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Daratumumab Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration in Combination with Standard of Care Regimens for Previously Treated Multiple Myeloma

On July 26, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for DARZALEX (daratumumab) injection in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy (Press release, Genmab, JUL 26, 2016, View Source [SID:1234514029]). Breakthrough Therapy Designation is a program intended to expedite the development and review of drugs to treat serious or life-threatening diseases in cases where preliminary clinical evidence shows that the drug may provide substantial improvements over available therapy. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop and commercialize daratumumab.

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"This is the second time daratumumab has earned the distinction of a Breakthrough Therapy Designation. We are pleased that the FDA continues to recognize the potential of daratumumab to help patients with multiple myeloma. We continue to work with our strategic partner Janssen and the regulatory authorities to advance daratumumab to bring this treatment to more patients suffering from multiple myeloma as quickly as possible," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The Breakthrough Therapy Designation for daratumumab was granted on the basis of data from two Phase III studies: CASTOR (MMY3004; NCT02136134) evaluating daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma, and POLLUX (MMY3003; NCT02076009) evaluating daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma.

About Breakthrough Therapy Designation
The Breakthrough Therapy Designation was enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA) and is intended to expedite development of drugs to treat serious and life-threatening medical conditions when preliminary clinical evidence demonstrates that the drug may have substantial improvement on at least one clinically significant endpoint over available therapies. Breakthrough Therapy Designation includes all the features of the Fast Track Designation, as well as more intensive guidance from the FDA on a drug’s clinical development program.

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.1,5

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 indication.

Bristol-Myers Squibb Announces New Research Collaboration with Janssen in Immuno-Oncology Focused on Lung Cancer

On July 26, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported a new clinical research collaboration with Janssen Biotech, Inc. to evaluate Bristol-Myers Squibb’s Immuno-Oncology (I-O) agent Opdivo (nivolumab) and Janssen’s Live Attenuated Double–Deleted (LADD) Listerial monocytogenes cancer immunotherapy, expressing mesothelin and EGFRvIII (JNJ-64041757), in patients with non-small cell lung cancer (NSCLC) (Press release, Bristol-Myers Squibb, JUL 26, 2016, View Source [SID:1234514027]).

Opdivo is a human antibody designed to alleviate immune suppression. JNJ-64041757 is designed to induce the local recruitment and activation of innate and adaptive effector cells and expansion of mesothelin-specific T cells. The Phase 2 clinical trial will evaluate the tolerability and clinical activity of the combination of these agents in NSCLC patients.

"We are excited to collaborate with Janssen as we explore how the emerging science of antigen-presentation therapeutics, in combination with Opdivo, can potentially provide a new treatment approach for patients with lung cancer," said Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 54 countries including the United States, Japan, and in the European Union.

JNJ-64041757 (previously referred to as ADU-214) is an antigen-presentation therapeutic, based on Live Attenuated Double-Deleted (LADD) Listeria monocytogenes strains engineered to induce an immune response against NSCLC tumors. It is currently in Phase 1 clinical development for lung cancer. Opdivo is indicated for the treatment of patients with NSCLC with progression on or after platinum-based chemotherapy.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.

We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for overall survival and other important measures like durability of response. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents and continue to study the role of combinations in cancer.

We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.

Our collaboration with academia, as well as small and large biotech and pharmaceutical companies, to research the potential of Immuno-Oncology and non-Immuno-Oncology combinations helps achieve our goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the way patients live with cancer.

About Opdivo

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating overall survival as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

U.S. INDICATIONS & IMPORTANT SAFETY INFORMATION

INDICATIONS

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the CheckMate trials.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in Checkmate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In Checkmate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In Checkmate 205 and 039, diarrhea or colitis occurred in 30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In Checkmate 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Dermatitis

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In Checkmate 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25), and Grade 1 (n=3). In Checkmate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 069 and 067, adrenal insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In Checkmate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In Checkmate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 205 and 039, adrenal insufficiency (Grade 2) occurred in 0.4% (1/263) of patients receiving OPDIVO. In Checkmate 069 and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In Checkmate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 205 and 039, hypothyroidism/thyroiditis occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2 (n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5% (4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1 (n=1). In Checkmate 069 and 067, diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In Checkmate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1). In Checkmate 025, hyperglycemic adverse events occurred in 9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1). In Checkmate 205 and 039, diabetes mellitus occurred in 0.8% (2/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 069 and 067, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In Checkmate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6). In Checkmate 205 and 039, nephritis and renal dysfunction occurred in 4.9% (13/263) of patients treated with OPDIVO. This included one reported case (0.3%) of Grade 3 autoimmune nephritis.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In Checkmate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In Checkmate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In Checkmate 205 and 039, rash occurred in 22% (58/263) of patients receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In Checkmate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO. In Checkmate 205 and 039, encephalitis occurred in 0.8% (2/263) of patients after allogeneic HSCT after OPDIVO.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In Checkmate 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In Checkmate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In Checkmate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In Checkmate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In Checkmate 205 and 039, hypersensitivity/infusion-related reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic SCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Embryo-fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]).

Common Adverse Reactions

In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (reported in at least 20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

CHECKMATE Trials and Patient Populations

Checkmate 069 and 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 057 – non-squamous non-small cell lung cancer (NSCLC); Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma

Please see U.S. Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, for YERVOY.

Please see U.S. Full Prescribing Information for OPDIVO.

Seattle Genetics Reports Second Quarter 2016 Financial Results

On July 26, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN) reported financial results for the second quarter ended June 30, 2016 (Press release, Seattle Genetics, JUL 26, 2016, View Source [SID:1234514047]).

“We reported record ADCETRIS net sales in the second quarter, which were up 20 percent for the quarter and year-to-date compared to the same periods in 2015. To expand on the ADCETRIS opportunity, we are executing on three ongoing phase 3 clinical trials that are approaching data, starting with ALCANZA top-line results this quarter,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “We also demonstrated progress in the second quarter with our clinical-stage pipeline towards our goal of becoming a multi-product oncology company. We advanced 33A into a phase 3 trial for acute myeloid leukemia (AML) and reported encouraging phase 1 data from two ADCs for urothelial cancer, ASG-15ME and enfortumab vedotin (ASG-22ME). We anticipate advancing several new programs and generating additional data from our pipeline over the remainder of 2016.”

Recent ADCETRIS Highlights

The European Commission approved ADCETRIS for the treatment of adult patients with CD30+ Hodgkin lymphoma at increased risk of relapse or progression following autologous stem cell transplant based on data from the phase 3 AETHERA clinical trial. This is the third approved indication for ADCETRIS in the European Union.
Announced that final data from the ADCETRIS monotherapy pivotal phase 2 clinical trial in relapsed or refractory classical Hodgkin lymphoma were published in the journal Blood. The manuscript, which summarizes the five-year, end-of-study results, highlights that many patients who achieved a complete remission remained in remission at the time of this final analysis.
Takeda continues to receive additional marketing approvals for ADCETRIS, which is now commercially available in 65 countries worldwide.
Recent Vadastuximab Talirine (SGN-CD33A) Highlights

Initiated the pivotal phase 3 CASCADE clinical trial evaluating 33A in combination with the hypomethylating agents (HMAs) azacitidine or decitabine in approximately 500 older patients with newly diagnosed AML. The trial is designed to determine if the 33A-containing regimen improves overall survival compared to patients receiving HMAs alone.
Reported data from a phase 1 trial of 33A plus HMAs in older, newly diagnosed patients with AML in an oral presentation at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper). The data showed a 76 percent objective response rate, including a 41 percent complete remission rate with manageable tolerability profile. The median overall survival for all patients in the phase 1 trial is interim and expected to evolve. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months.
Recent Pipeline and Other Highlights

Reported data at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting from phase 1 trials of ASG-15ME and enfortumab vedotin in metastatic urothelial cancer, primarily bladder carcinoma. The data showed that both ADCs had manageable safety profiles and objective response rates of 40 to 50 percent at the likely recommended doses for future development. ASG-15ME and enfortumab vedotin are being co-developed with Astellas.
Triggered milestones under ongoing ADC collaborations based on progress with programs utilizing Seattle Genetics technology, including from:
Astellas, upon its initiation of a phase 2 clinical trial in metastatic renal cell carcinoma; and,
AbbVie, based on progress with a preclinical program.
Added to and promoted several members of the senior management team, including:
Promoting Naomi Hunder, M.D., to Vice President, Clinical Development. Dr. Hunder joined Seattle Genetics in 2010. She has most recently served as the clinical lead for the ADCETRIS program, notably for the company’s successful FDA approval in post-autologous transplant high-risk Hodgkin lymphoma based on data from the phase 3 AETHERA trial.
Promoting Dana Kennedy, Pharm.D., to Vice President, Clinical Development. Dr. Kennedy joined Seattle Genetics in 2007. Her contributions have included the clinical development work that led to the approval of ADCETRIS in systemic anaplastic large cell lymphoma and serving as clinical and program leader for SGN-CD33A.
Hiring Ian Pyrah, Ph.D., as Vice President, Non-Clinical Sciences. Prior to joining Seattle Genetics, Dr. Pyrah spent 10 years at Amgen in several leadership roles, including responsibility for the non-clinical component of a number of successful regulatory submissions.
Hiring Venkat Ramanan, Ph.D., as Vice President, Finance. Dr. Ramanan previously spent nine years at Gilead Sciences and prior to that he was at Amgen and ZS Associates. He has served in a range of roles in finance, business planning and operations supporting U.S. and international markets.
Anticipated ADCETRIS Upcoming Activities

Report top-line data in the third quarter of 2016 from the phase 3 ALCANZA trial in patients with CD30-expressing cutaneous T-cell lymphoma (CTCL).
Report data in the 2017 through mid-2018 timeframe from the phase 3 ECHELON-1 trial in frontline classical Hodgkin lymphoma.
Complete enrollment in the phase 3 ECHELON-2 trial in frontline mature T-cell lymphoma (MTCL) during 2016 and report data in the 2017 to 2018 timeframe.
ADCETRIS is not currently approved for use in CTCL, frontline Hodgkin lymphoma or frontline MTCL.

Anticipated Vadastuximab Talirine (SGN-CD33A) Upcoming Activities

Continue clinical site initiations and enrollment of 500 patients to the pivotal phase 3 CASCADE clinical trial evaluating 33A in combination with HMAs in older patients with newly diagnosed AML.
Report data from ongoing phase 1 trials, including a phase 1b trial of 33A in combination with cytarabine and daunorubicin (7+3) for frontline, younger AML patients.
More information about 33A and ongoing clinical trials can be found at www.ADC-CD33.com.

Anticipated Pipeline Programs Upcoming Activities

Initiate a randomized phase 2 trial of denintuzumab mafodotin (SGN-CD19A; 19A) in frontline diffuse large B-cell lymphoma (DLBCL) during 2016.
Report additional data from phase 1 trials of ASG-15ME and enfortumab vedotin at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) annual congress being held October 7 to 11, 2016 in Copenhagen, Denmark.
Report clinical data during 2016 from other pipeline programs, including SGN-LIV1A.
Initiate a phase 1 trial of SGN-CD123A in relapsed or refractory AML. SGN-CD123A is an ADC targeted to CD123 utilizing Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer. CD123 is expressed across AML subtypes, and is particularly prominent on leukemic stem cells.
Advance SGN-CD352A, a novel ADC for multiple myeloma, into a phase 1 clinical trial. SGN-CD352A targets CD352, and utilizes the company’s PBD and EC-mAb technology. CD352 is highly expressed on multiple myeloma as well as B-cell malignancies, including chronic lymphocytic leukemia and non-Hodgkin lymphoma.
Second Quarter and Six Months 2016 Financial Results

Total revenues in the quarter and six month periods ended June 30, 2016 increased to $95.4 million and $206.6 million, respectively, compared to $77.1 million and $159.3 million from the same periods in 2015. Revenues included:

ADCETRIS net sales in the second quarter were $66.2 million, a 20 percent increase from net sales of $55.1 million in the second quarter of 2015. For the year-to-date, ADCETRIS sales were $124.9 million, compared to $104.0 million for the year-to-date period in 2015, a 20 percent increase.
Royalty revenues in the second quarter of 2016 were $9.2 million, compared to $7.6 million in the second quarter of 2015. For the year-to-date in 2016, royalty revenues were $41.5 million, compared to $18.7 million for the first six months of 2015. Royalty revenues are primarily driven by international sales of ADCETRIS by Takeda. Royalty revenues for the year-to-date in 2016 also included a $20.0 million sales milestone payment from Takeda earned in the first quarter of 2016.
Amounts earned under the company’s ADCETRIS and ADC collaborations totaled $20.0 million in the second quarter and $40.2 million for the first six months of 2016, compared to $14.4 million and $36.6 million for the same periods in 2015.
Total costs and expenses for the second quarter of 2016 were $128.8 million, compared to $124.7 million for the second quarter of 2015. For the first six months of 2016, total costs and expenses were $261.0 million, compared to $228.6 million in the first six months of 2015. The increase in 2016 costs and expenses was primarily driven by progress with ADCETRIS, 33A clinical development and manufacturing activities and investment in the company’s pipeline programs.

Non-cash, share-based compensation cost for the first six months of 2016 was $24.3 million, compared to $17.6 million for the same period in 2015.

Net loss for the second quarter of 2016 was $32.7 million, or $0.23 per share, compared to a net loss of $47.5 million, or $0.38 per share, for the second quarter of 2015. For the six months ended June 30, 2016, net loss was $53.2 million, or $0.38 per share, compared to a net loss of $69.2 million, or $0.55 per share, for the same period in 2015.

As of June 30, 2016, Seattle Genetics had $659.5 million in cash, cash equivalents and investments, compared to $712.7 million as of December 31, 2015.

Seattle Genetics Reports Second Quarter 2016 Financial Results

The company also highlighted ADCETRIS (brentuximab vedotin) commercialization and clinical development accomplishments, vadastuximab talirine (SGN-CD33A; 33A) activities and progress with its pipeline of antibody-drug conjugates (ADCs) and other proprietary programs.

"We reported record ADCETRIS net sales in the second quarter, which were up 20 percent for the quarter and year-to-date compared to the same periods in 2015. To expand on the ADCETRIS opportunity, we are executing on three ongoing phase 3 clinical trials that are approaching data, starting with ALCANZA top-line results this quarter," said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "We also demonstrated progress in the second quarter with our clinical-stage pipeline towards our goal of becoming a multi-product oncology company. We advanced 33A into a phase 3 trial for acute myeloid leukemia (AML) and reported encouraging phase 1 data from two ADCs for urothelial cancer, ASG-15ME and enfortumab vedotin (ASG-22ME). We anticipate advancing several new programs and generating additional data from our pipeline over the remainder of 2016."

Recent ADCETRIS Highlights

The European Commission approved ADCETRIS for the treatment of adult patients with CD30+ Hodgkin lymphoma at increased risk of relapse or progression following autologous stem cell transplant based on data from the phase 3 AETHERA clinical trial. This is the third approved indication for ADCETRIS in the European Union.
Announced that final data from the ADCETRIS monotherapy pivotal phase 2 clinical trial in relapsed or refractory classical Hodgkin lymphoma were published in the journal Blood. The manuscript, which summarizes the five-year, end-of-study results, highlights that many patients who achieved a complete remission remained in remission at the time of this final analysis.
Takeda continues to receive additional marketing approvals for ADCETRIS, which is now commercially available in 65 countries worldwide.
Recent Vadastuximab Talirine (SGN-CD33A) Highlights

Initiated the pivotal phase 3 CASCADE clinical trial evaluating 33A in combination with the hypomethylating agents (HMAs) azacitidine or decitabine in approximately 500 older patients with newly diagnosed AML. The trial is designed to determine if the 33A-containing regimen improves overall survival compared to patients receiving HMAs alone.
Reported data from a phase 1 trial of 33A plus HMAs in older, newly diagnosed patients with AML in an oral presentation at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper). The data showed a 76 percent objective response rate, including a 41 percent complete remission rate with manageable tolerability profile. The median overall survival for all patients in the phase 1 trial is interim and expected to evolve. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months.
Recent Pipeline and Other Highlights

Reported data at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting from phase 1 trials of ASG-15ME and enfortumab vedotin in metastatic urothelial cancer, primarily bladder carcinoma. The data showed that both ADCs had manageable safety profiles and objective response rates of 40 to 50 percent at the likely recommended doses for future development. ASG-15ME and enfortumab vedotin are being co-developed with Astellas.
Triggered milestones under ongoing ADC collaborations based on progress with programs utilizing Seattle Genetics technology, including from:
Astellas, upon its initiation of a phase 2 clinical trial in metastatic renal cell carcinoma; and,
AbbVie, based on progress with a preclinical program.
Added to and promoted several members of the senior management team, including:
Promoting Naomi Hunder, M.D., to Vice President, Clinical Development. Dr. Hunder joined Seattle Genetics in 2010. She has most recently served as the clinical lead for the ADCETRIS program, notably for the company’s successful FDA approval in post-autologous transplant high-risk Hodgkin lymphoma based on data from the phase 3 AETHERA trial.
Promoting Dana Kennedy, Pharm.D., to Vice President, Clinical Development. Dr. Kennedy joined Seattle Genetics in 2007. Her contributions have included the clinical development work that led to the approval of ADCETRIS in systemic anaplastic large cell lymphoma and serving as clinical and program leader for SGN-CD33A.
Hiring Ian Pyrah, Ph.D., as Vice President, Non-Clinical Sciences. Prior to joining Seattle Genetics, Dr. Pyrah spent 10 years at Amgen in several leadership roles, including responsibility for the non-clinical component of a number of successful regulatory submissions.
Hiring Venkat Ramanan, Ph.D., as Vice President, Finance. Dr. Ramanan previously spent nine years at Gilead Sciences and prior to that he was at Amgen and ZS Associates. He has served in a range of roles in finance, business planning and operations supporting U.S. and international markets.
Anticipated ADCETRIS Upcoming Activities

Report top-line data in the third quarter of 2016 from the phase 3 ALCANZA trial in patients with CD30-expressing cutaneous T-cell lymphoma (CTCL).
Report data in the 2017 through mid-2018 timeframe from the phase 3 ECHELON-1 trial in frontline classical Hodgkin lymphoma.
Complete enrollment in the phase 3 ECHELON-2 trial in frontline mature T-cell lymphoma (MTCL) during 2016 and report data in the 2017 to 2018 timeframe.
ADCETRIS is not currently approved for use in CTCL, frontline Hodgkin lymphoma or frontline MTCL.

Anticipated Vadastuximab Talirine (SGN-CD33A) Upcoming Activities

Continue clinical site initiations and enrollment of 500 patients to the pivotal phase 3 CASCADE clinical trial evaluating 33A in combination with HMAs in older patients with newly diagnosed AML.
Report data from ongoing phase 1 trials, including a phase 1b trial of 33A in combination with cytarabine and daunorubicin (7+3) for frontline, younger AML patients.
More information about 33A and ongoing clinical trials can be found at www.ADC-CD33.com.

Anticipated Pipeline Programs Upcoming Activities

Initiate a randomized phase 2 trial of denintuzumab mafodotin (SGN-CD19A; 19A) in frontline diffuse large B-cell lymphoma (DLBCL) during 2016.
Report additional data from phase 1 trials of ASG-15ME and enfortumab vedotin at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) annual congress being held October 7 to 11, 2016 in Copenhagen, Denmark.
Report clinical data during 2016 from other pipeline programs, including SGN-LIV1A.
Initiate a phase 1 trial of SGN-CD123A in relapsed or refractory AML. SGN-CD123A is an ADC targeted to CD123 utilizing Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer. CD123 is expressed across AML subtypes, and is particularly prominent on leukemic stem cells.
Advance SGN-CD352A, a novel ADC for multiple myeloma, into a phase 1 clinical trial. SGN-CD352A targets CD352, and utilizes the company’s PBD and EC-mAb technology. CD352 is highly expressed on multiple myeloma as well as B-cell malignancies, including chronic lymphocytic leukemia and non-Hodgkin lymphoma.
Second Quarter and Six Months 2016 Financial Results

Total revenues in the quarter and six month periods ended June 30, 2016 increased to $95.4 million and $206.6 million, respectively, compared to $77.1 million and $159.3 million from the same periods in 2015. Revenues included:

ADCETRIS net sales in the second quarter were $66.2 million, a 20 percent increase from net sales of $55.1 million in the second quarter of 2015. For the year-to-date, ADCETRIS sales were $124.9 million, compared to $104.0 million for the year-to-date period in 2015, a 20 percent increase.
Royalty revenues in the second quarter of 2016 were $9.2 million, compared to $7.6 million in the second quarter of 2015. For the year-to-date in 2016, royalty revenues were $41.5 million, compared to $18.7 million for the first six months of 2015. Royalty revenues are primarily driven by international sales of ADCETRIS by Takeda. Royalty revenues for the year-to-date in 2016 also included a $20.0 million sales milestone payment from Takeda earned in the first quarter of 2016.
Amounts earned under the company’s ADCETRIS and ADC collaborations totaled $20.0 million in the second quarter and $40.2 million for the first six months of 2016, compared to $14.4 million and $36.6 million for the same periods in 2015.
Total costs and expenses for the second quarter of 2016 were $128.8 million, compared to $124.7 million for the second quarter of 2015. For the first six months of 2016, total costs and expenses were $261.0 million, compared to $228.6 million in the first six months of 2015. The increase in 2016 costs and expenses was primarily driven by progress with ADCETRIS, 33A clinical development and manufacturing activities and investment in the company’s pipeline programs.

Non-cash, share-based compensation cost for the first six months of 2016 was $24.3 million, compared to $17.6 million for the same period in 2015.

Net loss for the second quarter of 2016 was $32.7 million, or $0.23 per share, compared to a net loss of $47.5 million, or $0.38 per share, for the second quarter of 2015. For the six months ended June 30, 2016, net loss was $53.2 million, or $0.38 per share, compared to a net loss of $69.2 million, or $0.55 per share, for the same period in 2015.

As of June 30, 2016, Seattle Genetics had $659.5 million in cash, cash equivalents and investments, compared to $712.7 million as of December 31, 2015.

Lilly Reports Second-Quarter 2016 Results, Provides Financial Expectations Through the Remainder of the Decade

On July 26, 2016 Eli Lilly and Company (NYSE: LLY) reported financial results for the second quarter of 2016 (Press release, Eli Lilly, JUL 26, 2016, View Source [SID:1234514028]).

$ in millions, except per share data
Second Quarter
%

2016
2015
Change
Revenue – Reported
$
5,404.8
$
4,978.7
9
%
Net Income – Reported
747.7
600.8
24
%
EPS – Reported
0.71
0.56
27
%

Net Income – non-GAAP
908.8
954.8
(5)
%
EPS – non-GAAP
0.86
0.90
(4)
%

Certain financial information for 2016 and 2015 is presented on both a reported and a non-GAAP basis. Some numbers in this press release may not add due to rounding. Reported results were prepared in accordance with generally accepted accounting principles (GAAP) and include all revenue and expenses recognized during the periods. Non-GAAP measures exclude the items described in the reconciliation tables later in the release. The company’s 2016 financial guidance is also being provided on both a reported and a non-GAAP basis. The non-GAAP measures are presented to provide additional insights into the underlying trends in the company’s business.

“Lilly is in the midst of one of the most productive periods of new product launches in our company’s history, with new medicines making a substantial contribution to our revenue growth for the first half of the year,” said John C. Lechleiter, Ph.D., Lilly’s chairman, president and chief executive officer.

Lechleiter continued, “We’ve made great progress building an R&D engine that has the potential to launch 20 new products in 10 years beginning in 2014 and extending through 2023. Because of our confidence in our future growth prospects, we are providing updated financial expectations through the balance of the decade, including at least 5 percent average annual revenue growth driven by volume and an increase in gross margin as a percent of revenue. We are also returning to annual dividend increases for shareholders and reaffirming our commitment to achieve an OPEX-to-revenue ratio of 50 percent or less in 2018.”

Key Events Over the Last Three Months

Commercial

The company is launching Taltz in Europe for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy.
Elanco Animal Health launched InteprityTM, a first-in-class, animal-use only, in-feed antibiotic approved for the prevention of necrotic enteritis, an intestinal disease in poultry.
Regulatory

The U.S. Food and Drug Administration (FDA) approved once-daily Jentadueto XR (linagliptin and metformin hydrochloride extended-release) tablets as an adjunct to diet and exercise for the treatment of type 2 diabetes in adults. Jentadueto XR is part of the company’s alliance with Boehringer Ingelheim.

The company received approval of Cyramza in Japan for the treatment of:
unresectable, advanced or recurrent colorectal cancer; and
unresectable, advanced or recurrent non-small cell lung cancer for patients who have received prior platinum therapy.

The company received approval of Taltz in Japan for the treatment of patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and erythrodermic psoriasis after insufficient response to existing treatments.

The FDA granted Priority Review for olaratumab in combination with doxorubicin, for the potential treatment of people with advanced soft tissue sarcoma not amenable to curative treatment with radiotherapy or surgery.

An FDA Advisory Committee voted 12-11 that substantial evidence exists to establish that Jardiance (empagliflozin) reduces cardiovascular (CV) death in adults with type 2 diabetes and established CV disease. Jardiance is marketed by Boehringer Ingelheim and Lilly.

The FDA determined that the company met the requirements for pediatric exclusivity for Effient. Based on this decision by the FDA, Lilly has gained an additional six months of U.S. market exclusivity for Effient.
Clinical

The company announced results from the Phase 2 study of abemaciclib, a cyclin-dependent kinase CDK 4 and CDK 6 inhibitor, in patients with hormone-receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. The data showed single-agent activity in metastatic breast cancer patients for whom endocrine therapy was no longer a suitable treatment option.

The company and Incyte Corporation announced data from a pivotal long-term extension study, which demonstrated baricitinib was superior to placebo at inhibiting progressive radiographic joint damage in patients with rheumatoid arthritis.

The company and Boehringer Ingelheim announced clinical results on two jointly marketed medicines:
Results from a clinical trial demonstrated that Trajenta (linagliptin) reduced blood sugar in adults with type 2 diabetes who are at risk for kidney impairment, with a renal safety profile similar to that seen in other trials.

New data showed Jardiance reduced the risk for new-onset or worsening kidney disease by 39 percent versus placebo when added to standard of care in adults with type 2 diabetes with established cardiovascular disease.
Business Development/Other

The German Federal Supreme Court granted the appeal by the company in the case of Lilly v. Actavis, vacating the prior decision denying infringement. The German Supreme Court returned the case to the Court of Appeal (Dusseldorf) to reconsider infringement based on its judgment. The case concerns whether Lilly’s vitamin regimen patent for Alimta (pemetrexed disodium) would be infringed by a generic competitor that had stated an intention to market a dipotassium salt form of pemetrexed in Germany.

Elanco Animal Health and EnBiotix, Inc. announced a collaboration to explore the application of EnBiotix’s engineered phage technology in specific animal health targets, which could result in alternatives for traditional antibiotics in animals.
Second-Quarter Reported Results

In the second quarter of 2016, worldwide revenue was $5.405 billion, an increase of 9 percent compared with the second quarter of 2015. The increase in revenue was driven by an 8 percent increase in volume, as realized prices and the impact of foreign exchange rates remained relatively flat, compared with the second quarter of 2015. The increase in worldwide volume was driven by new pharmaceutical products, including Trulicity and Cyramza, as well as Humalog. Revenue in the U.S. increased 14 percent to $2.890 billion, primarily driven by increased volume for several pharmaceutical products, including Trulicity and Humalog, and to a lesser extent, higher realized prices, primarily for Cialis and Forteo , partially offset by lower realized prices for Humalog. Revenue outside the U.S. increased 3 percent to $2.515 billion, driven by increased volume for several pharmaceutical products, primarily Cyramza, Trulicity and Humalog, partially offset by the loss of exclusivity for Cymbalta in Europe in 2014.

Gross margin increased 5 percent to $3.940 billion in the second quarter of 2016 compared with the second quarter of 2015. Gross margin as a percent of revenue was 72.9 percent, a decrease of 2.6 percentage points compared with the second quarter of 2015. The decline in gross margin percent was primarily due to a lower benefit from foreign exchange rates on international inventories sold and, to a lesser extent, the transfer of Erbitux commercialization rights in North America, partially offset by 2015 inventory step-up costs related to the acquisition of Novartis Animal Health.

Operating expenses in the second quarter of 2016, defined as the sum of research and development and marketing, selling and administrative expenses, were $2.959 billion, an increase of 5 percent compared with the second quarter of 2015. Research and development expenses increased 14 percent to $1.336 billion, driven primarily by higher late-stage clinical development costs, including a $100.0 million charge related to a development milestone for AZD3293, an oral beta secretase cleaving enzyme (BACE) inhibitor currently in development with AstraZeneca as a potential treatment for early Alzheimer’s disease. Marketing, selling and administrative expenses decreased 1 percent to $1.623 billion, primarily due to lower litigation expenses and reduced spending on late-life-cycle products, partially offset by expenses related to new products.

There were no acquired in-process research and development charges in the second quarter of 2016. In the second quarter of 2015, the company recognized acquired in-process research and development charges totaling $80.0 million. These charges included a $50.0 million payment to Hanmi Pharmaceutical Co., Ltd. (Hanmi), related to an exclusive license and collaboration agreement for Hanmi’s oral Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of autoimmune and other diseases, and a $30.0 million payment to BioNTech AG related to a research collaboration to discover novel cancer immunotherapies.

The company recognized asset impairment, restructuring and other special charges of $58.0 million and $72.4 million in the second quarters of 2016 and 2015, respectively, related to integration costs for Novartis Animal Health, severance costs and asset impairments.

Operating income in the second quarter of 2016 was $923.3 million, an increase of 15 percent compared with the second quarter of 2015, driven by higher gross margin and lower acquired in-process research and development charges, partially offset by higher operating expenses.

Other income (expense) was income of $21.2 million in the second quarter of 2016, compared with expense of $123.3 million in the second quarter of 2015. Other expense during the second quarter of 2015 was driven by a net charge of $152.7 million related to the repurchase of $1.65 billion of debt.

The effective tax rate was 20.8 percent in the second quarter of 2016, compared with 11.6 percent in the second quarter of 2015. The increase in the effective tax rate for the second quarter of 2016 as compared with the second quarter of 2015 is primarily due to the tax impact of 2015 charges, including a net charge related to the repurchase of debt; asset impairment, restructuring and other special charges; and acquired in-process research and development charges.

In the second quarter of 2016, net income increased 24 percent to $747.7 million, and earnings per share increased 27 percent to $0.71, compared with $600.8 million and $0.56, respectively, in the second quarter of 2015. The increases in net income and earnings per share were driven by 2015 charges related to the repurchase of debt, as well as higher operating income, partially offset by higher income taxes. Earnings per share also benefited from a lower number of shares outstanding in the second quarter of 2016 compared with the second quarter of 2015.

Second-Quarter 2016 Non-GAAP Measures
On a non-GAAP basis, second-quarter 2016 gross margin increased 4 percent to $4.106 billion. Gross margin as a percent of revenue was 76.0 percent, a decline of 3.2 percentage points compared with the second quarter of 2015. The decline in gross margin percent was primarily due to a lower benefit from foreign exchange rates on international inventories sold.

Operating income decreased $25.8 million, or 2 percent, to $1.150 billion in the second quarter of 2016, driven by higher operating expenses, largely offset by higher gross margin.

Other income (expense) was income of $21.2 million in the second quarter of 2016, compared with income of $29.4 million in the second quarter of 2015.

The effective tax rate was 22.4 percent in the second quarter of 2016, compared with 20.8 percent in the second quarter of 2015. The second-quarter 2016 effective tax rate reflects the benefit of certain U.S. tax provisions, including the R&D tax credit, reinstated for 2016, largely offset by the tax impact of an increased percentage of earnings in higher-tax jurisdictions. The second-quarter 2015 effective tax rate includes a net discrete tax benefit of approximately $24 million and does not include the benefit of certain then-expired U.S. tax provisions, including the R&D tax credit.

Net income decreased 5 percent to $908.8 million, and earnings per share decreased 4 percent to $0.86 in the second quarter of 2016, compared with $954.8 million and $0.90, respectively, in the second quarter of 2015. The declines in net income and earnings per share were driven by lower operating income and a higher effective tax rate. Earnings per share benefited from a lower number of shares outstanding in the second quarter of 2016 compared with the second quarter of 2015.

For further detail of non-GAAP measures, see the reconciliation below as well as the Reconciliation of GAAP Reported to Selected Non-GAAP Adjusted Information table later in this press release.

Second Quarter

2016
2015
% Change
Earnings per share (reported)
$
0.71
$
0.56
27%
Amortization of intangible assets
.11
.10

Asset impairment, restructuring and other special charges
.04
.05

Acquired in-process research and development
—
.05

Net charge related to repurchase of debt
—
.09

Novartis Animal Health inventory step-up
—
.05

Earnings per share (non-GAAP)
$
0.86
$
0.90
(4)%

Numbers may not add due to rounding.

Year-to-Date Results
For the first six months of 2016, worldwide revenue increased 7 percent to $10.270 billion compared with $9.623 billion in the same period in 2015. Reported net income and earnings per share were $1.188 billion and $1.12, respectively. Net income and earnings per share, on a non-GAAP basis, were $1.791 billion and $1.69, respectively.

For further detail, see the reconciliation below as well as the Reconciliation of GAAP Reported to Selected Non-GAAP Adjusted Information table later in this release.

Year-to-Date

2016
2015
% Change
Earnings per share (reported)
$
1.12
$
1.06
6%
Amortization of intangible assets
.22
.20

Asset impairment, restructuring and other special charges
.16
.12

Acquired in-process research and development
—
.20

Venezuela charge
.19
—

Net charge related to repurchase of debt
—
.09

Novartis Animal Health inventory step-up
—
.09

Earnings per share (non-GAAP)
$
1.69
$
1.76
(4)%

Numbers may not add due to rounding.

Select Revenue Highlights

(Dollars in millions)

Second Quarter

Year-to-Date

Established
Pharmaceutical
Products
2016

2015

% Change

2016

2015

% Change

Humalog
$
701.9

$
654.3

$
1,308.2

$
1,338.2

(2)%

Cialis
630.5

567.9

11%

1,207.2

1,106.2

Alimta
607.1

664.3

(9)%

1,171.3

1,237.4

(5)%

Humulin
332.3

316.4

688.7

632.1

Forteo
367.6

328.4

12%

686.3

621.4

10%

Cymbalta
236.5

274.1

(14)%

435.2

561.1

(22)%

Zyprexa
210.7

253.7

(17)%

423.4

473.2

(11)%

Strattera
224.6

191.8

17%

412.7

365.5

13%

Erbitux
180.6

134.6

34%

348.6

222.8

56%

Effient
135.1

128.8

266.6

250.6

New
Pharmaceutical
Products

Trulicity
201.3

44.3

344.9

62.6

Cyramza
147.0

87.7

68%

278.0

155.2

79%

Jardiance(a)
40.1

11.1

78.3

30.3

Basaglar
16.3

—

27.2

—

Taltz
19.3

—

19.3

—

Portrazza
4.0

—

5.7

—

Animal Health
859.8

840.8

1,614.4

1,590.5

Total Revenue
5,404.8

4,978.7

10,269.9

9,623.4

(a) Jardiance includes Glyxambi and Synjardy
NM – not meaningful

Certain Established Pharmaceutical Products

Humalog
For the second quarter of 2016, worldwide Humalog revenues increased 7 percent compared with the second quarter of 2015 to $701.9 million. Revenues in the U.S. increased 5 percent to $420.0 million, driven by increased demand, partially offset by lower realized prices. Revenues outside the U.S. increased 11 percent to $281.9 million, primarily driven by increased volume, partially offset by the unfavorable impact of foreign exchange rates.

Cialis
Cialis revenues for the second quarter of 2016 increased 11 percent compared with the second quarter of 2015 to $630.5 million. U.S. revenues of Cialis were $383.2 million, a 24 percent increase compared with the second quarter of 2015, driven primarily by higher realized prices and, to a lesser extent, increased volume. Revenues of Cialis outside the U.S. decreased 4 percent to $247.3 million, driven by the unfavorable impact of foreign exchange rates and decreased volume.

Alimta
For the second quarter of 2016, Alimta generated revenues of $607.1 million, a decline of 9 percent compared with the second quarter of 2015. U.S. revenues of Alimta decreased 12 percent to $291.0 million, driven primarily by decreased demand due to competitive pressure. Revenues outside the U.S. decreased 5 percent to $316.1 million, driven by decreased volume and lower realized prices, partially offset by the favorable impact of foreign exchange rates.

Humulin
Worldwide Humulin revenues for the second quarter of 2016 increased 5 percent compared with the second quarter of 2015 to $332.3 million. U.S. revenues increased 9 percent to $204.3 million, driven by increased volume. Revenues outside the U.S. remained relatively flat at $128.0 million.

Forteo
Second-quarter 2016 revenues of Forteo were $367.6 million, a 12 percent increase compared with the second quarter of 2015. U.S. revenues of Forteo increased 29 percent to $186.4 million, driven by higher realized prices. Revenues outside the U.S. decreased 1 percent to $181.2 million, driven by lower realized prices, largely offset by increased volume and the favorable impact of foreign exchange rates.

New Pharmaceutical Products
Trulicity
Second-quarter 2016 revenues of Trulicity were $201.3 million. U.S. revenues of Trulicity were $161.4 million, driven by growth in the GLP-1 market and increased share of market for Trulicity. Revenues of Trulicity outside the U.S. were $39.9 million.

Cyramza
For the second quarter of 2016, Cyramza revenues were $147.0 million. U.S. revenues were $67.9 million, a decrease of 4 percent compared with the second quarter of 2015, due to competitive pressure in the non-small cell lung cancer indication. Revenues outside the U.S. were $79.1 million, primarily due to strong uptake for the gastric cancer indication in Japan.

Jardiance
The company’s revenues for Jardiance during the second quarter of 2016 were $40.1 million. U.S. revenues were $26.0 million, driven by growth in the SGLT2 class and increased share of market for Jardiance. Revenues outside the U.S. were $14.1 million. Jardiance is part of the company’s alliance with Boehringer Ingelheim, and Lilly reports as revenue a portion of Jardiance’s gross margin.

Basaglar
Second-quarter 2016 revenues of Basaglar, which has launched in multiple countries outside the U.S., were $16.3 million, driven by early uptake in Japan and various European countries.

Taltz
For the second quarter of 2016, Taltz revenues were $19.3 million. Taltz launched in the U.S. in April 2016.

Portrazza
For the second quarter of 2016, Portrazza revenues were $4.0 million. Portrazza launched in the U.S. in December 2015 and began launching in Europe in April 2016.

Animal Health
In the second quarter of 2016, worldwide animal health revenues totaled $859.8 million, an increase of 2 percent compared with the second quarter of 2015. U.S. animal health revenues increased 8 percent to $444.5 million, due to wholesaler buying patterns and uptake of new companion animal products, partially offset by decreased revenues for food animal products. Animal health revenues outside the U.S. decreased 3 percent to $415.3 million, primarily due to the unfavorable impact of foreign exchange rates. Excluding the unfavorable impact of foreign exchange rates, worldwide animal health revenues increased 4 percent.

2016 Financial Guidance

The company confirmed its 2016 financial guidance on a reported basis and on a non-GAAP basis, consistent with the explanations provided in the company’s first-quarter 2016 earnings press release.

Full-year 2016 earnings per share are still expected to be in the range of $2.68 to $2.78 on a reported basis. On a non-GAAP basis, full-year 2016 earnings per share are still expected to be in the range of $3.50 to $3.60.

2016
Expectations

Earnings per share (reported)
$2.68 to $2.78

Amortization of intangible assets
.42

Asset impairment, restructuring and other special charges, including
Novartis Animal Health integration costs and closure of an animal
health manufacturing facility in Ireland
.21

Venezuela charge
.19

Earnings per share (non-GAAP)
$3.50 to $3.60

Numbers may not add due to rounding.

The following table summarizes the company’s 2016 financial guidance:

2016 Guidance

Revenue
$20.6 to $21.1 billion

Gross Margin % of Revenue (reported)
Approx. 73%
Gross Margin % of Revenue (non-GAAP)
Approx. 76%

Marketing, Selling & Administrative
$6.1 to $6.3 billion

Research & Development
$4.9 to $5.1 billion

Other Income/(Expense) (reported)
$(200 million) to $(125 million)
Other Income/(Expense) (non-GAAP)
$0 to $75 million

Tax Rate
Approx. 21.0%

Earnings per share (reported)
$2.68 to $2.78
Earnings per share (non-GAAP)
$3.50 to $3.60

Capital Expenditures
Approx. $1.1 billion

Non-GAAP adjustments are consistent with the earnings per share table above.