On February 15, 2020 Eisai reported that results from a Phase 2 trial assessing the efficacy and safety of lenvatinib (marketed as LENVIMA) in combination with everolimus (LEN+EVE) in patients with unresectable advanced or metastatic non-clear cell renal cell carcinoma (nccRCC) (Abstract #685) at the 2020 Genitourinary Cancers Symposium (#GU20) in San Francisco from February 13-15 (Press release, Eisai, FEB 15, 2020, View Source [SID1234554381]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

This single-arm, multicenter, Phase 2 study (Study 221) of lenvatinib (18 mg/day) in combination with everolimus (5 mg/day) enrolled 31 patients with unresectable advanced or metastatic nccRCC (papillary, n=20; chromophobe, n=9; unclassified, n=2) who had not received any chemotherapy for advanced disease. The primary endpoint was objective response rate (ORR) as assessed by investigators using RECIST 1.1. The secondary endpoints included progression-free survival (PFS) and overall survival (OS).

On primary analysis, the ORR was 25.8% (95% Confidence Interval [CI]: 11.9-44.6) with 8 patients (papillary, n=3; chromophobe, n=4; unclassified, n=1) having achieved a partial response (PR). Fifty eight percent (n=18) had stable disease (SD) and the clinical benefit rate (CR + PR + durable SD [duration ≥ 23 weeks]) was 61.3% (95% CI: 42.2-78.2). No patients achieved a complete response. The median duration of response was not reached at the time of data cutoff (July 17, 2019).

The median PFS was 9.23 months (95% CI: 5.49-Not Estimable [NE]) and median OS was 15.64 months (95% CI: 9.23–NE).

In the study, treatment-emergent adverse events (TEAEs) leading to withdrawal or discontinuation of lenvatinib plus everolimus occurred in 32.3% of patients. TEAEs leading to dose reduction occurred in 45.2% of patients. TEAEs leading to interruption of lenvatinib and everolimus occurred in 67.7% of patients. The five most common TEAEs (any grade) were fatigue (71%), diarrhea (58.1%), decreased appetite (54.8%), nausea (54.8%) and vomiting (51.6%). Treatment-related TEAEs (Grade 3 or higher) occurred in 48.4% of patients receiving lenvatinib plus everolimus. Among the most common TEAEs (Grade 3 or higher) were hypertension (16.1%), malignant neoplasm progression (12.9%), diarrhea (9.7%) and fatigue, nausea, vomiting, proteinuria and decreased platelet count (6.5% each).

"Non-clear cell RCC is a less studied subtype of the disease that encompasses a biologically varied group of tumor types with diverse prognoses and responses to therapy," said Thomas Hutson, D.O., Director of the Genitourinary Oncology Program and Co-director of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center, and Primary Investigator of the study. "I was pleased to have been involved in this trial and look forward to continuing research to enhance our understanding of nccRCC."

"We are striving to improve care for people living with cancers with high unmet needs such as non-clear cell RCC," said Dr. Kirk Shepard, Senior Vice President, Chief Medical Officer and Head of Global Medical Affairs for the Oncology Business Group at Eisai. "While there continue to be advancements in clear cell RCC, non-clear cell RCC continues to be an area where a strong need remains for more options, and we look forward to further exploring the potential this regimen may have for patients."

This release discusses investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.

In March 2018, Eisai and Merck (known as MSD outside the United States and Canada), through an affiliate, entered into a strategic collaboration or the worldwide co-development and co-commercialization of lenvatinib.

About Non-Clear Cell Renal Cell Carcinoma (nccRCC)
The latest SEER data state that more than half a million Americans (533,204) were living with kidney and renal pelvis cancer as of 2016. It is estimated that approximately 73,750 new cases of kidney cancer will occur in 2020, and about 14,830 people will die from the disease. Renal cell carcinoma (RCC), also known as renal cell cancer or renal cell adenocarcinoma, is the most common type of kidney cancer, representing about 90% of cases in the United States. RCC occurs when malignant cells form in the lining of the tubules in the kidney. Non-clear cell renal cell carcinoma (nccRCC) accounts for up to 20% of all RCC cases. Non-clear cell RCC includes a heterogeneous group of diseases, including but not limited to papillary, chromophobe, and sarcomatoid carcinomas, among others.

About LENVIMA (lenvatinib) Capsules 10 mg and 4 mg

LENVIMA is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC)
In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
Important Safety Information

Warnings and Precautions

Hypertension. In DTC, hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC, hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC, hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials. Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to hepatic encephalopathy and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus– treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome. Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications. Wound healing complications, including fistula formation and wound dehiscence, can occur with LENVIMA. Withhold for at least 6 days prior to scheduled surgery. Resume after surgery based on clinical judgment of adequate wound healing. Permanently discontinue in patients with wound healing complications.

Embryo-fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.

Adverse Reactions
In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%).

The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with RCC or DTC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

No dose adjustment is recommended for patients with DTC or RCC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe hepatic impairment. Reduce the dose for patients with DTC or RCC and severe hepatic impairment.

About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.

In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, the companies will jointly initiate new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program, which will evaluate the combination to support 11 potential indications in six types of cancer (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial cancer). The LEAP clinical program also includes a new basket trial targeting six additional cancer types (biliary tract cancer, breast cancer, colorectal cancer, gastric cancer, glioblastoma and ovarian cancer).

On February 14, 2020 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that it filed regulatory applications with the Ministry of Health, Labour and Welfare for the anti-cancer agent/humanized anti-PD-L1 monoclonal antibody Tecentriq Intravenous Infusion 1200 mg [generic name: atezolizumab (genetical recombination)] and the anti-cancer agent/humanized anti-VEGF monoclonal antibody Avastin Intravenous Infusion 100 mg/4 mL and 400 mg/16 mL [generic name: bevacizumab (genetical recombination)] for the treatment of unresectable, advanced or metastatic hepatocellular carcinoma (HCC) (Press release, Chugai, FEB 14, 2020, View Source [SID1234554347]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The combination of Tecentriq and Avastin is the first immunotherapy-based treatment regimen that showed efficacy in HCC, and may improve outcome for patients," said Dr. Yasushi Ito, Chugai’s Executive Vice President, Co-Head of Project & Lifecycle Management Unit. "We are committed to obtain regulatory approval to provide the new treatment as soon as possible for patients with this devastating disease who currently have limited treatment options."

This filing is based on the phase III IMbrave150 study in patients with unresectable HCC who have not received prior systemic therapy. Roche filed an application for Tecentriq in combination with Avastin for the treatment of HCC both in the US and EU. In the US, FDA accepted the filing in January 2020, and is reviewing the application under the Real-Time Oncology Review pilot program, which aims to explore a more efficient review process to ensure treatments are available to patients as early as possible.

Roche presents pivotal data demonstrating Tecentriq in combination with Avastin improves overall survival in people with the most common form of liver cancer (A press release issued by Roche in November 22, 2019)
View Source

Tecentriq in Combination with Avastin Increases Overall Survival and Progression-free Survival as an Initial Treatment in People with Unresectable Hepatocellular Carcinoma (A press release issued by Chugai in October 21, 2019)
View Source

As a leading company in the field of oncology, Chugai is committed to contribute to patients and medical professionals by offering Tecentriq as a new treatment option.

About IMbrave150 study
IMbrave150 is a global Phase III, multicenter, open-label study of 501 people with unresectable HCC who have not received prior systemic therapy. People are randomized 2:1 to receive the combination of Tecentriq and Avastin or sorafenib. People receive the combination or the control arm treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Co-primary endpoints were overall survival (OS) and progression free survival (PFS) by independent-review facility (IRF) per RECIST v1.1. Secondary efficacy endpoints included objective response rate (ORR), time to progression (TTP) and duration of response (DOR) as well as patient-reported outcomes (PROs), safety and pharmacokinetics.

About hepatocellular carcinoma (HCC)
HCC accounts for over 90% of liver cancer and is an aggressive type of cancer with limited treatment options hence it is a major cause of cancer deaths worldwide.1, 2) In Japan, about 40,000 people are diagnosed with liver cancer every year and the number of deaths accounts for about 28,000 per year.3) HCC develops predominantly in people with cirrhosis due to chronic hepatitis (B or C) or alcohol consumption, and typically presents at an advanced stage.1) The prognosis for unresectable HCC remains limited, with few systemic therapeutic options and a 1-year survival rate of less than 50%.4)

Trademarks used or mentioned in this release are protected by law.

On February 14, 2020 Mallinckrodt plc (NYSE: MNK), a global biopharmaceutical company, reported that it will report fourth quarter and fiscal 2019 earnings results for the period ending Dec. 27, 2019 on Tuesday, Feb. 25, 2020 (Press release, Mallinckrodt, FEB 14, 2020, View Source [SID1234554368]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

A conference call for investors will begin at 8:30 a.m. Eastern. The call can be accessed in three ways:

At the Mallinckrodt website: http://www.mallinckrodt.com/investors.
By telephone: For both listen-only participants and those who wish to take part in the question-and-answer portion of the call, the telephone dial-in number in the U.S. is (877) 359-9508. For participants outside the U.S., the dial-in number is (224) 357-2393. Callers will need to provide the Conference ID of 4168459.
Through an audio replay: A replay of the call will be available beginning at 11:30 a.m. Eastern Time on Tuesday, Feb. 25, 2020, and ending at 11:30 a.m. Eastern Time on Tuesday, March 10, 2020. Dial-in numbers for U.S.-based participants are (855) 859-2056 or (800) 585-8367. Participants outside the U.S. should use the replay dial-in number of (404) 537-3406. All callers will be required to provide the Conference ID of 4168459.

On February 14, 2020 AstraZeneca reported a year of strong revenue growth, supported by the launch of new medicines1 and further good progress on its pipeline, with several approvals and data readouts (Press release, AstraZeneca, FEB 14, 2020, View Source [SID1234554348]). These trends are set to continue in 2020, accompanied by growth in earnings and cash. In maintaining its focus on patients and science, the Company remains on track to deliver its strategic ambitions.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Full-year Product Sales growth of 12% (15% at CER2) to $23,565m included fourth-quarter Product Sales of $6,250m (+8%, +9% at CER).
All three therapy areas and every sales region grew at CER in the quarter and over the full year.

Highlights for the year included:-

Sales of new medicines increased by 59% (62% at CER) to $9,906m, including new-medicine growth in Emerging Markets of 75% (84% at CER) to $1,865m. New medicines represented 42% of total Product Sales (FY 2018: 30%)-Sales growth across the therapy areas: Oncology +44% (+47% at CER) to $8,667m, New CVRM3 +9% (+12% at CER) to $4,376m and Respiratory +10% (+13% at CER) to $5,391m-For the first time, around half of Product Sales in the year were within the specialty-care4 setting-Sales growth across regions: total Emerging Markets sales increased by 18% (24% at CER) to $8,165m, with China sales growth of 29% (35% at CER); China sales in the quarter increased by 25% (28% at CER) to $1,189m. US sales increased by 13% in the year to $7,747m; Europe sales declined by 2% in the year (up by 2% at CER) to $4,350m; Japan sales increased by 27% (26% at CER) to $2,548m FY 2019 Q4 2019 Pascal Soriot, Chief Executive Officer, commenting on the results said: "In the first full year of our return to growth, we made good progress in line with our strategy.

Results from our new medicines and Emerging Markets accompanied positive news for patients, most recently including regulatory approvals of Enhertu in breast cancer and Calquence in leukaemia. Our collaborations also progressed at pace, including that with Daiichi Sankyo, while there were several regulatory approvals for new medicines in China at the end of the year, such as Lynparza in first-line ovarian cancer. Driven by a strong team, 2020 is anticipated to be another year of progress for AstraZeneca. We are becoming a better-balanced business, both regionally and through our medicines. This transition is a further step towards improving operating leverage and cash generation. As we accelerate our commitments to achieving our longterm climate-change and decarbonisation targets, we will maintain our focus on executing a strategy centred on science and patients."

2 Guidance The Company provides guidance for FY 2020 at CER; Company guidance is on:-Total Revenue, comprising Product Sales and Collaboration Revenue-Core EPS Prior guidance was on Product Sales and Core EPS. The change to guiding on Total Revenue and Core EPS reflects the changing nature and growing strategic impact of Collaboration Revenue, which will primarily comprise potential income from existing collaborations as follows:-

A share of gross profits derived from sales of Enhertu (trastuzumab deruxtecan) in several markets, where those sales are recorded by Daiichi Sankyo Company, Limited (Daiichi Sankyo)-A share of gross profits derived from sales of roxadustat in China, recorded by FibroGen Inc. (FibroGen)8-Milestone revenue from the MSD9 collaboration on Lynparza and selumetinib-Smaller amounts of milestone and royalty revenue from other marketed and pipeline medicines All guidance assumes an unfavourable impact from China lasting up to a few months as a result of the recent novel coronavirus (Covid-19) outbreak. The Company will monitor closely the development of the epidemic and anticipates providing an update at the time of the Q1 2020 results.

Depending on the impact of the Covid-19 epidemic, Total Revenue is expected to increase by a high single-digit to a low double-digit percentage and Core EPS is expected to increase by a mid-to high-teens percentage. Variations in performance between quarters can be expected to continue. The Company is unable to provide guidance and indications on a Reported basis because the Company cannot reliably forecast material elements of the Reported result, including any fair-value adjustments arising on acquisition-related liabilities, intangible asset impairment charges and legal-settlement provisions. Please refer to the section Cautionary Statements Regarding Forward-Looking Statements at the end of this announcement. Indications The Company provides indications for FY 2020 at CER:-

The Company is focused on improving operating leverage-A Core Tax Rate of 18-22%. Variations in the Core Tax Rate between quarters are anticipated to continue-Capital Expenditure is expected to be broadly stable versus the prior year Currency impact If foreign-exchange rates for February to December 2020 were to remain at the average of rates seen in January 2020, it is anticipated that there would be a neutral impact on Total Revenue and a low single-digit adverse impact on Core EPS, versus the prior year. In addition, the Company’s foreign-exchange rate sensitivity analysis is contained within the operating and financial review. Financial summary-Product Sales increased by 12% in the year (15% at CER) to $23,565m, driven by the performances of new medicines and Emerging Markets-The Reported Gross Profit Margin increased by three percentage points in the year (two at CER) to 79%, partly reflecting the mix of sales; the Core Gross Profit Margin was stable at 80%.

The performance came despite the impact of a provision regarding Epanova for inventory and supply-related costs of $115m, recorded in Reported and Core Cost of Sales-Reported Operating Expense increased by 11% in the year (14% at CER) to $18,080m and represented 74% of Total Revenue (FY 2018: 74%); part of the rise reflected an increased level of intangible asset impairments. Core Operating Expense increased by 4% (7% at CER) to $14,748m and represented 60% of 3 Total Revenue (FY 2018: 64%); the increase was driven by investment in the launches of new medicines and in Emerging Markets-The Reported Operating Profit Margin declined in the year by three percentage points (four at CER) to 12%; the Core Operating Profit Margin increased by one percentage point (stable at CER) to 26%-Reported EPS of $1.03 in the year, based on a weighted-average number of shares of 1,301m, represented a decline of 40% (44% at CER); Core EPS increased by 1% (stable at CER) to $3.50-The Board has reaffirmed its commitment to the progressive dividend policy; a second interim dividend of $1.90 per share has been declared, taking the unchanged full-year dividend per share to $2.80

The strong Oncology performance continued to benefit from new medicines such as Tagrisso, Lynparza and Imfinzi. The full impact of recent regulatory approvals for Calquence and Enhertu is anticipated to favourably affect Total Revenue growth in 2020. The performance from legacy Oncology medicines in the year included a decline in Faslodex sales of 13% (11% at CER) to $892m; the fall in the fourth quarter of 39% (38% at CER) led to sales of Faslodex of $166m. These declines reflected the 2019 launch of multiple generic Faslodex medicines in the US. Iressa sales also declined in the year by 18% (15% at CER) to $423m and in the quarter by 29% (28% at CER) to $80m; Iressa continued to be included on the China volume-based procurement programme in the year. The Company anticipates continued declines for both medicines. Oncology sales increased in Emerging Markets by 45% (52% at CER) to $2,211m. Recent developments and progress against the Company’s sustainability priorities are reported below:-Access to healthcare: the Company announced that the Young Health Programme (YHP) will partner with UNICEF10 to prevent non-communicable diseases among young people. AstraZeneca and UNICEF will collaborate on initiatives that will reach more than five million young people, train c.1,000 youth advocates, and potentially help to shape public policy around the world over the next six years-Environmental protection: AstraZeneca recently unveiled an ambitious programme for zero-carbon emissions from its global operations by 2025 and a carbon-negative value chain by 2030. The strategy brings forward decarbonisation plans by more than a decade. In 2019, the Company was ranked 56th overall, as 5 one of the world’s one hundred most sustainable companies by environmental research and media group, Corporate Knights, and second for biopharmaceutical companies-Ethics and transparency: the Hampton-Alexander independent review body, which works to support improvements in women’s representation at board level and in leadership roles two layers below the board, recently published its latest review. In the reviews FTSE 100 ranking, AstraZeneca moved up from seventh place in 2018 to sixth in 2019 for women represented in the top-three layers of management A more extensive sustainability update is provided later in this announcement.

Notes These notes refer to pages one to five.

1. Tagrisso, Imfinzi, Lynparza, Calquence, Farxiga, Brilinta, Lokelma, Fasenra, Bevespi and Breztri. These new medicines are pillars in the main therapy areas and are important platforms for future growth. Over time, Enhertu and roxadustat will be added to this list.

2. Constant exchange rates. These are financial measures that are not accounted for according to generallyaccepted accounting principles (GAAP) because they remove the effects of currency movements from Reported results.

3. New Cardiovascular (CV), Renal & Metabolism comprises Diabetes medicines, Brilinta and Lokelma. Over time, roxadustat will be added to this list.

4. Specialty-care medicines comprise all Oncology medicines, Brilinta, Lokelma and Fasenra.

5. Reported financial measures are the financial results presented in accordance with International Financial Reporting Standards, as issued by the International Accounting Standards Board and adopted by the EU. The UK is yet to announce its IFRS endorsement process and is anticipated to continue to follow the EU endorsement process for the foreseeable future.

6. Core financial measures.
These are non-GAAP financial measures because, unlike Reported performance, they cannot be derived directly from the information in the Group’s Financial Statements. See the operating and financial review for a definition of Core financial measures and a reconciliation of Core to Reported financial measures.

7. Earnings per share.

8. FibroGen and AstraZeneca are collaborating on the development and commercialisation of roxadustat in the US, China, and other global markets. FibroGen and Astellas Pharma Inc. (Astellas) are collaborating on the development and commercialisation of roxadustat in territories including Japan, Europe, the Commonwealth of Independent States, the Middle East, and South Africa. 9. Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada. 10. United Nations International Children’s Emergency Fund.

Conference call
A conference call and webcast for investors and analysts will begin at 12pm UK time today. Details can be accessed via astrazeneca.com.

Reporting calendar
The Company intends to publish its first quarter financial results on 29 April 2020.

On February 14, 2020 CTI BioPharma Corp. (Nasdaq: CTIC) reported that rights offering to raise gross proceeds of approximately $60.0 million (the "Rights Offering") (Press release, CTI BioPharma, FEB 14, 2020, View Source [SID1234554369]). Under the terms of the Rights Offering, the holders, as of 5:00 p.m., New York time, on February 13, 2020, of CTI BioPharma’s common stock (the "Common Stock") and series O convertible preferred stock (the "Series O Preferred"), are entitled to exercise their subscription rights to purchase their pro rata share (assuming full conversion of the Series O Preferred into shares of Common Stock) of the $60.0 million offering amount, as more fully described in the prospectus supplement (and accompanying prospectus), dated February 14, 2020, relating to the Rights Offering (the "Prospectus"). Each subscription right may be exercised to purchase a share of Common Stock at a subscription price equal to $1.00 per share of Common Stock or, in lieu of Common Stock, an equivalent number of shares of non-voting series X convertible preferred stock (the "Series X Preferred") at a purchase price equal to $10,000 per share of Series X Preferred. The subscription rights may be exercised at any time during the subscription period of February 14, 2020 through 5:00 p.m., New York time, on March 2, 2020.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The Rights Offering will be fully backstopped by BVF Partners L.P., Stonepine Capital, L.P., OrbiMed Private Investments VI, LP and New Enterprise Associates, Inc. (the "Backstop Investors") each of which have agreed to purchase its respective as-converted pro rata share of the offering amount, plus an additional amount of Common Stock or Series X Preferred that are not subscribed for by other purchasers in the Rights Offering, for a total of up to $60.0 million.

CTI BioPharma reserves the right to modify, extend, postpone or cancel the Rights Offering at any time prior to the closing of the sale of the securities offered in the Rights Offering. CTI BioPharma has engaged Georgeson LLC to act as information agent with respect to the Rights Offering. For questions regarding the Rights Offering, or to obtain copies of the Prospectus and any related materials, please contact Georgeson LLC by telephone at 888-613-9988.

CTI BioPharma has filed a shelf registration statement (including a prospectus supplement) with the Securities and Exchange Commission (the "SEC"). Before you invest, you should read the Prospectus and the other documents CTI BioPharma has filed with the SEC for more complete information about CTI BioPharma and the Rights Offering. This press release is not intended to and does not constitute an offer to sell or the solicitation of an offer to subscribe for or buy or an invitation to purchase or subscribe for any securities in any jurisdiction, nor shall there be any sale, issuance or transfer of securities in any jurisdiction in contravention of applicable law. No offer of securities shall be made except by means of a prospectus meeting the requirements of Section 10 of the Securities Act of 1933, as amended.