1stOncology™: Cancer Intelligence Service – Page 14776 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Abbott Reports Third-Quarter 2018 Results

On October 17, 2018 Abbott (NYSE: ABT) reported financial results for the third quarter ended Sept. 30, 2018 (Press release, Abbott, OCT 17, 2018, View Source [SID1234529970]).

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

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

Schedule Your 30 min Free Demo!

Third-quarter worldwide sales of $7.7 billion increased 12.1 percent on a reported basis and 7.8 percent on an organic* basis.
Reported diluted EPS from continuing operations under GAAP was $0.31 in the third quarter.
Adjusted diluted EPS from continuing operations, which excludes specified items, was $0.75.
Abbott narrowed its full-year 2018 diluted EPS guidance range from continuing operations on a GAAP basis to $1.33 to $1.35 and adjusted diluted EPS from continuing operations to $2.87 to $2.89.
In the U.S., Abbott received FDA approval of its FreeStyle Libre 14 day sensor, making it the longest lasting wearable glucose sensor available. In October, Abbott obtained CE Mark for its FreeStyle Libre 2 system, a next-generation product offering with optional real-time alarms.

FreeStyle Libre achieving rapid market uptake, with third-quarter worldwide sales of $304 million, an increase of 101 percent versus prior year.
In July, Abbott received U.S. FDA approval for its third-generation version of its minimally invasive MitraClip heart valve repair device. This new version includes design advancements that simplify the procedure and enable more patients to be treated with MitraClip.
In September, Abbott announced positive clinical results from its landmark COAPT study, which demonstrated that its minimally invasive MitraClip heart valve repair device improved survival and clinical outcomes for select patients with functional mitral regurgitation, a leaky heart valve resulting from advanced heart failure. The COAPT study data will be submitted to the U.S. FDA to support consideration of an expanded indication for MitraClip.
"We achieved another quarter of strong growth and our new product pipeline continues to be highly productive," said Miles D. White, chairman and chief executive officer, Abbott. "In spite of increasing currency headwinds, we’re well-positioned to achieve the upper end of our initial full-year guidance."

* See note on organic growth below.

THIRD-QUARTER BUSINESS OVERVIEW
Note: Management believes that measuring sales growth rates on an organic basis is an appropriate way for investors to best understand the underlying performance of the business.

Organic sales growth:

Excludes prior year results for the Abbott Medical Optics (AMO) and St. Jude Medical vascular closure businesses, which were divested during the first quarter 2017;
Excludes the current and prior year results for Rapid Diagnostics, which reflect results for Alere Inc., which was acquired on Oct. 3, 2017; and
Excludes the impact of foreign exchange.
Following are sales by business segment and commentary for the third quarter and first nine months of 2018:

* Total 2018 Abbott sales from continuing operations include Other Sales of $45 million.

Note: In order to compute results excluding the impact of exchange rates, current year U.S. dollar sales are multiplied or divided, as appropriate, by the current year average foreign exchange rates and then those amounts are multiplied or divided, as appropriate, by the prior year average foreign exchange rates.

Third-quarter 2018 worldwide sales of $7.7 billion increased 12.1 percent on a reported basis. On an organic basis, worldwide sales increased 7.8 percent. Refer to tables titled "Non-GAAP Reconciliation of Adjusted Historical Revenue" for a reconciliation of adjusted historical revenue.

Worldwide Nutrition sales increased 4.0 percent on a reported basis in the third quarter, including an unfavorable 2.1 percent effect of foreign exchange, and increased 6.1 percent on an organic basis.

Worldwide Pediatric Nutrition sales increased 6.6 percent on a reported basis in the third quarter, including an unfavorable 1.9 percent effect of foreign exchange, and increased 8.5 percent on an organic basis. International pediatric sales increased 7.4 percent on a reported basis, including an unfavorable 3.5 percent effect of foreign exchange, and increased 10.9 percent on an organic basis. Strong performance in the quarter was led by above-market growth in the U.S. and double-digit growth in both Asia and Latin America.

Worldwide Adult Nutrition sales increased 0.8 percent on a reported basis in the third quarter, including an unfavorable 2.4 percent effect of foreign exchange, and increased 3.2 percent on an organic basis. International adult sales increased 2.9 percent on a reported basis, including an unfavorable 4.2 percent effect of foreign exchange, and increased 7.1 percent on an organic basis. Sales performance was led by strong growth of Ensure, Abbott’s market-leading complete and balanced nutrition brand, and Glucerna, Abbott’s market-leading diabetes-specific nutrition brand. U.S. sales were negatively impacted by Abbott’s wind down of a non-core product line.

Diagnostics

* Rapid Diagnostics reflects sales from Alere Inc., which was acquired on Oct. 3, 2017. Organic growth rates above exclude results from the Rapid Diagnostics business.

Worldwide Diagnostics sales increased 42.6 percent on a reported basis in the third quarter. On an organic basis, sales increased 7.5 percent. Refer to tables titled "Non-GAAP Reconciliation of Adjusted Historical Revenue" for a reconciliation of adjusted historical revenue.

Core Laboratory Diagnostics sales increased 5.2 percent on a reported basis in the third quarter, including an unfavorable 2.9 percent effect of foreign exchange, and increased 8.1 percent on an organic basis, reflecting above-market growth in the U.S. and internationally.

Molecular Diagnostics sales increased 4.7 percent on a reported basis in the third quarter, including an unfavorable 1.4 percent effect of foreign exchange, and increased 6.1 percent on an organic basis. Worldwide sales were led by growth in infectious disease testing, Abbott’s core area of focus in the molecular diagnostics market.

Point of Care Diagnostics sales increased 3.7 percent on a reported basis in the third quarter, including an unfavorable 0.3 percent effect of foreign exchange, and increased 4.0 percent on an organic basis, led by strong international growth of Abbott’s i-STAT handheld system.

Rapid Diagnostics worldwide sales of $481 million were led by cardiometabolic testing.

Established Pharmaceuticals sales decreased 0.9 percent on a reported basis in the third quarter, including an unfavorable 6.8 percent effect of foreign exchange, and increased 5.9 percent on an organic basis. As expected, sales growth in the quarter was negatively impacted by a comparison versus the third-quarter 2017, when sales were higher than normal due to channel restocking across the market after implementation of a new tax system in India.

Key Emerging Markets include India, Brazil, Russia and China along with several additional emerging countries that represent the most attractive long-term growth opportunities for Abbott’s branded generics product portfolio. Sales in these geographies decreased 2.1 percent on a reported basis in the third quarter, including an unfavorable 8.9 percent effect of foreign exchange, and increased 6.8 percent on an organic basis. Sales growth was led by double-digit growth in China and Russia. Excluding the negative impact from prior year purchasing patterns associated with the implementation of a new tax system in India, Abbott’s Key Emerging Markets sales would have increased high-single digits on an organic basis in the third quarter.

Worldwide Medical Devices sales increased 8.4 percent on a reported basis in the third quarter. On an organic basis, sales increased 9.8 percent. Refer to table titled "Non-GAAP Reconciliation of Adjusted Historical Revenue" for a reconciliation of adjusted historical revenue.

In Electrophysiology, growth was led by strong performance in cardiac mapping and ablation catheters as well as strong growth of Abbott’s Confirm RxTM Insertable Cardiac Monitor (ICM), the world’s first and only smartphone-compatible ICM designed to help physicians remotely identify cardiac arrhythmias.

Growth in Structural Heart was driven by several product areas across Abbott’s broad portfolio, including AMPLATZERTM PFO Occluder, a device designed to close a hole-like opening in the heart, and MitraClip, Abbott’s market-leading device for the minimally invasive treatment of mitral regurgitation, a leaky heart valve. In September, Abbott announced positive clinical results from its landmark COAPT study, which demonstrated that MitraClip improved survival and clinical outcomes for select patients with functional mitral regurgitation. The COAPT study data will be submitted to the U.S. FDA to support consideration of an expanded indication for MitraClip.

In Diabetes Care, sales increased 37.4 percent on a reported basis and 39.8 percent on an organic basis, led by rapid market uptake of FreeStyle Libre, Abbott’s revolutionary sensor-based continuous glucose monitoring system, which removes the need for routine fingersticks1 for people with diabetes. During the quarter, Abbott received U.S. FDA approval of its FreeStyle Libre 14 day sensor, the longest lasting glucose wearable sensor available. In October, Abbott obtained CE Mark for its FreeStyle Libre 2 system, a next-generation product offering optional real-time alarms.

ABBOTT’S FULL-YEAR EARNINGS-PER-SHARE GUIDANCE

Abbott is narrowing its 2018 diluted earnings per share from continuing operations under Generally Accepted Accounting Principles (GAAP) to $1.33 to $1.35.

Abbott forecasts net specified items for the full year 2018 of approximately $1.54 per share. Specified items include intangible amortization expense, acquisition-related expenses, charges associated with cost reduction initiatives and other expenses.

Excluding specified items, projected adjusted diluted earnings per share from continuing operations would be $2.87 to $2.89 for the full year 2018.

Abbott is issuing fourth-quarter 2018 guidance for diluted earnings per share from continuing operations under GAAP of $0.39 to $0.41. Abbott forecasts specified items for the fourth quarter 2018 of $0.41 primarily related to intangible amortization, acquisition-related expenses, cost reduction initiatives and other expenses. Excluding specified items, projected adjusted diluted earnings per share from continuing operations would be $0.80 to $0.82 for the fourth quarter.

ABBOTT DECLARES 379TH CONSECUTIVE QUARTERLY DIVIDEND

On Sept. 13, 2018, the board of directors of Abbott declared the company’s quarterly dividend of $0.28 per share. Abbott’s cash dividend is payable Nov. 15, 2018, to shareholders of record at the close of business on Oct. 15, 2018.

Abbott has increased its dividend payout for 46 consecutive years and is a member of the S&P 500 Dividend Aristocrats Index, which tracks companies that have annually increased their dividend for at least 25 consecutive years.

Castle Biosciences’ Cutaneous Squamous Cell Carcinoma Prognostic Test Development Progress Highlighted in Oral Presentation at American Society for Dermatologic Surgery Annual Meeting

On October 17, 2018 Castle Biosciences, Inc., the skin cancer diagnostics company providing molecular diagnostics to improve cancer management decisions, reported the presentation of data demonstrating progress in the development of a prognostic gene expression profile test for cutaneous squamous cell carcinoma (cSCC), one of the most common types of cancer (Press release, Castle Biosciences, OCT 17, 2018, View Source [SID1234529966]). The goal of the research program is to validate a gene expression profile test that improves upon current staging systems and identifies patients with cSCC with a high risk for recurrence, enabling more informed clinical management decisions. Aaron Farberg, M.D., Icahn School of Medicine at Mount Sinai, New York, presented the study last week during the Reconstructive, Skin Cancer and Mohs Micrographic Surgery session of the 2018 American Society for Dermatologic Surgery Annual Meeting held in Phoenix.

In this multi-center development study, more than 500 primary cSCC specimens were accrued from 14 centers, and gene expression analysis of candidate genes selected based on literature and pathway analysis was performed through reverse transcription polymerase chain reaction (RT-PCR). Predictive modeling with machine learning was performed on a preliminary development set that included both non-recurrent and recurrent cases with verified clinical data and outcomes.

Researchers successfully identified genes that exhibited significant differential expression between non-recurrent and recurrent cases, including several specific to regional/distant metastasis (p<0.05). An average of the top performing preliminary models for predicting metastasis or local recurrence had higher sensitivity and positive predictive value when compared to current staging methods, and maintained or improved comparable specificity and negative predictive value.

In addition to candidate genes selected from the literature, microarray analysis on 80 recurrent and non-recurrent cases permitted an unbiased, genome-wide approach for selection of additional genes through machine learning for validation.

"These study findings demonstrate continued progress in the development of a prognostic test for cSCC that can identify patients with a risk of metastasis more accurately than currently used staging systems," commented Chrysalyne D. Schmults, M.D., Brigham and Women’s Hospital, Boston, an investigator in the study. "Successful validation and clinical application of a test such as this could help inform clinical decision-making regarding the potential need for adjuvant therapy."

Based on demonstrated progress with initial development work, collaborative site recruitment and clinical study activities are actively continuing.

About Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is one of the most common cancers with an estimated incidence of more than 1,000,000 cases in the U.S. each year. Approximately 20% of patients have high-risk features based on tumor depth, histology, anatomic location and/or immunosuppression. Most patients have a favorable prognosis, but a subset of patients will develop metastasis and up to 15,000 patients each year die from their disease. As current staging parameters have a low positive predictive value, many more patients are considered high risk than actually develop metastatic disease. Conversely, many patients that develop metastatic disease are misidentified as low risk. This leads to over and undertreatment of a substantial number of cSCC patients. To address this clinical need, Castle Biosciences is developing a gene expression profile test to improve upon current staging systems and identify patients with cSCC at high risk for metastasis and death, enabling more informed clinical decisions regarding adjuvant therapy and other management options.

Daiichi Sankyo Submits Application in Japan for FLT3 Inhibitor Quizartinib for Treatment of Patients with Relapsed/Refractory FLT3-ITD AML

On October 17, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that it has submitted a New Drug Application (NDA) to Japan’s Ministry of Health, Labor and Welfare (MHLW) for marketing approval of quizartinib for the treatment of adult patients with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML) (Press release, Daiichi Sankyo, OCT 17, 2018, https://www.prnewswire.com/news-releases/daiichi-sankyo-submits-application-in-japan-for-flt3-inhibitor-quizartinib-for-treatment-of-patients-with-relapsedrefractory-flt3-itd-aml-300732661.html [SID1234529954]). The submission to Japan MHLW is based on the results of the pivotal randomized phase 3 QuANTUM-R study in the U.S., EU and Asia excluding Japan, and an open-label phase 2 study of quizartinib in Japan in patients with relapsed/refractory FLT3-ITD AML.

"Quizartinib has been designed as a specific inhibitor of FLT3 with high affinity for FLT3-ITD, a driver mutation in AML that is linked to poor prognosis and is associated with aggressive disease that results in increased relapse rate and reduced overall survival for patients compared to those without this mutation," said Kouichi Akahane, PhD, MBA, Executive Officer, Head of Oncology Function, R&D Division, Daiichi Sankyo. "We look forward to working closely with the Japan Health Authority on our application for quizartinib in order to bring this important potential new targeted treatment option to patients with relapsed/refractory FLT3-ITD AML in Japan."

Quizartinib is the first FLT3 inhibitor to prolong overall survival as an oral, single agent compared to chemotherapy in patients with relapsed/refractory FLT3-ITD AML. This was demonstrated in a randomized phase 3 trial (QuANTUM-R) and topline results of QuANTUM-R were presented during the plenary program at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in June 2018.

The open-label, single arm phase 2 study evaluating quizartinib in Japanese patients with relapsed/refractory FLT3-ITD AML met its primary endpoint of achieving a predetermined composite complete remission rate at interim analysis, triggering an early stop of the study due to efficacy. The quizartinib efficacy and safety profile observed in the phase 2 study in Japan appears consistent with that of QuANTUM-R. These data were presented at the 80th Annual Meeting of the Japanese Society of Hematology (JSH) in October 2018.

In the QuANTUM-R study, the median treatment duration with quizartinib was 4 cyles of 28 days versus 1 cycle in the salvage chemotherapy arm. Incidence of treatment-emergent adverse events was comparable between patients who received single agent quizartinib and those who received salvage chemotherapy. The most common adverse events (>30 percent, any Grade) in patients treated with quizartinib included nausea, thrombocytopenia, fatigue, musculoskeletal pain, pyrexia, anemia, neutropenia, febrile neutropenia, vomiting and hypokalemia, and the most common Grade ≥ 3 adverse events (>20 percent) were thrombocytopenia, anemia, neutropenia and febrile neutropenia. The safety profile observed in QuANTUM-R appears consistent with that observed at similar doses in the quizartinib clinical development program.

About FLT3-ITD Acute Myeloid Leukemia
AML is an aggressive blood and bone marrow cancer that causes uncontrolled growth and accumulation of malignant white blood cells that fail to function normally and interfere with the production of normal blood cells.1 FLT3 gene mutations are one of the most common genetic abnormalities in AML.2 FLT3-ITD is the most common FLT3 mutation, affecting approximately one in four patients with AML.3,4,5,6 FLT3-ITD is a driver mutation that presents with high leukemic burden and has poor prognosis and a significant impact on disease management for patients with AML.4,7

Patients with FLT3-ITD AML have a worse overall prognosis, including an increased incidence of relapse, an increased risk of death following relapse and a higher likelihood of relapse following hematopoietic stem cell transplantation as compared to those without this mutation.8,9

About Quizartinib
Quizartinib, the lead investigational agent in the AML Franchise of the Daiichi Sankyo Cancer Enterprise, is an oral selective FLT3 inhibitor currently in phase 3 development for relapsed/refractory FLT3-ITD AML (QuANTUM-R) in the U.S. and EU; phase 3 development for newly-diagnosed FLT3-ITD AML (QuANTUM-First) in the U.S., EU and Japan; and, phase 2 development for relapsed/refractory FLT3-ITD AML in Japan.

Quizartinib has been granted Breakthrough Therapy designation for the treatment of adult patients with relapsed/refractory FLT3-ITD AML, and Fast Track designation for the treatment of relapsed/refractory AML by the U.S. Food and Drug Administration (FDA). Quizartinib also has been granted Orphan Drug designation by both the FDA and the European Commission (EC) for the treatment of AML and by the Japan Ministry of Health, Labour and Welfare (MHLW) for the treatment of FLT3-mutated AML.

Quizartinib is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

AbbVie Announces Supplemental New Drug Application Accepted for Priority Review by U.S. FDA for IMBRUVICA® (ibrutinib) in Combination with Obinutuzumab (GAZYVA®) for Previously Untreated Chronic Lymphocytic Leukemia (CLL)

On October 17, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported the U.S. Food and Drug Administration (FDA) has accepted its supplemental New Drug Application (sNDA) for Priority Review for IMBRUVICA (ibrutinib) in combination with obinutuzumab (GAZYVA) in previously untreated adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, OCT 17, 2018, View Source [SID1234529953]). If the sNDA is approved, the use of IMBRUVICA with obinutuzumab could become the first chemotherapy-free, anti-CD20 combination approved by the FDA for the first-line treatment of CLL/SLL. IMBRUVICA is currently FDA-approved to treat adults with CLL/SLL as a single-agent for all lines of therapy and in combination with bendamustine and rituximab (BR).1 IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"Our robust clinical research program with IMBRUVICA continues to reinforce the evidence for its use as an efficacious treatment option in CLL and SLL, this time versus a National Comprehensive Cancer Network guidelines Category 1 treatment, which is the chemoimmunotherapy combination of chlorambucil plus obinutuzumab,"2 said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "Further, for the first time in CLL, results from iLLUMINATE have shown the potential benefits of using an IMBRUVICA-based, chemotherapy-free, anti-CD20 combination. Since its initial approval five years ago, IMBRUVICA has received nine FDA approvals across six different diseases, and we remain committed to advancing new research to understand its full potential in blood cancers like CLL and SLL, as well as other difficult-to-treat diseases with unmet medical needs."

The sNDA submission is based on positive results from the Phase 3 iLLUMINATE (PCYC-1130) trial announced in May 2018, which showed IMBRUVICA plus obinutuzumab was associated with significantly longer progression-free survival (PFS) versus chlorambucil plus obinutuzumab in adults with previously untreated CLL/SLL, as assessed by an Independent Review Committee.

CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).3 While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year.4,5 SLL is a slow-growing lymphoma biologically similar to CLL in which too many immature white blood cells cause lymph nodes to become larger than normal.6 CLL/SLL are predominately diseases of the elderly, with a median age diagnosis ranging from 65-70 years.7

About iLLUMINATE
iLLUMINATE (NCT 02264574) is a Pharmacyclics-sponsored, randomized, multi-center, open-label, Phase 3 study of IMBRUVICA in combination with obinutuzumab versus chlorambucil in combination with obinutuzumab in patients with previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). According to the study protocol, patients enrolled are age 65 years and older or if less than age 65 years must have had at least one of the following criteria: Cumulative Illness Rating Score (CIRS) >6 and Creatinine clearance estimated <70 mL/min using Cockcroft-Gault equation. In the study, patients were randomized to receive IMBRUVICA 420 mg continuously in combination with obinutuzumab 1000 mg intravenously over 6 cycles or chlorambucil on Days 1 and 15 of each cycle plus obinutuzumab 1000 mg intravenously over 6 cycles. The primary endpoint is progression-free survival by Independent Review Committee (IRC), with secondary objectives including overall response rate and rate of minimal residual disease (MRD)-negative responses. As announced in May 2018, the study met its primary endpoint, showing significantly longer progression-free survival (PFS) was associated with adult CLL/SLL patients treated with IMBRUVICA plus obinutuzumab versus chlorambucil plus obinutuzumab, as assessed by an IRC.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by inhibiting a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.8 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).1

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
In August 2018, IMBRUVICA plus rituximab was approved for adult patients with WM.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.9 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, more than 120,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,011 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,011 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustments may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

First patient treated with Transgene TG6002 oncolytic virus in a Phase 1/2 trial in patients with advanced gastrointestinal tumors

On October 17, 2018 Transgene (Paris: TNG) (Euronext Paris: TNG), a biotechnology company that designs and develops viral vector-based immunotherapies, reported the treatment of the first patient in the TG6002 Phase 1/2 trial in patients with advanced gastrointestinal tumors such as colon cancer, in the Léon Bérard center (Lyon) (Press release, Transgene, OCT 17, 2018, View Source [SID1234529952]). This multicenter trial is authorized in France, Belgium and Spain. It will include up to 59 patients.

TG6002 is a new generation multi-functional oncolytic virus that can be administered intravenously and combines several mechanisms of action . It was designed to combine the mechanism of oncolysis (destruction of the cancer cell) with local production of chemotherapy (5-FU), directly into the tumor. Induction of an immune response against tumor cells is another expected effect. TG6002 expresses the patented FCU1 gene in tumor cells that it has infected, leading to the local conversion of 5-FC (administered orally) to 5-FU. This is particularly important because of the sensitivity of most gastrointestinal tumors to 5-FU.

TG6002 has demonstrated in preclinical its ability to induce a response in the primary tumor as well as a distant effect on metastases by causing immunogenic cell death.

Dr. Philippe Cassier, PhD, principal investigator of the trial and head of the early phase trial unit at the Léon Bérard Center, explains: "Despite the improved prognosis of patients over the last 20 years, the median survival of metastatic colorectal cancer (CRC) patients remains below three years. Patients receive up to four successive treatment lines, which can be associated with significant side effects. In addition, the majority of these do not respond to immune checkpoint inhibitors. For this reason, 5-FU-based chemotherapy remains the standard treatment for this disease. TG6002, an oncolytic virus that destroys cancer cells and produces 5-FU at the heart of the tumor, is a promising therapy with the potential to be more effective and better tolerated by patients. "

Dr. Maud Brandely, PhD, Director, Clinical Development, Clinical Operations & Regulatory Affairs at Transgene, adds, "With its multiple mechanisms of action, TG6002 is an extremely promising oncolytic virus that is administered intravenously in this trial. The destruction of cancer cells, the production of chemotherapy in the tumor and the induction of a targeted immune response are all complementary approaches to better attack this disease. We look forward to the results that the oncolytic virus TG6002 will generate in this clinical trial. "

This half-open, single-arm trial is being conducted in Europe. It evaluates the safety and tolerability of multiple and increasing doses of intravenously administered TG6002 in combination with orally administered 5-FC. 5-FC is a non-cytotoxic precursor that can be converted to 5-FU. The primary endpoint of the Phase 1 part of the trial is safety; that of Phase 2 is efficiency. This trial will also evaluate the pharmacokinetic properties and biodistribution of TG6002, as well as the immune modulation of the tumor microenvironment.

About TG6002 A
new generation of oncolytic immunotherapy, TG6002 has been designed to induce the destruction of cancer cells (oncolysis) and to allow the production of 5-FU directly in the tumor. TG6002 is a modified, double-deleted Vaccinia virus (TK-RR-), expressing the patented FCU1 gene in tumor cells that it has infected in order to locally convert 5-FC (flucytosine), into 5-FU, a chemotherapy commonly used. Oncolytic virus TG6002 has shown its efficacy and good tolerability profile in several preclinical models. For Transgene, TG6002 represents a new therapeutic option for patients with recurrent solid tumors.
Another trial of TG6002 is underway in France in recurrent glioblastoma.

About gastrointestinal tumors
Gastrointestinal cancers include several forms of cancers of the digestive system. They include cancers of the esophagus, gall bladder, liver, pancreas, stomach, small bowel, colon, rectum and anus. Colorectal cancer (CRC) is the second most frequently diagnosed cancer in Europe and one of the leading causes of death in Europe and worldwide. In 2012, 447,000 new cases of CRC were reported in Europe, with 215,000 deaths. Worldwide, this represented 1.4 million new cases and 694,000 deaths (Ferlay J. et al., 2013, Ferlay J. et al., 2015). Over the last decade, the prognosis of patients with metastatic CRC has improved