April 2006

FACILITIES

Eisai Plans $105-Million Pharma Production and Formulation R&D Facility

Eisai Inc. (Teaneck, NJ, www.eisai.com), the US pharmaceutical subsidiary of Eisai Co. Ltd. (Tokyo, Japan, www.eisai.co.jp), plans to invest $105 million for a new pharmaceutical production and formulation research and development facility for parenteral oncology treatments in Research Triangle Park, North Carolina.

Of the $105-million capital project, $90 million will be used to build a roughly 65,000-ft² facility that will encompass aseptic processing suites, laboratories, and other support functions. The remaining $15 million will be used to construct a separate central utilities building to supply power, steam, chilled water, and compressed air to existing operations and the new parenteral facility.

Eisai's existing facility at Research Triangle Park encompasses roughly 190,000 ft² . It is used for the manufacture of "Aricpet" (donepezil) and "Aciphex" (rabeprazole), formulation research and development, and manufacturing of compounds for use in clinical trials.

Groundbreaking for the project is expected in the fall, and operations are expected to begin in 2009.

–Patricia Van Arnum

BMS Plans to Build $660-Million Bulk Biologics Manufacturing Facility

Bristol-Myers Squibb Company (BMS, New York, NY, www.bms.com) plans to build a large-scale multiproduct bulk biologics manufacturing facility in the United States. The company's board of directors approved a capital expenditure of $660 million for the project.

BMS has not made a final decision about the location of the facility, but it has narrowed its choice to four possible states—Massachusetts, Rhode Island, New York, or North Carolina—said Anthony Hooper, BMS's president of US Pharmaceuticals, at an investor briefing in early March. The company will make a decision regarding the location by the end of the second quarter of this year and will begin construction in the third quarter. The company plans to complete construction by 2009 and bring the first commercial supply on-line by 2011.

The new capacity provided by the new biologics facility will be in addition to biologics supply agreements that BMS has with Lonza AG (Basel, Switzerland, www.lonza.com) and Celltrion Inc. (Incheon, South Korea, www.celltrion.com), said Hooper.

The new bulk biologics manufacturing facility will be used to support current and pipeline biologics drugs. BMS has two biologics on the market: "Orenica" (abatacept) and "Erbitux" (cetuximab). Orenica, its first internally developed biologic, was approved by the US Food and Drug Administration (Rockville, MD, www.fda.gov) in December 2005 for treating rheumatoid arthritis. In January 2006, BMS submitted a supplemental biologics license application to FDA for the licensure of a third-party manufacturing facility to support increased production capacity for Orenica. Erbitux was approved for a second cancer indication earlier this month to treat head and neck cancer. It also is approved for treating colorectal cancer.

Key biologics in development are belatacept for treating solid-organ-transplant rejection and the anticancer therapy ipilimumab, which BMS has licensed from Medarex Inc. (Princeton, NJ, www.medarex.com).

Board approval for the $660-million capital project comes as BMS continues its cost-cutting program. The company has a goal of reducing costs by $500 million before 2007 and by an additional $100 million before 2008. These savings will be in addition to annual reductions of $200 million already achieved in 2004 and 2005, primarily gained through realigning its US and European sales forces, restructuring pharmaceutical development, and some outsourcing of information technology activities.

Separately, BMS received FDA priority review for its investigational oncology treatment, dasatinib.

–Patricia Van Arnum

Novartis Plans Manufacturing Site in China

Novartis International AG (Basel, Switzerland, www.novartis.com) plans to build a manufacturing facility in China to synthesize small amounts of different Novartis developmental active pharmaceutical ingredients to support early-phase preclinical development activities (e.g., toxicology and formulation development) in the company's other European and US sites, says a company spokesperson.

Novartis initially will invest $83 million in the project, which includes building, equipment, and leasing of land. The new site will be located in Suzhou City, China. It is scheduled to be operational in the first quarter of 2007 and will include infrastructure, laboratories, and one production building.

During the initial phase of the project, Novartis will acquire the land-use right for a 228,000-m² site from the Changshu Economic Development Zone. The workshop will have a total floorage area of two production buildings of about 8000 m² each. The development facility will cover a floorage area of about 4000 m² . Other auxiliary facilities (e.g., offices, warehouses, substation, utilities building, and maintenance building) will cover roughly 12,000 m² .

The plant is Novartis's first such facility in China.

–Patricia Van Arnum

ANTICOUNTERFEITING

RFID: A Slow Go in Pharmaceutical Adoption; Proposed Legislation to Help Fight Counterfeit Drugs

The pharmaceutical industry has been slow in adopting radio frequency identification (RFID) technology to help control diversion and counterfeiting, according to a recent study by ABI Research (Oyster Bay, NY, www.abiresearch.com).

In fact, only 10 drug products are expected to be shipped with RFID tags or smart chips embedded in the labeling in the coming year. As previously reported in Pharmaceutical Technology ePT, companies with highly counterfeited drugs such as Pfizer and Purdue Pharma have already pioneered tracking technology on shipments of "Viagra" and "OxyContin," respectively. Nonetheless, the lionshare of manufactures have yet to embrace RFID, citing the high costs of implementation and the need for more pilots as key reasons for not taking the plunge.

ABI says that one reason for the slow adoption is the US Prescription Drug Marketing Act (PDMA), which has been put on hold until January 2007. The legislation requires drug makers to implement some form of pedigree or track- and-trace technology to determine a drug's point of origin and where it has traveled throughout the supply chain. When the act was met with frustration by industry, it was given a temporary stay, allowing individual states to create their own pedigree laws.

Because there has been no federal mandate for companies to use RFID as the sole form of pedigree tracking, drug manufacturers use cheaper methods of tracking drugs such as 2-D bar codes that hold more information than standard bar codes, but cost significantly less than the far more robust RFID tags.

New legislation

Meanwhile, in Washington, DC, Democrats and Republicans have been pursuing a new bipartisan proposal that calls for a mandatory track-and-trace system.

Sponsored by Rep. Dan Burton (R-IN), the draft bill would require drug manufacturers to use RFID track-and-trace tagging technologies, tamper-indicating security measures, and blister security packaging when possible.

According to the bill, track-and trace technology could also be used to implement inventory control, verify the shipment or receipt of prescription drugs, authenticate finished prescription drugs, and electronically authenticate the pedigree of prescription drugs.

In addition, the secretary of Health and Human Services would be required to publish a list of the 30 most frequently counterfeited prescription drugs in the United States within 180 days of the legislation's approval. The list would be named the "National Specified List of Susceptible Prescription Drugs."

Drug products on that list would have to be made traceable no later than one year after the initial publication date, or by Dec. 31, 2007, and the list would be revised every year until the end of 2009. The bill requires that all prescription drugs have a supply-chain pedigree system by Dec. 31, 2010.

"This legislation is about safety and security," Burton stated in a release. "We need to ensure the safety of the American consumer as well as ensure and verify the security of the prescription drug supply-chain in order to protect Americans from potentially harmful counterfeit drugs."

The RFID Act has been referred to the Energy and Commerce Committee. The bill faces opposition from Rep. Steve Israel (D-NY) who feels that it relies too heavily on RFID, which has yet to receive industry-wide acceptance, as discussed previously. Israel has proposed a separate legislation "Tim Fagan's Law" that gives the US Food and Drug Administration the authority to recall drugs, implement harsher penalties for criminals who pawn off fake medicine on innocent consumers, and requires paper pedigrees, according to an official statement from Israel.

–George Koroneos

VACCINES

Vaccine Update: New Avian Strain, FDA Guidelines, and Clinical Funding

A flurry of industry collaborations, international agreements, and breakthroughs in cellular and DNA technology fuel new developments in vaccines for cancer, trivalent and avian flu, and Ebola.

Development begins on mutated H5N1 virus vaccine

Following an announcement of the emergence of a mutated strain of the deadly H5N1 virus, Health and Human Services Secretary Michael Leavitt authorized the National Institutes of Health (NIH, Bethesda, MD, www.nih.gov) and the Centers for Disease Control (CDC, Atlanta, GA, www.cdc.gov) to begin developing a new vaccine. This vaccine will be produced from the newly identified and isolated mutated strain from Indonesia.

After the production of pilot lots, NIH will perform clinical testing of the vaccine similar to that of the first H5N1 vaccine. "We will continue this approach as different versions of H5N1 virus or other viruses with pandemic potential appear," said Leavitt.

So far, eight million doses of the first NIH-developed vaccine have been produced for the Strategic National Stockpile and are undergoing clinical trials. But, this vaccine is based on a strain that was found in a patient from Vietnam and is effective only for the virus currently circulating in Thailand and Vietnam. It would be ineffective against the mutated H5N1 strain now circulating in Europe, Africa, and parts of Asia.

Reuben Donis, one of the researchers who isolated the new strain, explained in a CNN report that there are "at least" two groups of the H5N1 virus, the Indonesia- and Vietnam-originating strains, and "there may also be a couple of other groups."

"It is probable that H5N1 will continue to evolve, producing even more viruses with pandemic potential and making it necessary to develop a series of vaccines," said Leavitt in a statement given at the CDC's 40th National Immunization Conference in Atlanta, Georgia. "There is simply no way to predict which strain, if any, might produce a virus capable of mass human-to-human transmission."

FDA drafts new guidelines to facilitate influenza vaccine development

The US Food and Drug Administration (Rockville, MD, www.fda.gov) has issued two draft guidance documents outlining the clinical data needed to support the licensure of pandemic influenza vaccines and seasonal (trivalent) inactivated influenza vaccines.

According to FDA, the guidance documents describe the process for rapidly changing from currently licensed seasonal vaccines to new pandemic vaccines by supplementing the existing license. The agency also describes pathways toward traditional and accelerated approval of new vaccines. The approaches apply not only to split-virus and whole-virus inactivated vaccines (trivalent and pandemic), but also to new technologies such as cell culture and recombinant development and the application of adjuvants.

The draft guidances do not address the nonclinical or early-clinical development of investigational vaccines nor the chemistry, manufacturing, control, or inspection of the manufacturing facility needed for licensure.

Bharat Biotech to fund South Asian clinical trials for Novavax vaccine

Bharat Biotech International (BBIL, Hyderabad, India, www.bharatbiotech.com) agreed to fully fund the preclinical and clinical studies supporting the development of an H5N1 influenza vaccine by Novavax (Malvern, PA, www.novavax.com) for market in India and South Asia. Vaccines to protect against other strains of avian influenza also will be investigated. The strategic alliance makes BBIL responsible for the sale and distribution of the vaccine in these markets and provides Novavax unrestricted access to all preclinical and clinical data generated by BBIL.

Novavax will apply its recombinant DNA technology to produce virus-like particle vaccines of antigenic structures, which mimic a virus to produce an immune response, as well its "Novasome" adjuvant technology for vaccine development.

FDA recommends changes for 2006–2007 seasonal flu vaccine

The emergence of two new influenza strains has led FDA to recommend changes for next season's flu vaccine.

The trivalent flu vaccine typically comprises two "A" influenza strains and one "B" strain. The strain A/New Caledonia will remain the same. The panel recommended replacing the current A/California strain with a Wisconsin strain and the current B influenza strain from a Shanghai virus with a Malaysian virus. The World Health Organization made similar recommendations.

The panel also recommended that FDA convene a workshop to discuss the possibility of having the annual influenza vaccine include four flu strains rather than the current three. Panel members debated whether putting an additional B strain in each year's influenza vaccine could make it more protective, while some manufacturers argued that adding a fourth strain could cut overall vaccine manufacturing capacity by about 25% under current egg-based manufacturing processes.

Chiron and Novartis Advance Programs for Pandemic Flu

Chiron Corporation (Emeryville, CA, www.chiron.com) advanced several strategies to treat and prevent pandemic flu.

Chiron seeks European regulatory approval for a pandemic influenza vaccine. Chiron has submitted an application for a pandemic flu vaccine to the European Medicines Agency (EMEA, London, England, www.emea.eu.int), making it the second company to do so. GlaxoSmithKline PLC (London, England, www.gsk.com) had filed an application with the EMEA in January 2006.

Both applications use the "core dossier" approach, which allows the evaluation and approval of an application based on a "mock-up vaccine" before the outbreak of a pandemic. Once the actual virus strain has been identified at the time of the outbreak of the influenza pandemic, a variation to the core dossier is submitted to incorporate that strain.

Chiron's mock-up file for the pandemic influenza vaccine contains its MF59 adjuvant and is based on previous avian influenza vaccine clinical studies that will be augmented with an upcoming study of the H5N1 vaccine to take place in Italy this year.

Chiron also entered into a supply contract with the UK government for stockpiled prepandemic influenza vaccines based on the H5N1 avian influenza virus strain. Under the UK contract, Chiron agreed to supply the British government with H5N1 avian influenza vaccine containing its MF59 adjuvant. The delivery of the stockpile remains subject to internal and regulatory-release procedures.

The UK stockpile vaccine is based on an inactivated influenza strain similar to the H5N1 avian subtype that has circulated throughout Southeast Asia and more recently in Central Asia and part of Europe, said Chiron in statement. Chiron will produce the vaccine for this stockpile at its manufacturing facilities in Italy.

US extends delivery terms for stockpile of H5N1 bulk influenza vaccine. Meanwhile, Chiron reported that the US Department of Health and Human Services (HHS, Washington, DC, www.hhs.gov) agreed to extend delivery terms for a stockpile of H5N1 bulk influenza vaccine for the US government. Chiron entered into a contract with the US government to stockpile H5N1 bulk vaccine in October 2005.

Chiron is producing this stockpile at its facility in Liverpool, England, and expects to complete roughly 70% of the order before turning operations to annual production of "Fluvirin" influenza virus vaccine in March. Chiron expects to resume work on fulfilling the contract following the conclusion of the Fluvirin vaccine campaign in the fall of 2006.

As part of its avian flu vaccine strategy, Chiron expects that it can manufacture avian flu vaccines during the traditional break between seasonal influenza vaccine campaigns, finishing these activities in time for the seasonal influenza vaccine production to avoid an interruption of the normal manufacturing cycle, the company said in a statement.

Novartis, Alynlam collaborate in RNAi therapeutics for pandemic flu

Novartis (Basel, Switzerland, www.novartis.com) and Alnylam Pharmaceuticals Inc. (Cambridge, MA, www.alnylam.com) formed a new collaboration to develop therapeutics for pandemic flu based on RNAi. The two companies already have a multiyear alliance focused on developing RNAi therapeutics across multiple disease areas.

Alnylam announced in December 2005 that it was developing a pandemic flu program. It received initial government funding from the US Department of Defense's "Defense Advanced Research Projects Agency" to develop RNAi therapeutics targeting sequences, both specific for particular strains and conserved strains across all flu strains, including those of avian origin. This RNAi therapeutic would be expected to have antiviral activity against any newly emerging strain of influenza, including any variant for the H5N1 strain.

The pact further positions Novartis in developing therapeutic approaches to the pandemic flu. Novartis agreed to acquire the vaccine-maker Chiron last year for $5.1 billion. The deal is expected to close in the first half of 2006.

Cambrex to produce Geron's cell-based telomerase vaccine

Biopharmaceutical developer Geron Corp. (Menlo Park, CA, www.geron.com) has established a contract manufacturing agreement with Cambrex Bio Science Walkersville Inc. (East Rutherford, NJ, www.cambrex.com), a subsidiary of Cambrex Corp., to manufacture its GRNVAC1 telomerase vaccine. Cambrex will apply its cell therapy technologies to advance the development and CGMP manufacture of GRNVAC1 for clinical studies.

As a therapeutic cancer vaccine, GRNVAC1 comprises autologous dendritic cells loaded ex vivo with telomerase mRNA. In an ex vivo process, dendritic cells (the most efficient antigen-presenting cells) are isolated from the patient's blood, pulsed with RNA for the telomerase protein component, and then returned to the patient's body where they "instruct" cytotoxic T-cells to kill tumor cells that express telomerase.

GRNVAC1 is undergoing multiple Phase 1–2 trials at Duke University Medical Center where researchers are evaluating "various strategies" to optimize its performance in prostate cancer patients.

Generex, Antigen express prepare IND for synthetically manufactured Avian flu vaccine

Antigen Express (www.antigenexpress.com), the wholly owned immunotherapeutics subsidiary of Generex Biotechnology (www.generex.com, Toronto, ON, Canada) has concluded a preinvestigational new drug application meeting with FDA regarding its vaccine to protect against H5N1 avian influenza.

As a consequence of the meeting, Antigen Express has clarified the development path, including clinical study design, and regulatory timetable for its vaccine. Before submitting its IND, Antigen Express will conduct a toxicology study and a preclinical study to establish the vaccine's dosing regimen.

The avian influenza vaccine is based on a platform technology presently in the form of a breast cancer vaccine currently undergoing human clinical trials at Walter Reed Army Medical Center.

The vaccine is designed to induce a strong T-helper cell response using a synthetically manufactured peptide. According to the company, "A strong T-helper cell response plays a major role in helping the body to develop neutralizing antibodies to viral infections. The induction of a good T helper response is expected to greatly reduce the amount of classically produced vaccine necessary to achieve protective immunity in prime/boost regimens. The study will attempt to establish whether application of the vaccine on its own will provide a significant degree of protection in humans who have received no other vaccination."

Because the vaccine can be manufactured synthetically in large quantities and in existing facilities, its associated development costs are expected to be lower than those of cell-culture or hen-egg-produced vaccines.

World's first plant-made vaccine wins USDA approval

Dow AgroSciences (www.dowagro.com, Indianapolis, IN), a wholly owned subsidiary of The Dow Chemical Company, has won approval from the US Department of Agriculture (USDA) Center for Veterinary Biologics for its plant-made vaccine. The "Concert" system uses plant cells, instead of whole plants, in a secure biocontained environment. Although the vaccine's current applications are intended for animal health, the company reports that its use for treating human diseases is "a real possibility."

G-8 nations plan financial support of vaccine production

During a recent meeting held in Moscow, Russia, finance ministers from the Group of Eight major industrialized nations discussed an advance market commitment plan to promote the development of vaccines for diseases that primarily affect developing countries. The plan would call for G8 nations (United States, Britain, Russia, Germany, France, Italy, Japan, and Canada) to provide between $800 million and $6 billion to subsidize the purchase of new vaccines, according to a Feb. 13 Wall Street Journal article (WSJ, M. Phillips, "G8 Nations Shape Plan to Fight Diseases," www.wsj.com).

Under the plan, G8 nations would provide funding to pharmaceutical companies that show they can produce safe and effective vaccines. In turn, the companies would sell the vaccines at reduced prices in developing countries. The total amount of the G8 pledge and the price per dose of each vaccine will be determined ahead of time.

The WSJ article quotes a report by Italy's finance minister Giulio Tremonti: "By restoring appropriate incentives, [advance market commitments] can stimulate private research and investment, accelerate the discovery of new vaccines, save lives, and contribute to economic development in a cost-effective way."

Although G8 officials are expected to approve the plan during its April 2006 meeting in Washington, DC, many details remain to be finalized. G8 officials, the World Bank, and other organizations must not only decide how much each nation should contribute to sponsor the vaccine project, but also decide on the initial focus or "test case" disease. Under discussion are the six major health concerns affecting developing nations: HIV/AIDS, malaria, tuberculosis, pneumococcus (which causes pneumonia and meningitis), rotavirus (which causes fatal diarrhea in infants and children), and human papillomavirus (which causes cervical cancer).

First Phase I study proves safety, immune response of Ebola DNA vaccine

A Phase I trial conducted on an Ebola vaccine candidate developed by the National Institute of Allergy and Infectious Diseases (NIAID) and administered using proprietary DNA delivery technology from Vical Inc. (San Diego, CA, www.vical.com) has shown the vaccine to be safe, well tolerated, and capable of producing both antibody and T-cell Ebola-specific responses in humans.

The DNA vaccine incorporates genetic material encoding core and surface proteins from two strains of Ebola. The vaccine used in the Phase I trial included three bacterial plasmids (pDNAs), one each encoding the surface glycoprotein (GP) from the Zaire strain of Ebola, GP from the Sudan–Gulu strain, and the internal nucleoprotein (NP) from the Zaire strain.

According to Vical, plasmids can be manufactured using "uniform methods" of fermentation and processing. The company secured a nonexclusive license from the National Institute of Health (NIH) to proprietary gene sequences used in the vaccine.

Conducted at the NIH Clinical Center, the Phase I study was the first human trial for any Ebola vaccine. "The high rates of immune responses at all dose levels in this initial human Ebola vaccine study support continued development of this vaccine and further evaluation of our technology for potential additional biodefense and emerging disease applications," said David C. Kaslow, MD, Vical's chief scientific officer, in a company statement.

–Maribel Rios and Patricia Van Arnum

EXPANSION

North American Pharma–Bio Capital Investment to Total $14.7-Billion for 2006

According to a recently published report from Industrial Info Resources (IIR, Houston, TX, www.industrialinfo.com), pharmaceutical and biotechnology companies and life science research institutions are planning a building boom. The capital-projects-intelligence firm is tracking "more than 320 active projects expected to begin construction this year." The number of projects is about flat (the 2005 figure was 322), but the total planned investment has jumped by $1.2 billion.

Capital spending in 2005 was spread throughout the continent, according to IIR, "with the Great Lakes emerging as the somewhat surprising leader, with 54 projects valued at $2.8 billion scheduled to begin construction.... Not unexpectedly, the Mid-Atlantic region was not far behind the Great Lakes in 2005 project activity. With 40 projects, carrying a value of $2.5 billion, expected to begin construction in during the year."

For IIR's summary, see http://www.industrialinfo.com/showNews.jsp?newsitemID=78403 (free registration required).

–Douglas McCormick

Chiron to Sell Betaseron Assets to Schering

Schering AG (Berlin, Germany, www.schering.de) has provided Chiron Corporation (Emeryville, CA, www.chiron.com) with formal notice of its intention to purchase or lease all assets used by Chiron in the manufacture of Schering's "Betaseron" interferon beta-1b products, including all contractual rights at their fair market or lease value.

Schering is exercising its option under a change-in-control clause in a collaboration agreement with Chiron. The collaboration agreement between Schering and Chiron is expected to expire in October 2008. The purchase–lease option is subject to the closing of the pending acquisition of Chiron by Novartis International AG (Basel, Switzerland, www.novartis.com).

–Patricia Van Arnum

Baxter Wins Contract to Develop Cell-Based H5N1 Vaccine

The European subsidiary of Baxter International (Deerfield, IL, www.baxter.com) has won a UK National Health Service (www.nhs.uk) contract to develop two million doses of a cell-based candidate H5N1 influenza vaccine and complete delivery of the stockpile this year.

High-yield production of the candidate vaccine is based on Baxter's vero-cell platform, which does not require the addition of any animal serum and has been successfully used to grow wild-type virus. Baxter's vaccine production facilities are engineered for BioSafety Level 3 production, which allows the company to use wild-type strains to accelerate production.

The candidate H5N1 vaccine has yet to undergo full clinical testing to demonstrate safety and immunogenicity for pandemic flu.

Baxter also is in discussion with the US National Institute of Allergy and Infectious Diseases to develop a cell-culture-based H5N1 candidate pandemic influenza vaccine for initial clinical testing this year.

–Maribel Rios

DRUG SALES

Drug Sales Up 5.4%...But Growth Rate Slowing

As IMS Health (Fairfield, CT, www.imshealth.com) is reporting that prescription drug sales grew by 5.4%, a task force of the federal Centers for Medicare and Medicaid Services (CMS) reports that the spending-growth-rate is falling, thanks to increasing reliance on generics.

IMS reported that US prescription drug sales grew 5.4% to $251.8 billion in 2005, up from with $238.9 billion in sales the previous year, while the total number of prescriptions was up significantly by 4.7%. The report called biotechnology products "a major growth engine," with sales up 17.2%, though the sector accounted for just 13% of total drug sales. to $32.8 billion.

IMS found that generic drug sales grew by 20.6%. The rise of generics helped account for the slowing in drug-spending-growth reported by a CMS team in "National Health Spending In 2004: Recent Slowdown Led By Prescription Drug Spending," (Health Affairs, 25 (1), 1, 186–196, [2006], content.healthaffairs.org/cgi/content/full/25/1/186). "Across all payers," the paper reported, "growth in retail drug sales continued to decelerate in 2004, increasing 8.2 percent. This was the first year of single-digit growth in the retail market in ten years; as a result, drug spending held steady at about 11 percent of aggregate health spending...."

The CMS analysis credits increasing reliance on generic and over-the-counter medicines as alternatives to branded pharmaceuticals, a shift to mail-order distribution, and drops in product use because of safety concerns.

–Douglas McCormick