Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

(GSK) will invest £200 million ($327 million) to expand its manufacturing facilities in Ware, Hertfordshire and Worthing, Sussex in the United Kingdom and establish a new manufacturing innovation facility. The investment is in addition to a £500 million ($818 million) investment that GSK made in March 2012, which included a commitment to build a new factory in Ulverston, Cumbria in the UK.

GSK will invest in new manufacturing facilities in Ware for its Relvar (zanamivir) Ellipta used for respiratory disease. The Ellipta device was developed at Ware and will now be produced at the site before being exported worldwide. GSK’s manufacturing site at Ware employs 800 staff, of whom more than 500 make respiratory products. The site exports more than 35 million packs of respiratory products to 120 countries as well as shipping more than 400 million tablets a year.

In Worthing, GSK will build a new bulk sterile building and filling line for its antibiotic Augmentin (amoxicillin and clavulanate), which is exported to 150 countries. GSK’s Worthing site has more than 950 employees making both active ingredients and finished medicines that are supplied to 157 markets worldwide. In the last full year, the site supplied more than 100 million packs of medicines and more than 1000 metric tons of bulk products. 

GSK will also build a new center for manufacturing innovation dedicated to transforming emerging science and technologies, such as nanotechnology and biocatalysis, into practical manufacturing applications. Although subject to further decisions, GSK’s preferred site for the location of the new center is Ware, Hertfordshire, where the company already has manufacturing and R&D facilities in one location.

Roger Connor, GSK’s president of global manufacturing and supply, says the new investments in the UK were encouraged by the UK's Patent Box, a corporate tax incentive based on investment in patents. The Patent Box scheme came into force in April 2013. The scheme allows companies to apply a lower rate of corporation tax to profits earned from its patents after this date (as well as profits arising from supplementary protection certificates, regulatory data protection and plant variety rights). The relief is phased in over a four-year period from April 2013. Once the full benefit of the regime is in effect, the lower rate of corporation tax to be applied to these profits will be 10%. This 10% rate will apply from April 2017, according to the UK Intellectual Property Office. 

Articles

GlaxoSmithKline plans to expand its facilities in Ware and Worthing in the United Kingdom and will build a new facility for manufacturing innovation.

GlaxoSmithKline To Invest in UK-Based Manufacturing

 released a financial outlook for 2014 based on two possible scenarios concerning Copaxone (glatiramer acetate). One scenario outlines the financial implications for generic-drug competition in the US on June 1, 2014, and the second scenario assumes no generic-drug competition for Copaxone in the US during 2014. 

Teva’s non-GAAP financial outlook projects net revenues of $19.3 billion to $20.3 billion with a generic launch of Copaxone in the US on June 1, 2014, and net revenues of $19.8 billion to $20.8 billion if Copaxone remains exclusive in the US. Both scenarios assume the launch of Copaxone 40-mg three-times-a-week in early 2014 and exclusive sales of the generic version of Pulmicort (budesonide) in the US throughout 2014. The outlook is based on organic growth and does not include the potential impact of any business development activities. Teva estimates that each month of delay in the launch of generic competitors to Copaxone in the US will contribute on average of approximately $78 million to net revenues 

“2014 will be a pivotal year for Teva and a year of major transitions across the company", said Eyal Desheh, acting president and CEO of Teva, in a Dec. 10, 2013 company press release. "We will continue to make significant progress in implementing our strategy. We will focus our efforts on our generics business and core R&D programs, including high-value complex generics, promising specialty medicines and new therapeutic entities. In our specialty business, we anticipate six important launches and the potential submission of ten additional medicines for approval. At the same time, we are focused on increasing our organizational effectiveness through our cost reduction program to ensure Teva’s leadership position, growth and sustainable profitability.”

In other news, Teva announced that the vice-chairman of its board of directors, Professor Moshe Many, will leave his position as vice-chairman, effective Jan. 1, 2014, for personal reasons. Professor Many will remain a member of Teva's Board. Following Professor Many's announcement, Teva's board of directors announced that Amir Elstein has been appointed to the position of vice-chairman, effective January 1, 2014, and will serve in this position until the 2014 annual meeting of shareholders.

Teva Pharmaceutical Industries releases a financial outlook for 2014 based on two possible scenarios concerning its multiple-sclerosis drug Copaxone (glatiramer acetate).

Teva Releases Financial Guidance Dependent on Copaxone Generic Competition

Looking at the first 11 months of 2013, mergers and acquisitions (M&A) in the pharmaceutical/biopharmaceutical industry have increased on both a value and volume basis compared to the same period last year. Although there were no megamergers in the industry, there were several noteworthy deals. 

Thus far in 2013, there have been several noteworthy transactions. Amgen’s $10.4-billion acquisition of the biopharmaceutical company Onyx Pharmaceuticals, is one of the largest therapeutics transactions of the year. In August 2013, seeking to build its oncology drug portfolio, Amgen agreed to acquire the biopharmaceutical Onyx Pharmaceuticals for $10.4 billion ($9.7 billion net of estimated Onxy cash) and closed on the deal in October 2013. Onyx Pharmaceuticals has a growing multiple myeloma franchise, which includes Kyprolis (carfilzomib) for injection already approved in the United States. Onyx holds global rights to Kyprolis, excluding Japan. Kyprolis has orphan-drug designation in the United States with exclusivity until July 2019, and patents in the US that extend until at least 2025. In addition, Onyx has three partnered oncology assets: Nexavar (sorafenib) tablets (an Onyx and Bayer HealthCare Pharmaceuticals compound), an oral kinase inhibitor, approved in the US for unresectable hepatocellular carcinoma and advanced renal cell carcinoma; Stivarga (regorafenib) tablets (a Bayer compound), an oral kinase inhibitor, approved in the US for for metastatic colorectal cancer; and palbociclib (a Pfizer compound), an oral, small-molecule cyclin-dependent kinase 4/6 inhibitor, now in Phase III trials, to treat ER+, HER2-negative advanced breast cancer. Amgen says that the acquisition of Onyx will add to Amgen's late-stage pipeline. This pipeline includes nine innovative products for which registration-enabling data are anticipated by 2016. Four of these products are oncology products. Onyx's pipeline complements Amgen's oncology portfolio, according to Amgen.

Also, in August 2013, Amgen closed on its deal with the French pharmaceutical company Servier under which Amgen has obtained commercial rights in the US to Servier's oral drug, approved in the European Union as Procoralan (ivabradine), for chronic heart failure and stable angina in patients with elevated heart rates. Amgen also received an exclusive option to develop and commercialize Servier's investigational molecule, S38844, for cardiovascular diseases in the US. Currently, S38844 is in Phase II studies for the treatment of heart failure. Through the collaboration, Servier obtained an exclusive option to commercialize omecamtiv mecarbil in Europe. Omecamtiv mecarbil is an activator of cardiac myosin, which is currently being tested for potential applications in the treatment of heart failure in patients with systolic dysfunction.

Thus far, AstraZeneca has been active on the M&A front. In August 2013, MedImmune, the company’s biologics arm, agreed to acquire the biopharmaceutical company Amplimmune for $500 million with $225 million upfront and the rest contingent on the achievement of specified milestones. It closed on the deal in October 2013. Amplimmune is a Maryland-based developer of cancer immunotherapeutics.

The acquisitions strengthen MedImmune’s oncology pipeline by obtaining multiple early-stage assets for its immune-mediated cancer therapy (IMT-C) portfolio, including AMP-514, an antiprogrammed cell death 1 monoclonal antibody (mAb). AMP-514 is in late-stage preclinical development, and Amplimmune expects to file an investigational new drug filing before the end of 2013. Other Amplimmune assets include multiple preclinical molecules targeting the B7 pathways.

Founded in 2007 and headquartered in Gaithersburg, Marlyand, Amplimmune is focused on developing costimulatory/co-inhibitory molecules that rebalance the immune system and are intended for treating cancer, autoimmune disease, infectious disease, and transplantation. Amplimmune has three biologic product candidates: AMP-224 is in Phase Ib trials in cancer; AMP-110 for autoimmune diseases in partnership with Daiichi Sankyo; and AMP-514 for cancer. The acquisition builds on MedImmune's oncology R&D activities. MedImmune’s oncology research is focused on IMT-C, a therapeutic approach that may lead to durable and prolonged response rates across a range of cancer types. IMT-Cs are being designed for the immune system to counteract the tactics employed by cancer cells to avoid detection and attack the body. MedImmune's clinical-stage program includes tremelimumab, an anti-OX40 mAb, and MEDI-4736, an anti-PD-L1 mAb. The acquisition of the Amplimmune technology and pipeline strengthens AstraZeneca's and MedImmune portfolio to enable the use of data-driven combinations of IMT-C molecules as well as combinations with highly targeted small molecules.

In another deal, in June 2013, AstraZeneca completed its $1.2-billion acquisition of Pearl Therapeutics, which is focused on the development of inhaled small-molecule therapeutics for respiratory disease. The acquisition gives AstraZeneca access to a potential new treatment for chronic obstructive pulmonary disease currently in late-stage development and inhaler and formulation technology that provides a platform for future combination products. The $1.2-billion deal included $560 million in upfront payments, $450 million in deferred compensation contingent on reaching certain development and regulatory milestones, and $140 million in sales payments, contingent on reaching sales thresholds. 

In May 2013, AstraZeneca agreed to acquire Omthera Pharmaceuticals, a specialty pharmaceutical company based in Princeton, New Jersey, focused on the development and commercialization of new therapies for abnormal levels of lipids in the blood for $323 million ($260 million in cash and $63 million for Omthera’s cash balance). Omthera’s investigational product, Epanova, being developed for the treatment of patients with very high triglycerides, is a omega-3 free fatty acid composition that has been shown to bolster levels of eicosapentaenoic acid and docosahexaenoic acid in the blood. In addition to the cash payment, each Omthera shareholder will receive contingent value rights of up to approximately $4.70 per share, equating to approximately $120 million in total, if specified milestones related to Epanova are achieved, or if a milestone related to global net sales is achieved. This will bring the total potential acquisition cost to approximately $443 million. The transaction is expected to close in the third quarter of 2013. Also in April 2013, MedImmune, the biologics arm of AstraZeneca, acquired AlphaCore Pharma, an Ann Arbor, Michigan-based biotechnology company focused on the development of ACP-501, a recombinant human lecithin-cholesterol acyltransferase (LCAT) enzyme.

In a move to bolster its oncology portfolio, Johnson & Johnson completed its $1-billion acquisition of Aragon Pharmaceuticals, a privately held pharmaceutical discovery and development company focused on drugs to treat hormonally driven cancers. The acquisition includes Aragon’s androgen receptor antagonist program. Aragon’s lead product candidate is a second-generation androgen receptor signaling inhibitor, ARN-509, in Phase III development for castration-resistant prostate cancer (CRPC). Under the terms of the agreement, Johnson & Johnson is making an upfront cash payment of $650 million, plus additional contingent payments of up to $350 million based on reaching predetermined milestones.

In May 2013, GlaxoSmithKline acquired Okairos, a Swiss privately held developer of vaccine platform technologies for EUR 250 million ($325 million) in cash. GSK plans to use the vaccine platform in its of new prophylactic vaccines (designed to prevent infection) as well as new classes of therapeutic vaccines (designed to treat infection or disease). The deal also includes a small number of early-stage assets.

Other deals include: Perrigo's proposed $8.6-billion acquisition of Elan; Shire's proposed $4.2-billion acquisition of Viro Pharma, a company specializing in treatments for rare diseases; Valeant's $8.7-billion acquisition of Bausch + Lomb; and Actavis' $8.5-billion acquisition of Warner Chillcott. 

Among contract service providers, two key moves were the merger of Cambridge Major Laboratories and AAIPharma Services and the proposed merger of Patheon with DSM Pharmaceutical Products. 

Pharmaceutical Technology takes a look at the major deals and moves of 2013.

Pharma's Year in Review

Global spending on medicines is expected to meet the $1 trillion threshold in 2014 and reach $1.17 trillion by 2017, according to a recent report by the IMS Institute for Healthcare Informatics. The report, 

The Global Use of Medicines: Outlook through 2017,

 found that 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) over the next five years. 

IMS projects a gradual increase in global medicine spending growth during the next five years. Annual growth in spending 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 years. 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 medicine spending levels. 

“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, according to 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, notes IMS. 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).

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 the growing availability of lower cost generic versions of brands following their patent expiry.

In the US, the next five years will see the greatest impact from the implementation of the Affordable Care Act, notes IMS. 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, notes the IMS report. For the US pharmaceutical market, IMS estimates a compound annual growth rate (CAGR) of 1 to 4% from 2013–2017. The US pharmaceutical market is projected to 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 EU5 (Germany, France, Italy, United Kingdom, and Spain) is expected to between zero and 3% for the period of 2013 to 2017 compared to 2.4% for 2008–2012, notes the IMS report. Pharmaceutical spending in the EU 5 is projected to reach $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 that the market will increase at a CAGR of 10–13% and reach between $370 billion and $400 billion by 2017. For China, the largest pharmerging market,  IMS projects a CAGR of 14–17% in the next five years 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 due to a loss in business confidence, along with lower investment, in the market, notes IMS, which points to several key issues. 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 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, notes IMS. 

 Growth in Tier 2 countries (Brazil, Russia, and India) will show a CAGR of 10-13% for the period of 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 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, according to IMS. Growth in the Tier 3 pharmerging markets (Mexico, Turkey, Venezuela, Poland, Argentina, Saudi Arabia, Indonesia, Colombia, Thailand, Ukraine, South Africa, Egypt, Romania, Algeria, Vietnam, Pakistan, and Nigeria) will be between 5% and 8% during the next five years with the market expected to reach between $100 billion and $130 billion by 2017. 

Global spending on medicines is expected to meet the $1 trillion threshold in 2014 and reach $1.17 trillion by 2017, according to a recent report by the IMS Institute for Healthcare Informatics

The Global Divide in Pharma Industry Growth

Organic chemists are tasked with optimizing synthetic routes for pharmaceutical compounds. Catalysts, both chemical catalysts and biocatalysts, play a crucial role in improving reaction efficiencies and conditions, increasing yield, and achieving desired stereoselectivity. Fine-chemical companies, contract manufacturers, and other researchers are advancing this field for producing pharmaceutical intermediates and APIs. 


  Codexis, a company specializing in biocatalysis, recently reported on its development of industrial  biocatalysts for sulfide oxidation and Baeyer-Villiger-type monooxygenations (BVMO). These BVMO enzymes can be used to improve methods to manufacture chiral sulfoxides, which are important molecules for pharmaceutical synthesis. Codexis used these enzymes to develop biocatalytic processes for producing esomeprazole and armodafinil to improve enantiometric purity and reduce sulfone impurity, according to an Oct. 3, 2013 Codexis press release. The enzyme and API manufacturing processes are currently being scaled up for commercial supply. Codexis’ BVMO enzymes are commercially available as a screening kit that process chemists can use to develop new biocatalytic oxidation processes. 
  
Earlier this year, Codexis partnered with Purolite, a provider of ion-exchange, catalyst, adsorbent, and specialty resins, to develop and market immobilized enzymes for the pharmaceutical industry. The enzymes are immobilized through binding to inert resins to allow for easier separation from a reaction mixture, and immobilization allows the enzymes to be used under different reactions conditions and re-used at a commercial scale. The collaboration is focused on immobilized transaminase enzymes. 

Codexis also partnered earlier this year with the CMO AMRI in a nonexclusive, two-year agreement focused on identifying and implementing new and improved manufacturing routes for select APIs. Codexis is providing its directed evolution technology for enzyme discovery and optimization, and AMRI is providing process development and manufacturing capabilities, including using AMRI’s proprietary microbial strains.

Johnson Matthey Catalysis and Chiral Technologies (JMCCT) business unit, which provides heterogeneous, homogeneous, chiral, and biocatalytic technologies, is expanding its existing specialty ligand-manufacturing capability to include commercial-scale manufacturing up to 100 kilograms. The expansion is largely focused on the Buchwald ligands from the Massachusetts Institute of Technology. The Buchwald ligands offered by JMCCT are a class of dialkylbiaryl monophosphine ligands, which are used for the

 generation of active catalysts for coupling reactions in the manufacture of pharmaceuticals and specialty chemicals. The XPhos and SPhos ligands are used for Suzuki-Miyaura reactions, in particular with hindered aryl substrates and heteroaryl halides. In addition, the combination of Buchwald ligands, such as XPhos, SPhos, RuPhos, and BrettPhos with several palladium catalyst precursors, such as Pd(OAc)

 generation of active catalysts. These catalysts can be applied in carbon-carbon, carbon-nitrogen, carbon-oxygen, carbon-sulfur, and carbon-born bond formations, including the Suzuki-Miyaura, Negishi, Sonogashira, Buchwald-Hartwig amination and carbonyl alpha-arylation reactions.

The biocatalysis company evocatal is relocating to Monheim, Germany, to a facility that doubles the company’s laboratory and production area to add additional capacity for research, process development, and production. The expansion adds new industrial fermenters to optimize the manufacture of biocatalysts up to the 100-L pilot scale. In addition, the new location will house multipurpose equipment for the synthesis of fine chemicals up to the kilogram scale. 

Almac recently reported on its collaboration agreement with DSM Pharmaceutical Products in biocatalysis, which includes the successful transfer of enzymes for enzyme screening, process development, and scale-up manufacture. The agreement grants both companies access to their enzyme platform technologies, services, and expertise for API manufacturing. Almac is bringing expertise in enzyme identification, scale-up, and implementation into early-phase projects, and DSM is providing commercial-manufacturing expertise, which gives Almac a preferred partner for large-scale production. Since forming their agreement in 2012, Almac and DSM have initiated and completed multiple projects in the fields of ketoreductases, transaminases, bio-oxidations, and hydrolases. Almac also recently completed a knowledge transfer partnership with Queens University Belfast to develop, improve, and embed bioprocesses.


Researchers at Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr, Germany recently reported on their work in immobilizing various catalysts on nylon and applying them in pharmaceutical synthesis among other reactions. Working in collaboration with scientists from the Deutsches Textilforschungszentrum in Krefeld, Germany and Sungkyunkwan University in Suwon, Korea, the researchers at the Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr developed a process for immobilizing different organic catalysts on textiles with the help of ultraviolet light. The fabric acts as a support for the substances on which a chemical reaction occurs.

The researchers used three organic catalysts: a base (dimethylaminopyridine, DMAP), a sulfonic acid, and a catalyst that functions as both an acid and a base, according to a Sept. 13, 2013 Max-Planck-Institut für Kohlenforschung press release.  To attach the catalysts to the nylon fibers, the chemists irradiated the textile to which a catalyst was applied with ultraviolet light for five minutes. All three catalysts converted approximately 90% of the source materials to the desired products. 

Compared with other ways of immobilizing catalysts, organotextile catalysis has several advantages. In particular, it provides the reagents with a larger surface than other supports, such as plastic spheres or foils, with the larger surface enabling a more efficient reaction. Moreover, the nylon is flexible and inexpensive. In the approach for  immobilization of organocatalysts on the textile nylon using ultraviolet light, the catalyst and the textile material require no chemical modification for the immobilization (1). All of the prepared textile-immobilized organocatalysts (a Lewis basic, a Brønsted acidic, and a chiral organocatalyst) showed “excellent” stability, activity, and recyclability for various organic transformations, according to the researchers (1). They reported good enantioselectivity (> 95:5 enantiomeric ratio) that was maintained for more than 250 cycles of asymmetric catalysis. The researchers asserted that textile organocatalysis may be beneficial for various fields by offering inexpensive and accessible functionalized catalytic materials (1).

In another development, researchers at Boston College in Massachusetts reported on the enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts. The researchers noted that catalytic enantioselective monosilylations of diols and polyols provide alcohol-containing molecules in high enantiomeric purity, but that these transformations require high catalyst loadings (20-30 mol%) and long reaction times (2-5 days) (2). To resolve those challenges, the researchers used an achiral cocatalyst structurally similar to a chiral catalyst. A combination of Lewis basic molecules served as an achiral nucleophilic promoter and the other molecule performed as a chiral stereoselectivity base. On the addition of 7.5-20 mol% of a commercially available N-heterocycle (5-ethylthiotetrazole), reactions typically proceeded within one hour, with high product yields and enantiomeric ratios (2). In certain examples, there were no reaction in the absence of the achiral base, but the presence of the achiral cocatalyst facilitated product formation in high enantiomeric purity (2). Overall, the new approach reduced the reaction time to less than an hour, down from a period of two to five days, reduced catalyst loading, and produced a more efficient transformation for enantioselective alcohol silylation, according to a July 2013 Boston College press release. 

“The use of cocatalysts can be tricky, especially in procedures intended to deliver handedness in the molecules you want your reaction to produce,” said Amir Hoveyda, the Joseph T. and Patricia Vanderslice Millennium Professor of Chemistry at Boston College, in the Boston College press release. “What we’ve shown is that in this procedure, you can take two cocatalysts, which on the surface are competing with one another, and effectively keep them from interfering with one another.”

Hoveyda and Boston College Professor of Chemistry Marc Snapper have worked since 2006 on this method of catalysis. These catalysts, originally developed in their laboratories seven years ago, are valued for producing reactions that offer a high level of enantioselective purity. The relatively slow reaction time of two to five days was a key problem, but which was mitigated by applying a computational approach. The researchers used the cocatalyst model involving two Lewis base molecules, adding an achiral molecule to an already present chiral molecule. These cocatalysts operated in concert, with the chiral molecule activating alcohol and the additional achiral molecule (from commercially available 5-ethylthiotetrazole) activating silicon. Identification of the positive influence of ethylthiotetrazole proved to be the key component of the discovery, giving the team the ability to fine-tune the reaction and effectively control the interplay between the cocatalysts. Together, the Lewis bases served as a closely related Brønsted base to allow the catalyst to work faster while retaining high enantioselectivity.


  1.	Ji-Woong Lee, Science 341 (6151) 1225-1229 (2013). 
  2.	A. Hoveyda,

Fine-chemical companies, contract manufacturers, and researchers advance chemocatalysis and biocatalysis.

Applying Catalysis to Optimize API Synthesis

As 2013 nears a close, how has the pharmaceutical industry fared in new drug approvals? Through Nov. 14, 2013, the Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) had approved 24 new molecular entities (NMEs) and biologics license application (BLAs) (1). Although the end-of-the-year activity of FDA typically results in additional approvals, it is unlikely that the industry will match in 2013 the 39 NMEs and BLAs approved by FDA in 2012, which was a recent high. This year’s crop of NMEs and BLAs, however, show several interesting developments: the approval of two new breakthrough therapies, a new designation by FDA to accelerate approval for drugs with high unmet medical need; three drug approvals with companion diagnostics; and an approval of an antibody drug conjugate (ADC). 
  
  


  On a company basis, thus far in 2013, the winners in the race for NMEs and BLA approvals by FDA’s CDER are Bayer Healthcare, GlaxoSmithKline (GSK), Johnson & Johnson, Roche and Takeda, each with two or more new drug approvals (see 

). GSK led the pack with three NME approvals: Breo Ellipta (fluticasone furoate and vilanterol trifenatate), Mekinist (trametinib dimethyl sulfoxide), and Tafinlar (dabrafenib mesylate). Breo Ellipta is a combination of fluticasone furoate, an inhaled corticosteroid, and vilanterol, a long-acting beta

-adrenergic agonist, used to treat airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease. GSK also received FDA approval for two drugs to treat metastatic melanoma: Mekinist, a kinase inhibitor for treating unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test, and Tafinlar, also a kinase inhibitor indicated for treating unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. In 2010, GSK formed a collaboration with the molecular diagnostics company bioMerieux to develop a companion diagnostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma. bioMerieux received FDA premarket approval of its companion diagnostic, THxID-BRAF, in May 2013.  
  


 Approvals of new   molecular entities (NMEs) and biologic license applications (BLAs) in 2013 by   FDA’s Center for Drug Evaluation and Research.*

Mekinist (trametinib   dimethyl sulfoxide); NME

Breo Ellipta (fluticasone furoate; vilanterol   trifenatate); NME

Lymphoseek Kit (technetium Tc-99m tilmanocept); NME

Duavee (bazedoxifene acetate; estrogens, conjugated); new   combination

Kadcyla   (ado-trastuzumab emtansine); BLA

Brintellix   (vortioxetine hydrobromide); NME

* Source: FDA’s Center for Drug Evaluation. FDA approvals   as of Nov. 14, 2013 (Reference 1). 
      • Bayer Healthcare formed an agreement in September 2009   with Algeta ASA (Oslo, Norway) for the development and commercialization of   Xofigo.  
      • Janssen Biotech and Janssen Pharmaceuticals are part of   Johnson & Johnson. Janssen Biotech and Pharmacyclics are partnered for   Imbruvica. Janssen Pharmaceuticals has rights to Invokana through a license   agreement with Mitsubishi Tanabe Pharma. 
      • Roche Glycart AG, a wholly owned, independent research   unit of Roche, discovered Gazyva. In the US, Gazyva is part of a   collaboration between Genentech and Biogen Idec.
      • Roche licenses technology for Kadcyla under an agreement   with ImmunoGen.
      • Sanofi’s subsidiary, Genzyme, partnered with ISIS   Pharmaceuticals and Genzyme for the development of Kynamro. 
      • Sunovion Pharmaceuticals is an indirect, wholly owned US   subsidiary of Dainippon Sumitomo Pharma.
      • Takeda Pharmaceutical and H. Lundbeck A/S formed a   strategic alliance for Brintellix in September 2007 under a broader alliance   for several compounds in Lundbeck’s pipeline for the treatment of mood and   anxiety disorders. The companies plan to copromote Brintellix in the US.
      • Valeant Pharmaceuticals acquired Medicis Pharmaceutical   in 2012. Luzu (luliconazole) has been approved in Japan since 2005.  
      • ViiV Healthcare is an independent pharmaceutical company   focused on HIV established in 2009 by GlaxoSmithKline and Pfizer. Shionogi   joined as a 10% shareholder in 2012. 

Through its bio/pharmaceutical units, Janssen Biotech and Janssen Pharmaceuticals, Johnson & Johnson had two NMEs approved in 2013. Janssen Biotech partnered with the biopharmaceutical company Pharmacyclics for Imbruvica (ibrutinib), a kinase inhibitor for treating mantle-cell lymphoma (MCL), a rare type of blood cancer. Imbruvica is the second drug with breakthrough-therapy designation to receive FDA approval; Roche’s Gazyva (obinutuzumab), a drug to treat chronic lymphocytic leukemia (CLL), also approved in 2013, was the first. The Food and Drug Administration Safety and Innovation Act, passed in July 2012, gave FDA the ability to designate a drug as a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicated the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. In addition to Imbruvica, there are two other FDA-approved drugs to treat MCL: Velcade (bortezomib) by Millennium Pharmaceuticals, the oncology company of Takeda Pharmaceuticals, and Celgene’s Revlimid (lenalidomide) (2). 

J&J’s second NME approval was for Invokana (canagliflozin), a sodium-glucose cotransporter 2 (SGLT2) inhibitor for treating Type 2 diabetes. Invokana is the first drug in a new class of SGLT2 inhibitors to be approved in the United States. Forxiga (dapagliflozin), developed by Bristol-Myers Squibb and AstraZeneca and also a SGLT2 inhibitor, was approved by the European Medicines Agency in November 2012. The companies submitted a new drug application for Foriziga to FDA in July 2013.  

Roche had two new BLAs approved by FDA thus far in 2013: Gazyva (obinutuzumab) and Kadcyla (ado-trastuzumab emtansine). Gazyva is a humanized anti-CD20 monoclonal antibody (mAb) of the IgG1 subclass for treating CLL. It is produced by mammalian cell (Chinese hamster ovary [CHO]) suspension culture (3). Kadcyla is a HER2-targeted ADC, which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex. Trastuzumab is a well-characterized recombinant mAb produced by mammalian CHO cells, and the small-molecule components (DM1 and MCC) are produced by chemical synthesis (4). Kadcyla is the first Roche ADC approved by FDA. 

Takeda scored with two NME approvals thus far in 2013: Brintellix (vortioxetine hydrobromide) and Nesina (alogliptin benzoate). Brintellix, for treating major depressive disorder, was developed with H. Lundbeck. Nesina is a dipeptidyl peptidase-4 inhibitor designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) for treating Type 2 diabetes. 

Bayer had two NMEs approved  by FDA thus far in 2013: Adempas (riociguat) and Xofigo (radium RA-223 dichloride). Adempas is a soluble guanylate cyclase stimulator to treat two forms of pulmonary hypertension. Xofigo is an alpha particle-emitting radioactive therapeutic agent for treating castration-resistant prostate cancer, symptomatic bone metastases, and no-known visceral metastatic disease. In 2009, Bayer partnered with Algeta for the development and commercialization of Xofigo.


Other large companies earned FDA approvals in 2013. Biogen Idec received FDA approval for its oral multiple-sclerosis drug Tecfidera (dimethyl fumarate). Boehringer Ingelheim received FDA approval for Gilotrif (afatinib dimaleate), a kinase inhibitor for treating metastatic nonsmall-cell lung cancer with common epidermal growth factor receptor mutations as detected by an FDA-approved test. Sanofi received approval for Kynamro (mipomersen sodium), a synthetic phosphorothioate oligonucleotide sodium salt (20 nucleotides in length) to treat homozygous familial hypercholesterolemia, a rare type of high cholesterol (5). 

ViiV Healthcare, an independent joint pharmaceutical company focused on HIV treatments formed by Pfizer, GSK, and Shionogi, received approval for Tivicay (dolutegravir sodium), an integrase inhibitor indicated for use in combination with other antiretroviral agents for treating HIV-1 in adults and children aged 12 years and older weighing at least 40 kg. Tivicay is the first new treatment delivered by

ViiV Healthcare, which was established in November 2009 by GSK and Pfizer. Shionogi joined as a 10% shareholder in October 2012. Shionogi also received approval for Osphena (ospemifene) for treating moderate to severe dyspareunia. Pfizer received approval of a its combination therapy, Duavee (conjugated estrogens/bazedoxifene), for treating vasomotor symptoms associated with menopause and preventing postmenopausal osteoporosis.


  1.	FDA, “New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products of 2013” 

www.fda.gov/drugs/developmentapprovalprocess/druginnovation/default.htm

, accessed 19 Nov. 2013. 
  2.	FDA, “FDA Approves Imbruvica for Rare Blood Cancer,” Press Release, 13 Nov. 2013.
  3.	FDA, “Label for Gazyva,” 

www.accessdata.fda.gov/drugsatfda_docs/label/2013/125486s000lbl.pdf

, accessed 15 Nov. 2013.  
  4.	FDA, “Label for Kadcyla,” 

www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf

, accessed 15 Nov. 2013. 
  5.	FDA, “Label for Kynamro,” 

www.accessdata.fda.gov/drugsatfda_docs/label/2013/203568s000lbl.pdf

A review of this year's crop of the new molecular entities and new biologics license applications approved by FDA thus far in 2013.