Drug discovery is a high-stakes business. The cost of developing a new prescription medicine that gains marketing approval from regulators is about $3.5 billion 鈥� and 7 out of 8 new drug candidates in clinical development fail, according to a Journal of Health Economics study.
In the discovery phase, research groups are working to transform the way companies assess new drug candidates. A group of scientists from 看片视频, Universit茅 de Montr茅al (UdeM), Universit茅 de Sherbrooke and Le Centre hospitalier universitaire Sainte-Justine has developed an innovative toolkit of over 80 luminescent biosensors that can be used to light up all the signalling pathways (rather than just a few) of a drug while in cells. From his laboratory at the Glen site of the Research Institute of the 看片视频 University Health Centre (RI-MUHC), 看片视频 Professor Stephane Laporte plays a pivotal role in this team, led by Dr. Michel Bouvier of the Universit茅 de Montr茅al (l鈥橴deM).
鈥淒rug screening tools were very rudimentary in the past鈥�, explains Laporte.
鈥淭hey looked at the signalling pathways activated (what鈥檚 being lighted up) in the biggest room in the house. Our biosensing technology allows you to look at how a new drug candidate activates signalling pathways in all the rooms in the house.鈥�
With biosensors lighting the way, Laporte and the team aim at providing more targeted treatments for a variety of afflictions, including heart disease, neuropsychiatric disorders, and cancers.
Business bets on biosensors
From a commercial perspective, sophisticated drug screening tools offer the promise of reducing the risk of costly drug candidate failures while boosting the odds of successfully launching blockbuster medicines that will improve patients鈥� health.
The novel screening technology developed by this inter-university research team can be deployed in early-stage, in vitro drug testing 鈥� before undertaking expensive pre-clinical animal studies and clinical trials in humans 鈥� to provide a complete signalling profile and more accurately predict how a candidate molecule will perform, both in terms of desired therapeutic effects and safety.
French Biopharmaceutical Company, Domain Therapeutics, took notice of the practical potential of this research.
This company has entered into various licensing, sublicensing and partnership agreements for the use of the biosensing technology. The deals have generated substantial upfront and ongoing payments to the inventors and their institutions, as well as creating jobs in Montreal. What鈥檚 more, research contracts provide valuable industry training opportunities for 看片视频, UdeM, and the University of Sherbrooke students, post-doctoral fellows and research assistants to advance the technology.
For help in the patenting process and finding a commercial partner, the team worked closely with the Institute for Research in Immunology and Cancer 鈥� Commercialization of Research. 看片视频鈥檚 Innovation and Partnerships, and Olivia Novac, Associate Director of Technology Transfer, also lent her expertise.
鈥淯sually, research tools don鈥檛 have much commercial value and it鈥檚 unusual to attract such interest from big pharmaceutical companies,鈥� says Novac. 鈥淭he team was there at the right time, with the right people, with the right invention.鈥�
While he has acquired business acumen along the way, Laporte doesn鈥檛 see himself as a commercialization expert: 鈥淚t鈥檚 like a lottery. As scientists we鈥檙e excited about our discoveries, but we don鈥檛 have the experience to know if these discoveries are valuable for companies.鈥�
Spark of curiosity leads to a life of research
Laporte鈥檚 scientific interest in designing and developing medicinal drugs was sparked by youthful curiosity. In the course of completing M.Sc. and Ph.D. degrees in Pharmacology at the Universit茅 de Sherbrooke, Laporte became specifically interested in an important class of signalling proteins in the human body called G protein-coupled receptors (GPCRs), the most common targets for prescription medicines embedded within the plasma membrane of cells. Their role is to transfer a signal from the external environment into a cellular response. GPCRs are involved in many physiological responses, such as contractions of the heart and the uterus, control of blood pressure, release of glucose, and even our capacity to see, taste or smell.
鈥淎bout 30% of all available drugs target GPCRs. We only have drugs that target about 100 different GPCRs and there are at least 800 types. I was interested in how drugs work on these receptors. There were more questions than answers and I could see the potential for new drug discovery,鈥� he says.
To find answers, Laporte trained in the late 1990s as a postdoctoral fellow at Duke University under the supervision of Marc Caron, a researcher from Quebec who collaborated with Dr. Robert Lefkowitz, co-winner of the 2012 Nobel Prize in Chemistry for the discovery of this superfamily of receptors and their inner workings. Laporte developed expertise in GPCR signalling and trafficking (what happens after a receptor is activated by a drug, or other stimulus, and leaves the cell surface to get inside the cell), as well as witnessed an American university approach to commercializing research.
A coalition of Quebec researchers light the way
After returning to Quebec and joining 看片视频 in 2001, Laporte collaborated with UdeM biochemist Michel Bouvier on a GPCR project funded by a Canadian Institutes of Health Research (CIHR) team grant. Bouvier had trained as a post-doc with Lefkowitz at Duke in the late 1980s and is a world-leading GPCR specialist. He also had a strong commercialization background as a founding member and later CEO of IRICoR (Institute for Research in Immunology and Cancer 鈥� Commercialization of Research), as well as consulting for both emerging and established drug companies.
鈥淚t was a good fit between our two labs,鈥� says Laporte. 鈥淢ichel was well known in the field of GPCRs, with more commercial experience. He came from the same environment at Duke, but we each worked on different types of receptors and my expertise in receptor trafficking was complementary to his.鈥�
Bouvier had developed a novel drug-screening assay, based on bioluminescence resonance energy transfer (BRET) that used fluorescent and luminescent proteins from sea creatures to display the effects of a drug activated by targeting GPCRs in living cells.
鈥淢ichel had this idea to assemble a group of GPCR researchers from Quebec with different types of expertise to develop a panel of BRET-based biosensors to address important questions about drug activity in cells,鈥� says Laporte. 鈥淒rug screening assays were very basic then and we didn鈥檛 have good tools to do high-throughput analysis [screening of thousands of compounds quickly and cost-effectively], so there was an unmet need in science and drug development,鈥� explains Laporte. 鈥淥ur group鈥檚 goal was to build a set of tools that could give a broad view of all the different effects of a drug and do high-throughput analysis.鈥�
In 2009, the Quebec Consortium for Drug Discovery (CDQM) awarded the research team a multi-year grant of nearly $2 million to develop a high-throughput drug-screening toolkit consisting of 40 new GPCR-specific biosensors. Along with Bouvier as principal investigator, the co-investigators included Laporte and Terence H茅bert from 看片视频, Graciela Pineyro and Christian Le Gouill from UdeM, and Richard Leduc from Universit茅 de Sherbrooke.
As project leader, Bouvier brought a laser-minded focus to the team in producing the deliverables on time to the highest standard. 鈥淲e did this project in a very systematic, goal-oriented manner, almost like it would happen in industry, expect this was in academia,鈥� says Bouvier. 鈥淚t was like building a bridge and we surpassed what was requested. We produced not just 40, but 60 different biosensors.鈥�
Doing the right deal
In 2013, France-based Domaine Therapeutics signed a licensing and partnership agreement with UdeM, IRICoR, 看片视频 University, and Universit茅 de Sherbrooke, for the rights and use of the GPCR biosensing technology the team had developed and patented.
Bouvier had met a group of investors in Domain through a research collaborator in France. The company specialized in research and development of new drug candidates that target GPCRs and was looking for better access to the North American pharmaceutical and biotechnology industries. There was an excellent fit between Domain and the Quebec researchers in terms of technology and culture, and they had mutually compatible goals.
Partnering on future development of the technology, in addition to licensing fees, was a top priority for the Quebec research group. 鈥淭he technology was developed by Quebec scientists with funding from the Quebec and Canadian governments,鈥� explained Bouvier. 鈥淲e wanted the technology to help the economy, provide opportunities for young scientists here and maintain a vibrant ecosystem for GPCRs in Montreal. Domain, in turn, wanted to keep close to our R&D consortium because they could see we were continuing to develop the technology. They saw its potential for developing more selective, specific and safer drugs more efficiently,鈥� he says.
Domain set up a North American subsidiary in Montreal and provided financial support for the discovery of new biosensors. 鈥淲e were able to hire trainees to work with Domain, who benefited from being exposed much earlier to the industry drug discovery environment,鈥� says Laporte.
Taking the lead
Laporte seized that R&D opportunity and took the lead with Christian LeGouill, a research Associate in the Bouvier Lab, in developing the next generation of GPCR-specific biosensors that made it possible to visualize all the signalling pathways activated by a drug and more accurately measure the levels of a drug鈥檚 action in different pathways. 鈥淭he second version of our biosensors was more attractive and useful for drug companies because it had much greater sensitivity,鈥� he says.
In 2016, Domain Therapeutics signed a second licensing and partnership agreement with UdeM, IRICoR and 看片视频 for this new set of biosensors, which provided upfront payments, annual access fees, and financial support for further R&D. The invention also led to Domain signing partnership agreements with Pfizer and Boeringher Ingelheim, and sublicensing agreements with Bristol-Myers Squibb and Alkermes, in 2016, 2017 and 2018 for use of the new biosensors. 鈥淒omain鈥檚 sublicensing and partnership agreements with large pharmaceutical companies provide substantial additional revenues for the inventors and their universities to keep improving and broadening applications of the technology,鈥� says 看片视频鈥檚 Novac.
Expanding the repertoire
Laporte is excited about how the BRET biosensors are deployed in different ways by university researchers and industry to develop personalized treatments for patients. Today, researchers use the biosensors at a very early stage to screen tens of thousands of pharmaceutical compounds to choose the most promising drug candidates and Laporte expects more innovation to come from this technology.
On what illuminated the path from invention to successful innovation and commercialization, Laporte cites the fruitful collaborations with his research colleagues from several Quebec universities, his UdeM commercialization mentor, his own students and trainees, and the right industry partner: 鈥淵ou have to trust in your collaborators and industrial partners鈥�, he says. 鈥淏e generous with your time, involvement, and sharing of data.鈥�
His strong focus on the science of driving the technology forward has been just as important. 鈥淚f you stop improving the technology, it will become obsolete,鈥� says Laporte. 鈥淲e鈥檙e continually improving the technology because we ask research questions and that鈥檚 been instrumental in achieving both scientific and commercial success.鈥�