A number of strategic reasons exist for partnering among life sciences companies. For emerging biotech companies, partnerships and strategic alliances provide a number of benefits, including much needed capital infusions, sharing risks for continued drug development, and access to pharma or biopharma clinical, regulatory, or commercialization expertise. 

While collaborations between emerging biotechnology companies and pharma–biopharma companies are not new, these deals have dramatically increased in sheer number and deal value. Perhaps the most important recent trend to note is a structural one—a trend of moving away from the conventional royalty model toward 50–50 cost and profit sharing collaborations. Last year even small, emerging biotech companies successfully negotiated balanced deals with 50–50 economics. In spite of the resource constraints small biotech companies face and the inherent complexity in negotiating 50–50 collaborations, these partnering deals are on the rise.   

Two main factors are driving pharma's ongoing collaborative fervor. In today's market, pharma companies are experiencing falling productivity from their internal pipelines. Gaining access to new products through alliances with biotech companies allows pharma companies to expand their pipelines and increase their probability of success. Also, due to the complexity of manufacturing, biologics tend to have less competition than conventional synthetic chemical medicines, thus increasing the probability of providing a more stable revenue stream. 

Increasingly, pharmaceutical companies are capitalizing on these benefits to drive significant revenue. Wyeth (Collegeville, PA), for example, today relies on biotech product revenues to drive approximately 25% of its revenues. Within the next 5–10 years, the company expects revenues generated from biotech products to grow to 40% of its total revenues. Another compelling factor is that a significant number of blockbuster drugs are now coming off patent. As a result, pharma companies—and increasingly large biotech companies—have expanded their hunt for products to in-license from smaller biotechs. This, in turn, creates significant leverage for emerging biotech companies. The October 2005 deal between Merck (West Point, PA) and Agensys (Santa Monica, CA) is a clear illustration of this trend (See Deal in Focus—Merck and Agensys). 

Biotech companies operate in an environment of significant financial constraints. One key obstacle is the ever-increasing amount of cash required to support continued drug development. Most emerging biotechnology companies do not have sufficient capital, research and development capabilities, regulatory expertise, commercial infrastructure, or manufacturing capacity to fully develop and commercialize a product on their own. As a result, collaborative deals with pharma offer biotech companies access to critical resources to fill operational gaps—global sales capabilities, regulatory expertise, R&D depth, and commercial and manufacturing infrastructure.  

CODEVELOPMENT AND COPROMOTION CONSIDERATIONS

In the not-too-distant past, biotech product deals were fairly straightforward. A small biotech company with an innovative drug in early stage clinical development turned to a large pharmaceutical company to assume future development and commercialization of the product. These deals were generally structured as exclusive licenses to the pharma partner, in return for an upfront fee, milestone payments, and royalties on product sales. 

While the prospect of sharing the costs of late-stage development through product commercialization can be a high-risk proposition for small, financially-strapped biotechnology companies, 50–50 economic structures provide the smaller partner with an opportunity to retain some degree of control over development and to ultimately capture a larger piece of a successfully approved and launched product. Just as important, a 50–50 deal represents a significant statement that the partners have strategic synergies and a shared operating philosophy that will be deployed by both parties to successfully drive product development and commercialization.  

The deal flow in recent years demonstrates an increasing trend away from the royalty model toward 50–50 shared economics, with the smaller company actively participating in the project and retaining equal control over critical development decisions, including determining where clinical trials will be conducted, deciding who will provide the clinical supply material, and who will take the lead in interacting with the regulatory agencies in the US, Europe, and other major markets. 

If a copromotion arrangement (usually in the US market) is added to the mix, then the deal becomes more complex, but also more exciting for the emerging biotechnology company. In a copromotion agreement, the small biotech company can bargain for the right to participate in the marketing and promotion of its drug product in the largest pharmaceutical market in the world—the US market. 

Fifty-fifty codevelopment arrangements or copromotion deals represent attractive options for smaller companies who want to control their product's destiny. However, these types of deal structures are much more complex than those based on the larger pharma partner taking full responsibility for product development and commercialization. Consequently, these evenly split collaboration agreements require extensive planning and detailed negotiations. 

Companies considering such a partnership or alliance with pharma or biopharma must consider a number of critical factors, including:   					

Can the smaller company afford a 50–50 cost sharing arrangement? This type of structure means, not only sharing product revenues, but also the expenses, which can be considerable. Companies contemplating shared development cost arrangements must do their financial homework in the form of cost models, a risk-adjusted net present value analysis, and a detailed cash flow forecast. At each step of the analysis, be sure to identify the assumptions embedded in the financial forecasting. Remember that each assumption about the product's development path, launch time, and commercial market potential will be tested by the larger pharma partner during its due diligence. 

As part of the analysis, companies should consider the size of the market opportunity, potential market share over time as well as development, marketing, and other commercialization costs. Product pricing and pay or reimbursement issues should also be factored into the analysis. Finally, the analysis should incorporate realistic development, approval, launch, and peak sales time lines. Of course, the competitive environment, and its potential impact on these time lines, also should be included in the analysis. 

The long-term nature of life sciences collaborations and strategic alliances makes these arrangements inherently unpredictable. It is important then to consider multiple scenarios when completing the financial analysis. The small biotech company should perform a sensitivity analysis varying the ramp-up period, market share attainment, and cost scenarios. Biotech companies also need to carefully consider the timing of cash inflows and outflows because cash availability often is the most significant limiting factor. 

In a copromotion deal, negotiations will need to cover, among other things, financial issues such as allocation of promotional costs and expenses, number and quality of detailing, responsibility for sales force training, and monitoring and auditing of promotion expenses. Historically, biotech companies have wanted to play a key role in promoting and marketing products to learn from the process and to build their own commercial infrastructure. But a key question that biotech companies should ask before making any decision is, "Do we know what we're getting into?" It is easy to underestimate the cost and resource requirements associated with a copromotion structure. Building a sales force and a marketing team, and establishing the brand for the product can cost a company millions of dollars—before any product sales revenue is ever recorded.  

The PDL BioPharma (Fremont, CA)/Roche (Basel, Switzerland) global asthma collaboration is an example of a biotech or pharma deal that includes both a 50–50 shared economic structure and a copromotion arrangement. This deal amply illustrates the complexities that a biotech company must address to successfully negotiate and execute such deals.  

PDL's relationship with Roche dates back to 1989, when it licensed to Roche worldwide rights for Zenapax, the first humanized monoclonal antibody approved by the FDA for the treatment of acute kidney transplant rejection. Over the years, PDL continued to conduct investigator-sponsored trials to test Zenapax's potential in autoimmune diseases and asthma applications. In 2003, PDL paid $80 million to Roche to buy back the rights to Zenapax, except for use in kidney transplant patients. Following the announcement of positive Phase 2 data in asthma, PDL approached Roche to negotiate a collaborative deal for Zenapax use in asthma and other respiratory disorders. Key features in the asthma collaboration include equal representation and decision-making on development and commercialization decisions, a 50–50 cost-profit split, and a copromotion arrangement in the US. Prior to agreeing to the deal with Roche, PDL committed substantial resources to the diligence process, with a focus on: the potential product market share in asthma; the need to track sales in multiple indications, including transplant, asthma, and multiple sclerosis; development costs and risks, including the costs of developing a new high yield antibody manufacturing process; estimated approval and launch dates; and post-launch marketing and promotion costs. 

In today's deal environment, biotech companies find that it is possible to obtain development funding from a larger partner without ceding control. An illustration of this is the 2005 deal between Theravance Inc. (South San Francisco, CA)/Astellas Pharma (Tokyo

 Japan). Astellas agreed to pay $65 million upfront and another $136 million in milestone payments based on clinical filings and approvals for the Theravance Phase 3 antibiotic Telavancin. Theravance successfully retained significant control over the clinical development and launch of this antibiotic.  

As with a copromotion arrangement, successful negotiation of balanced development terms requires a substantial amount of strategic thinking and planning, along with detailed financial analysis. Some key considerations that must be assessed in a co-development deal include determining how and where clinical studies will be conducted, and which party will assume oversight responsibility over the trials. Responsibility for development expenses and internal FTE rates and costs also must be discussed in detail, and agreed on. A "meeting of the minds" on these key issues, generally through a negotiated development plan and budget, will solve a lot of potential problems down the road. 

Whether collaboration will be successful depends a great deal on the often unpredictable component of human capital. Therefore, it is important to consider the following before entering into a long-term collaboration:  					

—Make sure that all major department heads are on board and have input into the deal parameters, e.g. finance, clinical, regulatory, and marketing divisions. 

—Everyone—senior management, the board of directors, the project managers—should understand that company capital and resources will be focused on the partnership and that these resources may not be available for other projects. 

—Both parties must be willing to negotiate and execute a deal  based on long-term 50/50 economics. It is important to confirm with your partner that there is a shared operating philosophy going forward. 

—Pharma companies typically have several products and therapeutic areas in their portfolio. Key questions here include: What is the pharma company's experience in the relevant therapeutic area? Will the pharma company champion the therapeutic and market potential of the product? Will the pharma partner give the product the appropriate level of attention and resources it will require?

As with any other key business decisions, various scenarios and strategies should be thoroughly evaluated. In particular, biotech companies should consider the potential downside of a 50–50 collaboration with pharma or biopharma. While sharing the risks and costs can be attractive, it comes at a price. Virtually any significant collaboration means that the smaller biotech company will give up certain rights to the drug candidate and the related technology as well as relinquish significant management control. Sharing the "upside" can also be emotionally difficult for a company and its team when early sweat equity and risk-taking went into building the company and the product.  

Finally, when considering any long-term partnering arrangement, companies need to have extensive internal discussions to address a number of key questions: 									

Why is this proposed deal important for the company?

What skill set do we expect our partner to bring to the table?

Do we want this partner for the US only?  For the EU?  For a global collaboration?

If it is a global collaboration that is desired, should specific territories be carved out to facilitate licensing opportunities with other partners?

How does the proposed deal fit within the company's short- and long-term goals?

Thorough advance preparation results in better deal-making and avoids unexpected surprises during the negotiation process.  

When considering a 50–50 profit and cost share arrangement, or a co-promotion deal, a company should keep in mind alternative structures and scenarios, including the following, to maximize long-term flexibility: 					

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Wyeth today relies on biotech product revenue to drive approximately 25% of its revenues.

Legal Forum: Putting the "Co" in Development and Promotion: The New Biotech-Pharma Collaborations

In April 2006, Cytovance Biologics LLC (Oklahoma City, OK), a clinical-scale contract manufacturing and process development organization (CMO), finished installing two new bioreactor systems into its custom-designed multiproduct cGMP contract manufacturing facility. The installation was the culmination of a difficult endeavor that began in September 2005, when the bioreactors were ordered, and ended in March 2006, when the systems were delivered. 

This article describes the importance of incorporating critical design elements into the quotation before placing the order, clearly defining roles and responsibilities, and managing the project effectively. The installation was completed on time and on budget without any project change orders. 

Cytovance Biologics required two mammalian cell-culture bioreactors for its newly constructed, early clinical phase cGMP contract manufacturing facility at the Presbyterian Health Foundation Research Park in Oklahoma City, OK. One hundred liter and 500 L mammalian cell-culture stainless steel units were specified for separate manufacturing trains in dedicated suites. They needed to be operational by the summer of 2006 to support customer cGMP production batches. 

Because Cytovance Biologics is a multiproduct contract manufacturer, there was no single product or process to tailor the bioreactor systems to. It was necessary to accommodate a wide range of mammalian cell-culture products and processes to maintain the company's ability to bid on a wide variety of contract proposals. Many design issues were addressed early on, such as the sizing of the mass flow controllers, the addition of baffles to the bioreactor vessels, and whether the bioreactors would be capable of running perfusion processes. 			

The cGMP facility design was completed before the bioreactor design, so it was necessary for the bioreactor system design to accommodate facility restrictions on dimensions and utility services. Cost and timelines were also concerns because a CMO must carefully control expenditures. An aggressive budget was set. In addition, it was important that the bioreactors be installed and validated as quickly as possible to accelerate the acquisition of customer projects and associated revenue generation. 

We solicited competitive quotes from three vendors and selected Sartorius BBI systems of Bethlehem, PA (SBBI, 

). We also hired Certified Facilities Corporation, of Seattle, WA (

), as a design contractor to ensure that our formal quotation included process and facility requirements and provided protection against change orders because of design alterations. We sought and received assurances from the highest executive levels at Sartorius that the systems would be delivered within 26 weeks of placing the order.  

Finally, we conducted a one-day, face-to-face meeting with Sartorius to tour their facility and identify final bioreactor specifications.  

Once we formally placed the order, we established roles, responsibilities, and key contacts for each team. At Cytovance, I was the main point of contact. Steven D. Perry, vice president of manufacturing operations, was responsible for final decisions, and Debra Greiner-Powell director of quality systems, was responsible for quality assurance on the customer side. Steven J. Ruhl, vice president of Certified Facilities, was also a key consultant to the bioreactor project team.  

At SBBI, Stanley Hawrylo, senior project engineer, was the main point of contact and project manager. Kenneth Clapp, senior vice president, manufacturing and operations, was responsible for final decisions, and David Koiro, quality control supervisor, managed quality control on the vendor side. 

We instituted weekly update meetings by phone, where we took detailed minutes and established a formalized system for tracking action items. The meetings were invaluable—they provided a forum for consistent communication for the duration of the project. The minutes also created a historical record of the project's development, which was reviewed whenever disputes arose. Project teams from Cytovance Biologics and SBBI participated in the weekly meetings throughout the course of the project. 

Additionally, SBBI developed a detailed project schedule with descriptions, dates, assignments, and percentage-completion metrics for each task. The detailed schedule, which incorporated approval times for documents, was essential to maintain the aggressive delivery date.  

During the first few weeks of the project, SBBI generated several key documents for our review and approval. The two most critical were the Piping and Instrumentation Diagrams (P&IDs) and the Master Component Lists (MCL). SBBI required our approval before ordering components with the longest lead time, including the actual bioreactor vessels. 

The P&IDs were reviewed to ensure that the proposed design met our requirements. We confirmed that utilities were sized properly, flow paths were correct and sterilizable (as required), components were clearly labeled, and that the vessel had the required ports for additional feeds and instrumentation.  

The MCL identified specific manufacturers and materials that would be used in system fabrication. For example, If Cytovance Biologics had a preferred supplier for diaphragm valves (to minimize the different types of spare diaphragms to keep in stock), or supplier for pH and DO probes, those concerns would be addressed in the MCL. 

After we approved the P&IDs and the MCL, SBBI issued the functional requirement specifications (FRS) for our review and approval. The FRS provided detailed descriptions for how the bioreactor control software would handle control loops and sequences. The control system included with the bioreactors is a proprietary software developed by SBBI, entitled DCU3. 

Control loops, such as pH and the cascade loop for dissolved oxygen (DO), were spelled out in detail within the FRS. Sequences such as steam-in-place (SIP) and clean-in-place (CIP) were also detailed. The FRS listed available alarm functions for the various parameters and readings that are monitored. In addition, the FRS listed valve tables to help Cytovance Biologics employees generate standard operating procedures. 

SBBI then issued fabrication arrangement drawings for our review. These documents provided a means for reviewing the system footprint and height, functionality of operator manipulations, and the ability to tie utility connections into the facility. 

Next, SBBI issued electrical wiring drawings. These provided the schematic for understanding exactly how the bioreactor systems and various digital and analog I/O, as well as power supplies, were connected.   

Factory Acceptance Test (FAT) documents detailed the series of tests to be performed to ensure that the bioreactor system was fabricated per the approved drawings and MCL, and that the system was functionally sound (per the FRS with respect to performance) before shipment was approved. 

FAT activities included verification of all drawings, MCL verification, I/O check, calibration checks, alarm testing, control loop checks, sequence testing, a riboflavin challenge, and a sterile media hold challenge. Any non-conformances between expected test results per the approved documents and what was actually verified in the field had to be resolved to our satisfaction before the system could be cleared for shipment.    

SBBI's timely generation of these documents, and Cytovance Biologics's prompt review helped maintain the schedule. Weekly project meetings also provided a useful forum for addressing any questions and comments about the documents, from initial generation to final review and approval. 

Inspection of the systems during their fabrication also reassured us that they would meet our expectations when delivered. Cytovance Biologics was on site to supervise and observe the vessel FAT (at the vessel manufacturer, T&C Stainless in Mount Vernon, MO, 

) and at the system FAT (performed onsite at SBBI in Bethlehem, PA). Both FATs were formally executed by SBBI representatives. 

The vessel FAT was a one-day test for both the 100 L and 500 L vessels. SBBI verified that they matched specifications per the official vessel P&ID. Test verifications performed included the following: 					

Drainability to ensure no pooling at the bottom of the vessels or any ports

Interior and exterior finish with a calibrated profilometer 

After the vessel FAT was executed, SBBI prepared a final report  identifying any nonconformances that the vessel manufacturer needed to address before SBBI would authorize shipment.  

The system FAT was a three-week test SBBI conducted to verify the fabrication and functionality of the bioreactor systems. Members of the Cytovance team traveled to Bethlehem, PA for the duration of the FAT to supervise and observe the process.  

Two problems initially threatened to delay the FAT process for the 500 L bioreactor system. First, the vessel arrived from the manufacturer with shipping damage. Second, there were difficulties in ensuring that all the 500 L agitator impellors were delivered in time. 

Cytovance Biologics and SBBI worked creatively to avoid delays and keep the project on schedule. The shipping damage to the 500 L vessel consisted of a dent to the vessel jacket, requiring jacket  replacement. Functionally, this did not affect any of the FAT tests, so we first decided to continue with the FAT and repair the vessel after testing. It was more economical time-wise to ship the vessel from Pennsylvania to Missouri (where it could be turned around in less than one day) on its way to Oklahoma, rather than delay the FAT schedule.  

Second, we decided that having all agitator impellors installed was not functionally important for most of the FAT execution. The second impellor that SBBI was waiting to receive was required only for the riboflavin and sterile media hold challenges. This allowed SBBI to continue testing the 500 L system for one-and-a-half weeks before the last impellor arrived, which preserved the original schedule.   

The system FAT proved to be a critical test. By performing an extremely thorough inspection of  system fabrication and functionality, non-conformances that were found could be corrected on site at the SBBI manufacturing facility. Various flaws in the programming, piping slopes, and CIP flow paths were easily addressed during the FAT process.  

Additionally, Cytovance Biologics had also ordered a CIP skid that was ready for testing at the same time as the bioreactor systems. This enabled us to test the communication between the CIP skid and each bioreactor system during the FAT and verify that the systems communicated as designed.   

At the end of the FAT, we developed a formal list of action items required to be addressed before  shipment. The FAT was successful in ensuring that Cytovance Biologics received functionally sound bioreactor systems that were fabricated according to approved specifications and documented any nonconformances that were found.  

The 100 L bioreactor system arrived on site at our facilities in Oklahoma City on March 20. The 500 L bioreactor system arrived on March 27 and the vessel followed closely behind (after stopping through Missouri for the jacket repair). SBBI was scheduled for two visits to complete the project: the first for installation of the bioreactor system and the second for system start-up training.   

Cytovance Biologics rapidly executed system set-up and tie-in to the utility systems in each cell-culture suite, to allow SBBI to perform their installation functions on time. The installation included reassembly of the bioreactor systems, leveling of each system, and assurance that the vessels were  correctly mounted on the load cells .  

SBBI returned for the second visit two weeks later to perform system start-up training. SBBI provided instruction on operation of the DCU3 controller, performed some system checks, and tested sequences. 

Understand your company's requirements, define responsibilities,and manage your team effectively.

Successful Bioreactor Installation: What it Takes

What do you do about something that seems incredibly useful, but is inherently uncontrollable? This is the challenge posed by phage therapy. 

Phage therapy appears to be an elegant solution to the problem of bacterial resistance to antibiotics. Phage therapy is not new; it has been practiced since the early 1900s, most notably Russia. The principle is fascinating: it uses bacteriophages, tiny viruses that live by infecting and destroying specific bacteria. Phage therapy avoids the resistance problem because the phages evolve as the bacteria evolve. Biology adapts to biology; both organisms evolve and flow in relation to each other. 

The challenge lies in ensuring the safety of such therapy, and even proving its efficacy using traditional approaches to clinical trial design. In hopes of getting FDA approval, some companies are working on ways to modify phages so that they can characterize and control the phages better, but these approaches run the risk of eliminating the very feature that was desired: the ability of the living organism to adapt and remain effective against mutating bacteria that cause infection and death. 

In today's biopharmaceutical industry, regulatory authorities and companies alike strive to apply good science to every action, particularly in manufacturing controls. The days when we ran a manufacturing step for 

 minutes because "it seems to produce good quality" are on their way out. Today's approach applies manufacturing science to achieve in-depth process understanding; process developers identify the critical quality attributes required in the end product and the critical process parameters that will ensure that those quality attributes are achieved consistently. As a result, a quiet revolution in process validation is taking place. Instead of believing that three successful batches in a row means a process is validated, companies are using design of experiments up front to develop robust process understanding and a defined design space, so that they have knowledge, backed by hard data, about the allowable limits of process variability. 

FDA has been at the forefront of this drive to apply sound science, starting in 2002 with its CGMP and PAT initiatives. Now FDA is on to the next stage, implementing new harmonized approaches, rooting out old guidances that reflect outdated thinking, and working to revise the guidance on process validation to reflect a scientific approach. The agency is restructuring offices and systems involved in reviewing applications for new product approvals. In short, FDA is hammering away to ensure that this thinking pervades every level of the organization and every aspect of what they do, from each review of an investigational new drug application to every site inspection. 

Can this emphasis on careful control be reconciled with phage therapy, the very effectiveness of which lies in its variability? 

I can't envision a way to ensure the safety and efficacy of phage therapy that follows the rigorous scientific approaches that FDA and industry apply to protect patients. Is there a creative solution? I hope so. In the meantime, some companies are starting by finding applications in agriculture. Perhaps those will lead us to a way to resolve this fascinating conundrum. 

Is it possible to reconcile phage therapy, which is inherently variable, with requirements for tight product characterization and control?

From the Editor in Chief: Science, Control, and the Seemingly Uncontrollable

Although the Food and Drug Administration is celebrating its 100th birthday this year, federal government regulation of biologics is even older. FDA's Center for Biologics Evaluation and Research (CBER) dates its origins to Congressional approval of the Biologics Control Act of 1902, following a wave of deaths from tainted diphtheria antitoxin. The law established CBER's predecessor, the Hygienic Laboratory of the Public Health and Marine Hospital Service, and gave it authority to license and inspect manufacturers of smallpox and rabies vaccines, diphtheria and tetanus antitoxins, and various serums to protect against bacterial infections such as scarlet fever. 

Four years later, Congress passed the 1906 Pure Food and Drugs Act, which established FDA's predecessor, the Drug Laboratory in the Bureau of Chemistry of the Department of Agriculture. This law authorized testing drug product strength and purity, but did not establish premarket approval requirements and gave the government little authority to remove even ineffective drugs from the market. FDA was established around 1930, at the same time that the Hygienic Laboratory became the National Institutes of Health (NIH); biologics control remained part of NIH until it was transferred to FDA in 1972 (see  Coordination Challenges). 			

FDA did not gain any real teeth for regulating unsafe and ineffective products until another national health disaster roused a public outcry. Congress approved the Food, Drug, and Cosmetic Act of 1938 after more than 100 people, including many children, died in 1937 from a poisonous ingredient in Elixir Sulfanilamide. To prevent such catastrophes in the future, the new law required manufacturers of drugs and biologics to test the safety of new products and submit the results in a new drug application (NDA) before marketing (biologics still had to submit a biologics licensing application, or BLA). The law authorized inspections of drug manufacturing facilities and established requirements for product labels.  

Congress further expanded FDA's responsibilities in 1941 by requiring premarket testing of all batches of insulin for purity, strength, quality, and identity. The Public Health Service Act of 1944 updated the 1902 biologics policy. And a Penicillin Amendment passed in 1945 mandated similar testing requirements for that drug.  

Vaccine development rapidly moved forward during this period. In the 1940s, government researchers developed methods to determine vaccine potency, which led to improvements in vaccines for pertussis (whooping cough) and influenza. A major success was realized with the development and testing of the Salk polio vaccine in the mid-1950s. And in 1966, agency researchers developed the first effective experimental vaccine for rubella (German measles). The safety of blood and blood plasma products also improved during World War II and beyond with the development of tests to detect hepatitis.  

A major regulatory change occurred in 1962 when the dangers of Thalidomide use prompted Congress to adopt the Kefauver-Harris Amendments. The new law required manufacturers to prove that drugs are safe and effective before marketing; it also formalized good manufacturing practices, required adverse event reporting, and called for sponsors of clinical trials to obtain informed consent from study participants. 

The 1980s was a time of important social and biomedical change in the US, with major consequences for FDA and biotech companies. The first reports of HIV/AIDS cases appeared in 1981, prompting coordinated efforts to develop and approve immunoassay tests and test kits to screen donated blood for the AIDS virus. AZT, the first drug to treat AIDS, was approved by FDA in 1987, along with additional treatments for certain opportunistic infections. Demands from AIDS advocates for quicker access to promising therapies also spurred a more risk-averse attitude at FDA, leading to rules expanding access to experimental drugs for seriously ill patients, and permitting FDA approval of AIDS and cancer treatments based on early clinical results.  

At the same time, policy makers encouraged development of innovative treatments for rare diseases by enacting the Orphan Drug Act of 1983. The legislation provided extended market exclusivity for therapies that treat diseases affecting less than 200,000 people in the US, which has led to approval of nearly 300 drugs and biological products. These policies spurred development of new therapeutic proteins and monoclonal antibodies able to target cancer cells more effectively, clear clots from coronary arteries, and prevent anemia in ill patients.  

The modern generic drug industry also emerged with Congressional approval of the 1984 Drug Price Competition and Patent Term Restoration Act, or Hatch-Waxman Act. The bill allowed FDA to approve identical versions of brand-name drugs based on innovator preclinical and clinical testing. In return, brand-name companies gained up to five years additional patent protection to compensate for time spent waiting for FDA to approve a new drug. Because this legislation applies only to drugs, a major legal battle to authorize "similar" versions of biotech therapies has erupted as significant biologics are beginning to lose patent protection. 

All of these new programs greatly increased FDA's responsibilities and made it difficult for staffers to review applications and inspect manufacturing facilities in a timely manner. The resulting delays generated support for the Prescription Drug User Fee Act of 1992, which required pharmaceutical and biotech companies to pay fees to support a more efficient FDA review process for NDAs and BLAs.  

A global initiative to accelerate drug development by harmonizing product testing standards also was launched at this time.  

In 1992, FDA joined regulators and manufacturers from Europe and Japan to establish the International Conference on Harmonization, which produced numerous guidelines for assessing drug quality and for conducting preclinical animal tests and clinical studies.  

In reauthorizing the user fee program in 1997 (PDUFA II), Congress enacted the FDA Modernization Act (FDAMA) that revised many agency practices. A key section of this law provides six months of added exclusivity on a drug if the manufacturer conducts additional studies to add pediatric information to the product's label.  

Efforts to support biomedical innovation and streamline FDA regulatory processes have become even more visible in recent years. In the wake of 9/11, Congress approved the Project BioShield Act of 2004, which encourages development of drugs and vaccines to prevent or treat bioterrorist threats. FDA launched a major project in 2002 to update the regulation of good manufacturing practices for drugs and biologics that advocates a more risk-based approach for inspecting manufacturing facilities and ensuring product quality.  

Another key initiative champions new approaches and new tools to encourage pharmaceutical innovation. FDA's Critical Path report of 2004 urges additional agency collaboration with industry to spur R&D, and a subsequent Opportunities List describes a range of research and regulatory initiatives with potential to lead to more biomedical discovery.  

At the same time, drug safety has emerged as a major public concern. Evidence linking Cox-2 inhibitor painkillers to cardiovascular events spurred a major outcry in 2004 that lax FDA policies were exposing patients to unsafe drugs. Manufacturers pulled a number of products off the market, and FDA launched several initiatives to make drug safety oversight more open and effective, with more changes still to come.  

Today, FDA has some 10,000 staffers and a $2 billion annual budget. Agency leaders strive to promote patient access to needed therapies as well as to keep unsafe products off the market. Globalization has transformed how FDA monitors regulated products; user fees have altered the agency's relationship with pharmaceutical and biotech manufacturers; and new technologies continually change how FDA conducts business, developments that will continue in FDA's next hundred years.  

 is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634 		

FDA did not gain any real teeth for regulating unsafe and ineffective products until a national health disaster in 1937 roused a public outcry.

Regulatory Beat: Biologics Oversight Challenges Federal Regulators

				When former Federal Reserve chairman Alan Greenspan's term in office expired on January 31, 2006, many people said, "There goes a legend." Maybe the better expression was, "Here comes the spin."			

The conventional belief was that Greenspan ran the nation's economy like a true cultural icon. Supposedly, he was an economic Merlin who assured prosperity by astute reading of the economic tea leaves and subtle policy adjustments. For 18 years, longer than any of his predecessors, he led the US Federal Reserve Bank (The Fed) very much in his own image—strong, deliberate, intelligent, and responding to the needs and desires of his time. 

Some see it differently. Ravi Batra, author of the myth-bashing book "Greenspan's Fraud" (Palgrave Macmillan, New York, 2005) says that the "real impact" of Greenspan's term was akin to a high-explosive detonation. 

A proponent of "rational selfishness" and a disciple of Ayn Rand, Greenspan "unwittingly effected a global crash and spread economic misery on our planet," writes Batra. "Duplicity underlies his actions. Whether it is Social Security, taxes, industrial deregulation, or financial markets, Greenspan sways it all." 

Batra accuses Greenspan of profiting from his own tax policies, engineering through his economic policies the dot-com bubble and subsequent recession, and sending millions of Americans into poverty.  

Whatever one thinks of Greenspan, he's history. That became official on February 1, when Ben Bernanke was sworn in as his replacement. The people on Wall Street and Main Street, who revered Greenspan for almost two decades, began speculating on how the new chief would perform. 

That's important—not just to the life sciences industry, but to investors everywhere. The Fed is crucial to the US economy; part gatekeeper and part financial manipulator. The Federal Reserve is the bank of the US government and, as such, regulates all US financial institutions. Many  have deep investment interests in the biopharm industry. One utterance from Ben Bernanke and the stock prices of Merck or Roche could plummet within minutes. The new Fed chair found that out the hard way when some cocktail party  comments on inflation and interest rates to CNBC reporter Maria Bartiromo went to her audience the next morning, sending the stock market into a steep dive.  

Past that glitch, Bernanke seems to be operating on an even keel, albeit steering a vessel across stormy economic seas. 

Consider that, in its first 100 or so days, Bernanke's Fed has had to grapple with a record $800 billion trade account deficit, a $319 billion budget deficit, and a population that has virtually stopped saving but loves borrowing.  

Bernanke's been focused on addressing these and other issues during his first few months—setting sound monetary policy that's heavy on growth and low on inflation. Unlike Greenspan, however, he has some very different notions for achieving it. 

The centerpiece of his plan is creating a transparent Federal Reserve, an approach contrary to how Greenspan steered the ship. Still, Bernanke is steadfast in his belief that the Fed should make its moves abundantly clear to stakeholders, stay focused on finances and interest rates instead of debts and deficits, and speak a language that the markets can understand without the need of a translator.  

"Fresh air," Bernanke's quoted as saying, "is good for the Federal Reserve." And the best way he sees to achieve it involves: 					

Communicating as clearly as possible about the Fed's intentions.

Greenspan and Bernanke both recognize the central bank's need to recalibrate its money strategy and maintain a low and stable rate of inflation. It's their philosophies for doing so, however, that are distinctly different.  

"Where [Bernanke] differs from Greenspan is that he is more in favor of explicitly putting a rule on monetary policy," says Victor Zarnowitz, a retired University of Chicago economist who now works at the Conference Board in New York City. 

That rule involves what economists call "inflation targeting," a practice that has been embraced in other countries. It involves setting a public target for inflation, preferably between one and three percent based on the Consumer Price Index. This target is then used as a benchmark against which the central bank can be accountable.   

Proponents of such targets, like Bernanke, view them as good for helping the Fed identify when it's time to clamp down on inflation (i.e., if rates exceed the designated range). They also see targets as a means for: 					

Providing greater confidence to investors in stocks, bonds, currency, and commodity markets, as they help clarify just where interest rates are headed. 

Reining in expectations. After all, European countries that have adopted inflation targeting have successfully controlled inflation without sending markets into sharp gyrations.

Managing unemployment and inflation, and controlling the growth of the money supply by signaling when to adjust interest rates. 

Building support for the Fed's actions. "The more guidance a central bank can provide to the public about how policy is likely to evolve," Bernanke said in 2004, "the greater the chance that market participants will make the appropriate inferences." 

Opponents of inflation targets, have typically shied away from using them as a motivator. "Greenspan would [prefer to] rely on judgment, which in his case, depends so much on the judgment of a single man," says Zarnowitz. And, in fact, Greenspan has publicly expressed his reluctance in using targets, in favor of a more discretionary approach. 

Critics worry that once you quantify an objective publicly, you become more accountable for it, and in the process, shift public attention to it, diminishing the visibility and viability of other important policies and initiatives.  

No one knows how the market might react to publicly announced inflation targets. "The markets would have to learn," says Michael Levy, chief economist at Bank of America. He adds that because Bernanke's written extensively on inflation targets, his credibility and expertise on the topic will help to bring investors along. 

Looking ahead, experts say that Bernanke's greatest challenge will be leading the Fed to act as a central bank for the world. This is something that Greenspan tried to embrace, despite the discomfort of some traditional economists. They argue that the Fed's primary mandate is to promote full employment and price stability at home.  

Still, it's becoming increasingly obvious that achieving this domestic mandate is the best way to contribute to the economic stability of the world. Due to economic and financial integration it is becoming difficult for any government agency to compartmentalize itself and its policies. 

Greenspan had his moments. He understood the importance of the world in setting monetary policy and participated by promoting cooperative research and solutions to common global policies (i.e., ranging from the Y2K transition and the aftermath of 9/11). His administration did it the careful way, choosing to be selective about the initiatives it undertook; engaging in international economic and financial issues only when they became too important to ignore.  

Now, with Bernanke at the helm, it remains to be seen how he'll address these things. The betting here is that he will take a proactive approach in managing international financial affairs and transforming banks into global institutions—as well as cultivating the public's confidence in a central banking system that recognizes the need for growth and risk-taking that have come to define the life sciences market. Here's hoping Big Ben is up to the task. 

Celebrity author and business/finance commentator for CNN and Fox News, 

, 79 Radcliffe Drive, Doylestown, PA 18901, 267.880.3144, fax 267.880.1939, 

When former Federal Reserve chairman Alan Greenspan's term in office expired on January 31, 2006, many people said, "There goes a legend." Maybe the better expression was, "Here comes the spin."

StreetTalk: Transition at the Fed: From Greenspan to Bernanke

To date, about 165 biopharmaceuticals have gained marketing approval in the United States or Europe; approximately one in every four drugs introduced on the market is a biopharmaceutical.

  The term "biopharmaceutical," as used here, refers to recombinant therapeutic proteins, monoclonal antibodies used for therapeutic or 

diagnostic purposes, or nucleic acid-based products. 

The global annual sales value of these products is about $33 billion, with recombinant erythropoietin (EPO) sales alone reaching $10.7 billion last year. Sales values of nonantibody-based therapeutic proteins are forecast to reach $52 billion by 2010,

  while sales values of therapeutic monoclonals will likely reach $16.7 billion by 2008.

  The biopharmaceutical market should approach or surpass $70 billion by the end of this decade. 			

In 2005, 10 biopharmaceuticals won approval in the United States or Europe. These were six hormones and growth factors, two antibody-based products, and two therapeutic enzymes (Table 1). Compared with previous approvals, this profile was somewhat out of the ordinary; there were no additional blood factors, anticoagulants, thrombolytics, interferons, interleukins, or recombinant vaccines. The profile of associated target indications also was atypical; for example, only one product (Avastin) was indicated for the treatment of cancer. 

Only five of the 10 approvals are genuinely new molecular entities. Levemir and Kepivance, and Xolair and Avastin, although approved in Europe last year, gained approval before 2005 in some other world regions. The active biotech ingredient of GEM 21S, on the other hand, is identical to the active ingredient in Regranex, a product approved in 1997. In terms of expression systems used, four of the approved biopharmaceuticals are produced in mammalian cell lines and in Escherichia coli (

. Two are produced in engineered Saccharomyces cerevisiae (

, again confirming that these three expression systems are the workhorses of the biopharmaceutical industry. 

Table 1. Biopharmaceuticals (defined as recombinant proteins, monoclonal antibody and nucleic acid-based products) approved in the United States or European Union in 2005. 			

In 2005, there were notable approvals of nonparenteral delivery systems and biosimiliars. Until last year, all approved biopharmaceuticals required to enter the bloodstream were administered parenterally. Parenteral drug administration, however, often results in reduced patient compliance and potential complications when in nonclinical settings. Fortical (Table 1) is the first biologic product delivered systemically by an alternative (intranasal) means. Nasal delivery is attractive because it is convenient. Also, the presence of high-density blood vessels, along with nasal microvilli, generates a large potential absorption surface area. Peptides and  smaller proteins are often absorbed intranasally with acceptable bioavailabilities. Larger molecules—with a molecular mass greater than 10 kDa—are poorly absorbed through nasal membranes, so this approach is less attractive for many biopharmaceuticals. 

In 2005, Omnitrope (a recombinant hGH produced by Sandoz (Princeton, NJ) became the first biosimiliar product to be approved in Australia, and this year won approval in both Europe and the US. 

Last year had its downside, to be sure. Tysabri was abruptly withdrawn in February after only four months on the market for patent safety issues. In June 2006 it was reintroduced under altered, more limited indications. 

The remainder of this article provides detailed information about the products approved in 2005. Data was gathered from regulatory sources,

  as well as the web sites of sponsoring companies. Details about Levemir, Kepivance, and Avastin were included in the May 2005 issue of 

(calcitonin-salmon, recombinant) is a 32-amino-acid, single- chain, polypeptide hormone produced by recombinant means in 

. It gained approval in the US in 2005 for the treatment of postmenopausal osteoporosis. Calcitonin is secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. The hormone increases the amount of calcium and phosphate in bones and also reduces serum calcium levels.  

Salmon calcitonin is 30 times more potent in humans when compared with the endogenous human hormone, hence its application in medicine. Chemically synthesized calcitonin of both human and salmon sequence has been used for over 20 years and recombinant salmon calcitonin (Forcaltonin) was approved in the EU in 1999 for the treatment of the bone disorder Paget's disease.  After fermentation of the producer microorganism, Fortical is chromatographically purified and formulated with citric acid, sodium chloride, phenylethyl and benzyl alcohol, and polysorbate as excipients. It is presented as a metered dose solution (3.7 mL), with an associated pumping mechanism for nasal delivery. A single spray delivers 200 IU calcitonin activity in a volume of 0.09 mL. The recommended dosage schedule is one intranasal spray daily. Mean product bioavailability is 3% (with a range of 0.3–30% reported), and absorption through the nasal mucosa is rapid. 

Postmenopausal osteoporosis is characterized by low bone mass and increased bone fragility, caused by a disproportionate rate of bone reabsorption, compared with bone formation. Consequently, there is an increased risk of fracture, particularly of the vertebrae, hip, and distal forearm. Calcitonin inhibits the bone reabsorption process. Intranasally administered product increases spinal bone mass in postmenopausal women with established osteoporosis as demonstrated by two randomized placebo controlled trials involving 325 women. Adverse reactions were generally mild to moderate, with nasal-related problems, such as irritation and soreness most commonly reported. Fortical is manufactured by Unigene Laboratories and distributed by Upsher-Smith Laboratories (Maple Grove, MN). 

(growth-factor-enhanced matrix), approved by FDA last year, is classified as a medical device. It consists of two components, tricalcium phosphate and recombinant human platelet-derived growth factor-BB (rhPDGF-BB). It is indicated for the treatment of specific defects of the tissue supporting the teeth (periodontal defects). 

The product is supplied as a kit consisting of a cup containing 0.5 mL of tricalcium phosphate and a syringe containing 0.5 mL of rhPDGF-BB (0.3 mg/mL). The two constituents are aseptically mixed immediately before use, allowed to stand for 10 minutes, and directly applied to the damaged area. The tricalcium phosphate generates a sponge-like porous scaffold for the PDGF, provides a framework for bone ingrowth, and helps stabilize the surrounding soft tissue. The PDGF exerts potent mitogenic and chemotactic effects on bone and periodontal ligament-derived cells, thereby accelerating periodontal healing.  

Native human PDGF is a dimer, with two constituent polypeptides identified (A and B) and three active isoforms: AA, AB, and BB. The BB isoform is glycosylated, with the two 109-amino-acid polypeptides held together by interchain disulphide bonds. The product is produced in engineered 

, followed by multistep chromatographic purification. The same active ingredient (but formulated as a gel and applied topically) has been on the market since the late 1990s under the tradename Regranex, for the treatment of diabetic ulcers. 

Initial animal studies show that PDGF promotes the regeneration of periodontal tissues including bone, cementium, and periodontal ligament. The safety and efficacy of GEM 21S in humans were primarily demonstrated via a multicenter, double-blinded, randomized, controlled, prospective clinical trial involving 180 patients who required surgical intervention to treat periodontal defects. 

Efficacy was monitored using clinical attachment-level measurements and radiographic bone measurements over a six-month period, with significantly increased endpoint values reported for the GEM 21S group. No serious adverse events attributable to the product were reported, although standard events associated with periodontal grafting procedures (e.g., pain, swelling, and bleeding) were noted. GEM 21S is manufactured by BioMimetic Pharmaceuticals (Franklin, TN) and is distributed by Osteohealth, a division of Luitpold Pharmaceuticals (both in Shirley, NY). 

(hyaluronidase recombinant human), as its generic name suggests, is a purified preparation of recombinant human hyaluronidase. It is a 447-amino-acid glycoprotein of approximate molecular mass 61 kDa. The FDA approved it in 2005 as an adjuvant to increase the absorption and dispersion of other injected drugs, as well as for hypodermoclysis (subcutaneous-based fluid replacement) and as an adjuvant in subcutaneous urography for improving resorption of radiopaque agents. 

Hyaluronidases are enzymes that degrade hyaluronan, a high-molecular mass, linear-structural polysaccharide consisting of repeating disaccharide units of D-glucuronic acid linked to N-acetyl D glucosamine. The enzyme is widely distributed in the extracellular matrix, vitreous humor, cartilage, and several other tissues of higher animals. Subcutaneous administration of hyaluronidase increases the permeability of the local connective tissue via hyaluronan degradation.   

The enzyme therefore can act as a spreading agent, facilitating more rapid diffusion of subcutaneously coadministered fluids or localized transudates or exudates, facilitating their more rapid systemic absorption. Bovine and ovine hyaluronidase directly extracted from native tissue traditionally has been used for cosmetic and pharmaceutical purposes in orthopedics, ophthalmology, and general medicine. 

The advent of bovine spongiform encephalitis has all but halted commercial use of the bovine enzyme. Production via recombinant means largely overcomes potential accidental pathogen transmission. Upstream processing entails cell culture of the producer CHO cell line with multistep chromatographic purification after initial product recovery. Final product is formulated as a solution for subcutaneious  administration. It contains 150 USP units of recombinant enzyme/mL, sodium chloride, sodium phosphate buffer components, human serum albumin, calcium chloride, and edentate disodium as excipients. 

Enhanced absorption and distribution of drugs are usually achieved by subcutaneous coadministration of 150 IU hyaluronidase activity. The most frequently reported adverse reactions occur at the local injection site and sometimes allergic reactions occur. Hylenex is manufactured by Baxter Healthcare Corporation (Deerfield, IL

 and distributed by Baxter and Halozyme Therapeutics  (San Diego, CA). 

(mecasermin) is a recombinant form of human insulin-like growth factor-1 (rhIGF-1) produced in 

. The 7.6 kDa, 70-amino-acid, single-chain polypeptide displays an amino acid sequence identical to that of the native human growth factor. It is characterized by the presence of three intrachain disulphide linkages. The product was approved for general medical use by the FDA last year and is indicated for the long-term treatment of growth failure in children with primary IGF-1 deficiency or growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH (see also IPLEX entry below). 

IGF, as its name suggests, bears a strong structural resemblance to proinsulin. IGF-1 is synthesized primarily in the liver, and then released into the bloodstream. Its cell surface receptors are found on a wide variety of cell types in the body. Transcription of the IGF-1 gene is strongly initiated when GH binds to its hepatic receptor, and most of the growth-promoting effects of GH are actually mediated by IGF-1. Direct injection of IGF-1 into animals whose pituitary gland (and hence source of GH) have been removed stimulated longitudinal bone growth, as well as growth of various organs, including the kidneys, spleen, and thymus. 

Increlex manufacture is initiated by fermentation of the producer 

 cells. After initial product recovery, it is subject to a number of high resolution chromatographic steps. Excipients added are sodium acetate buffer components, sodium chloride benzyl alcohol, and polysorbate 20. After filter sterilization, the product (10 mg/mL active) is aseptically filled into multidose glass vials (40 mg active/vial). 

Increlex is generally administered twice daily by subcutaneous injection at a starting dose of 40–80μg/kg. Long-term product dosage levels are individualized for each patient. Bioavailability following subcutaneous administration is close to 100% and mean terminal serum half life in pediatric patients is estimated at 5.8 hours. 

Product safety and efficacy were assessed by a total of five clinical studies conducted in 71 pediatric patients, with treatment supporting mean height velocities (cm growth per year) ranging from 2.8–8.0 over several years. Adverse events included hypoglycemia. The product is contraindicated in the presence of active or suspected neoplasia, because of the potential stimulatory effect on cancer cell growth. Increlex is manufactured by Baxter and distributed by Tercica (Brisbane, CA).  

(mecasermin rinfabate) contains a protein complex of rhIGF-1 and rhIGF-binding protein 3 (rhIGFBP-3), both of which are produced in (separate) 

 strains. rhIGF-1 is a single-chain, 70-amino-acid polypeptide (see Increlex entry). RhIGFBP-3 is a single-chain, 264-amino-acid, 28.7 kDa polypeptide containing 18 cysteine residues, all of which participate in disulphide bond formation. Both recombinant polypeptides present in IPLEX display amino acid sequences identical to the native human proteins. Naturally occurring IGFBP-3 is glycosylated, while the recombinant version is devoid of this post-translational modification, a consequence of expression in 

. When mixed together, the two molecules form a 1:1 molar ratio complex of overall molecular mass 36.4 kDa. The product gained approval in the US in 2005 and is indicated for the treatment of growth failure in children with primary IGF-1 deficiency or with GH gene deletion who have developed neutralizing antibodies to GH. 

As described in the context of Increlex, most of the growth-promoting effects of GH are actually mediated by IGF-1. The growth factor promotes linear growth, as well as additional anabolic effects. In serum, IGF is invariably complexed to an IFGBP, of which there are six (IGFBP-1 to IGFBP-6). Individual IGFBPs display differing amino acid sequences and molecular masses, although they generally exhibit in the region of 50% homology to each other. The bulk of serum IGF-1 is found as an equimolar (1:1:1) complex, with IGFBP-3 and an acid-labile polypeptide. IGFBPs most likely fulfill several biological functions, including stabilization and protection of IGF-1 from proteolysis in the serum, increasing serum half-life, and modulating IGF-1 function locally at the surface of IGF-1 sensitive cells. This includes modulating their potential to induce hypoglycemia. Free IGF-1 can interact with the insulin receptor, although relatively weakly, and it consequently displays about 5% of the hypoglycemic potential of insulin.   

Product manufacture entails separate fermentation and purification procedures of both recombinant proteins. After mixing, the final product is formulated to a concentration of 36 mg/0.6 mL filled in a single-use glass vial. The final product contains sodium acetate buffer components and sodium chloride as excipients. 

Pharmacokinetic studies indicate that the mean serum half-life of IGF-1 when complexed to its binding protein is 13 hours, which supports its once daily subcutaneous administration. Exact dosage levels may be individualized for each patient but starting doses are typically 0.5 mg/kg, increased to 1–2 mg/kg.  

Product approval was largely granted based on results from a single, open-label, multicenter study in 36 prepubertal subjects. Eighty-nine percent (32 subjects) had primary GH receptor deficiency (Laron syndrome), while three individuals (8%) had GH gene deletion with neutralizing antibodies to GH. After six months of treatment, annualized height velocity (cm/year) was almost doubled (from 3.4 to 7.4) upon treatment with 1 mg product/kg daily, while treatment with 2 mg/kg daily increased annualized height velocity levels to a mean of 8.8 cm. Adverse reactions sometimes associated with the product include hypoglycemia and lymphoid tissue hypertrophy. The product is contraindicated in the presence of active or suspected neoplasia. IPLEX is manufactured and marketed by Insmed (Glen Allen, VA). 

 (galsulfase) is a recombinant version of the human enzyme N-acetylgalactosamine 4-sulfatase produced by an engineered CHO cell line. The 495-amino-acid, 56 kDa enzyme, also contains six asparagine-linked (N-linked) glycosylation sites, carrying a mixture of complex high-mannose and phosphorylated high-mannose oligosaccharides. A second, post-translational modification characteristic of the enzyme is the conversion (within the endoplasmic reticulum of producing cells) of cysteine 53 into a formylglycine residue. This modification is essential for catalytic activity. 

Naglazyme, which holds orphan status, was approved in the US in 2005 (and subsequently in Europe this year) for the treatment of patients with the lysosomal storage disease, mucopolysaccharidosis VI (MPS). This rare genetic defect, with an estimated 1100 cases in the developed world, is characterized by the absence of lysosomal N-acetylgalactosamine 4-sulfatase. The enzyme normally participates in the degradation of the glycosaminoglycan dermatan sulphate (a sugar polymer), and in affected individuals it accumulates in the lysosomes. Accumulation ultimately causes multiple medical complications, including skeletal deformity, joint disease, and cardiopulmonary disease. Until the approval of Naglazyme, there had been no satisfactory treatment available for MPS. Naglazyme therapy is essentially an enzyme replacement therapy. Cellular and, subsequently, lysosomal entry from the blood are likely mediated by the binding of the enzyme's bisphosphorylated oligomannose, oligosaccharide side chains, to cell- surface, mannose-6-phosphate receptors. This triggers endocytotic uptake. The product is provided as a concentrated solution (1 mg/mL enzyme) administered by infusion once a week. Immediately before use, the product is diluted with saline to 250 mL, which is infused over a four-hour period. 

Product manufacture entails initial cell culture of the CHO producer strain with subsequent purification from the extracellular culture media. Initial harvest involves filtration, followed by an ultrafiltration-based concentration step. Purification is based on three, high-resolution chromatographic steps. Specific filtration, as well as incubation at low pH steps, are undertaken to inactivate any virus potentially present. Phosphate buffer constituents and polysorbate 80 are added as excipients. 

Clinical efficacy was assessed in three studies, in which a total of 56 MPS patients were enrolled. Primary endpoints measured were based on physical endurance tests. Product administration resulted in improved 12-minute walk distance and three-minute stairs climbing tests. Administration also resulted in decreased urinary glycosaminoglycan (GAG) levels. The most common serious adverse events noted were infusion related. Additional adverse events included headache, fever, and upper respiratory tract infections. Virtually all patients administered Naglazyme develop antibodies against the product within the first few weeks of treatment, although the long- term significance of this, if any, remains to be determined. Naglazyme is manufactured and distributed by BioMarin Pharmaceuticals (Novato, CA).  

 (omalizumab) is an engineered (humanized) IgG antibody that specifically binds to human immunoglobulin E (IgE). The 149 kDa, glycosylated antibody is produced by an engineered CHO cell line.  The product was approved in the EU in 2005, although it has been available in the US since 2003. It is indicated as an add-on treatment for asthma in individuals 12 years and older.  

Allergic asthma is a chronic condition of the respiratory tract, usually treated with inhaled corticosteroids and beta agonists. The condition is underpinned by over expression of IgE in response to environmental allergens, such as pollen or dust mites. Allergen-specific IgE in turn binds to high affinity (FcεR1) receptors on airway-associated effector cells, including mast cells and basophils.  Binding triggers release of histamine, prostaglandins, leukotrienes and cytokine-based proinflammatory mediators, thereby triggering a characteristic asthma attack. 

Xolair brings about its intended effect by binding to the IgE, thereby inhibiting their interaction with the FcεR1 receptors. Dosage regimes typically entail subtaneous  administration of 15–375 mg product every two to four weeks. The product is absorbed slowly from the site of injection, reaching peak serum concentrations after seven or eight days. 

The product is manufactured via initial cell culture in batch fed suspension mode. Purification is achieved using a combination of protein A affinity chromatography, followed by both cation exchange and anion exchange chromatographic steps. Chromatography is followed by product concentration (ultrafiltration) and diafiltration. Sucrose, histidine, and polysorbate 20 are used as excipients and the final filter-sterilized product is lyophilized in single-use vials containing either 75 or 150 mg active ingredient. 

Clinical safety and efficacy were determined mainly by five double-blind, placebo-controlled studies involving over 2,000 patients. In most trials, the number of asthma exacerbations per patient was significantly reduced by Xolair treatment. Exacerbations were defined as a worsening of asthma requiring either systemic corticosteroid administration, or a doubling of inhaled corticosteroid treatment levels. The most serious adverse reactions recorded were anaphylaxis and an increased malignancy rate (from 0.2 to 0.5% of patients). Additional adverse reactions included injection site reactions, headache, and an increased incidence of viral infection. Xolair is manufactured by Genentech (South San Francisco, CA) and is marketed by Genentech and Novartis (East Hanover, NJ).  

 senior lecturer, industrial biochemistry program, University of Limerick, Limerick City, Ireland, Tel. 353. 61. 202664, Fax 353.61.202568 		

 1 Walsh G. Biopharmaceutical benchmarks. Nature biotechnol. In press 

 2 Pavlou AK, Reichert JM. Recombinant protein therapeutics—success rates, market trends and values to 2010. Nature biotechnol. 2004;22:1513-19. 

 3 Pavlou A, Belsey, M. The therapeutic antibody market to 2008. Eur. J. Pharm. Biopharm. 2005; 59:389-396. 

In 2005, 10 biopharma- ceuticals gained marketing approval in the US or Europe, although only five of them were genuinely new molecular entities.

BioPharm International-08-01-2006

Legal Forum: Putting the "Co" in Development and Promotion: The New Biotech-Pharma Collaborations

Successful Bioreactor Installation: What it Takes

From the Editor in Chief: Science, Control, and the Seemingly Uncontrollable

Regulatory Beat: Biologics Oversight Challenges Federal Regulators

StreetTalk: Transition at the Fed: From Greenspan to Bernanke

Biopharmaceuticals: Approval Trends in 2005

Final Word: Omnitrope's Approval: What Does It Mean For Other Generics?

Production of Recombinant Therapeutic Proteins in the Milk of Transgenic Animals

Applying Process Analytical Technology to Biotech Unit Operations