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FDA NEWS RELEASE

For Immediate Release: January 12, 2010

 

FDA Unveils First Phase of Transparency Initiative

FDA Basics aims to help consumers gain better understanding of agency

 

 

The U.S. Food and Drug Administration today unveiled the first phase of its Transparency Initiative which is designed to explain agency operations, how it makes decisions, and the drug approval process.

 

During an online presentation, the chair of the FDAÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢s Transparency Task Force, Principal Deputy FDA Commissioner Joshua Sharfstein, described a Web-based curriculum called ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Â¦ÃƒƒÂ¢Ãƒ¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…âہ“FDA Basics,ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Å¡Ãƒƒâہ¡ÃƒÆ’‚ aimed at helping the public better understand what the agency does. The curriculum is accessible via a link on the FDA Web site.

 

The curriculum includes:

 

  • Questions and answers about the agency and the products it regulates
  • Short videos that explain various agency activities
  • Conversations with agency personnel about the work of their office
In addition, senior officials from FDA product centers and offices will answer questions on various topics during future online sessions. Each of these sessions will be announced on the FDA Web site.

 

In one of her first acts after assuming the office last spring, FDA Commissioner Margaret A. Hamburg, M.D. announced the formation of an internal task force to develop recommendations for enhancing the transparency of the FDAÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢s operations and decision-making processes.

 

The Transparency Initiative was launched in response to the Obama AdministrationÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢s commitment to an unprecedented level of openness in Government and with the strong support of the Department of Health and Human Services.

 

ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Â¦ÃƒƒÂ¢Ãƒ¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…âہ“This initiative will make information about the FDA more user-friendly and accessible to the public,ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Å¡Ãƒƒâہ¡ÃƒÆ’‚ said Dr. Hamburg. ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Â¦ÃƒƒÂ¢Ãƒ¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…âہ“It fosters a better understanding about what we do.ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Å¡Ãƒƒâہ¡ÃƒÆ’‚ÂÂ

 

ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Â¦ÃƒƒÂ¢Ãƒ¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…âہ“The launch of FDA Basicsis our first step towards making FDA a more transparent agency,ÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’â€Å¡Ãƒƒâہ¡ÃƒÆ’‚ said Dr. Sharfstein.

 

In recent months, the Task Force solicited public input on improving agency transparency through a public docket, an online blog, and two public meetings. The Transparency Task Force received hundreds of comments from various stakeholders, including regulated industry, consumers, patients, health care providers, and others. As a result of comments from the public, the Task Force decided to develop its recommendations in three phases. FDA Basics represents the result of the initial phase, to be followed by two additional phases.

 

In phase two of the initiative, the Task Force intends to make recommendations to the Commissioner regarding how to make information about agency activities more transparent, useful, and understandable to the public, in a manner compatible with the agencyÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢s goal of protecting confidential information, as appropriate.

 

In the final phase of the initiative, the Task Force intends to make recommendations to the Commissioner regarding FDAÃÆâ€â„¢ÃƒÆ’ƒâہ¡ÃƒÆ’‚¢ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¡Ãƒâہ¡ÃƒÆ’‚¬ÃƒÆ’¢Ã¢Ã¢Ã¢Ã¢â€š¬Ã…¡Ãƒâ€šÃ‚¬ÃƒÆ’…¾Ãƒâہ¡ÃƒÆ’‚¢s transparency to regulated industries.

 

For more information

 

FDA Transparency Task Force

http://www.fda.gov/transparency

 

FDA Basics

http://www.fda.gov/AboutFDA/Basics

 

Update on Phase I of the Transparency Initiative

http://www.fda.gov/AboutFDA/Basics/ucm197217.htm

 

 

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Monoclonal Antibodies: The Next Generation

 

Life Science Leader, April 2010

 

http://www.lifescienceleader.com/index.php...ge&aid=4003

 

The commercial success of therapeutic monoclonal antibodies (MAbs) to treat cancer, immune dysfunction, and infectious diseases has catapulted these once difficult-to-develop molecules to the forefront of modern molecular medicine. While MAbs are rapidly becoming commonplace in today's therapeutic treatment armamentarium, it wasn't until the mid to late 1990s that their full therapeutic and commercial potential were realized.

 

The gradual shift away from small molecule drugs in favor of therapeutic MAbs in the early 2000s was influenced by a variety of factors. First, unlike small molecules, MAbs offer an enormous amount of target specificity which reduces the likelihood of nonspecific, untoward side effects commonly observed with small molecules. Second, the variability that can be introduced within the antigen-binding domains of MAbs increases their molecular diversity and extends the ranges of potential therapeutic applications. Finally, the underlying molecular mechanisms responsible for the complex recombination events that take place during antibody development and maturation have been thoroughly vetted and are now completely understood. This has allowed scientists to devise cost-effective biomanufacturing strategies and production platforms to meet commercial demand for therapeutic MAbs.

 

The first therapeutic monoclonal antibody was introduced to the U.S. market in 1986. Largely ignored until almost a decade later, over 25 MAbs have garnered regulatory approval (Table 1) and there are over 100 in various phases of clinical development (Table 2). The size of the global MAb market in 2008 was valued at almost $28 billion and exhibited an annual growth rate of roughly 31% from 2002 to 2008. Industry analysts predict that the size of the MAb market will grow to almost $68 billion by 2015 with the largest growth occurring in oncology and autoimmune diseases. "The therapeutic protein gold rush of the late 1990s is over," said Tillman Gerngross, Ph.D., founder and CEO of Adimab, a New Hampshire-based therapeutic MAb discovery and development company. "If you want to be a player in the biologics space and expect to fill 20% to 30% of your pipeline with protein-based drugs, then therapeutic MAbs would be your best bet," he added.

 

Types Of MAbs Pioneering Studies

In 1975, Cesar Milstein and George Kohler developed a novel method to fuse antibody producing B cells from immunized mice with immortalized murine myeloma cells to create hybridoma cells capable of producing a single type of antibody with defined antigenic specificity. Milstein and Kohler called these molecules monoclonal antibodies (MAbs) because they were derived from a single B cell progenitor clone. The scientists were award the Nobel Prize in Medicine in 1984 for their pioneering work; shortly thereafter in 1986, the first commercial MAb Orthoclone OKT3 (Ortho Biotech) was approved for the prevention of kidney transplant rejection.

While mouse MAbs had enormous commercial potential, major roadblocks to early success were their high immunogenic potential and rapid clearance by strong human anti-mouse antigenic reactions that occurred in many of the patients who were treated with murine antibodies.

http://www.lifescienceleader.com/images/stories/Articles/2010_04/mabs_chart.jpg

Chimeric Antibodies

To overcome the limitations of murine MAbs, researchers in the early 90s used genetic engineering to link murine genes encoding the antigen binding regions (variable regions) to the genes encoding the constant region of human immunoglobulin heavy and light chains. Because over 75% of the resulting chimeric antibodies protein sequences were human in origin, the human antimurine antibody responses originally seen with mouse MAbs was much weaker in patients receiving the chimeric antibodies. Also, because the constant (Fc) regions of these MAbs was human, Fc-mediated effector functions such as complement-directed cell destruction), increased phagocytosis and enhanced tumor cell-killing properties of the chimeric MAbs were much improved over their murine predecessors. Many of the first generation of commercialized monoclonal antibodies (introduced in the 1990s) were chimeric MAbs. Examples of these include blockbusters like Remicade, Rituxan, and Eribitux (See table on page ).

 

Humanized Antibodies

In the early 1990s, scientists used molecular biological techniques to swap a portion of the variable antigen binding domain of a human MAb gene with that of a murine antigen binding sequence with known specificity. In contrast, with the previous generation of chimeric MAbs (which were 75% human); these new "humanized" MAbs contained 90% to 95% of human protein sequences. Because humanized MAbs contained less murine protein sequences than chimeric MAbs, they elicited a much weaker human antimurine antibody response and exhibited improved safety and efficacy profiles. Humanized MAbs represent the second generation of therapeutic MAbs and include products such as Synagis, Mylotarq, Xolair, and Avastin (Table 1).

 

Fully Human Antibodies

The third generation of MAbs are so-called "fully human" or human MAbs which are genetically engineered antibodies that contain only human immunoglobulin sequences. These MAbs are typically generated using either in vitro or in vivo methods. The preferred in vitro production method is called phage display in which millions of variations of human antibody sequences are expressed in phage libraries maintained in bacteria and screened for binding characteristics. The corresponding DNA sequence encoding the appropriate MAb antigen binding domain is subsequently cloned into a human MAb expression system. Transgenic mice whose antibody genes have been replaced with their human counterparts is the current preferred in vivo method used to generate human MAbs. The first fully humanized MAb to reach the market was Humira in 2002. Other previously commercialized human MAbs include Vectibix, Simponi, Ilaris, and Arzerra.

 

Because human MAbs are better tolerated and less likely to cause immunological side effects, there is a trend in the industry that favors development of human MAbs as compared with humanized and chimeric MAbs. At present there are more than 30 human MAbs in various stages of clinical development (Table 2). While phage display and transgenic mouse technologies are capable of producing fully human MAbs, they are not without their disadvantages. For example, both approaches are extremely time consuming and labor intensive and, in some instances, the antibody diversity and antigenic (epitopic) coverage was limited in therapeutic MAbs generated using these techniques. Further, and perhaps most importantly, both technologies are inordinately expensive and costly.

 

The Next Generation

The utility and commercial successes of therapeutic MAbs has induced several forward- looking biotechnology companies to develop novel antibody engineering platforms that promise to expand the therapeutic reach, improve the biological properties, and enhance the commercial value of the next generation of therapeutic MAbs.

 

Two venture-backed, private companies, AnaptysBio and Adimab, have developed innovative technology platforms designed to increase diversity, improve antigen binding, and optimize the performance of human therapeutic MAbs. Both companies offer their technology platforms to prospective pharmaceutical and biotechnology clients via partnerships or collaborative research agreements. While AnaptysBio is developing its own internal therapeutic MAb pipeline, Adimab is primarily a provider that is willing to enter into business relationships with customers who are developing antibodies.

 

The AnaptysBio platform is a human-like mammalian cell system based on the ability of a cellular DNA repair enzyme called activation-induced cytidine deaminase (AID) to induce large numbers of somatic mutations in the variable region of the MAb antigen binding domains during antibody maturation. According to CEO, Tom Smart, this iterative, laboratory-based process called somatic hypermutation (SHM) mimics the affinity maturation that normally occurs during normal antibody development in B cells.

 

By combining SHM technology with high throughput Fluorescence Activated Cell Sorting (FACS) technology, MAbs with predetermined epitopic coverage and binding characteristics and specificities can be identified and subsequently optimized to meet antibody design goals. One of the novel features of the AnaptysBio expression system is that candidate MAbs can be secreted as well as expressed on the SHM cell surface. "The ability of specific MAbs to be secreted during the SMH process helps to determine whether or not candidate antibodies can be manufactured in sufficient quantities for commercialization purposes," said Smart. Also, Smart suggested that if used correctly SMH could be used to discover and optimize MAbs (with picomolar binding affinities) within six months. To date, AnaptysBio has signed collaborative discovery agreements with Merck, Roche and an undisclosed pharmaceutical company.

 

Adimab has developed a therapeutic MAb discovery platform that is based on a fully synthetic human pre-immune repertoire of antibodies which are displayed on the surface of yeast. Therapeutically relevant antibodies in Adimab's libraries are identified and selected via FACS enrichment of yeast cells displaying candidate MAbs. Because yeast cells assemble antibodies and other proteins using a mammalian format, CEO Gerngross contends that fully human antibodies produced by the Adimab platform will work better than MAbs generated using phage display and related technologies.

 

"We can quickly hand our customers hundreds of fully human MAbs with a wide range of diversity and epitopic coverage in eight weeks," said Gerngross. Based on current industry standards this timeline may sound overly aggressive. However, two of Adimab's large pharmaceutical partners, Roche and Merck, have publicly acknowledged that, in fact, eight weeks after initiating a project they received literally hundreds of potential MAb candidate molecules. Adimab also has entered into R&D development deals with Pfizer and an undisclosed pharmaceutical company.

 

It is important to note that Adimab is the second technology company started by Gerngross. His first company, Glycofi, which developed a humanized yeast biomanufacturing platform mainly based on Gerngross' research conducted at Dartmouth, was sold to Merck in 2006 for over $400 million. In late 2009, Merck announced that it will use the Glycofi platform to enter and compete in the nascent biosimilar (aka follow-on biologics) space. Gerngross added that "Adimab will have a greater impact on protein-based therapeutics than Glycofi."

 

Unlike AnaptysBio and Adimab, Xencor developed a technology platform that can be used to molecularly manipulate an antibody's Fc region. In contrast with the antibody binding domains which bind antigens, the Fc portion mediates the biological effector functions of antibodies. These effector functions include antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent lysis (CDL), both of which can kill cancer cells or infectious agents like bacteria and viruses. Further, the protein sequence and glycosylation pattern found in the Fc portion of antibodies has long been known to affect circulation half-life, turnover rates, and pharmacological properties of these molecules. Recognizing this, Xencor developed a computational biology-driven, molecular engineering platform to modify or reengineer Fc domains to improve, optimize, or change the biological and pharmacological properties of extant or novel therapeutic MAbs.

 

Bassil Dahiyat, Ph.D., Xencor's President and CEO, suggests the company's Fc engineering platform offers companies with marketed MAbs an opportunity to develop improved second generation products. "I believe that reengineering the Fc portion of an antibody molecule to improve the performance of therapeutic MAb is certainly less labor intensive and easier than some of the other technologies like protein PEGylation that are out there," said Dahiyat. Also, Dahiyat stressed that Xencor's proprietary technology may help to extend the patent life of first generation therapeutic MAbs.

 

While biosimilar versions of therapeutic MAbs are not likely to appear on the U.S. market for another four to five years, Dahiyat contends that Xencor's Fc technology will allow innovator companies to quickly develop improved, competitively-priced second generation MAbs that will almost certainly outcompete first-generation antibodies offered by competitors. In addition to licensing deals, Xencor is also developing its own internal MAb pipeline and recently advanced one of its candidate molecules into Phase I human clinical trials. Some of Xencor's pharmaceutical and biotechnology partners include CSL, Pfizer, Merck, MedImmune, Genentech, Lilly, Boehringer Ingelheim, and Human Genome Sciences.

 

The Future

Over the past decade, protein-based drugs have begun to constitute a larger percentage of most pharmaceutical companies' drug development pipelines. This is because of the lack of innovation in small molecule drug discovery and the growing acceptance and rapid uptake of biotechnology drugs. While therapeutic proteins were early industry favorites, it is becoming increasingly difficult to discover and bring new ones to market. The molecular diversity, target specificity, and improved manufacturing and safety profiles of many of the commercialized therapeutic MAbs, (coupled with annual growth rate of 30%), suggest that MAbs will likely be in the spotlight for the foreseeable future. To that end, over the past year or so, no fewer than seven MAb developers were purchased by big pharmaceutical companies including Domantis (GlaxoSmithKline), Adnexus and Medarex (Bristol-Myers Squibb), Biorexis, CovX and Haptogen (Pfizer), and ImClone (Lilly). Companies such as Genmab, Morphosys, Micromet, and Dyax are examples of some of the few remaining independent MAb developers.

 

While many of the early commercialized MAbs were developed to treat inflammatory diseases like rheumatoid arthritis and psoriasis and several oncology indications (Table 1), the next generation of MAbs that are being developed are expected to target new therapeutic areas including cardiovascular disease, metabolic diseases like diabetes and obesity, neurological disorders including Alzheimer's disease, and infectious diseases. However, CEOs Gerngross, Smart, and Dahiyat all agree that oncology, inflammation, and autoimmune diseases will continue to remain therapeutic areas of intense interest.

 

Finally, while therapeutic MAbs appear to be center stage at the moment, expect more emphasis to be placed on the discovery and commercialization of MAbs as diagnostic and prognostic tools as the age of personalized medicine continues to evolve.

 

The first therapeutic monoclonal antibody was introduced to the U.S. market in 1986. Largely ignored until almost a decade later, over 25 MAbs have garnered regulatory approval (see table below) and there are over 100 in various phases of clinical development. The size of the global MAb market in 2008 was valued at almost $28 billion and exhibited an annual growth rate of roughly 31% from 2002 to 2008. Industry analysts predict that the size of the MAb market will grow to almost $68 billion by 2015 with the largest growth occurring in oncology and autoimmune diseases. "The therapeutic protein gold rush of the late 1990s is over," said Tillman Gerngross, Ph.D., founder and CEO of Adimab, a New Hampshire-based therapeutic MAb discovery and development company. "If you want to be a player in the biologics space and expect to fill 20% to 30% of your pipeline with protein-based drugs, then therapeutic MAbs would be your best bet," he added.

 

Types Of MAbs Pioneering Studies

In 1975, Cesar Milstein and George Kohler developed a novel method to fuse antibody-producing B cells from immunized mice with immortalized murine myeloma cells to create hybridoma cells capable of producing a single type of antibody with defined antigenic specificity. Milstein and Kohler called these molecules MAbs because they were derived from a single B cell progenitor clone. The scientists were awarded the Nobel Prize in Medicine in 1984 for their pioneering work; shortly thereafter in 1986, the first commercial MAb Orthoclone OKT3 (Ortho Biotech) was approved for the prevention of kidney transplant rejection.

 

While mouse MAbs had enormous commercial potential, major roadblocks to early success were their high immunogenic potential and rapid clearance by strong human antimouse antigenic reactions that occurred in many of the patients who were treated with murine antibodies.

 

Chimeric Antibodies

To overcome the limitations of murine MAbs, researchers in the early 1990s used genetic engineering to link murine genes encoding the antigen binding regions (variable regions) to the genes encoding the constant region of human immunoglobulin heavy and light chains. Because over 75% of the resulting chimeric antibodies' protein sequences were human in origin, the human antimurine antibody responses originally seen with mouse MAbs was much weaker in patients receiving the chimeric antibodies. Also, because the constant (Fc) regions of these MAbs was human, Fc-mediated effector functions such as complement-directed cell destruction, increased phagocytosis, and enhanced tumor cell-killing properties of the chimeric MAbs were much improved over their murine predecessors. Many of the first generation of commercialized monoclonal antibodies (introduced in the 1990s) were chimeric MAbs. Examples of these include blockbusters like Remicade, Rituxan, and Eribitux.

 

Humanized Antibodies

In the early 1990s, scientists used molecular biological techniques to swap a portion of the variable antigen-binding domain of a human MAb gene with that of a murine antigen-binding sequence with known specificity. In contrast, with the previous generation of chimeric MAbs (which were 75% human), these new "humanized" MAbs contained 90% to 95% of human protein sequences. Because humanized MAbs contained less murine protein sequences than chimeric MAbs, they elicited a much weaker human antimurine antibody response and exhibited improved safety and efficacy profiles. Humanized MAbs represent the second generation of therapeutic MAbs and include products such as Synagis, Mylotarq, Xolair, and Avastin.

 

Fully Human Antibodies

The third generation of MAbs are so-called "fully human" or human MAbs which are genetically engineered antibodies that contain only human immunoglobulin sequences. These MAbs are typically generated using either in vitro or in vivo methods. The preferred in vitro production method is called phage display in which millions of variations of human antibody sequences are expressed in phage libraries maintained in bacteria and screened for binding characteristics. The corresponding DNA sequence encoding the appropriate MAb antigen-binding domain is subsequently cloned into a human MAb expression system. Transgenic mice whose antibody genes have been replaced with their human counterparts is the current preferred in vivo method used to generate human MAbs. The first fully humanized MAb to reach the market was Humira in 2002. Other previously commercialized human MAbs include Vectibix, Simponi, Ilaris, and Arzerra.

 

Because human MAbs are better tolerated and less likely to cause immunological side effects, there is a trend in the industry that favors development of human MAbs as compared with humanized and chimeric MAbs. At present there are more than 30 human MAbs in various stages of clinical development. While phage display and transgenic mouse technologies are capable of producing fully human MAbs, they are not without their disadvantages. For example, both approaches are extremely time-consuming and labor- intensive, and, in some instances, the antibody diversity and antigenic (epitopic) coverage were limited in therapeutic MAbs generated using these techniques. Further, and perhaps most importantly, both technologies are inordinately expensive and costly.

 

The Next Generation

The utility and commercial successes of therapeutic MAbs has induced several forward-looking biotechnology companies to develop novel antibody engineering platforms that promise to expand the therapeutic reach, improve the biological properties, and enhance the commercial value of the next generation of therapeutic MAbs.

 

Two venture-backed, private companies, AnaptysBio and Adimab, have developed innovative technology platforms designed to increase diversity, improve antigen binding, and optimize the performance of human therapeutic MAbs. Both companies offer their technology platforms to prospective pharmaceutical and biotechnology clients via partnerships or collaborative research agreements. While AnaptysBio is developing its own internal therapeutic MAb pipeline, Adimab is primarily a provider that is willing to enter into business relationships with customers that are developing antibodies.

 

The AnaptysBio platform is a human-like mammalian cell system based on the ability of a cellular DNA repair enzyme called activation-induced cytidine deaminase (AID) to induce large numbers of somatic mutations in the variable region of the MAb antigen-binding domains during antibody maturation. According to AnaptysBio CEO, Tom Smart, this iterative, laboratory-based process called somatic hypermutation (SHM) mimics the affinity maturation that normally occurs during normal antibody development in B cells.

By combining SHM technology with high throughput Fluorescence Activated Cell Sorting (FACS) technology, MAbs with predetermined epitopic coverage and binding characteristics and specificities can be identified and subsequently optimized to meet antibody design goals. One of the novel features of the AnaptysBio expression system is that candidate MAbs can be secreted as well as expressed on the SHM cell surface. "The ability of specific MAbs to be secreted during the SMH process helps to determine whether or not candidate antibodies can be manufactured in sufficient quantities for commercialization purposes," said Smart. Also, Smart suggested that if used correctly, SMH could be used to discover and optimize MAbs (with picomolar-binding affinities) within six months. To date, AnaptysBio has signed collaborative discovery agreements with Merck, Roche, and an undisclosed pharmaceutical company.

 

Adimab has developed a therapeutic MAb discovery platform that is based on a fully synthetic human pre-immune repertoire of antibodies which are displayed on the surface of yeast. Therapeutically relevant antibodies in Adimab's libraries are identified and selected via FACS enrichment of yeast cells displaying candidate MAbs. Because yeast cells assemble antibodies and other proteins using a mammalian format, CEO Gerngross contends that fully human antibodies produced by the Adimab platform will work better than MAbs generated using phage display and related technologies.

 

"We can quickly hand our customers hundreds of fully human MAbs with a wide range of diversity and epitopic coverage in eight weeks," said Gerngross. Based on current industry standards this timeline may sound overly aggressive. However, two of Adimab's large pharmaceutical partners, Roche and Merck, have publicly acknowledged that, in fact, eight weeks after initiating a project they received literally hundreds of potential MAb candidate molecules. Adimab also has entered into R&D development deals with Pfizer and an undisclosed pharmaceutical company.

 

It is important to note that Adimab is the second technology company started by Gerngross. His first company, Glycofi, which developed a humanized yeast biomanufacturing platform mainly based on Gerngross' research conducted at Dartmouth, was sold to Merck in 2006 for over $400 million. In late 2009, Merck announced that it will use the Glycofi platform to enter and compete in the nascent biosimilar (aka follow-on biologics) space. Gerngross added that "Adimab will have a greater impact on protein-based therapeutics than Glycofi."

 

Unlike AnaptysBio and Adimab, Xencor developed a technology platform that can be used to molecularly manipulate an antibody's Fc region. In contrast with the antibody-binding domains which bind antigens, the Fc portion mediates the biological effector functions of antibodies. These effector functions include antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent lysis (CDL), both of which can kill cancer cells or infectious agents like bacteria and viruses. Further, the protein sequence and glycosylation pattern found in the Fc portion of antibodies has long been known to affect circulation half-life, turnover rates, and pharmacological properties of these molecules. Recognizing this, Xencor developed a computational biology-driven, molecular engineering platform to modify or reengineer Fc domains to improve, optimize, or change the biological and pharmacological properties of extant or novel therapeutic MAbs.

 

Bassil Dahiyat, Ph.D., Xencor's president and CEO, suggests the company's Fc engineering platform offers companies with marketed MAbs an opportunity to develop improved second generation products. "I believe that reengineering the Fc portion of an antibody molecule to improve the performance of therapeutic MAb is certainly less labor-intensive and easier than some of the other technologies like protein PEGylation that are out there," said Dahiyat. Also, Dahiyat stressed that Xencor's proprietary technology may help to extend the patent life of first generation therapeutic MAbs.

 

While biosimilar versions of therapeutic MAbs are not likely to appear on the U.S. market for another four to five years, Dahiyat contends that Xencor's Fc technology will allow innovator companies to quickly develop improved, competitively priced second generation MAbs that will almost certainly outcompete first-generation antibodies offered by competitors. In addition to licensing deals, Xencor is also developing its own internal MAb pipeline and recently advanced one of its candidate molecules into Phase 1 human clinical trials. Some of Xencor's pharmaceutical and biotechnology partners include CSL, Pfizer, Merck, MedImmune, Genentech, Lilly, Boehringer Ingelheim, and Human Genome Sciences.

 

The Future

Over the past decade, protein-based drugs have begun to constitute a larger percentage of most pharmaceutical companies' drug development pipelines. This is because of the lack of innovation in small molecule drug discovery and the growing acceptance and rapid uptake of biotechnology drugs. While therapeutic proteins were early industry favorites, it is becoming increasingly difficult to discover and bring new ones to market. The molecular diversity, target specificity, and improved manufacturing and safety profiles of many of the commercialized therapeutic MAbs (coupled with annual growth rate of 30%) suggest that MAbs will likely be in the spotlight for the foreseeable future. To that end, over the past year or so, no fewer than seven MAb developers were purchased by big pharmaceutical companies including Domantis (GlaxoSmithKline); Adnexus and Medarex (Bristol-Myers Squibb); Biorexis, CovX, and Haptogen (Pfizer); and ImClone (Lilly). Companies such as Genmab, Morphosys, Micromet, and Dyax are examples of some of the few remaining independent MAb developers.

 

While many of the early commercialized MAbs were developed to treat inflammatory diseases like rheumatoid arthritis and psoriasis and several oncology indications, the next generation of MAbs that are being developed are expected to target new therapeutic areas including cardiovascular disease, metabolic diseases like diabetes and obesity, neurological disorders including Alzheimer's disease, and infectious diseases. However, CEOs Gerngross, Smart, and Dahiyat all agree that oncology, inflammation, and autoimmune diseases will continue to remain therapeutic areas of intense interest.

 

Finally, while therapeutic MAbs appear to be center stage at the moment, expect more emphasis to be placed on the discovery and commercialization of MAbs as diagnostic and prognostic tools as the age of personalized medicine continues to evolve.

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Biotech-Healthcare: Snippets and Tips from RBS Morgans

 

Key Stories (US centric)

Christoph Westphal's Verastem, a preclinical-stage biotech focused on cancer stem cell research, seemingly defied gravity with an announcement late last night that its IPO raised $55 million from the sale of 5.5 million shares at $10 apiece. The price fell precisely in the middle of its range, qualifying it as a unicorn among the rare breed of companies that play in this field. And Verastem actually upped the offering by a million shares over what had originally been planned.

 

What the company's release fails to note is how much Westphal, a venture capitalist himself with a broad range of connections in the investment world, put up along with the biotech's other backers.

 

In an earlier SEC document, Verastem noted that investors had agreed to buy up to $16.3 million of the offering, a common ploy among the developers which have pulled off the occasional successful IPO over the past three years.

 

With more than 19 million common shares outstanding, the offering values Verastem at $192 million. Even so, analysts in the IPO field had a hard time understanding the logic behind a preclinical biotech IPO at a time late-stage companies are often given short shrift.

 

The company starts trading today under the VSTM symbol, joining a small group of biotechs going public.

 

As we noted in a recent special report, only 10 biotechs went public last year, down from a meagre 13 in 2010. This isn't the first time that Westphal has managed to pull off a financial coup for a high-risk company.

 

He launched Sirtris and sold it to GlaxoSmithKline (GSK) for a whopping $720 million, and GSK has stood by the company as researchers have raised serious questions over the science involved. Later he had a brief stint as the head of SR One, GSK's investment arm. And he founded Longwood Founders Fund, which has a 15.4 per cent stake in Verastem.

 

Other backers include CHP with 13.5 per cent; MPM Bioventures with 13.1 per cent; Bessemer Venture Partners with 12.9 per cent; Eastern Capital Ltd with 7.8 per cent; and Advanced Technology Ventures with 5 per cent, as Xconomy notes in its coverage of the event. (Source: FierceBiotech)

 

 

RBS Morgans and RBS Research

 

* ResMed (RMD, Hold, Price Target $2.73) - While 2Q results saw margins supported by an ongoing product mix shift and efficiency gains, solid top-line growth remains elusive.

 

Although product launches, improving mix and the continued evolution of home sleep testing are supportive, we continue to view channel pressure and regulatory scrutiny increasing, patient cost burden growing, and competition intensifying, with potential risk to margins and the strong mask/accessory annuity stream beyond ongoing FX headwinds and weak macros.(Source Dr Derek Jellinek)

 

 

Most recent FDA drug approvals

 

* January 18 - Voraxaze (glucarpidase); For the treatment of toxic plasma methotrexate concentrations (>1 micromole per litre) in patients with delayed methotrexate clearance due to Impaired Renal Function.

 

* January 4 - Subsys (fentanyl); For the treatment of cancer pain. Insys Therapeutics

 

Near-term milestones to watch

 

* Acrux (ACR) - 1QCY12 (was 2HCY11) - Patent extension for under-arm application.

 

* Impedimed (IPD) - 1QCY12 (was Dec 2011) - Securing 20m covered lives with US insurance companies.

 

* Phylogica (PYC) - 1HCY12 - Sign deal with large pharma.

 

* QRX Pharma (QRX) - June 25 - Drug approval date set by FDA

 

Source: RBS Morgans, Company Data (Note that Biotech & Healthcare Weekly Snippets provides a summary of views only. Full reports can be found at www.rbsmorgans.com).

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* Biota (BTA, Buy, Price Target $1.79) is expected to release the results of a Phase II trial for Human Rhinovirus (HRV) in patients with chronic asthma within one month. Although the HRV program only makes up 10 per cent of our valuation, we believe the market is not putting any value on this program, and if results are positive we would expect to see the share price closer to 90c. Phase IIa results achieved in June 2009 provide us with reasons to be optimistic about this more targeted Phase II trial.

 

* Analysts are re-jigging their sales estimates for Johnson & Johnson's prostate cancer pill Zytiga, on the promise that it could target a much larger set of patients. Yesterday, J&J (JNJ) said it unblinded a study of the drug in patients who'd never had chemotherapy, on indications that Zytiga slowed the cancer's growth and might improve survival. If Zytiga can win a new indication in that patient group, that would more than double its target market, analysts say. And with pre-chemo patients using the drug for a longer time frame, the gain in sales could be even larger. (Source: FierceBiotech)

 

* The FDA has officially denied AstraZeneca's petition to hold off generic versions of its antipsychotic drug Seroquel. The agency turned down AZ's (AZN) request that it withhold final approval of any knockoff version that didn't bear the same safety warnings as the branded drug. Seroquel is expected to face generic competition after the company's pediatric exclusivity expires later this month.

 

Credit AstraZeneca for trying: Seroquel is a multi-billion-dollar drug, and watching those sales erode will be painful for the drugmaker. Indeed, the FDA's decision only underscores how needy AstraZeneca soon will be. The company has announced another big round of cost cuts, but cutting can't continue forever.

 

Analysts are expecting the company to go on an acquisition spree, to make up for the fact that its internal pipeline has offered up several disappointments lately. Bernstein's Tim Anderson listed a few prospects, as the Philadelphia Inquirer reports: Amylin Pharmaceuticals (AMLN), which recently won approval for its long-lasting version of the diabetes drug Byetta, a deal that could run $4.5 billion. Shire, the growing UK drugmaker, a much bigger deal at $30 billion. Or Abbott Laboratories's (ABT) soon-to-be-split-off drug business at $52 billion. But he figures that sub-$10 billion deals are most likely. (Source: FiercePharma)

 

* Bayer Healthcare is on a roll in Asia. The German company toted up a 9.4 per cent increase in Asia Pacific sales last year, for a regional total of 3.6 billion euros, or $4.8 billion. And it has even bigger ambitions: The company said it expects Asia sales to grow to 11 billion euros by 2015, with six billion of that coming from the China region.

 

"We are confident about our growth prospects in the region based on the dynamic development of the economy and the innovative potential of the pipeline," regional chief Alok Kanti told Reuters. One of the best new performers is the clot-fighter Xarelto, which grew 109 per cent in the region last year in the hip-and-knee surgery market. With anticipated approvals for stroke prevention, Xarelto growth there is expected to accelerate. (Source: FiercePharma)

 

Near-term milestones to watch

*****************************

* Acrux (ACR) - 1QCY12 - Patent extension for under-arm application.

* Biota (BTA) - 2QCY12 - HRV Phase 2b results.

* Impedimed (IPD) - 1QCY12 - Securing 20m covered lives with US insurance companies (under review with explanation of benefits being a better measure).

* Phylogica (PYC) - 1HCY12 - Sign two deals with large pharma.

* QRX Pharma (QRX) - June 25 - Drug approval date set by FDA.

* Sunshine Heart (SHC) - 2QCY12 - EU approval for C-Pulse.

* Tissue Therapies (TIS) - 2QCY12 - EU approval for VitroGro.

 

Source: RBS Morgans, Company Data

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Key Stories

* Roche (RHHBY) has turned in positive data from a key Phase III study of its blockbuster hopeful T-DM1 and later this year plans to seek green lights to sell the breast cancer drug in the US and Europe, the company announced today.

 

The Swiss drug giant revealed top-line results from its 991-patient "EMILIA" study, saying that T-DM1, or trastuzumab emtansine, met one of the main goals of the study in providing a significant boost in survival without patients' cancer getting worse compared with patients who took the two cancer drugs lapatinib and Xeloda.

 

The company didn't have available data on overall survival, which is the second primary endpoint of the study. Detailed results of the trial are expected at an upcoming scientific meeting.Detailed results of the trial are expected at an upcoming scientific meeting.(Source: FierceBiotech)

 

* Developing new obesity drugs is notoriously arduous - and it could get tougher. An FDA panel endorsed a plan to have developers of obesity drugs conduct cardiovascular safety studies even when data on the treatments give no indication that heart risks exist. If the FDA takes the panel's advice, developers of obesity drugs could face a longer road to approval. (Source: FierceBiotech)

 

* The UK's NICE has recommended Bayer Healthcare's (BAY) Xarelto for stroke and embolisms in draft guidance. Final guidance may come in April. NICE originally ruled against the drug but requested additional information on the cost effectiveness of the anticoagulant, which is part of a new field of warfarin alternatives. Commissioners said the new data was just what they needed, reports Pharmaceutical Field. NICE has already approved Pradaxa, Boehringer Ingelheim's first-to-market drug in the category.

 

A number of the drugs have been jockeying for market share with similar treatments. Pradaxa and Xarelto have both been approved by the FDA for stroke prevention in patients with an abnormal heart rhythm known as atrial fibrillation, and Xarelto is also approved to reduce clotting risk in certain surgery patients.(Source: FiercePharma)

 

Near-term milestones to watch

* Acrux (ACR) - 1QCY12 - Patent extension for under-arm application.

* Phylogica (PYC) - 1HCY12 - Sign two deals with large pharma.

* Phosphagenics (POH) - 1HCY12 - Additional distribution agreements signed for skin care range and start of phase 3 trial for oxycodone patch in 2HCY12.

* QRX Pharma (QRX) - June 25 - Drug approval date set by FDA.

* Sunshine Heart (SHC) - 2QCY12 - EU approval for C-Pulse.

* Tissue Therapies (TIS) - 2QCY12 - EU approval for VitroGro.

 

Source: RBS Morgans, Company Data

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Key Stories:

 

* Pfizer (PFE) is prepping registration documents for an animal-health IPO. The company would offer a minority stake in the unit, dubbed Zoetis, as a step toward spinning off the unit completely. It's the latest update on Pfizer's efforts to refocus on its "innovative core."

Floating a minority stake could help build investor interest in Zoetis, supporting its eventual trading value as a standalone company. The company doesn't say how much of the unit it would offer to the market, but Financial Times sources have said the target is around 20 per cent. The minority stake could raise $3 billion, while the entire unit could be worth up to $18 billion. (Source: FiercePharma).

 

* Does any pharma CEO really need to take the no-megadeals pledge these days? The prevailing strategy is toward smaller bolt-on buys rather than the big mergers we saw back in 2009. But we still hear the "not for me, thanks" assurance on a fairly regular basis.

The latest: Eli Lilly (LLY) chief John Lechleiter. He told The Wall Street Journal that his company won't resort to a large deal to fix its current patent-cliff problems. And those patent-cliff problems are big: Its top-selling Zyprexa went off patent in October.

 

Even small deals and partnerships aren't a sure thing, he said. Lilly is betting that its own pipeline will offer a better bang for the buck than buying in a bunch of late-stage products. Lechleiter also pledged himself to the anti-diversification crowd. Rather than spending its $4 billion or so in cash on ancillary businesses to beef up sales, Lilly will focus on prescription drugs. "I don't think we can return to the Lilly of the 1970s, when we were buying up medical device companies," Lechleiter told the WSJ. "[O]ur core is pharmaceutical innovation."

 

According to FierceBiotech research, Lilly spent $5 billion, up 3per cent from 2010. At the end of the year, it had 11 late-stage products, including the risky-but-potentially-huge Alzheimer's candidate solanezumab. Key study results are due later this year.

In the meantime, he said, acquisitions don't always deliver returns for shareholders. So, Lechletier said, Lilly's cash might be better spent onkeeping up investor dividends. Our comment: Acrux maybe? (Source: FiercePharma)

 

* By the end of day tomorrow we should know whether Genentech's latest blockbuster hopeful on the cancer front has earned an FDA approval or faces a delay. The agency has a Friday PDUFA deadline to hit after providing pertuzumab a priority review on some significant data on the drug's ability to stall breast cancer when combined with Herceptin (trastuzumab). Vontobel analysts have projected peak potential sales of pertuzumab at $1.8 billion, though Genentech has yet to publicly discuss what it will charge for the treatment.

 

In an article on Xconomy today, Luke Timmerman offers an elegant description of the way researchers zeroed in on a new approach to breast cancer, proving that adding a separate antibody with a fresh target on HER2 molecules could add months to a patient's progression-free survival rate. That came after the drug offered only modest benefits as a standalone therapy. (Source: FierceBiotech)

 

Near-term milestones to watch:

 

* Acrux (ACR) - 2QCY12 - Patent extension for under-arm application.

* Phylogica (PYC) - 1HCY12 - Sign two deals with large pharma.

* Phosphagenics (POH) - 1QCY12 - Start of phase 3 trial for oxycodone patch.

* QRX Pharma (QRX) - June 25 - Drug approval date set by FDA.

* Sunshine Heart (SHC) - 2QCY12 - EU approval for C-Pulse.

* Tissue Therapies (TIS) - 2QCY12 - EU approval for VitroGro.

 

Source: RBS Morgans, Company Da

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There has been constant talk about the overall market being in a bubble. Is it a bubble? To some extent yes, however there is one particular sector that is in the stratosphere. The biotechnology sector is the equivalent of the dot.com sector in 1999. To see the type of moves I am talking about, take a quick look at Celgene Corporation (NASDAQ:CELG) and Gilead Sciences, Inc. (NASDAQ:GILD). Both stocks are up more than 100% in 2013 with market caps exceeding mega cap stature.

 

If you believe the market will pull back in 2014, which I believe. The biotech sector could see the biggest fall from these bubble levels. Imagine even a 50% retrace of the 2013 moves. Major profits to be had. If interested, you can short the iShares NASDAQ Biotechnology Index (NASDAQ:IBB) or buy the ProShares UltraShort Nasdaq Biotech ETF (NYSEARCA:BIS). Both give you plenty of exposure to the collapse in the biotech sector.

 

 

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Healthcare

 

"If the business model of health insurance is so unattractive that it requires a huge government subsidy every year and a taxation regime to coerce people to buy your product, it tends to suggest it's pretty weak. If the benefit of that $6 billion [government subsidy] was actually put into the creation and the subsidisation ...of a medical savings regime, I think that's much more durable than the current system"

Chris Rex, MD, Ramsay Health Care

 

"Healthcare spending hit 10 per cent of GDP according to a recent report, for the first time as a country, and we face a demographic time bomb. The way that healthcare is managed and delivered has to be addressed"

Robert Cooke, CEO, Healthscope

 

 

Vitamins/Infant Formula

 

"New cross-border ecommerce rules introduced in China created uncertainty for Daigou and we saw re-sellers sell off stock to reduce risk"

Michael Howard, Director, Swisse

 

 

"A significant proportion of our Chinese sales are to Daigou shoppers"

Laura McBain, CEO, Bellamy's

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