Takeda to Highlight Data in Hodgkin Lymphoma During the 11th International Symposium on Hodgkin Lymphoma

CAMBRIDGE, Mass. & OSAKA, Japan-Sunday 28 October 2018 [ AETOS Wire ]

– Six Abstracts to be Presented to Highlight the Potential Impact of ADCETRIS® (brentuximab vedotin) for the Treatment of Hodgkin Lymphoma –

(BUSINESS WIRE) -- Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that the company will feature a total of six company-sponsored abstracts, including two oral presentations, at the 11th International Symposium on Hodgkin Lymphoma (ISHL), October 27-29, 2018, in Cologne, Germany. This year’s presentations will highlight Phase 3 and other clinical data from ADCETRIS (brentuximab vedotin) and continue to build upon our research in CD30-positive lymphoma.

“Data to be presented at this year’s ISHL continue to reinforce Takeda’s dedication to advancing treatment for those affected by Hodgkin lymphoma,” said Jesús Gómez-Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. “The progress we have made in the development of ADCETRIS serves as a true testament to the leadership role we have established in the treatment of CD30-positive malignancies. We look forward to sharing positive data including results from the Phase 3 ECHELON-1 and AETHERA trials, which confirm the long-term benefits of ADCETRIS across treatment lines and support its role as an important targeted therapy for Hodgkin lymphoma.”

During the invited oral presentation, Takeda will share results from the ECHELON-1 trial, which showed that ADCETRIS, as part of a frontline combination chemotherapy regimen, improved outcomes versus a current standard of care in previously untreated patients with advanced Hodgkin lymphoma. The safety profile of the ADCETRIS arm in the ECHELON-1 trial was generally consistent with that known for the single-agent components of the regimen. In addition to the findings previously presented during the Plenary Scientific Session at the 59th American Society of Hematology Annual Meeting (ASH) in December 2017, the ISHL presentation will highlight progression-free survival (PFS) results and data demonstrating the benefit of ADCETRIS in patients with Stage IV disease. Additional data to be featured during the meeting include several sub-analyses from the ECHELON-1 trial.

Takeda, in partnership with Seattle Genetics, will present five-year follow-up data from the Phase 3 AETHERA trial, in which ADCETRIS demonstrated a sustained benefit in PFS, as a consolidation treatment option for patients at high risk of relapse or progression following autologous stem cell transplant (ASCT). The safety profile of ADCETRIS in the AETHERA trial was generally consistent with the existing prescribing information.

Takeda will also reveal results from a Phase 1/2 study evaluating ADCETRIS as part of a chemotherapy regimen in pediatric patients with advanced-stage Hodgkin lymphoma.

Also at the congress, ISHL invited Takeda to present on the company’s R&D Access to Medicine Oncology Program in Sub-Saharan Africa during the “Developing Healthcare Environments” workshop on Saturday, October 27, 8:45 – 10:15 a.m. CET.

The six Takeda Oncology-sponsored abstracts accepted for presentation during ISHL include:

    Frontline Brentuximab Vedotin Plus Chemotherapy Exhibits Superior Modified Progression-Free Survival vs Chemotherapy Alone In Patients With Stage III or IV Hodgkin Lymphoma: Phase 3 ECHELON-1 Study. Oral Presentation: “Advanced Stages” Session. Monday, October 29, 7:30 – 9:00 a.m. CET. Poster: Abstract 0038. Sunday, October 28 – Monday, October 29.
    Five-Year Progression-Free Survival Outcomes from a Pivotal Phase 3 Study of Consolidative Brentuximab Vedotin after Autologous Stem-Cell Transplantation in Patients with Hodgkin’s Lymphoma at Risk of Relapse or Progression (AETHERA).* Oral Presentation. “Relapsed/Refractory HL” Session. Monday, October 29, 4:00 – 5:30 p.m. CET.
    Phase 1/2 Study of Brentuximab Vedotin + AVD in Pediatric Patients with Advanced Stage Newly Diagnosed Classical Hodgkin Lymphoma. Abstract 0149. Sunday, October 28 – Monday, October 29.
    Serum sCD30 and TARC Do Not Correlate With PET-Based Response Assessment in Patients (Pts) with Stage III or IV Classical Hodgkin Lymphoma (cHL): Phase 3 ECHELON-1 Study of Brentuximab Vedotin Plus Chemotherapy vs Chemotherapy Alone. Abstract 0159. Sunday, October 28 – Monday, October 29.
    Brentuximab Vedotin Plus Chemotherapy in High Risk Advanced-Stage Classical Hodgkin Lymphoma (cHL) Patients: Results of Pre-Specified Sub-Group Analyses from the ECHELON-1 Study. Abstract 0136. Sunday, October 28 – Monday, October 29.
    Population Pharmacokinetic Modeling and Exposure-Response Assessment of Brentuximab Vedotin Efficacy and Safety in Patients with Advanced Classical Hodgkin Lymphoma from the Phase 3 ECHELON-1 Study. Abstract 0137. Sunday, October 28 – Monday, October 29.

*In partnership with Seattle Genetics

For more information, the ISHL program is available here: https://www.hodgkinsymposium.org/schedule.

About Hodgkin Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

According to the Lymphoma Coalition, approximately 67,000 people worldwide are diagnosed with Hodgkin lymphoma each year and more than 25,000 people die each year from this cancer.

Up to 30 percent of newly diagnosed Hodgkin lymphoma patients progress following frontline therapy depending on the stage of the disease. Only 50 percent of patients with relapsed or refractory Hodgkin lymphoma achieve long-term remission with high-dose chemotherapy and an autologous stem cell transplant (ASCT), a historically used treatment regimen, highlighting the importance of successful frontline treatment.

About ADCETRIS
ADCETRIS is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for five indications in adult patients with: (1) previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with chemotherapy, (2) cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation, (3) cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (4) sALCL after failure of at least one prior multi-agent chemotherapy regimen, and (5) primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-autologous stem cell transplant (ASCT) consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS received conditional marketing authorization from the European Commission in October 2012. The approved indications in Europe are: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, (2) the treatment of adult patients with relapsed or refractory sALCL, (3) for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT, and (4) for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization by regulatory authorities in more than 70 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See important safety information below.

ADCETRIS is being evaluated broadly in more than 70 clinical trials, including a Phase 3 study in first-line Hodgkin lymphoma (ECHELON-1) and another Phase 3 study in first-line CD30-positive peripheral T-cell lymphomas (ECHELON-2), as well as trials in many additional types of CD30-positive malignancies.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) Important Safety Information (European Union)

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

CONTRAINDICATIONS

ADCETRIS is contraindicated for patients with hypersensitivity to brentuximab vedotin and its excipients. In addition, combined use of ADCETRIS with bleomycin causes pulmonary toxicity.

SPECIAL WARNINGS & PRECAUTIONS

Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in patients treated with ADCETRIS. PML has been reported in patients who received ADCETRIS after receiving multiple prior chemotherapy regimens. PML is a rare demyelinating disease of the central nervous system that results from reactivation of latent JCV and is often fatal.

Closely monitor patients for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML. Suggested evaluation of PML includes neurology consultation, gadolinium-enhanced magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JCV DNA by polymerase chain reaction or a brain biopsy with evidence of JCV. A negative JCV PCR does not exclude PML. Additional follow up and evaluation may be warranted if no alternative diagnosis can be established Hold dosing for any suspected case of PML and permanently discontinue ADCETRIS if a diagnosis of PML is confirmed.

Be alert to PML symptoms that the patient may not notice (e.g., cognitive, neurological, or psychiatric symptoms).

Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Closely monitor patients for new or worsening abdominal pain, which may be suggestive of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation for serum amylase and serum lipase, and abdominal imaging, such as ultrasound and other appropriate diagnostic measures. Hold ADCETRIS for any suspected case of acute pancreatitis. ADCETRIS should be discontinued if a diagnosis of acute pancreatitis is confirmed.

Pulmonary Toxicity: Cases of pulmonary toxicity, some with fatal outcomes, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome (ARDS), have been reported in patients receiving ADCETRIS. Although a causal association with ADCETRIS has not been established, the risk of pulmonary toxicity cannot be ruled out. Promptly evaluate and treat new or worsening pulmonary symptoms appropriately. Consider holding dosing during evaluation and until symptomatic improvement.

Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteremia, sepsis/septic shock (including fatal outcomes), and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Carefully monitor patients during treatment for emergence of possible serious and opportunistic infections.

Infusion-related reactions (IRR): Immediate and delayed IRR, as well as anaphylaxis, have occurred with ADCETRIS. Carefully monitor patients during and after an infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS Appropriate medical therapy should be administered. If an IRR occurs, interrupt the infusion and institute appropriate medical management. The infusion may be restarted at a slower rate after symptom resolution. Patients who have experienced a prior IRR should be premedicated for subsequent infusions. IRRs are more frequent and more severe in patients with antibodies to ADCETRIS.

Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS. Monitor these patients closely and managed according to best medical practice.

Peripheral neuropathy (PN): ADCETRIS treatment may cause PN, both sensory and motor. ADCETRIS-induced PN is typically cumulative and reversible in most cases. Monitor patients for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay and a dose reduction or discontinuation of ADCETRIS.

Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Monitor complete blood counts prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia has been reported. Closely monitor patients for fever and manage according to best medical practice if febrile neutropenia develops.

Stevens-Johnson syndrome (SJS): SJS and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. Fatal outcomes have been reported. Discontinue treatment with ADCETRIS if SJS or TEN occurs and administer appropriate medical therapy.

Gastrointestinal (GI) Complications: GI complications, some with fatal outcomes, including intestinal obstruction, ileus, enterocolitis, neutropenic colitis, erosion, ulcer, perforation and haemorraghe, have been reported. Promptly evaluate and treat patients if new or worsening GI symptoms occur.

Hepatotoxicity: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Serious cases of hepatotoxicity, including fatal outcomes, have also occurred. Test liver function prior to treatment initiation and routinely monitor patients receiving ADCETRIS for liver elevations. Patients experiencing hepatotoxicity may require a delay, dose modification, or discontinuation of ADCETRIS.

Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Closely monitor serum glucose for patients who experiences an event of hyperglycemia. Administer anti-diabetic treatment as appropriate.

Renal and Hepatic Impairment: There is limited experience in patients with renal and hepatic impairment. Available data indicate that MMAE clearance might be affected by severe renal impairment, hepatic impairment, and by low serum albumin concentrations.

CD30+ CTCL: The size of the treatment effect in CD30 + CTCL subtypes other than mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) is not clear due to lack of high level evidence. In two single arm phase II studies of ADCETRIS, disease activity has been shown in the subtypes Sézary syndrome (SS), lymphomatoid papulosis (LyP) and mixed CTCL histology. These data suggest that efficacy and safety can be extrapolated to other CTCL CD30+ subtypes. Carefully consider the benefit-risk per patient and use caution in other CD30+ CTCL patient types.

Sodium content in excipients: ADCETRIS contains a maximum of 2.1 mmol (or 47 mg) of sodium per dose. Take this into consideration for patients on a controlled sodium diet.

INTERACTIONS
Patients who are receiving a strong CYP3A4 and P-gp inhibitor, concomitantly with ADCETRIS may have an increased risk of neutropenia and should be closely monitored. Co-administration of ADCETRIS with a CYP3A4 inducer did not alter the plasma exposure of ADCETRIS but it appeared to reduce plasma concentrations of MMAE metabolites that could be assayed. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

PREGNANCY: Advise women of childbearing potential to use two methods of effective contraception during treatment with ADCETRIS and until 6 months after treatment. There are no data from the use of ADCETRIS in pregnant women, although studies in animals have shown reproductive toxicity. Do not use ADCETRIS during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus.

LACTATION (breast-feeding): There are no data as to whether ADCETRIS or its metabolites are excreted in human milk, therefore a risk to the newborn/infant cannot be excluded. With the potential risk, a decision should be made whether to discontinue breast-feeding or discontinue/abstain from therapy with ADCETRIS.

FERTILITY: In nonclinical studies, ADCETRIS treatment has resulted in testicular toxicity, and may alter male fertility. Advise men being treated with ADCETRIS not to father a child during treatment and for up to 6 months following the last dose.

Effects on ability to drive and use machines: ADCETRIS may have a minor influence on the ability to drive and use machines.

UNDESIRABLE EFFECTS
The most frequent adverse reactions (≥10%) were infections, peripheral sensory neuropathy, nausea, fatigue, diarrhoea, pyrexia, upper respiratory tract infection, neutropenia, rash, cough, vomiting, arthralgia, peripheral motor neuropathy, infusion-related reactions, pruritus, constipation, dyspnoea, weight decreased, myalgia and abdominal pain.

Serious adverse drug reactions were: pneumonia, acute respiratory distress syndrome, headache, neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, nausea, pyrexia, peripheral motor neuropathy, peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome. Serious adverse drug reactions occurred in 12% of patients. The frequency of unique serious adverse drug reactions was ≤1%.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication
ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly.

Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.

Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each ADCETRIS dose. Consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.

Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.

Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Serious cases, including fatal outcomes, have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

PML: JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. Other possible contributory factors other than ADCETRIS include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary toxicity: Noninfectious pulmonary toxicity events including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Gastrointestinal (GI) complications: Acute pancreatitis, including fatal outcomes, has been reported in ADCETRIS-treated patients. Other fatal and serious GI complications, including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.

Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Most Common (≥20%) Adverse Reactions: peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, and pyrexia.

Drug Interactions
Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations
Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to use effective contraception during, and for at least 6 months after the final dose of ADCETRIS treatment.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

For additional Important Safety Information, including BOXED WARNING, please see the full Prescribing Information for ADCETRIS at www.seattlegenetics.com or www.ADCETRIS.com.

About Takeda Pharmaceutical Company

Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda’s presence in emerging markets, are currently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda’s partners in health care in more than 70 countries.
For more information, visit https://www.takeda.com/newsroom/.

Additional information about Takeda is available through its corporate website, www.takeda.com, and additional information about Takeda Oncology, the brand for the global oncology business unit of Takeda Pharmaceutical Company Limited, is available through its website, www.takedaoncology.com.

Contacts

Takeda Pharmaceutical Company Limited
Japanese Media
Kazumi Kobayashi, +81 (0) 3-3278-2095
kazumi.kobayashi@takeda.com
or
Media outside Japan
Sara Noonan, +1-617-551-3683
sara.noonan@takeda.com

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Malta and Austria Are Home to the World’s Best Investment Migration Programs

LONDON -Tuesday 23 October 2018 [ AETOS Wire ]

(BUSINESS WIRE)-- The Malta Individual Investor Program is the world’s top citizenship-by-investment program and the Austria Private Residence Program is the world’s top residence-by-investment program, according to the Global Residence and Citizenship Programs 2018–2019 report, released today by global residence and citizenship advisory firm Henley & Partners.

Dr. Christian H. Kälin, an international immigration and citizenship law expert and Group Chairman of Henley & Partners, says the annual report provides a systematic analysis and comprehensive benchmarking of the world’s most important programs. “It’s an invaluable tool for anyone interested in alternative residence or citizenship as well as for the professionals like private bankers and lawyers who advise them. It also provides governments with a detailed picture of the broader investment migration industry landscape and where they fit it.”

Malta is followed in the citizenship program ranking by Cyprus in 2nd place, Austria in 3rd place, and Antigua and Barbuda in 4th place. European newcomers Moldova and Montenegro performed strongly, in 5th and 6th place respectively, mostly on account of their competitive pricing structure, minimal physical-visit requirements, strong transparency, and streamlined processing.

The Austria Private Residence Program has knocked Portugal off the top spot for the first time, with newcomer Italy claiming 3rd place, the Thailand Elite Residence Program coming in at 4th place followed by the UK Tier 1 Investor Immigration Program in 5th place. The US’s EB-5 residence program only holds 8th position on the ranking.

“Demand for such programs is at an all-time high,” explains Dr. Kälin, “and new programs are being launched each year. In this high-growth climate, Henley & Partners is committed to providing authoritative, on-the-ground insights to those working in the field of investment migration as well as to the broader public. It is in precisely this spirit that we hold our annual Global Residence and Citizenship Conference, which is all about mapping the major trends and developments shaping our industry and our world.”

The annual event, now in its 12th year, will take place in Dubai from 4 to 6 November. Over 400 delegates from more than 40 different countries are expected to attend, including presidents, prime ministers, senior government officials, leading academics, industry professionals, and top-tier financial and business media.





View source version on businesswire.com: https://www.businesswire.com/news/home/20181023005113/en/



Contacts

Media
Henley & Partners
Sarah Nicklin
Senior Group Public Relations Manager
sarah.nicklin@henleyglobal.com



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Takeda to Present Results from Phase 3 ALTA-1L Trial Highlighting Intracranial Efficacy of ALUNBRIG® (brigatinib) Versus Crizotinib in First-Line Advanced ALK+ Non-Small Cell Lung Cancer

– In Patients with Brain Metastases at Baseline, ALUNBRIG Reduced the Risk of Progression in the Brain or Death by 73 Percent –

– Intracranial Efficacy Data Reinforces Superiority of ALUNBRIG Versus Crizotinib in the First-Line Treatment Setting –

– Data Will Be Presented in a Poster Discussion at the European Society for Medical Oncology 2018 Congress on Friday, October 19 –




CAMBRIDGE, Mass. & OSAKA, Japan-Tuesday 23 October 2018 [ AETOS Wire ]

(BUSINESS WIRE) -- Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that intracranial efficacy data from the Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial showed improved intracranial progression-free survival (PFS) and intracranial objective response rate (ORR) with ALUNBRIG (brigatinib) compared to crizotinib among anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) patients. Data for these secondary endpoints will be presented in a poster discussion at the European Society for Medical Oncology (ESMO) 2018 Congress on Friday, October 19 at 2:00 p.m. CET in Munich, Germany. These results further support ALUNBRIG as a potential treatment for adults with ALK+ locally advanced or metastatic NSCLC who had not received a prior ALK inhibitor. ALUNBRIG is currently not approved as first-line therapy for advanced ALK+ NSCLC.

“ALK+ NSCLC often spreads to the brain, so having options that can clearly demonstrate efficacy both in the brain and systemically is important for physicians and their patients,” said Sanjay Popat, PhD, FRCP, Medical Oncologist, Royal Marsden Hospital. “The ALTA-1L trial showed that treatment with brigatinib significantly delayed progression of disease in the brain compared to crizotinib, and we look forward to sharing the clinical evidence with the medical community at ESMO.”

In the first interim analysis of the ALTA-1L trial, intracranial PFS was significantly improved with ALUNBRIG compared to crizotinib in the Intention to Treat population (ITT) (Hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.24−0.70; log-rank P=0.0006) and the population with baseline brain metastases (HR: 0.27, 95% CI: 0.13−0.54; log-rank P<0.0001). Among patients with brain metastases at baseline, ALUNBRIG reduced the risk of progression in the brain or death by 73 percent. Intracranial PFS in patients without brain metastases at baseline is not yet mature as of this first interim analysis.

Treatment with ALUNBRIG also demonstrated an improved intracranial ORR compared to crizotinib. For patients with measurable brain metastases at baseline, 78 percent achieved confirmed intracranial OR in the ALUNBRIG arm versus 29 percent in the crizotinib arm. For patients with non-measurable brain metastases at baseline, 67 percent achieved confirmed intracranial OR in the ALUNBRIG arm versus 17 percent in the crizotinib arm.

In addition, ALUNBRIG significantly delayed both central nervous system (CNS) progression (without prior systemic progression) and systemic progression (without prior CNS progression) compared to crizotinib. Baseline factors related to the CNS, such as the proportion of patients with baseline brain metastases, mean number of brain metastases, and prior brain radiotherapy, including type, were balanced among patients in the two study arms. The safety profile associated with ALUNBRIG in the ALTA-1L trial was generally consistent with the existing U.S. prescribing information.

“CNS disease presents a significant burden for patients with ALK+ NSCLC,” said David Kerstein, MD, Global Clinical Lead for Brigatinib and Lung Cancer Clinical Portfolio Strategy Lead, Takeda. “These additional intracranial efficacy results from the ALTA-1L trial build upon activity previously reported with ALUNBRIG in patients with brain metastases in the post-crizotinib setting and demonstrate Takeda’s dedication to research that aims to improve outcomes for those living with this serious disease.”

These data build on results recently presented during the Presidential Symposium at the International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer (WCLC), which showed that treatment with ALUNBRIG resulted in superior PFS compared to crizotinib as assessed by a blinded independent review committee, corresponding to a 51 percent reduction in the risk of disease progression or death (HR: 0.49, 95% CI: 0.33−0.74]; log-rank P=0.0007).

Grade 3 to 5 treatment-emergent adverse events occurred in 61% of the patients in the brigatinib arm and 55% of the patients in the crizotinib arm. Most common grade 3 or greater treatment-emergent adverse events for brigatinib were increased blood creatine phosphokinase (16%), increased lipase (13%), hypertension (10%), and increased amylase (5%); and for crizotinib were increased alanine aminotransferase (9%), increased aspartate aminotransferase (6%), and increased lipase (5%).

About the ALTA-1L Trial
The Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial of ALUNBRIG in adults is a global, ongoing, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor. Patients received either ALUNBRIG, 180 mg once daily with seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice daily. Blinded Independent Review Committee (BIRC)-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, intracranial ORR, intracranial PFS, overall survival (OS), safety and tolerability. A total of approximately 198 PFS events are planned at the final analysis of the primary endpoint in order to demonstrate a minimum of six months PFS improvement over crizotinib. The trial is designed with two pre-specified interim analyses for the primary endpoint – one at approximately 50 percent of planned PFS events and one at approximately 75 percent of planned PFS events.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.

Takeda is committed to continuing research and development in NSCLC to improve the lives of the approximately 40,000 patients diagnosed with this serious and rare form of lung cancer worldwide each year.

About ALUNBRIG® (brigatinib)

ALUNBRIG is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 2017, ALUNBRIG received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for ALK+ metastatic NSCLC patients who have progressed on or are intolerant to crizotinib. This indication is approved under Accelerated Approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with ALK+ metastatic NSCLC who have progressed on or who were intolerant to an ALK inhibitor (crizotinib). The FDA and Health Canada approvals of ALUNBRIG were primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial.

ALUNBRIG received Breakthrough Therapy Designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib and was granted Orphan Drug Designation by the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.

The brigatinib clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with ALK+ NSCLC worldwide and the healthcare professionals who treat them. The comprehensive program includes the following clinical trials:

    Phase 1/2 trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG
    Pivotal Phase 2 ALTA trial investigating the efficacy and safety of ALUNBRIG at two dosing regimens in patients with ALK+ locally advanced or metastatic NSCLC who had progressed on crizotinib
    Phase 3 ALTA-1L, a global randomized trial assessing the efficacy and safety of ALUNBRIG in comparison to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor
    Phase 2 single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib
    Phase 2 global, single-arm trial evaluating ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib
    Phase 3 global randomized trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+ NSCLC who have progressed on crizotinib

For additional information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION (U.S.)

WARNINGS AND PRECAUTIONS

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of patients in the 90 mg group (90 mg once daily) and 9.1% of patients in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90 mg once daily). Adverse reactions consistent with possible ILD/pneumonitis occurred early (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension: In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia: Bradycardia can occur with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance: In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3-4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hyperglycemia: In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90→180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.

CYP3A Substrates: Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.

USE IN SPECIFIC POPULATIONS

Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.

Females and Males of Reproductive Potential:

Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.

Infertility: ALUNBRIG may cause reduced fertility in males.

Pediatric Use: The safety and efficacy of ALUNBRIG in pediatric patients have not been established.

Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 and younger patients.

Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild hepatic impairment or mild or moderate renal impairment. The safety of ALUNBRIG in patients with moderate or severe hepatic impairment or severe renal impairment has not been studied.

Please see the full U.S. Prescribing Information for ALUNBRIG at www.ALUNBRIG.com

About Takeda Pharmaceutical Company

Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda’s presence in emerging markets, are currently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda’s partners in health care in more than 70 countries. For more information, visit https://www.takeda.com/newsroom/.

Additional information about Takeda is available through its corporate website, www.takeda.com, and additional information about Takeda Oncology, the brand for the global oncology business unit of Takeda Pharmaceutical Company Limited, is available through its website, www.takedaoncology.com.




Contacts

Takeda Pharmaceutical Company Limited
Japanese Media
Kazumi Kobayashi, +81 3 3 278 2095
kazumi.kobayashi@takeda.com
or
Media outside Japan
Amanda Loder, +1 212-259-0491
Amanda.Loder@takeda.com




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Takeda Announces Execution of Senior Short Term Loan Facility Agreement and Subordinated Syndicated Loan Agreement and Second Amendment to Bridge Credit Agreement in Connection with Proposed Acquisition of Shire plc

NOT FOR RELEASE, PUBLICATION OR DISTRIBUTION, IN WHOLE OR IN PART, DIRECTLY OR INDIRECTLY, IN ANY JURISDICTION WHERE TO DO SO WOULD CONSTITUTE A VIOLATION OF THE RELEVANT LAWS OF SUCH JURISDICTION

•    Significant Milestone in Proposed Acquisition of Shire
•    Reduces Commitments under Takeda’s Bridge Credit Agreement
•    Supports Takeda’s Commitment to Maintain Investment Grade Credit Rating Post-Closing


OSAKA, Japan-Saturday 27 October 2018 [ AETOS Wire ]

(BUSINESS WIRE)-- Takeda Pharmaceutical Company Limited (TSE:4502) (the “Company or “Takeda”) announces that it has today entered into a Senior Short Term Loan Facility Agreement (the “SSTL”) for an aggregate principal amount of up to 500 billion Japanese Yen. The SSTL will finance a portion of the funds necessary for the acquisition of Shire plc (“Shire”) (the “Acquisition”) and reduce commitments under the 364-Day Bridge Credit Agreement entered into in connection with the Acquisition on May 8, 2018 (as amended on 8 June 2018) (the “Bridge Credit Agreement”). Takeda has also entered into a Subordinated Syndicated Loan Agreement (the “Subordinated Loan”) for an aggregate principal amount of up to 500 billion Japanese Yen which will be used to refinance the debt to be borrowed pursuant to the SSTL.

“We are pleased to have secured the senior short term loan facility and subordinated loan, which enables us to successfully de-risk a substantial portion of our bridge facility as we continue to make progress toward completing our proposed acquisition of Shire,” said Costa Saroukos, Chief Financial Officer of Takeda. “These agreements, along with our previously announced term loan agreement, support our intention to maintain our well-established dividend policy and investment grade credit rating following closing of the transaction.”

In connection with entering into the SSTL, certain technical amendments have been made to the Bridge Credit Agreement by way of the “Amendment No.2 to the Bridge Credit Agreement”. In accordance with Rule 26 of the City Code on Takeovers and Mergers, copies of the SSTL, the Subordinated Loan and the Amendment No.2 to the Bridge Credit Agreement will be published on Takeda's website and will be available to view at www.takeda.com/investors/offer-for-shire by no later than 12 noon (London time) on October 29, 2018. Please note that the Acquisition remains subject to certain conditions, including approval by the shareholders of both companies.

1. Details of the SSTL


(a) Borrower


Takeda Pharmaceutical Company Limited

(b) Lead Arranger and Bookrunner


Sumitomo Mitsui Banking Corporation and MUFG Bank, Ltd

(c) Arranger and Bookrunner

Mizuho Bank, Ltd.

(d) Arranger


The Norinchukin Bank and Sumitomo Mitsui Trust Bank, Limited

(e) Administrative Agent


Sumitomo Mitsui Banking Corporation

(f) Execution date of agreement


October 26, 2018

(g) Total borrowing limit


500 billion Japanese Yen

(h) Interest rate


Adjusted Japanese Yen TIBOR rate plus an applicable margin

(i) Use of proceeds

Payment of a portion of the Acquisition cash consideration and related fees, costs and expenses incurred by Takeda

(j) Maturity Date


The day that is one month, two months, three months or six months after the date such advance by a lender is made

(k) Pledge


None

(l) Security


None


2. Details of the Subordinated Loan


(a) Borrower


Takeda Pharmaceutical Company Limited

(b) Lead Arranger and Bookrunner


Sumitomo Mitsui Banking Corporation and MUFG Bank, Ltd

(c) Arranger and Bookrunner


Mizuho Bank, Ltd.

(d) Arranger


The Norinchukin Bank and Sumitomo Mitsui Trust Bank, Limited

(e) Administrative Agent


Sumitomo Mitsui Banking Corporation

(g) Execution date of agreement



October 26, 2018

(h) Total borrowing limit


500 billion Japanese Yen

(i) Interest rate

Japanese Yen TIBOR rate plus an applicable margin

(j) Use of proceeds


Refinancing of the debt to be borrowed pursuant to the SSTL

(k) Maturity Date


The sixtieth anniversary of the drawdown date.

The Company may, however, make an early repayment of all or part of the principal on any interest payment date on or after the sixth anniversary of the drawdown date

(l) Interest payment


The Company may, at its discretion, defer all or some of the payment of interest on the Subordinated Loan, subject to mandatory payment clauses

(m) Subordination


The Subordinated Loan is subordinated in liquidation proceedings, bankruptcy proceedings, reorganization proceedings, rehabilitation proceedings and similar proceedings in accordance with laws other than the laws of Japan

(n) Prohibition of changes to the disadvantage of senior creditors

Any amendment to any of the provisions of the Subordinated Loan to the disadvantage of the creditors of the Company other than the creditors of the subordinated claims (the claims under the Subordinated Loan and the claims which are subject to subordination clauses equivalent to those under the Subordinated Loan) is prohibited by any means, and any agreement on such amendment takes no effect by any means and with respect to any person

(o) Equity credit attributes of the Subordinated Loan evaluated by Ratings Institutions (expected)

50% (Rating and Investment Information, Inc. and S&P Global Ratings Japan Inc.)

The Company plans to apply to Moody’s Japan KK for the equity credit attributes of the Subordinated Loan (50%) after the drawdown occurs

(p) Pledge

None

(q) Security

None


Note: The Subordinated Loan is a committed term loan, and the timing and value of the drawdown will be decided after the closing of the Acquisition. The drawdown of all or a part of the Subordinated Loan may not be implemented if the Company obtains alternative financing.

3. Impact on the financial results for the fiscal year ending March 2019

Upon the execution of the SSTL, the commitments under the Bridge Credit Agreement will be reduced by 4.5 billion U.S. dollars. We will announce the impact of the SSTL and the Subordinated Loan on our business performance promptly after we estimate it.

About Takeda Pharmaceutical Company

Takeda Pharmaceutical Company Limited (TSE: 4502) is a global, research and development-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its R&D efforts on oncology, gastroenterology and neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products, especially in oncology and gastroenterology, as well as Takeda's presence in emerging markets, are currently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to improving quality of life for patients, working with Takeda's partners in health care in more than 70 countries. For more information, visit https://www.takeda.com/newsroom/.

Important Notice

This announcement is not intended to, and does not, constitute, represent or form part of any offer, invitation or solicitation of an offer to purchase, otherwise acquire, subscribe for, sell or otherwise dispose of, any securities whether pursuant to this announcement or otherwise.

The distribution of this announcement in jurisdictions outside the United Kingdom or Japan may be restricted by law or regulation and therefore any person who comes into possession of this announcement should inform themselves about, and comply with, such restrictions. Any failure to comply with such restrictions may constitute a violation of the securities laws or regulations of any such relevant jurisdiction.

Publication on Website

In accordance with Rule 26.1 of the Code, a copy of this announcement will be made available (subject to certain restrictions relating to persons resident in restricted jurisdictions) on Takeda's website at www.takeda.com/investors/offer-for-shire by no later than 12 noon (London time) on October 29, 2018. The content of the website referred to in this announcement is not incorporated into and does not form part of this announcement.

Disclosure requirements of the Code

Under Rule 8.3(a) of the Code, any person who is interested in 1% or more of any class of relevant securities of an offeree company or of any securities exchange offeror (being any offeror other than an offeror in respect of which it has been announced that its offer is, or is likely to be, solely in cash) must make an Opening Position Disclosure following the commencement of the offer period and, if later, following the announcement in which any securities exchange offeror is first identified. An Opening Position Disclosure must contain details of the person's interests and short positions in, and rights to subscribe for, any relevant securities of each of (i) the offeree company and (ii) any securities exchange offeror(s). An Opening Position Disclosure by a person to whom Rule 8.3(a) applies must be made by no later than 3.30 pm (London time) on the 10th business day following the commencement of the offer period and, if appropriate, by no later than 3.30 pm (London time) on the 10th business day following the announcement in which any securities exchange offeror is first identified. Relevant persons who deal in the relevant securities of the offeree company or of a securities exchange offeror prior to the deadline for making an Opening Position Disclosure must instead make a Dealing Disclosure.

Under Rule 8.3(b) of the Code, any person who is, or becomes, interested in 1% or more of any class of relevant securities of the offeree company or of any securities exchange offeror must make a Dealing Disclosure if the person deals in any relevant securities of the offeree company or of any securities exchange offeror. A Dealing Disclosure must contain details of the dealing concerned and of the person's interests and short positions in, and rights to subscribe for, any relevant securities of each of (i) the offeree company and (ii) any securities exchange offeror(s), save to the extent that these details have previously been disclosed under Rule 8. A Dealing Disclosure by a person to whom Rule 8.3(b) applies must be made by no later than 3.30 pm (London time) on the business day following the date of the relevant dealing.

If two or more persons act together pursuant to an agreement or understanding, whether formal or informal, to acquire or control an interest in relevant securities of an offeree company or a securities exchange offeror, they will be deemed to be a single person for the purpose of Rule 8.3.

Opening Position Disclosures must also be made by the offeree company and by any offeror and Dealing Disclosures must also be made by the offeree company, by any offeror and by any persons acting in concert with any of them (see Rules 8.1, 8.2 and 8.4).

Details of the offeree and offeror companies in respect of whose relevant securities Opening Position Disclosures and Dealing Disclosures must be made can be found in the Disclosure Table on the Panel's website at www.thetakeoverpanel.org.uk, including details of the number of relevant securities in issue, when the offer period commenced and when any offeror was first identified. You should contact the Panel's Market Surveillance Unit on +44 (0)20 7638 0129 if you are in any doubt as to whether you are required to make an Opening Position Disclosure or a Dealing Disclosure.

View source version on businesswire.com: https://www.businesswire.com/news/home/20181025006152/en/

Contacts
Media and Investor:
Takeda (Investor Relations)
Takashi Okubo
takeda.ir.contact@takeda.com
+81 3 3278 2306
or
Takeda (Media)
Tsuyoshi Tada
Tsuyoshi.Tada@takeda.com
+81 3 3278 2417
or
Elissa Johnsen
Elissa.Johnsen@takeda.com
+1 312 285 3203
or
Kazumi Kobayashi
kazumi.kobayashi@takeda.com
+81 (0) 3-3278-2095

https://www.aetoswire.com/news/takeda-announces-execution-of-senior-short-term-loan-facility-agreement-and-subordinated-syndicated-loan-agreement-and-second-amendment-to-bridge-credit-agreement-in-connection-with-proposed-acquisition-of-shire-plc/en

Cohn & Wolfe Wins Global Agency of the Year at the SABRE Awards

Two Campaigns Ranked Among 40 Best in the World


NEW YORK-Saturday 27 October 2018 [ AETOS Wire ]

(BUSINESS WIRE)-- Cohn & Wolfe was named Global Agency of the Year at The Holmes Report’s 2018 Global SABRE Awards ceremony held last night in Washington, D.C. The global communications agency – which merged with Burson-Marsteller in early 2018 to form BCW (Burson Cohn & Wolfe) – was honored for its continued double-digit growth and transformation into an integrated communications agency.

In recognizing Cohn & Wolfe, The Holmes Report said:

The growth record is impressive, obviously, but the path Cohn & Wolfe followed to get there is the real story. A decade ago, the firm was a strong player in consumer and healthcare, offering a blend of traditional media expertise and growing digital capabilities. In recent years, it has added an array of in-depth social know-how and the ability to integrate paid, earned, shared and owned channels. Last year saw a strengthening of the influencer marketing approach (“Trufluence”) and expanded AI and VR capabilities. As a result, Cohn & Wolfe can now legitimately claim to be an integrated firm, offering its clients the ability to deliver the complete brand experience, using social and experiential and more—supported by robust data—to deliver channel-neutral ideas and immersive content.

Cohn & Wolfe also won Agency of the Year recognition from The Holmes Report during the year for North America, UK, EMEA Healthcare and Asia-Pacific Midsize.

“It is an enormous honor for Cohn & Wolfe to be named Global Agency of the Year in its final year of operations,” said Donna Imperato, Cohn & Wolfe’s former CEO and Global CEO of BCW. “I am especially proud that The Holmes Report recognized Cohn & Wolfe for its successful journey to become a top integrated communications agency. I share this award with all of our colleagues at BCW, which is continuing this journey of being the best full-service integrated communications agency in the world.”

The Global SABRE Awards also recognize the top 40 campaigns in the world from the previous year. The agency’s “Check Your Balls” campaign with UNG Cancer was ranked 12th and “Women in the Driving Seat” with Ford Middle East & Africa ranked 38th.

About BCW

BCW is one of the world’s largest full-service global communications agencies. Founded by the merger of Burson-Marsteller and Cohn & Wolfe, BCW delivers digitally and data-driven creative content and integrated communications programs grounded in earned media and scaled across all channels for clients in the B2B, consumer, corporate, crisis management, CSR, healthcare, public affairs and technology sectors. BCW is a part of WPP (NYSE: WPP), the world leader in communications services. For more information, visit www.bcw-global.com.

Contacts

Media Contact:
Catherine Sullivan, +1-212-798-9501
Catherine.Sullivan@bcw-global.com

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ABB to Build the World’s Most Advanced Robotics Factory in Shanghai

Milestone investment will combine connected digital technologies, state-of-the-art collaborative robotics and cutting-edge artificial intelligence research to create the most sophisticated, automated and flexible Factory of the Future.

• US$150 million investment will expand ABB’s #1 position in the world’s largest robotics market

• Expanded, onsite R&D Center will accelerate digital innovations and advances in artificial intelligence

• Innovative factory design makes the most of every meter of production

• Builds on US$2.4 billion ABB has invested since 1992 in China, now the company’s second largest market



SHANGHAI-Saturday 27 October 2018 [ AETOS Wire ]

(BUSINESS WIRE)-- Pioneering digital technology company ABB today announced a major, new US$150 million investment in Shanghai, China to build the world’s most advanced, automated and flexible robotics factory - a cutting-edge center where robots make robots. The new Kangqiao manufacturing center, near ABB’s expansive China robotics campus, will combine the company’s connected digital technologies, including ABB Ability™ solutions, state-of-the-art collaborative robotics and innovative artificial intelligence research to create the most sophisticated and environmentally sustainable “factory of the future.” It is expected to begin operating by the end of 2020.

Today’s announcement marks a significant milestone for ABB as China’s #1 robotics manufacturer as well as a critical global growth investment for the company in the world’s largest robotics market. In 2017, one of every three robots sold in the world went to China, which purchased nearly 138,000 units. Today, ABB employs approximately 5,000 people in Shanghai, and the company’s robotics businesses in China employ more than 2,000 engineers, technology experts and operational leaders in 20 locations across the country. ABB has invested more than US$2.4 billion in China since 1992, with over 18,000 employees in total.

ABB and the Shanghai municipal government today also signed a comprehensive strategic cooperation agreement focused on supporting industry, energy, transport and infrastructure in the region, and to support the “Made in Shanghai” manufacturing initiative. The agreement was signed by Shanghai Mayor Ying Yong and ABB CEO Ulrich Spiesshofer.

“China’s commitment to transform its manufacturing is a torchlight for the rest of the world,” said Spiesshofer. “Its strategic embrace of the latest technologies for artificial intelligence, advanced robotics and cloud-based computing present a playbook for every country that wishes to have a globally competitive manufacturing base. Shanghai has become a vital center for advanced technology leadership – for ABB and the world. We look forward to working with Shanghai Mayor Ying Yong, other community leaders and our customers as we launch this major expansion of ABB’s substantial presence in China, building on our journey to become China’s leading Robotics manufacturer that started in Shanghai over two decades ago.”

Leading the Way with a Digital Factory of the Future – Tailored Solutions and Better Performance

The new Shanghai factory will feature a number of machine learning, digital and collaborative solutions to make it the most advanced, automated and flexible factory in the robotics industry, and an onsite R&D center will help accelerate innovations in artificial intelligence. Using a new, global design approach that ABB announced earlier this year, the factory will be able to dramatically increase both the breadth (type of robots) and depth (variants of each type) of robots that can be made onsite, allowing greater and faster customization to meet the needs of customers.

ABB will also be able to combine this expanded portfolio of robotics into an almost limitless number of tailored solutions. “The concept behind this factory is the same advice we give our customers every day: invest in automation solutions that provide flexibility and agility to grow in whichever direction the market goes,” said Sami Atiya, President of ABB’s Robotics and Motion division. “ABB is proud to help our customers in China and around the world with solutions that take full advantage of the latest technologies to meet the challenges of mass customization, faster cycles and constant change which have become the new normal – even in our own factories.”

The entire Shanghai factory will be modeled as a digital twin, which will provide intuitively tailored dashboards for management, engineers, operators and maintenance experts to make the best decisions. This includes gathering and analyzing intelligence through ABB Ability™ Connected Services on the health and performance of ABB robots in the factory to ensure early identification of potential anomalies. In addition to avoiding costly downtime, ABB Ability™ offers advanced digital solutions that can improve performance, reliability and energy usage, as well as providing access to the world’s best platforms, such as the Microsoft Azure enterprise cloud, which is the first international public cloud service operated in China.

An Innovative Design that Makes Better Use of Manufacturing Space

The new factory will have an innovative, flexible floorplan based on interlinked islands of automation rather than fixed assembly lines. ABB logistics automation solutions will be used throughout the plant, including automatic guided vehicles that can autonomously follow robots as they move through production, supplying them with parts from localized stations. This will allow production to adapt and scale efficiently to changes in China’s robot market without additional capacity expansions.

Per Vegard Nerseth, Managing Director of ABB’s Robotics business, said “There’s a large shift away from looking at factory size and CAPEX investments as the way to meet future demand. The concept behind our new factory is to make the smartest and most flexible use of every meter of production. That comes from combining agile automation solutions with the great capabilities of our people.”

To aid the move to mass customization in manufacturing and to ensure the highest levels of productivity and flexibility, the new Shanghai factory will make extensive use of ABB’s SafeMove2 software, which allows people and robots to work safely in close proximity. In addition, ABB’s YuMi robots will allow close collaboration on many of the small parts assembly tasks needed to manufacture an ABB robot.

ABB was an early entrant in the China robotics market and the first global robot supplier in the country to have a complete local value chain, including R&D, manufacturing, system integration and service. Through close customer collaboration, ABB has helped introduce many “firsts” to local manufacturing including: China’s first automotive press, welding and painting lines; the first assembly line for mobile phones; and the first automated press line for white goods.

“2018 marks the 40th anniversary of China's reform and opening-up policy,” said Dr. Chunyuan Gu, Chairman of ABB China and President, AMEA region. “ABB was an early arriver in China and we now have a fully localized value chain, supported by China’s remarkable economic and social development. As the market leader in China’s robotics industry, we are glad to build on this success and continue our investment momentum.”

The new Shanghai factory – with a comprehensive R&D center onsite – will become a key part of ABB’s global robotics supply system, together with the company’s recently upgraded factory in Västerås, Sweden and its factory in Auburn Hills, Michigan, where ABB remains the only global robot supplier with a US manufacturing footprint.

To learn more about the factory, watch the video.

ABB (ABBN: SIX Swiss Ex) is a pioneering technology leader in power grids, electrification products, industrial automation and robotics and motion, serving customers in utilities, industry and transport & infrastructure globally. Continuing a history of innovation spanning more than 130 years, ABB today is writing the future of industrial digitalization with two clear value propositions: bringing electricity from any power plant to any plug and automating industries from natural resources to finished products. As title partner in ABB Formula E, the fully electric international FIA motorsport class, ABB is pushing the boundaries of e-mobility to contribute to a sustainable future. ABB operates in more than 100 countries with approximately 147,000 employees. www.abb.com

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20181026005564/en/




Contacts

ABB Ltd
Affolternstrasse 44
8050 Zurich
Switzerland
Media Relations
Phone: +41 43 317 71 11
E-mail: media.relations@ch.abb.com




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Neustar Acquires Verisign’s Security Services Customer Contracts

Acquisition Consists of DDoS Protection, DNS Firewall, and Managed and Recursive DNS Services Customer Contracts


LONDON-Saturday 27 October 2018 [ AETOS Wire ]

(BUSINESS WIRE)-- Neustar®, Inc., a trusted, neutral provider of real-time information services, today announced that it has entered into a definitive agreement with VeriSign, Inc. to acquire Verisign’s Security Services customer contracts. The acquisition consists of Distributed Denial of Service (DDoS) Protection, Managed DNS, DNS Firewall and fee-based Recursive DNS services customer contracts. Trusted by the world’s largest brands, Neustar will provide Verisign’s former Security Services’ customers with exceptional service and world-class support backed by a global cloud infrastructure and a broad security services portfolio.

This acquisition will strategically grow Neustar’s leading Digital Defense and Performance solutions by expanding its enterprise customer footprint in several high-growth industries, such as technology, e-Commerce and financial services. Neustar features one of the industry’s most comprehensive security portfolios comprised of DDoS mitigation, web application firewall (WAF), authoritative and recursive DNS, IP and threat intelligence, and website performance management.

Neustar SiteProtect NG™ provides a cloud-based always-on approach to quickly stop the largest DDoS and highly sophisticated web application threats without reducing network performance or adding additional levels of complexity to customers’ existing security strategies. Neustar’s DNS solutions include Neustar UltraDNS, an enterprise grade, cloud-based authoritative service that securely delivers fast and accurate query responses to websites, and Neustar UltraRecursive, a cloud-based service that delivers reliable built-in security and threat intelligence. Neustar’s unique DNS Shield™ network secures private domain name system connections between Neustar and its partners, and strengthens defenses against attacks by removing traffic entirely from the public internet. These products are part of the broad Neustar security portfolio that leverages the unique OneIDTM system of trusted identity, which enhances the efficacy of detecting incoming threats and attacks.

“With this acquisition, Neustar will be able to accelerate its growth in the internet security market, supported by significant investments made to our DDoS and DNS infrastructure, and capacity over the last 12 months,” said Shailesh Shukla, General Manager, Digital Defense and Performance Solutions, Neustar. “We’re excited to introduce new customers to our broad portfolio of solutions and are dedicated to a seamless transition, working closely with the Verisign team. We are wholeheartedly committed to delivering innovative solutions that reduce the disruptions caused by malicious actors and providing world-class customer support.”

“We’ve grown the Neustar SiteProtect NG solution to be one of the world’s largest dedicated networks with more than 10 Tbps mitigation capacity and the Neustar NetProtect™ solution directly connects to a vast network of globally distributed data centers. This is a testament to our steadfast commitment to our customers and consumers. Our number one priority will remain providing all of our customers with a secure infrastructure built on a foundation of unmatched stability, resiliency and performance,” said Charles Gottdiener, President and Chief Executive Officer, Neustar.

“Verisign is committed to focusing on its core mission of providing critical internet infrastructure, including Root Zone management, operation of 2 of the 13 global internet root servers, operation of .gov and .edu, and authoritative resolution for the .com and .net top-level domains, which support the majority of global e-commerce. For this reason, Verisign is transitioning its Security Services customers to Neustar. Neustar has been focused on providing specialised web security and digital performance solutions for many years. Given this experience, we believe Neustar is well-suited to continue to deliver the innovative solutions and world-class performance to which Verisign’s Security Services customers are accustomed,” said Jim Bidzos, Verisign Founder, Chairman and CEO.

About Neustar

Neustar, Inc. is a leading global information services provider driving the connected world forward with responsible identity resolution. As a company built on a foundation of Privacy by Design, Neustar is depended upon by the world’s largest corporations to help grow, guard and guide their businesses with the most complete understanding of how to connect people, places and things. Neustar’s unique, accurate and real-time identity system, continuously corroborated through billions of transactions, empowers critical decisions across our clients’ enterprise needs. More information is available at https://www.home.neustar.

Contacts

Media Contact
Hotwire for Neustar
Hannah Lock
Hannah.lock@hotwireglobal.com
+4420 608 4656


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