Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

AET BioTech and BioXpress Therapeutics have entered into an agreement to codevelop a biosimilar version of Abbott’s tumor necrosis factor inhibitor monoclonal antibody (mAb) adalimumab, currently marketed under the trade name Humira. Both companies will be actively involved in the development, registration, and manufacture of the biosimilar, which will utilize BioXpress Therapeutics’ technology.

AET BioTech’s managing director Harm Peters believes that "the cooperation with BioXpress on the initial project is a key step in AET BioTech's mission to bring European quality biosimilar drugs to markets worldwide at fair prices." In a 

, Peters, said, "The BioXpress team has an impressive track record in the development of the initial originator mAbs, and access to the state of the art of mAb know-how and technology, and the partnership will unite our technical and commercial strengths behind the adalimumab biosimilar."

Under the terms of the agreement, AET BioTech will provide further investment for the long-term financing of this project and be responsible for any future commercialization of the biosimilar. The development strategy agreed on between the two partners also includes regulatory requirements for worldwide marketing of the biosimilar.

"The AET BioTech BioXpress agreement is an important step in moving one of our biosimilar projects to the market. AET is well known for quality drug development, executing complex development and registration strategies and successful commercialization worldwide, and this is particularly important when developing biosimilars," Cori Gorman, CEO and chair of BioXpress Therapeutics said in a 

. "AET BioTech's commercial contacts, biosimilar development, and registration experience and committed financial investment, and our mAb development expertise will help establish our companies as leaders in the biosimilar space."

The adalimumab biosimilar will be developed following the standard guidelines outlined in the European Medicines Agency’s "Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies," which is recognized by biosimilar legislation in countries worldwide. Non-EU requirements will also be taken to account during the early stage planning. Comprehensive analytical testing and clinical comparison studies will be conducted to establish the similarity between the biosimilar and the innovator biopharmaceutical product.

Global sales of adalimumab exceeded $7.9 billion in 2011. The product is marketed for the treatment of inflammatory diseases such rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis.

Articles

AET BioTech and BioXpress Therapeutics have entered into an agreement to codevelop a biosimilar version of Abbott's tumor necrosis factor inhibitor monoclonal antibody adalimumab.

AET BioTech and BioXpress Therapeutics to Codevelop Adalimumab Biosimilar

	As third quarter results were being released last week, we hear of several top drugmakers facing hard knocks from the fall off the patent cliff. Pharmaceutical news have been populated with headlines such as the following: Sanofi drops as major patent expiries take hold, Bristol-Myers results fall short as Plavix sales evaporate, AstraZeneca continues to see revenue decline, and Lilly revenues down as generics erode Zyprexa sales.

	French drugmaker, Sanofi, suffered net sales loss of EUR448 million (~US$578 million) as a result of generic competition, particularly with the loss of patent rights to its colorectal cancer drug, Eloxatin (oxaliplatin) in the United States this August. Sanofi’s share of revenues from its Bristol-Myers Squibb-partnered megablockbuster blood thinner, Plavix (clopidogrel), fell 10% to EUR505 million (~US$651 million), while global sales of its antihypertensive, Avapro (irbesartan), also partnered with BMS, plummeted 26% to EUR334 million (~US$431 million) in the third quarter.  According to analyst Stephen McGarry from Societe Generale in London, “this was the first full quarter with all three major patent expiries in 2012.” He added that this year “represents the trough year for Sanofi’s earnings.”

	Despite that, Christopher Viehbacher, CEO of Sanofi, believes that they are “seeing the light at the end of the tunnel,” thanks to the company’s growth platforms. During the third quarter, Sanofi received FDA approval for Zaltrap (aflibercept) for previously treated metastatic colorectal cancer, Aubagio (teriflunomide) for relapsing multiple sclerosis and Auvi-Q (epinephrine injection, USP) for patients with life-threatening allergies, all of which are expected to provide future sales some momentum. Plavix was also approved for two new indications in Japan, although this won’t make up for the loss from generics entering the market.

	Sanofi’s decline in profits was, however, not as bad as some of its rivals. Lilly endured another difficult quarter as revenues slumped 11% with its antipsychotic Zyprexa (olanzapine) now off patent while BMS saw an extremely poor third quarter where the downward slide of Plavix revenues was further bruised by the discontinuation of its hepatitis C candidate BMS-986094.

	AstraZeneca was hit the hardest with a worse-than-expected 15%-dip in third quarter sales, attributed to a big slump in Seroquel (quetiapine) sales as well as the costs relating the disposals of Astra Tech and Aptium Oncology. The company’s antipsychotic came off patent in March this year and looming ahead is the patent expiration of Nexium (esomeprazole), AstraZeneca’s proton pump inhibitor for heartburn relief, in the United States.

	These are times when pharmaceutical companies turn to their R&D pipeline, in hope of discovering the next blockbuster. Sanofi believes that it is making good progress with its pipeline and that its growth platform will continue to provide consistent revenues over the next few years, supported by its long-acting insulin, Lantus, for diabetes, and its acquisition of the US biotech unit, Genzyme, both of which achieved strong double-digit sales growth. AstraZeneca’s mid- to late-stage pipeline is, on the other hand, looking rather weak. One strategy the company has in mind is to turn to acquisitions to strengthen its R&D portfolio and increase productivity. It would be interesting to sit back and observe how pharma deals with such inevitable loss of patent exclusivities and see if they appreciate the lessons learned from Procardia XL (nifedipine extended release tablets) whereby exploiting innovative drug delivery solutions has helped extend product lifecycle.

As third quarter results were being released last week, we hear of several top drug makers facing hard knocks from the fall off the patent cliff. Pharmaceutical news have been populated.

Third Quarter Revenues Wounded by Patent Expiries

On Oct. 22, 2012, a consortium in France announced the establishment of Europe’s first ever industrial manufacturing facility dedicated to the large-scale production of novel, advanced cell-based therapy medicinal products. The plant, located in Les Ulis, near Paris, at the site of the French biopharmaceutical company LFB Biotechnologies, has the capacity to produce 3000 to 5000 therapeutic batches per year. The facility will be used for innovative R&D projects on autologous and allogeneic cell therapies that are progressing from early clinical research stage up to industrial production. 

The facility project, known as C4C, is coordinated by CELLforCURE, a subsidiary of LFB Biotechnologies, and will involve two biotech companies—Celogos and CleanCells—as well as seven public organizations and university medical centers. Members of the consortium have invested EUR80 million (US$104 million) in the project alongside EUR30 million (US$39 million) public-sector financial aid provided by OSEO, France’s state innovation agency. The project seeks to provide an efficient pharmaceutical and industrial tool for improving patient access to cell therapies. Academic, public and private sector stakeholders will have access to the new facility for routine production of phase III clinical trial batches and commercial batches of new cell therapy products. 

Five products are currently under development, with the first batches expected in late 2013, according to a 

Bordeaux University Medical Center is collaborating with France’s National Blood Service (EFS) on the GRAPA program, which involves the ex vivo amplification of haematopoietic stem cells from placental blood for use in the treatment of bone marrow or lymph node malignancies (e.g., leukemia, lymphoma and myeloma), aplastic anemia, congenital immunodeficiencies and congenital enzyme deficiencies. The project is currently in Phase I/II development and aims to enable the transplant of ex-vivo-amplified placental blood stem cells into targeted patients.

The CEL-02 cell therapeutic, developed by Celogos, is undergoing Phase II evaluation for the treatment of anal incontinence. Conditioned autologous muscle cells are injected directly into the damaged muscle to treat sphincter-related anal incontinence. Patient enrollment in the Phase II clinical trial has initiated at Rouen University Medical Center, with a Phase III clinical program planned for 2014. 

Autologous islet of Langerhans grafts for the treatment of post-pancreatectomy diabetes is in Phase I/II development. The procedure, developed by Professor François Pattou’s group at Lille University Medical Center/University of Lille 2, involves an intramuscular, autologous transplant of islets of Langerhans to provide long-term insulin independence in diabetic patients.

A cell-based immunotherapeutic, developed at the Cell and Gene Therapy Unit at Nantes University Medical Center, is undergoing Phase III evaluation for the treatment of melanoma at the loco-regional invasion stage. Tumour-infiltrating lymphocytes (TILs) are administered in combination with low doses of interleukin-2 (IL-2) with the hope of preventing/slowing metastatic recurrence and improving overall survival in stage III melanoma after lymph node excision with a single invaded lymph node. 

The MESAMI (Mesenchymal and Myocardial Ischemia) program, conducted by Toulouse University Medical Center in partnership with the EFS to evaluate the potential use of mesencymal stem cells from bone marrow in combating left ventricular myocardial ischemia, is in Phase II development. Autologous bone marrow cells are cultured according to a well-defined procedure that makes it possible to expand the patient’s mesenchymal stem cells.

The industrial manufacturing facility will be validated through the production of these five innovative cell therapeutics and aims to meet the criteria set out by the European and North American health authorities and regulatory agencies. In addition to the C4C project’s own cell therapy products, the facility will offer custom manufacturing services. 

On Oct. 22, 2012, a consortium in France announced the establishment of Europe's first ever industrial manufacturing facility dedicated to the large-scale production of novel, advanced cell-based therapy medicinal products.

Europe Establishes First Facility for Cell-Based Therapeutics

Teva has invested $110 million in a new sterile plant in Gödöllő, Hungary. With 15,000 m

 of production area and modular building, as well as an annual production capacity of 160–200 million units of injection products in six production lines, Teva hopes the plant will strengthen the company’s role in Hungarian drug production.

At the opening ceremony, which took place on Oct. 2, 2012, Jeremy Levin, president and CEO of Teva, highlighted the company’s commitment to quality drug production and its Hungarian employees. "This plant is the symbol of the harmony between the most up-to-date technology and the people, the creativity and hard work of our human capital." 

, Teva’s new plant is not only one of the biggest sterile pharmaceutical plants, but also one of the most flexible ones in the world. The large production potential and flexibility means that the company will be able to supply patients in more than 70 countries, mainly in the US, Europe, and Far East. 

Teva has been operating in Hungary since 1993 and employs more than 3500 people. 

Teva has invested $110 million in a new sterile plant in Hungary. The company hopes the plant will strengthen the company's role in Hungarian drug development.

Teva Opens New Sterile Plant in Hungary

	The CPhI Innovation Awards, this year rebranded as the CPhI Pharma Awards, took place last week at 

 in Madrid, and put into prominence some key scientific advances of exhibitors at CPhI. The awards were designed to encourage entries in diverse areas, including formulation development, drug delivery, chemical manufacturing of APIs and intermediates, and biomanufacturing.

	The Best Pharma Innovation award featured gold, silver, and bronze winners from five shortlisted entries. Earning the gold and top prize was Haemopharm for its needleless injection vial (NIV), a needle-free vial closure system that can be used on any product supplied in a glass or plastic vial, whether in a liquid, gel, or powder form. Merck Millipore took the silver for using bimodal silica as a drug-delivery platform. Merck Millipore’s innovation takes advantage of the two-fold pore structure of silica, which offers a large surface area and good transport properties for drug delivery. The bronze went to Bioclin for its Multi-Oral Remin remineralization gel, applied in the oral cavity to treat and prevent bleeding gums and tooth erosion. The other two finalists included Linhardt’s Multiflex collapsible tube technology, designed to improve on traditional laminate tubes, and YaoPharma’s alprostadil, formulated as a lyophilized emulsion for injection.

	In addition to recognizing technical advances in drug development and manufacturing, the CPhI Pharma Awards also recognized advances in sustainability. This year’s award included an award for Best Sustainable Packaging, a new award this year that was added to recognize a company for a specific material, machine, or process that facilitated sustainable packaging. The finalists for this award included Top Clean Packaging Group’s Unicadose plastic vials, which provide an alternative to glass single-dose vials; August Faller’s Eco Save Pack, a carton tray with product-adapted inlays for different market demands; and MeadWestvaco Healthcare’s Shellpak Renew. The award went to MeadWestvaco Healthcare for its adherence-enhancing drug packaging, which consists of a recyclable tear-resistant outer carton and an easy-slide blister with a calendar integrated to aid patients in tracking their medication. In another award recognizing sustainability, Solvias won Best Sustainable Stand Design.

	The diversity of advances represented by the CPhI Pharma Awards underscores the value of and opportunity for innovation in drug development and manufacturing. There is no doubt that the complexity of molecules, challenges in drug delivery, and evolving patient and market demands will continue to foster creative scientific solutions.

The CPhI Innovation Awards, this year rebranded as the CPhI Pharma Awards, took place last week at CPhI Worldwide in Madrid.

Recognizing Pharma Innovation

Innovation is the cornerstone of the pharmaceutical industry. That innovation is not only seen in new drug development but also in approaches to extend the lifecycle of a given product through improved formulations and drug-delivery systems. Recent advances and trends in drug-delivery systems were highlighted at one of the sessions at the Pre-Connect Conference held at CPhI Worldwide in Madrid this week.

		The value of innovation was emphasized by Catalent, who provided insight on the increasing role of drug-delivery systems in solving complex drug-development challenges, such as bioavailability problems, and improving patient outcomes. The company shared research showing that compared with conventional formulations, advanced drug-delivery systems can potentially increase the value of  existing drugs by 25–50% through patent-life extension, product differentiation, accelerated product development and market entry, better patient outcomes and compliance, and improved returns on R&D investment.

		Innovation in inhalation drug delivery was discussed by Philippe Rogueda, director of emerging technologies at Watson Pharmaceuticals and adjunct senior lecturer from Monash University in Melbourne, Australia, who put forth the idea of telehealth and the use of single-dose inhalers (SDIs). These “smart” nebulizers use an adaptive technology that monitors patients’ compliance, and unlike conventional multidose inhalers, are used to administer only a single dose of drug and then disposed of. The advantages? Discrete use, no expiration of remaining doses unlike multidose inhalers, no overdosing, no cross-contamination, and ease of use. SDIs could be designed for personalized therapies in providing treatment for respiratory conditions, pain, migraines, and cancer side-effects. As Rogueda pointed out, however, SDIs also raise some challenges, such as patient adoption and interest in using SDIs over conventional multidose inhalers and patient concerns over privacy with the data collected from “smart” inhalers. Additionally, large pharmaceutical companies may be somewhat reluctant to let go of their complex inhalation drug-delivery platforms and advance SDIs.

		Strategies for tackling poor solubility of APIs were discussed by David Lyon, senior vice-president of research at Bend Research, and Conrad Winters, director of drug product development, at Hovione. They discussed the use of amphorous solid dispersions produced by spraying drying as a tool for resolving solubility issues and the various considerations in optimizing and scaling up spray-drying processes.

		Insight into the development of controlled-release oral formulations was provided by Christian Seiler, senior principal scientist from Merck & Co. He discussed approaches such as matrix tablets and osmotic dosage forms in controlled-released formulations and diagnostic tools used to evaluate and optimize a formulation. These tools include the Enterion capsule (Quotient BioResearch), which is remotely activated 

to deliver the drug payload on reaching the target location in the gastrointenstional tract, and Medimetrics’ IntelliCap, an electronic capsule that is used to deliver a drug or therapeutic agent to a targeted location, with a user-defined dose and delivery profile.

		The insights provided at this session underscore the value that drug delivery brings to the table in the pharmaceutical industry’s drive to bring innovative products to improve patient compliance and outcomes.

Innovation is the cornerstone of the pharmaceutical industry. That innovation is not only seen in new drug development but also in approaches to extend the lifecycle of a given product through improved formulations and drug-delivery systems.