[PDF]Change in the Company Name of Western Pharmaceutical Subsidiaries of Kyowa Hakko Kirin

On January 29, 2016 Kyowa Hakko Kirin Co., Ltd. (Tokyo 4151; President and CEO: Nobuo Hanai, "Kyowa Hakko Kirin") reported that it will change the name of all its western pharmaceutical subsidiaries, using "Kyowa Kirin" as a common company brand name (Press release, Kyowa Hakko Kirin, JAN 28, 2016, View Source [SID:1234508911]). Every subsidiary will begin officially operating under this new company trade name at various points during 2016.

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Kyowa Hakko Kirin is expanding its business globally and, as shown in its business vision, "Kyowa Hakko Kirin will be a Japan-based Global Specialty Pharmaceutical Company contributing to human health and well-being worldwide through innovative drug discovery and global commercialization, driven by state-of-the art antibody technologies mainly in the core therapeutic areas of oncology, nephrology and immunology". The company plans to launch late stage development products in the US and Europe in this mid-term business plan. Kyowa Hakko Kirin’s decision to unify all of its western pharmaceutical subsidiaries under one name, "Kyowa Kirin", is in pursuit of its aim to become a Global Specialty Pharmaceutical Company.

"I am convinced that a unified brand name will strengthen interaction and integration in our group." said Nobuo Hanai, Ph.D., President and CEO of Kyowa Hakko Kirin. "This will assist us in leaping forward as a Global Specialty Pharmaceutical Company, creating innovations across the group’s various business bases."

The Kyowa Hakko Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

Celgene Reports Fourth Quarter and Full Year 2015 Operating and Financial Results

On January 28, 2016 Celgene Corporation (NASDAQ:CELG) reported operating results for the fourth quarter and full year of 2015(Press release, Celgene, JAN 28, 2016, View Source [SID:1234508890]). For the fourth quarter of 2015, net product sales were $2,539 million compared to $2,055 million from the same period in 2014, an increase of 24 percent. The net negative impact of currency on net product sales was 1 percent. Fourth quarter total revenue increased 23 percent to $2,563 million compared to $2,085 million in the fourth quarter of 2014. Adjusted net income for the fourth quarter of 2015 increased 14 percent to $961 million compared to $840 million in the fourth quarter of 2014. For the same period, adjusted diluted earnings per share (EPS) increased 17 percent to $1.18 from $1.01 and includes a $0.07 impact from a $70 million milestone achieved by OncoMed Pharmaceuticals, Inc. during the quarter.

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Net product sales for the full year of 2015 were $9,161 million compared to $7,564 million for the full year of 2014, an increase of 21 percent. Total revenue for the full year of 2015 was $9,256 million compared to $7,670 million for the previous year, an increase of 21 percent. Adjusted net income increased 25 percent to $3,882 million compared to the prior year. Adjusted diluted EPS increased 27 percent to $4.71 from $3.71 for the full year of 2014.

Based on U.S. GAAP (Generally Accepted Accounting Principles), Celgene reported net income of $561 million and diluted EPS of $0.69 for the fourth quarter of 2015. For the fourth quarter of 2014, GAAP net income was $614 million and diluted EPS was $0.74. Full year GAAP net income for 2015 was $1,602 million and diluted EPS was $1.94. Full year GAAP net income for 2014 was $2,000 million and diluted EPS was $2.39.

"Celgene delivered outstanding operating and financial results in 2015. Our extraordinary operating momentum and key regulatory approvals in 2015 increase our prospects for significant growth in 2016 and beyond," said Bob Hugin, Chairman and Chief Executive Officer of Celgene Corporation. "In 2016, we will continue to leverage our global operations and advance our deep and diverse pipeline to accelerate the next generation of transformational medicines."

Fourth Quarter and Full Year 2015 Financial Highlights

Unless otherwise stated, all comparisons are for the fourth quarter and full year of 2015 compared to the fourth quarter and full year of 2014. The adjusted operating expense categories presented below exclude share-based employee compensation expense, in-process research and development (IPR&D) impairments, upfront collaboration payments and settlement of contingent obligations. Please see the attached Reconciliation of GAAP to Adjusted Net Income for further information.

Net Product Sales Performance

REVLIMID sales for the fourth quarter increased 18 percent to $1,561 million and were driven by increased duration of therapy in the U.S. and market share gains in newly diagnosed multiple myeloma (NDMM) in Europe. Fourth quarter U.S. sales of $956 million and international sales of $605 million increased 20 percent and 15 percent, respectively. Full year REVLIMID sales were $5,801 million, an increase of 16 percent.

POMALYST/IMNOVID sales for the fourth quarter were $294 million. Fourth quarter U.S. sales of $170 million and international sales of $124 million increased 29 percent and 77 percent, respectively. Full year POMALYST/IMNOVID sales were $983 million. Sales were driven by increased market share and duration gains.

ABRAXANE sales for the fourth quarter were $270 million, an increase of 14 percent. U.S. sales were $180 million and international sales were $90 million, an increase of 5 percent and 41 percent, respectively. Full year ABRAXANE sales were $967 million, an increase of 14 percent.

OTEZLA sales in the fourth quarter were $183 million. Full year OTEZLA sales were $472 million. OTEZLA uptake and market share gains continued to accelerate in the fourth quarter in the U.S. with increased contribution from early launch countries in Europe.

In the fourth quarter, all other product sales, which include THALOMID, ISTODAX, VIDAZA and an authorized generic version of VIDAZA drug product in the U.S., were $231 million compared to $248 million in the fourth quarter of 2014. Full year sales for these products were $938 million.

Research and Development (R&D)

Adjusted R&D expenses were $649 million for the fourth quarter of 2015 compared to $478 million for the fourth quarter of 2014. The fourth quarter of 2015 included a $70 million milestone achieved by OncoMed Pharmaceuticals, Inc. and also reflected increased clinical trial activity for pipeline programs.

For the full year of 2015, adjusted R&D expenses were $2,044 million compared to $1,651 million for the full year of 2014. Adjusted R&D expenses included expenses related to advancing clinical trials and expenses for collaboration-related payments to partners.

On a GAAP basis, R&D expenses were $777 million for the fourth quarter of 2015 versus $585 million for the same period in 2014. The year-over-year increase in R&D expenses on a GAAP basis was primarily due to an increase in clinical trial activity. Full year of 2015 R&D expenses were $3,697 million compared to $2,431 million for 2014. The increase in R&D expenses on a GAAP basis was primarily due to upfront payments for collaboration arrangements and an increase in clinical trial activity, partially offset by an impairment recorded in the prior year.

Selling, General, and Administrative (SG&A)

Adjusted SG&A expenses were $533 million for the fourth quarter of 2015 compared to $479 million for the fourth quarter of 2014. For the full year of 2015, adjusted SG&A was $2,011 million versus $1,778 million in 2014. The increase was primarily due to launch expenses related to OTEZLA in the U.S. and Europe and the ongoing launch of REVLIMID for NDMM in Europe.

On a GAAP basis, SG&A expenses were $609 million for the fourth quarter of 2015 compared to $544 million for the same period in 2014. Full year SG&A expenses were $2,305 million for 2015 compared to $2,028 million for 2014.

Cash, Cash Equivalents, and Marketable Securities

Operations generated cash flow of $2,483 million for 2015, a decrease of 12 percent year-over-year, primarily driven by an increase in upfront collaboration payments. For the full year of 2015, Celgene purchased approximately $3,257 million of shares. As of December 31, 2015, the Company had $3,890 million remaining under the existing share repurchase program. The Company ended the year with $6,552 million in cash and marketable securities.

Product and Pipeline Updates

Hematology/Oncology

In December 2015, Celgene announced the settlement of litigations with Natco Pharma Ltd. and its partners and affiliates, relating to certain patents for REVLIMID. As part of the settlement, Celgene agreed to provide Natco with a license to Celgene’s patents required to manufacture and sell an unlimited quantity of generic lenalidomide in the U.S. beginning on January 31, 2026. In addition, Natco will receive a volume-limited license to sell generic lenalidomide in the U.S. commencing in March 2022, which is expected to be a mid-single-digit percentage of the total lenalidomide capsules dispensed in the U.S. during the first year of entry. The volume limitation is expected to increase gradually each twelve months until March 2025. Natco’s ability to market generic lenalidomide in the U.S. will be contingent on its obtaining approval of an Abbreviated New Drug Application.

In December, REVLIMID was granted full marketing authorization by Japan’s Ministry of Health, Labour and Welfare (MHLW) for use in combination with dexamethasone as a treatment for patients with NDMM. This marketing authorization expands upon the approval of REVLIMID in 2010 for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). Reimbursement discussions are ongoing.

Celgene, in collaboration with partner AstraZeneca, announced the initiation of the FUSION clinical development program with durvalumab in hematologic malignancies. The initial trials combine durvalumab with Celgene assets and novel compounds in RRMM, myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Additional trials in NDMM and diffuse large B-cell lymphoma (DLBCL) are expected to begin late in the first quarter of 2016.

At the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, data on the combination of REVLIMID, bortezomib and low-dose dexamethasone (RVd) in NDMM were presented. In the 471-patient study, patients receiving RVd achieved a median progression free survival (PFS) of 43 months compared to a median PFS of 30 months for patients who received Rd alone (HR = 0.712, 96% CI, one-sided p=0.0018 (two-sided p=0.0037)). The data also show that overall survival (OS) was improved for RVd compared to Rd. Patients who received RVd had a median OS of 75 months compared to a median 64 months for patients receiving Rd (HR=0.709, 96% CI, one-sided p=0.0125 (two-sided p=0.0250)). In January, the National Comprehensive Cancer Network (NCCN) added the RVd combination to the multiple myeloma guidelines as a category 1 preferred treatment for both stem-cell transplant and non stem-cell transplant candidates.

Subsequent to our October 2015 supplementary new drug application filed with the U.S. Food and Drug Administration (FDA) for the expanded indication of REVLIMID for the treatment of non-del 5q lower risk MDS, the FDA requested additional analyses and data for the submission to further support the risk/benefit assessment of REVLIMID in this population. Based on the request, Celgene has decided to withdraw the submission at this time. Celgene remains committed to continued development in myeloid disease with ongoing trials in MDS and AML with CC-486, luspatercept in collaboration with Acceleron and the IDH platform in collaboration with Agios.

Data on the combination of ABRAXANE with chemotherapy and with anti-PD-L1 compounds in neoadjuvant and triple-negative breast cancer were presented at the San Antonio Breast Cancer Symposium in December. Data from the phase III ETNA cooperative group trial with ABRAXANE in patients with HER2-negative high-risk breast cancer are expected to be presented in 2016. Celgene expects to submit ABRAXANE for early-stage breast cancer for regulatory approval in Europe in 2016.

Inflammation & Immunology

In January 2016, Celgene announced that radiographic data from long-term follow-up from the phase III POSTURE trial of OTEZLA in ankylosing spondylitis showed a delay in disease progression. Based on this result, Celgene is evaluating the next steps for OTEZLA in this disease. The data are expected to be presented at a major medical congress in 2016.

Results from the two phase III ESTEEM trials (ESTEEM 1 and ESTEEM 2) in patients with psoriasis were published in the Journal of the American Academy of Dermatology. At week 16, OTEZLA produced greater NAPSI-50 response (50% reduction from baseline in target Nail Psoriasis Severity Index score) versus placebo (both studies P < .0001) and ScPGA response (Scalp Physician Global Assessment score 0 or 1) versus placebo (both studies P < .0001). Improvements were generally maintained over 52 weeks in patients with Psoriasis Area and Severity Index response at week 32.

Three year efficacy and safety data of OTEZLA in patients with psoriatic arthritis from the phase III PALACE 1 trial were presented at the American College of Rheumatology meeting in November. Among patients remaining in the study on treatment at 156 weeks, OTEZLA demonstrated sustained and clinically meaningful improvements in ACR 20, ACR 50 and ACR 70 scores with a well-tolerated safety profile.

In the fourth quarter, a large phase III pivotal trial with GED-0301 in active Crohn’s disease began enrollment. In addition, a phase II trial with GED-0301 in ulcerative colitis also began enrollment. Data from the registration-enabling endoscopic trial with GED-0301 is expected in 2017. Also in the quarter, the phase II STEPSTONE trial with ozanimod in Crohn’s disease began enrollment.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) updated their Treatment Recommendations for Psoriatic Arthritis in 2015. OTEZLA was included for the first time in these recommendations including for peripheral arthritis, enthesitis, dactylitis, psoriasis and nail disease in psoriatic arthritis.

Business Update

Human Longevity, Inc. (HLI), a genomics and cell therapy-based diagnostic and therapeutic company based in San Diego, agreed to purchase Celgene Cellular Therapeutics’ (CCT) biobanking business known as LifebankUSA and CCT’s biomaterials portfolio of assets including Biovance. In addition, in this transaction HLI will also acquire the full rights to PSC-100, a placental stem cell program which CCT partnered with HLI in August 2014. CCT remains committed to advancing a pipeline of cell therapy and regenerative medicine products including PDA-002 in clinical trials for diabetic foot ulcers and diabetic peripheral neuropathy and PNK-007 (natural killer (NK) cells) in phase I trials for AML and multiple myeloma.

Data from at Least 18 Phase III Trials Expected from Mid-2016 Through Mid-2018

2016

REMARC trial with REVLIMID in DLBCL maintenance
CONTINUUM trial with REVLIMID in CLL maintenance
ETNA trial with ABRAXANE in neoadjuvant breast cancer
PSA-006 trial with OTEZLA in biologic naïve psoriatic arthritis

2017

RELEVANCE trial with REVLIMID in first-line follicular lymphoma
AUGMENT trial with REVLIMID in relapsed and/or refractory follicular lymphoma
IMpower 130 Roche-sponsored trial with ABRAXANE and atezolizumab in non-squamous non-small cell lung cancer (NSCLC)
IMpower 131 Roche-sponsored trial with ABRAXANE and atezolizumab in squamous NSCLC
apact trial with ABRAXANE in adjuvant pancreatic cancer
abound.sqm with ABRAXANE in squamous NSCLC maintenance
RELIEFTM trial with OTEZLA in Behçet’s disease
SUNBEAM trial with ozanimod in multiple sclerosis
RADIANCE trial with ozanimod in multiple sclerosis

2018

OPTIMISMM trial with POMALYST in second-line relapsed and/or refractory multiple myeloma
IMpassion 130 Roche-sponsored trial with ABRAXANE and atezolizumab in triple-negative breast cancer
CD-002 trial with GED-0301 in Crohn’s disease
CD-003 trial with GED-0301 in Crohn’s disease
TRUE NORTH trial with ozanimod in ulcerative colitis

Celgene Expects Strong Product Sales and Earnings Growth in 2016

Total net product sales of $10.5 billion to $11.0 billion, an increase of 17 percent year-over-year based on the mid-point of the range and includes a negative impact from foreign exchange of approximately $120 million

REVLIMID net sales in the range of $6.6 billion to $6.7 billion, an increase of 15 percent year-over-year based on the mid-point of the range

Adjusted operating margin of approximately 53.5 percent after investments across the entire organization, a 150 bps improvement over 2015. GAAP operating margin is expected to be approximately 42 percent

Adjusted diluted EPS in the range of $5.50 to $5.70, an increase of approximately 19 percent year-over-year based on the mid-point of the range. GAAP diluted EPS is expected to be in the range of $4.26 to $4.64

Fully diluted share count for the full-year 2016 of approximately 825 million

For the first quarter of 2016, adjusted diluted EPS in the range of $1.27 to $1.30. GAAP diluted EPS is expected to be in the range of $0.98 to $1.05

Please see the attached Reconciliations of 2016 Projected GAAP to Adjusted Net Income for further information.

Q4 and Full year 2015 Conference Call and Webcast Information

Celgene will host a conference call to discuss the fourth quarter and full-year of 2015 operational and financial performance on Thursday, January 28, 2016, at 9 a.m. ET. The conference call will be available by webcast at www.celgene.com. An audio replay of the call will be available from noon January 28, 2016, until midnight ET February 4, 2016. To access the replay in the U.S., dial 1-855-859-2056; outside the U.S. dial 404-537-3406. The participant passcode is 11177982.

Exelixis Announces U.S. FDA Deems New Drug Application Sufficiently Complete and Grants Priority Review for Cabozantinib as a Treatment for Advanced Renal Cell Carcinoma

On January 28, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported that the U.S. Food & Drug Administration (FDA) has determined the company’s New Drug Application (NDA) for cabozantinib as a treatment for patients with advanced renal cell carcinoma (RCC) who have received one prior therapy to be sufficiently complete to permit a substantive review (Press release, Exelixis, JAN 28, 2016, View Source;p=RssLanding&cat=news&id=2133086 [SID:1234508892]). The NDA will be considered officially filed 60 days from the date of the completion of the submission, or February 20, 2016. The FDA granted Priority Review to the filing and assigned a Prescription Drug User Fee Act action date of June 22, 2016.

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"With FDA granting Priority Review to our application, Exelixis is one step closer to offering physicians cabozantinib as an important new therapeutic option for their patients with advanced renal cell carcinoma," said Michael M. Morrissey, Ph.D., president and CEO of Exelixis. "While we work closely with the FDA during the review process, Exelixis will continue to execute on our commercial plans, including our commitment to be ready for a potential launch by April 1st of this year."

A Priority Review designation is granted by the FDA for drugs that, if approved, would be significant improvements in the treatment, prevention or diagnosis of a disease. Previously, the FDA granted cabozantinib Breakthrough Therapy designation (August 2015) and Fast Track designation (April 2015) for the compound’s proposed RCC indication.

The NDA is based on the results of METEOR, a phase 3 pivotal trial comparing cabozantinib to everolimus in patients with advanced RCC who experienced disease progression following treatment with a VEGF receptor tyrosine kinase inhibitor. In July 2015, Exelixis announced top-line results demonstrating that the trial had met its primary endpoint of improving progression-free survival; compared with everolimus, cabozantinib was associated with a 42% reduction in the rate of disease progression or death. These data were later presented at the European Cancer Congress in September 2015 and concurrently published in The New England Journal of Medicine.

On January 11, 2016, Exelixis announced the submission of a Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced RCC who have received one prior therapy to the European Medicines Agency (EMA). The EMA’s Committee for Medicinal Products for Human Use (CHMP) previously granted accelerated assessment to cabozantinib for advanced RCC. As a result, the company’s MAA will be eligible for a 150-day review, versus the standard 210 days (excluding clock stops when information is requested by CHMP).

Cabozantinib is currently marketed in capsule form under the brand name COMETRIQ in the United States for the treatment of progressive, metastatic medullary thyroid cancer (MTC), and in the European Union for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. COMETRIQ is not indicated for patients with RCC. In the METEOR trial, and all other cancer trials currently underway, Exelixis is investigating a tablet formulation of cabozantinib distinct from the COMETRIQ capsule form. The tablet formulation of cabozantinib is the subject of the NDA for advanced RCC.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2015 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; however, the five-year survival rate for patients with advanced or late-stage metastatic RCC is under 10 percent, with no identified cure for the disease.3

Until the introduction of targeted therapies into the RCC setting a decade ago, treatments for metastatic RCC had historically been limited to cytokine therapy (e.g., interleukin-2 and interferon). In the second and later-line settings, which encompass approximately 17,000 drug-eligible patients in the U.S. and 37,000 globally,4 two small-molecule therapies and an immune checkpoint inhibitor have been approved for the treatment of patients who have received prior VEGF receptor TKIs. The currently approved small-molecule agents have shown little differentiation in terms of efficacy and have demonstrated only modest progression-free survival benefit in patients refractory to sunitinib, a commonly-used first-line therapy.

The majority of clear cell RCC tumors exhibit down-regulation of von Hippel-Lindau (VHL) protein function, either due to gene inactivation or epigenetic silencing, resulting in a stabilization of the hypoxia-inducible transcription factors (HIFs) and consequent up-regulation of VEGF, MET and AXL.5 The up-regulation of VEGF may contribute to the angiogenic nature of clear cell RCC, and expression of MET or AXL may be associated with tumor cell viability, a more invasive tumor phenotype and reduced overall survival. 6 Up-regulation of MET and AXL in clear cell RCC has also been shown to occur in response to treatment with VEGF receptor TKIs in preclinical models, indicating a potential role for MET and AXL in the development of resistance to these therapies.7

About Cabozantinib

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGF receptors, AXL and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis and maintenance of the tumor microenvironment.

Cabozantinib, marketed under the brand name COMETRIQ, is currently approved by the U.S. Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted COMETRIQ conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

Important Safety Information, including Boxed WARNINGS

WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE

Serious and sometimes fatal gastrointestinal perforations and fistulas occur in COMETRIQ-treated patients.

Severe and sometimes fatal hemorrhage occurs in COMETRIQ-treated patients.

COMETRIQ treatment results in an increase in thrombotic events, such as heart attacks.

Wound complications have been reported with COMETRIQ.

COMETRIQ treatment results in an increase in hypertension.

Osteonecrosis of the jaw has been observed in COMETRIQ-treated patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES) occurs in patients treated with COMETRIQ.

The kidneys can be adversely affected by COMETRIQ. Proteinuria and nephrotic syndrome have been reported in patients receiving COMETRIQ.

Reversible Posterior Leukoencephalopathy Syndrome has been observed with COMETRIQ.

Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

COMETRIQ can cause fetal harm when administered to a pregnant woman.

Adverse Reactions – The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Please see full U.S. prescribing information, including Boxed WARNINGS, at www.COMETRIQ.com/downloads/Cometriq_Full_Prescribing_Information.pdf

Please refer to the full European Summary of Product Characteristics for full European Union prescribing information, including contraindication, special warnings and precautions for use at www.sobi.com once posted.

ArQule Provides Proprietary Pipeline Update for AKT Inhibitors

On January 28, 2016 ArQule, Inc. (NASDAQ:ARQL) reported a pipeline update for its AKT inhibitors, including ARQ 092 and ARQ 751, both orally available, selective pan-AKT inhibitors (Press release, ArQule, JAN 28, 2016, View Source [SID:1234508895]).

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ARQ 092 – Lead AKT Inhibitor

The phase 1 trial for ARQ 092 in Proteus syndrome, which was opened for enrollment in November 2015, has completed dosing of its first cohort. The first cohort, consisting of three patients, is being observed for safety. The phase 1 trial is being conducted by our collaborators at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH). Proteus syndrome is a rare disease that is characterized by overgrowth of the skeleton, skin, adipose tissue and central nervous system. ARQ 092 was recently granted orphan drug designation by the Food and Drug Administration (FDA) in this indication which impacts less than one in a million people worldwide.

Recently, a manuscript was published by the NHGRI of the NIH in Scientific Reports (available on-line at View Source) discussing pre-clinical research with ARQ 092 in Proteus syndrome. This pre-clinical study tested the efficacy of ARQ 092 in suppressing AKT signaling in cells and tissues from patients with Proteus syndrome. Reduced phosphorylation of AKT and downstream targets of AKT in a concentration-dependent manner were observed in as little as two hours without reduction in cell viability.

ArQule continues to enroll patients harboring AKT1 or PI3K mutations in the company sponsored phase 1b expansion cohort of its oncology trial. Cohorts for lymphoma and endometrial are fully enrolled. Thus far the company has observed five partial responses in the phase 1b portion of the trial, three of which occurred in patients whose tumors have AKT1 or PI3K mutations and two of which occurred in patients where the mutational status is unknown.

ARQ 751 – Next Generation AKT Inhibitor

ArQule received FDA approval of its investigational new drug (IND) application for ARQ 751, a next generation AKT inhibitor, in oncology. As published in PLOS ONE, (available on-line at View Source), ARQ 751 has demonstrated signal abrogation and efficacy in pre-clinical in vitro and in vivo models harboring AKT1 and PI3K mutations. The company expects to commence a phase 1 trial in oncology during the first half of 2016 targeting AKT1 and PI3K mutations.

"We are pleased with the two recent publications on our AKT program, and we look forward to further advancing our AKT pipeline in 2016 with ARQ 092 and our next generation AKT inhibitor, ARQ 751," said Brian Schwartz, Chief Medical Officer and Head of Research and Development at ArQule. "The understanding accumulated by us and our collaborators on our AKT program in oncology and rare diseases positions us for leadership in this class. We plan to explore opportunities to advance our trials in oncology as well as in rare over-growth indications beyond Proteus syndrome."

"2015 was an exciting year for ArQule as we were able to bring forward clinical results from our proprietary pipeline which now includes two orphan drug designations from the FDA," said Paolo Pucci, Chief Executive Officer at ArQule. "Looking ahead into 2016, we expect the interim analysis for the tivantinib phase 3 METIV-HCC trial to occur early in the second quarter, and we also expect to be able to make decisions on next steps in clinical development for ARQ 092 in oncology and Proteus syndrome, as well as for ARQ 087 in intrahepatic cholangiocarcinoma (iCCA)."

About Proteus Syndrome

According to the patient advocacy and support group, the Proteus syndrome Foundation (View Source), the condition was named for Proteus, the Greek god who could transform his shape. Patients experience changes in the shapes of certain body structures over time, including abnormal, often asymmetric, massive growth (overgrowth) of the skeleton, skin, adipose tissue and central nervous system out of proportion to the rest of the body, which may appear normal. Although patients may have minimal or no manifestations at birth, the disease develops and becomes apparent in early childhood (6-18 months) and rapidly progresses with intense growth in the first ten years of life. It is primarily a childhood-onset disease but there are very few living affected adults.

Proteus syndrome is a rare condition with an incidence of less than 1 in 1 million people worldwide. Only a few hundred individuals have been reported in the medical literature. At this time, there are more than 120 documented cases worldwide, but because not all cases are documented, it is not known how many individuals have this syndrome. The incidence of Proteus syndrome classifies it as a rare disorder, defined by the National Organization of Rare Diseases (NORD) as any disease affecting fewer than 200,000 Americans.

About the AKT Pathway, ARQ 092 and ARQ 751

ARQ 092 and ARQ 751 are orally bioavailable, selective small molecule inhibitors of the AKT kinases. The AKT pathway when abnormally activated is implicated in multiple oncogenic processes such as cell proliferation and apoptosis. This pathway has emerged as a target of potential therapeutic relevance for compounds that inhibit its activity, which has been linked to a variety of cancers as well as to select non-oncology indications.

ARQ 092, the lead compound in ArQule’s AKT program, has completed phase 1a clinical testing and has advanced into phase 1b expansion testing in cohorts of patients with endometrial cancer, lymphoma and tumors harboring either AKT or PI3K mutations. A number of next-generation compounds in the Company’s AKT program are in early to late stages of pre-clinical development. The company plans to initiate a phase 1 clinical trial in the first half of 2016 for ARQ 751, a next generation AKT inhibitor.

Kancera provides operational update of the small molecule patent portfolio

On January 27, 2016 Kancera reported the approval of their patent covering small molecule inhibitors of PFKFB3 in the United States (Press release, Kancera, JAN 27, 2016, View Source;releaseID=1097861 [SID:1234508869]). Further, a patent application covering new chemical series in the HDAC6 project has been filed according to plan. In the ROR project, the company intends in the near future to further strengthen the patent portfolio with new highly potent ROR inhibitors.

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The PFKFB3 project: To complement the patent approved in the United States (patent number US9233946), Kancera intends during the spring to file a divisional application for the use of anti-cancer PFKFB3 inhibitors by counteracting the ability of cancer cells to repair their DNA.

The HDAC6 project: As previously reported, Kancera filed a patent application in 2014 covering new inhibitors which in laboratory studies kill both cancer cells and helper cells in tumors. In December 2014, Kancera reported that the HDAC6 inhibitors also act by an additional unique mechanism ("Target 2"), which may contribute to decrease the survival of cancer cells. Kancera has now filed a patent application (EP15201841.2) covering new potent series of compounds that only inhibit HDAC6. In order to facilitate the filing of the new patent application Kancera has, as previously announced, decided to use the opportunity to postpone the publication of the first patent application for one year.

The ROR project: In February 2015, Kancera reported that a patent application (EP15153394.0) was filed which included ca 100 examples of small-molecule ROR inhibitors, including the drug candidate KAN0439834. This patent application is now entering the international phase and Kancera will now strengthen the application by adding examples of ca 300 substances. The application will then cover substances showing more than 20 times higher potency than KAN0439834 against cancer cells from CLL patients.

About the PFKFB3 project
By blocking mechanisms which enable the cancer cells to adapt to periods of oxygen deprivation, possibilities open for new treatment strategies. Kancera’s project is based on a specific inhibition of the enzyme PFKFB3 resulting in a decreased metabolism in cancer cells, and decreased cell growth. In addition, research shows that PFKFB3 is involved in the regulation of both angiogenesis and division of cells, two critical processes that contribute to tumor growth. PFKFB3 is more common in oxygen-deficient tumor tissue compared to healthy tissue, which makes a targeted effect therapy with fewer side effects than traditional chemotherapy possible. Inhibition of PFKFB3 is expected to starve and weaken the tumor cells by reducing their glycolysis and cell division. This is a way to overcome the current problems of tumor resistance to radiation and chemotherapy. Kancera’s PFKFB3 inhibitors have also been shown to prevent DNA repair in cancer cells following e.g. radiation treatment.

About the HDAC6 project
Histone deacetylases (HDACs) are primarily involved in removing acetyl groups from the so-called histones and thereby affect how our genes are stored and activated in the cell nucleus. Some HDACs also affect the cell function outside the cell nucleus. HDAC6 belongs to this group of HDACs with a major biological role in the regulation of the cancer cell´s ability to migrate and to form metastases. The use of HDAC inhibitors in the treatment of cancer patients has so far yielded promising results, but has been limited due to severe side effects. For this reason, the pharmaceutical industry is now looking for more selective inhibitors of individual HDAC enzymes. Kancera´s discovery of selective HDAC6 inhibitors may provide a solution on how health care could take advantage of the anti-cancer effects of HDAC inhibitors without causing the patient severe side effects.

About the ROR project
ROR is a family of receptors, ROR1 and ROR2. The ROR receptors mediate signals for growth and survival. Originally ROR was linked to fetal development, but it is now known that they also contribute to cancer cell development and proliferation. Professor Håkan Mellstedt, Kancera´s co-founder and professor at the Karolinska Institute, and his colleagues have shown that Kancera´s ROR inhibitors have the ability to kill cells from tumors in pancreas and leukemia cells. Professor Mellstedt and his colleagues as well as independent researchers have shown that ROR is also active as a target in prostate, breast, skin and lung cancer.

Because ROR primarily generates a survival and growth signal to tumor cells but is inactive in healthy cells in adults, there are good prospects that a drug directed against ROR hit the tumor much harder than the surrounding healthy cells. Kancera and Professor Mellstedt have shown that inhibition of ROR leads to that cancer