May 2016 – Page 5 – 1stOncology™: Cancer Intelligence Service

European Commission Approves IMBRUVICA® (ibrutinib) for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia

On May 31, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported that the European Commission (EC) approved IMBRUVICA (ibrutinib) as a first-line treatment option for adult patients with chronic lymphocytic leukemia (CLL), expanding upon the initial EC approval in October 2014 for certain patients with CLL (Press release, AbbVie, MAY 31, 2016, View Source [SID:1234512870]).

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

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

Schedule Your 30 min Free Demo!

This decision comes just one month after the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued an opinion in favor of the use of IMBRUVICA for the treatment of adult patients with first-line chronic lymphocytic leukemia (CLL) in the European Union (EU).

The broadened indication is based on data from the Phase 3 RESONATE-2 (PCYC-1115) trial, which also served as the basis for the March 2016 U.S. approval in the first-line CLL/SLL treatment setting and the May 2016 update to the U.S. Prescribing Information to include positive overall survival data.1

This approval marks a number of significant landmarks for IMBRUVICA: this is the drug’s fifth treatment indication in the EU and this approval means that IMBRUVICA is now available to treat all lines of CLL in the EU. Patients with treatment-naive CLL, relapsed/refractory CLL and those with the genetic mutations del 17p or TP53, can all now benefit from treatment with single-agent IMBRUVICA.

IMBRUVICA is jointly developed and commercialized in the U.S. by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc. In Europe, Janssen-Cilag International NV (Janssen) holds the marketing authorization and its affiliates market IMBRUVICA in EMEA (Europe, Middle East, Africa), as well as the rest of the world. IMBRUVICA is already approved in Europe to treat adult patients with relapsed/refractory mantle cell lymphoma (MCL), adult patients with CLL who have received at least one prior therapy or who have del 17p or TP53 mutations, and adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or as a first-line treatment for WM patients unsuitable for chemo-immunotherapy.2

The approval was based on data from the Phase 3, randomized, open-label RESONATE-2 (PCYC-1115) trial, which were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2015 and simultaneously published in The New England Journal of Medicine (NEJM). After a median of 18 months of follow-up, IMBRUVICA was associated with a significant improvement in several efficacy endpoints versus chlorambucil in patients aged 65 or older with newly diagnosed CLL. Specifically, IMBRUVICA was associated with a 90% progression-free survival rate (PFS; the primary endpoint) versus 52% for chlorambucil. Moreover, IMBRUVICA showed statistically significant prolonged overall survival (OS; a key secondary endpoint). The safety of IMBRUVICA in the treatment-naïve CLL patient population was consistent with previously reported studies.

About the RESONATE-2 Study
RESONATE-2 is a Pharmacyclics-sponsored study which enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The primary endpoint of the study was PFS as assessed by an Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis. Key secondary endpoints included overall response rate (ORR; based on the same iWCLL criteria), OS and safety.

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK).1 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.1,[3] IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.1

IMBRUVICA is approved in the U.S. to treat patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia (WM). Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.1

IMBRUVICA is approved in the EU to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL), previously untreated adult patients with chronic lymphocytic leukaemia (CLL) or those who have received at least one prior therapy, and adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or first line patients unsuitable for chemo-immunotherapy.2

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers. More than 6,000 patients have been treated with IMBRUVICA in clinical trials. Currently, 14 Phase 3 trials have been initiated with IMBRUVICA and more than 90 trials are registered on www.clinicaltrials.gov.

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 up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half 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 postsurgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 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 antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, 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.

ADVERSE REACTIONS

The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia*(41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia 21%).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.

Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and nuetropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source

Genmab Achieves USD 30 Million Milestone in DARZALEX® (daratumumab) Collaboration with Janssen

On May 30, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported it has achieved a USD 30 million milestone in its DARZALEX (daratumumab) collaboration with Janssen Biotech, Inc. (Janssen) (Press release, Genmab, MAY 30, 2016, View Source [SID:1234512868]).

The milestone payment was triggered by the first commercial sale of DARZALEX in Europe. The European Commission (EC) recently granted a conditional marketing authorization for first-in-class CD38 immunotherapy DARZALEX (daratumumab) for use as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

"We continue to be impressed by the rapid speed with which our collaboration partner, Janssen, has been able to develop and launch DARZALEX in Europe," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

This milestone was included in Genmab’s previously issued financial guidance for 2016.

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is indicated in Europe for use as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,2 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,2 antibody-dependent cellular phagocytosis3,4 and antibody-dependent cellular cytotoxicity.1,2 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor.

Thermo Fisher Scientific to Acquire FEI Company

On May 27, 2016 Thermo Fisher Scientific Inc. (NYSE:TMO), the world leader in serving science, and FEI Company (NASDAQ:FEIC), the leader in high-performance electron microscopy, reported that their boards of directors have unanimously approved Thermo Fisher’s acquisition of FEI for $107.50 per share in cash. The transaction represents a purchase price of approximately $4.2 billion (Press release, Thermo Fisher Scientific, MAY 27, 2016, View Source [SID:1234512844]).

FEI designs, manufactures and supports high-performance electron microscopy workflows that provide images and information at micro-, nano- and picometer scales. Through its industry-leading offering, FEI enables customers across life sciences and materials science markets to make breakthrough discoveries and increase productivity. Based in Hillsboro, Oregon, FEI has more than 3,000 employees worldwide and maintains R&D, sales and manufacturing operations primarily in Europe and the U.S. The business, which had 2015 revenues of $930 million, will become part of Thermo Fisher’s Analytical Instruments Segment.

"The addition of FEI’s leading electron microscopy platform is an outstanding strategic fit with our company and will create significant value for our customers and our shareholders," said Marc N. Casper, president and chief executive officer of Thermo Fisher Scientific. "In life sciences, there is growing adoption of electron microscopy to study the structure of proteins. The technologies we gain with FEI will complement our mass spectrometry leadership, putting Thermo Fisher in the best position to capitalize on this important trend. As the unrivaled leader in life sciences, we will also be able to leverage our global scale and commercial reach to extend the use of FEI’s products within our large biopharma customer base. Finally, the transaction will be immediately accretive to our earnings and will create value for our shareholders through cost and revenue synergies."

Don Kania, president and chief executive officer of FEI, said, "We are pleased to reach this agreement with Thermo Fisher, which offers a number of important benefits to FEI shareholders, customers and employees. Our shareholders will see substantial and immediate value through the terms of this transaction. Our customers will benefit from the shared commitment Thermo Fisher and FEI have to innovation and customer service. And our employees will see new opportunities as our development and market expansion plans accelerate by being part of Thermo Fisher, a large and growing company. Fundamentally, this transaction bolsters our already strong position in the marketplace and allows us to play an increasing role in enabling our customers to accelerate breakthrough discoveries, increase productivity and provide solutions to global challenges."

Casper concluded, "We are very excited to welcome our new colleagues from FEI to the Thermo Fisher team and look forward to realizing the significant benefits of the transaction for all our key stakeholders. FEI’s commitment to R&D, strong IP foundation, and excellent services and software offerings are a great fit with our Analytical Instruments business and will create exciting new opportunities to drive growth."

Benefits of the Transaction

Leading Electron Microscopy Platform Complements Mass Spectrometry Leadership to Accelerate Advancements in Structural Biology. FEI’s high-end electron microscopes (EM) are complementary to Thermo Fisher’s mass spectrometry systems used for protein identification and characterization. FEI’s Cryo-EM technology, for example, is a disruptive technique used increasingly for the analysis of proteins in structural biology. With its global scale and commercial reach, Thermo Fisher also has the opportunity to drive the adoption of FEI’s technologies among its life sciences customers, particularly in biopharma.
Creates New Opportunities to Expand Presence in Attractive Materials Science Market. FEI brings unique imaging technologies that improve quality and productivity, and expand Thermo Fisher’s capabilities in materials science. Its 3D nano-characterization and nano-prototyping technologies, for example, are critical tools that support the growing trend toward development of devices that are increasingly smaller and more complex to manufacture. Thermo Fisher will benefit from FEI’s strong presence in the semiconductor market, creating a new growth opportunity within this customer set.
Proprietary, Global Services Business Generates High-Margin, Recurring Revenue Stream. FEI brings an industry-leading services business supported by more than 800 employees in over 20 countries, enabling customers to achieve maximum productivity from their instruments. The services business drives high-margin, recurring revenues that represent approximately 25% of total FEI sales, and will contribute to Thermo Fisher’s growing services capabilities.
Delivers Attractive Financial Benefits. The transaction is expected to be accretive to Thermo Fisher’s adjusted EPS1 by $0.30 in the first full year after close. Thermo Fisher expects to realize total synergies of approximately $80 million by year three following the close, consisting of approximately $55 million of cost synergies and approximately $25 million of adjusted operating income1 benefit from revenue-related synergies.
Approvals and Close

The transaction, which is expected to be completed by early 2017, is subject to the approval of FEI shareholders and the satisfaction of customary closing conditions, including applicable regulatory approvals. Thermo Fisher intends to use proceeds from committed debt financing and cash on hand to fund the transaction.

Advisors

JP Morgan is acting as financial advisor to Thermo Fisher, and Wachtell, Lipton, Rosen & Katz is serving as legal counsel. Goldman, Sachs & Co. is acting as financial advisor to FEI, and Wilson Sonsini Goodrich & Rosati is serving as legal counsel.

Use of Non-GAAP Financial Measures

In addition to the financial measures prepared in accordance with generally accepted accounting principles (GAAP), we use certain non-GAAP financial measures, including adjusted EPS and adjusted operating income, which exclude certain acquisition-related costs, including charges for the sale of inventories revalued at the date of acquisition and significant transaction costs; restructuring and other costs/income; and amortization of acquisition-related intangible assets. Adjusted EPS also excludes certain other gains and losses that are either isolated or cannot be expected to occur again with any regularity or predictability, tax provisions/benefits related to the previous items, benefits from tax credit carryforwards, the impact of significant tax audits or events and the results of discontinued operations. We exclude the above items because they are outside of our normal operations and/or, in certain cases, are difficult to forecast accurately for future periods. We believe that the use of non-GAAP measures helps investors to gain a better understanding of our core operating results and future prospects, consistent with how management measures and forecasts the company’s performance, especially when comparing such results to previous periods or forecasts.

8-K/A [Amend] – Current report

On May 27, 2016 Baxalta Incorporated (NYSE: BXLT) reported the results of a vote on the proposals identified in the definitive proxy statement/prospectus, dated April 18, 2016, at a special meeting of shareholders held earlier this morning relating to the proposed combination with Shire plc (LSE: SHP, NASDAQ: SHPG) (Filing, 8-K/A [Amend], Baxalta, MAY 27, 2016, View Source [SID:1234512841]). Baxalta shareholders approved the definitive merger agreement with Shire, dated as of January 11, 2016, and the merger transaction, with approximately 76.9 percent of shares outstanding cast in favor of the proposal, which represents approximately 98.9 percent of the votes cast at the meeting.

Earlier today, Shire shareholders of approximately 93.8 percent of the votes cast voted in favor of the adoption of the merger agreement with Baxalta. This represents approximately 75.5 percent of Shire’s total outstanding shares of common stock as of 8:00 a.m. (London time) on May 25, 2016, the record date for the special meeting.

As announced on January 11, 2016, Baxalta and Shire entered into a definitive merger agreement pursuant to which Shire would acquire Baxalta in a stock and cash transaction. Baxalta stockholder approval and Shire shareholder approval are conditions to the merger. The completion of the transaction remains subject to certain other closing conditions, but the companies expect that this transaction will be completed on or about June 3, 2016.

Baxalta Shareholders Vote to Approve Combination

On May 27, 2016 Baxalta Incorporated (NYSE:BXLT) reported the results of a vote on the proposals identified in the definitive proxy statement/prospectus, dated April 18, 2016, at a special meeting of shareholders held earlier this morning relating to the proposed combination with Shire plc (LSE: SHP, NASDAQ: SHPG) (Press release, Baxalta, MAY 27, 2016, View Source [SID:1234512840]). Baxalta shareholders approved the definitive merger agreement with Shire, dated as of January 11, 2016, and the merger transaction, with approximately 98.9 percent of shares outstanding cast in favor of the proposal.

1stOncology is recognized as a
Top 10 Global Pharma Analytic Provider

Continue your journey with 1stOncology by accessing our Free Leading Cancer Conference Whitepapers, signing up for our Free Weekly Newsletter and requesting a Free Demo to see how we can help you be 1st in Oncology!

Month: May 2016

European Commission Approves IMBRUVICA® (ibrutinib) for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia

Genmab Achieves USD 30 Million Milestone in DARZALEX® (daratumumab) Collaboration with Janssen

Thermo Fisher Scientific to Acquire FEI Company

8-K/A [Amend] – Current report

Baxalta Shareholders Vote to Approve Combination