On December 21, 2016 Sumitomo Dainippon Pharma Co., Ltd. (Head office: Osaka, Japan; President: Masayo Tada; Securities Code: 4506, First Section of TSE, "Sumitomo Dainippon Pharma") reported that the company and Tolero Pharmaceuticals, Inc. (Head office: Lehi, UT, U.S., CEO: David J. Bearss., "Tolero") have reached an agreement on December 21, 2016 on the acquisition of Tolero through U.S. Holding company wholly owned by Sumitomo Dainippon Pharma (Press release, Dainippon Sumitomo Pharma, DEC 21, 2016, View Source [SID1234517153]).

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According to the terms of the agreement, Sumitomo Dainippon Pharma will make an upfront payment of US$ 200 million to the shareholders of Tolero on closing of the acquisition, and thereafter it will make development milestone payments up to US$ 430 million related to the compounds being developed by Tolero based on its progress. Furthermore, after the launch, Sumitomo Dainippon Pharma will also make commercial milestone payments up to US$ 150 million, based on the net sales of the compounds.

1. Objectives of acquisition
Tolero is a biotechnology company in the U.S. specializing in research and development of therapeutic agents in the areas of oncology and hematological disorders. Tolero possesses excellent drug discovery capabilities for kinase inhibitors and other drug targets, and is developing the six compounds below, including cyclin-dependent kinase 9 (CDK9) inhibitor alvocidib, which is under clinical development for hematologic malignancies.

Compound Mechanism Stage alvocidib CDK9 inhibitor Phase 2 study completed / Acute myeloid leukemia Phase 2 study ongoing / Acute myeloid leukemia with biomarker Preclinical Myelodysplastic syndromes with biomarker TP-0903 AXL Kinase inhibitor Phase 1 study ongoing / Solid tumors TP-1287 Oral CDK9 inhibitor Preclinical TP-0184 ALK2 inhibitor Preclinical

In addition to the above list, Tolero possesses two compounds in the preclinical stage.

Torelo has demonstrated POC (Proof of Concept) of alvocidib in a randomized Phase 2 study for acute myeloid leukemia (AML). Tolero is also currently conducting a Phase 2 study for 2 biomarker-positive patients of the disease in the U.S. Tolero aims for a New Drug Application to the FDA in fiscal 2018 at the earliest.

Masayo Tada, Representative Director, President and CEO of Sumitomo Dainippon Pharma, stated that "Oncology, which is one of our focus therapeutic areas, has extremely high unmet medical needs, and we believe that it is the vital mission of any R&D-oriented pharmaceutical company to deliver innovative treatment options to patients and their families. As Tolero possesses a group of attractive development compounds, including alvocidib, we expect that this acquisition will help us to reinforce our oncology pipeline and achieve sustained growth of the Sumitomo Dainippon Pharma Group after the expiry of the exclusivity period of our mainstay atypical antipsychotic LATUDA. Now that Tolero’s high drug discovery abilities are on our side, we also expect to create a continuous flow of development compounds going forward."

2. Outline of the acquisition After the acquisition, Tolero will become a wholly-owned subsidiary of Dainippon Sumitomo Pharma America Holdings, Inc. (Head office: MA, U.S., "Holding company"), a holding company wholly-owned by Sumitomo Dainippon Pharma, and continue its research and development in Lehi, Utah. The boards of directors of Sumitomo Dainippon Pharma and Tolero have each approved this acquisition. However, fulfillment of the terms and conditions of the U.S. Antitrust Law and completion of statutory procedures (including approval from Tolero’s shareholders) are required to complete the acquisition. After completion of these procedures, the acquisition is expected to be deemed closed in February 2017. In this transaction, Lazard Frères K.K. serves as Sumitomo Dainippon Pharma’s financial advisor and Jones Day serves as its legal advisor. The acquisition will be implemented by way of a merger between Tolero and a special purpose company which has been established under the Holding company for facilitating this deal. Tolero will be the surviving company. The existing shareholders of Tolero will receive cash in compensation for the merger.

3. Outline of Tolero (1) Company Name Tolero Pharmaceuticals, Inc. (2) Address of Headquarters 2975 Executive Parkway Suite # 320 Lehi, UT 84043, U.S. (3) Representative CEO：David J. Bearss (4) Business Description Research and Development of pharmaceuticals in the areas of oncology and hematological disorders. (5) Share Capital US$ 866 (As of December 14,2016) (6) Date Established June 2011 (7) Major shareholders and shareholding ratio David J. Bearss (22.1%), Orelot LLC (15.2%), Alger Health Sciences Fund（8.9%）and others (As of December 14, 2016) › (8) Relationship with Nothing particular in terms of capital tie, personal connection. 3 Sumitomo Dainippon Pharma In November 2016, Sumitomo Dainippon Pharma and Tolero entered into a loan agreement (where Sumitomo Dainippon Pharma is a creditor) with the upper limit being set at US$ 6 million. (9) Financial status for recent business years (consolidated) Fiscal Year (US$) FY2013 FY2014 FY2015 Shareholder’s equity △7,691thousand △14,461 thousand △25,473 thousand Total assets 844 thousand 13,172 thousand 3,546 thousand Shareholder’s equity per share △0.9 △1.7 △2.9 Revenue 142 thousand － － Operating profit △2,958 thousand △4,557 thousand △9,742 thousand Net income △4,473 thousand △6,328 thousand △9,340 thousand Earnings per share △0.5 △0.7 △1.1 Dividend per share － － － › Shown the name of the representative investor and shareholding ratio of aggregate amount of shares jointly held by the joint holders where applicable

4. Number of owned shares and percentage of ownership before and after acquisition (1) Number of shares already acquired 0 shares Percentage of voting rights: 0% (2) Number of shares to be acquired 100 shares ›Note 1 Percentage of voting rights: 100% (Planned) (3) Total value for the acquisition Approximately up to US$ 780 million ›Note 2 Details: Upfront payment: US$ 200 million Development and commercial milestone: up to US$ 580 million Note 1: This acquisition will be made through a cash merger. Sumitomo Dainippon Pharma will not acquire Tolero’ shares because all outstanding shares of Tolero will be extinguished in exchange for cash payment to existing shareholders as consideration for the merger. Note 2: Total value for the acquisition does not include advisory fees and so forth (approximately ￥700 million).

5. Schedule (1) Sumitomo Dainippon Pharma’s Board Meeting Resolution December 21, 2016 (2) Signing Date December 21, 2016 (3) Completion of Acquisition February, 2017 (will be completed) › › As stated in (2) above, fulfillment of the terms and conditions of the U.S. Antitrust Law and the completion of statutory procedures (including approval from Tolero’s shareholders) are 4 required to complete the acquisition.

6. Financial impact on group performance Financial impact on the Sumitomo Dainippon Pharma’s consolidated financial results for fiscal year ending March 31, 2017 and beyond is currently under review. We will make an announcement if any other disclosure is required. (Reference)

Cyclin-dependent kinase (CDK) 9 inhibitor; alvocidib

Alvocidib targets CDK9, a member of cyclin-dependent kinase family, which activates transcription of cancer-related genes. The subsequent down-regulation of MCL-1, an anti-apoptotic gene, may be responsible for the potential clinical anti-cancer activity observed with alvocidib.
Alvocidib is an investigational intravenous small-molecule agent and it received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the treatment of acute myeloid leukemia (AML). National Cancer Institute (NCI) conducted alvocidib’s Phase 2 study（J-1101/NCI-8972, Haematologica 2015;100(9)） comparing ACM regimen (alvocidib, cytarabine and mitoxantrone) to the standard-of-care (cytarabine and daunorubicin), in front line AML patients who had one or more poor-risk features. In this study, ACM regimen (alvocidib combination therapy) demonstrated a statistically significant improvement in the complete remission (CR) rate, one of primary endpoints for AML therapy, compared to the standard-of-care, 70 % and 46 %, respectively. Moreover, the tolerability of both regimens was similar.
Alvocidib is licensed from Sanofi S.A. (Head office: France) to Tolero for exclusive worldwide rights to develop and commercialize. Torelo will make payments to Sanofi on the successful achievement of milestones related to the commercialization and pay tiered royalties on sales of alvocidib.

Torelo is also developing TP-1287 (oral delivery), a prodrug of alvocidib.

AXL receptor tyrosine kinase inhibitor; TP-0903

AXL is known to be involved in acquiring resistance to conventional agents and developing metastatic capacity in cancer cells. TP-0903 targeting AXL is a potential anti-cancer agent for a variety of cancer types. ALK2 inhibitor; TP-0184 TP-0184 inhibits enzymatic activity of activin receptor-like kinase-2(ALK2）, a member of bone morphogenetic protein (BMP) receptor family, leading to decreased expression of hepcidin, which is a circulating peptide overexpressed in hepatic cells in response to chronic inflammation related to cancer and auto immune diseases. TP-0184 has a potential to ameliorate anemia of chronic disease.

On December 21, 2016 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) has accepted for review a supplemental New Drug Application (sNDA) for its first-in-class CDK 4/6 inhibitor, IBRANCE (palbociclib) (Press release, Pfizer, DEC 21, 2016, View Source [SID1234517152]). The sNDA supports the conversion of the accelerated approval of IBRANCE in combination with letrozole to regular approval and includes data from the Phase 3 PALOMA-2 trial, which evaluated IBRANCE as initial therapy in combination with letrozole for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) metastatic breast cancer. This is the same patient population as the randomized Phase 2 PALOMA-1 trial upon which the accelerated approval of IBRANCE plus letrozole was granted in February 2015.

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The sNDA was granted Priority Review status, which accelerates FDA review time from 10 months to a goal of six months from the day of acceptance of filing.1 The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in April 2017.

"Since its introduction in 2015, more than 45,000 patients have been prescribed IBRANCE by more than 9,000 providers in the U.S.," said Liz Barrett, global president and general manager, Pfizer Oncology. "We are pleased that the PALOMA-2 trial has further demonstrated the significant clinical benefit of IBRANCE in the first-line setting, providing additional evidence for its continued use as a standard of care medicine."

PALOMA-2 is a randomized (2:1), multicenter, double-blind Phase 3 study that evaluated a total of 666 women from 186 global sites in 17 countries. The results of PALOMA-2 were presented at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June and recently published in the November 17, 2016 issue of The New England Journal of Medicine. The study demonstrated that IBRANCE in combination with letrozole improved progression-free survival compared to letrozole plus placebo as a first-line treatment for postmenopausal women with ER+, HER2- metastatic breast cancer. The adverse events observed with IBRANCE in combination with letrozole in PALOMA-2 were generally consistent with their respective known adverse event profiles.

About IBRANCE (palbociclib) 125 mg capsules

IBRANCE is the first and only FDA approved oral inhibitor of CDKs 4 and 6,2 which are key regulators of the cell cycle that trigger cellular progression.3,4 IBRANCE is approved in more than 50 countries.

In the U.S., IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.2 The indication in combination with letrozole is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The full prescribing information for IBRANCE can be found at www.pfizer.com.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-1 (75%) and PALOMA-3 (83%). In PALOMA-1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in PALOMA-1 (5%) and in patients treated with IBRANCE plus fulvestrant in PALOMA-3 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-1 of IBRANCE plus letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-1 reported at a higher incidence in the IBRANCE plus letrozole group vs the letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (4%) and diarrhea (2%).

Lab abnormalities occurring in PALOMA-1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased WBC (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-3 reported at a higher incidence in the IBRANCE plus fulvestrant group vs the fulvestrant plus placebo group included neutropenia (66% vs 1%) and leukopenia (31% vs 2%). The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Lab abnormalities occurring in PALOMA-3 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

On December 21, 2016 Bristol-Myers Squibb Company (NYSE:BMY) and Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on discovering and developing novel small molecule drugs directed against tumor metabolism and tumor immunology targets for the treatment of cancer, reported a clinical trial collaboration to evaluate Bristol-Myers Squibb’s Opdivo in combination with Calithera’s CB-839 in patients with clear cell renal cell carcinoma (ccRCC) (Press release, Bristol-Myers Squibb, DEC 21, 2016, View Source [SID1234517145]). CB-839 is an orally administered glutaminase inhibitor currently in Phase 1/2 clinical studies.

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Preclinical data suggest that CB-839, which is designed to target a pathway to starve tumor cells of the key nutrient glutamine, may enhance the effects of checkpoint inhibitors and may also reverse tumor resistance to checkpoint inhibitors by altering the immune-suppressive microenvironment and promoting an anti-tumor immune response. Opdivo is designed to overcome immune suppression. The companies will explore the potential of combining these two agents with the goal of achieving improved and sustained efficacy in ccRCC patients with cancer that is stable or growing on a PD-1 inhibitor therapy.

"Influencing the tumor microenvironment remains a key area of focus of research, and we are excited to explore the potential benefits of Opdivo plus CB-839 in an effort to advance new combination therapies for difficult to treat cancers," said Fouad Namouni, M.D., senior vice president, head of Oncology Development, Bristol-Myers Squibb.

"The combination with Opdivo follows our strategy to combine CB-839 with therapies to improve outcomes for RCC patients," said Susan Molineaux, CEO of Calithera Biosciences. "We believe that by blocking glutamine consumption in tumors, and redirecting this key nutrient for cell growth and proliferation to T-cells, CB-839 could enhance the effects of Opdivo. With support from Bristol-Myers Squibb, Calithera is excited to advance this combination into the Phase 2 portion of CX-839-004, our ongoing study in ccRCC patients."

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.

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 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 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.

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.

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

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 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

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. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. 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 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 adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: 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), myositis, myocarditis, rhabdomyolysis, 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, 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]). 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 infections, and sepsis.

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, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (≥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 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 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 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.

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.

On December 21, 2016 Exelixis, Inc. (NASDAQ:EXEL) and Ipsen (Euronext:IPN; ADR:IPSEY) jointly reported an amendment to the exclusive collaboration and licensing agreement for the commercialization and continued development of cabozantinib, to include commercialization rights in Canada for Ipsen where Ipsen has an established business (Mississauga, Ontario) (Press release, Exelixis, DEC 21, 2016, View Source [SID1234517144]). Signed in February 2016, the original agreement gave Ipsen exclusive commercialization rights for current and potential future cabozantinib indications outside of the United States, Canada and Japan. Following the amendment, Exelixis maintains exclusive rights for cabozantinib in the United States and Japan, and is continuing discussions with potential partners for commercial rights in Japan.

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Under the terms of the amendment, Exelixis will receive a $10 million upfront payment. Exelixis is eligible to receive regulatory milestones, for the approvals of cabozantinib in Canada for advanced renal cell carcinoma (RCC) after prior treatment, for first-line RCC, and advanced hepatocellular carcinoma (HCC), as well as additional regulatory milestones for potential further indications. In line with the prior transaction between the parties, the agreement also includes commercial milestones and provides for Exelixis to receive tiered royalties on Ipsen’s net sales of cabozantinib in Canada.

"Exelixis and Ipsen have made significant progress together since signing our collaboration and licensing agreement in February, and considering the substantial business resources that Ipsen has in Canada, amending the terms to grant Ipsen Canadian rights is a natural next step," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "Over the past nine months, CABOMETYX received regulatory approval for advanced RCC in the United States as well as the European Union, where Ipsen recently began launching the product. Our collaboration with Ipsen is strong, and we look forward to continued progress as they pursue approval and commercialization in Canada."

David Meek, Chief Executive Officer of Ipsen, said, "Gaining commercial rights for CABOMETYX in Canada expands our geographic footprint and strengthens our Oncology franchise in North America, one of our key geographic regions and main drivers of growth. This announcement follows numerous advancements in the CABOMETYX program, including the recent approval in Europe. We are now focused on a successful European launch and are pleased to offer advanced renal cell carcinoma patients a new treatment option supported by a strong clinical profile. We look forward to continue working with our partner Exelixis to advance the cabozantinib program."

CABOMETYX was approved in the European Union (EU) on September 9, 2016 for the treatment of RCC in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. Ipsen is currently initiating the launch of CABOMETYX in the EU. The regulatory filing in Canada is expected in 2017, with regulatory approval anticipated in early 2018.

About CABOMETYX

CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced renal cell carcinoma in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.

About Exelixis’ Exclusive Licensing Agreement with Ipsen

In February 2016, Exelixis granted Ipsen exclusive commercialization rights for current and potential future cabozantinib indications outside of the United States, Canada and Japan. On 20 December 2016, Exelixis granted Ipsen the commercial and development rights for cabozantinib in Canada. As provided in their agreement, Exelixis and Ipsen are also collaborating on the development of cabozantinib for current and potential future indications.