On January 27, 2017 Celgene International Sàrl, a wholly owned subsidiary of Celgene Corporation (NASDAQ:CELG), reported that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for the use of REVLIMID as monotherapy for the maintenance treatment of adult patients with newly diagnosed multiple myeloma (MM) who have undergone autologous stem cell transplantation (ASCT) (Press release, Celgene, JAN 27, 2017, View Source [SID1234517580]). Once approved by the European Commission, REVLIMID will be the first and only licensed maintenance treatment available to these patients.

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Multiple myeloma is an incurable and life-threatening blood cancer that is characterised by tumour proliferation and suppression of the immune system.1 It is a rare but deadly disease—around 39,000 people are diagnosed with MM in Europe, and around 24,000 people die from the disease each year.2 The median age at diagnosis in Europe is between 65 and 70 years.3 In Europe, patients who are under 65 years, fit and in good clinical condition are typically considered eligible for ASCT.4

For newly diagnosed, transplant-eligible MM patients, key treatment goals are to obtain and to maintain a deep response to therapy, with the ultimate objective of delaying disease progression.5,6 These patients typically receive induction therapy and high-dose chemotherapy with melphalan followed by ASCT. This treatment approach has been an established standard of care for over 20 years.7 Considering that over half of patients relapse within 2 to 3 years after ASCT,8,9 trials have been conducted to assess whether maintenance therapy following ASCT could enable more durable remissions.

"Studies show that maintenance treatment after ASCT with REVLIMID may help control residual malignant cells and delay tumour growth by enhancing immune function," says Professor Michel Attal, Executive Director of the Institut Universitaire du Cancer Toulouse Oncopole and Institut Claudius Regaud, France. "Our primary goal is to delay disease progression for as long as possible, and we have seen in several independent studies, that REVLIMID maintenance after ASCT can halve the risk of disease progression by sustaining the response."

The CHMP recommendation was based on the results of two cooperative group-led studies, CALGB 10010410 and IFM 2005-0211:

CALGB 100104 was a phase III, controlled, double-blind, multi-centre study of 460 patients with newly diagnosed MM undergoing ASCT who received continuous daily treatment with REVLIMID or placebo until relapse.
IFM 2005-02 was an international, phase III, controlled, double-blind, multi-centre study of 614 patients newly diagnosed with MM who were randomized to receive a 2-month consolidation regimen post-ASCT of REVLIMID monotherapy, followed by continuous daily treatment with either REVLIMID or placebo until relapse.
In the two phase III studies, REVLIMID monotherapy as maintenance treatment post-ASCT significantly reduced the risk of disease progression or death in patients with MM, leading to the studies being unblinded based on passing their pre-specified boundary for superiority at interim analysis.

In these studies, the safety profile was in line with other clinical data in newly diagnosed non-stem cell transplant (NSCT) and post-approval safety study in relapsed/refractory MM (rrMM). Across both phase III clinical studies, the most commonly reported adverse events (AE) were haematological and included neutropenia and thrombocytopenia. The most commonly reported non-haematological AE were infections. In both trials, an increased incidence rate of haematologic second primary malignancies (SPMs) has been observed in the REVLIMID group compared with the placebo group. However, the CHMP positive opinion confirms that the benefit-risk ratio for REVLIMID is positive in this expanded indication.

Tuomo Pätsi, President of Celgene in Europe, the Middle East and Africa (EMEA), said, "Despite substantial progress made so far in multiple myeloma treatment, it remains an incurable disease. We welcome this CHMP opinion as it confirms the important role that REVLIMID plays in treating multiple myeloma, extending the use of REVLIMID across the disease continuum. At Celgene, we aspire to turn some of the most challenging diseases, like multiple myeloma, into manageable conditions. Therefore, we will continue to invest more than one-third of our revenues back into research and development."

The CHMP reviews applications for all 28 member states in the European Union (EU), as well as Norway, Liechtenstein and Iceland. The European Commission, which generally follows the recommendation of the CHMP, is expected to make its final decision in approximately two months. If approval is granted, detailed conditions for the use of this product will be described in the Summary of Product Characteristics (SmPC), which will be published in the revised European Public Assessment Report (EPAR).

About CALGB 100104

CALGB 100104 was a phase III, randomised, controlled, double-blind, multi-centre study conducted in 47 centres in the United States. 460 newly diagnosed multiple myeloma patients – aged between 18 and 70 years – who achieved at least stable disease (SD) or better 100 days after undergoing autologous stem cell transplant (ASCT), were randomised to receive either REVLIMID maintenance (10 mg/day for 3 months, then 15 mg/day) or placebo until disease progression, intolerable side effects or death.

About IFM 2005-02

IFM 2005-02 was a phase III, controlled, double-blind, multi-centre study conducted in 77 centres across 3 countries in Europe. 614 newly diagnosed multiple myeloma patients younger than 65 years without signs of disease progression within 6 months of undergoing ASCT, were then randomised to receive a two-month consolidation regimen of REVLIMID monotherapy 25 mg per day on 21/28 days, followed by either REVLIMID maintenance (10 mg/day for 3 months, then 15 mg/day) or placebo until disease progression, intolerable side effects or death.

About REVLIMID

REVLIMID in combination with dexamethasone is approved in Europe, in the United States, in Japan and in around 25 other countries for the treatment of adult patients with previously untreated multiple myeloma (MM) who are not eligible for transplant. REVLIMID is also approved in combination with dexamethasone for the treatment of patients with MM who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle-East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.

REVLIMID is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in Europe for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.

In addition, REVLIMID is approved in Europe and in the United States for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. In Switzerland, REVLIMID is indicated for the treatment of patients with relapsed or refractory MCL after prior therapy that included bortezomib and chemotherapy/rituximab.

ADDITIONAL IMPORTANT SAFETY INFORMATION based on EU SmPC

Contraindications

REVLIMID (lenalidomide) is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients in the formulation.

REVLIMID (lenalidomide) is contraindicated during pregnancy, and also in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met.

Warnings and precautions

Pregnancy: the conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential.

Cardiovascular disorders: patients with known risk factors for myocardial infarction or thromboembolism should be closely monitored.

Neutropenia and thrombocytopenia: complete blood cell counts should be performed every week for the first 8 weeks of treatment and monthly thereafter to monitor for cytopenias. A dose reduction may be required.

Infection with or without neutropenia: all patients should be advised to seek medical attention promptly at the first sign of infection.

Renal impairment: monitoring of renal function is advised in patients with renal impairment.

Thyroid disorders: optimal control of co-morbid conditions influencing thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.

Tumour lysis syndrome: patients with high tumour burden prior to treatment should be monitored closely and appropriate precautions taken.

Allergic reactions: patients who had previous allergic reactions while treated with thalidomide should be monitored closely.

Severe skin reactions: REVLIMID (lenalidomide) must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected, and should not be resumed following discontinuation for these reactions. Interruption or discontinuation of lenalidomide should be considered for other forms of skin reaction depending on severity. Patients with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.

Lactose intolerance: patients with rare hereditary problems of galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Second primary malignancies (SPM): the risk of occurrence of hematologic SPM must be taken into account before initiating treatment with REVLIMID (lenalidomide) either in combination with melphalan or immediately following high-dose melphalan and autologous stem cell transplant (ASCT). Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of SPM and institute treatment as indicated.

Hepatic disorders: dose adjustments should be made in patients with renal impairment. Monitoring of liver function is recommended, particularly when there is a history of or concurrent viral liver infection or when REVLIMID (lenalidomide) is combined with medicinal products known to be associated with liver dysfunction.

Newly diagnosed multiple myeloma patients: patients should be carefully assessed for their ability to tolerate REVLIMID (lenalidomide) in combination, with consideration to age, ISS stage III, ECOG PS≤2 or CLcr < 60 mL/min.

Cataract: regular monitoring of visual ability is recommended.

Summary of the safety profile in multiple myeloma

Newly diagnosed multiple myeloma in patients treated with REVLIMID (lenalidomide) in combination with low dose dexamethasone:

The serious adverse reactions observed more frequently (≥5%) with REVLIMID (lenalidomide) in combination with low dose dexamethasone (Rd and Rd18) than with melphalan, prednisone and thalidomide (MPT) were pneumonia (9.8%) and renal failure (including acute) (6.3%).
The adverse reactions observed more frequently with Rd or Rd18 than MPT were: diarrhoea (45.5%), fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), and muscle spasms (20.5%).
Newly diagnosed multiple myeloma patients treated with REVLIMID (lenalidomide) in combination with melphalan and prednisone:

The serious adverse reactions observed more frequently (≥5%) with melphalan prednisone, and REVLIMID (lenalidomide) followed by REVLIMID (lenalidomide) maintenance (MPR+R) or melphalan prednisone, and REVLIMID (lenalidomide) followed by placebo (MPR+p) than melphalan, prednisone and placebo followed by placebo (MPp+p) were febrile neutropenia (6.0%) and anaemia (5.3%).
The adverse reactions observed more frequently with MPR+R or MPR+p than MPp+p were: neutropenia (83.3%), anaemia (70.7%), thrombocytopenia (70.0%), leukopenia (38.8%), constipation (34.0%), diarrhoea (33.3%), rash (28.9%), pyrexia (27.0%), peripheral oedema (25.0%), cough (24.0%), decreased appetite (23.7%), and asthenia (22.0%).
Patients with multiple myeloma who have received at least one prior therapy:

The most serious adverse reactions observed more frequently with REVLIMID (lenalidomide) and dexamethasone than with placebo and dexamethasone in combination were venous thromboembolism (deep vein thrombosis, pulmonary embolism) and grade 4 neutropenia.
The observed adverse reactions which occurred more frequently with REVLIMID (lenalidomide) and dexamethasone than placebo and dexamethasone in pooled multiple myeloma clinical trials (MM-009 and MM-010) were fatigue (43.9%), neutropenia (42.2%), constipation (40.5%), diarrhoea (38.5%), muscle cramp (33.4%), anaemia (31.4%), thrombocytopenia (21.5%), and rash (21.2%).
Special populations

Paediatric population: REVLIMID (lenalidomide) should not be used in children and adolescents from birth to less than 18 years.

Older people with newly diagnosed multiple myeloma: for patients older than 75 years of age treated with REVLIMID (lenalidomide) in combination with dexamethasone, the starting dose of dexamethasone is 20 mg/day on Days 1, 8, 15 and 22 of each 28-day treatment cycle. No dose adjustment is proposed for patients older than 75 years who are treated with REVLIMID (lenalidomide) in combination with melphalan and prednisone.

Older people with multiple myeloma who have received at least one prior therapy: care should be taken in dose selection and it would be prudent to monitor renal function.

Patients with renal impairment: care should be taken in dose selection and monitoring of renal function is advised. No dose adjustments are required for patients with mild renal impairment and multiple myeloma. Dose adjustments are recommended at the start of therapy and throughout treatment for patients with moderate or severe impaired renal function or end stage renal disease.

Patients with hepatic impairment: REVLIMID (lenalidomide) has not formally been studied in patients with impaired hepatic function and there are no specific dose recommendations.

Please refer to the Summary of Product Characteristics for full European Prescribing Information.

On January 27, 2017 AbbVie (NYSE:ABBV) reported financial results for the fourth quarter and full year ended December 31, 2016 (Press release, AbbVie, JAN 27, 2017, View Source [SID1234517579]).

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"The fourth quarter was a continuation of the strong performance and business momentum AbbVie has delivered since we became an independent company in 2013. Our 2016 revenue and EPS growth rank us among the leaders in our industry," said Richard A. Gonzalez, chairman and chief executive officer, AbbVie. "We continue to make significant progress on our objectives across each aspect of our company strategy, with strong commercial execution, financial discipline and a focus on our advancing pipeline to drive long-term sustainable growth. Our guidance for 2017 reflects continued strong performance and confidence in our business fundamentals."

Fourth-Quarter Results

Worldwide GAAP net revenues were $6.796 billion in the fourth quarter, up 6.2 percent. Worldwide adjusted net revenues of $6.784 billion increased 6.9 percent, excluding a 0.2 percent unfavorable impact from foreign exchange rate fluctuations.
Global HUMIRA sales increased 15.5 percent on a reported basis, or 16.2 percent operationally, excluding a 0.7 percent unfavorable impact from foreign exchange. In the U.S., HUMIRA sales grew 23.5 percent in the quarter. Internationally, HUMIRA sales grew 4.1 percent, excluding a 2.0 percent unfavorable impact from foreign exchange. Strong sales growth was driven by continued momentum across all three major market categories – rheumatology, dermatology and gastroenterology.
Fourth-quarter global IMBRUVICA net revenue was $511 million, with U.S. sales of $434 million and international profit sharing of $77 million for the quarter.
On a GAAP basis, the gross margin ratio in the fourth quarter was 77.1 percent. The adjusted gross margin ratio was 81.0 percent.
On a GAAP basis, selling, general and administrative expense was 24.3 percent of net revenues. The adjusted SG&A expense was 23.9 percent of net revenues.
On a GAAP basis, research and development expense was 17.5 percent of net revenues. The adjusted R&D expense was 17.3 percent, reflecting funding actions supporting all stages of our pipeline.
On a GAAP basis, the operating margin in the fourth quarter was 34.7 percent. The adjusted operating margin was 39.8 percent.
On a GAAP basis, net interest expense was $290 million. Adjusted net interest expense was $251 million. On a GAAP basis, the tax rate in the quarter was 30.4 percent. The adjusted tax rate was 20.2 percent.
Diluted EPS in the fourth quarter was $0.85 on a GAAP basis. Adjusted diluted EPS, excluding intangible asset amortization expense and other specified items, was $1.20, up 6.2 percent.
Key Events from the Fourth Quarter

AbbVie announced that the U.S. Food and Drug Administration (FDA) approved IMBRUVICA to treat patients with marginal zone lymphoma (MZL), an indolent form of non-Hodgkin’s lymphoma (NHL). There are currently no other approved treatments specifically indicated for patients with MZL. This approval marks the fifth unique type of blood cancer indication for IMBRUVICA.
AbbVie presented long-term follow-up data evaluating up to five years of IMBRUVICA use in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. In this analysis, 89 percent of treatment-naïve and relapsed/refractory patients with CLL/SLL, including those with high-risk disease, show a complete or partial response. Additionally, at the meeting, AbbVie presented encouraging efficacy and safety findings from a number of ongoing trials in NHL.
AbbVie announced positive results from a registration-enabling Phase 2 study evaluating IMBRUVICA in patients with chronic graft-versus-host-disease (cGVHD), a serious and debilitating complication of stem cell or bone marrow transplant, who failed prior systemic therapy. The study found IMBRUVICA demonstrated efficacy, sustained responses and reduced symptom severity, with an overall response rate of 67 percent. In 2016, the U.S. FDA granted Breakthrough Therapy Designation and Orphan Drug Designation for IMBRUVICA as a potential treatment for cGVHD after failure of one or more lines of systemic therapy, and the company expects to submit its regulatory application in the first quarter of 2017.
AbbVie announced the European Commission has granted conditional marketing authorization for VENCLYXTO (venetoclax) monotherapy for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor. In 2016, the U.S. FDA granted accelerated approval of Venclexta for the treatment of patients with CLL with 17p deletion who have received at least one prior therapy. Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group.
AbbVie submitted a New Drug Application to the U.S. FDA for its investigational, pan-genotypic, once-daily, ribavirin-free regimen of glecaprevir (ABT-493)/pibrentasvir (ABT-530) (G/P), being evaluated for the treatment of chronic hepatitis C virus (HCV). In Phase 3 clinical studies, eight weeks of therapy with G/P achieved high sustained virologic response (SVR) rates across all major genotypes (GT 1-6) in patients without cirrhosis, which represents the majority of HCV patients. In patients with compensated cirrhosis, high SVR rates were achieved after 12 weeks of therapy. High SVR rates were also achieved in patients with limited treatment options, such as those with severe chronic kidney disease. In historically difficult to treat populations, including those not cured by prior direct-acting antiviral (DAA) treatment regimens, high SVR rates were achieved with durations as short as 12 weeks. AbbVie received U.S. FDA Breakthrough Therapy Designation for its investigational regimen for the treatment of patients who failed previous therapy with DAAs in genotype 1. AbbVie also submitted its regulatory application in the EU and remains on track for submission in Japan in the first quarter of 2017. The company anticipates commercialization of the next-generation combination in 2017.
AbbVie announced several new global research collaborations with leading healthcare innovators to advance early-stage research in key therapeutic areas such as oncology and immunology. These included a research and license agreement with Pure MHC, a privately-held target discovery company, to discover and validate peptide targets for use with T-cell receptor therapeutics in several types of cancers; an exclusive license with Dong-A-ST, a leading specialty healthcare company in South Korea, for MerTK inhibitors in pre-clinical development for use in conjunction with immuno-oncology therapies; and a partnership with Zebra Biologics, Inc., a discovery stage biotechnology company, to discover agonist antibody therapeutics for inflammatory diseases.
Full-Year 2017 Outlook

AbbVie is issuing GAAP diluted EPS guidance for the full-year 2017 of $4.55 to $4.65. AbbVie expects to deliver adjusted diluted EPS guidance for the full-year 2017 of $5.44 to $5.54, representing growth of 13.9 percent at the mid-point. The company’s 2017 adjusted diluted EPS guidance excludes $0.89 per share of intangible asset amortization expense and other specified items.

On January 26, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported results for the fourth quarter and full year of 2016, which were highlighted by strong sales for key products Opdivo and Eliquis, regulatory approvals for Opdivo in the U.S. and Europe, and strategic transactions in oncology and fibrosis that further strengthened the company’s pipeline (Press release, Bristol-Myers Squibb, JAN 26, 2017, View Source [SID1234517569]).

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"Bristol-Myers Squibb achieved outstanding operating and financial results in 2016, driven by strong commercial performance across our portfolio," said Giovanni Caforio, M.D., chief executive officer, Bristol-Myers Squibb. "In 2017, we will continue to advance our pipeline, drive strong commercial execution across the business and progress our broad portfolio of Immuno-Oncology medicines."


Fourth Quarter
$ amounts in millions, except per share amounts
2016 2015 Change
Total Revenues $5,243 $4,287 22%
GAAP Diluted EPS 0.53 (0.12) **
Non-GAAP Diluted EPS 0.63 0.38 66%


Full Year
$ amounts in millions, except per share amounts
2016 2015 Change
Total Revenues $19,427 $16,560 17%
GAAP Diluted EPS 2.65 0.93 **
Non-GAAP Diluted EPS 2.83 2.01 41%


** In excess of +/- 100%

FOURTH QUARTER FINANCIAL RESULTS

Bristol-Myers Squibb posted fourth quarter 2016 revenues of $5.2 billion, an increase of 22% compared to the same period a year ago. Global revenues increased 24% adjusted for foreign exchange impact.
U.S. revenues increased 20% to $2.7 billion in the quarter compared to the same period a year ago. International revenues increased 25%. When adjusted for foreign exchange impact, international revenues increased 28%.
Gross margin as a percentage of revenue decreased from 77.8% to 73.6% in the quarter primarily due to product mix.
Marketing, selling and administrative expenses decreased 3% to $1.5 billion in the quarter.
Research and development expenses decreased 27% to $1.4 billion in the quarter due to lower charges resulting from business development transactions and in-process research and development impairments.
The effective tax rate was 17.3% in the quarter, compared to a benefit of 54.1% in the fourth quarter last year. Income taxes in both periods include net tax benefits attributed to specified items.
The company reported net earnings attributable to Bristol-Myers Squibb of $894 million, or $0.53 per share, in the quarter compared to a net loss of $197 million, or $0.12 per share, a year ago. The results in the fourth quarter of 2015 included per share after tax charges of $0.24 from the Five Prime Therapeutics, Inc. and Cardioxyl Pharmaceuticals, Inc. business development transactions and $0.08 for the transfer of the Erbitux business in North America to Eli Lilly and Company.
The company reported non-GAAP net earnings attributable to Bristol-Myers Squibb of $1.1 billion, or $0.63 per share, in the fourth quarter, compared to $647 million, or $0.38 per share, for the same period in 2015. An overview of specified items is discussed under the "Use of Non-GAAP Financial Information" section.
Cash, cash equivalents and marketable securities were $9.1 billion, with a net cash position of $2.4 billion, as of December 31, 2016.
FOURTH QUARTER PRODUCT AND PIPELINE UPDATE

Product Sales/Business Highlights

Global revenues for the fourth quarter of 2016, compared to the fourth quarter of 2015, were driven by:

Opdivo , which grew by $835 million
Eliquis , which grew by $346 million or 57% increase
Orencia , which grew by 16%
Sprycel , which grew by 15%
Yervoy , which had sales of $264 million
Opdivo

Litigation

In January, the company and Ono Pharmaceutical Company, Ltd. (Ono) announced they signed a global patent license agreement with Merck & Co., Inc. to settle all patent-infringement litigation related to Merck’s PD-1 antibody Keytruda. The agreement will result in the dismissal with prejudice of all patent litigation between the companies pertaining to Keytruda.
Regulatory

In November, the company announced the U.S. Food and Drug Administration (FDA) approved Opdivo 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.
In November, the company announced the European Commission approved Opdivo for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma (cHL) after autologous stem cell transplant (ASCT) and treatment with brentuximab vedotin.
In December, the company and Ono announced Opdivo was approved in Japan for the treatment of patients with relapsed or refractory cHL.
In December, the company and Ono announced that Ono submitted a supplemental application for Opdivo for the treatment of unresectable advanced or recurrent gastric cancer.
In January, the company announced it decided not to pursue an accelerated regulatory pathway for the regimen of Opdivo plus Yervoy in first-line lung cancer in the U.S. based on a review of data available at this time. Because these are ongoing registrational studies, the company will not be providing additional details.
Clinical

In November, the company announced that ONO-4538-12, a Phase 3, randomized, double-blind clinical trial evaluating the efficacy and safety of Opdivo in patients with unresectable advanced or recurrent gastric cancer refractory to, or intolerant of, standard therapy, met its primary endpoint of overall survival. In January, the company announced the results from the trial.
In November, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting, the company announced new data and analysis from studies evaluating urelumab, lirilumab, Opdivo and the Opdivo + Yervoy regimen:
Safety and efficacy data from a Phase 1/2 study of urelumab in combination with Opdivo in patients with hematologic and solid tumors, including biomarker analyses by level of PD-L1 expression.
Interim efficacy analysis, announced by the company and Innate Pharma S.A., from a Phase 1/2 study of the combination of lirilumab and Opdivo in the cohort of advanced platinum refractory squamous cell carcinoma of the head and neck, including exploratory biomarker analyses of patient response by level of PD-L1 expression.
CheckMate -032: Results from cohorts of the Phase 1/2 open-label trial investigating two combination schedules of Opdivo plus Yervoy in patients with locally advanced or metastatic urothelial carcinoma previously treated with platinum-based therapy.
In December, at the International Association for the Study of Lung Cancer World Conference on Lung Cancer, the company announced new data from studies evaluating Opdivo and the Opdivo + Yervoy regimen:
Checkmate -012: Updated findings from the Phase 1b trial in chemotherapy-naïve advanced non-small cell lung cancer patients evaluating Opdivo monotherapy, or in combination with Yervoy at different doses and schedules.
CheckMate -032: Updated results for Opdivo monotherapy and in combination with Yervoy in previously treated small cell lung cancer patients, a cohort of the Phase 1/2 open-label trial.
In December, during the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, the company and Seattle Genetics announced the first reported data from an ongoing Phase 1/2 clinical trial evaluating Adcetris (brentuximab vedotin) in combination with Opdivo in relapsed or refractory cHL.
FOURTH QUARTER BUSINESS DEVELOPMENT UPDATE

In November, the company and Enterome announced a collaboration agreement for the discovery and development of microbiome-derived biomarkers, drug targets and bioactive molecules to be developed as potential companion diagnostics and therapeutics for cancer. Additionally, the collaboration will seek to identify novel microbiome-derived biomarkers in an effort to improve clinical outcomes for patients treated with Bristol-Myers Squibb’s Immuno-Oncology portfolio.
In November, the company and Infinity Pharmaceuticals announced a clinical trial collaboration to evaluate Bristol-Myers Squibb’s Opdivo in combination with Infinity’s IPI-549 in patients with advanced solid tumors.
In November, the company and Nitto Denko Corporation (Nitto) announced an agreement granting Bristol-Myers Squibb exclusive worldwide rights for the development and commercialization of Nitto’s investigational siRNA molecules targeting heat shock protein 47 (HSP47) in vitamin A containing formulations, which includes Nitto’s lead asset ND-L02-s0201, currently in Phase 1b study for the treatment of advanced liver fibrosis. The agreement also grants Bristol-Myers Squibb the option to receive exclusive licenses for HSP47 siRNAs in vitamin A containing formulations for the treatment of lung fibrosis and other organ fibrosis.
In November, the company announced a five-year research collaboration with the Johns Hopkins University designed to identify mechanisms of response and resistance in patients whose cancer is being treated with checkpoint inhibitor-based immunotherapies, including Opdivo monotherapy, or Opdivo in combination with Yervoy or other investigational immunotherapies.
In December, the company and PsiOxus Therapeutics, Ltd. announced an agreement granting Bristol-Myers Squibb exclusive worldwide rights to NG-348, a pre-clinical stage, "armed" oncolytic virus with the goal of addressing solid tumors.
In December, the company and Calithera Biosciences announced a clinical collaboration to evaluate Opdivo in combination with CB-839 in clear cell renal cell carcinoma.
In January, the company announced a new clinical research collaboration to evaluate the combination of Opdivo and Janssen’s CD38-directed cytolytic antibody Darzalex in Phase 1b/2 clinical studies in multiple myeloma and solid tumors including non-small cell lung cancer, pancreatic cancer, colorectal cancer, triple negative breast cancer and head and neck cancer.
In January, the company and GeneCentric Diagnostics, Inc. announced a research collaboration to explore whether the application of GeneCentric’s Cancer Subtype Platform (CSP) might be able to identify translational biomarkers for Opdivo. Additionally, GeneCentric announced it had secured equity funding from the company to support the clinical development of its CSP and new research laboratory.
2017 FINANCIAL GUIDANCE

Bristol-Myers Squibb is confirming its 2017 GAAP EPS guidance range of $2.47 – $2.67 and is adjusting its non-GAAP EPS guidance range from $2.85 – $3.05 to $2.70 – $2.90. Both GAAP and non-GAAP guidance assume current exchange rates. 2017 GAAP and non-GAAP line-item guidance assumptions include:

Worldwide revenues increasing in the low-single digits.
Gross margin as a percentage of revenue to be approximately 72% to 73% for both GAAP and non-GAAP.
Marketing, selling and administrative expenses decreasing in the mid- to high-single digit range for both GAAP and non-GAAP.
Research and development expenses increasing in the high-single digit range for both GAAP and non-GAAP.
An effective tax rate of approximately 21% for both GAAP and non-GAAP.
As previously announced in the third quarter of 2016, the company’s operating model is evolving, to drive the company’s continued success in the near- and long-term. The majority of costs are expected to be incurred by 2020. Although GAAP operating expenses may increase initially as restructuring and other charges are incurred relating to this evolution, the company expects non-GAAP operating expenses to be roughly flat with 2016 levels through 2020.

The financial guidance excludes the impact of any potential future strategic acquisitions and divestitures and any specified items that have not yet been identified and quantified. The guidance also assumes no generic entry for Sprycel in Europe following the appeal of the European Patent Office’s decision. The non-GAAP guidance also excludes other specified items as discussed under "Use of Non-GAAP Financial Information." Details reconciling GAAP amounts to non-GAAP amounts, with non-GAAP reflecting specified items are provided in supplemental materials attached to this press release and available on the company’s website.

Erbitux is a trademark of ImClone LLC.
Keytruda is a trademark of Merck & Co., Inc.
Adcetris is a trademark of Seattle Genetics, Inc.
Darzalex is a trademark of Janssen Biotech, Inc.

Use of Non-GAAP Financial Information

This press release contains non-GAAP financial measures, including non-GAAP earnings and related EPS information, that are adjusted to exclude certain costs, expenses, gains and losses and other specified items that are evaluated on an individual basis. These items are adjusted after considering their quantitative and qualitative aspects and typically have one or more of the following characteristics, such as being highly variable, difficult to project, unusual in nature, significant to the results of a particular period or not indicative of future operating results. Similar charges or gains were recognized in prior periods and will likely reoccur in future periods including restructuring costs, accelerated depreciation and impairment of property, plant and equipment and intangible assets, R&D charges in connection with the acquisition or licensing of third party intellectual property rights, divestiture gains or losses, pension, legal and other contractual settlement charges and debt redemption gains or losses, among other items. Deferred and current income taxes attributed to these items are also adjusted for considering their individual impact to the overall tax expense, deductibility and jurisdictional tax rates. Non-GAAP information is intended to portray the results of our baseline performance, supplement or enhance management, analysts and investors overall understanding of our underlying financial performance and facilitate comparisons among current, past and future periods. For example, non-GAAP earnings and EPS information is an indication of our baseline performance before items that are considered by us to not be reflective of our ongoing results. In addition, this information is among the primary indicators we use as a basis for evaluating performance, allocating resources, setting incentive compensation targets and planning and forecasting for future periods. This information is not intended to be considered in isolation or as a substitute for net earnings or diluted EPS prepared in accordance with GAAP.

Statement on Cautionary Factors

This press release contains certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, statements relating to goals, plans and projections regarding the company’s financial position, results of operations, market position, product development and business strategy. These statements may be identified by the fact that they use words such as "anticipate", "estimates", "should", "expect", "guidance", "project", "intend", "plan", "believe" and other words and terms of similar meaning in connection with any discussion of future operating or financial performance. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. These factors include, among other things, effects of the continuing implementation of governmental laws and regulations related to Medicare, Medicaid, Medicaid managed care organizations and entities under the Public Health Service 340B program, pharmaceutical rebates and reimbursement, market factors, competitive product development and approvals, pricing controls and pressures (including changes in rules and practices of managed care groups and institutional and governmental purchasers), economic conditions such as interest rate and currency exchange rate fluctuations, judicial decisions, claims and concerns that may arise regarding the safety and efficacy of in-line products and product candidates, changes to wholesaler inventory levels, variability in data provided by third parties, changes in, and interpretation of, governmental regulations and legislation affecting domestic or foreign operations, including tax obligations, changes to business or tax planning strategies, difficulties and delays in product development, manufacturing or sales including any potential future recalls, patent positions and the ultimate outcome of any litigation matter. These factors also include the company’s ability to execute successfully its strategic plans, including its business development strategy, the expiration of patents or data protection on certain products, including assumptions about the company’s ability to retain patent exclusivity of certain products, and the impact and result of governmental investigations. There can be no guarantees with respect to pipeline products that future clinical studies will support the data described in this release, that the compounds will receive necessary regulatory approvals, or that they will prove to be commercially successful; nor are there guarantees that regulatory approvals will be sought, or sought within currently expected timeframes, or that contractual milestones will be achieved. For further details and a discussion of these and other risks and uncertainties, see the company’s periodic reports, including the annual report on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K, filed with or furnished to the Securities and Exchange Commission. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

On January 26, 2017 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 inhibitor drugs to improve immune cell trafficking and increase the ability for T-cells to track and destroy cancer, reported dosing of the first patient in a Phase 1/2 study of X4P-001, the company’s lead CXCR4 inhibitor, in patients with advanced clear cell renal cell carcinoma (ccRCC) (Press release, X4 Pharmaceuticals, JAN 26, 2017, View Source [SID1234517577]). This is the second clinical study of X4P-001 that combines the company’s CXCR4 inhibitor with an approved cancer therapy for the treatment of ccRCC.

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The primary objective of the newly-initiated study is to evaluate the safety and tolerability of X4P-001 in combination with Opdivo (nivolumab), an approved immunotherapy for the treatment of advanced RCC after failure of prior anti-angiogenic therapy that blocks a signal preventing T-cells from attacking cancer. The study will enroll patients who have not responded to nivolumab. In addition to safety and tolerability, the trial will evaluate early signs of biological activity using biomarkers, and clinical efficacy as measured by objective response rate and progression free survival over a 12 month time frame. Multiple U.S. cancer centers with leading renal cell carcinoma researchers will participate in the study.

"Enabling the immune system to recognize and attack cancer cells is one of the most promising new approaches to improving outcomes for cancer patients," said Dr. David McDermott, Associate Professor of Harvard Medical School and Director of the Biologic Therapy Kidney Cancer Program at the Beth Israel Deaconness Medical Center and X4 study investigator. "While benefical for some patients, single-agent immuno-therapy treatments have room for significant improvements in the durability and number of responses. The evaluation of combination immuno-therapies is an important next step in cancer reseach. We are hopeful that X4P-001’s complementary mechanism of CXCR4 antagonism with PD-1 inhibition will demonstrate an innovative approach to modulating the immune system that yields improved patient outcomes."

"Initation of this study is an important milestone in our strategy to develop X4P-001 in ccRCC in combination with dual classes of existing approved drugs," said Paula Ragan, PhD, President and CEO of X4. "Approved therapies address certain processes in the tumor microenvironment, but we believe more can be done to address the complex biology of challenging cancers, like ccRCC. By modulating cell trafficking in the microenvironment where cancer hijacks normal immune function, X4P-001 may be synergistic with other cancer therapies to result in enhanced responses."

In addition to this new Phase 1/2 study of X4P-001 in combination with Opdivo, X4 has another Phase 1/2 study ongoing in patients with advanced ccRCC to evaluate X4P-001 in combination with Inlyta (axitinib), a kinase inhibitor approved for the treatment of advanced RCC after failure of one prior systemic therapy, and a Phase 1b biomarker study in patients with advanced melanoma to evaluate X4P-001 in combination with Keytruda (pembrolizumab).

About X4P-001 in Cancer

X4P-001, the company’s lead drug candidate, is currently in Phase 1/2 testing in refractory clear cell renal cell carcinoma (ccRCC) and other solid tumor indications. Based on promising preclinical studies, X4P-001 is being evaluated in clinical studies in combination with approved cancer therapies, including tyrosine kinase inhibitors and checkpoint inhibitors. X4P-001 is an oral, small molecule inhibitor of CXCR4, or C-X-C receptor type 4, the receptor for the chemokine CXCL12. Recent studies demonstrate that CXCR4/CXCL12 is a primary receptor-ligand pair that cancer cells and surrounding stromal cells use to block normal immune function and promote angiogenesis through the trafficking of T-effector and T-regulatory cells, as well as myeloid derived suppressor cells (MDSCs), in the tumor microenvironment.1, 2 X4P-001 was previously tested in over 70 subjects in four prior clinical trials in healthy volunteers and HIV-infected patients and was shown to be safe and well tolerated.

About Renal Cell Carcinoma

Kidney cancer is among the ten most common cancers in both men and women with more than 60,000 new diagnoses each year in the United States.3 Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, and advanced ccRCC accounts for approximately 20% of the patient population. Therapies for advanced ccRCC include immunotherapies, mammalian target of rapamycin (mTOR) kinase inhibitors, and angiogenesis inhibitors, such as vascular endothelial growth factor (VEGF) inhibitors.4 There continue to be unmet medical needs with advanced ccRCC because durable responses remain a serious clinical challenge for patients with advanced disease.