On December 3, 2016 Seattle Genetics, Inc. (Nasdaq: SGEN), a global biotechnology company, reported data from a phase 2 clinical trial evaluating ADCETRIS (brentuximab vedotin) combination therapy in frontline diffuse large B-cell lymphoma (DLBCL) at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in San Diego, California, December 3-6, 2016 (Press release, Seattle Genetics, DEC 3, 2016, View Source;p=RssLanding&cat=news&id=2227322 [SID1234516888]). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, expressed on several types of non-Hodgkin lymphoma. ADCETRIS is currently not approved for the treatment of DLBCL.

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Data from the phase 2 study in newly diagnosed intermediate-high or high-risk DLBCL included the evaluation of ADCETRIS in combination with either rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine and prednisone (referred to as RCHOP) in 51 patients (Part 1); or RCHP (removing the vincristine) in 11 patients (Part 2). In Part 1, the objective response rate was 83 percent, including 69 percent complete remissions. In Part 2, the objective response rate was 91 percent, including 82 percent complete remissions. The most common adverse events in Part 1 and 2 were fatigue, peripheral sensory neuropathy, diarrhea, nausea, alopecia and constipation.

"The data from this phase 2 trial demonstrate that ADCETRIS is an active agent in the treatment of frontline DLBCL," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "However, based on prioritization of our pipeline, we are discontinuing this trial and have decided not to pursue a registrational pathway for ADCETRIS in frontline DLBCL. We continue to evaluate ADCETRIS in the treatment of relapsed or refractory DLBCL through an ongoing randomized phase 2 trial, as well as more broadly for other CD30-expressing lymphomas, including the ECHELON-1 and ECHELON-2 phase 3 trials in frontline classical Hodgkin lymphoma and frontline mature T-cell lymphoma, respectively."

Results of an Ongoing Phase 2 Study of Brentuximab Vedotin with RCHP as Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B-Cell Lymphoma (Abstract #104, oral presentation at 9:45 a.m. PT)

Data were reported from Parts 1 and 2 of the phase 2 clinical trial for intermediate-high or high-risk frontline DLBCL. In Part 1, 51 patients were treated once every three weeks with up to six cycles of either 1.2 milligrams per kilogram (mg/kg) or 1.8 mg/kg of ADCETRIS plus RCHOP. In Part 2, 11 patients were treated once every three weeks with up to six cycles of 1.8 mg/kg of ADCETRIS plus RCHP. The median age of patients in Part 1 was 67 years and in Part 2 was 59 years. More than 90 percent of patients had stage III or IV disease.

Key findings presented in an oral presentation include:

For the 49 response-evaluable patients in Part 1, 25 patients had CD30-expressing disease and 24 patients had CD30-undetectable disease. Of the 25 with CD30-expressing disease, 21 patients (84 percent) had an objective response, with 19 patients (76 percent) achieving a complete remission. Of the 24 patients who had CD30-undetectable disease, 20 patients (83 percent) had an objective response, with 15 patients (63 percent) achieving a complete remission. Median progression-free survival (PFS) and overall survival have not yet been reached. For CD30-expressing patients, the estimated PFS rate at two years was 79 percent and the estimated two-year overall survival rate was 92 percent. For CD30-undetectable patients, the estimated two-year PFS rate at was 52 percent and the estimated two-year overall survival rate was 67 percent.
For the 11 patients in Part 2, ten patients (91 percent) had an objective response, with nine patients (82 percent) achieving a complete remission. One patient (nine percent) had a partial remission and one patient (nine percent) had progressive disease. All responding patients had confirmed CD30-expression by central review; the patient with progressive disease was determined to be CD30-undetectable.
The most common treatment-emergent adverse events of any grade in Part 1 and 2 were fatigue (65 and 64 percent, respectively), peripheral sensory neuropathy (63 and 55 percent, respectively), diarrhea (57 and 27 percent, respectively), nausea (56 and 73 percent, respectively), alopecia (27 and 73 percent, respectively) and constipation (33 and 55 percent, respectively). The most common Grade 3 or 4 adverse events were neutropenia, febrile neutropenia, dyspnea and anemia. When combined with RCHP, 1.8 mg/kg of ADCETRIS appears more tolerable than in combination with RCHOP, with no Grade 3 neuropathy, no motor neuropathy and lower incidence of febrile neutropenia.
About ADCETRIS (Brentuximab Vedotin)

ADCETRIS is being evaluated broadly in more than 70 ongoing clinical trials, including three phase 3 studies, the ongoing ECHELON-1 trial in frontline classical Hodgkin lymphoma and the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, as well as the completed ALCANZA trial in cutaneous T-cell lymphoma for which a supplemental BLA is planned in the first half of 2017.

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 for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. The European Commission extended the current conditional approval of ADCETRIS and approved ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT.

ADCETRIS has received marketing authorization by regulatory authorities in 65 countries. See important safety information below.

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.

About Seattle Genetics

Seattle Genetics is an innovative biotechnology company that develops and commercializes novel antibody-based therapies for the treatment of cancer. The company’s industry-leading antibody-drug conjugate (ADC) technology harnesses the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. ADCETRIS (brentuximab vedotin), the company’s lead product, in collaboration with Takeda Pharmaceutical Company Limited, is the first in a new class of ADCs commercially available globally in 65 countries for relapsed classical Hodgkin lymphoma and relapsed systemic anaplastic large cell lymphoma (sALCL). Seattle Genetics is also advancing vadastuximab talirine (SGN-CD33A; 33A), an ADC in a phase 3 trial for acute myeloid leukemia. Headquartered in Bothell, Washington, Seattle Genetics has a robust pipeline of innovative therapies for blood-related cancers and solid tumors designed to address significant unmet medical needs and improve treatment outcomes for patients. The company has collaborations for its proprietary ADC technology with a number of companies including AbbVie, Astellas, Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com

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

BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Contraindication

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

Warnings and Precautions

Peripheral neuropathy (PN): ADCETRIS treatment causes a PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.
Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Patients who experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.
Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.
Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious GI complications, including perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in ADCETRIS-treated patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
Embryo-fetal toxicity: Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Adverse Reactions

In two uncontrolled single-arm trials of ADCETRIS as monotherapy in 160 patients with relapsed classical HL and sALCL, the most common adverse reactions (≥20%), regardless of causality, were: neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

In a placebo-controlled trial of ADCETRIS in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT, the most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were: neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions

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

Use in Specific Populations

MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.

Advise females of reproductive potential to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

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

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

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

On December 3, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported long-term follow-up results evaluating up to five years of IMBRUVICA (ibrutinib) use in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, DEC 3, 2016, View Source [SID1234516881]). In this analysis, 89% of treatment-naïve (TN) and relapsed/refractory (R/R) patients with CLL/SLL, including those with high-risk disease, show a complete or partial response. Further, almost one-third of patients (29%) who received ibrutinib as their first treatment for the disease achieved a complete response (CR), and patients lived without disease progression longer when treatment was started earlier in the course of the disease (abstract #233).

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These data from the Phase 1b/2 PCYC-1102 trial and PCYC-1103 extension study of single-agent ibrutinib will be presented today in an oral presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, CA. Additional ibrutinib data in CLL/SLL to be presented include longer-term efficacy and safety analyses of IMBRUVICA (abstract #234). IMBRUVICA, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc.

"These five-year results suggest that both previously treated or untreated CLL/SLL patients may achieve robust and long-lasting responses with single-agent ibrutinib, with more patients developing a complete response over time," said Susan O’Brien, M.D., Associate Director for Clinical Science, Chao Family Comprehensive Cancer Center at University of California Irvine Health and lead investigator of the study.* "Our data also suggest that starting treatment with ibrutinib as early as possible in CLL/SLL has promising clinical potential for long-term progression-free and overall survival."

CLL is a type of cancer that starts from cells that become certain white blood cells (called lymphocytes) in the bone marrow. The cancer (leukemia) cells start in the bone marrow but then go into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S.2 with approximately 19,000 newly diagnosed patients every year.3 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.4 CLL/SLL are predominately a disease of the elderly, with a median age of 71 at diagnosis.3

"These long-term data, coupled with other ibrutinib studies presented at ASH (Free ASH Whitepaper), add to the evidence that extended treatment with IMBRUVICA may benefit a wide range of CLL/SLL patients, even those with genetic mutations such as deletion 11q that make their disease difficult to control with chemoimmunotherapy," said Danelle James, M.D., M.S., Head of Oncology, Pharmacyclics LLC, an AbbVie company. "We are excited about the potential for this first-in-class BTK inhibitor to continue to reshape treatment expectations and survival benefits in CLL/SLL."

About the Studies

Abstract #233: Five-Year Experience With Single-Agent Ibrutinib In Patients With Previously Untreated And Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Oral presentation: Saturday, December 3, 2016, 5:00 PM PT
With five years of follow-up, the overall response rate (ORR) in patients treated with IMBRUVICA was 89%, with 14% of patients achieving CR [87% ORR with 29% CR in TN patients (n=31) and 89% ORR with 10% CR in R/R patients (n=101)]. Median time on study was 62 months for TN patients and 49 months for R/R patients. At five years, progression-free survival (PFS) was 92% in TN patients and 43% in R/R patients, and overall survival (OS) was 92% for TN patients and 57% for R/R patients. Median PFS was not reached in the TN group and was 52 months for previously treated R/R patients. Median OS was not reached for TN or R/R patients.1

These results were observed in the subgroup of R/R patients with genetic alterations that put them at high risk for poor outcomes, typically not experiencing durable responses to standard chemotherapies. In these patients, median PFS was 55 months for those with deletion 11q (del11q), 26 months for those with deletion 17p (del17p), 43 months for those with unmutated IGVH, and was not reached for those with deletion 13q (del13q). Additionally, PFS and OS was higher when treatment with IMBRUVICA was started in earlier lines of therapy. Median PFS was not reached in TN patients; 63 months for R/R patients who received one to two prior regimens, 59 months for those who had three prior regimens, and 39 months for those who had four or more prior regimens.1

Among all patients, the onset of most Grade 3 or higher treatment-emergent adverse events (TEAEs) was highest in the first year and decreased over time. With about 5 years of follow up, the most frequent Grade 3 or higher adverse events (AEs) were hypertension (26%), pneumonia (22%), neutropenia (17%), thrombocytopenia (9%), and atrial fibrillation (8%).1

The Phase 1b/2 PCYC-1102 trial evaluated safety and efficacy of single-agent ibrutinib in 132 patients with CLL/SLL: 31 patients were TN and 101 patients were R/R. Patients received either 420 mg or 840 mg once daily until disease progression or unacceptable toxicity. Among R/R patients, 34% had del17p, 35% had del11q, 47% had del13q, and 78% had unmutated IGVH. The primary endpoint was ORR, and secondary endpoints included duration of response, PFS, and safety. PCYC-1103 is the long-term extension study. Primary results from this trial were published in The New England Journal of Medicine in June 20135 and were the basis for the initial approval of IMBRUVICA in CLL via Breakthrough Therapy Designation in February 2014.

Abstract #234: Updated Efficacy and Safety From the Phase 3 RESONATE-2 Study: Ibrutinib as First-Line Treatment Option in Patients 65 Years and Older with Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Oral presentation: Saturday, December 3, 2016, 5:15 PM PT
Updated results from the pivotal Phase 3 RESONATE-2 trial (PCYC-1115) showed that IMBRUVICA continued to be efficacious as first-line therapy in CLL/SLL at a median 29 months of follow-up. IMBRUVICA reduced the risk of progression or death by 88% compared with chlorambucil, a commonly used chemotherapy agent. At 24 months, PFS was 89% for patients taking IMBRUVICA and 34% for chlorambucil (HR= 0.121; 95% CI (0.074-0.198); p<0.0001). Of note, in the high-risk del11q subgroup ibrutinib was associated with a 99% reduction in risk of progression or death compared to chlorambucil (HR= 0.014; 95% CI (0.002-0.108); p<0.0001) and 82% reduction for those without del11q (HR=0.180, 95% CI (0.106-0.303), p<0.0001). With longer follow-up, investigator-assessed ORR was 92% with ibrutinib and 36% with chlorambucil; in the ibrutinib arm, CR or CR with incomplete bone marrow recovery (Cri) improved from 11% at 18.4 months to 18%. In ibrutinib-treated patients, ORR was 100% for patients with del11q and 90% for those without the genetic alteration.6

Safety was consistent with the primary analysis of the study and showed that Grade 3 or higher AEs decreased over time. Most AEs that led to discontinuation occurred in the first year of treatment.2 The most frequent AEs were neutropenia (12%), pneumonia (7%), anemia (7%) and hypertension (5%). These data will be presented at an oral presentation on Saturday, December 3.

RESONATE-2 is a Pharmacyclics-sponsored, randomized multi-center, open-label, Phase 3 study which enrolled 269 TN patients with CLL/SLL aged 65 years or older in the U.S, EU and other regions. Patients were randomized to receive 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 study met its primary endpoint, demonstrating improved PFS, as assessed by an Independent Review Committee (IRC). 7

Results from RESONATE-2 were first presented in an oral session at the ASH (Free ASH Whitepaper) meeting in December 2015 and simultaneously published in The New England Journal of Medicine.9 The results were also part of the official press program at ASH (Free ASH Whitepaper) 2015.

Additional Phase 3 ibrutinib data to be presented at ASH (Free ASH Whitepaper) that reinforce its safety and efficacy across patient types in CLL/SLL include: 8,9

Abstract #4383: Integrated and Long-Term Safety Analysis of Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Poster Presentation: Monday, December 5, 2016, 6:00 PM – 8:00 PM PT
Abstract #2042: 11q Deletion (del11q) is not a Prognostic Factor for Adverse Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Ibrutinib: Pooled Data From Three Randomized Phase 3 Studies
Poster Presentation: Saturday, December 3, 2016, 5:30 PM – 7:30 PM PT
"The data gathered on ibrutinib’s role in treating chronic and small lymphocytic leukemia patients with 11q deletion are encouraging for these patients. As physicians we always want patients to understand that they have options and for our part it’s a matter of understanding how to adjust treatment for them," said Thomas J. Kipps, M.D., Ph.D., University of California San Diego, Moores Cancer Center and lead investigator of the study.*

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits 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.10,11 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.10

IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, 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.10

IMBRUVICA was one of the first medicines to receive U.S. 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 nearly 30 (n=27) company-sponsored trials underway, 14 of which are Phase 3. In addition, there are more than 40 (n=44) investigator-sponsored trials taking place around the world. To date, more than 65,000 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 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 neutropenia (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

On December 3, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported the presentation of data from preclinical studies supporting the clinical development of the company’s proprietary monoclonal antibody (mAb) BION-1301, a humanized anti-APRIL (A PRoliferation-Inducing Ligand) antibody for the treatment of multiple myeloma (Press release, Aduro BioTech, DEC 3, 2016, View Source;p=RssLanding&cat=news&id=2227318 [SID1234516873]). Data from these in vivo and in vitro preclinical studies demonstrated that BION-1301 effectively neutralized APRIL, preventing its binding to BCMA (B cell maturation antigen), an essential receptor expressed on multiple myeloma cells. Based on the mechanism of action and anti-tumor activity observed in earlier preclinical studies with the parental anti-APRIL antibody, hAPRIL.01A, BION-1301 has the potential to inhibit multiple myeloma tumor growth, survival and chemoresistance. These data, which will be highlighted in a poster presentation (Poster #2112) at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, further underscore the potential application of BION-1301 for use as a single agent, or in combination with current standard of care therapies, for the treatment of multiple myeloma.

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"In patients with multiple myeloma, there is an overabundance of APRIL, a ligand which plays a critical role in the proliferation of multiple myeloma cells," stated Andrea van Elsas, Ph.D., chief scientific officer of Aduro Biotech Europe. "With BION-1301, which was derived from Aduro’s proprietary B-select antibody platform, we are blocking APRIL from binding to its target receptor, thereby inhibiting the growth and survival of multiple myeloma cells."

Dr. van Elsas continued, "Based on the data to be presented later today, we believe BION-1301 represents a novel antibody with a novel mechanism of action that has potential in the treatment of multiple myeloma, alone or in combination regimens. We look forward to advancing BION-1301 into clinical development in the coming year in our effort to bring much needed new treatment options to patients with multiple myeloma."

Researchers conducted in vivo and in vitro studies in preclinical models of multiple myeloma comparing anti-tumor activity achieved with BION-1301 and its parental antibody, hAPRIL.01A. Data from these studies demonstrate the successful creation and functional characterization of BION-1301 as a novel APRIL-neutralizing antibody.

In April 2016, Aduro announced the publication of a study entitled, "APRIL and BCMA promote human multiple myeloma growth, chemoresistance, and immunosuppression in the bone marrow microenvironment," by Kenneth Anderson, M.D. Ph.D., and Tai Yu-Tzu, Ph.D. of the Dana-Farber Cancer Institute. The article appeared in the June 2016 issue (Volume 127, Number 25) of the peer-reviewed journal Blood. The publication elucidates the roles of BCMA and its ligand APRIL in multiple myeloma, highlighting the potential therapeutic use of an agent that targets APRIL and fully blocks its interaction with its receptors. The authors demonstrated through in vivo and in vitro preclinical studies that the APRIL/BCMA ligand/receptor pair drives multiple myeloma tumor growth and survival, and activates immunosuppressive mechanisms that allow the tumor to thrive. Importantly, the studies demonstrated that the parental antibody to BION-1301 halts tumor growth and overcomes drug resistance to chemotherapeutic agents lenalidomide and bortezomib in preclinical models.

About Multiple Myeloma
Lymphocytes (B cells and T cells) are the primary cell types within the immune system that work together to fight infection and disease. As B cells respond to normal infection in the body, they mature and change into plasma cells, which in turn make antibodies that help the body attack infection. While lymphocytes circulate throughout the body, plasma cells remain primarily in the bone marrow. Multiple myeloma is a blood cancer that occurs when malignant plasma cells proliferate uncontrollably. Approximately 50,000 new cases of multiple myeloma will be diagnosed in the United States and Europe each year. While many new therapies have become available in recent years, multiple myeloma remains incurable and significant unmet needs exist among patients who relapse following, are resistant to, or cannot tolerate currently available agents.

About APRIL and BION-1301
APRIL is a member of the tumor necrosis factor (TNF) superfamily and is primarily secreted by bone marrow and/or myeloid cells. APRIL is overproduced in patients with multiple myeloma and binds to BCMA to stimulate a wide variety of responses that promote multiple myeloma growth and suppress the immune system so that the tumor cells are allowed to proliferate. The team at Aduro Biotech Europe, in collaboration with Jan Paul Medema, Ph.D. of the Amsterdam Medical Center, developed BION-1301, a humanized antibody that blocks APRIL from binding to its receptors, using Aduro’s B-select monoclonal antibody platform. In preclinical studies, BION-1301 eliminated malignant cells and reduced resistance to therapy in models of multiple myeloma. In addition to multiple myeloma, APRIL’s role in other cancers and in B cell dependent autoimmune and inflammatory diseases indicate that BION-1301 may also be useful in treating chronic lymphocytic leukemia, colorectal cancer and Berger’s disease (caused by IgA antibody lodging in the kidneys).