On November 6, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported a three-year overall survival (OS) update from its phase 3 CheckMate -025 study, evaluating patients treated with Opdivo (nivolumab) versus everolimus in previously treated advanced renal cell carcinoma (RCC) (Press release, Bristol-Myers Squibb, NOV 6, 2017, View Source [SID1234521580]). These data are the first of any anti-PD-1 agent to demonstrate durable survival at three years in previously treated RCC. No new safety signals were identified and the data showed a safety profile consistent with two-year results. Findings from CheckMate -025 were presented on November 4 during the 16th International Kidney Cancer Symposium (KCS) in Miami, Florida.

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The median OS, the primary endpoint in this study, for Opdivo was 25.8 months compared to 19.7 months with everolimus (HR 0.74; 95.45% CI: 0.63 to 0.88; p: 0.0005). The three-year OS rate was 39% for Opdivo and 30% for everolimus. The safety profile of Opdivo was consistent with that of previous reports.

"The updated results of CheckMate -025 reinforce the overall survival benefit and safety profile of Opdivo and provide further support for this therapeutic option as a standard of care for patients with previously treated advanced renal cell carcinoma," said Padmanee Sharma, M.D., PhD., scientific director, Immunotherapy Platform, MD Anderson Cancer Center.

At 36 months, Opdivo demonstrated an objective response rate (ORR), a secondary endpoint, of 26% compared to 5% with everolimus (95% CI: 3.82 to 10.06), and the median durations of response for Opdivo and everolimus were 12.3 (95% CI: 9.1 to 18.2) and 12 months (95% CI: 6.4 to 21.7), respectively. Median progression-free survival (PFS), another secondary endpoint, was 4.2 months for Opdivo and 4.5 months for everolimus (HR 0.85; 95% CI: 0.73 to 0.99; p: 0.0371).

"The CheckMate -025 data reinforce Opdivo as the standard of care in previously treated renal cell carcinoma, with the three-year data demonstrating a continued survival benefit with a greater than six-month improvement over everolimus," said Arvin Yang, M.D., Ph.D., development lead, melanoma and genitourinary cancers, Bristol-Myers Squibb. "Building on the unprecedented two-year overall survival data from this trial, these are the first three-year overall survival for an anti-PD-1 agent in advanced RCC, showcasing our ongoing commitment to improving survival rates for people living with the most common type of kidney cancer in adults worldwide."

About CheckMate -025

CheckMate -025 is an open-label, randomized phase 3 study of Opdivo versus everolimus in patients with previously treated advanced renal cell carcinoma (RCC) after prior anti-angiogenic therapy. Patients (N=803) received either Opdivo (N=406) 3 mg/kg intravenously (IV) every two weeks or everolimus (N=397) 10 mg orally once daily until disease progression or unacceptable toxicity. The primary endpoint of the study was overall survival (OS). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), quality of life (QoL) and safety. Patient-reported QoL was measured using the kidney-specific, Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease Related Symptoms (FKSI-DRS) scale, and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D) questionnaire.

With a minimum of three years of follow-up, the incidence and type of treatment-related adverse events (AEs) were consistent with the primary analysis. Treatment-related grade 3/4 AEs were experienced by 21% of patients in the Opdivo group and 37% in the everolimus group. Treatment-related grade AEs leading to discontinuation were experienced by 8% of patients in the Opdivo group and 13% in the everolimus group. The most common grade 3/4 AEs in the Opdivo arm were hepatic (3%) and GI (2%). In the everolimus arm, the most common grade 3/4 AEs were pulmonary (3%), GI (2%), and skin (1%). There were no treatment-related deaths reported in the Opdivo group and two treatment-related deaths reported in the everolimus arm at three years.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to 90% of all patients. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. Globally, the five-year survival rate for those diagnosed with metastatic, or advanced, kidney cancer is 12.1%.

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

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

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 the confirmatory trials.

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

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 adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. 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.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory 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

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

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

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

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 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

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and 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. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

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

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

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 Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. 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 patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. 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 patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

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 HSCT 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 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). 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 (n=206). 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 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 (n=313) relative to the OPDIVO arm (n=313). 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 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). 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, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) 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 (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) 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, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).. In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). The most common adverse reactions (≥20%) in patients who received OPDIVO as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.

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%).

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

Checkmate Trials and Patient Populations

Checkmate 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 017 – squamous non-small cell lung cancer (NSCLC); Checkmate 057 – non-squamous NSCLC; Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck; Checkmate 275 – urothelial carcinoma; Checkmate 040 – hepatocellular carcinoma.

About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd (Ono), Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

On November 6, 2017 Cellular Biomedicine Group Inc. (NASDAQ: CBMG) ("CBMG" or the "Company"), a leading clinical-stage biopharmaceutical firm engaged in the development of immunotherapies for cancer and effective stem cell therapies for degenerative diseases, reported the establishment of a strategic partnership with Thermo Fisher Scientific (China) Ltd. (Thermo Fisher) to build a joint Cell Therapy Technology Innovation and Application Center (Center) at CBMG’s newly opened Shanghai Zhangjiang GMP facility (Press release, Cellular Biomedicine Group, NOV 6, 2017, View Source [SID1234521571]). The Center is named "CBMG-Thermo Fisher Scientific Joint Innovation & Application Center". The partnership focuses on the research and development of an automated cell therapy manufacturing system.

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"Break-through cell therapy technology such as CAR-T provides unprecedented medical needs to cancer patients, yet the successful commercialization of this technology will require robust logistics, manufacturing and complex management systems," commented Tony (Bizuo) Liu, CEO of CBMG. "When we combine Thermo Fisher’s strengths in biopharmaceutical products and manufacturing quality control processes with CBMG’s vertically integrated cell therapy manufacturing system, we believe we can further increase productivity, reduce cost, improve batch stability, reduce variability and institutionalize the Chemistry, Manufacturing, and Controls (CMC) processes, which we believe will help to address some of the primary logistical challenges faced by the CAR-T cell therapy industry. We are optimistic that this partnership will not only bring mutual benefit to CBMG and Thermo Fisher, but also to the cell therapy industry sector as a whole."

"This cooperation demonstrates our commitment to China. As a world leader in serving science, Thermo Fisher seeks to provide total solutions for cell therapy research, development, and manufacturing. We believe this will help to accelerate the development of the cell therapy industry in China. Based on our broad product portfolio, Thermo Fisher has developed outstanding capabilities in global CAR-T manufacturing, including our Cell Therapy Systems (CTS) Dynabeads technology in the first FDA-approved cell therapy." said Gianluca Pettiti, President of Thermo Fisher China, "We look forward to this strategic partnership and the benefits that the Joint Innovation and Application Center will provide to a vast Chinese patient population."

CBMG’s new Zhangjiang facility, together with an expanded Wuxi and Beijing GMP facilities combined, comprises 70,000 square feet for development and production. This will enable CBMG to conduct simultaneous clinical trials for multiple CAR-T and stem cell product candidates. At full production volumes, these facilities could support treating 10,000 cancer patients and 10,000 Knee Osteoarthritis patients per year. The Company’s combined GMP expansion will enable scaled-up supply for current and future CAR-T clinical trials and streamline efficiency from R&D into manufacturing of CAR-T cells for clinical use, IND filings and future commercialization. The Company currently has ongoing CAR-T Phase I clinical trials in China; CARD-1 for Diffuse Large B-cell Lymphoma (DLBCL) and Non-Hodgkin Lymphoma (NHL) and CALL-1 for adult Acute Lymphoblastic Leukemia (ALL), utilizing CBMG’s proprietary and optimized CD19 construct.

On November 6, 2017 AVEO Oncology (NASDAQ:AVEO) and EUSA Pharma reported the presentation of promising results from the ongoing Phase 1 portion of the TiNivo study, a Phase 1/2 multicenter trial of tivozanib (FOTIVDA) in combination with Bristol-Myers Squibb’s nivolumab (OPDIVO), an immune checkpoint, or PD-1, inhibitor, for the treatment of advanced renal cell carcinoma (RCC) (Press release, AVEO, NOV 6, 2017, View Source;p=RssLanding&cat=news&id=2314412 [SID1234521570]). The results were presented on Friday, November 3, at the 16th International Kidney Cancer Symposium in Miami, in an oral presentation titled "TiNivo: A Phase Ib Dose Escalation Trial of Tivozanib and Nivolumab in Renal Cell Carcinoma" by Laurence Albiges, M.D., Ph.D., Head, Genitourinary Unit, Institute Gustave Roussy, and a lead investigator of the study. A copy of the presentation is available at www.aveooncology.com or further information can be obtained via EUSA Pharma Medical Information.

The Phase 1 portion of the trial enrolled six patients, three with previously untreated metastatic RCC and three who had received first-line treatment. RCC tumor histology included five clear cell (one with sarcomatoid features) and one papillary. Tivozanib was administered to patients in two escalating dose cohorts (1.0 mg/QD and 1.5 mg/QD) in combination with nivolumab at a constant 240 mg every 2 weeks. The combination was well tolerated to the full dose and schedule of single agent tivozanib, with no dose limiting toxicities. The most common adverse events (any grade) were hypertension, asthenia and decreased appetite. No grade 4 adverse events were reported. Two grade 3 events were reported beyond cycle 1 (stomatitis and increased ALT), which did not lead to study discontinuation and were managed concurrently. Unconfirmed best response to date includes a 67% (4/6) partial response (PR) rate and a 100% disease control rate (PR + stable disease). Enrollment of approximately 20 patients in the Phase 2 portion of the trial is ongoing.

"Combining VEGF TKIs and PD-1s holds the potential for synergistic activity against renal cell carcinoma, yet most such combinations demonstrate a high rate of toxicity in the clinic," said Dr. Albiges. "Tivozanib has several distinguishing properties that may enhance its ability to combine with checkpoint inhibitors, including a highest in-class selectivity for the VEGF-Receptor (types 1, 2 and 3), and therefore fewer off-target effects, and the ability to significantly reduce regulatory T cells, thereby enhancing immune activity against the tumor. Tivozanib’s favorable tolerability profile has been demonstrated against sorafenib in the pivotal TIVO-1 study, and early results from the TiNivo study show a tolerable combination and evidence of promising activity."

"We are encouraged by the preliminary tolerability and activity results from the TiNivo study, as we believe they begin to underscore the unique potential of tivozanib-immunotherapy combinations," said Michael Needle, M.D., chief medical officer of AVEO. "With immunotherapy combinations continuing to demonstrate improved outcomes in patients with RCC, it will become increasingly important to leverage the best-in-class VEGF therapies and immunotherapies to optimize efficacy and tolerability in defined populations within this disease. We believe tivozanib is well-positioned within this evolving landscape, and we look forward to presenting the Phase 2 portion of TiNivo in the first half of next year. We also anticipate moving into additional combination studies in the coming quarters."

Lee Morley, EUSA Pharma’s Chief Executive Officer said, "Following the recent European approval of tivozanib (FOTIVDA) for the first-line treatment of patients with advanced RCC, emerging data from the TiNivo study indicates the potential for tivozanib in the setting of combination treatment with immunotherapies. The initial results of the TiNivo study are promising and, in partnership with AVEO, we look forward to developing new and innovative options based on the unique profile of tivozanib which will be important for the future management of patients."

About Tivozanib (FOTIVDA)

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Hakko Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma in the European Union plus Norway and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.1,2 Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers.

On November 6, 2017 QIAGEN N.V. (NASDAQ: QGEN; Frankfurt Prime Standard: QIA) reported results of operations for the third quarter and first nine months of 2017, delivering on goals for improvements in adjusted net sales and adjusted earnings (Press release, QIAGEN, NOV 6, 2017, View Source [SID1234521719]).

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"QIAGEN’s results for the third quarter of 2017 confirm that our Sample to Insight molecular testing solutions are delivering growth across the continuum of customer needs from basic research to clinical healthcare. All customer classes and regions supported growth trends in the third quarter, which were led by our Molecular Diagnostics and Applied Testing customer classes growing at solid rates and complemented by gains in Pharma and Academia," said Peer M. Schatz, Chief Executive Officer of QIAGEN N.V. "These results demonstrate that we are progressing well and delivering on our full-year ambitions during 2017, especially against a very strong performance in the second half of 2016, with market share gains, solid sales growth and a double-digit increase in adjusted earnings per share while strengthening our foundation for 2018 and beyond."

Third quarter 2017 results
Net sales grew 7% at actual rates to $364.0 million in the third quarter of 2017 over the year-ago period and also advanced at 7% CER. Organic expansion contributed six percentage points to total CER growth, with about one percentage point from the January 2017 acquisition of OmicSoft Corporation, a leading provider of omics data solutions. Adjusted net sales, which include all revenue contributions from OmicSoft, increased 8% at actual rates to $364.4 million in the third quarter of 2017, and rose 7% CER with one percentage point of favorable currency movements.

Consumables and related revenues (+8% CER / 88% of sales) led the performance, and supported by single-digit CER growth in instrument sales (+2% CER / 12% of sales). Among the customer classes, Molecular Diagnostics (+9% CER / 49% of sales) was led by ongoing solid growth of the QuantiFERON-TB franchise above the annual 25% CER growth target, consumables used for the QIAsymphony automation system and solid contributions from companion diagnostic pharma collaborations.

In the Life Sciences, Applied Testing delivered 14% CER (+15% CER adjusted sales) growth thanks to solid gains in the Human Identification / Forensics portfolio, and supported by single-digit CER growth in Pharma (+4% CER, +5% CER adjusted sales) and Academia (+2% CER).

Among the regions, Europe / Middle East / Africa (+15% CER) had the fastest pace due to double-digit CER growth in France, Turkey and the Netherlands, along with single-digit CER contributions from the United Kingdom and Germany. Asia-Pacific / Japan (+7% CER) benefited from dynamic growth in Korea and India, and supported by single-digit gains in China, while Japan showed a modest single-digit CER decline. The Americas (+3% CER) grew on increased sales in the U.S. and Brazil, but faced a significant expected decline in Mexico due to the expiry of a tender.

Operating income was $63.9 million in the third quarter of 2017 compared to $48.3 million in the same period of 2016. Adjusted operating income, which excludes items such as business integration, acquisition-related costs and the amortization of intangible assets acquired in business combinations, rose 9% to $96.1 million compared to $88.1 million in the year-ago period. The adjusted operating income margin was steady at 26% of sales compared to the same period of 2016. Excluding the pre-tax restructuring charge taken in the third quarter of 2017, which was $1.8 million, adjusted operating income rose 11% to $97.9 million and the adjusted operating income margin was 27% of sales.
Net income attributable to owners of QIAGEN N.V. was $48.5 million, or $0.21 per diluted share (based on 232.7 million diluted shares) compared to $34.8 million, or $0.15 per share (based on 239.3 million diluted shares) in the third quarter of 2016. Adjusted net income was $75.3 million, or $0.32 per share ($0.32 CER), up from $69.3 million, or $0.29, in the year-ago period. Excluding the restructuring charge taken in the third quarter of 2017, which was $0.2 million on adjusted net income, adjusted diluted EPS was $0.32 per share ($0.32 CER).

First nine months 2017 results
Net sales grew 5% to $1.021 billion in the first nine months of 2017 over the same period in 2016, and were up 6% CER with one percentage point of adverse currency movements. Adjusted net sales also rose 5% to $1.022 billion in the first nine months of 2017, and were up 6% CER. Organic expansion contributed four percentage points to total CER growth, while two percentage points came from the acquisitions of Exiqon A/S in June 2016 and OmicSoft in January 2017. The expected decline in U.S. HPV test sales created about one percentage point of headwind, with adjusted net sales rising about 7% CER over the same period in 2016 when excluding these specific product sales.
Higher sales of consumables and related revenues (+7% CER, +8% CER adjusted sales / 88% of sales) more than offset a decline in instruments (-2% CER / 12% of sales). Molecular Diagnostics (+6% CER / 48% of sales) advanced +7% CER when excluding U.S. HPV test sales. In the Life Sciences, Applied Testing delivered double-digit CER gains (+15% CER, +16% CER adjusted sales), supported by single-digit CER growth in Pharma (+6% CER, +7% CER adjusted sales) and Academia (+3% CER). Among the regions, Europe / Middle East / Africa (+10% CER) led the performance, and supported by Asia-Pacific / Japan (+9% CER) and the Americas (+3% CER).

Operating income was $110.0 million in the first nine months of 2017 compared to $94.6 million in the same period of 2016. Adjusted operating income, which excludes items such as business integration, acquisition-related costs and the amortization of intangible assets acquired in business combinations, rose 9% to $230.5 million compared to $212.1 million in the 2016 period. The adjusted operating income margin rose to 23% of sales from 22% in the same period of 2016. Excluding the pre-tax restructuring charge in the first nine months of 2017, which was $19.2 million, adjusted operating income rose 18% to $249.7 million and the adjusted operating income margin was 24% of sales.
Net income attributable to owners of QIAGEN N.V. was $80.1 million, or $0.34 per diluted share (based on 233.4 million diluted shares) compared to $71.8 million, or $0.30 per share (based on 238.8 million diluted shares) in the first nine months of 2016. Adjusted net income was $180.8 million, or $0.77 per share ($0.78 CER), up from $171.3 million, or $0.72, in the year-ago period. Excluding the restructuring charge taken in the first nine months of 2017, which was $14.2 million on adjusted net income, adjusted diluted EPS was $0.84 per share ($0.84 CER).

Balance sheet and cash flows
At September 30, 2017, cash and cash equivalents increased to $671.8 million from $439.2 million at December 31, 2016. Net cash provided by operating activities was $210.7 million in the first nine months of 2017, down from $241.6 million in the year-ago period. Free cash flow for the first nine months of 2017 was $146.1 million, down from $186.7 million in the prior-year period, due mainly to the approximately $41 million impact of cash payments related to the restructuring activities launched in late 2016. Purchases of Property, Plant and Equipment rose to $64.6 million in the first nine months of 2017 from $54.8 million in 2016. Net cash used in investing activities was $371.9 million in the first nine months of 2017, which included payments for the OmicSoft acquisition, compared to $163.3 million in the first nine months of 2016. Net cash provided by financing activities was $386.0 million, which included net proceeds of $726.3 million from debt issuances during 2017 partially offset by $304.9 million of payments in connection with the share repurchase commitment, compared to cash used in financing activities of $15.8 million in the first nine months of 2016.

During the third quarter of 2017, QIAGEN completed the issuance of $400 million of new senior unsecured cash-settled convertible notes outside the U.S. at a 0.5% annual interest rate, and with an effective conversion price of $50.97 due to the entry into derivative transactions.

"QIAGEN has fulfilled its commitment to return $300 million to shareholders ahead of the scheduled end of 2017 target. We are reaffirming our commitment to a disciplined approach to capital allocation, and will review new opportunities to create more value," said Roland Sackers, Chief Financial Officer of QIAGEN N.V. "We are also making significant progress on initiatives to support the improvements in sales and profitability. Related to these initiatives, we have launched a new project in China to increase investments in high-growth areas and streamline our portfolio. We will be putting more resources toward areas such as the QuantiFERON-TB test, the new MAQGEN joint venture with Maccura for the GeneReader NGS System and the life sciences portfolio. At the same time, we have also decided to discontinue some non-core diagnostic PCR tests, and are in the process of divesting the distribution of our China HPV franchise to a third-party aggregator / distributor to improve our competitive position through a more tailored product offering and better adapt to local market needs."

Top 7 emerging markets: Brazil, Russia, India, China, South Korea, Mexico and Turkey (Q3 2017: $61 million, +19% CER, 17% of sales; 9M 2017: $162 million, +15% CER, 16% of sales)
Q3 and 9M 2017: Rest of world represented less than 1% of net sales.
Growth rates at constant exchange rates (CER), sales and sales contributions at actual FX rates. Tables may have rounding differences.

Sustaining growth trajectory with Sample to Insight portfolio
QIAGEN continues to capture growth opportunities with differentiated Sample to Insight solutions enabling molecular testing across the continuum from basic research to clinical healthcare. Among recent developments:
QuantiFERON-TB Gold-Plus (QFT-Plus), the fourth generation of QIAGEN’s market-leading blood test for detecting latent tuberculosis (TB) infection, was launched in the United States. QFT-Plus provides significant detection and workflow benefits for screening programs that form the basis of global TB control efforts, and studies have demonstrated the valuable potential of the test to measure the risk of progression to active, contagious TB. The test’s proprietary CD4+/CD8+ design captures a broad picture of an individual’s immune status and delivers a comprehensive evaluation of immune response to TB infection with the potential for enhanced clinical insights. The U.S. launch of the fourth-generation version follows the launch and uptake in over 75 countries following the start of commercialization in 2016.

Personalized Healthcare surpassed a milestone of 25 master collaboration agreements with pharma and biotech companies to develop QIAGEN companion diagnostic tests that guide medical decision-making based on individualized genomic insights. QIAGEN has launched 15 new companion diagnostic projects so far in 2017, more than any prior year. In the third quarter of 2017, submissions were initiated for five Premarket Approval (PMA) applications and one PMA supplement, pointing to several potential product launches in 2018. QIAGEN also expanded its footprint in cancer immunotherapy (I-O), adding two new collaborations for development of molecular tests to identify patients who could benefit from I-O therapies.

Next-generation sequencing (NGS) solutions ranging from digital sequencing assays to bioinformatics software were highlighted in multiple studies presented in October 2017 at the American Society of Human Genetics (ASHG) meeting. A study by Counsyl, Inc., a leader in DNA testing and genetic counseling services, found that the QIAGEN Clinical Insight (QCI) platform reduced the time required to interpret and score genetic variants by 75%. QIAGEN and Counsyl have entered a collaboration to deploy QCI as part of Counsyl’s scale-up of their genetic screening technologies. QIAGEN also began a collaboration with CENTOGENE AG to provide more complete Sample to Insight research and clinical testing solutions in rare genetic diseases. The GeneReader NGS System is rapidly gaining acceptance worldwide with a focus on clinical benchtop oncology testing. In October, the ICMP opened its new forensics laboratory in The Hague with GeneReader workflows optimized for human identification, innovative panels designed for identification of missing persons and integrated bioinformatics, marking the first additional application of this system outside of clinical research.

QIAsymphony, the leading Sample to Insight workflow automation solution for molecular labs worldwide, continues to expand its base of global placements, which are nearing the full-year goal for more than 2,000 cumulative systems, up from more than 1,750 at the end of 2016.

Differentiated technologies that enable scientists to gain better insights in large and fast-growing research areas are driving growth, in particular QIAGEN’s industry-leading solutions for liquid biopsies and state-of-the-art technologies in Applied Testing. As non-invasive liquid biopsies disseminate in clinical diagnostics, QIAGEN is partnering with leading providers to incorporate its differentiated solutions for liquid biopsy testing. For example, Clinical Genomics partnered with QIAGEN to use the PAXgene Blood ccfDNA Tube in sample collection with Clinical Genomics’ assay to monitor patients for recurrence of colorectal cancer. In forensics, QIAGEN has pioneered efforts for years to develop international standards of quality for human identity testing products, and a third-party agency recently certified QIAGEN for meeting the state-of-the-art requirements for forensics supply chain and manufacturing (ISO18385:2016).

Initiatives to sustain faster sales momentum while delivering margin benefits

QIAGEN announced initiatives during the fourth quarter of 2016 to sustain faster sales momentum while improving efficiency and accountability to increase margins. Significant efficiency benefits have already been delivered, and targeted actions are continuing during 2017. QIAGEN has expanded the scope of these programs, in particular aiming to capture greater benefits from shared service centers and digitization. In the third quarter of 2017, QIAGEN recorded a pre-tax restructuring charge of $1.8 million, which was less than $0.01 per share, that was included in adjusted results, bringing the nine-month 2017 pre-tax restructuring charge to $19.2 million (or about $0.06 per share on an after-tax basis). QIAGEN continues to review ways to improve efficiency and effectiveness, and continues to expect a pre-tax restructuring charge for full-year 2017 of approximately $20 million related to these initiatives, or about $0.07 per share, which will be included in adjusted results.

QIAGEN completes $300 million share repurchase commitment
QIAGEN has completed a commitment to return $300 million to shareholders by the end of 2017. The final tranche of approximately $60 million was completed on September 15, 2017, through the open-market repurchase of 1.91 million shares on the Frankfurt Stock Exchange at an average price of EUR 26.84 (or about $31.94 per share based on exchange rates at that time). This tranche came after QIAGEN completed the return of $245 million in January 2017 through a synthetic share repurchase that combined a direct capital repayment with a reverse stock split.

Changes in QIAGEN Executive Committee
After 12 years with QIAGEN, Douglas Liu is retiring from his role as Senior Vice President, Global Operations and member of the Executive Committee. During his tenure, he successfully ensured reliable supply and growth of QIAGEN’s portfolio and effective supply chains while helping to ensure the successful integration of more than 20 companies. He will continue to work closely with QIAGEN in an advisory role. QIAGEN is pleased to announce that Mark Gladwell has joined QIAGEN to assume the role of Senior Vice President, Global Operations and member of the Executive Committee. He brings to QIAGEN more than two decades of experience in manufacturing high-volume, high technology in vitro diagnostics and medical devices, and most recently served as Senior Vice President, Global Operations, at Alere Inc.
Dr. Laura Furmanski, who has served as Senior Vice President of the Bioinformatics Business Area and a member of the Executive Committee since 2014, will be resigning and return to management consulting. She was responsible for leading QIAGEN’s presence in bioinformatics, and oversaw the integration of important acquisitions to strengthen this differentiating leadership position. A search for a successor is in an advanced stage.

Outlook
For full-year 2017, QIAGEN expects adjusted net sales to grow approximately 7% CER. This excludes the 2016 and 2017 revenues related to the decision to streamline the China portfolio as part of the new growth initiative. These revenues amount to about 1-2% of total sales for both years. Further, this guidance is based on about five to six percentage points of organic sales growth from the portfolio (including about one percentage point of headwind from reduced HPV test sales in the U.S.) and approximately one to two percentage points from the acquisitions of Exiqon (June 2016) and, to a lesser extent, OmicSoft (January 2017).

QIAGEN reaffirms its full-year 2017 guidance for adjusted diluted EPS of about $1.25-1.27 CER per share based on operating and financial leverage, which includes benefits from completion of the $300 million share repurchase and efficiency actions initiated in 2016, but excludes $0.07 per share of restructuring costs expected for 2017. The portfolio changes in China are not expected to have any material impact on adjusted EPS excluding the restructuring charge. Based on exchange rates as of November 3, 2017, currency movements against the U.S. dollar are expected to have a negative impact on full-year 2017 adjusted net sales of about one percentage point, and a negative impact of about $0.01 per share on adjusted diluted EPS. These expectations do not take into account any further acquisitions that could be completed in 2017.

For the fourth quarter of 2017, adjusted net sales are expected to rise approximately 5-6% CER compared to the same period in 2016. This excludes the 2016 and 2017 revenues in this quarter related to the decision to streamline the China portfolio. This guidance is based on approximately four to five percentage points of organic growth (including about two percentage points of U.S. HPV headwinds) and about one percentage point from the OmicSoft acquisition. Adjusted diluted EPS is expected to be about $0.41-0.42 CER excluding restructuring charges (~$0.01 per share). The portfolio changes in China are not expected to have any material impact on adjusted EPS. Based on exchange rates as of November 3, 2017, currency movements against the U.S. dollar are expected to have a positive impact on adjusted net sales of about two percentage points, and a neutral impact on adjusted diluted EPS.

Quarterly results presentation, conference call and webcast details
A presentation with additional information can be downloaded at View Source A conference call will be held on Tuesday, November 7, 2017, at 15:00 Central European Time (CET) / 14:00 GMT / 9:00 Eastern Standard Time (EST). A live webcast will be made available at this website, and a replay will also be made available after the event.

Use of adjusted results
QIAGEN reports adjusted results, as well as results on a constant exchange rate (CER) basis, and other non-U.S. GAAP figures (generally accepted accounting principles), to provide additional insight into its performance. These results include adjusted net sales, adjusted gross profit, adjusted operating income, adjusted net income attributable to owners of QIAGEN N.V., adjusted diluted EPS and free cash flow. Adjusted results are non-GAAP financial measures that QIAGEN believes should be considered in addition to reported results prepared in accordance with GAAP, but should not be considered as a substitute.

Free cash flow is calculated by deducting capital expenditures for Property, Plant & Equipment from cash flow from operating activities. QIAGEN believes certain items should be excluded from adjusted results when they are outside of ongoing core operations, vary significantly from period to period, or affect the comparability of results with competitors and its own prior periods. Furthermore, QIAGEN uses non-GAAP and constant currency financial measures internally in planning, forecasting and reporting, as well as to measure and compensate employees.
QIAGEN also uses adjusted results when comparing current performance to historical operating results, which have consistently been presented on an adjusted basis. For these reasons, we are also presenting adjusted results excluding the impact of the restructuring charge taken in the first nine months of 2017.

Reconciliations are included in the tables accompanying this report. QIAGEN does not reconcile forward-looking non-GAAP financial measures to the corresponding GAAP measures due to the high variability and difficulty in making accurate forecasts and projections that are impacted by future decisions and actions. Accordingly, reconciliations of these forward-looking non-GAAP measures are not available without unreasonable effort. However, the actual amounts of these excluded items will have a significant impact on QIAGEN’s GAAP results.

Change in accounting principle for equity-based compensation
In the fourth quarter of 2016, QIAGEN made a change in accounting principle for equity-based compensation to the "multiple attribution method," which now aligns QIAGEN’s U.S. GAAP (Generally Accepted Accounting Principles) and IFRS (International Financial Reporting Standards) reporting. QIAGEN believes this change is preferable since it provides better alignment of cost recognition over vesting periods. Results for previous years have been revised without any meaningful impact. For the first nine months of 2016, diluted EPS was revised to $0.30 from $0.29 and adjusted diluted EPS was revised to $0.72 from $0.71, as a reduction of $2.1 million in after-tax equity-based compensation was offset by an increase of about 1.3 million in the weighted average number of shares. For the third quarter of 2016, diluted EPS was revised to $0.15 from $0.14, as a reduction of $1.0 million in after-tax equity-based compensation was offset by an increase of about 1.0 million in the weighted average number of shares. For more information, please see table accompanying this press release and filings with the U.S. Securities and Exchange Commission.

On November 7, 2017 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX; OTC: MPSYY), a leader in the field of therapeutic antibodies, reported results for the third quarter of 2017 (Press release, MorphoSys, NOV 7, 2017, View Source [SID1234521632]).

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"Our proprietary development program MOR208 for aggressive lymphoma was recently awarded Breakthrough Therapy designation by the FDA based on encouraging clinical data from our L-MIND trial in relapsed/refractory DLBCL. We are now focused on working closely with the regulatory authorities to bring MOR208 to market as fast as possible. The launch in the United States of Janssen’s TremfyaTM (guselkumab) for moderate to severe plaque psoriasis was a major highlight of this quarter. Approval in a second major territory may be imminent based on the positive recommendation for guselkumab by the European regulatory authority. We expect guselkumab to become an important pillar of our revenue in the years ahead", commented Dr. Simon Moroney, Chief Executive Officer of MorphoSys AG.

"We will continue to drive our proprietary portfolio forward. The approval of TremfyaTM (guselkumab) marks our transition to a company whose revenues will be increasingly based on recurring income from product sales in the years to come. This will contribute to the funding of our proprietary development activities," stated Jens Holstein, Chief Financial Officer of MorphoSys AG.

Financial Review for the third quarter of 2017 (IFRS; all figures rounded)

MorphoSys continues to focus on applying its proprietary technology and expertise to the research and development of innovative drug candidates. In the third quarter of 2017, group revenues amounted to EUR 15.0 million, up 20% compared to Q3 2016 (EUR 12.5 million). The revenue increase was mainly driven by licence income as well as milestone payments from Janssen. Q3 2017 revenues do not include royalties on TremfyaTM (guselkumab) sales as the first royalty reporting from Janssen has not yet been received. Thus, royalties on TremfyaTM (guselkumab) sales for Q3 2017 since launch in late July 2017 will be part of Q4 2017 results.

In the Proprietary Development segment, MorphoSys focuses on research and clinical development of its own drug candidates in cancer and inflammation. In Q3 2017, this segment recorded revenues of EUR 0.2 million (Q3 2016: EUR 0.1 million).

In the Partnered Discovery segment, MorphoSys applies its proprietary technology to discover new antibodies for pharmaceutical companies, receiving R&D funding and licensing fees from its partners and benefiting from the partners’ development progress through success-based milestone payments and royalties. In Q3 2017, revenues from this segment reached EUR 14.8 million (Q3 2016: EUR 12.3 million). The increase was particularly based on license income as well as milestone payments from Janssen.

Earnings before interest and taxes (EBIT) in Q3 2017 amounted to EUR -23.5 million (Q3 2016: EUR -13.1 million). As anticipated, the Proprietary Development segment reported an EBIT of EUR -29.8 million in Q3 2017 (Q3 2016: EUR -17.7), while the Partnered Discovery segment achieved an EBIT of EUR 10.4 million (Q3 2016: EUR 7.7 million).

In Q3 2017, the consolidated net loss amounted to EUR 24.0 million (Q3 2016: consolidated net loss of EUR 12.8 million). The consolidated net loss per share for Q3 2017 was EUR 0.83 (Q3 2016: consolidated net loss per share of EUR 0.49).

At the end of Q3 2017, the Company had a cash position of EUR 319.5 million compared to EUR 359.5 million on December 31, 2016. On the balance sheet, this cash position is reported under the following items: cash and cash equivalents; available-for-sale financial assets; bonds, available-for-sale; and current and non-current financial assets classified as loans & receivables. The number of shares issued totaled 29,345,748 at the end of Q3 2017 (year-end 2016: 29,159,770).

Results for the first nine months 2017

During the first nine months of 2017, group revenues amounted to EUR 38.6 million, 5% higher than the previous year (Q1-Q3 2016: EUR 36.7 million). For the first nine months of 2017, revenues do not include royalties on TremfyaTM (guselkumab) sales as the first royalty reporting from Janssen has not yet been received. Thus, Q3 2017 royalties on TremfyaTM (guselkumab) sales since launch in late July 2017, will be reflected in the Company’s Q4 2017 revenues.

As planned, R&D expenses for proprietary drug development and technology development increased considerably to EUR 67.9 million in the first nine months of 2017 (Q1-Q3 2016: EUR 46.2 million). This increase is due to intensified activities in the clinical development of proprietary drug candidates that are transitioning into advanced development stages, requiring larger clinical studies. Consequently, the EBIT in the first nine months of 2017 amounted to EUR -53.8 million (Q1-Q3 2016: EUR -32.3 million).

Financial guidance confirmed

For the financial year 2017, MorphoSys continues to expect Group revenues in the range of EUR 46 to 51 million. R&D expenses for proprietary drug development and technology development are confirmed to be in a corridor of EUR 85 to 95 million. Guidance for earnings before interest and taxes (EBIT) continues to be in the range of EUR -75 to -85 million. This guidance does not include any additional revenue from potential future collaborations and/or licensing partnerships, nor effects from potential in-licensing or co-development deals for new development candidates. As first royalty reporting from Janssen has not been received yet, royalties on net sales for TremfyaTM (guselkumab) cannot be accurately projected at this point in time. Hence the guidance for the financial year 2017 does not include any assumptions on royalty income for sales on TremfyaTM (guselkumab).

Transition in the CSO position

Dr. Markus Enzelberger, who has been serving as Interim CSO since April 15, 2017, was appointed Chief Scientific Officer (CSO) effective November 1, 2017. He succeeds Dr. Marlies Sproll who resigned from her CSO position effective end of October 31, 2017 due to ongoing family reasons. Dr. Sproll has taken on a new part-time role at MorphoSys as Special Adviser to the CEO as of November 1, 2017.

Operational outlook for 2017

In the Proprietary Development segment, MorphoSys expects the following events in 2017:

– MOR208: Presentation of further data from more patients in the ongoing phase 2 trial of MOR208 in combination with lenalidomide in DLBCL (L-MIND study) at the ASH (Free ASH Whitepaper) 2017 conference in December.

– MOR202: Continuation of phase 1/2a dose-escalation trial in multiple myeloma, including MOR202 in the highest dosing cohorts in combinations with pomalidomide and with lenalidomide. The Company is currently pursuing opportunities for a deal with MOR202 with an external partner in order to facilitate its further clinical development.

– MOR103/GSK3196165: According to clinicaltrials.gov, several studies conducted by GSK may reach primary completion including a phase 2b and a phase 2a study in rheumatoid arthritis as well as a phase 2a study in hand osteoarthritis. MorphoSys does not control its partners’ mode of communication. This HuCAL antibody originated in MorphoSys’s Proprietary Development segment, and has been fully out-licensed to GSK.

In its Partnered Discovery segment, the following events are expected:

– TremfyaTM (guselkumab): after the positive opinion of European Medical Agency’s CHMP in September 2017 recommending EU approval for treatment of patients with moderate-to-severe plaque psoriasis, the Company expects a decision by the European Commission soon.

– Novartis collaboration: As previously communicated and as reflected in the Company’s 2017 guidance, the collaboration with Novartis will conclude at the end of November 2017 in accordance with the contract.

– For the remainder of the year, up to 19 different clinical studies in various phases conducted by partners with antibodies made using MorphoSys technology may reach primary completion according to clinicaltrials.gov. MorphoSys does not control its partners’ mode of communication.

As always, MorphoSys is in discussions with other companies in the pharmaceutical industry about technology and/or product-based collaborations, with the goal of strengthening its participation in drug programs aimed at unmet medical needs.