N Engl J Med 2015; 372:1166-1167March 19, 2015DOI: 10.1056/NEJMe1415053

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Crohn's disease is characterized by relapsing inflammation leading to ulcers in the ileum and colon. Crohn's disease also affects the perianal region in more than half of patients. The disease is caused by a defective recognition, tolerance, or elimination of microbiota in a person who is genetically susceptible. An inappropriately overrobust reaction of the adaptive immune system leads to chronic transmural inflammation and is the cause of progressive intestinal damage, which occurs in more than two thirds of patients. In their landmark paper in 1932, Burrill Crohn and colleagues described the consequences of the disease: “a disproportionate connective tissue reaction was frequently observed leading to stenosis of the lumen of the intestine and the formation of multiple fistulas.”1

The current generally accepted goal of Crohn's disease management is ulcer healing, made possible through the introduction of biologic therapies against tumor necrosis factor (TNF) a. But despite almost two decades of anti-TNF use, no convincing reduction in disease progression or surgical rates has been reported. One explanation for this lack of progress in the clinical management of Crohn's disease is that treatment with anti-TNF agents, such as infliximab and adalimumab, is usually initiated after the disease is long established. This explanation, however, seems unsatisfactory; mechanisms other than those mediated by TNF must play a role in the perpetuation of the inflammatory cascade.

And indeed, it seems that counterregulatory processes are deficient in the pathogenesis of Crohn's disease and thereby contribute to inflammation. One such mechanism involves transforming growth factor (TGF) ß1. Its moniker notwithstanding, TGF-ß1 inhibits T-cell proliferation and differentiation and reduces macrophage activation and dendritic-cell maturation. It has an essential regulatory role in the control of experimental colitis: mice lacking TGF-ß1 die soon after birth as a result of systemic inflammation, and severe colitis and pulmonary inflammation develop in TGF-ß1–transgenic mice that are unresponsive to TGF-ß1 signaling.2 In patients with Crohn's disease, TGF-ß intracellular signaling is blocked by high levels of the SMAD7 protein. An oral antisense oligonucleotide called mongersen binds to and causes the degradation of SMAD7 messenger RNA; it therefore has the potential to restore TGF-ß signaling and reduce proinflammatory cytokine production.

Monteleone and colleagues now report in the Journal the results of a phase 2 study evaluating the efficacy of mongersen in patients with moderate-to-severe active Crohn's disease.3 A total of 160 patients, recruited almost exclusively in 16 Italian centers, underwent randomization and were treated with one of three doses of mongersen (10, 40, or 160 mg) or with placebo for 2 weeks. The primary end point was clinical remission, defined as a Crohn's disease activity index (CDAI) score of less than 150 at day 15 (scores can range from 0 to 600, with higher scores indicating greater disease activity). The proportion of patients meeting this end point was 10% for the placebo group and 12%, 55%, and 65% in the 10-mg group, 40-mg group, and 160-mg group, respectively. The primary end point was met, and the secondary outcome of clinical response (defined as a reduction in CDAI score of at least 100 points by day 28) was highly significant for the two highest doses.

The remission rates of between 55 and 65% for the two highest doses are unprecedented when compared with those reported in the large pivotal induction studies of infliximab (32.5% glucocorticoid-free clinical remission at week 6 in the SONIC trial),4 adalimumab (36% clinical remission at week 4 in the CLASSIC-I trial),5 and more recently, vedolizumab (14.5% clinical remission at week 6 and 39% at week 54 in the GEMINI 2 trial),6 all of which also involved patients with moderate-to-severe active Crohn's disease. However, the inclusion criteria used by Monteleone and colleagues were based on the CDAI score and did not include more objective criteria for active disease. Endoscopic confirmation of active Crohn's disease was not an inclusion criterion, so it is unclear what proportion of patients underwent randomization without actually having mucosal lesions. The SONIC study provided important lessons in this respect4: it, too, recruited persons with Crohn's disease defined according to CDAI score only, and analyses performed after the completion of the study showed that 18.3% of the participants had normal results on colonoscopic examination.

Moreover, the median level of C-reactive protein among patients at the beginning of the study was surprisingly low (4 to 5 mg per liter), and 39% of patients did not have elevated levels. Not all persons with Crohn's disease have elevated C-reactive protein levels, but 39% of trial participants with normal levels seems unusually high.

The choice of end points also warrants discussion. Clinical response and remission, measured as changes in the CDAI score, are end points recommended by regulatory bodies for randomized, controlled trials involving patients with inflammatory bowel disease, but there has been increasing emphasis on other end points, such as mucosal healing demonstrated by endoscopy or normalization of biomarkers such as fecal calprotectin or C-reactive protein. The impressive data on clinical remission reported by Monteleone et al. contrast with the relatively modest effect on the normalization of C-reactive protein levels: only 18% of the patients randomly assigned to the 40-mg or 160-mg group who had elevated C-reactive protein levels at baseline had normalization of C-reactive protein levels at the end of the treatment period, a proportion similar to that of the group who received 10 mg of mongersen, a dose that was not associated with clinical remission. In fact, among the patients with an elevated level of C-reactive protein at baseline, none of the doses of mongersen reduced the median levels. In short, there is a lack of congruence between clinical remission and biologic remission, an issue that will need to be addressed in future studies.

Another intriguing finding is that clinical remission was maintained for almost 3 months, even though the drug was administered for only 14 days. A total of 83% of patients completed follow-up at day 84; 62% and 67% of patients in the 40-mg and 160-mg groups, respectively, remained in clinical remission at day 84. This contrasts with the rapid recurrence of symptoms on withdrawal of existing antiinflammatory drugs. It is possible that unblocking TGF-ß1 signaling with short cycles of mongersen treatment would be sufficient to restore immunoregulatory processes and bring about a durable remission. If confirmed in future studies, this durable effect of mongersen would be unprecedented and would represent a first step toward curing the disease.

Among the adverse events the authors observed in their study, there was only one instance of intestinal obstruction, in the 40-mg dose group, although the duration of the trial was probably too short to draw firm conclusions about safety. One might expect fibrosis and possibly narrowing or stenosis of the bowel, because TGF-ß1 induces the synthesis of collagen and fibronectin and promotes fibrosis.7,8 In conclusion, the impressive clinical effects of mongersen beg for follow-up studies to confirm that we have indeed entered a new phase of Crohn's disease treatment.

Phase II Data for Celgene's Investigational Oral GED-0301 for Patients with Active Crohn's Disease Published in New England Journal of Medicine
65 percent of patients treated with GED-0301 160 mg once daily for two weeks achieved clinical remission at both day 15 and day 28, versus 10 percent of patients on placebo

72 and 67 percent of patients treated with 160 mg once daily were in clinical remission at day 28 and at day 84, respectively

Overall rates of adverse events and serious adverse events were similar across treatment groups, including placebo

SUMMIT, N.J.--(BUSINESS WIRE)-- Celgene Corporation (NASDAQ:CELG) today announced that results from a double-blind, placebo-controlled, multicenter phase II trial of three doses of GED-0301 (mongersen) in patients with active Crohn's disease were published in the March 19 issue of The New England Journal of Medicine.

"GED-0301 offers a unique approach to treating Crohn's, using antisense technology to target a key intracellular signaling protein thought to be involved in intestinal inflammation and the pathogenesis of the disease," said Professor Giovanni Monteleone, University of Rome Tor Vergata. "This orally administered therapy is designed to act locally with its novel mechanism of action. The results from the phase II trial suggest that GED-0301 should be studied further in phase III trials for Crohn's disease."

This phase II trial enrolled 166 adult patients with moderate-to-severe Crohn's disease, defined as Crohn's Disease Activity Index (CDAI) ranging from 220 to 400 at least one week prior to enrollment, with documented inflammatory lesions in the terminal ileum and/or right colon.

The newly published findings from this phase II study showed that a significantly greater proportion of patients with active Crohn's disease achieved the primary endpoint of clinical remission at both day 15 and day 28 with once daily GED-0301 40 mg (55 percent) or 160 mg (65 percent) than with GED-0301 10 mg (12 percent) or placebo (10 percent; P < 0.001). Additionally, 67 (6/9 patients) percent of patients reached glucocorticoid-free remission at day 84 with 160 mg GED-0301 once daily, versus 11 (1/9 patients) percent with placebo (P=0.04).

For patients treated with GED-0301 160 mg once daily, 67 percent, 72 percent and 67 percent were in clinical remission (had a CDAI score less than 150) on day 15, day 28 and day 84, respectively, compared with 21 percent, 14 percent and 21 percent on placebo (P < 0.0001 vs. placebo, for each time point). Similar results were seen in the GED-0301 40 mg once daily group (58 percent, 70 percent and 63 percent, respectively). For patients treated with GED-0301 10 mg once daily, clinical remission was achieved by 15 percent, 29 percent and 29 percent on day 15, day 28 and day 84, respectively (P=n.s. vs. placebo).

On day 28, 37 percent, 58 percent and 72 percent of patients treated with once daily GED-0301 10 mg, 40 mg or 160 mg once daily, respectively, achieved a clinical response (a 100-point reduction in CDAI score; a secondary endpoint), compared with 17 percent with placebo (P=0.04, P < 0.001 and P < 0.001, respectively).

The rates of patients with at least one adverse event (AE) in the GED-0301 groups were 49 percent, 62 percent and 49 percent for 10 mg, 40 mg and 160 mg once daily, respectively, compared with 67 percent for the placebo group. The most commonly reported AEs in the GED-0301 treatment groups were abdominal pain (10-12 percent), Crohn's disease worsening (10-15 percent), urinary tract infection (5-15 percent) and C-reactive protein increase (5-9 percent). The rates of serious adverse events in the GED-0301 dose groups were 7 percent, 2 percent and 2 percent for 10 mg, 40 mg and 160 mg once daily, respectively, compared with 2 percent for the placebo group.

"A significant number of Crohn's disease patients don't reach remission with current therapies and are looking for additional options," said Scott Smith, President of Celgene Inflammation and Immunology. "GED-0301 offers a completely different mechanism of action that has the potential to transform the Crohn's treatment landscape. We are encouraged by the phase II data and are committed to bringing innovative medicine to patients with Crohn's disease, starting with advancing the phase III trial for GED-0301."

About the Study

This phase II trial enrolled 166 adult patients with moderate-to-severe Crohn's disease with documented inflammatory lesions in the terminal ileum and/or right colon. Patients with known lesions in the stomach, proximal small intestine, transverse colon, and/or left colon, strictures, fistulae, perianal disease, extraintestinal manifestations, active or recent infections or a history of malignancy were excluded.

Patients were randomly assigned to receive treatment for two weeks with one of three daily doses of GED-0301 (10 mg, 40 mg or 160 mg tablets, once daily) or placebo and then evaluated for responses at days 15, 28 and 84. The primary efficacy endpoint of the study was the percentage of patients with clinical remission, defined as a CDAI score below 150 at day 15, which was maintained at day 28. The secondary endpoints included clinical response defined as a reduction of CDAI score of 100 points or 70 points at day 15 and day 28.

Patients could continue receiving stable doses of oral prednisolone (=40 mg/day), budesonide (=9 mg/day), or mesalamine during the 2-week treatment and/or a stable dose of immunomodulators (e.g., azathioprine, mercaptopurine, methotrexate) if therapy was initiated =6 months before treatment. Antibiotics, steroids, immunosuppressive drugs and biologics could not be initiated prior to study entry and during the 2-week treatment. Patients received no treatment with anti-TNF-a antibodies or other biologics within 90 days, or antibiotics within 3 weeks of the date of their initiation into the trial.

About GED-0301

The investigational oral antisense therapy GED-0301 is an oligonucleotide that targets the messenger RNA (mRNA) for Smad7, thereby reducing Smad7 protein levels. In patients with Crohn's disease, abnormally high levels of Smad7 interfere with TGF-ß1 anti-inflammatory pathways in the gut, leading to increased inflammation. GED-0301 is designed to act locally to reduce Smad7 levels with negligible systemic exposure.

About Crohn's Disease

Crohn's disease is an immune-mediated, chronic inflammatory condition of the gastrointestinal tract. Estimated to affect as many as three out of every 1,000 people in Europe and North America, the disease is becoming more common for all ethnic groups. Symptoms of Crohn's disease — including abdominal pain, diarrhea, fatigue, fever, weight loss and malnutrition — most commonly begin to appear between the ages of 13 and 30, although the disease can strike at any age. The disease may affect any part of the GI tract, from the mouth to the anus, but most commonly affects the end of the small bowel (the ileum) and the beginning of the colon. The exact cause of Crohn's disease is unknown, and there is no cure. People with Crohn's disease have a slightly reduced life expectancy.

About Celgene

Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit www.celgene.com. Follow Celgene on Twitter @Celgene, and on Pinterest and LinkedIn.

Valeant Pharmaceuticals International Inc. has recut its agreed deal to buy Salix Pharmaceuticals International Inc., increasing the price to $173 a share, or about $11.1 billion, according to people familiar with the matter.

The amended agreement is meant to fend off a rival cash-and-stock bid lobbed in last week by Endo International PLC. That bid was worth about $172.50 at Friday’s close, and could take longer to close and face more uncertainty as it requires a vote of Endo’s shareholders.

As part of the recut deal, Salix increased by $100 million, to about $450 million, the breakup fee it would owe Valeant if Salix walked away, the people said. That change makes another topping bid by Endo more expensive.

Salix also agreed to shorten from Aug. 20 to May 1 the date until which Valeant must keep its offer on the table, the people said.

...Hope that wasn't too technical.

New technology or medicines may render their approach obsolete. Any oral treatment, for example, that produced similar clinical results would present a serious challenge to Juno and its competitors’ business plans. Similarly, having an “off-the-shelf” immunotherapy treatment that didn’t have to be custom-made for each patient would be a huge step forward over individualized treatments. The field is still in its early days, and we don’t know how these things will sort themselves out.

The recent collapse in oil prices has prompted global producers to make drastic cuts in exploration and production. This year, capital expenditures for oil and gas will likely be slashed by some $24 billion, including $17 billion in the U.S. alone, although budgets are being revised almost daily as the market tests the “floor” for oil prices.

In absolute terms, these are large cuts. However, relative to the oil and gas industry’s overall global capital expenditures, expected to be close to $1 trillion this year, the amount is small. So small, in fact, that the cuts are unlikely to pose any real risk of supply shortages in the near future and should not threaten securing global supply of 93 million barrels per day. Even though many U.S. companies are dropping capex sharply, the international oil majors and national oil companies are committed to very large long term investment programs that remain in place despite short term volatility in prices.

Over the past decade, a surge in investments in exploration and production has transformed the industry dynamics, with supply ample and more diversified and OPEC’s share in decline. Upstream capex has grown three-fold over the 10 years ending in 2014: Output grew 10.6%.The U.S. shale revolution has been the main contributor to diversification and security of supply. U.S. shale accounts for 17% of total global oil and gas capex including exploration, drilling, development and completion. That said, opportunities in frontier areas such as West Africa – where capex growth since 2004 has almost equaled that in the U.S. – and a more stable political and legal environment for investment have also made other countries more attractive. Investment in oil and gas over the past 10 years has been concentrated on diversifying supply outside of traditional basins and OPEC countries. This expansion has helped to secure the biggest growth in non-OPEC supply in two decades, and triggered the recent decision from OPEC to abstain from its traditional intervention and let prices fall in order to maintain market share.

But oil investments have also been rising on the back of a pro-cyclical cost curve. That is, service costs and development costs tend to rise as oil prices go up, driven by excessive increases in investment. The oil industry has gone from underspending in the late 1990s to overspending on the back of growth in demand that has proven elusive. Many of the investments made in the 2004–2013 period have created overcapacity in the system. Additionally, improvements in efficiency and a transition to a less industrial-based model have broken the correlation between real GDP growth and energy demand. We do more with less: The number of barrels of oil consumed per additional unit of GDP in the U.S. is lower today than 30 years ago, while the world´s oil intensity (barrels consumed per $1,000 of GDP) has been declining by 2.4% per annum for a decade.

What we are seeing now is that oil prices, when OPEC refuses to balance the market, test the marginal cost of production, and costs fall. Some of the costs of the largest components of oil projects – high-spec sixth-generation rigs, pressure pumping, seismic, completion – have fallen between 20% and 45% in the space of months as overcapacity became evident and capital expenditure was revised downward. In a very short period of time, from September 2014 to January 2015, we have seen industry talk of overall cost reductions of 15% to 20%; this should lead to improving breakevens, and the widespread perception that the industry requires prices north of $65-$70 per barrel to deliver production growth will likely be rethought.

We have seen this before in previous periods of excess supply: Costs go down. Between 1985 and 1986, capex fell across the international majors, and operating costs per barrel plummeted 30% on average in one year. Quite similar to the cuts we have seen in the past months.

In the U.S., recently announced cuts already surpass $12 billion, and could rise as high as $17 billion for all of 2015. This, added to the 20%–25% cost reductions noted by the large service providers, could lower the average U.S. shale breakeven to $40–$45 per barrel. Industry self-help comes to the rescue!

The cathartic effect of low oil prices for the global oil and gas companies has so far created a strong enough response through reduced expenditure to allow the industry to survive the lean period. But where is the growth?

Unlike in the 1986–1998 period or in 2009, when the reduction in international oil companies´ capex was more than offset by investment from state-owned companies, this time investments are being reduced both at the National Oil Company (NOC) and international (IOC) level.

Waiting for prices to rise or other bottlenecks will be obstacles to achieving cleaner, safer and more affordable energy. Technology and improvements in efficiency will be the answer. Therefore, the industry will need to find new ways to finance investments to guarantee the security of supply in the next years as well as to continue the journey down the path to energy independence underway in the U.S.

There needs to be a process of restructuring and consolidation where the inefficient or highly indebted producers give way to stronger, more efficient companies that structure their business and investment to attain solid returns at mid-cycle prices, instead of betting on “higher for longer.”

Companies must start planning for a demand that is not going to grow as the old models predicted. OECD demand peaked in 2007 and non-OECD demand has partially been a self-fulfilling prophecy, driven by oil-producing countries´ own energy demand growth as prices rose. Higher revenues from oil exports created stronger GDP growth, larger investments in infrastructure and an unprecedented growth in energy demand in the oil-producing countries – well above certain developed countries’ average in some cases. This phenomenon also reduced effective exportable capacity. Therefore, as oil prices fall, it is likely that producers’ own oil demand will also moderate and exportable capacity will normalize. Non-OECD demand is also likely to be disappointing as China changes its model to a more sustainable one and technology and efficiency help the world improve its growth prospects with less energy consumption.

The financial industry will be instrumental in changing the landscape of energy investing. Capital increases to reduce the debt burden are required at both large and small companies, while mergers will be necessary to create stronger entities with diversified and robust portfolios where investments in growth are not dependent on peak cycle prices. In the same way that investors partnered with companies to solve the problems of natural gas producers when Henry Hub gas prices collapsed, investors can help reshape the position of alternative energy (wind and solar) companies to be able to deliver returns without betting on more subsidies or aggressive prices.

Investors should try to avoid waiting for or banking on an “oil back to $110” scenario and focus on four main points:

Avoid value traps and “cheap-for-a-reason” stocks: There are plenty in the oil and gas space, which is still discounting an oil price of $75 per barrel and trading at a large price-to-earnings premium to the market, with no earnings-per-share (EPS) growth expected in the next two to three years, and very poor dividend coverage. Even a recovery in prices that we expect wouldn't warrant these valuations.

Invest in the “unique” and best: Conglomerates don´t create value. Seek out innovative and competitive companies. M&A will happen but, as we have seen in the past, in the least expected, non-consensus names. Investors should keep in mind that consolidators look for scale, strong growth prospects, good footprints in sought-after acreage as well as new technologies in M&A candidates.

Debt matters: With the majors averaging net debt-to-equity of 31%–37%, optimistic dividend estimates and unachievable production growth targets pose real risks. In the case of independent exploration and production (E&P) companies, an average of 1.15x capex-to-cash-flow ratio might force companies to slow down if the focus is shifted to balance sheets and they see reduced shareholder interest. E&Ps have very large levels of debt, and the least efficient will likely find it difficult to recover lost valuation.

Service companies face lean years of lower margins and weaker backlog, and the sector cannot perform unless those two metrics improve. Consolidation, write-downs and retirement of old equipment are part of the cleanup process necessary to regain pricing power.
The International Energy Agency (IEA) estimates that the oil and gas industry will need to spend $23 trillion through 2035 to deliver the growth in production required to meet the world’s energy needs. Even assuming lower costs and more realistic demand, investments are unlikely to fall below the level, which should guarantee ample supply. The biggest mistake that the oil and gas industry can make is to believe that commodity prices need to or will return to peak levels. Once technology and innovation kick in, many projects undertaken in the past become sunk costs, companies become more efficient and old estimates of breakeven become irrelevant. Disruptive technologies are here to stay. The winners will be the most efficient, not the ones waiting for “the good old days.”

CALGARY, ALBERTA--(Marketwired - Jan 13, 2015) - Suncor Energy Inc. announced today significant spending reductions to its 2015 budget in response to the current lower crude price environment. The cuts include a $1 billion decrease in the company's capital spending program, as well as sustainable operating expense reductions of $600 million to $800 million to be phased in over two years offsetting inflation and growth.

"Our integrated model and strong balance sheet have positioned us well for the price downturn," said Steve Williams, president and chief executive officer. "Cost management has been an ongoing focus, with successful efforts to reduce both capital and operating costs well underway before the decline in oil prices. However, in today's low crude price environment, it's essential we accelerate this work. Today's spending reductions are consistent with our commitment to spend within our means and maintain a strong balance sheet. We will monitor the pricing environment and take further action as required."

Suncor is implementing a number of initiatives to achieve the cost reduction targets. These include deferral of some capital projects that have not yet been sanctioned, such as MacKay River 2 and the White Rose Extension, as well as reductions to discretionary spending. Budgets affecting the company's safety, reliability and environmental performance have been specifically excluded from the cost reduction program.

Suncor has also implemented a series of workforce initiatives that will reduce total workforce numbers in 2015 by approximately 1000 people, primarily through its contract workforce, in addition to reducing employee positions. There will also be an overall hiring freeze for roles that are not critical to operations and safety.

Major projects in construction such as Fort Hills and Hebron will move forward as planned and take full advantage of the current economic environment. These are long-term growth projects that are expected to provide strong returns when they come online in late 2017.

Suncor has issued an update to its 2015 guidance to reflect, among other items, reduced spending and lower pricing and related assumptions. Production guidance for 2015 has not changed.

Suncor's fundamental goals remain the same, with operational excellence, capital discipline and profitable growth remaining key to its business strategy. In fact, today's announcement reflects the application of these principles, in the context of the current low price environment.

"The strategic decisions we've made are consistent with our unwavering focus on capital discipline and operational excellence," said Williams. "We will continue to carefully manage our spending priorities: sustaining safe, reliable and environmentally responsible operations, providing a meaningful, competitive dividend for our shareholders and investing in profitable growth."

For further detail on Suncor's outlook and capital spending plan, see suncor.com/guidance.

SUMMIT, N.J.--(BUSINESS WIRE)--

Celgene Corporation (CELG) provided a business update as well as its preliminary 2014 results and financial outlook for 2015 and beyond at the 33rd Annual J.P. Morgan Healthcare Conference. In 2015, total net product sales are expected to be approximately $9,000 million to $9,500 million, a 22 percent increase year-over-year, based on the mid-point of the range. The negative impact of foreign exchange on net product sales is expected to approach $100 million in 2015 compared to 2014. For the full-year 2015, REVLIMID® net sales are expected to be in the range of $5,600 million to $5,700 million. Adjusted diluted earnings per share (EPS) for the full-year 2015 is expected to be in the range of $4.60 to $4.75, a 26 percent increase year-over-year, based on the mid-point of the range. Based on U.S. Generally Accepted Accounting Principles (GAAP), diluted EPS is expected to be in the range of $3.68 to $3.92.

“2014 was an exceptional year for Celgene and the momentum from our core businesses positions us for another year of outstanding execution,” said Bob Hugin, Celgene’s Chairman and Chief Executive Officer. “The depth of our 2014 accomplishments creates an inflection point, providing greater clarity on the opportunities for 2020 and beyond.”

Preliminary 2014 Financial Results Year-Over-Year (Unaudited)

Total net product sales are expected to be approximately $7,560 million, up 19 percent year-over-year. Fourth quarter of 2014 net product sales are expected to be approximately $2,050 million, including approximately $25 million of negative year-over-year foreign exchange impact
REVLIMID®: $4,980 million, 16 percent year-over-year increase
ABRAXANE®: $848 million, 31 percent year-over-year increase
POMALYST®/IMNOVID®: $680 million, 123 percent year-over-year increase
OTEZLA®: $70 million
Adjusted operating margin is expected to be approximately 50.6 percent for the full year, up 220 basis points (bps) year-over-year. GAAP operating margin is expected to be approximately 32.8 percent, an increase of 490 bps year-over-year, primarily due to decreased upfront payments to collaboration partners in 2014
Adjusted diluted EPS is expected to be approximately $3.71, a 24 percent year-over-year increase, on a split-adjusted basis. GAAP diluted EPS is expected to be in the range of $2.38 to $2.41
For the fourth quarter of 2014 adjusted diluted EPS is expected to be approximately $1.01. GAAP diluted EPS is expected to be in the range of $0.71 to $0.74
Certain activities involved in determining the audited results for the fiscal year ended December 31, 2014 are in process and could result in the final reported audited results being different from the unaudited results noted in this press release. Please see the attached Reconciliation of Estimated/Projected GAAP to Adjusted (Non-GAAP) Measures for further information.

Celgene Forecasts Strong Product Sales and Earnings Growth in 2015

Total net product sales are expected to be $9,000 million to $9,500 million, an increase of 22.3 percent year-over-year based on the mid-point of the range and includes a negative impact from foreign exchange approaching $100 million
REVLIMID® net sales are expected to be in the range of $5,600 million to $5,700 million, an increase of 13.5 percent year-over-year based on the mid-point of the range
Adjusted operating margin is expected to be approximately 52 percent after investments across the entire organization, a 140 bps improvement over 2014. GAAP operating margin is expected to be approximately 41.7 percent
Adjusted diluted EPS is expected to be in the range of $4.60 to $4.75, an increase of approximately 26.0 percent year-over-year based on the mid-point of the range. GAAP diluted EPS is expected to be in the range of $3.68 to $3.92
2017 and 2020 Long-term Financial Targets

Reaffirming 2017 financial targets:
Net product sales target of $13,000 million to $14,000 million
2017 net product sales expected to be:
REVLIMID®: $7,000 million
POMALYST®/IMNOVID®: $1,500 million
ABRAXANE®: $1,500 million to $2,000 million
OTEZLA®: $1,500 million to $2,000 million
Adjusted diluted EPS is expected to be approximately $7.50
Fully diluted share count is expected to be approximately 830 million
New 2020 financial targets:
2020 net product sales expected to exceed $20,000 million
Hematology franchise expected to exceed $14,800 million
Oncology franchise expected to exceed $2,200 million
I&I franchise expected to exceed $3,000 million
Adjusted diluted EPS expected to exceed $12.50
Fully diluted share count expected to be approximately 830 million
2015 Expected Operational Milestones

Hematology/Oncology

U.S. Food and Drug Administration decision on REVLIMID® for newly diagnosed multiple myeloma (NDMM)
Approval decision by the European Commission (EC) on REVLIMID® for NDMM
Approval in Japan of REVLIMID® for NDMM
Submit REVLIMID® for non-deletion 5q myelodysplastic syndrome (MDS) in the U.S. and Japan
Discuss REVLIMID® for non-deletion 5q MDS with regulatory authorities in additional geographies
Initiate a phase III trial with REVLIMID® maintenance in patients with NDMM who are post stem cell transplant and are minimal residual disease positive
Data from the FLASH (Follicular Lymphoma Analysis of Surrogacy Hypothesis) Group meta-analysis of durable complete response as a surrogate for progression-free survival in follicular lymphoma
Initiate enrollment in the ROBUSTTM phase III trial with REVLIMID® in newly diagnosed diffuse large B-cell lymphoma (DLBCL)
Complete enrollment in the phase III CONTINUUM® trial of REVLIMID® as maintenance in second-line chronic lymphocytic leukemia
Ongoing geographic expansion of REVLIMID® in RRMM, notably in Russia, Mexico and Brazil
Approval of POMALYST®/IMNOVID® in Japan for relapsed and/or refractory multiple myeloma
Opinion from the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) on VIDAZA® for elderly acute myeloid leukemia (AML)
Advance the phase I/II trials of CC-122 as monotherapy and combination therapy in DLBCL
Advance the programs with sotatercept and/or luspatercept in beta-thalassemia and MDS
Initiate pivotal program with AG-221 in AML with IDH-2 mutation
Approval decision from the EC on ABRAXANE® in non-small cell lung cancer
I&I

Approval decision from the EC on OTEZLA® for psoriasis and psoriatic arthritis
Expansion of OTEZLA® in key geographies
Complete enrollment in the phase II trial of OTEZLA® for atopic dermatitis
Publication of phase II trial of GED-0301 in Crohn’s disease in a major medical journal
Complete enrollment of the registration-enabling endoscopy trial for GED-0301 in Crohn’s disease
Initiate enrollment in phase III trials of GED-0301 in Crohn’s disease
Initiate clinical program in ulcerative colitis for GED-0301
Complete phase IIb enrollment for sotatercept in end-stage renal disease patients with anemia
Complete enrollment in the phase II trial with CC-220 in patients with systemic lupus erythematosus
Q4 and Full year 2014 Conference Call and Webcast Information

Celgene will host a conference call to discuss the results and achievements of its fourth quarter and full year 2014 operating and financial performance on January 29, 2015, at 9 a.m. ET. The conference call will be available by webcast on the Investor Relations webpage at www.celgene.com. An audio replay of the call will be available from noon ET January 29, 2015, until midnight ET February 5, 2015. To access the replay, in the U.S. dial (855) 859-2056; outside the U.S. dial (404) 537-3406; and enter conference ID number 61454428.

DALLAS--(BUSINESS WIRE)--Jan. 6, 2015-- Pioneer Natural Resources Company (NYSE:PXD) (“Pioneer” or “the Company”) today announced that it has converted approximately 85% of its 2015 oil derivative contracts from three-way collars to fixed-price swaps. Pioneer’s 2015 fixed-price oil swaps cover 82,000 barrels of oil production per day at an average NYMEX price of $71.18 per barrel. These fixed-price derivative swaps and Pioneer's remaining three-way collar contracts for 2015 (13,767 barrels of oil production per day) currently cover approximately 85% of the Company's forecasted oil production in 2015. The Company continues to maintain its three-way collar contracts for 2016 ($96.46 per barrel call price, $85.47 per barrel put price and $74.35 per barrel short put price), which currently account for 73,000 barrels of oil production per day.

The Company also has derivatives in-place covering approximately 85% of forecasted gas production in 2015 through a combination of three-way collar contracts that cover 285,000 million British thermal units (MMBTU) per day at a NYMEX Henry Hub call price of $5.07 per MMBTU, a put price of $4.00 per MMBTU and a short put price of $3.00 per MMBTU, and derivative swap contracts that cover 20,000 MMBTU per day at an average NYMEX Henry Hub price of $4.31 per MMBTU.

Scott D. Sheffield, Chairman and CEO, stated, “Over the past five years, our derivative strategy has successfully protected our cash flow and allowed us to execute a highly productive drilling program. In light of the weak oil price environment forecasted for 2015, we elected to convert most of our 2015 oil derivatives from three-way collars to fixed-price swaps to establish a firm oil price floor and lock in the corresponding cash flow. Pioneer’s adjusted derivative portfolio, combined with our exceptional assets and strong balance sheet, positions the Company to manage through the current price downturn and emerge as an even stronger company when oil prices recover.”

The Company plans to release its 2015 business plan and capital budget as part of its fourth quarter 2014 earnings release on February 10, 2015.

Third Quarter 2014 and Operational Highlights

Completed enrollment of the global Solitaire-Oral Phase 3 clinical trial of oral solithromycin in adult patients with moderate to moderately severe community-acquired bacterial pneumonia (CABP)
Received a $10 million milestone payment from Toyama Chemical Co., a subsidiary of FUJIFILM Holdings Corporation, triggered by Toyama's receipt of regulatory clearance to begin a Phase 2 trial of solithromycin in Japan, the world's second largest antibiotic market
Initiated the Solitaire-U study, a Phase 3 clinical study of a single 1000 mg dose of oral solithromycin in patients with uncomplicated gonorrhea and chlamydia infections
Completed a Phase 1a study with solithromycin capsules as add on therapy in adolescents, age 12 to 17 years old, with suspected or confirmed bacterial infections. The study demonstrated safety and a pharmacokinetic profile similar to that seen in adults. Based on these positive results, a Phase 1b study is planned pending funding approval from Biomedical Advanced Research and Development Authority (BARDA)
"I am thrilled by the progress we have made on our broad solithromycin development plan during the quarter, including completion of enrollment for our global Solitaire - oral Phase 3 study, as well as initiation of our Solitaire-U Phase 3 study for oral solithromycin in uncomplicated gonorrhea," stated Prabhavathi Fernandes, Ph.D., president and chief executive officer of Cempra. "We are also very pleased that Toyama, our partner in Japan, where the regulatory criteria are quite stringent, successfully demonstrated safety in a Phase 1 study with solithromycin and has advanced quickly into a Phase 2 trial. We look forward to a strong finish to 2014 and to the release of topline data from Solitaire-oral which is expected during the first quarter of 2015."

Clinical Development Update

Cempra is focused on the development of its two lead clinical-stage candidates: solithromycin, a novel fluoroketolide antibiotic, and Taksta(TM), an oral fusidic acid based therapy in development for staphylococcal infections. Upcoming potential development and regulatory milestones include:

Solithromycin

4Q 2014: Initiate NAIAD-funded urogenital solithromycin PK study
4Q 2014/1Q2015: Regulatory documents have been submitted for investigator-sponsored Phase 2 study in COPD and initiation of dosing is expected late 2014/early 2015
1Q 2015: Report top-line data from Solitaire-Oral Phase 3
Taksta(TM)

4Q 2014: Meet with the FDA to define pivotal study for Taksta(TM)
Financial Results for the Three and Nine Months Ended September 30, 2014

For the quarter ended September 30, 2014, Cempra reported a net loss of $11.4 million, or $0.34 per share, compared to a net loss of $13.6 million, or $0.41 per share, for the same period in 2013. Research and development expense in the quarter ended September 30, 2014, was $15.7 million, an increase of 32% compared to the same quarter in 2013. The higher R&D expense was primarily due to increased clinical trial activities, with three Phase 3 trials running for solithromycin. General and administrative expense was $2.9 million, a 32% increase compared to the quarter ended September 30, 2013, driven primarily by increased employee compensation expense.

For the nine months ended September 30, 2014, Cempra reported a net loss of $44.8 million, or $1.34 per share, compared to a net loss of $28.2 million, or $1.00 per share, for the nine months ended September 30, 2013. Research and development expense was $47.2 million, an increase of 84% compared to the nine months ended September 30, 2013. The increase was primarily due to increased clinical trial activities. General and administrative expense was $8.6 million, a 25% increase compared to the nine months ended September 30, 2013.

As of September 30, 2014, Cempra had cash and equivalents of $74.2 million compared to $96.5 million as of December 31, 2013. During the quarter, Cempra's balance sheet was strengthened by the receipt of a $10 million milestone payment from Toyama and $10.6 million from the sale of newly issued shares through an At The Market (ATM) financing vehicle. In October Cempra received approximately $19.8 million of additional proceeds under its ATM.