On September 22, 2018 Takeda Pharmaceutical Company Limited ( TSE: 4502 ) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending full approval of ALUNBRIG (brigatinib) as part of a monotherapy for the treatment of adult patients with anaplastic lymphoma (ALK +) kinase positive, advanced non-small cell lung cancer (NSCLC) and previously treated with crizotinib. ALUNBRIG is a tyrosine kinase inhibitor (TKI), designed to target and inhibit the ALK mutation in NSCLC (Press release, Takeda, SEP 22, 2018, View Source [SID1234529524]). Approximately 3% to 5% of patients with NSCLC worldwide have the ALK mutation. If the opinion of the CHMP is confirmed and the European Commission approves the ALUNBRIG, it will be the only ALK inhibitor available in the European Union as a dose of one tablet per day, which can be taken with or without food.

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The Randomized Phase 2 ALTA trial was designed to investigate the efficacy and safety of ALUNBRIG in patients with locally advanced or metastatic ALK + NSCLC who presented progress with crizotinib. Patients were randomized to receive one of two ALUNBRIG regimens: ALUNBRIG 90 mg once daily (n = 112) or 180 mg once daily with induction from 7 days to 90 mg once daily (n = 110) .

"ALK + NSCLC is a serious, life-threatening disease that affects approximately 40,000 people worldwide each year, with many patients progressing or failing to respond to first-line treatment," said Stefania Vallone, president, Lung Cancer Europe . "For Europeans with ALK + NSCLC, there remains a significant need not met by new and effective treatment options."

"Although ALK inhibitors have shown tremendous growth over this period of treatment over the past decade, another targeted therapy option available for ALK + NSCLC treatment has been awaited with anticipation and anticipation," said Enriqueta Felip, MD, PhD, chief of the Thoracic Oncology Unit, Department of Oncology at the Vall d’Hebron University Hospital in Barcelona. "With a median progression free survival of 16.7 months and an overall survival of 34.1 months, ALUNBRIG demonstrated impressive results, representing new progress for ALK + NSCLC treatment in this setting."

"The ALTA trial established ALUNBRIG as a possible second-line treatment option for ALK + NSCLC, demonstrating significant efficacy with a manageable safety profile," said Jesús Gómez-Navarro, MD, vice president, chief of Clinical Research and Development in Oncology in Takeda. "With 16.7 months of progression-free median survival, the longest of any ALK inhibitors to be reported in this setting, ALUNBRIG offers great potential for patients who progressed with crizotinib. Today’s positive opinion brings us closer to the ultimate goal of advancing the treatment paradigm for the considerable number of critically ill ALK + patients treated with crizotinib who live in Europe.

As part of this submission, the CHMP also analyzed data from the first interim review of the Phase 3 ALTA-1L trial, which fulfilled its main objective as evidence of support. In ALTA-1L, treatment with ALUNBRIG resulted in a statistically and clinically significant improvement in progression-free survival (PFS) versus crizotinib, as assessed by an independent blind review committee. The safety profile associated with ALUNBRIG has generally been consistent with previous studies and with labeling approved in the USA and Canada.

The CHMP’s positive opinion on ALUNBRIG will now be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 member states of the European Union, as well as in Norway, Liechtenstein and Iceland.

About the ALTA test

The Phase 2 ALTA (acronym for A LK in L ung Cancer T rial of AP26113) in adults is a multicenter, open, randomized, continuous, multi-center trial involving 222 patients with locally advanced or metastatic ALK + NSCLC who progressed on crizotinib. Patients received ALUNBRIG at a dose of 90 mg once daily (n = 112) or 180 mg once daily with induction of seven days at 90 gm once daily (n = 110). The confirmed objective response rate (ORT), evaluated by the investigator according to RECIST v1.1, was the primary endpoint. Additional major endpoints included ORT, independent response committee (IRR), duration of response (DOR), progression-free survival (PFS), intracranial ORT, intracranial DOR, safety and tolerability.

The results of the ALTA trial demonstrated that, of the patients who received the 180 mg dosing regimen, 56% achieved an objective response rate as measured by the investigator and 56% by the CRI assessment. The median DOR was 13.8 months, as assessed by the investigator, and 15.7 months for the IRC evaluation. The median SLP was 15.6 months, as assessed by the investigator, and 16.7 months by the IRC evaluation. In addition, of the patients with measurable brain metastases at baseline (n = 18), 67% achieved intracranial ORR due to CRI; the median duration of intracranial response was 16.6 months by the CRI assessment. Median overall survival was 34.1 months, as assessed by the investigator.

The most frequent (≥ 25%) adverse reactions reported in ALUNBRIG-treated patients on the 180 mg dosing regimen were increased aspartate aminotransferase (AST), hyperglycemia, hyperinsulinemia, anemia, increased creatine phosphokinase (CPK), nausea, increased lipase, decreased lymphocyte count, increased alanine aminotransferase (ALT), diarrhea, increased amylase, fatigue, cough, headache, increased alkaline phosphatase, hypophosphataemia, increased abnormal activated partial thromboplastin time (APTT), rash, vomiting, dyspnoea, hypertension, decreased blood cell count, myalgia, and peripheral neuropathy.

About the ALTA-1L test

The Phase 3 ALTA-1L (acronym for A LK in L ung Cancer T rial of Brig A tinibe in 1 to Linha) in adults is an open, randomized, continuous, multicenter, global trial involving 275 patients with locally advanced or metastatic ALK + NSCLC who did not receive prior treatment with an ALK inhibitor. Patients received ALUNBRIG at the dose of 180 mg once daily with induction from 7 days to 90 mg once daily, or crizotinib at the dose of 250 mg twice daily. Progression-free survival (SLP) evaluated by the Independent Review Committee (IRC) was the primary endpoint. Secondary endpoints included objective response rate (ORT) according to RECIST v1.1, intracranial ORT, intracranial SLP, overall survival (OS), safety, and tolerability. A total of approximately 198 SLP events were planned in the final analysis of the primary endpoint to demonstrate a minimum of six months of improvement of SLP over crizotinib. The assay was developed with two pre-specified intermediate analyzes for the primary endpoint – one in approximately 50% of the planned PFS events and one in approximately 75% of the planned events of the SLP.

About CPNPC ALK +

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for about 85% of the estimated 1.8 million new lung cancer cases diagnosed each year worldwide, according to the Organization World Health Organization. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma (ALK) kinase are fundamental motivators in a subset of patients with NSCLC. About 3% to 5% of patients with metastatic NSCLC have a rearrangement in the ALK gene.

Takeda is committed to continuing research and development at CPNPC to enhance the lives of the approximately 40,000 patients diagnosed with this severe and rare form of lung cancer worldwide each year.

About ALUNBRIG (brigatinib)

ALUNBRIG is a cancer-fighting drug discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 2017, ALUNBRIG received accelerated approval from the US Food and Drug Administration (FDA) for patients with ALK + metastatic NSCLC, which have progressed or are intolerant to crizotinib. This indication was approved from accelerated approval, based on the tumor response rate and duration of response. Continuous approval for this indication may be conditional upon verification and description of clinical benefits in a confirmatory trial. In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with metastatic ALK + NSCLC, who progressed or who were intolerant of an ALK inhibitor (crizotinib). ALUNBRIG’s approvals by the FDA and Health Canada were based primarily on the results of the ALTA Phase 2 trial (acronym forThe LK in U UNG Cancer T rial of the P26113).

ALUNBRIG has received the Breakthrough Therapy (FDA) designation of the FDA for the treatment of patients with critically ill ALK + NSCLC whose tumors are resistant to crizotinib and has been granted the Orphan Drug Designation by the FDA for the treatment of ALK + NSCLC, ROS1 + NSCLC and CPNPC EGFR +.

The brigatinib clinical development program further enhances Takeda’s continued commitment to the development of innovative therapies for people living with ALK + NSCLC worldwide and healthcare professionals who treat this disease. The comprehensive program includes the following clinical trials:

Phase 1/2 trial, which was designed to assess ALUNBRIG’s safety, tolerability, pharmacokinetics and antitumor activity
A phase 2 ALTA pivotal trial investigating the efficacy and safety of ALUNBRIG in two dosing regimens in patients with locally advanced or metastatic ALK + NSCLC who progressed with crizotinib
Phase 3 ALTA-1L trial, a randomized, global trial evaluating the efficacy and safety of ALUNBRIG in relation to crizotinib in patients with locally advanced or metastatic ALK + NSCLC who did not receive prior treatment with an ALK inhibitor
Single-phase, multicenter, phase 2 study in Japanese patients with ALK + NSCLC, focusing on patients who progressed in alectinib
A single-arm global phase 2 study evaluating ALUNBRIG in patients with advanced ALK + NSCLC who progressed in alectinib or ceritinib
A global randomized phase 3 trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK + NSCLC who progressed in crizotinib
For more information on brigatinib’s clinical trials, visit www.clinicaltrials.gov .

IMPORTANT SAFETY INFORMATION (USA)

WARNINGS AND PRECAUTIONS

Interstitial lung disease (IPD) / pneumonia: fatal life-threatening pulmonary adverse events consistent with interstitial lung disease (IPD) / pneumonia occurred with ALUNBRIG. In the ALTA trial, IPD / pneumonia 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). once daily with induction from 7 days to 90 mg once daily). Adverse reactions consistent with IPD / pneumonia occurred earlier (in 9 days after ALUNBRIG started, 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 (eg, dyspnoea, cough, etc.), particularly during the first week of ALUNBRIG. Discontinue ALUNBRIG in any patient with new or worsening respiratory symptoms and immediately assess whether there is an IPD / pneumonia or other causes of respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 PID / pneumonia, restart ALUNBRIG with dosage reduction after recovering the initial level or permanently discontinuing ALUNBRIG. Permanently discontinue ALUNBRIG for grade 3 or 4 PID / pneumonia or recurrence of grade 1 or 2 IPD / pneumonia. restart the ALUNBRIG with reduction of the dosage, after recovering the initial level or interrupt ALUNBRIG permanently. Permanently discontinue ALUNBRIG for grade 3 or 4 PID / pneumonia or recurrence of grade 1 or 2 IPD / pneumonia. restart the ALUNBRIG with reduction of the dosage, after recovering the initial level or interrupt ALUNBRIG permanently. Permanently discontinue ALUNBRIG for grade 3 or 4 PID / pneumonia or recurrence of grade 1 or 2 IPD / pneumonia.

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. In general, grade 3 hypertension occurred in 5.9% of the patients. Check blood pressure before ALUNBRIG treatment. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Discontinue use of ALUNBRIG for grade 3 hypertension despite optimal antihypertensive therapy. After resolution or improvement to grade 1 severity, restart ALUNBRIG at a reduced dosage. Consider stopping ALUNBRIG treatment for grade 4 hypertension or recurrence of grade 3 hypertension.

Bradycardia: bradycardia may occur with ALUNBRIG. At ALTA, heart rates below 50 beats per minute (bpm) occurred in 5.7% of the patients in the 90 mg group and 7.6% of the patients in the 90 → 180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor your heart rate and blood pressure during ALUNBRIG treatment. Monitor patients more often if it is not possible to avoid the concomitant use of medication known to cause bradycardia. For symptomatic bradycardia, discontinue ALUNBRIG and review the concomitant use of medicines for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or the dosage adjusted, restart ALUNBRIG at the same dosage, after symptomatic bradycardia has subsided; Otherwise, reduce ALUNBRIG dosage after reduction of symptomatic bradycardia. Stop ALUNBRIG for life-threatening bradycardia if the contribution of a concomitant medication is not identified.

Visual disturbance: in ALTA, adverse reactions that caused visual disturbance, including blurred vision, diplopia and reduced visual acuity, were recorded in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of the patients in the 90 → 180 group mg. Grade 3 macular edema and cataract occurred in one patient in each case in the 90 → 180 mg group. Advise patients to report any visual symptoms. Discontinue ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening grade 2 or greater severity of visual symptoms. After grade 2 or 3 visual impairment is restored for grade 1 or initial plateau pain, restart ALUNBRIG at a reduced dosage..

Elevated creatine phosphokinase (CPK): in ALTA, elevated creatine phosphokinase (CPK) 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 or 4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90 → 180 mg group. The reduction in CPK elevation was observed 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 pain, tenderness, or muscle weakness. Monitor CPK levels during treatment with ALUNBRIG. Discontinue ALUNBRIG if CPK grade 3 or 4 is elevated. After resolving or restoring to grade 1 or the initial plateau, restart ALUNBRIG at the same dosage or at a reduced dosage.

Elevation of pancreatic enzymes: in ALTA, increased amylase occurred in 27% of patients in the 90 mg group and 39% in the 90 → 180 mg group. Lipase elevations occurred in 21% of the patients in the 90 mg group and 45% of the patients in the 90 → 180 mg group. Elevation of grade 3 or 4 amylase occurred in 3.7% of patients in the 90 mg group and 2.7% in the 90 → 180 mg group. Elevation of grade 3 or 4 lipase occurred in 4.6% of patients in the 90 mg group and 5.5% in the 90 → 180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Discontinue use of ALUNBRIG if there is elevation of pancreatic enzymes to grade 3 or 4. After resolution or recovery to grade 1 or baseline, restart ALUNBRIG at the same dosage or with a reduced dosage.

Hyperglycemia: in ALTA, 43% of patients receiving ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on the laboratory evaluation of fasting serum glucose levels, occurred in 3.7% of the patients. Two of 20 (10%) patients with diabetes or glucose intolerance at the initial level requested the start of insulin use while receiving ALUNBRIG. Analyze fasting serum glucose before ALUNBRIG starts and then monitor periodically. Initiate or optimize antihyperglycemic medications as needed. If adequate control of hyperglycaemia can not be achieved with optimal medical management,

Embryo-fetal toxicity : Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal injury when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise the pregnant women about the potential risk to the fetus. Advise women with reproductive capacity to use effective non-hormonal contraceptives during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise men with reproductive partners to use effective contraceptives during treatment and for at least 3 months after the last dose of ALUNBRIG .

ADVERSE REACTIONS

Serious adverse reactions occurred in 38% of the patients in the 90 mg group and 40% of the 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 IPD / pneumonia (4.6% in total , 1.8% in the 90 mg group and 7.3% in the 90 → 180 mg group). Fatal adverse reactions occurred in 3.7% of the patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory arrest, 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 dyspnoea (27%), and in the group of 90 → 180 mg (40%), diarrhea (38%), fatigue (36%), cough (34%) and headache (27%).

DRUG INTERACTIONS

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

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

CYP3A Substrates: Co-administration of ALUNBRIG with substrates of CYP3A, including hormonal contraceptives, may result in decreased concentrations and loss of efficacy of CYP3A substrates.

USE ON SPECIFIC GROUPS

Pregnancy: ALUNBRIG can harm the fetus. Advise women with reproductive capacity about the potential risk to the fetus.

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

Men and women with reproductive capacity:

Contraception : advise women with reproductive potential to use effective non-hormonal contraceptives during ALUNBRIG treatment and for at least 4 months after final dosing. Advise men living with women in reproductive capacity to use effective contraceptives during treatment with ALUNBRIG and for at least 3 months after the final dosing.

Infertility : ALUNBRIG can cause fertility reduction in men.

Pediatric use: The safety and efficacy of ALUNBRIG in pediatric patients has not been established.

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

Hepatic or renal impairment: no dosage 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.

On September 21, 2018 Seattle Genetics, Inc. (Nasdaq: SGEN) reported that its collaborator, Takeda Pharmaceutical Company Limited (Takeda), has received approval from the Japanese Ministry of Health, Labour and Welfare for ADCETRIS (brentuximab vedotin) in combination with doxorubicin, vinblastine and dacarbazine (AVD) as a frontline treatment option for CD30-positive Hodgkin lymphoma patients in Japan (Press release, Seattle Genetics, SEP 21, 2018, View Source;p=RssLanding&cat=news&id=2368435 [SID1234529705]). As a result, Seattle Genetics will receive a milestone payment from Takeda of $10 million. The approval in Japan was based on the positive outcome from the phase 3 ECHELON-1 trial.

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"This approval marks another important milestone in expanding the ADCETRIS brand globally and redefining the way newly diagnosed Hodgkin lymphoma patients are treated around the world," said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "ADCETRIS is approved in 71 countries and generated global sales of approximately $640 million in 2017, underscoring its progress toward becoming the foundation of therapy for patients with CD30-expressing lymphomas."

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. Seattle Genetics is entitled to receive progress- and sales-dependent milestone payments. In addition, Seattle Genetics receives tiered double-digit royalties with percentages ranging from the mid-teens to mid-twenties based on net sales of ADCETRIS within Takeda’s territories.

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. Classical 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, over 62,000 people worldwide are diagnosed with Hodgkin lymphoma each year and approximately 25,000 people die each year from this cancer.

About ADCETRIS (brentuximab vedotin)

ADCETRIS is being evaluated broadly in more than 70 clinical trials, including the ongoing phase 3 ECHELON-2 trial in frontline peripheral T-cell lymphomas (also known as mature T-cell lymphoma), the completed phase 3 ALCANZA trial in cutaneous T-cell lymphoma (CTCL) and the completed ECHELON-1 trial in previously untreated Hodgkin lymphoma, as well as trials in many additional types of CD30-positive lymphomas.

ADCETRIS is an 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-expressing 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 transplantation (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 71 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See select important safety information, including Boxed Warning, below.

On September 21, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has granted a positive opinion for VENCLYXTO (venetoclax tablets) in combination with rituximab for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who have received at least one prior therapy (Press release, AbbVie, SEP 21, 2018, View Source [SID1234529545]). The positive CHMP opinion is a scientific recommendation for marketing authorization to the European Commission (EC), which will deliver its final decision, valid in all 28 member states of the European Union, as well as Iceland, Liechtenstein and Norway.

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In 2016, VENCLYXTO was approved by the EC as a monotherapy for the treatment of R/R CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor. If approved by the EC, VENCLYXTO plus rituximab could be prescribed to a broader patient population with R/R CLL than the currently approved indication for VENCLYXTO monotherapy in the EU.

"This positive CHMP opinion is one important step forward as AbbVie continues to further the research and development of novel medicines with the potential to transform the standard of care in blood cancers," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "The combination of VENCLYXTO with rituximab has the potential to give patients with relapsed/refractory chronic lymphocytic leukemia a chance to live longer without their disease progressing, and to stop treatment after their two-year course."

The CHMP positive opinion is based on results from the MURANO Phase 3 clinical trial, which evaluated the efficacy and safety of VENCLYXTO in combination with rituximab compared with bendamustine in combination with rituximab. At the time of the primary analysis, the trial demonstrated a statistically significant improvement in investigator-assessed progression-free survival (PFS; the time on treatment without disease progression or death2) for patients who received VENCLYXTO plus rituximab compared with bendamustine plus rituximab.1

In the MURANO clinical trial, undetectable minimal residual disease (uMRD), also known as minimal residual disease negativity (MRD-) was a secondary endpoint assessed at the end of combination therapy (nine-month assessment). The majority of patients in the trial who received VENCLYXTO plus rituximab achieved uMRD in the peripheral blood.1 Undetectable minimal residual disease, is defined as the presence of less than one CLL cell in 10,000 white blood cells remaining in the blood or bone marrow following treatment.2

"The venetoclax plus rituximab combination has the potential to be truly transformative for patients with relapsed/refractory CLL," said Prof. John Seymour, MBBS, Ph.D., lead investigator of the MURANO trial and Director of Cancer Medicine at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia. "The progression-free survival observed in the MURANO trial, and the fixed duration of treatment that may allow patients to stop treatment, are encouraging developments with the potential to advance the care and management of patients with relapsed/refractory CLL."

CLL is a slow-growing form of leukemia, or blood cancer, in which too many immature lymphocytes (a type of white blood cell) are found predominantly in the blood and bone marrow.3 CLL accounts for approximately one third of new leukemia diagnoses.4

VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the MURANO Trial
A total of 389 patients with R/R CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized, Phase 3 MURANO trial. The trial was designed to evaluate the efficacy and safety of VENCLYXTO in combination with rituximab (N=194) compared with bendamustine in combination with rituximab (N=195). The median age of patients in the trial was 65 years (range: 22-85).1

The primary efficacy endpoint was investigator (INV)-assessed PFS. Additional efficacy endpoints included independent review committee (IRC)-assessed PFS, INV- and IRC-assessed overall response rate (defined as complete response + complete response with incomplete marrow recovery + partial response + nodular partial response), overall survival, and rates of uMRD.1

About VENCLYXTO (venetoclax tablets)
VENCLEXTA (VENCLYXTO in the EU) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other cancerous tumors, BCL-2 builds up and prevents cancer cells from undergoing their natural death or self-destruction process, which is called apoptosis. VENCLEXTA targets the BCL-2 protein and works to restore the process of apoptosis.

VENCLEXTA/ VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers.

VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S. AbbVie and Roche are currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

Important VENCLYXTO (venetoclax tablets) EU Safety Information5

Contraindications
Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use
Tumor lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS. Blood chemistries should be monitored and abnormalities managed promptly. More intensive measures (including IV hydration, frequent monitoring and hospitalization) should be employed as overall risk increases.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period. Serious infections including events of sepsis with fatal outcome have been reported. Supportive measures including antimicrobials for any signs of infection should be considered.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations.

Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Coadministration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade were neutropenia/neutrophil count decreased, diarrhea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation.

The most frequently occurring adverse reactions (>=2%) were pneumonia, febrile neutropenia and TLS.

Discontinuations due to adverse reactions occurred in 9.1% of patients and dosage adjustments due to adverse reactions occurred in 11.8% of patients.

Specific Populations
Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined. VENCLYXTO should be administered to patients with severe renal impairment only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS.

VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment. Advise nursing women to discontinue breastfeeding during treatment.

On September 21, 2018 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas" ) reported that XOSPATA Tablets 40 mg (generic name: gilteritinib), a FLT3 (FMS-like tyrosine kinase 3) inhibitor received manufacturing and marketing approval for the treatment of FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML) in Japan (Press release, Astellas, SEP 21, 2018, View Source [SID1234536692]).

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AML is a cancer that impacts the blood and bone marrow, and its incidence increases with age. In Japan, approximately 5,500 patients are diagnosed with AML each year1. XOSPATA has demonstrated inhibitory activity against both internal tandem duplication (ITD) and tyrosine kinase domain (TKD), FLT3 mutations that are seen in approximately one-third of patients with AML.

This approval is based on the CR/CRh2 rate results from the interim analysis of the multinational Phase 3 ADMIRAL study. In October 2015, gilteritinib was designated as one of the first products in Japan to be included in the SAKIGAKE3 designation system. A similar application for approval was filed in the United States in March, 2018 and is currently under review.

With this approval, Astellas hopes to further contribute to the health of patients suffering from AML and to support healthcare professionals involved in the treatment of AML by providing new treatment options.

Astellas reflected the impact from this approval in its financial forecasts of the current fiscal year ending March 31, 2019.

On November 21, 2018 Kyowa Hakko Kirin Co., Ltd., (Kyowa Kirin) reported that the Committee for Medicinal Products for Human Use (CHMP), the European Medicines Agency’s (EMA) scientific committee, has adopted a Positive Opinion recommending approval of the marketing authorisation of mogamulizumab, a humanised monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4), for the treatment of adult patients with mycosis fungoides (MF) or Sézary syndrome (SS) who have received at least one prior systemic therapy (Press release, Kyowa Hakko Kirin, NOV 21, 2018, View Source [SID1234531624]).
MF and SS are the two most common subtypes of cutaneous T-cell lymphoma (CTCL), a rare type of non-Hodgkin’s lymphoma.

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The CHMP’s opinion is now being referred to the European Commission (EC), for a final decision on the grant of a marketing authorisation. This decision is expected by the end of 2018 and will apply to all 28 countries of the European Union, Norway, Iceland and Liechtenstein.

"At Kyowa Kirin we are fully committed to contributing to the health and wellbeing of patients across Europe who are living with mycosis fungoides and Sézary syndrome," said Mitsuo Satoh, Ph.D., Executive Officer, Vice President Head of R&D Division of Kyowa Hakko Kirin. "I am happy about the CHMP’s opinion which takes us one step closer to obtaining an EU marketing authorisation, launching mogamulizumab and to leaping forward to becoming a global specialty pharmaceutical company."

"Mycosis fungoides (MF) and Sézary syndrome (SS) can be disfiguring, debilitating, and even life-threatening, and there are limited treatment options for these rare lymphoma subtypes in Europe today," said Jeffrey S. Humphrey, MD, President of Kyowa Kirin Pharmaceutical Development, Inc. "MAVORIC, the pivotal Phase 3 trial of mogamulizumab, is the largest study of systemic therapy ever conducted in MF and SS. The study showed that mogamulizumab prolonged progression-free survival compared to vorinostat in patients with MF or SS. We will continue to work with the scientific community to advance the understanding of these complex diseases, and we look forward to working with health authorities to bring this important new option to Europe."

If mogamulizumab is approved, Kyowa Kirin International PLC, a Kyowa Hakko Kirin Group company, will be responsible for commercializing mogamulizumab in Europe.

The Kyowa Hakko Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

Mogamulizumab Regulatory Status in EU
The EMA’s scientific committee, CHMP adopted a Positive Opinion recommending the approval of the marketing authorisation of mogamulizumab for the treatment of adult patients with mycosis fungoides (MF) or Sézary syndrome (SS) after at least one prior systemic therapy. The CHMP’s recommendation is now being referred to the European Commission (EC), which is expected to render its final decision by the end of 2018. The EC typically adheres to the recommendation of the CHMP, but is not obligated to do so.