The grant application entitled “Interrogation of Somatic and Inherited Gene-variations for Human Therapy (INSIGHT)” was ranked first amongst all applications received in the UK and Italy, and third across the entire EU.

Recent advances in high-throughput DNA-sequencing, such as those pioneered by the Sanger Centre, have given medical researchers a detailed view of the array of genetic variations capable of influencing the incidence or severity of human diseases. This is particularly true of diseases such as cancer, diabetes and the many other conditions that increasingly manifest as we age. However, much work is required to definitively link a specific genetic-marker, or combination of markers, with actual disease pre-disposition, onset, or in directing the discovery and prescription of improved ‘targeted’ or ‘personalised’ therapies.

The availability of genetically-defined and predictive in vitro human disease models has been a key missing link in achieving these goals until the development of Horizon’s proprietary AAV-virus mediated method of human genome-engineering (GENESIS™). GENESIS allows for the first time the efficient, precise and stable alteration of any endogenous gene in a human cell-line to create a wide array of disease model types.

The ‘INSIGHT’ program will explore a novel class of inherited and somatic non-coding mutations associated with cancer causation. Once their biological role and mechanisms in cancer have been confirmed or elucidated, these disease models will be made available to the wider research community and profiled (by Horizon) for all known existing cancer drugs that may target these cancer genetic variations, to discover potential new therapeutic options for patients.

Horizon will perform the in vitro gene engineering and drug screening; and Professor Alberto Bardelli will identify other cancer associated SNPs for modeling. Professor Bardelli is a leader in the field of cancer genetics and therapy and his work is actively leading to the adoption of new and more effective ‘Personalised Medicine’ strategies by pharmaceutical companies and healthcare agencies; in particular his landmark research recently linking mutant K-Ras and other genetic mutations to resistance to novel EGFR-targeted therapies in colon cancer.

Dr Chris Torrance, CEO of Horizon Discovery Ltd says “the development of effective personalized cancer medicines and companion diagnostics is becoming a closer reality with advances in high-throughput genetic testing. The bottleneck now is decoding which of the thousands of genetic variations that are truly important in driving the progression of cancer and other diseases; and the development of accurate disease models to speed up the search for many more rational targeted cancer therapies. This is Horizon’s overarching mission and this grant will significantly add to our ability to provide novel information, as well as gold standard disease models to pharmaceutical, diagnostic and academic R&D researchers”.

Professor Alberto Bardelli says “Genomics research over the past 20 years has seen incredible growth in the number of SNPs identified that are believed to increase an individual’s susceptibility to cancer. The statistical evidence provided by populations’ studies has not been paralleled by experimental evidences that the identified SNPs play a functional role at the cellular level. INSIGHT is designed to unequivocally establish the causal relationship between cancer associated SNPs and biological perturbations of key cellular features such as gene transcription, alterations in DNA-protein interactions and drug response”

The grant which begins in March 2010 is spread over a period of three years and will contribute toward a $1,000,000 program of work that will lead to the marketing by Horizon of a panel of new patient relevant X-MAN™ disease models and the co-ownership of new inventions that will be commercialized via Horizon.

Horizon’s X-MAN (Mutant And Normal) cell-line technology provides the first genetically-defined and patient-relevant in vitro models of human cancer. These models are being used by a growing number of Pharma and Biotech companies to rationalize key steps of the ‘targeted’ drug development process, and thus accelerate and economize the burgeoning field of ‘personalised’ medicine.

The agreements cover the licensing of and the development of new X-MAN cell lines including major cancer causing genes and their matched normal genetic backgrounds. The approach should enable Sanofi-Aventis and Centacor to gather information relating to the selectivity and mode-of-action of their compounds using model in-vitro systems.

“Dr Darrin M Disley, Chairman of Horizon says “it has always been our aim to work with the leading players in oncology research and Sanofi-Aventis and Centacor certainly fall into that category and we hope to build a long and productive relationship.”

The Companies will pay Horizon undisclosed fees during the terms of the agreements.

Horizon’s X-MAN (Mutant And Normal) cell-line technology provides the first genetically-defined and patient-relevant in vitro models of human cancer. These models are being used by a growing number of Pharma and Biotech companies to rationalize key steps of the ‘targeted’ drug development process, and thus accelerate and economize the burgeoning field of ‘personalised’ medicine.

The agreement covers the screening of Sunesis’ lead compound, voreloxin, a first-in-class anticancer quinolone derivative (AQD), on certain human isogenic cell-lines comprising target genotypes of interest to Sunesis. The approach may enable Sunesis to gather information relating to the selectivity and mode-of-action of voreloxin using model in-vitro systems.

Dr. Darrin M. Disley, Chairman of Horizon said “working with Sunesis is an exciting development for Horizon. In this agreement, we hope to further prove the potential of our human X-MAN models in a drug screening / profiling environment”

The agreement begins in February 2010 for an initial period of 12months.

A research-collaboration and sub-licensing agreement will allow TGen investigators to use Horizon’s GENESIS™ and X-MAN™ technologies to accelerate the search for new drug targets, biomarkers and anti-cancer agents, which could provide patients with more effective treatments.

Dr. Daniel Von Hoff, TGen’s Physician-In-Chief and senior investigator, will head the effort at TGen. Dr. Von Hoff is a leading advocate of developing precision cancer therapies. Dr. Von Hoff also is a leader in clinical trial design for agents that are based on an understanding of the cancer genes in patients’ tumors.

“TGen is eager to partner with Horizon in the use of these new technologies, which should enhance our research efforts to provide patients with significantly better outcomes,’’ Dr. Von Hoff said.

Horizon’s core gene-targeting technology and human isogenic cell-lines are expected to enable TGen to create a key center of excellence in translational medicine for generating and applying predictive human disease models in drug discovery.

“Our over-arching mission is to speed up the research, development and prescription of more rational therapies that target the root causes of cancer development in each patient’s tumor,” said Dr. Chris Torrance, CEO of Horizon. “TGen investigators are visionaries in this respect and we are honored to enable them with Horizon’s GENESIS technology to generate a novel pipeline of X-MAN cancer models to support cutting-edge translational oncology research.”

Under terms of the collaboration, TGen will use Horizon proprietary technology and know-how to develop a panel of novel cancer cell-lines, which will be licensed back to Horizon for future licensing to the broader academic, biotech and pharma research communities. The parties also have agreed to share, publish and commercialize data from the research program, subject to future commercial terms.

This type of open-source relationship will be replicated in the future by Horizon at selected centers of excellence for translational research with the aim of deciphering the genetic links to cancer and other debilitating diseases.

At the center of the venture will be Horizon’s expanding panel of 175+ human isogenic cell models that recapitulate key drug sensitivity and resistance mechanisms in cancer patients. These ‘X-MANTM’ (Mutant And Normal) models are being developed using a proprietary gene-engineering technology called GENESISTM that enables (for the first time) the rapid and precise alteration of any endogenous gene loci in human cells. Using this revolutionary technology advance, in vitro cell models comprising any SNP or activating point-mutation can be routinely developed to rationally develop targeted drugs or diagnostics to ‘real-world’ patient genetics.

The first commercial products supplied by the new venture is a source of genetically-defined mutant vs. normal human DNA, as well as isogenic cell-admixtures situated within formalin fixed paraffin embedded (FFPE) samples. These high-quality and consistent human genomic DNA and cell-based control materials will enable companion diagnostic kit developers and their customers to validate and standardize assay performance; as well as accurately recapitulate the diverse mixtures of mutant versus normal cell populations found in patient tumour samples.

These X-MAN control reagents will be used in conjunction with companion diagnostic kits that are currently enabling clinicians to ascertain which patients will respond to novel cancer therapies, such as the anti-EGFR targeted colorectal cancer drugs Erbitux™ and Vectibix™, based on their K-RAS mutational status. Through research conducted by Horizon’s co-founder Professor Alberto Bardelli (Cancer Research in March 2007) and other groups, it is now known that approximately 40% of colorectal patients who test positive for K-RAS mutations will not respond to Erbitux and Vectibix.

The European Medicines Agency (EMEA) and Food and Drug Administration (FDA) have now mandated that all colon cancer patients be tested for KRAS mutations before EGFR-targeted drugs can be prescribed. Current estimates indicate that approximately $750 million/year of savings will be conferred onto taxpayers and healthcare re-imbursers by the prescription of EGFR-drugs only to patients with a non-mutated K-RAS gene, who will benefit from the drugs.

Other mutations implicated in primary response or resistance to currently prescribed EGFR targeted colorectal and lung cancer drugs include B-RAF, PI3CA, EGFR and AKT and ‘R&D only’ kits are already available to identify responders. The next five years will therefore see a rapid adoption of new diagnostic kits as companions for specific targeted cancer agents.

Dr Darrin M Disley, Chairman of Horizon said “the initial focus of HDx will be on evaluating new diagnostic kits in partnership with key sector players and supplying isogenic human mutant vs. normal DNA-controls to end users via a premier distribution partner, which we feel represent a ‘gold-standard’ means of bench-marking companion diagnostics where mutations often need to be detected in humans within a background of excess isogenic normal DNA. The second phase of the business model is to expand the work Horizon is already undertaking with academic and industrial partners to identify novel genomic, proteomic, metabalomic and other in-vitro and in-vivo biomarkers and disease signatures from X-MAN models that can form the basis of developing new companion diagnostic kits in partnership”. Disley goes onto say “Horizon and HDx will move forward in partnership and with a shared vision for personalised medicine and are leading the world in providing critical new tools that will enable a future where cancer patients will be screened for the genetic changes that drive their disease and then given the most effective targeted treatments to combat them”.

Horizon is initially funding HDx from its balance sheet but hopes to secure a multi-million dollar investment into the company by the end of H1 2010.

X-MAN ‘Mutant And Normal’ cell-lines provide researchers with a consistent source of human cell-types that harbor a specific cancer causing gene (or genes), plus a matched reference normal cell as a control; enabling the rational development of novel drugs or treatments that more effectively target specific patient populations.

Dr Paul Morrill, Business Development Director of Horizon says “Genentech have been a model early-adopter and pivotal to Horizon validating its GENESIS™ and X-MAN technology in an industrial setting. The relationship has yielded some exciting findings which are being translated into publications that will help others striving to develop targeted cancer agents. We believe the new open-access deal with Genentech will further enable Horizon to continue to supply first-in-class, in-vitro models of human cancer for Rx and Dx applications.”

Through its agreements, Genentech pays Horizon undisclosed up-front, milestone and renewal fees.

The new agreements give Horizon a world-wide exclusive right to commercialize inventions made by Professor David Russell, Professor of Medicine, Division of Hematology; Adjunct Professor of Biochemistry, University of Washington School of Medicine relating to the use of parvoviral vectors in human genome engineering. Horizon will use its new rights and associated know how to: (a) develop mammalian cell-lines that have been genetically-altered to optimize the bio-production of bio-pharmaceutical agents and; (b) to engineer pluripotent human stem cells as a means of generating an expanded array of human isogenic cell-lines that are capable of predicting the response of drugs targeted at the genetic defects (mutations, deletions, substitutions) that represent the make-up of individual cancer patients tumors.

Using key know-how from Professor Russell and Horizon’s GENESIS platform, a range of genetically-stable and high-yielding bio-production cell-lines will be created by knocking-out, or modifying, specific host cell gene-targets (such as glutamine synthetase). Such targets currently hamper the efficient manufacturing of biopharmaceutical agents, such as the therapeutic antibodies Erbitux and Avastin.

The genetic engineering of human adult stem cells, or re-programmed stem cells derived from differentiated somatic human cell-lines in the laboratory, opens up a myriad of possibilities to firstly; rapidly expand and diversify Horizon’s existing portfolio of X-MAN research and development tools; and secondly provide a gold-standard source of parental cell-lines for bio-production that have infinite self-renewable capacity.

Dr Darrin M Disley, Chairman of Horizon said “our relationship with the University of Washington has been fundamental to the development of Horizon and the early market penetration the company has made. The new agreements, along with the appointment of Professor Russell who represents a world-leader in human genome engineering and stem-cell research, as a special member of our SAB, will align the technical and commercial interests of Horizon and UW. The ability to precisely and stably alter the genome of mammalian (and especially human) cell-lines, without introducing errors or exogenous vector sequences; opens up several opportunities for our products and services in Rx and Dx development as well as Bioproduction markets”

Linden Rhoads, Vice Provost of UW TechTransfer said “the University of Washington is delighted that one of its most innovative technology platforms has found such early commercial success via the GENESIS and X-MAN product and service offerings marketed by Horizon. The latest agreements expand the rights of Horizon into two new lucrative market areas and further align the technical and commercial interests of UW, Professor David Russell and Horizon”.

Under the new agreements, UW will be granted an undisclosed number of share options in Horizon and will receive ongoing product royalties from licensed products and services marketed by Horizon. The license comes into effect in December 2009.

X-MAN ‘Mutant And Normal’ cell-lines may represent a missing link in the rational discovery of modern cancer therapies that aim to better target the root causes of cancer. X-MAN models provide researchers with the first consistent source of human cell-types that harbor a specific cancer causing gene (or genes), as they occur in the real patient, plus a matched reference normal cell as a control. This opens the possibility of: earlier definition of appropriately targeted drug candidates and; the design of streamlined clinical trials based around the patients most likely to respond.

Dr Chris Torrance, CEO of Horizon says “the comprehensive nature of this collaboration with Novartis, who are at the forefront of research into new and improved targeted and personalized cancer therapeutics, is a significant breakthrough for our company. Horizon’s proprietary GENESIS platform enables the routine generation of a wide-range of human disease models that were difficult or impossible to generate using historical gene-engineering techniques.” Torrance goes on to say “We look forward to a long and fruitful relationship with Novartis.”

Through its agreements, Novartis pays Horizon undisclosed up-front, milestone and renewal fees.

The move will enable the company to service over $12,000,000 of commercial orders received in 2009. The facility is complimented by the company’s state-of-art molecular biology facility in Torino, Italy which employs eight staff and is funded in part by the Piedmonte Region government.

Horizon is providing a road-map to drug developers, regulatory bodies, clinicians and healthcare providers to break the cycle of ‘irrational’ cancer drug development. This is being achieved by developing and marketing key in-vitro discovery and diagnostic tools that will enable both the faster development of improved ‘targeted’ anti-cancer drugs like Herceptin, Vectibix and Erbitux and the validation and standardization of companion diagnostic tools to ensure that the correct treatments are administered to patients based upon the unique genetic-signature of their cancer.

Horizon has moved quickly into the global market via performing direct business development activities around its world-leading human gene-targeting platform technology called GENESIS™ and its derived portfolio of 150+ genetically defined X-MAN™ human cancer models. The company has announced 40+ commercial deals over the past two-years with world-leading pharmaceutical companies such as AstraZeneca, Genentech, GSK, Novartis, OSI Pharma, SuperGen and Millennium.

“Dr Darrin M Disley, Chairman of Horizon says “we are delighted to establish our new HQ facility at IQ Cambridge. Horizon is hiring right now to meet current demand for our products and services and to support our expansion into the companion diagnostics and bio-production markets. We are actively recruiting research scientists who want to work for a company of substance that does not sell-out to foreign competitors at the first opportunity to turn a quick buck for their investors. We have world-class science; people and the best Pharma partners in the industry and anyone who joins the team will be challenged, be respected and be given the opportunity of embarking on the adventure of a life-time.”

Due to the demand for the companies technology, products and services we are looking to hire the following lab-based positions at our new facility on the IQ Cambridge Research Park:

2 PhD-level Scientists with extensive molecular biology and cell-culture expertise
3 BSc. or MSc. Senior Lab Technicians with cell-culture or molecular biology experience

Horizon offers an innovative, entrepreneurial, dynamic and “can-do” work environment and rewards its employees directly in line with their performance. We are growing rapidly and happy to accept applications (no agencies) at any time from suitable candidates.

To apply for one of these roles, or for more information, contact Dr Rob Howes, Research & Development Director (r.howes@horizondiscovery.com).