11 EMERGING TECHNOLOGIES
In Rapid Pursuit of Pharmaceutical Proteins FivePrime Therapeutics Offers Potent Discovery Platform Executive summary In recent years, an increasing number of therapeutic proteins such as monoclonal antibodies have become licensed for pharmaceutical use. Protein-based drugs are associated with high production costs and efficient discovery methods are needed to help offset this financial burden. FivePrime Therapeutics, a San Francisco-based biopharmaceutical company, offers a unique technology platform that promises rapid and comprehensive discovery of novel therapeutic proteins. FivePrime’s protein discovery platform comprises a complementary DNA (cDNA) collection encoding virtually all human secreted and receptor proteins, as well as systems for high-throughput protein production and screening, and animal models for rapid in vivo validation. The potential of FivePrime’s technology platform was recognized by a global top 20 pharma company in April 2006, when Boehringer Ingelheim entered a 2-year $US75 million research and development collaboration for discovery of novel protein therapies for rheumatoid arthritis. FivePrime is also discovering and developing inhouse a range of therapeutic proteins targeting commercially attractive chronic diseases where proteins are established as viable pharmaceutical agents. Lead candidates for cancer (FPT039), and type 2 diabetes (FPT038) are being investigated preclinically and studies are ongoing to validate a novel immunomodulating cytokine with potential for therapy of cancer, inflammation and infections. FivePrime is also seeking to identify proteins that can activate adult stem cells for use in regenerative medicine.
FivePrime Therapeutics is an emerging private biopharmaceutical company that hit the news recently when Boehringer Ingelheim signed a multi-million dollar, 2-year collaborative agreement for the discovery of novel therapies for rheumatoid arthritis. The interest shown by one of the world’s top 20 pharmaceutical companies prompts a closer look at the technologies and strategies of FivePrime. Although the name might suggest a focus on nucleic acid technology, San Francisco-based FivePrime’s mission is actually to discover protein-based therapies. Differentiating FivePrime from other companies with a similar focus are its proprietary technologies for protein drug discovery that promise more rapid progress from research to clinical development.
Mining the ‘Pharmanome’ – technology platform for discovery of therapeutic proteins FivePrime Therapeutics has developed a technology platform for the discovery of novel protein drug candidates that incorporates rapid production, highthroughput screening (HTS) and validation of all secreted proteins, peptide hormones and receptors against clinically relevant disease models. The key differentiating features of FivePrime’s pharmaceutical protein discovery platform is its speed and comprehensive nature. The company aims to reduce the time from initial idea to entering clinical development to 30 months or less. FivePrime’s highthroughput protein screening system is based on the same principles as, and approaches the speed of, small-molecule HTS technologies.
Comprehensive protein library derived from 5′-complete cDNA clones FivePrime has a comprehensive human complementary DNA (cDNA) collection comprising over 300 000 cDNAs, more than 90% of which are full-length 5′complete clones (hence the company name). The cDNA collection is derived from a tissue bank containing several thousand samples from over 150 different normal and diseased tissues. From this cDNA collection, FivePrime can generate libraries containing virtually all human secreted proteins, peptide hormones and receptors, which company employees have termed the Pharmanome™ – the subset of the proteome containing all pharmaceutically relevant proteins. Although many companies employ expressed sequence tags (EST) rather than full-length cDNAs, the use of 5′-complete cDNAs instead increases the chances of producing functional proteins. High-throughput production and screening Proteins are produced from the cDNA library in a highthroughput manner using an automated human cell expression system that ensures correct protein structure and activity. This system can produce >2000 different proteins per week at therapeutically relevant concentrations. The proteins produced are then screened for therapeutic activity in disease-related cell-based assays that employ primary human cells rather than cell lines. The type of cell used in the screening depends on the disease against which the drug discovery process is being applied. Several assays are performed on each protein to rigorously identify potential drug candidates. A key element for lead selection is the database capture of activity profiles for all proteins across all screens. 1176-3469/06/0007-0011/$39.95 © 2006 Adis Data Information BV. All rights reserved.
12 Table I. FivePrime’s R&D pipeline Candidate
Type of protein
Mechanism of action
Indication
Development status
FPT039
Modified growth factor receptor
Growth factor antagonist
Breast, lung, ovarian cancers
Preclinical
FPT038
Skeletal muscle-targeting small protein
Insulin sensitizer
Type 2 diabetes
Preclinical
FPT025
Cytokine
Immunomodulator
Cancer, inflammation, infections
Lead validation
FPT040
Related to FPT039
Not specified
Cancer
Lead validation
Not specified
Not specified
Regeneration of cardiac muscle
Congestive heart failure, acute myocardial infarction
Lead validation
Not specified
Not specified
Regeneration of intestinal epithelium
Bowel disease, mucositis
Lead validation
In vivo validation of therapeutic protein candidates FivePrime has developed an in vivo testing system that rapidly generates preliminary efficacy and safety data in rodents for therapeutic protein candidates identified in vitro. This technology produces pharmacological levels of protein in the blood for extended periods, mimicking the results of intravenous injection without requiring expensive and time-consuming production and purification of large amounts of protein. Using this system, animal data can be obtained in weeks rather than months.
Strategic focus on chronic diseases and regenerative medicine FivePrime is applying its technology platform to develop novel protein therapeutics in areas where there is a convincing medical rationale for protein-based drugs, with possible advantages over small-molecule therapies, and compelling commercial opportunities. The company is targeting cancer, metabolic diseases such as type 2 diabetes and obesity, and immunological disorders. FivePrime also has discovery programs in the area of regenerative medicine, where the repair and regrowth of tissues is potentially therapeutic or curative in several diseases – including heart disease (acute myocardial infarction and congestive heart failure), bowel disease, osteoarthritis, eye diseases (macular degeneration) and muscular wasting disease (muscular dystrophy). The company is seeking to identify and develop proteins that can stimulate adult stem cells lying dormant in tissues and organs to grow and replace damaged cells.
Pipeline headed by proteins for cancer and type 2 diabetes FivePrime has therapeutic protein candidates in preclinical studies for therapy of cancer (FPT039) and type 2 diabetes (FPT038), as well as a novel cytokine Pharmaceutical & Diagnostic Innovation 2006; Vol. 4, No. 7
being validated for possible use in cancer, inflammation and infections (FPT025). Further down the pipeline, validation studies are being conducted with proteins for cancer (FPT040) and regeneration of heart muscle and intestine (table I).
FPT039 for breast, lung and ovarian cancers FPT039 is a modified form of a cell-surface receptor that binds to several growth factors able to stimulate the growth and development of tumor cells. Increased activity of the receptor, and elevated levels of the growth factors that bind it, are associated with decreased survival in several major types of cancer. In preclinical studies, FPT039 was stable in vivo and inhibited growth of tumors. A phase I clinical trial of FPT039 is scheduled to begin in 2007, with development targeted towards solid tumors such as breast, lung and ovarian cancers.
FPT038 for type 2 diabetes FPT038 is a small protein that increases the insulinmediated uptake of glucose from the bloodstream by skeletal muscle cells, specifically. Preclinical studies have shown that FPT038 can rapidly and substantially reduce elevated blood glucose levels without causing low blood sugar (hypoglycemia). By sensitizing skeletal muscle to the effects of insulin, FPT038 could prevent the progressive failure of insulin-secreting pancreatic β cells that occurs in type 2 diabetes. FPT038 also appears to improve lean bodyweight without promoting weight gain. A proof-of-concept, phase I clinical trial is scheduled to begin in 2007. FPT038 also increases the uptake of circulating amino acids by skeletal muscles and is therefore being investigated for possible therapeutic use in conditions involving muscle wastage, such as sarcopenia (loss of muscle mass and strength in the elderly) and cachexia (loss of bodyweight and muscle during chronic disease).
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FPT025 for cancer, inflammation and infections FPT025 is a novel cytokine that stimulates the growth of monocytes and early differentiation of dendritic cells – both of these types of white blood cell help the immune system recognize invading cells. Its immunomodulatory activity means that FPT025 may have therapeutic effects in conditions such as cancer, inflammation and infectious disease, either alone or with other therapies such as vaccines. Validation studies are ongoing.
Corporate collaborations and financing The most notable collaboration FivePrime has entered to date is the 2-year research and development agreement with Boehringer Ingelheim announced in April 2006. This deal covers the discovery and development of novel therapies for rheumatoid arthritis and other diseases and is potentially worth $US75 million. In exchange for an initial fee, ongoing funding and future sales royalties, Boehringer Ingelheim has exclusive global rights to further develop and commercialize protein drug candidates and targets discovered. FivePrime also has an ongoing collaboration with Biosite for development of diagnostic products. Under the terms of the February 2006 agreement, FivePrime is providing Biosite with disease targets that have potential diagnostic applications and, in return, will have access to
Biosite’s Omniclonal® antibodies against selected targets to accelerate development programs. FivePrime continues to seek other corporate and academic collaboration and licensing agreements. In addition to research and development funding, FivePrime has also received around $US85 million in financing from venture capital and investment banking firms such as Versant Ventures, Domain Associates, Kleiner Perkins Caufield & Byers and Texas Pacific Group Ventures.
Powering protein drug discovery into the future The past decade has seen an increasing number of therapeutic proteins such as monoclonal antibodies become licensed medicines. The growing validation of pharmaceutical proteins has stimulated research and development efforts in this area and efficient methods for discovery are vital to support these programs. FivePrime’s technology platform offers a powerful method to speed up the discovery and initial development process, which the company believes can enable a proteinbased therapy to progress from initial concept into early clinical trials within 30 months. Ongoing development of FivePrime’s inhouse and out-licensed therapeutic protein candidates discovered on this platform will be an area to follow over the next few years.
1176-3469/06/0007-0013/$39.95 © 2006 Adis Data Information BV. All rights reserved.
