the power of ideas 2012 annual report table of content

1 Word from Management 2 An innovative consortium for co-creation of value 4 Mission, Values & Scope of Activities 5 CQDM in Numbers 2008-2012 6 Highlights 2012

Success Stories: 8 VLPExpress – Towards fast discovery of new vaccines 10 Molecular signature: New biosensors to better understand the effects of drugs 12 Tracking new proteomic biomarker panels for type 2 diabetes 14 PulmoBind: A novel, safe and non-invasive diagnostic tool for pulmonary hypertension 16 Use of light to non-invasively profile patients with psychiatric disorders

18 Focus Projects 22 Explore Projects 24 Quebec/Alsace Projects 26 Quebec/Ontario Projects 28 Impact of CQDM projects 30 Financial Summary 2012 32 Corporate Information and the CQDM Team WORD FROM commitment MANAGEMENT

collaboration

innovation

imes change but challenges remain to be addressed... CQDM was founded four years ago in Quebec to tap into the excellence of the many large T Montreal-based pharmaceutical research centers focusing on new drug discovery. In the last two years, three of these prestigious centers closed their doors as they succumbed to an industry-wide trend favouring outsourced research and open innovation. This shift is partially driven by the slowdown in commercialization of new drugs year after year. Open innovation, creative partnerships and profitable collaborations strongly rely on the involvement of intermediary organizations and centers of excellence, which share an intimate knowledge of the industry – especially university research centers and biotechs – and have the means to fund early stages of collaborative research. This is precisely the role of CQDM, although there is a growing need to involve more globally our pharmaceutical partners to identify experts capable of assessing projects, defining industry needs and mentoring selected projects. Today, CQDM’s purpose is more important than ever in view of the industry turmoil and the recent departure of research centers. However, we must excel at “selling” Quebec in order to secure the ongoing contribution of 7 pharmas (among the 12 world-leading companies) to CQDM’s activities. To achieve this, we must appeal to them based on the excellence of our academic research, our numerous key opinion leaders in clinical research, and the sustainability of our fiscal incentives. The wonders of Quebec’s quality of life will do the rest...

President and CEO Diane Gosselin

Vice President, Finance and Administration, Assistant Corporate Secretary, and Treasurer Michael Bridges

Former President and CEO Member of the Board Max Fehlmann

CQDM 2012 annual Report 1 An innovative consortium for co-creation of value The funding awarded by CQDM to innovation research projects is only possible thanks to the generous support of its public and private partners and collaborators. This year, we are pleased to welcome Novartis as a new program specific member, which brings to seven the number of top leading pharmaceutical companies contributing to CQDM. These partners not only bring financial contribution, but they also provide highly valuable expertise and support necessary for the expansion of CQDM’s mission.

CQDM is a pooled public/private research We are also grateful to our external consortium, sharing all project results equally co-funding partners. among its industrial members. As a result of MaRS Innovation, the Ontario Brain Institute, the complete buy in of all of our stakeholders and the Ontario Centers of Excellence in achieving our shared mission and objectives who are providing important support we have been able therefore to extract the best for the Quebec/Ontario collaborative from the local R&D ecosystem... funding program. • Strategic innovation initiatives Alsace BioValley and LyonBiopôle who of the governments are working closely with CQDM in the • Leadership from industry - Innovation from organization and funding of the Quebec/ academia - Entrepreneurship from SMEs France collaborative funding program. ... for the benefit of everyone.

2 CQDM 2012 annual Report Founding members

Program specific members

Government Sponsors

CQDM 2012 annual Report 3 VALUES CQDM is a unique one-stop shop where various actors of the Quebec drug development industry can liaise. CQDM promotes the co-creation of value through synergies emerging from a collaborative network of researchers across universities, hospitals, biotechnology companies and the pharmaceutical industry. As a pooled research consortium, CQDM’s industry partners share all project results and are entitled to use the technology for research purposes only, if they so desire. Investigators retain full ownership of MISSION the intellectual property derived from CQDM-funded research projects, VALUEs & Scope thereby establishing a business model that benefits everyone. of activities

Mission CQDM is a not for profit organization whose mission is to identify, fund and support joint research projects between the academic and private biopharmaceutical sectors. Projects funded by CQDM target the development of innovative tools and technologies that accelerate the drug discovery process.

Scope of activities Each year, CQDM has the means to support 5-10 research projects via its four funding programs. While each boast specific features, all programs aim to develop tools, platforms and technologies enabling drug discovery and development processes. CQDM’s programs address various productivity issues associated with new drug R&D, yet they all focus on scientific excellence, innovation and technologies to resolve pressing challenges of biopharmaceutical research. CQDM’s unique business model is designed to bring added value to the entire scientific community. In addition to providing a significant source of non-dilutive funds to the public and private research network, it offers the opportunity to validate technologies on a larger scale via the use of results by the pharma industry. Moreover, CQDM’s funding promotes strong ties with the pharma industry, a key success factor for translational research.

4 CQDM 2012 annual Report CQDM 327 IN NUMBERS 2008 proposals submitted 2012 25 funded research projects 156 37 scientists students $29,4M directly supported by CQDM funding committed in research A network of 360 researchers collaborating on CQDM-funded 20 105 projects international PI + 32 collaborators co-investigators research entities involved in CQDM-funded projects 42 19 public institutions and 13 private SMEs mentors

4 funding programs The Focus program supports large-scale 1 multidisciplinary, innovative research that Cardiology has the potential to deliver enabling 7 general 6 technologies with high impact on drug discovery. Oncology The Explore program is a unique gateway to capture true early-stage innovation that can lead to a breakthrough discovery. 1 25 The Quebec/France funding program is dedicated Inflammation projects 6 to collaborative research projects between Neurology Quebec and the regions of Alsace or Rhône-Alpes. The Quebec/Ontario collaborative funding program is designed to leverage the strengths 3 infectiology 1 and synergies between both provinces. Diabetes

CQDM 2012 annual Report 5 highlights 2012 achievements A strong involvement from the pharma industry • An additional pharma, Novartis, joins CQDM. • World-leading pharma Novartis joined CQDM, thereby bringing • Launch of the Quebec/Ontario collaborative program. the number of CQDM pharma members to seven. • Initiation of a new Quebec/France funding program. • CQDM-funded projects benefited from the active involvement • Important partnership agreements with Lyonbiopôle, of 42 mentors (senior scientists recruited from pharmas MaRS Innovation, Ontario Brain Institute and Ontario worldwide) who brought unique industrial expertise toward Centres of Excellence. delivering results with the highest impact. The mentors also • Eight new outstanding research projects funded provided some critical guidance, in-kind contribution and in 2011-2012. fostered new partnerships. • First CQDM-funded projects successfully completed • CQDM projects brought about several expressions of interest and generated substantial pharma interest. in applying results (e.g. Drs. Bouvier, Vézina and Dupuis) with th • Completion of the 4 edition of the annual Forum. specific focus on pursuing late-stage research. • A special project on Alzheimer’s disease was initiated in close collaboration with Merck, Pfizer and Biospective.

Tangible results generated by CQDM-funded projects in diverse therapeutic areas • G protein-coupled receptor drugs: Dr. Bouvier developed • Pulmonary hypertension: In less than one year, Dr. Dupuis a panel of 38 biosensors covering the full range of GPCR has clearly demonstrated the safety (in a human Phase I signaling pathways. CQDM pharma members are already trial) of PulmoBind and its ability to non-invasively image using the biosensors and are now considering working with the lung. As the first non-invasive diagnostic test for early the investigator (with some additional in-kind and/or in-cash pulmonary hypertension, PulmoBind has the potential to contribution) to develop signaling signatures for molecules impact the development of new drugs by facilitating patient of interest. recruitment and early treatment with the potential for better • Vaccines: The VLPExpress HTS discovery platform for VLP drug efficacy. Merck is currently in discussions with the vaccine antigens developed by Medicago has led to the iden- investigators to develop a PET-imaging version of this tification of promising candidates for rabies and Ebola viruses peptide in monkeys. which prompted the company to launch two new discovery • Schizophrenia: Dr. Maziade identified new biomarkers for programs. The VLPExpress platform is also the stratification of patients with schizophrenia in a clinical being used by a CQDM pharma member. trial involving 150 patients. This non-invasive approach • Diabetes: A set of 30 clinically validated plasma biomarkers is based on the measurement of retinal responses have demonstrated the ability to discriminate diabetes at to photo-stimulation. various stages of the disease with a level of accuracy of at least 94% (Caprion). The mentors have expressed interest in further validating these biomarkers in a clinical trial.

6 CQDM 2012 annual Report A new initiative on Alzheimer’s disease with Merck, Pfizer and Biospective CQDM has initiated a special project involving Montreal-based Biospective Inc. and two US-based leading pharmaceutical companies, Merck and Pfizer. This initiative will undertake an in-depth characterization of animal models for Alzheimer’s disease (AD) with the goal of improving models of disease progression and evaluating responses to treatment. In this project, Pfizer and Merck will provide expertise, resources and critical materials, while Biospective will perform a high-level and comprehensive characterization of an AD animal model in addition to treatment evaluations using its unique image analysis platforms, PIANOTM and PERMITSTM. CQDM has committed $1M in this project, in addition to fostering this collaboration and coordinating the research activities. Once the study is complete, results will be released to the public domain in order to advance basic research and further accelerate drug development programs in the challenging AD field.T his new way to work with our pharma partners maximizes the co-creation of value for the benefit of all.

First concrete outcome The 4th edition of within the Quebec/ the annual Forum, Ontario corridor a remarkable success in life sciences Over 200 participants across all segments of CQDM partnered with MaRS Innovation, Extension of the the industry attended this event. This year, we Ontario Brain Institute and Ontario Centres CQDM/Alsace BioValley were privileged to welcome Uwe Schoenbeck, of Excellence in launching the CQDM Quebec/ funding program to the CSO External R&D Innovation Pfizer Worldwide, Ontario funding program. This initiative aimed region of Rhône-Alpes as the keynote speaker and several other distinguished speakers from venture capital, at leveraging existing synergies between the After two years of successful collaboration pharma and life science industries as well as two provinces stems from two previously with Alsace BioValley, CQDM has extended its the academic sector. The closing remark funded pilot projects (Encycle and CRP40 Inc.). collaborative funding program to the region was delivered by Christyne Tremblay, Launched in June 2012, the first funding of Rhône-Alpes. Initiated in September 2012, Deputy Minister, MDEIE. initiative focused on collaborative research this new funding is dedicated to collaborative projects between Quebec and Ontario up projects between Quebec and the regions of to a maximum of $750K. Alsace or Rhône-Alpes. A partnering event was organized in November 2012 in Lyon.

CQDM 2012 annual Report 7 Investigators: Success Louis-Philippe Vézina (Medicago Inc.), Alain Garnier (Université Laval) and Brian Ward (McGill University). Stories

Date of initiation: 09/2009

$1.8M over 2 years

“ VLPExpress represents a dramatic advance in our capacity to expand VLPExprEss our pipeline both in terms of cost and time-efficiency and is now a towards fast discovery key strategic development tool.” Dr. Louis-Philippe Vézina of new vaccines

main The challenge The solution accomplishments A large number of deadly diseases have been eliminated Nanoparticles such as Virus-Like Particles (VLP) can Cost-effective VLPExpress platform, through the development of effective vaccines. However, potentially address many of the above concerns and while many whole inactivated, live attenuated and an operational small-scale, challenges. Specifically, the inherent particulate nature sub-unit vaccines are available, safety issues have of VLPs is a significant advantage over soluble antigens high-throughput platform for been observed such as disease exacerbation following that consistently failed in several vaccine trials due the discovery of VLP vaccines. vaccination or occurrence of vaccine-related disease. to weak immunogenicity or instability. Additionally, Platform validated with various In addition, efficacious vaccines are still awaited for since VLPs are not infectious and do not replicate, they influenza types and sub-types as some of the most widespread endemic diseases such as represent a safer alternative to attenuated viruses. malaria, dengue and RSV. One of the greatest challenges Medicago, a clinical-stage biopharmaceutical company well as additional virus classes. is not only to identify the best antigen candidates, but developing novel vaccines and therapeutic proteins, to present multiple copies of these antigens in native internally developed a proprietary VLP technology conformation to the immune system to exploit their which fits the platform expectations. The objective of the full immunogenic potential. A platform that allows VLPExpress project led by Louis-Philippe Vézina from accelerated discovery of target vaccine antigens coupled Medicago was to adapt their clinical scale plant-based with the ability to rapidly produce sufficient quantities expression technology to a ‘small-scale’ vaccine antigen of high-grade vaccine material for testing hundreds of discovery program. antigens would significantly aid in the development of safe and efficacious vaccines for unmet medical needs. Furthermore, the selected platform should show flexibility to allow production of multimeric and chimeric vaccines so as to enhance the probability of success. 8 success Stories – CQDM 2012 annual Report Mentors

Amy Espeseth Director of Vaccines and Biologics in External Basic Research, Impact on drug discovery Merck Research Laboratories • Flagship high-throughput platform for native and chimeric Nancy Ulbrandt vaccine antigen discovery: Principal Scientist, Dept. of Infectious Disease, Enveloped and non-enveloped vaccine development in diverse MedImmune Inc., AstraZeneca therapeutic areas such as infectious diseases and cancer • 10 x faster to vaccine lead than traditional methods. • Substantial reductions in costs from $1M to the low $100Ks. • Novel proprietary antigens readily transferable to partner’s preferred vaccine manufacturing system.

Overview The VLPExpress™ platform identifies the best Virus-Like Particle-based vaccine for a disease-causing agent within 10 weeks. Key facts Immunization: most successful, cost-effective public health intervention, preventing between two and three million deaths yearly. However, several infectious diseases remain a major health The team successfully developed the VLPExpress This platform has been key for Medicago in reinforcing concern. platform, an operational small-scale, high throughput its leadership position in a very competitive field. Over 1 million young children die platform for the discovery of VLP vaccines. Its key Medicago is currently using the platform for the every year from pneumococcal component consists of an automated multi-infiltration expansion of its pipeline (i.e. rabies, one undisclosed disease and rotavirus diarrhoea. device (herein referred to as “infiltration robot”) that enterovirus) and recently invested $2M in its Quebec Globally 64 million respiratory supports an integrated high-throughput VLP design, facility to accelerate the clinical development of syncytial virus (RSV) cases with production, and purification platform. The platform was VLP-based vaccine candidates. The VLPExpress worldwide market estimated to be validated with various influenza types, sub-types and platform played a critical role in Medicago’s corporate in the billions of $. additional virus classes. Medicago has convincingly development in Asia (strategic alliance with Mitsubishi shown that this novel and cost-effective platform is Tanabe) and is a key component of Medicago’s R&D An astounding 99% of cervical rapidly capable of identifying lead vaccine antigens expansion in Évry, France. Overall the integration of the cancer cases are linked to an from hundreds of potentials in a diversity of enveloped VLPExpress discovery platform into the existing plant- infection with a human papilloma and non-enveloped viruses. These include viruses such based manufacturing technology owned by Medicago virus (HPV). as influenza, rabies, Ebola virus and an undisclosed has allowed the company to attract the attention of Between 170 and 200 million non-enveloped VLP. The efficiency of the VLPExpress many key players in the vaccine industry as well as people are chronically infected platform has been pivotal in the signing of a contractual major health agencies, as it represents one of the most with the hepatitis C virus (HCV) agreement between Medicago and at least one CQDM plausible approaches facilitating rapid responses worldwide. pharma partner for the development of a new to new emerging infectious diseases as well as threats vaccine candidate. posed by bio warfare.

CQDM 2012 annual Report – success Stories 9 Investigators: Success Michel Bouvier (Université de Montréal), Terence Hébert and Stéphane Laporte (McGill University), Stories Richard Leduc (Université de Sherbrooke), Graciela Piñeyro (Hôpital Sainte-Justine), Jean-Claude Tardif and Eric Thorin (Montreal Heart Institute).

Date of initiation: 09/2009 $1.8M over 3 years

“The financial support and industrial mentorship program of the CQDM allowed the transformation of our basic knowledge into a new generation of Molecular signature: biosensors that will be used by the pharmaceutical industry to new biosensors to better developed better and safer drugs.” Dr. Michel Bouvier understand the effects of drugs

main The challenge signaling signature for lead drugs in diverse therapeutic accomplishments GPCRs represent the most important family of areas within a realistic timeframe represents a ‘druggable’ targets with up to 40% of currently significant challenge, as many of the available assays Panel of 38 cell-based biosensors remain laborious, time consuming, expensive and are broadly covering the GPCR signaling marketed drugs coming from this group. One of the major challenges is identifying drugs that have the presented in non-homogeneous formats. repertoire including heterotrimeric ability to trigger defined signaling pathways for a given and monomeric G proteins, second receptor, while completely sparing others. If this could messengers, protein kinases and be achieved, efficient selection of therapeutic-selective ion channels. drugs with minimal side effects would be possible very early in drug development, resulting in a revolutionary approach to the discovery of safe, new and efficacious drugs. Presently however, establishing a complete

10 success Stories – CQDM 2012 annual Report Mentors

Anne Schmidt Senior Director, COE Primary Screening, Pfizer Inc., Groton, Connecticut, USA Impact on drug discovery Anka Ehrhardt Cellular Analysis, • Revolutionary approach for the discovery of G protein-receptor Merck Research Laboratories, targeted drugs with a panel of 38 biosensors monitoring diverse Merck & Co., Inc., Rahway, USA GPCR signaling pathways: Sylvain Armando • Substantial upfront screening savings due to high-throughput Associate Principal Scientist, AstraZeneca Discovery Sciences, GPCR biosensor format. Mölndal, Sweden • Important early and late stage benefits in drug development due to early identification of best candidates based on therapeutic efficacy as well as safety.

Overview The validated high-throughput screening (HTS) biosensor tool kit established in this project pioneers a timely shift from the current single functional assay screening approach to a rapid parallel multidimensional platform for GPCR screens. The biological readouts not only predict therapeutic efficacy, but importantly undesirable side effects of candidates thus leading to overall better drugs.

Key facts The solution single functional assay screening approach to parallel GPCRs represent the most multidimensional pharmacology screens, facilitating important family of ‘druggable’ With this in mind, Michel Bouvier and his team set targets. out to develop a panel of diverse but complementary exploration of avenues for drug repositioning and biosensors to monitor the various signaling pathways mechanistic studies of new drugs. Furthermore, the Approximately 40% of currently engaged by GPCRs. The group successfully delivered biological readouts may predict both therapeutic efficacy marketed drugs target GPCRs, a panel of 38 biosensors that broadly cover the GPCR and undesirable side effects of candidates, thus leading including Claritin® (allergies), signaling repertoire including heterotrimeric and to overall better drugs. Signaling signatures have now Prozac® (depression), Vasotec monomeric G proteins (Rho, Ras, G12, G14, G15), been obtained for many compounds on two GPCRs (hypertension) and Serevent® second messengers (Ca2+, cAMP), protein kinases revealing a high level of functional selectivity. This (asthma). CQDM-funded project received significant interest from (PKC, PKG, MAP kinases, Src, JAK/STATs) and ion Six of the top ten best-selling its pharma partners. In fact, Merck and AstraZeneca are channels (Kir3). The high-throughput screening (HTS) drugs in the US in 2010 targeted already using the biosensors internally and Pfizer is in compatible biosensors are validated and ready for GPCRs generating multi-billion discussion to develop specific signaling signatures and use in established cell lines. This HTS format enables dollar sales annually. considerable savings during screening (estimated at proof of principle of their predictive value for drugs of $500K per receptor target) and allows, for the first their choice. time, monitoring of multiple GPCR signal transduction pathways in homogeneous assays performed in living cells. The tool kit represents a shift from the current

CQDM 2012 annual Report – success Stories 11 Investigators: Success Eustache Paramithiotis (Caprion Proteomics Inc.), Marc Prentki and Rémi Rabasa-Lhoret (Université Stories de Montréal).

Date of initiation: 09/2009

$2.3M over 3 years

“CQDM support positioned Caprion’s unique proteomic platform technology in the field Tracking new of metabolic disease which led to strategic partnerships with proteomic biomarker a major pharma.” Dr. Eustache Paramithiotis panels for type 2 diabetes

main The challenge stage, and continues thereafter to decline with disease accomplishments Type 2 diabetes (T2D) is a chronic disease that progression. If a panel of pancreatic ß-cell biomarkers were available, it would allow for precise assessment of Panel of 30 ß-cell biomarkers are affects an increasing number of people. It commonly leads to severe complications such as retinopathy, a subjects’ diabetes disease state and enable a better readily detected in plasma that nephropathy, neuropathy and cardiovascular diseases. and more relevant monitoring of disease progression. segregate diabetes into stages of However, if diagnosed early at the pre-diabetes stage, More importantly, this panel should facilitate the disease with excellent individual the progression of this debilitating disease can be development of novel drugs targeting ß-cells with discriminatory power and high arrested or even prevented with significant savings potential to guide individualized treatment selection in accuracy (94%). to the health care industry. Pancreatic ß-cells play a addition to monitoring efficacy. critical role in diabetes with functional assessments Mass spectrometry-based multiple currently approximated through measurements of reaction monitoring assays basal and stimulated blood glucose, c-peptide, insulin combined with ELISA assays were levels and glycated haemoglobin (HbA1c) levels. set-up to monitor the 30 ß-cell Together, these tests have limited ability to directly biomarker panel. assess pancreatic ß-cell activity, the target tissue whose function is compromised even at the pre-diabetic

12 success Stories – CQDM 2012 annual Report Mentors Impact on drug discovery Lisa Norquay CVMED Diabetes Prevention • Allows for rapid identification of pre-diabetic subjects and Remission – Islet Lab Head, Pfizer Global Research and for clinical trials: Development, Groton, USA Targets group with best potential for successful treatment Daniel Kemp of diabetes Team leader, Diabetes group, Merck Research Laboratories, Enables novel therapeutic approaches to diabetes New York, USA (such as islet transplantation) currently hampered by lack Sotirios Karathanasis of useful and sensitive biomarkers Vice-President Bioscience, • Unique opportunity to directly follow the decline of ß-cell AstraZeneca, Mölndal, Sweden function in subjects leading to the development of novel early-stage diabetic therapies.

Overview A unique panel of clinically validated pancreatic ß-cell biomarkers readily detected in blood were discovered which serve to rapidly identify early pre-diabetic subjects and follow their disease progression. Treating this group early has the best chance to impact subjects with this long-term debilitating disease.

Key facts

combinations. Thirty of these putative ß-cell biomarkers Diabetes affects 25.8 million The solution people worldwide. To tackle this complex problem, Caprion and its showed good individual discriminatory power defined complimentary multi-disciplinary team hypothesized as being able to discriminate between two cohorts with In the US alone, 80 million people that proteins secreted into the circulation from healthy an accuracy of 94% or more. Mass spectrometry-based (25%) over the age of 20 are and dysfunctional ß-cells would be the best source multiple reaction monitoring assays combined with pre-diabetic. ELISA assays have been set-up to monitor the selected of clinically relevant pancreatic ß-cell biomarkers. If diagnosed early at the biomarkers and are ready for further clinical validation. To enhance the potential for success, they targeted pre-diabetes stage, disease secretory vesicles isolated from human and rat primary This panel biomarker strategy using putative mass progression can be arrested ß-cells, as well as related cell lines rather than directly and functional ß-cell biomarkers to rapidly identify or even prevented. searching in plasma for biomarkers. After enrichment early pre-diabetic subjects is unique to the industry. Diabetes is a major risk factor through exclusion of secreted proteins detected in Furthermore, it will clearly aid in the development of for many diseases such heart other organs, 329 candidates were selected new diabetic therapies that tackle early diabetic disease disease, renal insufficiency, for clinical evaluation. in the group that has the highest potential to benefit and stroke. A total of 300 subjects presenting a spectrum of from a treatment. These biomarkers have led Caprion diabetes disease states (normal, pre-diabetic and to establish a new diagnostic division showcasing diabetic) were tested and they were readily segregated its unique proteomic capabilities. into staged disease progression using the subjects’ plasma samples and specific defined biomarker

CQDM 2012 annual Report – success Stories 13 Investigators: Success Jocelyn Dupuis and François Harel (Montreal Heart Institute) and Alain Fournier (INRS – Institut Stories Armand Frappier)

Date of initiation: 09/2011

$2.8M over 3 years

PulmoBind: “PulmoBind, a biomarker of pulmonary hypertension, has all A novel, safe and non-invasive the appropriate qualities awaited by clinicians who treat this diagnostic tool for pulmonary devastating disease.” Dr. Jocelyn Dupuis hypertension

main The challenge is too large to enter small pulmonary vessels. This accomplishments Pulmonary hypertension (PH), defined as an increase limits its sensitivity to the detection of larger vascular in blood pressure in pulmonary blood vessels, is very defects caused by blood clots (pulmonary embolism) Safety of PulmoBind established which explains its lack of utility in the diagnosis of PH in a human Phase I clinical trial. often associated with cardiovascular and lung disorders. It is a serious illness that continues to deteriorate and caused by occlusion of smaller pulmonary vessels. Capability for PulmoBind to can be fatal. There is currently no reliable, non-invasive Clearly, there is a need for new small lung tracers with image the pulmonary circulation test to aid detection of early abnormalities of the good safety profiles that enable functional as well as anatomical imaging of pulmonary circulation. demonstrated in humans. pulmonary circulation. As a consequence, diagnosis is made typically two years after patients have sought medical help, with confirmation of disease performed under sedation through right heart catheterization. An alternative non-invasive approach to PH diagnosis could use anatomical imaging of the pulmonary circulation. To date, the only imaging agent approved in Canada

14 success Stories – CQDM 2012 annual Report Mentors

Michael Klimas Executive Director, Discovery Imaging; Impact on drug discovery Imaging Lead Cardiovascular and Diabetes, Pioneer in the field of pulmonary hypertension Merck, West Point, USA • Early, non-invasive diagnosis of pulmonary hypertension: William McPheat Principal Scientist & Project Cost efficient recruitment of patients for clinical trials Generation Leader, Atherosclerotic Cardiovascular Disease, Early treatment with potential for better drug efficacy AstraZeneca R&D, Mölndal, Sweden Could replace the non-specific 6 min. walk test as the endpoint in clinical trials • Use in animal models to better predict drug efficacy by directly probing the status of the pulmonary circulation.

Overview In less than one year, the safety of PulmoBind in humans was established in a Phase I clinical trial. It is the first sensitive and non-invasive molecular imaging agent for early diagnosis of pulmonary hypertension.

Key facts The solution In less than one year, Dr. Dupuis’s team has clearly Pulmonary hypertension remains demonstrated (in a human Phase I trial) the safety of a devastating, life-threatening Early stage research performed by Dr. Dupuis’s team disorder and commonly occurs led to the idea that adrenomedullin receptors residing PulmoBind and its capacity to image the lung. A Phase II trial is planned for year two and three of the project along with other diseases or in pulmonary vascular endothelium could be exploited conditions. in the development of a new sensitive imaging agent to evaluate the ability of PulmoBind for early and for PH. Their seminal work led to PulmoBind, a synthetic precise PH diagnosis. As the first potential non-invasive Pulmonary arterial hypertension peptide derived from human adrenomedullin. The diagnostic test for early pulmonary hypertension, is estimated to affect between peptide, labelled with the most commonly used imaging PulmoBind will impact drug discovery by facilitating 2,000 and 10,000 Canadians. isotope in nuclear medicine, 99mTc, acts as a tracer patient recruitment, and early treatment of the disease for the molecular imaging of pulmonary circulation with the potential for better drug efficacy. Moreover, thereby allowing the sensitive detection of pulmonary PulmoBind could potentially substitute for the present vascular occlusion and PH diagnosis. Once delivered questionable 6 min. walking distance test, an indirect intravenously, PulmoBind specifically binds to the inner measure of functional pulmonary capacity used in PH walls of the circulatory system in the lungs. Use of drug development for testing drug effectiveness. an external camera allows imaging of the integrity One CQDM pharma partner, Merck, has already of the blood vessels throughout the lungs by expressed great interest in this project and has agreed a diagnostic clinician. to work in close collaboration with the investigators to develop a positron emission tomography (PET) imaging version of this peptide and to establish proof-of-concept in non-human primates.

CQDM 2012 annual Report – success Stories 15 Investiga tors: Success Michel Maziade (Université Laval, NDEI Inc.), Marc Hébert and Chantal Mérette (Université Laval). Stories

Date of initiation: 09/2010

$2.1M over 3 years

“No diagnostic tests yet exist for schizophrenia and bipolar disorder, a situation leading to tremendous Use of light human and financial costs: this new diagnostic technology is to non-invasively profile patients filling a pressing need” Dr. Michel Maziade with psychiatric disorders

main The challenge etiology is very heterogeneous and is challenging accomplishments The stratification of patients with major psychiatric to classify and treat. As a consequence, the power disorders is very challenging due to the diversity of of current pharmacological and clinical trials is Six novel ERG-measured biomarkers substantially diminished. This results in a tremendous identified, based on the dynamic causes and symptoms. In the case of schizophrenia, the process involves ruling out other mental health loss of resources and funding due to an inability responses originating from retinal disorders and determining symptoms that are not to replicate trial results and thereby identify new photoreceptors in cones and rods due to substance abuse, medication or a medical psychiatric disorder-specific drug treatment regimens. that allow rapid stratification condition. This elimination approach to diagnosis is long of schizophrenia patients from and requires the involvement of many professional control subjects. experts. Of critical importance, this lengthy approach to diagnosis does not target the early identification of untreated patients who have the best chance of responding to treatment. Similarly, bipolar disorder

16 success Stories – CQDM 2012 annual Report Impact on drug discovery Mentors Alan Cross • Diagnostic test substantially reduces patient recruitment time Chief Scientist in Neuroscience, from months to weeks: Disease Area Leader Psychiatry, AstraZeneca Pharmaceuticals, Immediate up-front direct savings in the order of $4.5M Wilmington, DE, USA for pivotal trials Robert J Mathers • Increased efficiency of clinical trials: Senior Principal Scientist, Neuroscience Research Unit, Reduced false-positive patient selection rates due to ill-defined Pfizer Inc., Groton, CT, USA DSM criteria. Potential to enrich clinical trials with good Andrea Houghton responders Site Lead Pain & Migraine, • Reduces mental health costs by decreasing from years to Merck & Co. West Point, PA, USA months the time for making more definite differential diagnosis Magnus Ivarsson at onset of schizophrenia and bipolar disorder. Director, Function lab Head, CNSP iMed Translational Sciences, AstraZeneca, Stockholm, Sweden

Overview Very rapid non-invasive electroretinography diagnostic test allows for efficient stratification of schizophrenia and bipolar patients with impressive clinical trial cost savings.

Key facts

patient stratification requires a very short (<2 hour) visit The schizophrenia prevalence The solution rate is approximately 1.1% of the Dr. Maziade and his colleagues, Dr. Hébert and Dr. and has immediate application with significant clinical trial cost savings to the industry. population over the age of 18 with Mérette, proposed that patients with major psychiatric similar figures for bipolar disorder. disorders such as schizophrenia may be stratified by These unique biomarkers are not only very promising a simple, straightforward and non-invasive method for the clinical diagnosis of schizophrenic patients but Schizophrenia is long considered of measuring retinal responses to photo-stimulation, have potential to lead to better drugs for schizophrenia. the most chronic, debilitating a process termed electroretinography (ERG). This In this regard, Dr. Maziade and his colleagues identified and costly mental illness, non-invasive approach to diagnosis uses the retina as four schizophrenia patient strata profiles that allowed accounting for $63 billion a a means to access the central nervous system and is them to establish relationships between the patient’s year in direct treatment, societal based on the general consensus that changes in ERG ERG strata and response to treatment. One the four and family costs. in major psychiatric disorders reflect a disturbance strata in particular showed promise in identifying in monoamines such as dopamine and serotonin. good responders from intermediate/poor responders This project was funded by CQDM in 2010 and, within (76% versus 24% respectively). Focusing on an early one year, the team delivered exceptional results. A clinical proof-of-concept study for a new schizophrenia total of six novel ERG-measured biomarkers, based treatment in this positive-responder group could on the dynamic responses originating from retinal substantially reduce clinical trial costs. Ongoing photoreceptors in cones and rods, were identified work focuses on confirming the validity of the novel and allowed stratification of schizophrenia patients ERG schizophrenia diagnostic biomarkers through from control subjects (150 subjects in each category). comparative studies with patients classified with Implementation of this diagnostic test for schizophrenia bipolar disorder.

CQDM 2012 annual Report – success Stories 17 FOCUS PROJECTs

A miniaturized biosensor for The multidisciplinary project led by continuous monitoring of Dr. Emanuel Escher focuses on the Impact on drug discovery development of a biosensor offering the • Accelerate preclinical animal multiple analytes in vivo ability of sensing multiple analytes in real efficacy and toxicity studies: Investigators: time, for use ex vivo and in vivo. The principle Emanuel Escher, Vincent Aimez, André Carpentier, of this cutting-edge device is based on the – Accurately measure multiple Paul Charrette, Michel Grandbois and ability of evanescent fields to induce changes analytes in vivo, in real time and Éric Marsault (Université de Sherbrooke), in the fluorescence of quantum dots (Q dots) under various disease conditions Claudine Allen (Université Laval), Didier following the recognition of an analyte. The Leconte (MSBi Valorisation) and Vincent Poitout biosensor uses a combination of surface- – Measure biomarkers in their (Université de Montréal). tethered reagents associated with Q-dots which natural environment in different Funding: $1.8M over 3 years recognize specific analytes and prevent the anatomical parts of the body loss of reagents into the medium. The sensor Date of initiation: 09/2010 • Improve the monitoring of anti- is linked to the excitation and read-out unit by diabetic drug efficacy in animal a new fibre optic connection technology for models. The ability to monitor drug-related analytes bi-directional signal generation, transmission in biological fluids in the course of pre-clinical and processing. A major and critical milestone • Provide an opportunity to develop and clinical studies is crucial to drug discovery. has been successfully achieved with the human applications by facilitating It enables researchers to establish drug dosage conclusion of a proof-of-concept study drug efficacy testing in clinical and correlations with drug efficacy demonstrating that the first assembled trials through real-time continuous and therefore directly influences the biosensor is functional and able to detect an monitoring of several analytes in a analyte. The team will adapt and apply the development of drugs and diagnostic tools. minimally invasive way. Current biosensors are limited in that biosensor for the simultaneous real-time detection of glucose and insulin in rats. they do not permit real-time measurement Mentors of simultaneous analytes in their natural The performance and validation of the new states as they occur in vivo. biosensor will then be evaluated in vitro and in Shane Weber, Pfizer vivo using several biological fluids. Cyrille Sur, Merck Beverly Isherwood, AstraZeneca

A novel phage-based screening based and/or cell-free assays to screen and technology for antivirals assess candidate compounds have hampered the development of anti-herpetic drugs. For Investigators: most herpesviruses, it is extremely difficult Matthias Götte (McGill University) and Guy Boivin to produce large concentrations of virus (Université Laval). stocks in cell culture systems. Moreover, Funding: $1.4M over 3 years the development of biochemical assays is Impact on drug discovery Date of initiation: 09/2010 compromised by difficulties to express and • Reduce the time and costs for purify major viral targets. In this project, the the discovery of anti-herpetic team has taken advantage of the structural agents through rapid screening This ambitious project conducted by Dr. Götte and functional similarities among viral DNA and testing of small molecules aims to develop a system of rapid screening polymerases and their orthologs in bacterial with proprietary chimeric viral DNA for compounds with a broad spectrum of phages to address this challenge. Phage- derived chimeric polymerases containing polymerases. antiviral activity across the eight major human herpesviruses. These pathogens can critical parts of the viral enzyme which • Improve the treatment of cause a variety of severe diseases in adults are sensitive to antiviral drugs are used to herpesvirus infection via the and children. In particular, the infection with identify novel classes of compounds that discovery of novel antivirals with herpesviruses can be life threatening in people inhibit essential functions of the virus. The broad-spectrum activity against with immune deficiencies and can enhance team has successfully generated chimeric the whole family of herpesviruses. pathogenicity of the human immunodeficiency phage constructs with critical functions of virus despite the availability of potent anti- human herpesvirus polymerases. The chimeric polymerases demonstrate increased sensitivity Mentors HIV therapeutics. Unfortunately, the use of approved drugs against herpesviruses such as to the available antiviral drugs in various newly Michael Westby, Pfizer HSV, HCMV and VZV are often associated with established biochemical and cell-based assays. Terry Roemer, Merck severe side effects, the development of drug The mechanism that determines the sensitivity Stewart L. Fisher, AstraZeneca resistance, and a narrow spectrum of antiviral of chimeric polymerases to antiviral drugs activities. In addition, technical problems in is currently under assessment. the development of quick, convenient cell-

18 focus projects – CQDM 2012 annual Report Synthetic lethality: A step This new platform uses preclinical proof- forward toward effective of-concept models to identify what drug combinations would be most effective in anti-cancer therapy patients. The team has successfully completed Investigators: work on two gene knock-down and screening Gordon Shore, William Muller, Jerry Pelletier, methodologies for the discovery process: Nahum Sonenberg and Michel Tremblay human genome-wide siRNAs screened in (McGill University). high-throughput format and targeted lentiviral shRNAs screened in a pooled format. These Funding: $2 M over 3 years screens target an astounding number of key Date of initiation: 09/2010 genes involved in tumorigenesis, which include regulators of protein synthesis and translation Impact on drug discovery control, protein tyrosine phosphatases, and cell • Identification of more effective In recent years, only 8% of new oncology death regulators, as well as many others. Early drugs have been approved for clinical use. drug combination treatment proof-of-concept studies have been initiated One of the major challenges has been matching strategies thereby increasing the in multiple myeloma with a focus on genetic an appropriate therapeutic strategy to a scope of use for approved anti- markers of sensitivity to dexamethasone, cancer indication due to the heterogeneity cancer agents. a widely used anti-cancer agent in multiple of the disease. In the development of new hematological cancer indications. To date, • Identification of new anti-cancer experimental agents, there is a desperate the team has identified two promising drug targets for future anti-cancer need to identify which patients would respond combination strategies with dexamethasone, best to a given treatment. This personalized therapeutic development. one involving the inhibition of survival medicine approach is not a simple process, as • Bringing new personalized protein Mcl-1 and a second associated with each cancer type represents a unique disease the inhibition of Aurora B kinase, a protein therapeutic options to patients. which harbours a variety of genetic mutations. integrally involved in mitosis and cytokinesis. One approach taken by Dr. Shore and his team Future work will concentrate on the in vivo Mentors is based on synthetic lethality. This refers to validation of both strategies in relevant a requirement that two genes, if eliminated Oivin M. Guicheret, Pfizer murine cancer models. individually, have little impact on cancer cells, Cynthia Seidel-Dugan, Merck but together their elimination results in Keith Mikule, AstraZeneca cell lethality.

Integrated tumour- information with tumor-intrinsic data increased microenvironment biomarkers prognostic accuracy. As there are currently no accurate and standardized tests for this for improved targeting of breast purpose, optimization of stromal signatures cancer therapy to classify tumor samples is critical for breast cancer research with direct implications in Impact on drug discovery Investigators: treatment regime decisions. Morag Park, Michael Hallet and Atilla Omeroglu • Stratify breast tumors by (McGill University), Patrice Hugo (Independent With this in mind, the goal of the CQDM- combining tumor-intrinsic and Consultant). funded project is to generate and validate stromal features to identify distinct tumor-microenvironment profiles. Funding: $1.3M over 3 years specific groups of patients for The identification of new tissue and blood Date of initiation: 09/2011 responders to therapies. biomarkers, which integrate the intrinsic and stromal characteristics of the tumor, will allow • Selection of most appropriate for better stratification of patients with breast The genetic heterogeneity of breast cancer treatments based on integrated cancer with potential to predict responders tumors has long been recognized. Tumor- tumor-microenvironment to treatments. In the first year of this project, intrinsic features and subtypes are associated classification. the team completed laser capture micro- with differential outcomes and are used to dissection and tissue isolation of a total of • Identify stromal features as personalize cancer treatment regimes. It has 48 HER2‐positive and triple‐negative breast targets for the development become increasingly evident however that cancer patients. The generation of sample- interactions between a primary tumor and its of new therapies. specific gene expression profiles is ongoing. surrounding stromal environment, in addition Mentors to genetic changes within the tumor itself, are significant predictors of disease progression. Paul Rejto, Pfizer Prior to the CQDM funding of this project, Dr. Leigh Zawel, Merck Park’s team showed that sub-classification of Celina D’Cruz, AstraZeneca the stromal environment can predict disease outcome. Moreover, combining stromal

CQDM 2012 annual Report – FOCUS Projects 19 FOCUS PROJECTs

Magnetically guided drug the result of increased rates of disease-free delivery platform based on survival for cancer patients. Dr. Martel has pioneered a revolutionary drug delivery system bio-carriers for the treatment using magnetotactic bacteria to address this of colorectal cancer challenge. These non-pathogenic bacteria, with a diameter of approximately two micrometers, Investigators: are able to navigate through the smallest Sylvain Martel (École Polytechnique de Impact on drug discovery capillaries to reach targets that are inaccessible Montréal), Michael Atkin (Syzent Partners), • Direct targeting of chemotherapy Gerald Batist, Nicole Beauchemin, Danuta to larger microcarriers. Loaded with liposome encapsulated cancer-fighting drugs attached drugs to the cancer site, leading Radzioch, Maryam Tabrizian and Te Vuong to better tumor penetration and (McGill University), Louis Gaboury and physically to their cellular envelop, and guided Michel Lafleur (Université de Montréal). by a computer-controlled external magnetic improved drug efficacy. field, the bacteria flagella propel themselves • Decreased maximal effective Funding: $1.9M over 3 years efficiently through small blood vessels. This anti-cancer drug dose and Date of initiation: 09/2011 multidisciplinary project involves renowned consequentially limited secondary researchers whose collaborative work in primary colorectal cancer models seeks to systemic toxicity. Many cancers are treated with cocktails of demonstrate through proof-of-concept studies • Deliver various generic anti-cancer chemotherapy drugs designed to prevent that this platform is efficacious in targeting or novel drugs to treat localized growth and spread of cancerous cells. Although cancer cells. In doing so, the devastating cancers that reduce the need for recent decades have brought significant side effects caused by systemic delivery invasive surgery. improvements in patient survival and morbidity of chemotherapy drugs should drastically reduction, chemotherapy drugs still damage be reduced. After the first year, the team Mentors healthy cells, causing undesired side effects successfully developed the magnetic tool such as myelosuppression and cardiotoxicity. prototype and its software control system, and Ronald P. Gladue, Pfizer Localized therapy could have a major impact established the safety profile of magnetotactic Robert M. Garbaccio, Merck on quality of life and treatment efficacy, with bacteria in mice and rats. Corinne Reimer, AstraZeneca

Quantitative O2 MRI: a new Alzheimer’s disease (AD) is a progressive, emission tomography (PET) enables imaging of window on mitochondrial debilitating neurodegenerative condition that oxidative metabolism, however, it is presently can affect individuals in middle or old age. cumbersome, requiring three administrations dysfunction in Alzheimer’s Almost half of cases require a high level of of 15O labelled tracers. After each imagining Disease long-term care, resulting in significant social scan multiple samples are collected to and economic burden. In 2006, 26.6 million determine blood radioactivity levels. This Investigators: individuals were affected by AD worldwide, with is arduous for patients and entails risks Richard Hoge, Pierre Bellec, Sylvie Belleville, Oury Monchi , Yan Deschaintre, some estimates predicting a fourfold increase due to both the ionizing radiation exposure, Julien Doyon (Université de Montréal), in global incidence to 1 person in 85 by the and the need for arterial catheterization. To Christian Bocti (Université de Sherbrooke), year 2050. The prevalence and severity of overcome these challenges, Dr. Hoge and Serge Gauthier (McGill University). this disorder thus makes it a significant his multidisciplinary team developed a novel public health issue and an important target MRI technology allowing for the rapid and Funding: $1.5M over 3 years for drug discovery. Current treatment options non-invasive imaging of oxidative metabolism Date of initiation: 09/2012 are unfortunately limited, providing at in the human brain. Their approach, termed best a modest and transient reduction QUO2 (QUantitative O2) MRI, enables imaging of specific symptoms. during the delivery and following consumption There is strong evidence that mitochondrial of oxygen with superior spatial resolution and dysfunction is the primary causal factor sensitivity and, importantly, without radiation in AD. However, the detailed exploration of exposure to PET. It can thus be repeated serially mitochondrial impairment has been in part on individual patients, making it well suited limited by the lack of a robust and non-invasive to large-scale clinical trials, including method for the quantitative characterization of longitudinal studies. oxidative function in the human brain. Positron

20 focus projects – CQDM 2012 annual Report Selectomics to monitor and transferring resistance genes to pathogens. predict the emergence of His research team is pursuing a novel approach designed to study the potential resistance resistance to antibiotics gene reservoir of gut bacteria as a means Investigators: to identify the resistance potential of novel Michel Bergeron, (Université Laval, CHUQ, antibiotics. Specifically, the group is studying Pavillon CHUL), Jacques Corbeil, Marc Ouellette, the gut ecosystem to see if it can be used Paul H. Roy and Sylvie Trottier (Université to predict the emergence of resistance to Laval, CHUQ, Pavillon CHUL), Maurice Boissinot antimicrobial agents in vivo and determine if (GenePOC). antibiotic exposure has the potential to alter this reservoir of antibiotic resistance genes. Funding: $2M over 3 years Studies on the occurrence and characterisation Impact on drug discovery Date of initiation: 09/2011 of novel genes encoding resistance to clinically • Access early potential for relevant antibiotics in human fecal flora is resistance to novel antimicrobials. being carried out with both cultivable and The development of antibiotic resistance is a non-cultivable members of the aerobic and • Guide drug development for more challenging problem posing a serious threat anaerobic communities of microbes obtained effective antimicrobial treatments. to human health. The emergence of multidrug- from healthy individuals exposed to antibiotics. resistant organisms is worrisome, as it hinders • Develop better, faster During the first year, the team has enrolled the ability to treat bacterial infections and is antimicrobial diagnostic tools. healthy volunteers and collected all subject challenging for the development of effective fecal samples. A database of resistance gene • Personalize antibiotic treatments. new antimicrobial agents. The primary focus sequences was constructed and protocols to of studies on antibiotic resistance genes culture and identify resistant isolates from historically was on bacterial pathogens. Mentors the microbiome were established. Protocols Richard Korsmeyer, Pfizer Dr. Bergeron’s team, on the other hand, for construction of metagenomic libraries to Terry Roemer, Merck hypothesized that human microflora, normally characterize new resistance genes were tested considered innocuous or even beneficial, could and finally, a bioinformatics pipeline to analyze Humphrey Gardner, AstraZeneca play a detrimental role in human health by high throughput sequence data was created.

Impact on drug discovery • Significant potential to identify new mechanisms of action for future AD drugs. • Improve patient selection for appropriate treatment selection in clinical trials. • Provide new therapeutic endpoints for assessment of drug efficacy in clinical trials. • Guide personalized therapeutic intervention in individual patients depending on their relative vascular and mitochondrial burdens.

Mentors Michael Klimas, Merck Ross Fredenburg, AstraZeneca

CQDM 2012 annual Report – FOCUS Projects 21 explore projects

Virtual optimization hamper the rapid development of therapeutic of therapeutic antibodies antibodies. Currently, they are generated in animals and subsequently assessed for Investigators: functionality, potency and specificity. This long, Enrico Purisima, Yves Durocher and Maureen labor-intensive approach requires substantial O’Connor-McCourt (National Research Council, investments in time and resources with a Biotechnology Research Institute). limited success rate. The use of computer-aided Funding: $300K over 2 years drug design techniques for the de novo design of antibodies to target specific antigens could Date of initiation: 12/2011 help alleviate these constraints. Dr. Purisima proposed to develop ADAPT Therapeutic antibodies have made important (Automated Design Applied to Protein Impact on drug discovery breakthroughs in the pharmaceutical market, Therapeutics), a novel platform to design • In silico based rapid identification traditionally occupied by small molecule antibodies with optimal binding characteristics of high affinity antibodies against drugs. Their success stems from the high to a specific antigen. Using a database of therapeutic targets of choice. specificity and high affinity of antibodies for 230 antibody mutants and their measured their targets, resulting in reduced side effects. binding affinities as an initial test, he was able • Reduce costs and time for Moreover, antibodies share a common general to predict with good reliability which mutations therapeutic antibody development overall scaffold. This allows the use of similar led to enhanced affinity over the wild type through early integration of the technologies for antibody production and sequence. As a next step, he took an antibody platform in the antibody discovery optimization across different targets, which is with weak affinity towards two targets, VEGF-A phase. in contrast to small molecules, where different and HER2, and applied virtual mutagenesis to targets require different scaffolds and different redesign the sequence for improved binding Mentors chemistries. All these benefits contribute to an affinity against each of the targets. The mutants outstanding approval rate, estimated to be 17%. are in the process of being produced and Eric Bennett, Pfizer their affinities will be measured using surface Grigori Ermakov, Merck Presently, there are more than 30 therapeutic Bojana Popovic, MedImmune Inc. antibodies on the market and an additional plasmon resonance methods. Xuan Hong, GlaxoSmithKline 350 in various stages of development. However, technical constraints continue to

FlAsH-walk mapping: Dr. Hébert and his team will pursue the use of a step-by-step approach to receptor dynamics from diverse conformational vantage points to better understand the GPCR conformation interactions between drugs and their target cartography GPCRs, thereby enabling the design of more effective GPCR-based therapeutics. Investigators: Specifically, they are developing and validating Terence Hébert, Sylvain Chemtob (Hôpital a new method to establish conformational Sainte-Justine), Audrey Claing and William Lubell (Université de Montréal), Stéphane Laporte signatures, or FlAsH-walk maps. This focuses (MUHC Royal Victoria Hospital). on the various conformations that GPCRs can adopt following ligand binding which leads to Funding: $300K over 2 years activation of their distinct signaling pathways. Date of initiation: 12/2011 Impact on drug discovery To this end, in vitro assays will be established based on resonance energy transfer (BRET or • Novel GPCR-based therapeutics FRET) to analyze conformational dynamics of G protein-coupled receptors (GPCRs) are identified through drug induced receptor activation upon ligand binding and the largest target class for approved drugs. conformational activation of engagement of G proteins and other effectors. Identification of new drug candidates has distinct signaling pathways. These interactions between GPCRs and their relied exclusively on high-throughput assays partners can be measured in real-time allowing which track binding properties and are limited Mentors cell-based assays to be used in HTS modes. to a restricted number of signaling pathways. Recent progress in the project shows that Arjan Snijder, AstraZeneca GPCRs however are highly dynamic proteins the engineered tags are well tolerated Thomas Rimele, GlaxoSmithKline that undergo numerous conformational functionally by the target receptors. These changes upon receptor association with ligands tags provide distinct measures of conformation and related protein partners. Use of such drug- depending on where they are placed in the induced conformational changes has in general receptors when used as BRET acceptors with been overlooked as an approach to enhance interacting proteins. efficient discovery of novel drugs for GPCRs due to the difficulty in adapting structural 22 EXPLORE PROJECTS – CQDM 2012 annual Report approaches to high-throughput screening (HTS). Powerful bioinformatic tool for on the specific relative position of atoms in the rational selective drug design surface of binding-sites, a more global vision of the combined total interactions (termed Investigator: Molecular Interaction Field; MIF) is considered Rafael Najmanovich (Université de Sherbrooke). critical for selective rational drug design. This permits the identification of distinct atomic Funding: $300K over 2 years configurations across families that produce 12/2011 Date of initiation: similar MIFs. The novel platform will be validated using Drugs act by modulating the function of existing and newly generated experimental Impact on drug discovery target proteins. However, additional off-site data across protein families, and with a subset non-target proteins may also be affected of human protein kinases over-expressed in • Predict off-target toxicities early due to similarities between binding sites. triple negative breast cancer, a devastating in the drug discovery process. This unintentional action may lead to the form of breast cancer that is unresponsive • Reposition approved drugs in to existing therapies. With such kinases, serendipitous discovery of new applications new unmet medical indications. for a particular drug, but equally it can result experimental differential scanning fluorometry in unwanted safety concerns. Detection of binding profile similarities will be compared • Identify novel drugs with such similarities early in the process of drug to MIF similarities. In addition MIF makes it multi-therapeutic opportunities. discovery may prevent deleterious side effects. possible to detect off-family potential cross- On the other hand, rationally designed multi- reactivity targets which can be used for rational Mentors functional drugs that interact with more than drug design. Overall, the program will have Stephan K. Grant, Pfizer one target may equally be designed upfront global application in the large-scale analysis with a multitude of potential applications. of binding site similarities leading to rational Pierre R. Bonneau, To achieve this level of specificity in drugs, selective design of drugs based on predicted Boehringer Ingelheim Dr. Najmanovich proposed to develop protein functional binding sites. a technique for detection of 3D atomic similarities. Rather than limiting the focus

Explore projects 2012 Pinpointing critical drugs targets Based on this understanding, Dr. Richards Monitoring conformational for autoimmune disease and his team proposed that somatic mutations changes of channel proteins: could in fact lead to uncontrolled cellular a novel approach for rapid Investigators: proliferation causing autoimmunity. They have screening of ion channel hits Brent Richards and Constantin Polychronakos secured joint-space aspirates from individuals (McGill University). having new-onset arthritis, in addition to their Principal Investigator: circulating white blood cells. They are presently Funding: $300K over 2 years Graciela Piñeyro (Institut de Recherche comparing their genomes for evidence of Date of initiation: 12/2011 de l’Hôpital Ste-Justine). mutations present in the inflammatory cells Date of initiation: 12/2012 in the joint space, but absent from the circulating periphery. Autoimmune diseases affect millions of Circumventing the need for individuals in North America. They are a predictive biomarkers in major health and economic burden as people personalized ovarian cancer with such conditions suffer from debilitating Impact on drug discovery symptoms that can lead to life-long disability therapies: empirical • Pioneer new autoimmune disease and mortality. Although progress has been chemosensitivity using a made in the last few years, many autoimmune treatment through novel disease microfluidics-based diseases lack effective, targeted therapies with specific targets. multiplex platform acceptable safety profiles primarily due to a Mentors Principal Investigator: lack of knowledge on what selectively activated Anne-Marie Mes-Masson (Université de Montréal). pathways are involved in the disease. Somatic Quintus Medley, Pfizer mutations, in addition to hereditary mutations Date of initiation: 12/2012 Chris Larminie, GlaxoSmithKline and environment effects, are considered a driving force in proliferative cell diseases Platform for the enrichment such as cancer that are not too dissimilar to of circulating tumor cells (CTCs) for inflammatory disorders. If a single mutation characterization and sensitivity to in a pivotal gene were sufficient to cause anti-cancer drugs (PREDICT) autoimmune disease, this would highlight a potential drug target. Principal Investigator: Richard Kremer (McGill University). Date of initiation: 12/2012 CQDM 2012 annual Report – EXPLORE PROJECTS 23 QUEBEC/ALSACE PROJECTS

Optical imaging and Despite the huge resources that have been spectral detection technology for cellular biosimulation platforms invested in central nervous system (CNS) imaging, and ii) an in silico biosimulation research, the development of efficient drugs to accelerate CNS drug platform to model and predict drug effects targeting CNS diseases remains a challenge. at different levels of neuronal signaling, discovery Investigators This is in part due to a lack of effective methods based on Rhenovia’s powerful and unique for studying the complex CNS molecular program capable of handling multiple levels Investigators: processes, in particular those occurring at Quebec: Sébastien Blais-Ouellette of brain function analyses. For the first (Photon etc.) and Paul De Koninck the synaptic level. Protein recruitment and proof-of-concept, the team is focusing on (Université Laval). interactions at the synapse are known to be the spatial dynamics of glutamate receptors, modified under pathological conditions and to Alsace: Serge Bischoff a group of receptors implicated in several (Rhenovia Pharma, Mulhouse). induce important changes in cellular functions. neurodegenerative conditions, and their Despite great advances in imaging techniques, interactions with intracellular anchors. These Funding: $700 K over 3 years it remains difficult to define this synaptic ongoing experiments involve the development (for the research being performed in Quebec) plasticity. A better understanding of receptor of methods to specifically tag multiple Date of initiation: 06/2012 dynamics and protein-protein interactions receptors with fluorescent probes, in addition is essential, as it could provide explanations to establishing algorithms to analyze their for efficacy limitations and guidelines for the trajectories simultaneously in neurons. The development of new drug candidates. combination of these platforms will provide Two highly innovative and complementary unique guidelines for the development of new platforms are currently being developed drug candidates targeting CNS disorders. to address this challenge: i) a multiplexed optical imaging platform for the simultaneous observation of multiple cellular events, based on Photon etc.’s highly sensitive hyper-

Identification of new biomarkers and poor prognosis of these tumors appears to for neuroendocrine cancers be linked to the high level of protein secretion by the tumor. Investigators: The main objective of this collaborative project Quebec: Daniel Chelsky and Eustache is to investigate the mechanisms resulting Paramithiotis (Caprion Proteomics). in neuroendocrine tumor hyper-secretion, Alsace: Stéphane Gasman (Centre National and to identify and validate diagnostic and de la Recherche Scientifique, Strasbourg). prognostic biomarkers for clinical treatment Funding: $700 K over 2 years of neuroendocrine tumors. A diversity of (for the research being performed in Quebec) approaches using in vitro cell lines as well Date of initiation: 06/2011 as neuroendocrine tumor tissues are being used to identify and validate candidate protein biomarkers. The well-established Cancer is the second leading cause of death large-scale Caprion proteomics platform in the developed world and despite intense will identify candidate protein biomarkers Impact on drug discovery efforts to reduce its mortality rate, only that display reproducible, condition-specific • Identification of cancer-related modest progress has been made. Particularly expression changes. To date proteomic proteins that have potential as problematic are cancers derived from analyses on cell lines and neuroendocrine new therapeutic targets. endocrine tumors. Because endocrine tumors tumors have led to the identification of more arise from hormone-producing cells, the than two thousand differentially expressed • Biomarkers for early diagnosis tumor itself can over-produce hormones that proteins. Candidate protein biomarkers were of neuroendocrine cancers and can cause serious illness and complications. selected and validation of these candidate facilitating patient recruitment These neuroendocrine tumors are very difficult proteins is currently underway. in clinical trials. to diagnose. The existing treatments are • Discover better prognostic ineffective in late stage tumors. Therefore, markers and profile response there is an urgent need to improve diagnosis to treatment. and develop more effective therapies against neuroendocrine tumors. The aggressiveness

24 QUEBEC/ALSACE PROJECTS – CQDM 2012 annual Report Impact on drug discovery • Enable better drug development in the challenging CNS field using in silico prediction of dynamic protein-protein interactions, particularly those occurring at the synaptic level.

Mentor Martin Main, AstraZeneca

Monitoring the signaling side effects is to develop drugs that operate pathways of GPCRs in living at selected receptor-signaling pathways in vivo. However, due to the complexity of GPCR animals physiology and associated diseases in living animals, this goal represents a true challenge Investigators: Quebec: Michel Bouvier (Université de Montréal) and drugs are typically developed based on and Michel Tremblay (Mispro Biotech in vitro cellular models. Services Inc.). The overall objective of this innovative proposal Alsace: Brigitte Kieffer (Institut de Génétique, is to generate and characterize new genetically Biologie Moléculaire et Cellulaire, Strasbourg) engineered mice to observe directly in vivo the and Pascal Neuville (Domain Therapeutics Inc., action of drug candidates on specific GPCRs, Strasbourg). effectors and signaling events using newly Funding: $530K over 3 years developed microscopy imaging techniques. The (for the research being performed in Quebec) mouse lines will be constructed by homologous Date of initiation: 11/2012 recombination such that mutant animals will express functional fluorescent versions Impact on drug discovery of the receptor or the effector in place of the • Improve preclinical drug G protein coupled receptors (GPCR) represent endogenous protein (knock-in mice). This gene discovery programs targeting the largest family of cell surface receptors targeting strategy will lead to physiological and GPCRs by developing new involved in signal transduction. They respond directly detectable expression of the targeted models for screening desirable/ to a wide variety of compounds and are major receptor and/or effector protein. Receptors and undesirable signaling effects attractive targets for the development of new signaling pathways to be studied are selected under physiological conditions of drug candidates with potential applications in for their potential therapeutic value in cancer receptor and effector expression. many clinical fields. Currently, an estimated as well as neurologic and psychiatric disorders. 40% of drugs on the market target GPCRs. This project will have a high impact on the • Develop drugs with greater At the cellular level, once a drug binds to a preclinical drug discovery programs targeting therapeutic efficacy and fewer GPCR, a complex set of intracellular signals is GPCRs and will involve a truly synergistic undesirable side effects. initiated leading to a physiological response. It collaboration between two leading academic is currently understood that the best approach teams and two industrial partners. to designing effective therapies with limited

CQDM 2012 annual Report – QUEBEC/ALSACE PROJECTS 25 QUEBEC/ONTARIO PROJECTS

Catecholamine-regulated protein (CRP40) and Parkinson’s disease: implications for early diagnosis and treatment

Investigators: Ram Mishra (McMaster University), Joseph Gabriele (CRP40 Inc., McMaster University); Thérèse Di Paolo (Université Laval), Pierre Blanchet (Université de Montréal).

Funding: $750K over 3 years Date of initiation: 04/2012

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder afflicting 1% to 2% of the population over 65 years of age and for which there is neither a reliable diagnostic test nor cure. While the exact cause of PD is unknown, it is recognized that pathological features are progressive death of dopaminergic neurons. Dopamine (DA) constitutes approximately 80% of catecholamines in the brain and aberrations in DA activity have been implicated in abnormal behavior involving impairments in fine motor movement. However, relatively little is known about the molecular mechanisms that regulate levels of DA. Work performed by Drs. Di Paolo and Mishra have shed light on potential avenues to develop Impact on drug discovery a diagnostic marker for PD. Specifically, they • Facilitate diagnosis of Parkinson’s have shown that CRP40, a novel heat-shock- disease and patient recruitment like protein that is an alternate splice variant in clinical trials. of a mitochondrial heat-shock protein, mortalin-2 (mot-2) is involved in regulation With this impressive data at hand, this • Monitor therapeutic effects of new of DA. They detected significant reduction CQDM-funded project will validate CRP40 drugs tested in human clinical of CRP40 mRNA and protein levels in in vitro as a biomarker for the early diagnosis of PD trials. cell models and in in vivo preclinical models in preclinical animal models (rodents and of PD. Furthermore, significant reduction non-human primates), as well as in human Mentors of CRP40 was detected in post-mortem subjects with PD (drug naïve and drug treated). Hugh Salter, AstraZeneca brain specimens of PD patients and in blood To achieve this, longitudinal studies are platelets of human PD patients. Moreover, planned to follow the progression of disease Matt Troyer, Merck recent studies demonstrated the capability and therapeutic effects of drugs in both of a CRP40 recombinant fusion protein to preclinical animal models and human subjects. correct rotational behavioral impairments of the The aim is to develop a reliable diagnostic kit, preclinical hemi-lesioned 6-hydroxydopamine based on CRP40 levels that can be utilized in (6-OHDA) rat model of PD, thus demonstrating laboratories and clinics worldwide. Ultimately, that this novel protein may act as a possible it is anticipated that this will establish the use therapeutic agent. Furthermore, CRP40 appears of the CRP40 technology in screening for PD to be specific to PD as it is unaltered in other patients in addition to aiding the development neurological disorders such as Alzheimer‘s of novel drugs for the treatment of PD. disease, stroke, or unaffected by the ageing process.

26 QUEBEC/ONTARIO PROJECTS – CQDM 2012 annual Report Cycloinformatics: This very recent CQDM-funded project will A platform for rapid expand on this early proof-of-concept work to develop a set of scaffold-specific rules, production of medium-sized termed Macrocycle Cell Permeability Rules, so macrocycles as protein-protein as to guide the future design and selection of interaction probes bioavailable drugs. These novel macrocyclic peptides should allow the development of drugs Investigators: with an ability to not only target extracellular Andrei Yudin (University of Toronto, Encycle Inc.), proteins, but should potentially open the door Eric Marsault (University of Sherbrooke). to the extensive untapped area of intracellular Funding: $750K over 3 years protein-protein interaction targets. Date of initiation: 05/2012

Human genome-wide studies of diseases have provided an exhaustive number of novel therapeutic targets, many with a high level of complexity. A number of these targets engage protein-protein interaction (PPI) surfaces, which have emerged in the last decade as druggable targets. While small molecules are ideally suited to interact with well-defined pockets such as those found in enzymes, their ability to antagonize PPIs is limited because inter-protein contacts tend to be featureless and cover large surface areas. Extended protein surfaces can be probed by macrocycles, a privileged and under-explored cyclic class of compounds that possesses intermediate properties between small molecules and protein drugs. Their relatively small size facilitates identification of enviable drug properties such as enhanced oral bioavailability and cellular permeability, which are not possible for larger peptides or proteins. Currently however, there is no group of macrocyclic scaffolds specifically designed to target PPIs. To succeed, compounds that mimic protein secondary structures such as beta turns, beta sheets, alpha helices with incorporated specific molecular recognition elements, need to be developed. To address this challenge, Dr. Yudin’s team Impact on drug discovery recently developed a powerful chemistry platform based on constraining linear peptides • Cycloinformatics platform delivers into their macrocyclic forms using amphoteric macrocycles with small-molecule- reagents developed in his laboratories. like properties from peptides of any length. • Cell-permeable macrocyclic peptidomimetics suitable to target intracellular protein-protein interactions targets. • Oral bioavailable potential for novel macrocyclic peptidomimetics.

Mentors Scott Cowen, AstraZeneca Spiros Liras, Pfizer

CQDM 2012 annual Report – QUEBEC/ONTARIO PROJECTS 27 IMPACT TARGET DISCOVERY & LEAD OF CQDM IDENTIFICATION SCREENING OPTIMIZATION PROJECTS

through the Shore Bouvier Synthetic lethality Biosensors various stages oncology GPCR signalling Chelsky/Gasman Götte of the drug Drug targets Screening methods neuroendocrine antivirals discovery process tumours Vezina Blais-Ouellette/Bischoff Discovery platform Protein-protein VLP vaccine Ag interactions CNS target discovery Bouvier/Kieffer New engineered Richards mice Somatic mutations of for GPCR studies reacting T cells inflammatory diseases Yudin/Marsault Macrocycles library Protein-protein interactions

Hébert Dynamic response to GPCR drugs

Pineyro Biosensors for ion channels

Mes-Masson Microfluidic platform for cancer therapy

28 CQDM 2012 annual Report LEAD PRECLINICAL CLINICAL FDA MARKET OPTIMIZATION STUDIES development

Najmanovich Escher Bergeron Molecular Real-time in vivo Resistance interactions analyte measurement to antibiotics field platform ADME studies Martel Purisima Mishra/DiPaolo Magnetic guided In silico Parkinson’s disease drug delivery platform predictivity Early diagnosis of mAb affinity and treatment Maziade ERG biomarkers Bedell psychiatric disorders Animal models Alzheimer’s disease Dupuis Imaging biomarker pulmonary hypertension

Paramithiotis Early diagnostics diabetes

Park Stromal biomarkers breast cancer

Hoge Patient stratification Alzheimer’s disease

Kremer Method to isolate circulating cancer cells

CQDM 2012 annual Report 29 FINANCIAL SUMMARY 2012

The Statement of Financial Position as at March 31, 2012 and 2011 and Statement of Operations for the years ended March 31, 2012 and 2011 that follow are provided as illustrative summaries only and are not intended to replace the full financial statements of CQDM. These full financial statements were audited and reported on July 19, 2012 by Raymond Chabot Grant Thornton LLP, Chartered Accountants.

Statement of Financial Position As at March 31, 2012 and 2011 (Expressed in Canadian dollars) 2012 2011

ASSETS Current assets $ $ Cash and short-term investments 15,356,066 20,895,145 Other current assets 265,135 222,131 15,621,201 21,117,276 Long-term investments 8,000,000 1,000,000 Capital assets 15,743 18,798 23,636,944 22,136,074

LIABILITIES Accounts payable and accrued liabilities 340,132 137,323 Long-term deferred contributions 23,296,812 21,998,751 23,636,944 22,136,074 NET ASSETS Unrestricted – – 23,636,944 22,136,074

Statement of Operations For years ended March 31, 2012 and 2011 (Expressed in Canadian dollars) 2012 2011

REVENUES $ $ Contributions 7,703,439 5,507,418 Other income 365,312 223,988 8,068,751 5,731,406

EXPENSES Project expenditures and other mission fulfillment expenses 7,657,062 5,288,184 Administrative and governance 411,689 443,222 8,068,751 5,731,406

Excess of expenses over revenues – –

30 CQDM 2012 annual Report Revenues and contributions Our consortium has signed contribution agreements with members from Collaborations ($ millions) both the private and public sectors. Our private members include seven of the 2 world’s leading pharmaceutical companies, namely AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Merck, Pfizer and Novartis (which joined our consortium in 2012 as an Explore program sponsor). Their direct cash commitments, with initial terms expiring at various dates through 2016, total $22.3 million. These private members not only provide us financial support, but are also actively involved in the affairs of the consortium as a Private ($ millions) 22.3 whole. Our industrial members sit on our board and committees overseeing the selection, evaluation, approval, and management of research projects. In addition, they provide scientists from their global organizations to mentor the approved projects, thereby providing the requisite expertise and guidance to ensure constant alignment with the defined commercial/industrial goals. On a conservative basis we believe that such invaluable in-kind support adds Public ($ millions) an additional $250,000 annually to their already significant cash contributions. 25 Our public members, including the CIHR, NSERC, and SSHRC through their joint funding of the federal government’s Business-led NCE program, and the MDEIE and FRQS in Quebec are also strong proponents of CQDM and its mission. To date, both levels of governments have invested $24.8 million in direct cash contributions to our consortium. $49.3 million in Total CQDM is also proud to count on the support of a number of other prestigious Funding Commitments organizations as collaborators to help us expand the reach of Quebec research on a national and international scale. MaRS Innovation (MaRS), the Ontario Brain Institute (OBI), and the Ontario Centers of Excellence (OCE) recently joined CQDM in launching a research program in the Quebec/Ontario Life Expenditures and commitments Sciences Corridor. CQDM will finance the Quebec arm of any joint Quebec/ CQDM has invested or earmarked for investment $32.4 million and our Ontario research project while MaRS, OBI, and OCE will be responsible for collaborators $2.0 million in research projects and expenditures. On a helping to secure financing for the Ontario arm. Alsace BioValley in 2010 and program/project basis, these commitments/expenditures are as follows: Lyonbiopôle in 2012, both non-profit organizations constituted in France, are participating similarly in the CQDM/France joint research program by their financing of the French arm of any joint Quebec/France research project. We Program/Project ($ millions) estimate that these collaborations will add an additional $2.4 million annually in Focus 25.2 support of pharmaceutical research when fully in place next year. To date, initial Explore 2.3 or pilot collaborations in these programs have contributed $1.6 million of in-kind CQDM/France 2.1 support to the benefit of all our stakeholders. Quebec/Ontario 1.7 The total amount of funding commitments received since the inception Special project (Biospective) 1.1 of CQDM now stands at $49.3 million, an increase of 10% since last year. 32.4

The new funding commitments/contributions in the year include: General and administration expenses incurred by CQDM since its inception Sector ($ millions) total $1.4 million, representing only 3.9% of all funds committed Private 0.3 or spent to date. Public 3.4 Collaborators 0.6 4.3 expenditures and commitments (%)

CQDM /France joint research projects (committed) 4.1 A strong financial leverage Biospective projects (committed) 0.8 Québec /Ontario research projects (committed) Funding Program Leverage Effect 0.5 Focus 11:1 CQDM research projects (committed) 81.1 Explore 15:1 CQDM research projects (reserved) 8.0 Quebec / France 19:1 General and administration expenses 3.9 Quebec / Ontario 21:1 Incorporation Costs 1.6

CQDM 2012 annual Report 31 BOARD AND COMMITTEE MEMBERS Max Fehlmann The Corporation acts through its representative Former President and CEO bodies: the Board of Directors and its Committees, CQDM the Officers, the Members and its other representatives. Director since 2008 The Board meets at least three times a year to: Neil Maresky • Ensure the Corporation’s financial stability Vice President, Medical Affairs and overall performance. AstraZeneca Canada Inc. • Ensure that the objectives of the Corporation Committees: Executive and Nominating are properly carried out. Director since 2010 • Perform the duties and responsibilities related CORPORATE to the director’s position. Donald Olds President and CEO The Audit Committee meets at least two times a year to review the financial statements and to receive Presagia Corporation INFORMATION notification of any errors or misstatements contained Committees: Executive, in financial statements from the external auditors. Nominating, and Audit (Chair) Director since 2008 The Executive Committee meets at least three times a year and consults with, and assists, the Officers Vassilios Papadopoulos in all business regarding the Corporation and its Director CQDM MEMBERS management. Global Industrial Members Research Institute of the McGill University AstraZeneca Canada Inc. The Nominating Committee is responsible Health Center (MUHC) Merck Canada Inc. for overseeing the recruitment process of Director since 2009 Pfizer Canada Inc. members of the Board of Directors, their removal, and replacement. Ken Pastor Program-Specific Industrial Members General Partner Boehringer Ingelheim (Canada) Ltd. / Ltée Léon Gosselin (Chairman of the Board) CTI Capital Inc. Eli Lilly Canada Inc. Corporate Director Committee: Audit GlaxoSmithKline Inc. Committees: Executive and Nominating (Chair) Director since 2009 Novartis Pharmaceuticals Canada Inc. Director since 2008 Bruno-Marie Béchard Marinier HONORARY MEMBERS Research Grant Members Elaine Campbell Professor/Honorary Rector Caprion Proteomics Inc. President and CEO Université de Sherbrooke Centre hospitalier de l’Université de Montréal (CHUM) AstraZeneca Canada Inc. Centre hospitalier universitaire de Québec (CHUQ) Director since 2009 John Helou Centre hospitalier universitaire Sainte-Justine Jennifer Chan President CRP40 Inc. Vice President, Policy and Communications Pfizer Canada Inc. École Polytechnique de Montréal Merck Canada Inc. Encycle Therapeutics Inc. Director since 2012 Rémi Quirion GenePoc Inc. Chief Scientist Michel Chrétien Innovacor SEC Fonds de la recherche en santé du Québec (FRSQ) Institut de cardiologie de Montréal Professor Institut national de la recherche scientifique (INRS) University of Ottawa Cyril Schiever Institut universitaire en santé mentale de Québec Director since 2009 President and Managing Director McGill University Merck Canada Inc. Michael Cordingley McMaster University Senior Vice President, Research and Development Medicago Inc. Boehringer Ingelheim (Canada) Ltd. / Ltée OBSERVERS Montréal InVivo Director since 2009 Michèle Houpert National Research Council Manager of Health and Biotechnology Neuropsychiatre, Découverte Jean Davignon Ministère des Finances et de l’Économie et Innovation Inc. (NDEI) Professor, Université de Montréal Photon etc. Inc. Director since 2009 Stéphanie Michaud Université de Montréal Program Deputy Director Université de Sherbrooke Richard Fajzel Networks of Centres of Excellence Université Laval General Manager, Oncology Business Unit University of Toronto Pfizer Canada Inc. SECRETARY Committees: Executive and Nominating François Painchaud Independent Members Director since 2011 Lawyer, Partner Bruno-Marie Béchard Marinier Robic LLP Michel Chrétien Jean Davignon Léon Gosselin Donald Olds Vassilios Papadopoulos Ken Pastor

32 CQDM 2012 annual Report STRATEGIC ORIENTATION COMMITTEE Explore Advisory Committee The role of the Strategic Orientation Committee The role of the Explore Advisory Committee is to (COS) is to establish CQDM’s strategic and scientific decide on the themes of calls for proposals and orientations. It also carries out the functions of to select the projects that will be subject to an a scientific board and a steering committee. external scientific evaluation. This preselection The CQDM is based on innovation and the potential impact Steven Xanthoudakis (Chairman) on biopharmaceutical research. Team Director, Licensing and External Research Merck Canada Inc. Julie Edwards (Chairman) Associate Director, Scientific Affairs, Terry Fetterhoff Research & Development Senior Director, Technology Management Boehringer Ingelheim (Canada) Ltd. F. Hoffmann-LaRoche, Ltd. Kevin Canning Diane Gosselin Mark Lim Manager, Medical Science Liaison Teams, Vaccines, President and CEO Former Deputy Program Director, Rheumatology, Hematology and Oncology T: 514-766-6661, ext. 2191 Program for Innovative Molecular Analysis GlaxoSmithKline Inc. E-mail: [email protected] National Cancer Institute, NIH, USA Jean Godin Michael Bridges Luc Paquet Chief Scientific Officer Vice President, Finance and Administration, Vice-Dean, Development and Partnerships, Novartis Canada Assistant Corporate Secretary, Professor and Director and Treasurer Institut de Pharmacologie de Sherbrooke (IPS) Jennifer Laird T: 514-766-6661, ext. 2193 Université de Sherbrooke Director, Global External Research and Development E-mail: [email protected] Eli Lilly Canada Inc. Steve Rees Max Fehlmann Vice-President, Screening Sciences & Sample Luc Paquet Former President and CEO Member of the Board Management, Innovative Medicines – Vice-Dean, Development and Partnerships, T: 514-766-6661, ext. 2190 Discovery Sciences Professor and Director E-mail: [email protected] AstraZeneca R&D UK Institut de Pharmacologie de Sherbrooke (IPS), Université de Sherbrooke Helen Loughrey Patrice Roy Senior Director, Scientific Affairs Director of Research & Development, Steve Rees T: 514-766-6661, ext. 2197 Quebec and Atlantic Region Vice-President, Screening Sciences & Sample E-mail: [email protected] Pfizer Canada Inc. Management, Innovative Medicines – Discovery Sciences Mounia Azzi Patrick Tremblay AstraZeneca R&D UK Director of Programs Senior Vice-President, Corporate Development Until November 2012 and Diagnostics Patrice Roy Caprion Proteomics Inc. Director of Research & Development, Judith Caron Quebec and Atlantic Region Director of Programs HONORARY MEMBER Pfizer Canada Inc. T: 514-766-6661, ext. 2195 Bernard Prigent Steven Xanthoudakis E-mail: [email protected] Vice President and Medical Director Director, Licensing and External Research Pfizer Canada Inc. Eugénie Bergeron-Côté Merck Canada Inc. Project Coordinator OBSERVERS T: 514-766-6661, ext. 2196 Corporate & IP Counsel E-mail: [email protected] Yvon Fréchette Robic LLP Direction of University and College Research 1001, Square-Victoria - Bloc E – 8th floor Line Vigeant Ministère de l’Enseignement supérieur, Montreal, Quebec Administration and Accounting Coordinator de la Recherche, de la Science et de la H2Z 2B7 Canada T: 514-766-6661, ext. 2192 Technologie (MESRST) E-mail: [email protected] Agnes Klein Auditors Director KPMG Centre for the Evaluation of Tour KPMG Radiopharmaceuticals and Biotherapeutics 600 de la Gauchetière West, Suite 1500 Montreal, Quebec Health Canada Head Office H3A 0A3 Canada Stéphanie Michaud 2 Place du Commerce Program Deputy Director Nuns’ Island, Quebec Financial Institution H3E 1A1 Canada Networks of Centres of Excellence Royal Bank of Canada th T: 514-766-6661 1 Place Ville Marie, 8 Floor F: 514-766-4269 Montreal, Quebec H3C 3A9 Canada Contact Information Diane Gosselin President and CEO T: 514-766-6661, ext. 2191 E-mail: [email protected] www.cqdm.org