On February 8, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that the U.S. Food and Drug Administration (FDA) has approved a new indication for ZYTIGA (abiraterone acetate) in combination with prednisone for the treatment of patients with metastatic high-risk castration-sensitive prostate cancer (CSPC) (Press release, Johnson & Johnson, FEB 8, 2018, View Source [SID1234523841]). The approval is based on Phase 3 data from the pivotal LATITUDE clinical trial, which found that in patients with metastatic high-risk CSPC, ZYTIGA in combination with prednisone reduced the risk of death by 38 percent compared to placebos.

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"LATITUDE was a large global trial which produced impressive and clinically significant results in overall survival," said Karim Fizazi, M.D., Ph.D., Principal Investigator and Head of the Medical Oncology Department at Institute Gustave Roussy, Villejuif, France. "With today’s approval, abiraterone acetate plus prednisone could become a standard of care for patients with metastatic high-risk castration-sensitive prostate cancer."

"Today’s approval marks an important step in addressing the unmet needs of patients with metastatic high-risk castration-sensitive prostate cancer by providing an option that has demonstrated improvement in overall survival," said Andree Amelsberg, M.D., Vice President of Oncology Medical Affairs at Janssen Biotech, Inc., part of the Janssen Pharmaceutical Companies of Johnson & Johnson. "This milestone is an exciting turning point for researchers and clinicians, and most importantly, for patients suffering from this disease and their families who now have an important additional therapeutic option."

LATITUDE was a multinational, multicenter, randomized, double-blind, placebo-controlled clinical trial that examined the use of ZYTIGA 1,000 mg once daily in combination with prednisone 5 mg once daily, compared to placebos (N=1,199) in patients with newly diagnosed, metastatic high-risk CSPC, who had not received prior cytotoxic chemotherapy. All the patients received a gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy. The study data were presented at the plenary session of the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, and simultaneously published in The New England Journal of Medicine.1 The study showed ZYTIGA in combination with prednisone reduced the risk of death by 38 percent compared to placebos (median OS not estimable vs. 34.7 months, respectively; hazard ratio (HR)=0.62; 95% confidence interval (CI): [0.51, 0.76], p<0.0001). Additional data demonstrated statistically significant delay in time to initiation of chemotherapy for patients in the ZYTIGA arm compared to those in the placebo arm (median time to initiation of chemotherapy not reached vs. 38.9 months, respectively; HR=0.44; 95% CI: [0.35, 0.56], p < 0.0001).

The most common adverse reactions (≥10%) that occurred more commonly (>2%) in the ZYTIGA arm from an analysis of pooled safety data were fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough and headache.

On November 20, 2017, the European Commission (EC) granted approval to broaden the marketing authorization for ZYTIGA in combination with prednisone or prednisolone to include newly-diagnosed high-risk metastatic hormone-sensitive prostate cancer (HSPC). Similar submissions have been made in Japan, Canada, Mexico, Switzerland, Singapore, and the Philippines, and approved in Brazil and Taiwan. If approved, these submissions will broaden the use of ZYTIGA in combination with prednisone or prednisolone to include an earlier stage of prostate cancer than its current indications.

Metastatic prostate cancer is cancer that has spread to another part of the body.2 Metastatic castration-sensitive prostate cancer (CSPC), also referred to as metastatic hormone-sensitive prostate cancer (HSPC) in literature, refers to prostate cancer that still responds to testosterone suppression therapy.2 Patients with newly-diagnosed metastatic disease and high-risk disease characteristics tend to have a poorer prognosis.3

About the LATITUDE Clinical Trial4
The Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled LATITUDE study enrolled 1,199 patients with newly diagnosed metastatic, high-risk castration-sensitive prostate cancer (CSPC), who had not received prior cytotoxic chemotherapy. The study was conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada. A total number of 597 patients were randomized to receive ZYTIGA plus prednisone, while 602 patients were randomized to receive placebos. All patients received a gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy. High-risk disease was defined as having at least two of three risk factors at baseline: a total Gleason score of ≥8, presence of ≥3 lesions on bone scan, and evidence of measurable visceral metastases. Patients with significant cardiac, adrenal, or hepatic dysfunction were excluded. The median duration of treatment with ZYTIGA and prednisone was 24 months.

About ZYTIGA

ZYTIGA (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients

with metastatic castration-resistant prostate cancer (CRPC)
with metastatic high-risk castration-sensitive prostate cancer (CSPC)
Since its first approval in the U.S. in 2011, ZYTIGA has been approved in combination with prednisone or prednisolone, in 105 countries. More than 330,000 patients worldwide, including 113,000 in the U.S., have received treatment with it, and it was the number one prescribed oral medication in the U.S. for patients with metastatic CRPC in 2016.

For more information about ZYTIGA, visit www.ZYTIGA.com.

IMPORTANT SAFETY INFORMATION

Contraindications – ZYTIGA (abiraterone acetate) can cause fetal harm and potential loss of pregnancy.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess – ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment.

Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in COU-AA-301) or NYHA Class II to IV heart failure (in COU-AA-302 and LATITUDE) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14)].

Adrenocortical Insufficiency (AI) – AI was reported in patients receiving ZYTIGA in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity – In postmarketing experience, there have been ZYTIGA-associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure and deaths. Measure serum transaminases alanine aminotransferase (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment, and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [See Dosage and Administration (2.4)].

Permanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3X ULN and total bilirubin greater than 2X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation.

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Adverse Reactions – The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory tract infection, cough, and headache.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia and hypokalemia.

Drug Interactions – Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA.

Use in Specific Populations

Females and Males of Reproductive Potential: Advise males with female partners of reproductive potential to use effective contraception.
Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C).

On February 8, 2018 Teva Pharmaceutical Industries Ltd. (NYSE:TEVA) today reported results for the year and the quarter ended December 31, 2017 (Press release, Teva, FEB 8, 2018, View Source;p=RssLanding&cat=news&id=2331263 [SID1234523870]).

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FY 2017

Q4 2017

Revenues $22.4 billion $5.5 billion
Cash flow from operations $3.5 billion $1.2 billion
GAAP earnings (loss) per share ($16.26) ($11.41)
Non-GAAP EPS $4.01 $0.93

2018 Business outlook:

Revenues are expected to be $18.3 – 18.8 billion
Non-GAAP EPS is expected to be $2.25-2.50
Kåre Schultz, Teva’s President and CEO, said, "2017 was a challenging year for Teva. Starting 2018 we are focused on meeting our financial obligations and ensuring a much more solid and sustainable business model going forward. We are making strong progress on the restructuring plan, and I am optimistic about the progress made and remain confident in our ability to deliver on our targets in the coming year.

Teva remains a recognized world-class leader in global healthcare, delivering unique value through accessible treatments and innovative medicines. By improving our financial profile through stabilization of our operating profit and cash flow, we will be better positioned to continue serving patients worldwide."

Goodwill Impairment In 2017, we noted significant adverse challenges in the U.S. generics market and the economic environment. These challenges included: (i) additional pricing pressure in the U.S. generics market as a result of customer consolidation into larger buying groups capable of extracting greater price reductions; (ii) pricing challenges due to government regulation; (iii) accelerated FDA approval of additional generic versions of off-patent medicines, resulting in increased competition for these products; (iv) delays in new launches of certain of our generic products; (v) originator strategies to maintain market share, reducing the value of newly launched complex or novel generics (vi) changes to traditional distribution model, and (vii) the recently-enacted U.S. tax reform legislation is expected to limit our ability to achieve targeted tax efficiencies compared to prior estimates. Consequently, we recorded goodwill impairments of $17.1 billion, mainly with respect to our U.S. generics reporting unit.

During the fourth quarter of 2017, we noted further deterioration in the U.S. generics market and economic environment, further limitations on our ability to influence generic medicines pricing in the long term and a decrease in value from future launches. These developments included: (i) additional pricing pressure in the U.S. generics market as a result of customer consolidation into larger buying groups capable of extracting greater price reductions; (ii) pricing challenges due to government regulation; (iii) accelerated FDA approval of additional generic versions of off-patent medicines, resulting in increased competition for these products; (iv) originator strategies to maintain market share, reducing the value of newly launched complex or novel generics; (v) changes to traditional distribution model; and (vi) the recently-enacted U.S. tax reform legislation, which is expected to limit our ability to achieve targeted tax efficiencies compared to prior estimates.

Consequently, we recorded goodwill impairments totaling $17.1 billion in 2017, mainly with respect to our U.S. generics reporting unit.

2017 Annual Results

Revenues in 2017 were $22.4 billion, an increase of 2%, or 6% in local currency terms, compared to 2016, primarily due to: (i) an increase in our generic medicines segment from the inclusion of Actavis Generics revenues for the full year of 2017 as compared to five month in 2016, partially offset by the adverse market dynamics in the United States; (ii) the acquisition of Anda in the fourth quarter of 2016; and (iii) a decrease in revenues of our specialty medicines segment due to generic competition to certain key products.

Exchange rate differences, including the impact of Venezuela, between 2017 and 2016 negatively impacted our revenues by $914 million, our GAAP operating income by $290 million and our non-GAAP operating income by $335 million. Adjustments to the exchange rates used for the Venezuelan bolivar and the November 30, 2017 deconsolidation of our subsidiaries in Venezuela resulted in a decrease of $1,062 million in revenues, a decrease of $249 million in GAAP operating income and a decrease of $323 million in non-GAAP operating income, compared to results in 2016. In light of the political and economic conditions in Venezuela, we excluded changes in revenues and operating profit in Venezuela from any discussion of local currency results.

GAAP gross profit was $10.8 billion in 2017, down 9% compared to 2016. GAAP gross profit margin for the year was 48.4%, compared to 54.1% in 2016. Non-GAAP gross profit was $12.2 billion in 2017, down 9% compared to 2016. Non-GAAP gross profit margin was 54.7% in 2017, compared to 61.3% in 2016. The decrease in GAAP gross profit as a percentage of revenues primarily reflects lower profitability of our generic medicines segment, higher amortization of purchased intangible assets, lower profitability of our specialty medicines segment and the inclusion of Anda, and lower profitability of our other activities, partially offset by lower inventory step-up expenses, inventory related expenses in connection with the devaluation in Venezuela and lower costs related to regulatory actions taken in certain facilities. The decrease in non-GAAP gross profit as a percentage of revenues primarily reflects lower profitability of our generic medicines segment, lower profitability of our specialty medicines segment due to loss of exclusivity of key products, the inclusion of Anda as well as lower profitability of our other activities.

Research and Development (R&D) expenses in 2017 were $1.8 billion, a decrease of 12.5% compared to 2016. R&D expenses excluding equity compensation expenses and purchase of in-process R&D in 2017 were $1.6 billion, or 7.1% of revenues, compared to $1.7 billion, or 7.6%, in 2016. R&D expenses related to our generic medicines segment were $702 million, compared to $659 million in 2016. R&D expenses related to our specialty medicines segment were $884 million, compared to $998 million in 2016.

Selling and Marketing (S&M) expenses in 2017 were $3.7 billion, a decrease of 5.3% compared to 2016. S&M expenses excluding amortization of purchased intangible assets and equity compensation expenses were $3.4 billion, or 15.2% of revenues, in 2017, compared to $3.7 billion, or 17.0% of revenues, in 2016. S&M expenses related to our generic medicines segment were $1.6 billion, a decrease of 8% compared to $1.7 billion in 2016. S&M expenses related to our specialty medicines segment were $1.7 billion, a decrease of 13% compared to $1.9 billion in 2016.

General and Administrative (G&A) expenses in 2017 were $1.3 billion, an increase of $45 million compared to 2016. G&A expenses excluding equity compensation expenses and other expenses were $1.2 billion in 2017, or 5.5% of revenues, compared to $1.2 billion and 5.4% in 2016.

Operating loss was $17.5 billion in 2017, compared to operating income of $2.2 billion in 2016. Non-GAAP operating income was $6.1 billion, down 11% compared to $6.8 billion in 2016.

Adjusted EBITDA (non-GAAP operating income, which excludes amortization and certain other items, and excluding depreciation expenses) for 2017 was $6.7 billion, down 9% compared to 2016.

In 2017, financial expenses were $895 million, compared to $1.3 billion in 2016. Non-GAAP financial expenses were $908 million in 2017, compared to $442 million in 2016.

GAAP income tax expenses in 2017 were $1.9 billion or 11% on a pre-tax loss of $18 billion. In 2016, the provision for income taxes was $521 million or 63% on pre-tax income of $824 million. The provision for non-GAAP income taxes for 2017 amounted to $788 million on pre-tax non-GAAP income of $5.2 billion, for an annual tax rate of 15.3%. The provision for non-GAAP income taxes in 2016 was $1.1 billion on pre-tax non-GAAP income of $6.4 billion, for an annual tax rate of 17.4%.

GAAP net loss attributable to Teva and GAAP diluted loss per share were $16.3 billion and $16.26, respectively, in 2017, compared to net income attributable to Teva of $68 million and a gain per share of $0.07 in 2016. Non-GAAP net income attributable to ordinary shareholders for calculating diluted EPS and non-GAAP diluted EPS were $4.3 billion and $4.01, respectively in 2017, compared to $5.2 billion and $5.14 in 2016.

Non-GAAP information: Net non-GAAP adjustments in 2017 were $20.6 billion. Non-GAAP net income and non-GAAP EPS for the year were adjusted to exclude the following items:

an impairment of goodwill of $17.1 billion, mainly related to our U.S. generics reporting unit;
impairment of long-lived assets of $3.8 billion, mainly related to revaluation of generic products acquired from Actavis Generics, discontinued Actavis Generics products and Rimsa products, product and marketing rights related to our business venture in Japan and an impairment of property, plant and equipment of $544 million
amortization of purchased intangible assets totaling $1.4 billion, of which $1.2 billion is included in cost of goods sold and the remaining $209 million in selling and marketing expenses;
restructuring expenses of $535 million;
charge due to deconsolidation of our subsidiaries in Venezuela of $396 million;
legal settlements and loss contingencies of $500 million ;
contingent consideration of $154 million;
equity compensation of $129 million;
acquisition and integration expenses of $105 million;
other R&D expenses of $221 million;
inventory step-up of $67 million;
costs related to regulatory actions taken in certain facilities of $47 million;
financial income of $13 million;
other non-GAAP items of $160 million;
gain on sale of business of $1.1 billion;
minority interest adjustment of negative $270 million; and
tax effect and other income tax items of $2.7 billion (includes $1.0 billion U.S Tax Cuts and Job Act effect)
We believe that excluding such items facilitates investors’ understanding of Teva’s business. See the attached tables for a reconciliation of our U.S. GAAP results to the adjusted non-GAAP figures.

In light of conditions in Venezuela, we concluded that as of November 30, 2017, we do not meet the accounting criteria for control over our wholly-owned subsidiaries in Venezuela and that we no longer have significant influence over such subsidiaries. Therefore, effective November 30, 2017, we deconsolidated the investment in our subsidiaries in Venezuela, recording deconsolidation charges of $396 million.

Cash flow from operations generated during 2017 was $3.5 billion, down 33% compared to $5.2 billion in 2016. Free cash flow, excluding net capital expenditures, was $2.7 billion compared to $4.4 billion in 2016, a decrease of 38%. The decrease was mainly due to business performance as well as higher payments for legal settlements.

Total balance sheet assets were $70.6 billion as of December 31, 2017, compared to $86.1 billion as of September 30, 2017 and $93.1 billion as of December 31, 2016. The decrease from September 30, 2017 was mainly due to impairment of goodwill and long-lived assets.

Cash and investments at December 31, 2017 decreased to $1.1 billion, compared to $0.9 billion at September 30, 2017 and to $1.9 billion at December 31, 2016.

As of December 31, 2017, our debt was $32.5 billion, a decrease of $2.2 billion compared to $34.7 billion as of September 30, 2017, and a decrease of $3.3 billion compared to $35.8 billion as of December 31, 2016. The decrease was mainly due to $4.4 billion of net debt repayments on our various term loans, our revolving credit facility and other short term loans, partially offset by foreign exchange fluctuations of $1.1 billion. The portion of total debt classified as short-term as of December 31, 2017 was 11%.

Total shareholders’ equity was $17.4 billion at December 31, 2017, compared to $30.3 billion at September 30, 2017 and to $35.0 billion at December 31, 2016.

Fourth Quarter 2017 Results

Revenues in the fourth quarter of 2017 were $5.5 billion, down 16% compared to the fourth quarter of 2016, primarily due to the decrease in revenues of our specialty medicines segment due to generic competition for our key products and the challenging market dynamics in the U.S. generics market. Excluding the impact of foreign exchange fluctuations, revenues decreased 12%.

Exchange rate differences including the impact of Venezuela between the fourth quarter of 2017 and the fourth quarter of 2016 reduced revenues by $274 million, GAAP operating income by $118 million and non-GAAP operating income by $181 million.

In the fourth quarter of 2017, the company announced that it would not be paying annual bonuses for 2017 due to the financial results of the company being significantly below the company’s original annual operating plan for the year. As a result, in the fourth quarter of 2017, we reversed amounts accrued for such bonuses during the first three quarters of 2017 and made no further accrual for such bonuses.

GAAP gross profit was $2.5 billion in the fourth quarter of 2017, down 25% compared to the fourth quarter of 2016. GAAP gross profit margin was 46.6% in the quarter, compared to 52.2% in the fourth quarter of 2016. Non-GAAP gross profit was $2.8 billion in the fourth quarter of 2017, down 26% from the fourth quarter of 2016. Non-GAAP gross profit margin was 52.2% in the fourth quarter of 2017, compared to 59.4% in the fourth quarter of 2016.

Research and Development (R&D) expenses in the fourth quarter of 2017 were $360 million, down 47% compared to the fourth quarter of 2016 mainly due to portfolio optimization ,various efficiency measures as well as the reversal of the annual bonus accrual. R&D expenses excluding equity compensation expenses and purchase of in-process R&D in the fourth quarter of 2017 were $310 million or 5.7% of quarterly revenues, compared to $514 million or 7.9% in the fourth quarter of 2016. R&D expenses related to our generic medicines segment were $149 million, compared to $211 million in the fourth quarter of 2016, a decrease of 29%. R&D expenses related to our specialty medicines segment were $162 million, a decrease of 45% compared to $296 million in the fourth quarter of 2016.

Selling and Marketing (S&M) expenses in the fourth quarter of 2017 were $865 million, a decrease of 23% compared to the fourth quarter of 2016. S&M expenses excluding amortization of purchased intangible assets and equity compensation expenses were $791 million, or 14.5% of revenues, in the fourth quarter of 2017, compared to $1.1 billion, or 17% of revenues, in the fourth quarter of 2016 mainly due to various efficiency measures as well as the reversal of the annual bonus accrual. S&M expenses related to our generic medicines segment were $382 million, a decrease of 30% compared to $549 million in the fourth quarter of 2016, mainly due to lower expenses in Venezuela following exchange rate adjustments as well as certain other efficiency measures. S&M expenses related to our specialty medicines segment were $372 million, a decrease of 26% compared to $506 million in the fourth quarter of 2016. The decrease was mainly due to cost reduction and efficiency measures in our commercial operations, aligning with the life cycle of our product portfolio.

General and Administrative (G&A) expenses in the fourth quarter of 2017 were $492 million, compared to $360 million in the fourth quarter of 2016. G&A expenses excluding equity compensation expenses were $477 million in the fourth quarter of 2017, or 8.7% of revenues, compared to $344 million and 53% in the fourth quarter of 2016.

GAAP operating loss was $13.0 billion in the fourth quarter of 2017, compared to an operating loss of $0.1 billion in the fourth quarter of 2016. Non-GAAP operating income was $1.4 billion, down 29%, compared to $1.9 billion in the fourth quarter of 2016.

Adjusted EBITDA (non-GAAP operating income, which excludes amortization and certain other items, and excluding depreciation expenses) was $1.5 billion, down 27% compared to $2.1 billion in the fourth quarter of 2016.

GAAP financial expenses for the fourth quarter of 2017 were $191 million, compared to $777 million in the fourth quarter of 2016. This decrease is mainly due to an impairment of our monetary assets balance sheet items related to Venezuela in the fourth quarter of 2016. Non-GAAP financial expenses were $209 million in the fourth quarter of 2017, compared to $233 million in the fourth quarter of 2016.

We recorded a GAAP income tax benefit for the fourth quarter of 2017 of $1.5 billion, or 11% on pre-tax loss of $13.2 billion., GAAP income taxes in the fourth quarter of 2016 were $57 million, or 6% on pre-tax loss of $914 million. Non-GAAP income taxes for the fourth quarter of 2017 were $183 million on pre-tax non-GAAP income of $1.2 billion, for a quarterly tax rate of 15.6%. Non-GAAP income taxes in the fourth quarter of 2016 were $218 million on pre-tax non-GAAP income of $1.7 billion, for a quarterly tax rate of 12.7%.

GAAP net loss attributable to Teva and GAAP diluted loss per share were $11.6 billion and a loss of $11.41, respectively, in the fourth quarter of 2017, compared to a GAAP net loss of $973 million and a loss of $1.10, respectively, in the fourth quarter of 2016. Non-GAAP net income attributable to ordinary shareholders for calculating diluted EPS and non-GAAP diluted EPS were $1.0 billion and $0.93, respectively, in the fourth quarter of 2017, compared to $1.5 billion and $1.38 in the fourth quarter of 2016.

For the fourth quarter of 2017, the weighted average outstanding shares for the fully diluted earnings per share calculation was 1,017 million on a GAAP basis and 1,018 million on a non-GAAP basis. The number of average weighted diluted shares outstanding used for the fully diluted share calculation for the fourth quarter of 2016 was 1,015 million shares on a GAAP basis and 1,076 million on a non-GAAP basis. The number of shares on a non-GAAP basis in 2016 includes the potential dilution resulting from our mandatory convertible preferred shares, which had a dilutive effect on our non-GAAP earnings per share.

As of December 31, 2017, the fully diluted share count for calculating Teva’s market capitalization was approximately 1,086 million shares.

Non-GAAP information: Net non-GAAP adjustments in the fourth quarter of 2017 were $12.5 billion. Non-GAAP net income and non-GAAP EPS for the quarter were adjusted to exclude the following items:

impairment of goodwill of $11.0 billion, mainly related to our U.S. generics reporting unit;
impairment of long lived assets of $3.2 billion, mainly related to revaluation of generics products acquired from Actavis Generics, as well as discontinued Actavis Generics and Rimsa products and an impairment of property, plant and equipment of $392 million
deconsolidation of our subsidiaries in Venezuela of $396 million;
amortization of purchased intangible assets totaling $356 million, of which $291 million is included in cost of goods sold and the remaining $65 million in selling and marketing expenses;
restructuring expenses of $235 million;
other R&D expenses of $45 million;
acquisition, integration and related expenses of $18 million;
contingent consideration income of $25 million;
equity compensation expenses of $26 million;
legal settlements and loss contingencies of $176 million;
other non GAAP items of $41million;
gain on sale of business of $1.1 billion;
minority interest adjustment of negative $226 million; and
tax benefit and other income tax items of $1.7 billion (includes $1.0 billion U.S Tax Cuts and Job Act Effect)
We believe that excluding such items facilitates investors’ understanding of its business. See the attached tables for a reconciliation of the GAAP results to the adjusted non-GAAP figures.

Cash flow from operations generated during the fourth quarter of 2017 was $1.2 billion, a decrease of 17% compared to the fourth quarter of 2016. Free cash flow, excluding net capital expenditures, was $0.9 billion, down 16% compared to the fourth quarter of 2016.

Segment Results for the Fourth Quarter 2017

Generic Medicines Segment

Three Months Ended December 31,
2017 2016
(U.S. $ in millions / % of Segment Revenues)

Revenues $ 3,114 100.0% $ 3,716 100.0%
Gross profit 1,271 40.8% 1,835 49.4%
R&D expenses 149 4.8% 211 5.7%
S&M expenses 382 12.2% 549 14.8%
Segment profit* $ 740 23.8% $ 1,075 28.9%
_______________

* Segment profit consists of gross profit for the segment, less R&D and S&M expenses related to the segment. Segment profit does not include G&A expenses, amortization and certain other items.

Generic Medicines Revenues

Generic medicines revenues in the fourth quarter of 2017 were $3.1 billion, a decrease of 16% compared to the fourth quarter of 2016.

Generic revenues consisted of:

U.S. revenues of $1.2 billion, a decrease of 15% compared to the fourth quarter of 2016, mainly due to challenging market dynamics including pricing declines resulting from customer consolidation into large buying groups and accelerated FDA approvals for additional generic versions of competing off-patent medicines, partially offset by new product launches.
European revenues of $1.1 billion, flat compared to the fourth quarter of 2016, or a decrease of 8% in local currency terms, compared to the fourth quarter of 2016, mainly due to the exclusion of revenues of Actavis U.K., which was divested in January 2017.
ROW revenues of $864 million, a decrease of 31%, or an increase of 2% in local currency terms, compared to the fourth quarter of 2016. The increase in local currency terms was mainly due to increased sales in Russia and Israel.
Our OTC revenues related to PGT were $217 million, a decrease of 46% compared to $399 million in the fourth quarter of 2016. In local currency terms, revenues increased 9%. PGT’s in-market sales excluding Venezuela were $353 million in the fourth quarter of 2017, an increase of $45 million, or 10% in local currency terms, compared to the fourth quarter of 2016.
API sales to third parties of $181 million (which are included in the market revenues above) were flat compared to the fourth quarter of 2016.
Generic medicines revenues comprised 57% of our total revenues in the fourth quarter of 2017, the same as in the fourth quarter of 2016.

Generic Medicines Gross Profit

Gross profit of our generic medicines segment in the fourth quarter of 2017 was $1.3 billion, a decrease of 31% compared to $1.8 billion in the fourth quarter of 2016. The lower gross profit was mainly due to higher production expenses, market dynamics in the United States as well as lower revenues in Venezuela following the continued currency devaluation.

Gross profit margin for our generic medicines segment in the fourth quarter of 2017 decreased to 40.8%, compared to 49.4% in the fourth quarter of 2016.

Generic Medicines Profit

Our generic medicines segment generated profit of $740 million in the fourth quarter of 2017, a decrease of 31% compared to the fourth quarter of 2016. Generic medicines profitability as a percentage of generic medicines revenues was 23.8% in the fourth quarter of 2017, down from 28.9% in the fourth quarter of 2016.

Specialty Medicines Segment

Three Months Ended December 31,
2017 2016
(U.S. $ in millions / % of Segment Revenues)

Revenues $ 1,795 100.0% $ 2,203 100.0%
Gross profit 1,515 84.4% 1,926 87.4%
R&D expenses 162 9.0% 296 13.4%
S&M expenses 372 20.7% 506 23.0%
Segment profit* $ 981 54.7% $ 1,124 51.0%
_______________

* Segment profit is comprised of gross profit for the segment, less R&D and S&M expenses related to the segment. Segment profit does not include G&A expenses, amortization and certain other items.

Specialty Medicines Revenues

Specialty medicines revenues in the fourth quarter of 2017 were $1.8 billion, down 19% compared to the fourth quarter of 2016. The decrease in specialty medicines revenues compared to the fourth quarter of 2016 was primarily due to lower sales of our CNS products and the November 2017 divestiture of certain women health products in the United States. In addition, in the fourth quarter of 2016, we also benefited from a payment of $150 million, which we received in connection with our agreement to sell our royalties and other rights in Ninlaro (ixazomib) to a subsidiary of Takeda.

U.S. specialty medicines revenues were $1.2 billion, down 32% compared to the fourth quarter of 2016. European specialty medicines revenues were $476 million, an increase of 24%, or 14% in local currency terms, compared to the fourth quarter of 2016. ROW specialty revenues were $154 million, up 51%, or 49% in local currency terms, compared to the fourth quarter of 2016. The increase in specialty medicines revenues in ROW compared to the fourth quarter of 2016 was primarily due to reclassification of income from certain intangible assets which were previously recorded in G&A accounts. Specialty medicines revenues comprised 33% of our total revenues in the quarter, compared to 34% in the fourth quarter of 2016.

The following table presents revenues by therapeutic area and key products for our specialty medicines segment for the three months ended December 31, 2017 and 2016:

Three Months Ended December 31
December 31,

Percentage Change
2017 2016 2017 – 2016
(U.S. $ in millions)
CNS $ 984 $ 1,243 (21%)
Copaxone 821 1,015 (19%)
Azilect 40 88 (55%)
Nuvigil 9 25 (64%)
Respiratory 293 325 (10%)
ProAir 102 139 (27%)
QVAR 61 116 (47%)
Oncology 283 268 6%
Bendeka and Treanda 157 150 5%
Women’s Health 68 122 (44%)
Other Specialty* 167 245 (32%)
Total Specialty Medicines $ 1,795 $ 2,203 (19%)

Global revenues of COPAXONE were $821 million in the fourth quarter of 2017, a decrease of 19% compared to the fourth quarter of 2016.

In October 2017, the FDA approved a generic version of Copaxone 40 mg /mL and an additional generic version of COPAXONE 20 mg/mL. A generic version of COPAXONE 40 mg /mL was launched in the U.S. market. In the EU, a non-substitutable version of COPAXONE 40 mg/mL was approved.

COPAXONE revenues in the United States were $622 million, down 25% compared to $829 million in the fourth quarter of 2016, mainly due to generic competition, which resulted in higher rebates and lower volumes, partially offset by a price increase of 7.9% in January 2017, for both the 20 mg/mL and 40 mg/mL versions. At the end of the fourth quarter of 2017, according to December 2017 IQVIA (formerly IMS Health) data, our U.S. market share for the COPAXONE products in terms of new and total prescriptions were 27.8% and 25.7%, respectively. Copaxone revenues outside the United States were $199 million, an increase of 7%, or flat in local currency terms, compared to the fourth quarter of 2016.

Our global AZILECT revenues were $40 million, a decrease of 55% compared to the fourth quarter of 2016 following the introduction of generic competition to AZILECT in the United States in 2017.

Revenues of our respiratory products were $293 million in the fourth quarter of 2017, down 10% compared to $325 million in the fourth quarter of 2016. ProAir revenues in the quarter were $102 million, down 27% compared to the fourth quarter of 2016. QVAR global revenues were $61 million in the fourth quarter of 2017, down 47% compared to the fourth quarter of 2016. Both ProAir and QVAR were affected by negative net pricing effects.

Revenues of our oncology products were $283 million in the fourth quarter of 2017, up 6% compared to the fourth quarter of 2016. Revenues of TREANDA and BENDEKA were $157 million, up 5% compared to the fourth quarter of 2016.

Specialty Medicines Gross Profit

Gross profit of our specialty medicines segment was $1.5 billion in the fourth quarter of 2017, down 21% compared to $1.9 billion in the fourth quarter of 2016. Gross profit margin for our specialty medicines segment in the fourth quarter of 2017 was 84.4%, compared to 87.4% in the fourth quarter of 2016.

Specialty Medicines Profit

Our specialty medicines segment profit was $1.0 billion in the fourth quarter of 2017, down 13% compared to the fourth quarter of 2016.

Specialty medicines profit as a percentage of segment revenues was 54.7% in the fourth quarter of 2017, up from 51.0% in the fourth quarter of 2016.

The following tables present details of our multiple sclerosis franchise and of our other specialty medicines for the three months ended December 31, 2017 and 2016:

Multiple Sclerosis
Three months ended December 31,
2017 2016
(U.S.$ in millions / % of MS Revenues)

Revenues $ 821 100.0% $ 1,015 100.0%
Gross profit 747 91.0% 927 91.3%
R&D expenses 11 1.3% 30 3.0%
S&M expenses 66 8.1% 81 7.9%
MS profit $ 670 81.6% $ 816 80.4%

Other Specialty
Three months ended December 31,
2017 2016
U.S.$ in millions / % of Other Specialty Revenues

Revenues $ 974 100.0% $ 1,188 100.0%
Gross profit 768 78.9% 999 84.1%
R&D expenses 151 15.5% 266 22.4%
S&M expenses 306 31.5% 425 35.8%
Other Specialty profit $ 311 31.9% $ 308 25.9%

In December 2017, our Biologics License Application for fremanezumab was accepted for filing by the FDA and was granted fast track designation for the prevention of cluster headache. On February 2, 2018, the EMA accepted a Marketing Authorization Application for fremanezumab.

Celltrion is our sole source for API production for fremanezumab and also for Celltrion’s products CT-P10 (biosimilar candidate to Rituxan US) and CT-P6 (biosimilar candidate to Herceptin US). In January 2018, Celltrion received an FDA warning letter for its facility in Incheon, South Korea. It is likely that the remediation by Celltrion of the issues addressed in the warning letter will result in a delayed approval of the biosimilar products by the FDA. We are in active dialogue with the FDA in an effort to maintain our priority date for the approval of fremanezumab.

Other Activities

Other revenues, primarily sales of third-party products for which we act as distributor, mostly in the United States via Anda, as well as in Israel and Hungary, sales of medical devices, contract manufacturing services related to products divested in connection with the Actavis Generics acquisition and other miscellaneous items, were $550 million in the fourth quarter of 2017, compared to $573 million, in the fourth quarter of 2016.

Outlook for 2018 Non-GAAP Results

FY 2018

Revenues $18.3-18.8 billion
Non-GAAP Operating Income $4.0-4.3 billion
EBITDA $4.7-5.0 billion
Non-GAAP EPS $2.25-2.50
Weighted average number of shares 1,030 million
Free Cash flow $2.6-2.8 billion

These estimates reflect management`s current expectations for Teva’s performance in 2018. Actual results may vary, whether as a result of market conditions, exchange rate fluctuations, or other factors. In addition, the non-GAAP figures exclude the amortization of purchased intangible assets, costs related to certain regulatory actions, inventory step-up, legal settlements and reserves, impairments and related tax effects.

Dividends

As part of our restructuring plan, in December 2017, we announced an immediate suspension of dividends on our ordinary shares and ADSs and that dividends on our mandatory convertible preferred shares will be evaluated on a quarterly basis per current practice.

Teva has suspended dividends on its mandatory convertible preferred shares in the fourth quarter of 2017, due to its negative net retained earnings

Conference Call

Teva will host a conference call and live webcast along with a slide presentation on Thursday, February 8, 2018 at 8:00 a.m. ET. to discuss its fourth quarter and annual 2017 results and overall business environment. A question & answer session will follow.

In order to participate, please dial the following numbers (at least 10 minutes before the scheduled start time): United States 1-866-869-2321; Canada 1-866-766-8269 or International +44(0) 203 0095710; passcode: 5279244. For a list of other international toll-free numbers, click here.

A live webcast of the call will also be available on Teva’s website at: ir.tevapharm.com. Please log in at least 10 minutes prior to the conference call in order to download the applicable audio software.

Following the conclusion of the call, a replay of the webcast will be available within 24 hours on the Company’s website. The replay can also be accessed until March 8, 2018, 9:00 a.m. ET by calling United States 1-866-247-4222; Canada 1-866-878-9237 or International +44(0) 1452550000; passcode: 5279244.

On February 8, 2018 Acorda Therapeutics, Inc. (Nasdaq: ACOR) reported that Ron Cohen, M.D., Acorda’s President and CEO, will present at the Leerink Global Healthcare Conference on Thursday, February 15 at 1:30pm EST (Press release, Acorda Therapeutics, FEB 8, 2018, View Source [SID1234523810]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

A live audio webcast of the presentation can be accessed under "Investor Events" in the Investor section of the Acorda website at www.acorda.com, or you may use the link:

View Source

On February 8, 2018 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a biotechnology company discovering and developing innovative immuno-oncology protein therapeutics, reported that Aron Knickerbocker, Chief Executive Officer, will present at the LEERINK Partners 7th Annual Global Healthcare Conference, Feb. 14, 2018, at 11:30 am ET (Press release, Five Prime Therapeutics, FEB 8, 2018, View Source [SID1234523833]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The presentation will be webcast and may be accessed at the "Events & Presentations" section of the Company’s website at View Source or directly at View Source Five Prime will maintain an archived replay of the webcast on its website for 30 days after the conference.

On February 8, 2018 Rexahn Pharmaceuticals, Inc. (NYSE American: RNN), a clinical stage biopharmaceutical company developing innovative, targeted therapeutics for the treatment of cancer, reported that it has entered into a collaboration and license agreement with Zhejiang Haichang Biotechnology Co., Ltd. (Haichang), to develop RX-0201 (Archexin) for the treatment of hepatocellular carcinoma (HCC), the most common form of liver cancer (Press release, Rexahn, FEB 8, 2018, View Source [SID1234523867]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Under the terms of the agreement, Haichang will develop a nano-liposomal formulation of RX-0201 using its proprietary QTsome technology and conduct certain pre-clinical and clinical activities through completion of a Phase IIa proof-of-concept clinical trial for the treatment of HCC. Any clinical trials conducted by Haichang will be designed to meet both U.S. and Chinese regulatory requirements. Haichang will fund all research and development activities through completion of the Phase IIa clinical trial.

The parties will share in an agreed ratio downstream licensing fees and royalties paid by third parties in connection with the further development and commercialization of the nano-liposomal formulation of RX-0201 for the treatment of HCC.

"We are delighted to enter into this collaboration to take RX-0201 forward in hepatocellular carcinoma," said Peter D. Suzdak, Ph.D., Chief Executive Officer of Rexahn. "We are impressed with Haichang’s QTsometechnology. It has the potential to target RX-0201 to the liver and to promote uptake into cancer cells to enhance efficacy. We are also very pleased to have non-dilutive funding to take the program through Phase IIa proof-of-concept studies."

"The incidence of liver cancer is growing worldwide, and especially in Asia," said Dr. Ben Zhao, Chief Executive Officer of Haichang. "There are very few treatment options for patients and unfortunately, the prognosis for patients with advanced disease is very poor. Akt-1 is an important signaling protein in liver cancer and we are excited about the potential for RX-0201. It is an ideal candidate for our liposomal technology and we look forward to advancing the development of RX-0201 in collaboration with Rexahn."

"While we continue to be encouraged by the safety and efficacy of RX-0201, the treatment landscape for metastatic renal cell carcinoma (mRCC) has significantly changed over the past two years with the approval of three new therapies by the FDA. This will limit the commercial viability of RX-0201 in mRCC. For this reason, Rexahn has decided to stop the development of RX-0201 for mRCC," said Lisa Nolan, Ph.D., Chief Business Officer for Rexahn. "The Haichang collaboration allows Rexahn to capitalize on the clinical data already generated in Phase I and Phase II clinical studies and change the focus of the RX-0201 program to hepatocellular carcinoma using non-dilutive funding to take the program through Phase IIa proof-of-concept studies while retaining the potential for future milestones/royalties for the product. This will also allow Rexahn to focus its own resources on progressing RX-3117 and Supinoxin (RX-5902) through Phase II clinical development."

In connection with the agreement with Haichang, Rexahn plans to discontinue the internally funded programs of Archexin and will cease enrollment in the current Phase IIa clinical study of Archexin in metastatic renal cell carcinoma (mRCC). Patients currently enrolled in the trial will continue to be followed

About Hepatocellular Carcinoma

Hepatocellular carcinoma (liver cancer) is the sixth most common type of cancer worldwide and the second-leading cause of cancer-related deaths. Each year approximately 780,000 new cases of liver cancer are diagnosed worldwide and over 740,000 people will die of the disease.1 The incidence of liver cancer in the U.S. has more than tripled since 1980.2 It is estimated that there will be approximately 41,000 new cases of liver and intrahepatic bile duct cancer and 29,000 deaths from these diseases in the U.S. in 2017.3 The majority of these cases are caused by Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infections. The increasing prevalence of metabolic syndrome and nonalcoholic steatohepatitis (NASH) is expected to contribute to increased rates of liver cancer in the U.S. in the foreseeable future.4 Outside the U.S., the incidence of liver cancer is approximately 40,000 in Europe and 36,000 Japan. Incidence is particularly high in China due to the prevalence of HBV and HCV infections and the incidence is estimated at 260,000 in 2017.

Treatment options are limited for patients with advanced liver cancer, which account for approximately 30% of newly diagnosed patients. Nexavar (sorafenib) is approved for first line treatment. Supportive care is the standard of care for second line treatment. Opdivo (nivolumab) has recently been approved for patients who have disease progression after treatment with Nexavar, but only 14% of patients respond to treatment. Overall, the prognosis for patients with advanced liver cancer is typically very poor.

About Zhejiang Haichang Biotechnology Co. Ltd

Zhejiang Haichang Biotechnology Co., Ltd. is a privately owned specialized biotechnology company headquartered in Hangzhou, China. The company is focused on the development and manufacture of complex intravenous pharmaceutical products including liposome and microsphere products, primarily for cancer treatment. The company has strategic collaborations with Sinopharm and and its liposomal doxorubicin product (Libaoduo) is marketed by Shanghai Fudan-Zhangjiang Bio-pharm Co., Ltd in China.

Haichang’s QTsome technology is a patented gene delivery technology that was co-developed with Professor Robert Lee at the Ohio State University. The technology is designed to enhance cellular uptake of large molecules such as oligonucleotides (antisense, siRNA and miRNA) and to target certain organs such as the liver where nanoparticles accumulate.

About RX-0201 (Archexin)

RX-0201 is an antisense oligonucleotide compound that is complementary to Akt-1 mRNA and highly selective for inhibiting its mRNA expression, which leads to reduced production of Akt-1. Akt-1 is a protein that is associated with cancer cell growth and proliferation and the development of resistance to certain anticancer agents. Akt-1 is over-expressed in multiple forms of cancer including hepatic, renal, breast, colorectal, gastric, pancreatic, prostate and melanoma. In a Phase I clinical trial in patients with advanced cancers, RX-0201 appears to be safe and well tolerated with minimal side effects. The dose-limiting adverse event in such clinical trial was Grade 3 fatigue with no significant hematological abnormalities observed.