On February 23, 2018 Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company developing targeted and immuno-oncology therapeutics, today reported financial results for the fourth quarter and year ended December 31, 2017 (Press release, Leap Therapeutics, FEB 23, 2018, View Source;p=RssLanding&cat=news&id=2334290 [SID1234524139]). Leap additionally announced that its Annual Meeting of Stockholders will be held on Thursday, May 3, 2018, at 11:00 a.m., Eastern Time, at the offices of Morgan, Lewis & Bockius LLP, One Federal Street, Boston, Massachusetts 02110.

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"We had a very successful 2017 at Leap, our first year as a public company. We have advanced clinical development of both of our innovative cancer programs to explore novel combinations with immunotherapies and chemotherapies and have laid the foundation for a data-rich 2018," said Christopher K. Mirabelli, Ph.D., Chief Executive Officer of Leap. "We additionally strengthened our balance sheet to continue to grow the company and further advance our pipeline."

2017 Accomplishments

DKN-01

Announced parallel development strategy to evaluate DKN-01 in patients with documented alterations of the Wnt signaling pathway and to evaluate DKN-01 as a combination immunotherapy.
Wnt Signaling Studies
Initiated a Phase 2 clinical trial evaluating DKN-01 as a monotherapy and in combination with paclitaxel in patients with advanced endometrioid gynecologic malignancies. The study will enroll approximately 50% of patients with Wnt signaling abnormalities.
Announced an investigator-sponsored clinical trial, DIAL-1, in patients with advanced hepatocellular carcinoma (HCC) with activated Wnt signaling at the University Medical Center of the Johannes Gutenberg-University Mainz in Germany.
Immunotherapy Studies:
Enrolled first patient in combination study evaluating DKN-01 with anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with esophagogastric cancer.
Announced an immunotherapy collaboration, DINAMIC, with the European Organisation for Research and Treatment of Cancer (EORTC). The cooperative group sponsored clinical trial will evaluate DKN-01 in combination with atezolizumab (TECENTRIQ) +/- paclitaxel in advanced esophagogastric malignancies and DKN-01 + atezolizumab in advanced biliary tract cancers at EORTC centers across Europe.
Presented proof of concept clinical data of DKN-01 in combination with chemotherapy in patients with advanced biliary tract or esophagogastric cancers at major medical conferences including the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting and the ASCO (Free ASCO Whitepaper) Gastrointestinal Cancer Symposium. The data included encouraging overall response and disease control rates, progression-free survival data, and biomarker data.
TRX518:

Fully enrolled the monotherapy cohorts of the 003 repeat-dose clinical trial evaluating TRX518 in patients with advanced solid tumors.
Presented interim data from the repeat-dose monotherapy study, including robust disease control and signs of pharmacodynamic activity including CD8+ T cell activation.
Initiated combination cohorts of study 003 evaluating TRX518 in combination with gemcitabine chemotherapy or in combination with KEYTRUDA (pembrolizumab) or Opdivo (nivolumab), anti-PD-1 therapies marketed by Merck (known as MSD outside the United States and Canada) or Bristol-Myers Squibb, respectively.
Business:

Completed $18M private-placement financing with participation from Eli Lilly and Company and other existing and new investors.
Completed a clinical collaboration agreement with Merck for the study of the combination of DKN-01 and KEYTRUDA (pembrolizumab).
2018 Objectives

DKN-01 Program Objectives

Present interim data from clinical trial evaluating DKN-01 and KEYTRUDA (pembrolizumab) in patients with advanced esophagogastric cancer.
Present interim data from the Phase 2 clinical trial evaluating DKN-01 ± paclitaxel in patients with advanced gynecologic cancers enriched for patients with Wnt pathway alterations.
Present final data from the combination study of DKN-01 with gemcitabine and cisplatin in advanced biliary tract cancers.
Enroll first patient in the DIAL-1 clinical trial.
Enroll first patient in the DINAMIC clinical trial.
TRX518 Program Objectives

Present interim data from study of TRX518 in combination with gemcitabine chemotherapy, KEYTRUDA (pembrolizumab), or Opdivo (nivolumab).
Present TRX518 clinical biomarker data from monotherapy studies.
Selected Year-End and Fourth Quarter 2017 Financial Results

Net loss was $29.7 million for the year ended December 31, 2017, compared to $25.6 million for the year ended December 31, 2016. Net loss was $6.6 million for the fourth quarter of 2017, compared to $5.7 million for the same period in 2016.

Research and development expenses were $22.5 million for the full year 2017, compared to $23.3 million for the same period in 2016. This decrease was primarily due to reduced manufacturing expenses of our clinical product candidates. Research and development expenses were $4.4 million for the fourth quarter of 2017, compared to $7.4 million for the same period in 2016.

General and administrative expenses were $9.8 million for the full year 2017, compared to $4.0 million for the same period in 2016. This increase was primarily due to increased personnel, stock-based compensation, and expenses related to operating as a public company. General and administrative expenses were $2.1 million for the fourth quarter of 2017, compared to $0.5 million for the same period in 2016.

Cash, cash equivalents and marketable securities totaled $25.7 million at December 31, 2017. Research and development incentive receivables totaled $1.7 million.

Annual Meeting of Stockholders

The Annual Meeting of Stockholders will be held on Thursday, May 3, 2018, at 11:00 a.m., Eastern Time, at the offices of Morgan, Lewis & Bockius LLP, One Federal Street, Boston, Massachusetts 02110. The record date for the Annual Meeting of Stockholders is March 28, 2018. Leap expects to mail its definitive proxy statement to all stockholders of record in the first week of April.

Rule 14a-8 Stockholder Proposal Deadline

The 2018 Annual Meeting date represents Leap’s first Annual Meeting of Stockholders. As a result, pursuant to Rule 14a-8 under the Securities Exchange Act of 1934, as amended, the deadline for the receipt of any stockholder proposals submitted pursuant to Rule 14a-8 for inclusion in Leap’s proxy materials for the 2018 Annual Meeting, is required to be a reasonable time before the Company begins to print and mail the proxy materials. Taking into consideration the time and process for addressing any deficiencies in proposals that may be submitted, the Company has determined that close of business on March 9, 2018 should be the deadline for receipt of proposals pursuant to Rule 14a-8. Such proposals should be delivered to: Leap Therapeutics, 47 Thorndike Street, Suite B1-1, Cambridge, Massachusetts 02141, Attention: Corporate Secretary. Leap recommends that such proposals be sent by certified mail, return receipt requested. Such proposals also will need to comply with the rules of the Securities and Exchange Commission regarding the inclusion of stockholder proposals in Leap’s proxy materials and may be omitted if not in compliance with applicable requirements.

Bylaws Advance Notice Deadline for Stockholder Proposals and Nominations

For stockholder proposals not submitted pursuant to Rule 14a-8 and stockholder nominations of directors, the stockholder must give timely notice thereof in writing and in accordance with the requirements set forth in the Company’s bylaws to the Company’s Secretary no later than 5:00 p.m., Eastern Time on March 9, 2018 at the address noted above.

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.