Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

The pharmaceutical industry as a whole is undergoing certain transformations, such as the move to specialty drugs targeted to specific patient groups and in the longer term, the move to personalized medicines. Although this emphasis is typically oriented toward tailoring an active ingredient to more specific patient groups, personalized/targeted dosing regimes will play an important role in realizing the paradigm of more specialized/personalized medicines. 

“Mass-customization offers individualized products for everyone to address individual health issues with tailored medication,” observes François Scheffler, vice-president of global marketing at BASF’s Pharma Ingredients & Services business unit. “Today’s medication is mostly bound to the indication, not to the individual patient or consumer and his specific needs. A prerequisite for a customized medication approach is probably a genetic and phenotypic assessment at affordable costs, basically looking into the human body and predicting the likelihood of possible health problems throughout life.”

Paving the Way for Personalized Medicine, FDA’s Role in a New Era of Medical Product Development

, FDA notes that the term “personalized medicine” is often described as providing “the right patient with the right drug at the right dose at the right time” (1), but more broadly, “personalized medicine may be thought of as the tailoring of medical treatment to the individual characteristics, needs, and preferences of a patient during all stages of care, including prevention, diagnosis, treatment, and follow-up” (1). Personalized medicine generally involves the use of two medical products--a diagnostic device and a therapeutic product--to improve patient outcomes. “While considerable attention in personalized medicine is currently being paid to the use of genetic tests to guide therapeutic decisions, a vast variety of medical devices can be used in a personalized approach to improve patient outcomes” (1). Many medical-device therapies can be tailored to specific patient characteristics, such as patient anatomy (e.g., size), physiology (e.g., nervous and cardiovascular systems, metabolism, and reproduction) and environment (e.g., intensive care unit, home use). Also, physiological sensors may predict treatment responses for individual patients, such as three-dimensional (3D) printing, to create personalized medical devices based on imaging of a patient’s anatomy (1). 

The confluence of traditional therapeutics with devices provides the foundation for the pharmaceutical of the future. Customization is taking root through emerging technologies, such as bioelectronic medicines and 3D printing of pharmaceuticals, through select investment by pharmaceutical companies, venture-capitalists, and academic researchers.


  In August 2013, GlaxoSmithKline (GSK) launched the Action Potential Venture Capital (APVC) Limited, a new $50-million strategic venture-capital fund that will invest in companies developing bioelectronic medicines and technologies (2). The fund’s first investment is in SetPoint Medical, a Valencia, California-based company, which has developed proprietary implantable neuromodulation devices that stimulate the body’s vagus nerve to treat inflammatory diseases, such as Crohn’s disease and rheumatoid arthritis (2, 3). In August 2013, SetPoint secured $27 million in financing from investors, which included GSK’s Action Potential Venture, Covidien Ventures, and Boston Scientific, to fund ongoing clinical development of the SetPoint bioelectronics therapy approach in rheumatoid arthritis and Crohn’s disease and advance development of its neuromodulation platform (2). 

APVC complements the work of GSK’s Bioelectronics R&D unit, which was established in 2012. The name of the fund comes from electrical signals called action potentials that pass along the nerves in the body. Irregular or altered patterns of these impulses may occur in association with a broad range of diseases (2). GSK believes that miniaturized devices, or bioelectronic medicines, can be designed to read these patterns. The devices could be designed to interface between the peripheral nervous system and specific organs to read, change, or generate electronic impulses that help treat disorders, such as inflammatory bowel disease, rheumatoid arthritis, and respiratory and metabolic diseases (2). In addition to working with the new venture fund, GSK’s Bioelectronics R&D will offer up to 20 new exploratory research grants and create a network of investigators. Work is focusing on the relationship between the nerves in the body and a range of diseases, the particular pattern of impulses along these nerves, and technologies that can interface with individual nerve fibers (2). In December 2013, GSK announced a $1-million dollar prize in bioelectronics research for creating a miniaturized, fully implantable device to read, write, and block the body’s electrical signals to treat disease. 

Action Potential Venture Capital intends to build a portfolio of five to seven companies over the next five years. The fund will focus investments in three areas: new start-up companies that seek to pursue the vision of bioelectronic medicines; existing companies with technologies that are interacting with the peripheral nervous system through first-generation devices that can stimulate or block electrical impulses; and companies advancing technology platforms that will underpin these treatment modalities (2).

In May 2013, Proteus Digital Health, a Redwood City, California-based company developing digital medicines, raised
$62.5 million, which included a new corporate investor Oracle, as well as investment from earlier investors Otsuka, Novartis, and Sino Portfolio. Proteus’ focus is on digital medicines based on ingestible sensing (4). In July 2012, Proteus received FDA clearance for its ingestible sensor for marketing as a medical device (5). The Proteus ingestible sensor (i.e., the ingestible event marker) is a prescription device used to record time-stamped patient-logged events. The ingestible component links wirelessly through intrabody communication to an external recorder that records the date and time of ingestion. The company’s personal monitor (i.e., patch) is a body-worn sensor that collects physiological and behavioral metrics, including heart rate, body angle, and time-stamped, user-logged events generated when a user marks an event by swallowing an ingestion event marker or by manually pressing an event marker button on the patch, which stores and wirelessly sends the ingestion event marker data to a general computing device. The ingestion event marker is attached to an excipient/tablet for ease of handling and swallowability. Software pairs the patch with a mobile computing device that organizes and displays ingestion events (6). Proteus received a CE Mark approval for its ingestible sensor personal physiologic monitor system in the European Union in 2010 (7). In their deal, Oracle and Proteus will work together to provide clinical investigators the ability to measure information about medication ingestion, dose timing, and associated physiologic response. The two companies will integrate Proteus’ ingestible sensor with Oracle’s clinical-trial products (8).

In October 2012, Qualcomm, a provider of wireless technology and services, granted $3.75 million to the Scripps Translational Science Institute to advance clinical trials of wireless biosensor systems, rapid pharmacogenomic diagnostic tests, apps, and embedded sensors for tracking and predicting disease. The money will support additional staffing and other resources for a three-year program, called Scripps Digital Medicine, designed to advance promising medical apps and devices for clinical development. Some start-up companies involved are: AirStrip Technologies (San Antonio, Texas), a provider of mobile healthcare software, and DNA Electronics (London), a spin-out from the Center of Bio-Inspired Technology in the Institute of Biomedical Engineering at Imperial College London and a provider of a handheld genotyping device (i.e., Genalysis) that can be used to better tailor prescriptions to individual patients. Other projects involve  a blood-borne biosensor system and a mobile apps for embedded sensors (9).

“Digital health feedback systems are a logical consequence of the trend toward preventive medication and healthier living,” notes Scheffler. “The influence on the formulation of the drugs and, therefore, the usage of excipients and ingredients and their interactions will be significant. For example, it would not just mean measuring certain body reactions but addressing them as quickly, as precisely, and as early as possible. An increase in life quality and significant cost savings will be the main benefits of this technology.” As a case in point, Metanomics Health, a company of BASF, is specialized in translating phenological indicators into potential dysfunctions of the body that can then be addressed early with changes of behaviors or medicine. 

A literature review shows some recent work using digital tablets. In one study, a digital health feedback system used a digital tablet, which consisted of an ingestion sensor that was embedded in a tablet containing nonpharmacologic excipients, in which subjects (12 adults with bipolar disorder and 16 adults with schizophrenia) coingested with their regularly prescribed medication (9). The formulation of this digital tablet allowed ingestion sensor separation and activation by stomach fluids after ingestion, followed by communication of a unique identifying signal from the ingestion sensor to an adhesive sensor worn on the torso, which automatically logged the date and time of each digital tablet ingestion. The wearable sensor also collected physiologic measures, including activity and heart rate (10). 

MicroCHIPs has developed an alternative to daily injections: a programmable, wirelessly controlled microchip with an implantable device that allows drugs to be released inside the body without percutaneous connections in or on the patient. An implantable microchip device also offers the potential for real-time dose schedule-tracking and for physicians to remotely adjust treatment schedules. The technologies use microreservoir arrays to hermetically store and protect pharmaceuticals or sensors for extended periods of time. The microchip is controlled by microprocessors, wireless communications, or sensor feedback loops for dynamic control of drug delivery or sensing. MicroCHIPs licensed the technology from the Massachusetts Institute of Technology, which reported in 2012, a successful human clinical trial for a wirelessly controlled drug-delivery chip. In the trial, human teriparatide, a parathyroid hormone fragment [hPTH(1-34)] and anabolic osteoporosis treatment, was delivered from the device in vivo. The microchip-based devices contained discrete doses of lyophilized hPTH(1-34) and were implanted in eight osteoporotic postmenopausal women for four months and wirelessly programed to release doses from the device once daily for up to 20 days. A computer-based programmer established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant confirmation status (11-13). 


3D printing of pharmaceuticals is another vision. “3D printing is probably the most innovative idea in the pharmaceutical industry since decades,” says Scheffler. “It will change our lives and will play a major role, in fact, in literally all industries. New formulations with existing and approved excipients and ingredients will benefit from these creative new ways because we can customize medicine to each individual patient. The effect is less waste, less costs, and less complexity for patients.”  

Journal of the American Pharmacists Association

 summarized the published literature on existing 3D printing technologies for pharmaceutical manufacturing and outlined the limitations and potential of these technologies (14). A structured search of PubMed and Embase identifed articles published between Jan. 1, 1990 and Aug. 31, 2012. Search terms included drug printing, drug 3D printing, and drug three-dimensional printing. Twenty-one of 511 identified references were included in the review. Inkjet and powder-based printing were the primary printing technologies used for drug development and fabrication. Eleven articles described a powder-delivery system, and 10 identified inkjet printing. These printing technologies allow for certain advantages, such as precise control of droplet size, high reproducibility, complex drug-release profiles, and personalized medication therapy (14). The article specified that printable dosage forms on paper may be easier to deliver than powder-based printed forms. Medications with narrow therapeutic indices or with a higher likelihood to be influenced by genetic polymorphisms may be the first to be printed via this technology (14).

A research team led by Simon Gaisford, reader in pharmaceutics at the University College London’s School of Pharmacy, has applied thermal inkjet printing technology to make personalized-dose oral films of salbutamol sulfate by replacing the paper in the printer with a sheet of polymer film that allowed the drug to be jetted onto the surface (15-17). A printer cartridge was modified so that aqueous drug solutions replaced the ink (15-17). Film strips were cut. Varying the concentration of drug solution, area printed, or number of print passes allowed the dose to be controlled (15-17). The print-solution viscosity and surface tension were used to determine the performance of the printer. A calibration curve for salbutamol sulfate was prepared, which showed that drug deposition onto an acetate film varied linearly with concentration. The printer was used to deposit salbutamol sulfate onto an oral film made of potato starch. The researchers found that when doses were deposited in a single pass under the print head, the measured dose was in good agreement with the theoretical dose. With multiple passes, the measured dose was always significantly less than the theoretical dose (15-17) The researchers surmised that the losses result from the printed layer eroding by shear forces during paper handling.

Paving the Way for Personalised Medicine: FDA’s Role in a New Era of Medical Product Development

 (Rockville, MD, Oct. 2013).
  2.	GlaxoSmithKline, “GSK Launches $50 Million Venture Capital Fund to Invest in Pioneering Bioelectronic Medicines and Technologies,” Press Release, Aug. 8, 2013.
  3.	SetPoint Medical, “SetPoint Medical Secures $27 Million Financing, Adding Action Potential Venture Capital/GSK, Boston Scientific and Covidien Ventures as New Investors,” Press Release, Aug. 8,  2013. 
  4.	Proteus Digital Health, “Proteus Digital Health Completes $62.5 Million Financing,” Press Release, May 1, 2013. 
  5.	Proteus Digital Health, “Proteus Digital Health Announces FDA Clearance of Ingestible Sensor, Press Release, July 30, 2013. 
  6.	FDA, “

Evaluation of Automatic Class II Designation (De Novo) for Proteus Personal Monitor Including Ingestion Marker

,” Decision Summary (Rockville, MD, May 14, 2012), accessed 17 Dec. 2012. 
  7.	Proteus Proteus Digital Health, “Proteus Biomedical Announces European CE Mark Approval of Ingestible Sensor and Monitor System,” Press Release, Aug. 13,  2010. 
  8.	Proteus Digital Health, “Oracle Invests in Proteus Digital Health and Its FDA-Approved Ingestible Sensor Platform,” Press Release, May 1, 2013. 
  9.	Scripps Translational Science Institute, “Scripps Creates Digital Medicine Program with Qualcomm,” Press Release, Oct. 13. 2013. 
  10.	J.M. Kane, Clin. 

 74 (6), 533-540 (2013). 
  11.	R. Farra et al., 

 online, DOI: 10.1126/scitranslmed.3003276, Feb. 16, 2012.
  12.	A. Trafton, “Successful Human Tests for First Wirelessly Controlled Drug-Delivery Chip,” Press Release, May 16, 2013. 
  13.	J. Santini, M. Cima, and R. Langer, Nature 397 (6717), 335-338 (1999). 
  14.	I.D. Ursan, L. Chiu,and A. Pierce, J. Am. 

. 53, 136-144 (2013). 
  15.	P. Van Arnum, 

 accessed 17 Dec. 2013.
17.	 S. Gaisford et al., 

Articles

How will the move to more specialized and personalized medicines impact drug delivery and dosage forms?

The Future of Dosage Forms

As the bio/pharmaceutical industry enters a new year, what is the outlook? Emerging markets will continue to play an important role in the broader pharmaceutical and custom-synthesis market. 


  A recent analysis of the Chemical Pharmaceutical Generic Association (CPA), which represents Italian generic API manufacturers, points to strong growth for the pharmaceutical contract research and manufacturing services (PCRAMS) industry. The overall world PCRAMS industry, which includes revenues from contract research organizations (CROs) and contract manufacturing organizations (CMOs), was valued at $72 billion in 2012, up from $21 billion in 2000. Contract manufacturing accounted for two-thirds of the 2012 market, or $47 billion, and contract research the remaining $25 billion, according to the CPA report, The World PCRAMS Industry (1).

Of the global contract manufacturing business, contract manufacturing of APIs and intermediates accounted for the largest sector for contract manufacturing at 64% or $30 billion. Contract manufacturing of finished dosage forms accounted for 9.6% or $4.5 billion, according to the CPA analysis. Development of finished dosage forms accounts for approximately 15% of the contract manufacturing market, or $7 billion, and packaging/labeling and other services represent the remainder or $5.5 billion.

Of the market for contract manufacturing of APIs and intermediates, custom synthesis (mainly focused on new, branded APIs) accounts for 40% or $12 billion, and toll manufacturing for the remaining 60% or $18 billion. For purposes of the analysis, “custom synthesis” denotes when a company outsources the manufacturing of an intermediate or API without indicating the operational modalities. “Toll manufacturing” denotes when the production of the intermediate or API is carried out by the external supplier according to operational modalities established by the sponsor company.

Overall, the global PCRAMS market is forecast to grow at an average of 13.6% yearly over the next five years to reach $136 billion by 2017 from $72 billion in 2012, according to the CPA analysis. The global CRO business is expected to increase from $25 billion to $43 billion in 2017, representing average yearly growth of 11.4%, according to CPA. The global CMO business is projected to increase from $47 billion in 2012 to $93 billion in 2017, an average of 14.6% in yearly growth, according to CPA estimates. Asia Pacific will show the strongest growth in the global PCRAMS market, with particularly strong growth for India and China. The share held by India in the world PCRAMS market will nearly triple in the next five years, and by 2017, India will be the second largest market for PCRAMS, accounting for 21.3% of the global market compared to only 8.3% in 2012. India will only be surpassed by the United States, which is expected to hold 24.9% of the global PCRAMS market in 2017 compared to a share of 33.7% in 2012. Just as the US market’s share in the global PCRAMS market will decline so will the share of Western Europe from 25.0% in 2012 to 17.1% in 2017. China’s share of the global PCRAMS market will increase from 12.2% in 2012 to 19.2% by 2017, according to CPA. 


  The growth patterns in the custom-manufacturing market parallel the pharmaceutical market as a whole, which reflects increased growth in emerging markets. Global spending on medicines is expected to meet the $1 trillion threshold in 2014 and reach $1.17 trillion by 2017, according to the IMS Institute for Healthcare Informatics’ report,

 The Global Use of Medicines: Outlook through 2017

, which shows growth in global spending on medicines increased 2.6% to $965 billion in 2012 and is forecast to grow at a 3-6% compound annual growth rate (CAGR) by 2017 (2). IMS projects a gradual increase in global annual medicine spending growth, which is expected to rise from 2-3% in 2013 to 5-7% in 2017, the highest pace of growth since 2009. The absolute global spend for pharmaceuticals will increase by $230-260 billion on a constant dollar basis compared to the $217 billion in the past-five year period. The single largest impact on growth levels is the continuing effect of many blockbuster drugs coming off patent and an increase in lower-cost generic alternatives. In addition, the gradual return of global growth in gross domestic product (GDP) to more than 4% by 2017 will contribute to an upward trend in drug spending. “As we pass the fifth anniversary of the global economic slowdown and with many countries moving toward universal health coverage, we expect to see continued divergence in growth rates between the pharmerging and developed markets,” said Murray Aitken, executive director of the IMS Institute for Healthcare Informatics, in an IMS press release. “Austerity measures aimed at medicine budgets, along with the growing availability of lower-cost generics, will lead to annual spending growth of 1-4% among the markets of North America, Europe, and Japan. In contrast, pharmerging nations will experience 10-13% spending growth.”
  
  

In 2012, the developed markets in aggregate reduced their medicine spending for the first time due to patent expiries and austerity measures, along with policy changes to increase generic-drug penetration, notes IMS. Growth in developed markets will rebound from negative $3 billion in 2012 to $20 billion to $25 billion by 2017. The US will resume increased spending levels in 2014 after two years of reduction due to expansion of healthcare access and lower patent-expiry levels. Growth in the “pharmerging” markets, as defined by IMS, will increase from $26 billion in 2012 to between $30 billion and $50 billion in 2017, primarily due to increased access to medicines as infrastructure and health systems evolve. The pharmerging countries include China, Tier 2 countries (Brazil, Russia, and India) and Tier 3 countries (Mexico, Turkey, Venezuela, Poland, Argentina, Saudi Arabia, Indonesia, Colombia, Thailand, Ukraine, South Africa, Egypt, Romania, Algeria, Vietnam, Pakistan, and Nigeria) (2).


    The developed markets of North America, Europe, and Japan will see modest single-digit spending growth during the next five years due to a combination of economic and healthcare austerity measures and savings realized from growing lower-cost generic versions. 

In the US, the next five years will see the greatest impact from the implementation of the Affordable Care Act. IMS notes that the uncertainty ranges from the level of enrollment of the currently insured to the speed with which the payment system changes from one based on fee-for-service to one based on performance and patient outcomes. The change in the service-delivery model, including the corporatization of medical care and the relative negotiating power between payers and providers, will impact medicine spending, though the direction and magnitude of that impact is uncertain. For the US pharmaceutical market, IMS estimates a CAGR of 1 to 4% from 2013-2017. The US pharma market will reach between $350 billion and $380 billion by 2017. Patent expiries and the impact of low-cost generics will impact spending growth throughout the forecast period, which had their strongest impact in 2012 and 2013. Less impact from expiries contributes to approximately half of the higher market growth in 2014 relative to 2013.

Pharmaceutical spending growth in the EU 5 (Germany, France, Italy, United Kingdom, and Spain) is expected to be between zero and 3% for the period of 2013 to 2017 compared to 2.4% for 2008-2012. Pharmaceutical spending in the EU 5 is projected to reach between $140 billion and $170 billion in 2017, according to IMS. Europe has seen a greater adoption of generics and more restrictive policies that have made patients in almost all European countries less likely to gain access to innovative medicines, notes the IMS report. The performance of the European pharmaceutical industry during the next five years will depend on the extent of the economic recovery in Europe. Higher growth is anticipated in Germany and the United Kingdom compared to Spain, Italy, and France as these markets already have generically efficient markets. All five major European countries have seen a lower uptake of new medicines in the most recent five-year period. Germany and the UK had strong uptake controls prior to the financial crisis and see the least deterioration. In Japan, forecast spending growth of a 2-5% CAGR is projected from 2013 to 2017, notes IMS. In Japan, the key issue is the establishment of a generic-drug market, driven by the Japanese Ministry of Health, Labor and Wealth’s (MHLW) goal of increasing generic volume as a percentage of generic and listed drugs to 60% in 2018. If the MHLW is successful, it would mean that 2018 generic levels in Japan would be at a level similar to that of France and Spain.  


    For the “pharmerging” markets, IMS projects a CAGR of 10-13% with the market reaching between $370 billion and $400 billion by 2017. For China, the largest pharmerging market, IMS projects a CAGR of 14-17% with the market reaching between $160 billion and $190 billion by 2017. Despite the healthy projections, pharmaceutical industry growth in China was revised downward due to a slowdown in GDP growth, a loss in business confidence, and lower investment. Volume-based growth will be driven by government efforts to improve healthcare and medical services, including expansion of insurance coverage to critical illness and increased use of private hospitals. Efforts to expand the essential drug list and the National Development and Reform Commission’s recent investigation into drug prices and cost could result in a cheaper, off-patent original brand market. Also, a new revision of the National Reimbursement Drug List could result in a more comprehensive list of innovative products receiving reimbursement. 

Growth in Tier 2 countries (Brazil, Russia, and India) will show a CAGR of 10-13% in 2013-2017 and reach between $90 billion and $110 billion by 2017. Growth in India’s pharmaceutical market, the second largest emerging market behind China and the largest pharmaceutical market among the Tier 2 countries, will show a CAGR of 5-8% between 2013 and 2017 with the market reaching between $100 billion and $130 billion by 2017. Growth in Tier 3 pharmerging markets will be between 5% and 8%  through 2017 with the market expected to reach between $100 billion and $130 billion by 2017 (2).


  1.	Chemical Pharmaceutical Association,  

The World Pharmaceutical Contract Research and Manufacturing Services Industry

The Global Use of Medicines: Outlook through 2017

Emerging markets are an engine for growth in the custom-manufacturing and pharma markets.

A Look Ahead for Custom Manufacturing and Pharma

 has agreed to sell its global diabetes business that was part of its collaboration with AstraZeneca for $2.7 billion with potential regulatory- and sales-based milestone payments of up to $1.4 billion and will make royalty payments based on net sales through 2025. In addition, AstraZeneca will make payments of up to $225 million if and when certain assets are subsequently transferred. The Bristol-Myers Squibb's board of directors has approved this transaction.

“This agreement will allow us to further evolve our business model as a leading specialty BioPharma company and increase resources behind the opportunities that drive the greatest long-term value for patients, our company and our shareholders,” said Bristol-Myers Squibb CEO 

Bristol-Myers Squibb and AstraZeneca entered into an alliance agreement in January 2007 to enable the companies to jointly research, develop and commercialize select investigational drugs for Type 2 diabetes. The alliance has since been expanded to collaborate on additional diabetes products. 

Bristol-Myers Squibb will sell its global diabetes business that was part of its collaboration with AstraZeneca, which includes Onglyza (saxagliptin), Kombiglyze XR/Komboglyze (saxagliptin and metformin HCl extended release), dapagliflozin (marketed as Forxiga outside the U.S.), Byetta (exenatide), Bydureon (exenatide extended release for injectable suspension), Symlin (pramlintide acetate) and metreleptin. The agreement also includes the sale of the former Amylin manufacturing facility in West Chester, Ohio, and covers the future purchase by AstraZeneca of Bristol-Myers Squibb’s Mt. Vernon, Indiana, manufacturing facility approximately 18 months following the closing of the transaction. 
As part of the transaction, and subject to local consultation and legislation, Bristol-Myers Squibb and AstraZeneca anticipate that substantially all employees of Bristol-Myers Squibb dedicated to the diabetes business will be transferred to AstraZeneca. A number of R&D and manufacturing employees dedicated to diabetes will remain with Bristol-Myers Squibb to progress the diabetes portfolio and support the transition for these areas. Bristol-Myers Squibb will work closely with AstraZeneca to ensure a smooth transition. 

The company expects to receive $3.4 billion in the first quarter of 2014, which includes $2.7 billion in an upfront payment and an additional $700 million assuming regulatory approvals of dapagliflozin

Bristol-Myers Squibb and AstraZeneca anticipate that the transaction will close during the first quarter of 2014. Closing of the transaction is subject to customary closing and antitrust conditions. The closing of the transaction as it relates to China is also subject to the satisfaction of certain conditions in the Sino-American Shanghai Squibb Pharmaceutical Company joint venture agreement between Bristol-Myers Squibb China and its joint venture partners. 

Bristol-Myers Squibb agrees to sell global diabetes business to AstraZeneca for $2.7 billion upfront plus an addition $1.4 billion in potential regulatory- and sales-based milestone payments.

Bristol-Myers Squibb To Sell Diabetes Business to AstraZeneca

 issued a statement regarding the launch of esomeprazole strontium in the United States by Seoul, South Korea-based 

and its US marketing partner Amneal Pharmaceuticals.
 
 Amneal Pharmaceuticals reported that the first shipping of esomeprazole strontium was made to three major US pharmaceutical wholesalers on Dec. 18, 2013. Esomeprazole strontium contains the same active moiety (esomeprazole) in a different salt form as found in AstraZeneca's branded proton-pump inhibitor Nexium (esomeprazole magnesium) and is used to treat adult patients for the short term treatment of gastroesophageal reflux disease (GERD). Hanmi Pharmaceutical received FDA approval for esomeprazole strontium delayed-release capsules for oral use in August 2013.  AstraZeneca's Nexium had 2012 sales of $3.9 billion.  

In a press statement, AstraZeneca said that it "is aware of reports that an 505(b)(2) NDA esomeprazole strontium product has been launched in the US by Hanmi Pharmaceutical and affiliates (Hanmi) and its US marketing partner Amneal Pharmaceuticals (Amneal). 
  
  AstraZeneca said that on Sept. 30, 2013, the US Court of Appeals for the Federal Circuit  (CAFC) lifted a temporary injunction against Hanmi’s US launch of its 505(b)(2) NDA esomeprazole strontium product (previously granted on Sept. 13,  2013). AstraZeneca’s appeal of the lower court’s December 2012 claim construction remains pending. After oral argument on Nov. 18, 2013, a decision is expected from the CAFC in early 2014. 
  
  "Depending on the outcome of the appeal, Hanmi's sales are at risk of owing AstraZeneca patent-infringement damages," said AstraZeneca in its statement. "AstraZeneca’s appeal concerns both patents-at-issue in the patent-infringement litigation against Hanmi (US Patent Nos. 5,714,504 and 5,877,192).  AstraZeneca understands that Hanmi’s 505(b)(2) NDA esomeprazole strontium product is not AB-rated and is not automatically substitutable for Nexium."
  
AstraZeneca said that the developments have no impact on AstraZeneca’s full-year 2013 financial guidance. 

AstraZeneca issues a statement regarding the launch of esomeprazole strontium in the United States.

AstraZeneca Issues Statement on Competitor to Nexium

and Samsung Bioepis, a joint venture between Samsung Biologics and Biogen Idec, has exercised its right to enter into an agreement to commercialize anti-TNF biosimilar product candidates in Europe, including biosimilars for widely used therapies to treat conditions such as rheumatoid arthritis and Crohn’s disease. Under the agreement, Biogen Idec will be responsible for commercialization of these product candidates across Europe, where there already exists a strong market for biosimilars and a defined regulatory pathway. The agreement with Samsung Bioepis aligns with Biogen Idec’s broader corporate objectives of remaining focused on its core business while applying expertise in manufacturing and specialty markets to meet the need for biosimilar therapies. 
  
  In February 2013, Samsung Bioepis and Merck & Co (known as MDS outside the United States) formed an agreement to develop and commercialize multiple prespecified and undisclosed biosimilar candidates. Under that agreement, Samsung Bioepis is responsible for preclinical and clinical development, process development and manufacturing, clinical trials and registration. Merck will be responsible for commercialization. Samsung Bioepis will receive an upfront payment from Merck, product supply income, and will be eligible for additional payments associated with prespecified clinical and regulatory milestones. Further financial terms were not disclosed.  

Biogen and Samsung Bioepis, a joint venture between Samsung Biologics and Biogen Idec, advance plans for anti-TNF biosimilar product candidates.

Biogen Idec, Samsung Bioepis Target Anti-TNF Biosimilars in Europe

 USA Inc., relating to Pfizer’s patent covering the use of Pfizer's Viagra (sildenafil citrate) to treat erectile dysfunction in 25-, 50-, and 100-mg tablets. The patent expires in April 2020, including pediatric exclusivity.  As a result of the settlement, Teva will be allowed to launch a generic version of Viagra under a royalty-bearing license on Dec. 11, 2017, in the United States on December 11, 2017, or earlier under certain circumstances. Teva will pay Pfizer a royalty for a license to produce its generic version.  The terms of the settlement agreement are otherwise confidential.  Teva has received tentative approval from FDA for its generic version of Viagra.  

Pfizer settles its litigation against Teva Pharmaceuticals regarding Pfizer's patent covering the use of Viagra.