the fourth quarter of 2017 was $0.9 million, due to cost of goods sold and royalties relating to commercialization activities. Cost of Revenues for the third quarter of 2017 was $0.9 million. There was no Cost of Revenues for the fourth quarter of 2016.

Gross Profit for the fourth quarter of 2017 was $1.1 million, an increase of 84% from the third quarter of 2017, primarily due to the increase in Net Revenues, as detailed above. Gross Profit for the fourth quarter of 2016 was $0.1 million.

Research and Development Expenses for the fourth quarter of 2017 were $8.3 million, an increase of 2% from the third quarter of 2017. Research and Development Expenses for the fourth quarter of 2016 were $7.5 million. The increase from the fourth quarter of 2016 was mainly due to the ongoing confirmatory Phase III study with TALICIA2 for H. pylori infection.

Selling, Marketing and Business DevelopmentExpenses for the fourth quarter of 2017 were $3.8 million, a decrease of 8% from the third quarter of 2017. The decrease was primarily due to a decrease in marketing material expenses. Selling, Marketing and Business Development Expenses for the fourth quarter of 2016 were $0.4 million. The Company recognized selling and marketing expenses for the first time in 2017 due to the establishment and advancement of the Company’s U.S. commercial operations.

General and Administrative Expenses for the fourth quarter of 2017 were $2.5 million, an increase of 11% from the third quarter of 2017. General and Administrative Expenses for the fourth quarter of 2016 were $1.2 million. The increase from the comparable periods was mainly due to the establishment and advancement of the Company’s U.S. commercial operations.

Operating Loss for the fourth quarter of 2017 was $14.4 million, compared to $9.0 million in the fourth quarter of 2016. The increase was mainly due to the establishment of the Company’s U.S. commercial operations.

Financial Income, net for the fourth quarter of 2017 was $4.0 million, compared to $0.6 million for the fourth quarter of 2016. The increase was mainly due to a fair value gain on derivative financial instruments resulting from a decrease in valuation of non-tradeable warrants, accounted as non-current liabilities.

Net Cash Used in Operating Activities for the fourth quarter of 2017 was $14.2 million, up 39%, compared to $10.2 million in the fourth quarter of 2016. The increase was a direct result of the increase in Operating Loss, as detailed above.

Net Cash Used in Investing Activities for the fourth quarter of 2017 was $9.0 million, compared to Net Cash Provided by Investing Activities of $21.3 million for the fourth quarter of 2016. The change from the comparable period was mainly due to bank deposits.

Net Cash Provided by Financing Activities for the fourth quarter of 2017 was $20.9 million compared to $35.9 million for the fourth quarter of 2016, both resulting from public offerings.

Full-Year 2017 Results3

Net Revenues for 2017 were $4.0 million, compared to $0.1 million for 2016. The increase was due to the initiation of the Company’s U.S. commercial operations in mid-2017.

Cost of Revenues for 2017 was $2.1 million, due to cost of goods sold and royalties relating to commercialization activities. There was no Cost of Revenues for 2016.

Gross Profit for 2017 was $1.9 million, compared to $0.1 million for 2016. The increase was due to the initiation of the Company’s U.S. commercial activities in mid-2017.

Research and Development Expenses for 2017 were $33.0 million, compared to $25.2 million for 2016. The increase was mainly due to the ongoing confirmatory Phase III study with TALICIA and from the Phase I/II studies with YELIVA.

Selling, Marketing and Business Development Expenses for 2017 were $12.0 million, compared to $1.6 million for 2016, which was comprised of business development expenses only. The Company recognized selling and marketing expenses for the first time in 2017 due to the establishment and advancement of the Company’s U.S. commercial operations.

General and Administrative Expenses for 2017 were approximately $8.0 million, compared to $3.8 million for 2016. The increase was mainly due to the establishment and advancement of the Company’s U.S. commercial operations in 2017.

Operating Loss for 2017 was $52.0 million, compared to $30.5 million for 2016. The increase was due to an increase in the Company’s research and development activities, as well as the establishment and advancement of the Company’s U.S commercial operations in 2017, as detailed above.

Financial Income, net for 2017 was $6.4 million, compared to $1.2 million for 2016. The increase was mainly related to a fair value gain on derivative financial instruments.

Net Cash Used in Operating Activities for 2017 was $44.8 million, compared to $28.3 million for 2016. The increase was a direct result of the increase in Operating Loss, as detailed above.

Net Cash Used in Investing Activities for 2017 was $18.6 million, compared to Net Cash Provided by Investing Activities of $24.5 million for 2016. The change from the comparable period was mainly due to withdrawal and deposit activities in bank deposits and financial assets at fair value through profit or loss.

Net Cash Provided by Financing Activities for 2017 was $25.7 million, compared to $36.0 million for 2016. For 2017, the Net Cash Provided by Financing Activities was mainly due to the November 2017 underwritten public offering and an exercise of warrants and options in the first quarter of 2017. For 2016, the Net Cash Provided by Financing Activities was mainly due to the December 2016 underwritten public offering and the concurrent registered direct offering.

Cash Balance4 as of December 31, 2017 was $46.2 million, a decrease of $20 million, compared to $66.2 million as of December 31, 2016, and an increase of $6.8 million, compared to $39.4 million as of September 30, 2017. The changes in the Cash Balance resulted mainly from Net Cash Provided by Financing Activities and Net Cash Used in Operating Activities.

Conference Call and Webcast Information:

The Company will host a conference call today,Thursday, February 22, 2018 at 9:00 am EDT to review the financial results and business highlights.

To participate in the conference call, please dial one of the following numbers 15 minutes prior to the start of the call: United States: +1-800-281-7829; International: +1-646-828-8143; and Israel: +972-3-721-9463. The access code for the call is: 2134987.

The conference call will be broadcasted live and will be available for replay on the Company’s website, View Source, for 30 days. Please access the Company’s website at least 15 minutes ahead of the conference call to register, download and install any necessary audio software.

Availability of RedHill Annual Report on Form 20-F Through Its Website

RedHill’s Annual Report on Form 20-F, containing audited financial statements for the year ended December 31, 2017, as filed with the Securities and Exchange Commission on February 22, 2018, is available on its website (View Source). Shareholders may receive a hard copy of the annual report free of charge upon request.

Select 2017 R&D highlights:

TALICIA (RHB-105)- H. pylori infection (confirmatory Phase III) (FDA Fast-Track QIDP status)

In June 2017, RedHill initiated the confirmatory Phase III study with TALICIA (RHB-105) for H. pylori infection (ERADICATE Hp2 study). To date, approximately 50% of the planned 444 patients have been enrolled in the study. Top-line results are expected in the second half of 2018.

RHB-104 – Crohn’s disease (Phase III)

In November 2017, RedHill completed enrollment of its first Phase III study with RHB-104 for Crohn’s disease (MAP US study). Top-line results are expected in mid-2018.

In October 2017, RedHill announced that it had curtailed the target sample size in the MAP US study from 410 to approximately 331 subjects, while maintaining statistical power of over 80% to detect the expected treatment effect.

In July 2017, RedHill reported, following a second pre-planned meeting by an independent Data and Safety Monitoring Board (DSMB) to assess safety and efficacy data from the MAP US study, that it had received a unanimous recommendation from the DSMB to continue the study as planned.

In March 2017, RedHill initiated an open-label extension Phase III study to the MAP US study (MAP US2 study).

RHB-104 – nontuberculous mycobacteria (NTM) infections (planned pivotal Phase III) (FDA Fast-Track QIDP status)

RedHill plans, subject to further input from the U.S. Food & Drug Administration (FDA), to initiate in mid-2018 a pivotal Phase III study to assess the safety and efficacy of RHB-104 as potential first-line treatment for nontuberculous mycobacteria (NTM) infections caused by mycobacterium avium complex (MAC) infection.

BEKINDA (RHB-102) 24 mg – acute gastroenteritis and gastritis (Phase III)

In June 2017, RedHill announced positive results from the first Phase III study with BEKINDA 24 mg for acute gastroenteritis and gastritis (GUARD study). The randomized, double-blind, placebo-controlled study successfully met its primary endpoint of efficacy and BEKINDA 24 mg was found to be safe and well tolerated in this indication. Top-line results indicated that the study successfully met its primary endpoint in the Intent to Treat (ITT) population (p = 0.04), despite high positive outcome rate in the placebo arm. BEKINDA 24 mg improved the efficacy outcome by 21%; 65.6% of BEKINDA-treated patients, as compared to 54.3% of placebo patients (p = 0.04; n=192 in the BEKINDA group and n=129 in the placebo group). In per-protocol (PP) analysis of patients who met all protocol entry criteria and for which the diagnosis of gastroenteritis was confirmed (n=177 in the BEKINDA group and n=122 in the placebo group), BEKINDA 24 mg improved the efficacy outcome by 27%; 69.5% of patients in the BEKINDA group vs. 54.9% in the placebo group (p = 0.01). RedHill met with the FDA to discuss the study results and the clinical and regulatory path towards potential marketing approval of BEKINDA 24 mg in the U.S. Following the guidance provided at the meeting, RedHill is currently working with the FDA to design a confirmatory Phase III study to support a potential New Drug Application (NDA) with BEKINDA 24 mg for acute gastroenteritis and gastritis.

BEKINDA(RHB-102) 12 mg – IBS-D (Phase II)

In January 2018, RedHill announced positive final results5 from the Phase II study with BEKINDA 12 mg for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D). The randomized, double-blind, placebo-controlled Phase II study successfully met its primary endpoint, improving the primary efficacy outcome of stool consistency (per FDA guidance definition) by an absolute difference of 20.7% vs. placebo (p-value=0.036). RedHill plans to meet with the FDA in the first half of 2018 to discuss plans for one or two pivotal Phase III studies with BEKINDA 12 mg for IBS-D to support a potential NDA.

YELIVA (ABC294640) – cholangiocarcinoma (Phase IIa) (FDA Orphan Drug designation)

In December 2017, RedHill initiated a Phase IIa study with YELIVA (ABC294640) for the treatment of cholangiocarcinoma (bile duct cancer). The single-arm Phase IIa study is evaluating YELIVA as a single agent in patients suffering from advanced, unresectable intrahepatic, perihilar and extrahepatic cholangiocarcinoma. The study is planned to enroll up to 39 patients at Mayo Clinic major campuses in Arizona and Minnesota and The University of Texas MD Anderson Cancer Center.

RHB-107 (MESUPRON) – gastrointestinal and other solid tumor cancers (Orphan Drug designation for pancreatic cancer)

In October 2017, RHB-107 (MESUPRON) (INN: upamostat) was granted FDA Orphan Drug designation for the treatment of pancreatic cancer. The Orphan Drug designation allows RedHill to benefit from various incentives to develop RHB-107 for this indication, including a seven-year marketing exclusivity period for the indication, if approved. Following the recent identification of a new mechanism of action for RHB-107, inhibition of trypsin-3, RedHill is currently evaluating potential utilization of RHB-107 in several gastrointestinal indications.

U.S. Commercial Highlights

As part of RedHill’s strategy to set the stage for the potential launch of its proprietary, late-clinical stage gastrointestinal products, if approved by the FDA, the Company established U.S. commercial operations in early 2017. RedHill’s U.S. commercial operations, with offices in Raleigh, NC, include a gastrointestinal-focused sales force of approximately 40 sales representatives.

As part of this initiative, RedHill entered into commercial agreements granting the Company certain rights to promote Donnatal (Phenobarbital, Hyoscyamine Sulfate, Atropine Sulfate, Scopolamine Hydrobromide)6 and Esomeprazole Strontium DR Capsules 49.3 mg7 and to commercialize EnteraGam (serum-derived bovine immunoglobulin/protein isolate, SBI)8. RedHill launched Donnatal and EnteraGam in June 2017, and Esomeprazole Strontium DR Capsules 49.3 mg in September 2017. The Company continues to pursue the acquisition of additional commercial gastrointestinal products in the U.S.

Financial Highlights

In November 2017, RedHill issued in a public offering 4,090,909 American Depositary Shares (ADSs), each representing ten of its ordinary shares, at a price of $5.50 per ADS, raising net proceeds of approximately $21 million.

A cost reduction plan was initiated at the end of 2017 to gradually reduce the average quarterly cash to be used in operating activities in 2018 to approximately $8.5 million.

Expanded Access Program (EAP)

RedHill adopted an Expanded Access Program (EAP), allowing patients with life-threatening diseases potential access to RedHill’s investigational new drugs that have not yet received regulatory marketing approval. Expanded access (sometimes referred to as "compassionate use") is possible outside RedHill’s clinical trials, under certain eligibility criteria, when a certain investigational new drug is needed to treat life-threatening condition and there is some clinical evidence suggesting that the drug might be effective in that condition. Following the adoption of the program, RedHill continues to receive patient requests to obtain access to investigational drugs. Subject to evaluation of eligibility and all the necessary regulatory and other approvals, RedHill is likely to provide certain patients with an investigational new drug under the EAP. Further information about RedHill’s EAP can be found on the Company’s website at: View Source/expandedaccess.