Biotechnology Focus August/September 2018 by Promotive Communications

INSIGHTS FOR THE LIFE SCIENCE INDUSTRY

August/september 2018 VOLUME 21, NUMBER 4

Special Report:

Scope of Innovation in Canada

INSIDE:

Publication Mail Registration Number: 40052410

Celebrating ten years of research commercialization: Q&A with IRICoR

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contents August/September 2018 – VOLUME 21 – NUMBER 4

Regulatory Approval of Biosimilars in Canada

The evolution and creation of innovative technologies, medications, and transformation of patient care continue to push forward at an astonishing pace.The biosimilars market in Canada may have its drawbacks, but this article gives a more eye-opening view of the underlying factors that involve an approval or notice of compliance in reference to Health Canada. (By Mahdis Dorkalam)

Celebrating ten years of research commercialization: Q&A session with Nadine Beauger and Steven Klein from IRICoR IRICoR (Institute for Research in Immunology and Cancer – Commercialization of Research) is a research commercialization hub, specializing in drug discovery that is celebrating their tenth year since inception.This Q&A provides insight into what made them a success. (By IRICoR Team)

Crossing the blood-brain barrier: Bioasis Technologies lead the way with their xB3 technology platform

SPECIAL REPORT: Scope of Innovation in Canada As the life sciences industry evolves, Canada is on the forefront of that change.With the support and input of the life sciences sector across the country, Biotechnology Focus has put together a report to showcase what this innovative industry has to offer the Canadian government and economy, and to entice the world to invest in the exceptional companies and break-through research this country stands to offer. (By Michelle Currie)

DEPARTMENTS 6

Research news

Business corner

31 Calendar of events www.biotechnologyfocus.ca

With neurological diseases predicted to rise exponentially across the globe, crossing the blood-brain barrier has never been more pertinent. Arising to this challenge is Bioasis Technologies by focusing on a single goal: revolutionizing science by transporting therapeutic payloads across the blood-brain barrier and into the brain. (By Michelle Currie)

Canadian technology and innovation: making strides in the global cell therapy landscape Cell therapies are integral to regenerative medicine: a swiftly advancing sector bearing the long-standing promise of revolutionizing health care as we know it. (By Tara Fernandez)

in every issue 30

The Last Word

Closing the Deal – Suggestions for a Successful Financing (By Roberto Bellini)

August/September 2018 BIOTECHNOLOGY FOCUS 3

PUBLISHER’S note PUBLISHER/ EDITOR-IN-CHIEF Writer CONTRIBUTING WRITERS

Terri Pavelic Michelle Currie Mahdis Dorkalam

IRICoR Team Tara Fernandez Roberto Bellini GRAPHIC DESIGNER CONTROLLER MARKETING MANAGER

As the life sciences industry evolves, Canada is on the forefront of that change. Research has shifted, and new technological breakthroughs are opening a vast new landscape of possibilities amongst the health and life sciences sector. We chose to focus this issue on the outstanding innovation that is being discovered from coast to coast. With the support and input of individuals in the life sciences sector across the country, Biotechnology Focus conducted an innovation survey and shares the results in a report to showcase what this ground-breaking industry has to offer the Canadian government and economy. Mahdis Dorkalam, the president of CRM Pharma Consulting Inc., explains the regulatory approval pathway for biosimilars in Canada in her article Regulatory approval of biosimilars in Canada discussing the Canadian landscape, drawbacks, and underlying factors that involve an approval or notice of compliance in reference to Health Canada. As a cell biologist, Tara Fernandez, elucidates how cell therapies are integral to regenerative medicine: a swiftly advancing sector bearing the long-standing promise of revolutionizing health care as we know it. Regenerative medicine has even been hailed a new era in medicine, and unlike drugs that merely relieve symptoms, cell-based treatments possess curative potential by delivering a dynamic, living product to both counteract the underlying disease cause and promote regeneration. Celebrating ten years of research commercialization, IRICoR (Institute for Research in Immunology and Cancer – Commercialization of Research), shares their insights for success in a Q&A with Nadine Beauger, IRICoR’s chief executive officer, and Steven Klein, vice president, Business Development at IRICoR. Crossing the blood-brain barrier has been an arduous task and has never been more pertinent with the predicted rise of neurodegenerative diseases. Michelle Currie discusses the obstacles that are faced with this task and how a Canadian company might be the one to rise against it and deliver therapeutic payloads into the brain in her article Crossing the blood-brain barrier: Bioasis Technologies lead the way with their xB3 technology platform. Last but not least, Roberto Bellini, the chief executive officer of BELLUS Health, describes his suggestions for a successful financing based upon the experiences that he has gone through and BELLUS Health’s most recent financing round.

Elena Pankova John R. Jones Melisa Sukhdeo

CIRCULATION DIRECTOR Katie Walker circulation@promotivemedia.ca Tel: 905-841-7389

EDITORIAL ADVISORY BOARD Barry Gee, CDRD; Christine Beyaert, Roche Canada; Nadine Beauger, IRIC; Peter van der Velden, Lumira Capital; Jason Field, Life Sciences Ontario; John Kelly, KeliRo Company Inc.; Raphael Hofstein, MaRS Innovation; Gail Garland, OBIO; Albert Friesen, Medicure Inc.; Andrew Casey, BIOTECanada; Ulrich Krull, UTM; Peter Pekos, Dalton Pharma Services

Biotechnology Focus is published 6 times per year by Promotive Communications Inc. 1-226 Edward Street, Aurora, ON L4G 3S8, Phone 905-727-3875 Fax 905-727-4428 www.biotechnologyfocus.ca E-mail: biotechnology_focus@promotive.net Subscription rate in Canada $35/year; USA $60/year; other countries $100/year. All rights reserved. No part of this publication may be reproduced without written consent. Publications Mail Registration Number: 40052410 Return undeliverable Canadian addresses to: circulation department – 1-226 Edward Street, Aurora, ON L4G 3S8 National Library of Canada ISSN 1486-3138 All opinions expressed herein are those of the contributors and do not necessarily reflect the views of the publisher or any person or organization associated with the magazine.

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R&D news Breathtaking therapy has high potential for spinal cord patients

Drs. Gillian Muir (left) and Valerie Verge. Photo: Debra Marshall New research from the University of Saskatchewan has scientists excited about the potential of a new therapy called acute intermittent hypoxia (AIH) for patients with partial spinal cord injuries. AIH therapy involves repeated exposure to low oxygen (hypoxic) levels for brief periods. This action triggers a chain of events in the nerve cells or neurons as they react to the mild stress. “The AIH alerts the cells that they’re under stress,” explains Valerie Verge, a professor of anatomy and cell biology in the College of Medicine. “The cell adapts by turning on specific genes and creating specific proteins that help the cell to survive the stress. They induce a strengthening of the existing neuronal connections which is referred to as plasticity.” As director of the Cameco MS Neuroscience Research Center, Verge has a keen interest in neurological research. She shares this passion with Dr. Gillian Muir, a professor at the Western College of Veterinary Medicine (WCVM) and the co-principal investigator in a recent study published in PLOS ONE. While Verge’s focus is on the cellular level, Muir is an expert in behavioural recovery after injury. She has collaborated on studies with professor Gordon Mitchell, a noted neuroscientist at the University of Florida, and she has been involved in multiple studies monitoring the functional recovery that occurs when AIH therapy is combined with rehabilitative training in patients with spinal cord injuries. The study used two groups of rat models with partial spinal cord injuries that received seven days of rehabilitative motor therapy, with only one group reviving the AIH therapy along with the daily regime. 6 BIOTECHNOLOGY FOCUS August/September 2018

Each AIH treatment consisted of 10 fiveminute cycles where the animals breathed hypoxic air (11 per cent oxygen) alternating with normal air (21 per cent oxygen). The research team compared the abilities of both groups each week as they performed specific motor tasks that had been mastered before the injury, and then they compared the cells in the spinal cords of both groups of animals. Results confirmed that AIH leads to increases in the amount of specific proteins within cells linked to hypoxia and plasticity. They also observed notable improvement in the functional abilities of the group that received both AIH and rehabilitative therapy. A noteworthy finding of the current study was evidence that the proteins connected with plasticity were increased in areas of the spinal cord other than just the injury site— an indication that hypoxia triggers a reaction from neurons in other parts of the body, including the brain. Since AIH treatments expose the whole body to hypoxia, it’s possible that the nerve cells of the peripheral nervous system and the brain are also reacting to the low-level stress by creating the proteins associated with plasticity. Verge and Muir are optimistic that AIH therapy will have a positive impact on a large spectrum of injuries and conditions that affect the nervous system; and although it is still too early to say, this study prompts further questions to the possibilities of AIH therapies and whether it can enhance the nervous system or even repair damaged cells. To see this story online visit https://biotechnologyfocus.ca/breathtaking-therapy-has-high-potential-forspinal-cord-patients/

Researchers discover a way to genetically screen for acute myeloid leukemia An international team of scientists discovers a technique that predicts healthy individuals who are at risk of developing acute myeloid leukemia (AML), which is an aggressive and often deadly form of blood cancer. The findings, published in Nature, illuminate the ‘black box of leukemia’ and answer the question of where, when and how the disease begins, says co-principal investigator Dr. John Dick, Senior Scientist at Princess Margaret Cancer Centre, University Health Network. “We have been able to identify people in the general population who have traces of mutations in their blood that represent the first steps in how normal blood cells begin on a pathway of becoming increasingly abnormal and puts them at risk of progressing to AML. We can find these traces up to 10 years before AML actually develops,” says Dr. Dick. “This long-time window gives us the first opportunity to think about how to prevent AML.” Study author Dr. Sagi Abelson, a post-doctoral fellow in the Dick lab, says: “AML is a devastating disease diagnosed too late, with a 90 per cent mortality rate after the age of 65. Our findings show it is possible to identify individuals in the general population who are at high risk of developing AML through a genetic test on a blood sample. The ultimate goal is to identify these individuals and study how we can target the mutated blood cells long before the disease actually begins.” The study stems from Dr. Dick’s 2014 discovery that a pre-leukemic stem cell could be found hiding amongst all the leukemia cells that are present in the blood sample taken when a person is first diagnosed with AML. The team extracted the data from more than 100 participants who developed AML six to 10 years after joining the study, plus the data from an agematched cohort of more than 400 who did not develop the disease. The gene sequencing tool was a Continued on page 7

R&D news New hypothesis on Huntington’s Disease may lead to promising drug development McMaster researchers develop a new theory regarding Huntington’s Disease that may shape the future of drug development for the condition. A team of researchers from the university found that a unique type of signalling found in damaged DNA that signals huntingtin – a protein found mutated in the genes of those diagnosed with Huntington’s Disease – to aid in DNA repair is defective for those with the condition. The new hypothesis was published in the Proceedings of the National Academy of Science (PNAS). “The concept was that if we applied the signalling molecule back in excess, even orally, this signalling can be restored in the Huntington’s disease mouse brain,” says Laura Bowie, a PhD student in the Department of Biochemistry and Biomedical Sciences at McMaster. “The net result was that we fixed the modification of huntingtin not seen in mutant huntingtin in Huntington’s disease.” Using this hypothesis, the study team discovered a molecule called N6-furfuryladenine, derived from the repair of DNA damage, which corrected the defect seen in mutant huntingtin. “Based on dosing by different ways of this molecule in mouse Huntington’s disease models, Huntington’s disease symptoms were reversed,” says Bowie. “The mutant huntingtin protein levels were also restored to normal, which was a surprise to us.” Ray Truant, senior author on the study, has dedicated his career to Huntington’s disease research and how mutation leads to Huntington’s disease. It was his lab that was the first to demonstrate that normal huntingtin

Professor Ray Truant (left) and Ph.D. student Laura Bowie of McMaster University have developed a new hypothesis on Huntington’s disease, published in PNAS, which shows promise to open new avenues for drug development for the condition. Credit: McMaster University was involved in DNA repair. Truant argues that the traditional and controversial amyloid/protein misfolding hypothesis, where a group of proteins stick together forming brain deposits, is likely the result of the disease, rather than its cause. He also stated that he considers this paper the most significant of his career. “This is an important new lead and a new hypothesis, but it is important for people to know this is not a drug or cure,” says Truant. “This is the first new hypothesis for Huntington’s disease in 25 years that does not rely on the version of the amyloid hypothesis

To see this story online visit https://biotechnologyfocus.ca/new-hypothesis-on-huntingtons-disease-maylead-to-promising-drug-development/

the Leukemia and Lymphoma Society, Ontario Institute for Cancer Research, Canadian Cancer Society, Canadian Institutes for Health Research, International Development Research Centre, Terry Fox Research Institute, Medicine by Design, the Benjamin Pearl Fellowship from the McEwen Centre for Regenerative Medicine, the Ontario Ministry of Health and Long-term Care, and The Princess Margaret Cancer Foundation.

Continued from page 6 success and picked up mutations years before an individual was diagnosed with AML to accurately predict those at risk. Moreover, the team used advanced computational technology to assay the information obtained from routinely collected blood tests taken over 15 years in Israel and housed in a massive database of 3.4 million electronic health records. The study has linked AML with a common feature of aging called ARCH-age related clonal hematopoiesis, whereby blood stem cells acquire mutations and become a little more proliferative. The

which has consistently failed in drug development for other diseases.” The study was conducted in partnership with the University of Alberta, Western University, Johns Hopkins University, and a collaboration with a U.S. biotech firm, Mitokinin LLC. Their work now continues in developing better derivatives of N6-furfuryladenine towards developing a drug.

majority of people that have ARCH will not develop AML. It is a requirement to have AML, but not the other way around. The UHN research team was funded by

To see this story online visit https://biotechnologyfocus.ca/researchers-discover-a-way-to-genetically-screen-for-acute-myeloid-leukemia/ August/September 2018 BIOTECHNOLOGY FOCUS 7

BUSINESS corner Akcea receives their first drug approval from the European Commission Ottawa-based Akcea Therapeutics Inc. receives their first drug approval from the European Commission for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR). Tegsedi is now the world’s first and only RNA-targeted therapeutic approved for patients with hATTR. “With the EC’s decision, Tegsedi is now the world’s first and only RNA-targeted therapeutic approved for patients with hATTR amyloidosis,” says Paula Soteropoulos, chief executive officer at Akcea Therapeutics. “With subcutaneous delivery, Tegsedi puts treatment in the patients’ hands while bringing the significant benefits shown in the NEURO-TTR study in both measures of neuropathy and quality of life for people living with this serious and fatal disease. This is an important day for the hATTR amyloidosis community as we believe Tegsedi enables people and their families impacted by this disease to move forward with their lives. Today is a milestone for Akcea with our first drug approval. It is an achievement we share with the courageous hATTR patient community in Europe and around the globe.

We are ready to launch Tegsedi along with our patient and physician support services across Europe,” she adds. The abnormal formation and aggregation of transthyretin (TTR) protein results in TTR amyloid deposits throughout the body and is the underlying cause of hATTR amyloidosis. Tegsedi is designed to block the production of the TTR protein. In the NEURO-TTR study, treatment with Tegsedi produced substantial reductions in the levels of the TTR protein regardless of mutation type or stage of the disease. The European Commission’s approval of Tegsedi was based on results from the Phase 3 NEURO-TTR study in patients with hATTR amyloidosis with symptoms of polyneuropathy. The study demonstrated that patients treated with Tegsedi experienced significant benefit compared to patients treated with a placebo across both co-primary endpoints: the Norfolk Quality of Life QuestionnaireDiabetic Neuropathy (Norfolk QoL-DN) and modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression. “Today, we are thrilled to see our success-

ful research and development efforts result in the approval of an important new medicine for patients with hATTR amyloidosis. Using our antisense technology platform, we set out to design a therapy to block the production of the underlying cause of this disease, the TTR protein,” says Brett P. Monia, Ph.D., chief operating officer at Ionis Pharmaceuticals, an affiliate of Akcea Therapeutics. “Approval of Tegsedi further establishes Ionis as a multi-product company. We are confident that the experienced team at Akcea will deliver on the promise of Tegsedi. We are grateful to all of the physicians and patients who participated in the Tegsedi clinical program and who made this landmark approval possible,” he adds. Health Canada granted priority review for the New Drug Submission (NDS) filed for Tegsedi and is anticipating approval at some point this year. To see this story online visit https://biotechnologyfocus.ca/akceareceives-their-first-drug-approval-fromthe-european-commission/

PlantForm collaborates to manufacture biosimilar to the South African market Guelph-based PlantForm Corporation of Canada is stretching across the ocean to collaborate with South Africa’s Council for Scientific and Industrial Research (CSIR) and BGM Pharmaceuticals to produce a biosimilar of trastuzumab using PlantForm’s vivoXPRESS® manufacturing system. This agreement will permit the CSIR to produce a biosimilar monoclonal antibody (trastuzumab) using the tobacco plantbased vivoXPRESS® expression technology on a laboratory scale. The CSIR will demonstrate the utility of PlantForm’s proprietary technology to produce a trastuzumab drug candidate with the long-term goal of manufacturing trastuzumab, and other possible drug candidates, in South Africa for sale in African markets. “This agreement represents a significant opportunity for PlantForm,” says Dr. Don Stewart, PlantForm’s president and CEO. “The South African pharmaceutical sector is the largest in the region, and by working with the CSIR and BGM Pharmaceuticals we continue to advance our global strategy for biosimilar drug development that will make life-saving medications more widely available at much lower cost.” 8 BIOTECHNOLOGY FOCUS August/September 2018

(Photo Credit: PlantForm Corp.) The vivoXPRESS® system is revolutionary, using fast-growing tobacco plants to produce a wide range of biologic (large molecule) drugs, including monoclonal antibodies and therapeutic proteins, at a fraction of the cost of manufacturing the same drugs using conventional methods. Studies have shown that PlantForm’s plant-produced trastuzumab drug candidate is equally as effective at inhibiting the growth of HER2positive breast cancer cells as the commercial brand-name antibody Herceptin. “We’re pleased to be working with PlantForm and BGM Pharmaceuticals to further development of the vivoXPRESS® technology,” says Dr. Tsepo Tsekoa, who heads the CSIR’s biomanufacturing technology demonstration research group. “The CSIR is committed to utilizing and enhancing our capability in

biologics production to assist South African industry with development and localization of cost-effective technology solutions for biopharmaceutical manufacture. This collaboration will strengthen this commitment and help us expand our research into using plant-based processes to develop biologics.” Looking farther into the future, the collaboration will advance BGM Pharmaceuticals’ mission to develop new biopharmaceuticals and improve existing therapies for emerging African markets, while at the same time showcasing some of Canada’s innovative and forwardthinking technologies. “We’re very excited about the opportunity to bring PlantForm’s low-cost manufacturing platform to the South African market to help make life-saving biopharmaceuticals more affordable and more widely available throughout the region,” says Martin Magwaza, BGM’s president and CEO. To see this story online visit https://laboratoryfocus.ca/plantformcollaborates-to-manufacture-biosimilar-to-the-south-african-market/

BUSINESS corner Inversago Pharma closes first Series A financing round for $7-M

(Photo Credit: Inversago Pharma) Inversago Pharma recently closed their first Series A financing round at $7 million. They join Accel-RX’s growing portfolio of promising next-generation Canadian start-ups, as well as co-investors Genesys Capital, AmorChem, Juvenile Diabetes Research Foundation T1D Fund, Anges Québec Capital as well as several angel investors. Inversago is developing new generations of CB1 receptor inverse agonists. First generation CB1 blockers were previously in development for a range of metabolic conditions but were permeable to the blood-brain barrier and targeted brain CB1 receptors. This brain occupancy led to psychiatric adverse events which caused the termination of all CB1 inverse agonist programs. The company’s technology, based on the work by CB1 world expert, George Kunos at the National Institutes of Health, has demonstrated that peripherally restricted CB1 blockade in preclinical models provides an equivalent therapeutic potential to treat conditions such as Obesity, NASH, type-1 and 2 Diabetes, Liver & Lung Fibrosis, without causing the CNS or behavioural effects associated with the earlier generations of CB1 blockers. The proceeds from this first round of financing will allow Inversago to focus on its first target indication, PraderWilli Syndrome, an orphan disease that often leads to obesity and type-2 diabetes, as well as explore potential in type-1 diabetes. “Inversago’s technology could provide game-changing treatments for a number of metabolic diseases with few treatment options,” says Accel-Rx president and CEO, Natalie Dakers. “Their novel approach to resolving prohibitive concerns involving the brain associated with this class of drug meshes with our investment philosophy of backing companies whose solutions are both innovative and designed for broad impact.”

This is Accel-Rx’s tenth investment in a portfolio that includes disruptive treatments and technologies to innovative approaches to neurodegenerative diseases, including Alzheimer’s and Lou Gehrig’s Disease. “We are pleased to join the Accel-Rx portfolio of innovative companies and are grateful for their help in securing the two lead investors and spearheading the diligence efforts,” says

Replicel solidifies co-development deal in Greater China Vancouver-based Replicel Life Sciences announces that they have signed definitive agreements with YOFOTO, a Chinese company, solidifying their partnership to commercialise three of Replicel’s programs in Greater China. The collaboration focuses on the development and commercialization in Greater China of RepliCel’s tendon regeneration cell therapy (RCT-01), skin rejuvenation cell therapy (RCS-01), and its injection technology in development for dermal applications (RCI-02) (excluding hair-related treatments). “YOFOTO is a fast-growing company built on values related to beauty and healthy, active lifestyles,” states YOFOTO Chairman Mr. Huang Jin Bao. “As a key part of developing and commercializing products related to these core values for our consumers, we are committed to being a leader in China in the commercialization of regenerative medicines. The RepliCel cell therapy and injection technologies focused on skin rejuvenation and tendon repair are important building blocks in YOFOTO’s strategic healthcare vision. We are pleased to have structured a deal with RepliCel which results in YOFOTO not only being a development partner and commercial licensee but also an investor committed to contributing to RepliCel’s global success.” YOFOTO’s investment in Replicel will include milestone payments, minimum pro-

Inversago founder and CEO, François Ravenelle. “Their involvement was instrumental in the success of this round and will enable the company to advance its program into clinical trials.” Since 2014, Accel-Rx has screened over 200 early-stage companies from across Canada, selecting ten for investment and attracting an additional $44.6 million in co-investment thereby leveraging their initial capital outlay by more than 9X. To see this story online visit https://biotechnologyfocus.ca/inversago-closes-first-series-a-financing-roundfor-7-m/

gram funding commitments, and sales royalties in exchange for an exclusive 15-year license to three of RepliCel products for Greater China (Mainland China, Hong Kong, Macau, and Taiwan). Additionally, YOFOTO commits to spending a minimum of C$7 million on Replicel’s programs and associated cell processing manufacturing facility over the next five years in Greater China. “In 2017 RepliCel delivered successful phase I data in all three of its cell therapy programs and functioning prototypes of its next-generation dermal injector,” says RepliCel president & CEO, Lee Buckler. “We were committed to delivering a landmark partnership to RepliCel shareholders in 2018. The partnership with YOFOTO represents such a deal and provides RepliCel with not only an outstanding partner in Greater China but capital to move our programs forward in Europe and North America,” he adds. The deposit of over $5 million has been paid by YOFOTO, but remains in escrow following the closing of the transaction. Once YOFOTO has met certain conditions and once relevant Chinese patents are issued in China, they will be assigned a YOFOTO-owned Canadian subsidiary. This is very exciting news for Replicel and Canada alike, as Canadian biotech companies begin to spread across the Pacific, with more foreign companies seeking to invest in Canadian innovation and research. To see this story online visit https://biotechnologyfocus.ca/replicelsolidifies-co-development-deal-ingreater-china/ August/September 2018 BIOTECHNOLOGY FOCUS 9

Biosimilars

| By Mahdis Dorkalam

Regulatory Approval of Biosimilars in Canada

he evolution and creation of innovative technologies, medications, and transformation of patient care continue to push forward at an astonishing pace. With the advancement of medicine over the years, we have seen how biologic drugs and treatments have transformed patient care. Biologics are therapies derived from living cells, as opposed to traditional drug products which are mainly comprised of synthesized chemicals. Today, physicians use biologics in effectively treating common disorders such as diabetes, multiple sclerosis, various forms of cancer and several other diseases. Despite their effectiveness, biologics have two key drawbacks to their use, and that is their high cost, coupled with limited accessibility through provincial and territorial formularies for most patients. With the aging Canadian population, increased life span, prolonged need for continued health care and the need for more complex and expensive treatments, the increased health care costs are inevitable. 10 BIOTECHNOLOGY FOCUS August/September 2018

Although Health Canada provides approval of new medications at a federal level, the reimbursement by public insurers is governed at the provincial level. This additional level of approval adds further complexity to the use of potential life saving, yet costly therapies. Hence, geographical location of a patient across our nation can have a huge bearing on availability and access to treatments. The large cost associated with biologics is due to the intricacies related to the development of biologics. As many widely used biologic therapies are reaching patent expiry – resulting in loss of exclusivity, along with the constant need for cost saving alternatives – development of biosimilars is on a rapid rise. A biosimilar must show high similarity to a biologic drug that has already been authorized for sale (known as the reference biologic drug (RBD)) by Health Canada. Biosimilars are approved based on a thorough comparison to a reference drug and may only enter the Canadian market after the expiry of the reference drug patents for each indication

being sought and resolution of data protection issues.1,2 The slow growth of the biosimilar market in Canada is due to several issues, such as lack of clear and transparent regulatory requirements, patient preferences, reluctance of physicians and health care providers and pharmacists to readily prescribe and substitute biosimilars. The difficulties being faced in developing a naming convention specific to biosimilars and the slow uptake by the provincial governments and insurers further adds to the complexity of this market. The European Union (EU) presently dominate the market with numerous biologics in use, owing to the favourable government regulations in this region. Meanwhile, in Canada and the United States (US), Health Canada and the Food and Drug Administration (FDA) respectively have been less flexible in the approval of biosimilars. In Canada, biosimilars are regulated as new drugs under the Food and Drugs Act and the Food and Drug Regulations. Health Canada’s

Biosimilars

Today, physicians use biologics in effectively treating common disorders such as diabetes, multiple sclerosis, various forms of cancer and several other diseases. Despite their effectiveness, biologics have two key drawbacks to their use, and that is their high cost, coupled with limited accessibility through provincial and territorial formularies for most patients. Biologics and Genetic Therapies Directorate (BGTD) regulates biosimilars in collaboration with the Regulatory Operations and Regions Branch (RORB) and the Marketed Health Products Directorate (MHPD). It is important to note that biosimilars are not generic biologics and many characteristics associated with the authorization process and marketed use for generic pharmaceutical drugs do not apply. In fact, biosimilars must submit a new drug submission (NDS) as biologic drugs. Authorization for marketing of a biosimilar is not a declaration of pharmaceutical equivalence, bioequivalence or clinical equivalence to the reference biologic drug. This last point may explain the hesitation in uptake of biosimilars by some patients and health care providers. In my opinion, biosimilars play a key role in the future of medicine and further education on their role for all parties involved from agencies and governmental bodies to patients and health care providers is needed. Today, the evaluation of each biosimilar is determined case by case, tailored to each product. Although the regulatory pathway for both biologics and biosimilars is the same and an NDS must be prepared, the difference lies in the specific data required for each submission. The focus of an NDS for a biosimilar is having adequate and well designed invitro (analytical characterization) and in-vivo (non-clinical) studies, with several detailed pharmacokinetic (PK) and pharmacodynamic

(PD) studies. For a biosimilar submission, the need for clinical studies is often limited and 1-3 small clinical trials compromise the data showing the safety, efficacy and immunogenicity of a given product. The purpose of the clinical studies in such submissions is to show comparative safety and efficacy of the biosimilar to the reference drug, with no clinically meaningful differences between the two biologics. Since a biosimilar is very similar in structure and function to a reference biologic drug with well-established safety and efficacy in many cases, clinical studies do not need to be repeated for each indication. Although a reduced non-clinical and clinical data package is required, prior to approval, the manufacturer is required to show similarity between the biosimilar and a suitable reference biologic drug using the most advanced and current technologies. The degree of similarity at the analytical level will determine the scope and extent of the non-clinical and clinical trials. This explains how the assessment of each new biosimilar product is determined case by case. In working with Health Canada, it is best for manufacturers to request meetings with the agency as early as possible and prior to initiation of the full development program. As time to market for any product is of essence, early meetings will enable the manufacturers to determine if additional studies are needed before filing the NDS. Health Canada provides a final determina-

tion of similarity based on the entire submission, including the entire data derived from comparative structural, functional, non-clinical and clinical studies. What is unique to Health Canada is the importance given to the reference drug’s patents. The reviewers at Health Canada do not consider the patent during their review of the application, but at the same time they will not authorize a biosimilar for market release until the issues related to the reference drug’s patents have been addressed. Hence, a biosimilar NDS that may receive notice of compliance (NOC), may still not reach the market for several years if the patent issues are not resolved. The updated Health Canada guidelines2 provide more details on requirements for a biosimilar NDS, but still several areas need to be clarified such as requirements for selection of reference product or requirements for post approval changes. The recent CARE™ publication issued on November 20173 provides an excellent tabular comparison of NDS submission requirements for a biologic vs a biosimilar, which is reproduced below. On a positive note for Canadians, Health Canada accepts use of a reference product from another International Conference of Harmonization (ICH) country / jurisdiction for the full biosimilar program development, including analytical similarity, non-clinical and clinical studies. The European Medicines Agency (EMA)4,5 and FDA’s6 requirements are not the same, and as a result the manufacturer has to invest significant time and capital to conduct the comparative testing of multiple reference products and biosimilars. The question remains, if conducting several comparative tests of EU and US-sourced reference products is a way to produce a more concrete body of evidence regarding the similarity or if this practice is only to fulfill the battle of regulatory bodies. On the road to simplifying manufacturing of biosimilars worldwide, another hurdle that must be overcome will be to unify a set of requirements regarding the sourcing of reference products for biosimilar development programs. This in turn may help in further reducing the cost of biosimilars for patients. August/September 2018 BIOTECHNOLOGY FOCUS 11

Biosimilars It is important to note that biosimilars are not generic biologics and many characteristics associated with the authorization process and marketed use for generic pharmaceutical drugs do not apply. To obtain an update on the currently approved biosimilars you can refer to Health Canada’s list titled Drug and Health Product Submissions Under Review (SUR) which lists all new drug submissions (including biosimilars) under review and approved.7 If a biosimilar application is approved but is on intellectual property (IP) hold, the product will not be listed as approved. By referring to the list it is evident that more applications for biosimilars are being made to Health Canada each year and the review process is certainly improving. To ensure all Canadians have full access to safe, efficacious and cost-effective medications each of us, regardless of our role in this process, can support the improvement and simplification of the review, approval and reimbursement processes for new treatments and ultimately support timely delivery of new medications to patients.

References 1. Health Canada. https://www.canada. ca/en/health-canada/services/drugshealth-products/biologics-radiopharmaceuticals-genetic-therapies/applicationssubmissions/guidance-documents/ fact-sheet-biosimilars.html. 2. Health Canada. https://www.canada. ca/en/health-canada/services/drugshealth-products/biologics-radiopharmaceuticals-genetic-therapies/applicationssubmissions/guidance-documents/ information-submission-requirementsbiosimilar-biologic-drugs-1.html. 3. S. Edwards et al. Table 1. New Drug Submission Data Requirements: Biologics Versus Biosimilars. CARE™ Primer on Biosimilars [CARE™ Publication, Online and Print - Version 1, page 4.]. November 2017. 4. EMA.http://www.ema.europa.eu/docs/

en_GB/document_library/Scientific_ guideline/2014/10/WC500176768.pdf 5. EMA.http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_ guideline/2015/01/WC500180219.pdf 6. FDA.https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ Biosimilars/ucm580429.htm. 7. Health Canada. https://www.canada.ca/ en/health-canada/services/drug-healthproduct-review-approval/submissionsunder-review.html. Mahdis Dorkalam – President CRM Pharma Consulting Inc - providing regulatory & clinical research expertise, with a focus on the needs of the Canadian market. All information provided is the sole opinion of the author and is for general informational purposes only. The author makes no warranties to the accuracy, completeness and reliability of statements for a particular purpose. To see this story online visit https://biotechnologyfocus.ca/regulatoryapproval-of-biosimilars-in-canada/

Table 1 BIOLOGICS Regulatory Pathway

BIOSIMILARS New Drug Submission (NDS)

Chemistry & Manufacturing (C&M) Studies

Full package

Full package Extensive comparative analytical studies between biosimilar and RBD

Non-Clinical Study

Full data package as per ICH S6(R1)

Reduced and comparative to RBD

PK/PD Study

Standard PK/PD studies

Comparative PK/PD profile to RBD

Clinical Efficacy

Required for all indications

In most cases, comparative to RBD for at least one indication in a representative indication and sensitive population

*Clinical Trial Design

Superiority, non-inferiority or equivalence trial design

Equivalence trial preferred over non-inferiority design. Adequately sensitive to rule out clinically meaningful differences within predefined comparability margins

*Study Endpoint

Clinical outcomes or validated surrogates

Sensitive and clinically relevant

Efficacy/Safety

Establishing evidence of efficacy and safety/Acceptable risk and benefit profile

No meaningful difference to RBD. Safety must be assessed in a sufficient number of patients treated for an acceptable period of time

Immunogenicity

Acceptable immunogenicity profile

No meaningful difference to RBD

Post Market 12 BIOTECHNOLOGY FOCUS August/September 2018

Risk management plan

Special Report:

| By Michelle Currie

survey results

Scope of Innovation in Canada

Innovation is happening every day and broadening the horizons of science. The Canadian life sciences industry is burgeoning with new drug development, technologies, and therapies that will improve the lives and health of Canadians. As the scope of this sector changes, it is important for the industry to concrete a voice to share their input to the government, investors, and health care institutions. August/September 2018 BIOTECHNOLOGY FOCUS 13

Special Report:

Scope of Innovation in Canada

wo years ago, Biotechnology Focus posed an innovation survey that expressed some of the inner workings of the life sciences sector in Canada. This year’s survey has unveiled comparable results but convey a slightly contrasting snapshot than in 2016. In support of Global Biotech Week (http://globalbiotechweek.ca/ September 24th to 30th) Biotechnology Focus conducted this survey to gauge Canada’s innovation sector. It ran from July 9th to July 27th and was open to everyone in the industry, including the business sector, academics, research institutions, service providers and more. We would like to thank all 96 respondents who participated in this year’s innovation survey that helped provide an outline of the current state of the industry.

Where in Canada is your company/ research organization located?

Snapshot of respondents Similar to the original survey, the first question we asked our readers was when their company/research organisation was established. Unlike in 2016 when it was dominated by companies or research organisations from 1992 or earlier, we can see that there has been an influx of newer companies or organisations coming to market from 2012 to the present. Comparatively, recent companies have been sprouting at almost double the pace jumping from 16 per cent to almost 30 per cent of the accounted response in the last two years. Bearing that in mind, we were surprised to see that the majority of the companies (42 per cent) classified themselves in the growth category with at least one stable, high-volume product design; although, those with radically new products in emerging phase (41 per cent) pulled a close second, with mature phase (18 per cent) coming out as the smaller section of the bunch and down from previous years. In terms of geographic regions, Ontario packed a punch with the bulk of individuals identifying they were from this region (58 per cent), while Quebec and British Columbia were neck and neck for second, but still fell way behind in contrast with close to 14 per cent representation.

When was your company/research organization established?

14 BIOTECHNOLOGY FOCUS August/September 2018

In which sub-sectors of the industry would your company/research organization be classified?

Special Report:

Scope of Innovation in Canada

In which category or categories would your company/research organization be classified?

How would you classify your company/research organization in its lifecycle?

In support of Global Biotech Week (http://globalbiotechweek.ca/ September 24th to 30th) Biotechnology Focus conducted this survey to gauge Canada’s innovation sector.

The sizing of the companies and research organisations operating in Canada reflected comparable scoring to the 2016 innovation survey with those employing 1 to 7 employees leading the way in taking the survey with approximately 38 per cent, and an approximate 57 per cent were part of staffs equal to or under 15 employees overall. Mid-sized companies and organisations were underrepresented but have stepped up since the last survey coming from 5 per cent in 2016 to 18 per cent in 2018. However, the larger companies and organisations with over 100 people on staff had the second highest figure at 25 per cent. In this group were the global biopharma Canadian subsidiaries, contract research and manufacturing organisations, but very few Canadian biotech companies. There are many subsectors of the life sciences industry that are covered across Canada, but the ones that stood out with the most respondents were in the fields of Health biotechnology & pharmaceuticals (63 per cent) and Medical technology & devices (32 per cent). The category that largely dominated the focus for most of the companies participating in the survey this year was research and development with 67 per cent of the respondents, while trailing a little way behind was consulting, conduct research or other service providers at approximately 34 per cent.

What biotech and life sciences businesses had to say: One of the topics that is always on the table and thwarts this industry is access to capital. From conferences that address this issue to blogs and subjective opinions, it is posed as one of the most difficult obstacles to overcome as a start-up or mid-sized enterprise. This is reflected in the questions we asked our readers so that we could better gauge where Canadian companies lay on the frontier of biotech and the life sciences industry. The majority of respondents fall into the under one-million-dollar category (64 per cent) when asked how much capital they acquired August/September 2018 BIOTECHNOLOGY FOCUS 15

Special Report:

Scope of Innovation in Canada

In the last 12 months, how much did your company/research organization spend on Research & Development?

In 2017, what was the average number of people employed at your company/ research organization?

According to Finance Minister Bill Morneau, this budget represents the “largest investment in fundamental and discovery research in Canadian history”. Overall, Budget 2018 proposed an investment of nearly $4 billion in Canada’s research system. 16 BIOTECHNOLOGY FOCUS August/September 2018

in 2017. Roughly 25 per cent were within the 2-10 million range, with 5 per cent within 11-50 million and 5 per cent in the 50+ category. This response carries the idea that most companies are in the emerging phase and may be competing for the same buck. Most of the respondents (52 per cent) found funding or financing opportunities harder to come by, which further elucidates the previous point. Only 13 per cent of respondents found capital easy to come by. These results reflected both years of the survey. Some Canadians are feeling a bit of a financial pinch this year as interest rates continue to rise, and for several start-up companies, access to capital can feel like it’s spread a bit thin. In fact, when combining both the private and public sectors, the majority of those that answered the survey (51 per cent) made under onemillion, with the bulk of those falling on the lower part of the scale, while another 19 per cent made no revenue at all. Only 13 per cent of companies or organisations have over 5 years cash on hand, while roughly half of respondents have a year or less. The revenue made is in sharp contrast to how much companies and organisations are spending on research & development, with 43 per cent climbing over the million-dollar mark while the other remaining 57 per cent were more or less under half a million. Considering the duration it takes companies to bring a drug to market (10-15 years and approximately $1.5 billion to commercialise a biotechnology product), it is pivotal for companies to raise capital and retain revenue. There are several ways to raise capital for a company or organisation. This year the federal Liberals made significant commitments to research and innovation spending in Budget 2018. According to Finance Minister Bill Morneau, this budget represents the “largest investment in fundamental and discovery research in Canadian history”. Overall, Budget 2018 proposed an investment of nearly $4 billion in Canada’s research system.

Special Report:

Scope of Innovation in Canada

What level of education do your employees have?

In terms of geographic regions, Ontario packed a punch with the bulk of individuals identifying they were from this region (58 per cent), while Quebec and British Columbia were neck and neck for second, but still fell way behind in contrast with close to 14 per cent representation.

There is also an increased focus on supporting entrepreneurship and high potential businesses. However, as much as there has been an overall increase in the level of investment for industry innovation support programs, there has also been a reduction of the overall number of programs available. Other potential methods of acquiring funding would be angel investors and venture capital investors. Access to talent is an imperative part of growing a business, and this is where Canada does not lack. According to the results, 100 per cent of employees have graduated from a post-secondary establishment, with an impressive 60 per cent having obtained a PhD. Furthermore, sometimes roles and especially executive roles, can be difficult to fill regardless of how big the talent pool may be. For survey respondents the most challenging positions are in business development and sales (35 per cent). While others that stood out that were very similar in number were clinical and medical devel-

How did you find funding or financing opportunities?

August/September 2018 BIOTECHNOLOGY FOCUS 17

Special Report:

Scope of Innovation in Canada

opment, regulatory affairs, chief executive officer, and the “other” category all roughly hovering around 14-20 per cent. But what initiatives make a company or organisation successful? The program that overwhelmingly was rated the most crucial was the Scientific Research & Experimental Design Program (SR&ED) at 66 per cent. The Scientific Research and Experimental Development Program offers tax incentives that encourages and supports scientific research and experimental development. The program lets you deduct your SR&ED costs from your income for tax purposes. Also, the program gives you an investment tax credit that you can use to reduce your income tax. The Industrial Research Assistance Program (IRAP) rated second

Which of the following initiatives have you used that you would consider most crucial to your success?

With all the investments the Liberal government has promised in the upcoming years ahead, it does appear as if the scope of innovation in Canada is changing. The funding is on the way for researchers and provides an opportunity to conduct clinical trials, further drug development and bring new medicines and technologies to commercialisation to this knowledge-based economy.

18 BIOTECHNOLOGY FOCUS August/September 2018

Special Report:

Scope of Innovation in Canada

How many months of cash do you have available?

highest at 44 per cent that is a vital component of the National Research Council (NRC) and a cornerstone in Canada’s innovation system. Private equity took third place at 33 per cent as most crucial initiatives for companies’ success. Looking again at Budget 2018, the Government of Canada proposes to invest $925 million over 5 years with an ongoing amount of $235 million per year to Tri-councils such as the Natural Sciences and Engineering Research Council (NSERC), Canadian Institutes of Health Research (CIHR), and the Social Sciences and Humanities Research Council (SSHRC). The government is also proposing a new tri-council fund and is heavily investing into the Canada Foundation for Innovation and big data funding. So how does Canada stack up in comparison to other jurisdictions? Despite all the recently announced investments, respondents say that Canada is mostly average. Only a mere 4 per cent consider Canada excellent in that regard, which is on par with the response to that same question only two years ago. The hope is that all that will change as the funding takes possibilities to new heights.

How much capital/funding did you raise in 2017?

Which of the following executive positions are the most challenging for your company/research organization to fill?

Conclusion With all the investments the Liberal government has promised in the upcoming years ahead, it does appear as if the scope of innovation in Canada is changing. The funding is on the way for researchers and provides an opportunity to conduct clinical trials, further drug development and bring new medicines and technologies to commercialisation to this knowledge-based economy. Comparing the results from both years of the innovation survey, there is momentum to invest in health and life sciences research

August/September 2018 BIOTECHNOLOGY FOCUS 19

Special Report:

Scope of Innovation in Canada

One of the topics that is always on the table and thwarts this industry is access to capital. From conferences that address this issue to blogs and subjective opinions, it is posed as one of the most difficult obstacles to overcome as a start-up or mid-sized enterprise.

What is your reported revenue (product, sales and services) for your fiscal year ending in 2017?

How does Canadian science/business policy compare with other jurisdictions?

from the government, increasing interest from entrepreneurs and investors, and an amplified awareness from the public that make striving for a cure to diseases, cancer, and other conditions that ail us a potentially attainable goal. One thing to be sure of is that Canada’s support for science will position Canada as a global leader in research excellence. We would like to thank those of you who took the survey and for sharing your top priorities with us. To see this story online visit https://biotechnologyfocus.ca/ special-report-scope-of-innovation-in-canada/ 20 BIOTECHNOLOGY FOCUS August/September 2018

| By IRICoR Team

INTERVIEW

Q&A

Celebrating ten years of research commercialization Q&A session with Nadine Beauger and Steven Klein from IRICoR

RICoR (Institute for Research in Immunology and Cancer – Commercialization of Research) is a research commercialization hub, specializing in drug discovery. Its team identifies and invests in the best projects from the academic world in order to transform them into therapeutics innovations. Q&A session with Nadine Beauger, Chief Executive Officer, and Steven Klein, Vice President, Business Development, at IRICoR.

Q: IRICoR is celebrating ten years of

activities in research commercialization. Can you tell us more about your business model and how it is unique?

NB: IRICoR as a hybrid business and research model, combining both scientific excellence and business expertise. At its inception in 2008, it was created as a Centre of Excellence in Commercialization and Research (CECR) and through the last decade, we have developed new and innovative ways of doing business to transform academic and basic research into tangible assets, such as innovative therapeutic solutions for cancer patients.

Q: What would you consider to be IRICoR’s main milestones and successes of the past decade? NB: The life cycle of the process of drug discovery and development is usually long, tak-

ing fifteen to twenty years. Considering this, I would say our major accomplishment is to have developed an effective way to accelerate this time line starting from the identification of promising projects in basic research and offering our support in drug development maturation towards the creation of partnerships with the biopharmaceutical industry, the creation of spin-off companies, and the development of potential therapeutic solutions for cancer patients. SK: The flexibility of our model and business dealings speaks for our success over the last ten years. From a commercialization point of view, we have established a number of partnerships with the private sector, working August/September 2018 BIOTECHNOLOGY FOCUS 21

INTERVIEW

We want to bring young scientists on new paths by taking advantage of our access to early-stage research. We are striving to make them see that drug discovery and development is not an alternative path or a second choice anymore, but rather a path in itself and a first choice when it comes to choosing a career. – Nadine Beauger

alongside larger companies such as Bristol-Myers Squibb (BMS), and AbbVie as well as with smaller companies such as Domain Therapeutics and Imagia, along with other companies based in Canada and internationally. The goal being to accelerate the development of new products and technologies and move them into the clinic. In the last ten years, we have had five projects reaching the clinic, a number through partnerships with the industry and two programs by the direct creation of companies, which have moved those assets into the clinic with the support of IRICoR. A good example of collaboration is with one of our spin-off companies, ExCellThera. It only took seven years for the concept around using stem cells to treat certain cancers, such as leukemia, to come to life with the development of molecules to help expand those stem cell populations, the creation of the company, and moving the asset into the clinic. In our field, it is very short period. The very promising results of the first clinical trial led to the initiation of a second trial for another cancer indication and the product will continue to move towards the market. Another example is our partnership with Domain Therapeutics, based in France. We have been working together for the past five years and completed two licences with them in order to develop a new technology to profile GPCRs (G protein-coupled receptors; the largest class of drug targets). With our support, the company has created a successful subsidiary in Montreal that has grown from two to eight employees. We are now looking at working with the team at Domain not only on technology development, but at also using the technology to develop new therapeutics targeting various GPCRs.

Q: IRICoR recently received a $25-mil-

lion dollar grant from the Network of Centres of Excellence of Canada (NCEC), a real show of confidence from the government. Considering this new support and additional resources, what are your 22 BIOTECHNOLOGY FOCUS August/September 2018

main objectives for the next five years? NB: One of our main objectives is to broaden our sourcing of projects, which has been mainly from our initial network (the Université de Montréal and the Institute for Research in Immunology and Cancer [IRIC] of the Université de Montréal), to other centres across Canada and abroad as well. We want our model and best practices, such as building close relationships to the investigators, understanding the scientific excellence of projects, and the skill set we provide in business development, management and intellectual property, to benefit to the greatest number of potential projects. Additionally, we have the goal to highlight the excellence of the infrastructure and expertise developed in Canadian centres such as IRICoR and transfer this knowledge and know-how to new projects in order to advance them further in development.

Q: Could you tell us more about the projects you will support? SK: We are looking for innovative high-risk/ high-reward types of projects that could benefit from our expertise around high throughput screening, assay development and medicinal chemistry in particular. We are open to other therapeutics approaches such as cell therapies and focusing on promising, early-stage research that would attract interest from the venture community and the pharmaceutical industry.

Q: How will you select those projects? SK: We are looking at two approaches to source projects. The first one being targeted calls for proposals and the second one being a proactive scouting. We are putting in place an advisory committee composed of external experts in drug discovery, commercialization and venture capital to complement our in-house exper-

tise and bring different skills to the table to help us select the best projects, increase their chances of success, maximize our return on investment, and offer Canadians new options for the treatment of cancer.

Q: Are you looking for Canadian-based projects in priority? Since we are based in Canada, we are going to be looking at many Canadian-sourced projects, but we have the mandate to look internationally and build ties between Canada and other regions such as the United States, Europe and Israel. We have taken steps in all those directions and we will continue along that path moving forward.

Q: IRICoR builds bridges between various areas of activity and stakeholders that do not necessarily always interact smoothly together, namely universities and the industry. How do you explain your success in this regard? The academic culture is certainly different from the industrial culture. This bridge needs to be traversed and those two solitudes need to better work together. The fact that IRICoR is directly based within an academic environment and the fact that our team has significant industry experience helps us develop the best practices to benefit both parties. We are smoothing the existing cultural issues by helping each party understand and speak to each other, instead of past each other. When trust is established and both parties speak the same business and scientific languages, it helps solidify partnerships.

Q: What differentiates IRICoR from other organizations evolving in the same field or with a similar business model? NB: From our creation, we have put a lot of emphasis on the expertise we have developed in specific indications within our initial

INTERVIEW

We are looking for innovative high-risk/high-reward types of projects that could benefit from our expertise around high throughput screening, assay development and medicinal chemistry in particular. We are open to other therapeutics approaches such as cell therapies and focusing on promising, early-stage research that would attract interest from the venture community and the pharmaceutical industry. – Steven Klein network, revolving mainly around cancer. Over the years, we have broadened our scope to attract projects from other areas linked to cancer, such as cancer immunotherapy. By leveraging the scientific knowledge from academia, we helped raise interest from the pharmaceutical and venture capital sectors looking exactly for these kinds of opportunities. We also leverage the expertise and infrastructure present at the IRIC in particular, having access to the largest medicinal chemistry group in an academic centre in Canada, also for the benefit of other Canadian centres. Our flexibility and access to cutting-edge drug discovery expertise help us add value to the projects we select.

We have recognized the need and demand for training and coaching from students to develop an alternative set of skills in life sciences. For example, we have partnered with Montréal InVivo, Concordia University’s John Molson School Executive Centre, and Université de Montréal’s Faculty of Pharmacy to develop the Life Sciences Entrepreneurship Development Program, exposing students to entrepreneurship and different aspects of drug discovery: preclinical research, market access, regulatory affairs, pricing and reimbursements, etc. These are all topics that they are not necessarily familiar with or have not explored in traditional studies. We will be announcing new initiatives in the near future.

Q: How and to which extent do your activities benefit Canadians?

NB: We want to bring young scientists on new paths by taking advantage of our access to early-stage research. We are striving to make them see that drug discovery and development is not an alternative path or a second choice anymore, but rather a path in itself and a first choice when it comes to choosing a career.

NB: Our model allows us to capture the value of research for which the provincial or federal governments have funded only the first stages, and that could remain trapped within those stages without further investments. IRICoR identifies those projects within universities, research centres, and even biotech companies, and provides them with drug discovery and development infrastructure needed to bring them to the next value inflection point. We aim to have exit events either through collaborations with biopharmaceutical companies or through the creation of companies. Entrepreneurship is also a way for us to bring value by adding these new assets into the Canadian network, creating collective expertise and attracting expertise internationally.

Q: You are also committed to training the next generation workforce in life sciences. What does this engagement entail? SK: There is an evolution from the traditional scientific career path. Students today are much more open to working with the industry and we feel their enthusiasm for entrepreneurship.

Q: Innovation is part of your mandate. How do you foresee the next few years in the field of drug discovery? NB: We have observed several trends in the past years in the field. It is important to follow them, not to be limited by them, and use them to drive our progress. There is a chain commonly established in drug discovery and development, but our network and the opportunities we seized, for example our partnerships with the Montreal Institute for Learning Algorithms based at the Université de Montreal led by Yoshua Bengio, allows us to include those emerging trends with the traditional drug discovery and development path and bring innovation further to develop new therapeutics for cancer patients. We also combine the drug discovery path with medical technologies developed in other centres, for instance, and bridge the gap between

those two to help a better delivery of the therapeutics.

Q: What kind of outreach do your activities have at the international level? NB: We have developed a number of collaborations on a project-by-project basis starting from the initiative of researchers themselves and with other centres in Europe, Israel, and the United States. Through the support of the Québec government, and a recognition of the need for international collaborations to help grow the biotech sector in the province, we have been taking part in missions to visit a few countries including Israel, Belgium, France and the United Kingdom. We will be attending industry events and conferences in the next months to continue our outreach in the academic and biotech sectors to find new ways to create interest for early-stage research from potential partners or investors.

Q: Where would you like IRICoR to be in five to ten years? NB: I see IRICoR being the reference for drug discovery in cancer therapeutics. With our innovative business model, the expertise we bring to each project we select and the renewed support and vision of the provincial and federal governments that has been crucial and a key of success through their innovation strategy and financial support, I am confident we will reach this vision. SK: IRICoR will be globally recognized as a leader in cancer drug therapeutics, bringing early stage research to the market. Nadine Beauger, Chief Executive Officer, IRICoR and Steven Klein, Vice President, Business Development, IRICoR To see this story online visit https:// biotechnologyfocus.ca/celebrating-tenyears-of-research-commercialization-iricor/ August/September 2018 BIOTECHNOLOGY FOCUS 23

innovator

| by Michelle Currie

Crossing the blood-brain barrier: Bioasis Technologies lead the way with their xB3 technology platform

Mark Day - President and CEO of Bioasis Technologies Inc. 24 BIOTECHNOLOGY FOCUS August/September 2018

ith neurological diseases predicted to rise exponentially across the globe, whether resulting from the extension of life expectancy or aging populations, more novel solutions are necessary so that health care can stay ahead of the game. Neurological diseases, disorders and injuries – such as Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, brain tumours, and Parkinson’s disease – are some of the leading causes of disability amongst the Canadian population that take a toll not only on the patient and the Canadian health care system, but also have a significant economic impact. To date, these neurological diseases and disorders have been largely incurable and tend to worsen over time, typically involving invasive procedures by scientists and researchers as they attempt to penetrate

the blood-brain barrier. Remarkable as the blood-brain barrier is to neuroscience, it is extremely fickle and highly selective, restricting the paracellular diffusion of watersoluble substances from the blood to the brain. Despite it being nature’s evolutionary way of protecting humans’ greatest asset, it does not come without its faults. Its defensive properties impede the way for medicinal compounds to penetrate the barrier and deliver the potential life-saving properties to their destination point. Statistics have shown that 1 in 6 will acquire a neurological disease, totalling about 1.25 billion people worldwide. It is for this reason Canadian company Bioasis Technologies Inc. is determined to deliver effective treatments to patients who suffer from one of these diseases. Vancouver-founded Bioasis has undertaken this challenge by focusing on a single

innovator If the xB3-001 and xB3-002 programs are successful, it would be the first time in human history that medicine for cancer has been properly received into the brain without having to drill into the patient’s head. This will be a breakthrough in science and open the doors to a floodgate of scientific possibilities. goal: revolutionizing science by transporting therapeutic payloads across the blood-brain barrier and into the brain. They have developed and are in the process of commercializing their proprietary brain delivery technology, the xB3 platform, to make life-saving drugs brain-penetrant and deliver those therapies at a therapeutically relevant dose. Inception of the company began back in 2007 when researchers discovered an extremely large peptide that was capable of crossing the blood-brain barrier with a substantial amount of cargo. The team did a couple of experiments with Doxorubicin in mice models with cancer that positively showed higher survival rates and became the first proof of concept. The also acquired Trastuzumab data whereby they transferred Herceptin across the blood-brain barrier in sufficient quantities to reduce the number of tumours.

xB3 Platform Delivers Trastuzumab to Brain Metastasis and Reduces Both Tumor Number and Size

120 Number of Tumors per animal (20 slides/animal)

Group

ns ns

100

***

*** ***

6.0E-06

4.0E-06

2.0E-06

0.0E+00

TZM

xB3 peptide-TZM

Mean ± STDEV; n = 61 (TZM ), n = 77 (xB3 peptide-TZM); single dose; up to 8 hrs post dose.

765

1.654 ± 1.673

223

0.710 ± 0.7271

TZM (n=13)

962

1.402 ± 1.217

xB3 peptide-TZM group vs. TZM group P<0.001

xB3 peptide-TZM vs. TZM Treatment

• xB³peptide

TZM

xB³peptide-TZM

Saline

Reduced tumor number by 68%

•

Tumor remained after treatment were 46% smaller

•

TZM treatment show no effect on reducing metastases number and negligible reduction in size

Nounou, M. I. et al. (2016) Pharm Res 33 (12), 2930-2942.

Although researchers have been speculating about less invasive methods that will penetrate the barrier, Mark Day, the president and chief executive officer of Bioasis, comments: “The key thing if you have brain cancer is that the only therapeutic benefit will come from a direct infusion into the brain – like drilling a hole in the head – and while some people are trying to inject into the spine and pump it into the central nervous system, none of it has worked. The brain methods do work, so there is at least some data if you inject it that you can get it approved for efficacy for small groups of patients.” Recently, MedImmune, a wholly-owned subsidiary of AstraZeneca, did an independent validation of Bioasis’ xB3 platform technology that transpired incredible results. The study found that the xB3 fusion protein maintained the systemic pharmacokinetics of its payload and had significantly improved and sustained brain exposure of the payload molecule. It

Brain Tumor

1.2E-05

Unidirectional drug uptake rate (mL/s/g)

8.0E-06

Saline control (n=8-9)

TZM: Trastuzumab; n= 13 for xB3, TZM groups; n=8-9 for xB3 peptide-TZM, Saline groups. One-way ANOVA **P<0.001, ***P<0.001, ***P<0.0001 Mean+/-SEM

Normal Brain Tissue

1.0E-05

Tumor size (mm2) Mean ± STDEV

xB3 peptide-TZM conjugate (n=89)

# of tumor ns

xB3 Platform Delivers 10-Fold Higher TZM to Brain Metastasis than TZM Alone 1.2E-05

Tumor size based on pooled data from all individual values in group

xB3 Peptide-TZM, Significant Tumor Reduction

1.0E-05

8.0E-06

6.0E-06

4.0E-06

2.0E-06

0.0E+00

TZM

xB³peptide-TZM

Mean ± STDEV; n = 336 (TZM ), n = 213 (xB3 peptide-TZM); single dose; up to 8 hrs post dose

Nounou, M. I. et al. (2016) Pharm Res 33 (12), 2930-2942.

provided evidence that Bioasis’ platform technology was recombinant and chemically conjugated drugs across the blood-brain barrier to increase brain exposure. These data and validation from MedImmune provide promising results that it will work in a phase 1 study. Bioasis figured out that once they attached Trastuzumab to 12 active amino acids (peptide 12aa), 10 times the amount of the drug passed through the blood-brain barrier. Mark Day adds: “What is really important is that once the drug is in the brain it hits the tumour. Looking at these results you can see that there are significant therapeutic doses in the brain and in controlled regions. This shows us that the drug gets into the brain, it gets to the site of action, and binds to those specifically where there are HER2 positive cells.” Bioasis has four main programs: • xB3-001: Brain Metastases, which is the most common form of brain cancer in adults and is often fatal due to anti-cancer drugs being unable to pass the bloodbrain barrier, and is also the program that will progress first to human trials in 2019; • xB3-002: Glioblastoma, one of the most aggressive cancers that originates within the brain, with 80 per cent of diagnosed primary malignant brain tumours as malignant gliomas. It is considered the deadliest form of brain cancer due to its high infiltration of surrounding brain tissue. This program is being done in collaboration with Minerva in Copenhagen; • xB3-007: Neurodegenerative diseases, which entail a progressive loss of function by the neurons in the brain and in being diagnosed at an alarming rate partly due to an aging population; and

August/September 2018 BIOTECHNOLOGY FOCUS 25

innovator

xB3 Peptide-Ab-1 Fusion Brain Exposure

xB3 Peptide-AB-IL 1RA Brain Exposure

3 xB³peptide-Ab-1 20mg/kg

Ab-1 20mg/kg

xB³peptide-Ab-IL 1RA 24mg/kg

2.5 % Injected dose per g brain

If the xB3-001 and xB3-002 programs are successful, it would be the first time in human history that medicine for cancer has been properly received into the brain without having to drill into the patient’s head. This will be a breakthrough in science and open the doors to a floodgate of scientific possibilities. Bioasis’ technology platform has been so efficacious that there simply have not been any competitors that have been able to keep up. The receptor with which they work with

xB3 Platform Resulted in Significant Exposure of Payloads in the Brain

% Injected dose per g brain

• xB3-008: Lysosomal storage diseases, which are inherited metabolic diseases that are characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies.

Ab-IL 1RA 24mg/kg

1.5

0.5

168

336

Time (Hrs) N = 6 per group; Mean ± SEM; single injection; wild type mice

Thom G. et al. (2018) J Cereb Blood Flow Metab. ePub May 30, 2018.

Biotechnology Focus delivers critical Canadian news and insights, trends and reports, from R&D to business.

www.biotechnologyfocus.ca Focused on moving innovation forward

is ubiquitous to the blood-brain barrier walls, providing more possible passageways for medicine to penetrate through. This receptor, even in its natural form, is critical in cleaning out harmful tissues in the brain like Alzheimer’s disease for example and is necessary to maintain brain integrity. “The other thing that differentiates us is how we develop drugs,” says Mark Day. “We know that if you engage the target and prove that the target engagement drives biologic effect – to schizophrenia that would be a lowering of dopamine – then you have a good sense of patient population. So, for some of these diseases, there is a very strong genetic basis to them and subsequent diseases that gives us the mechanism to recruit the patient who is most likely to benefit from the medicine in the first tranche. The proof of principal in the first point, get the proof of concept, on the back of a positive proof of concept then you would go earlier into the diseases. That’s what we can do with our last two neurodegeneration products. Basically, we go into a smaller niche indication, get the proof of concept and then expand it into other disease areas. That’s been the strategy,” he adds. With recent editions to their scientific advisory board and looking ahead to put them in the best financial position for Nasdaq, the future looks promising for this biotechnology company. Penetrating the blood-brain barrier has been an arduous task, but if Bioasis is successful, their technology will revolutionize the treatment for neurodegenerative diseases and brain tumours, potentially slowing the progression of disease, and maybe someday offer a cure. To see this story online visit https://biotechnologyfocus.ca/crossing-theblood-brain-barrier-bioasis-technologieslead-the-way/

Clinical Trials

| By Tara Fernandez

Canadian technology and innovation:

making strides in the global cell therapy landscape Cell therapies are integral to regenerative medicine: a swiftly advancing sector bearing the long-standing promise of revolutionizing health care as we know it.

nlike drugs that merely relieve symptoms, cell-based treatments possess curative potential by delivering a dynamic, living product to both counteract the underlying disease cause and promote regeneration. Healthy cells derived from either the patient or a compatible donor, once transplanted, can retain their ability to divide, migrate, differentiate and produce biological factors - mechanisms that have been shown to create lasting, transformative effects in an everwidening spectrum of clinical conditions. Regenerative medicine has been hailed a

new era in medicine, with 2017’s US Food and Drug Administration’s (FDA) approval of the CAR-T immunotherapeutics Kymriah (Novartis) and Yescarta (KITE Pharma) creating a new wave of excitement and activity in the industry. This has been elevated by a steady stream of positive clinical trial data from emerging cell therapies, for conditions from cancer and diabetes to neurodegenerative disorders. Regulatory bodies are responding to the quickly expanding market with appropriate measures to boost cell therapy product development for an equally growing patient August/September 2018 BIOTECHNOLOGY FOCUS 27

Clinical Trials

base. The 21st Century Cures Act, signed in 2016, provides cell therapies with a special designation through the FDA’s Regenerative Medicine Advanced Therapy pathway. Humacyte and Vericel are among the first to place their products on this expedited approval pathway, with many others expected to follow suit. The evolution of effective and accessible therapies for life-threatening diseases is further supported by a steep rise in investments being pumped into cell therapy product pipelines. Michael May, president and chief executive officer of the Centre for Commercialization of Regenerative Medicine (CCRM) in Toronto, sees a swell of investor funding in Canadian cell therapy enterprises as being a positive indicator of growth on the national front. “Companies such as BlueRock Therapeutics and AVROBIO are drawing capital from global investors and putting Canadian biotech on the map. There is a goldmine of opportunities for Canada to become a world leader in cell therapy manufacturing.” Toronto-based BlueRock Therapeutics, founded in 2016, pocketed a massive 28 BIOTECHNOLOGY FOCUS August/September 2018

US$225-million investment from Versant Ventures and Bayer AG, propelling their regenerative science straight into the clinical trial phase. Blue Rock’s product pipeline includes therapies for various conditions within the neurodegenerative and cardiovascular disease space. This is a prime example of Canada’s ability to attract investor dollars by leveraging world-class scientific research, access to commercialization consortiums such as CCRM and its capacity for manufacturing biological products for a global market. Another cell therapy rising star, RepliCel Life Sciences, is harnessing the healing properties of hair follicles to address unmet medical needs in acute, chronic and genetic conditions. RepliCel’s product pipeline features a diverse portfolio spanning tendinopathies, pattern baldness, skin damage and dermal injector medical devices. Lee Buckler, president, CEO and director of RepliCel describes highlights from his journey in the cell therapy sector: “The most exciting breakthrough during my time with the team has been transitioning from a pre-clinical to a clinical stage company.” RepliCel, with

headquarters in Vancouver, attributes its success to fruitful industry and academic collaborations: partnerships with Japan’s Shiseido and research stemming from the University of British Columbia. Buckler’s advice to other cell therapy entrepreneurs? “Don’t try to do this by yourself. Align yourself with sophisticated partners and capital out of the gate. Also, do not assume great technology results in great products - never lose focus on the eventual product.” Speaking on pathways specific to cell therapy development, he adds, “Ongoing basic research will continue to inform the process, the product, the assays and the regulatory strategy until much later in the development cycle than other biologics.” Despite recent successes and high hopes, however, the scarcity of cell therapies presently available to patients points to its relative infancy in the commercialization cycle. Manufacturing human cells as deliverable products represents a major hurdle standing in the way of a smooth “bench to bedside” transition. Scale up and scale out of cells while assuring their purity, safety, potency and commercial viability remains a

Clinical Trials

Despite recent successes and high hopes, however, the scarcity of cell therapies presently available to patients points to its relative infancy in the commercialization cycle. Manufacturing human cells as deliverable products represents a major hurdle standing in the way of a smooth “bench to bedside” transition.

challenge, even for well-established manufacturers. For some cell therapy applications, there is the possibility for generating cell banks of allogeneic cells from healthy donors. These “off-the-shelf” cell therapies are more costefficient, can be mass produced and allow for automated systems to be integrated into production lines. However, creating personalized immunotherapies, such as CAR-T, that harness the patient’s own immune system to fight disease, involve costly, labour-intensive and time-consuming procedures. In both cases, closed cell expansion and modification systems that reduce the risk of operator variability and contamination are ideal for preserving the quality of the final product. Canadian engineering innovation just may provide solutions to these remaining obstacles. Ontario’s Octane Biotech, for example, is in the business of developing next-generation bioreactors, bioprocesses and biomaterials that are set to transform cell therapy manufacturing. Octane’s Cocoon™ bioreactor offers customizable automation from donor to the eventual cell product, thus

doubling efficiency and slashing production costs. Besides cultivating cells for therapeutic use, manufacturing also involves an intricate genetic manipulation step prior to reintroduction into the patient. As CCRM’s CEO Michael May explains, “There is a rapid convergence of cell and gene therapy happening in the field. Most cell-based products in the future will be genetically modified in some way or other. The scale up of existing genetic modification tools like CRISPR-Cas9 and non-viral transfection methods also represent a barrier to full industrialization of these revolutionary products.” Vancouver-based Precision NanoSystems has developed breakthrough microfluidics platforms to streamline and enhance the delivery of nucleic acids to cells via the use of nanoparticles. This technology has immense potential in gene and cell therapy manufacturing applications. Using nanoparticle carriers with a plasmid, mRNA or siRNA cargo eliminates the safety hazards associated with the use of currently-used viral vectors like lentiviruses, while simultaneously minimizing the impact on sensitive cells to maximize therapeutic outputs. Though limitations in industrial scale cell therapy production still linger, the future looks bright for Canadian enterprises that are actively dedicating themselves to overcoming such challenges. “There is a lot of exciting activity happening in Toronto, Vancouver, Ottawa and Montreal right now,” May explains. “We should be coordinating our efforts across the country and collaborating with global partners to make cell therapies more accessible to patients.” With the monumental burden of serious diseases on health care systems set to skyrocket in the future, the time is now for Canada to drive cell therapies as a valuable complement to conventional medical approaches. Tara Fernandez is a Vancouver-based Cell Biologist and science communicator. Her research focuses on new ways to treat cells on the nanoscale.

To see this story online visit https://biotechnologyfocus.ca/canadiantechnology-and-innovation-making-stridesin-theglobal-cell-therapy-landscape/ August/September 2018 BIOTECHNOLOGY FOCUS 29

| By Roberto Bellini

LAST word

Closing the Deal – Suggestions for a Successful Financing

he Canadian life science sector has seen a significant increase in fund flows over the past five years1 and the US biotech bull market is now in its 6th year, yet access to capital continues to be one of the top concerns for Canadian biotech companies.2 Great science, a strong team and the potential for return on investment are essential to securing capital; but I’d like to share some suggestions to successfully complete a financing, based on my own experience and particularly our most recent financing completed in December 2017.

Have great investor materials Your pitch deck is probably the most important investor document. Invest time and energy to make it perfect. We spent months refining our pitch deck and hired a communications consultant to clarify the messaging and create personalized graphics. If you’re not PowerPoint savvy, I suggest you do the same. Then, extend the quality of your pitch deck to all your documents. We built several additional detailed presentations to address investors’ specific needs, such as understanding our candidate’s mechanism of action, market and competition. Providing additional, more detailed investor materials whose quality and messaging is consistent with your pitch deck makes the difference between looking sloppy and looking professional.

Build trust with investors Trust is undoubtedly one of the key factors for investors when considering whether to fund a project. You have likely built trust amongst your long standing network of potential investors, but how do you build trust with someone that you just met? When investors reached out via phone or email demonstrating serious interest in our project, I made a point of arranging face-to-face meetings with as many as possible. In a world where global investor networks can be very easily accessed online, I find that in-person meetings accelerate the establishment of a trusting relationship. Another way of building trust, and generally good business practice, is to highlight the risks inherent to your project, including those identified during your own diligence. Honesty and vulnerability play an important role in building trust with potential investors.

SELL the opportunity You may be selling an opportunity for investors to participate in the potential upside of your project, but remember that basic sales principles still apply. Competitive demand and deadlines, real or artificial, can help close financings. Financial advisors are masters in this art and I suggest hiring one that can help say the “right things to the right people at the right time” to help investors pull the trigger on an 30 BIOTECHNOLOGY FOCUS August/September 2018

order. A simple technique, not without risk, is to set a closing date and stick to it. Often, a deadline is sufficient to encourage a final investment decision.

“No” is “no”, most of the time I’ve heard the advice to not take “no” for an answer. Although I’ve never seen an investor change their mind once they give you a “no”, there are a couple of circumstances that can lead to an investment after a “no”. New data can change a “no” to a “yes”. If additional data addresses an investor’s specific concerns, that’s a great reason to go back to that investor. Also, a “no” from an investor isn’t always a “no” from their firm. A different partner from the same firm could have a totally different opinion on your project or could simply have more time to dedicate to exploring your opportunity.

Track progress There’s a reason why salesforce.com is one of the leading sales tools available – it helps close deals! Internet-based customer relationship management (CRM) technologies (many of which are free) can be easily adapted to track your investor interactions and ensure you follow them up during the sales process. The CRM I used throughout my last financing helped me keep track of more than 30 relationships from first meeting to due diligence and finally, to closing. Once the financing is complete, CRMs can also help ensure you maintain relationships with current and prospective investors by following up with them regularly. It takes solid science, a strong leadership and development team, and a compelling investment proposition to get the attention of investors, but there are other factors that are often key to filling the book. In my experience, presenting high-quality investor materials, establishing strong relationships, applying basic sales principles and reliably tracking your sales process can maximize the chances of closing a successful financing.

References: 1.

https://www.cvca.ca/wp-content/uploads/2018/03/Q4-2017_ Canada-Report-ENG_Final.pdf 2. http://www.biotech.ca/wp-content/uploads/2018/06/CanadasBiotechnology-Industry-Infographic-En.pdf Roberto Bellini is the CEO of BELLUS Health, a Montreal-based biotech company developing a drug for chronic cough. To see this story online visit https://biotechnologyfocus.ca/ closing-the-deal-suggestions-for-a-successful-financing/ Got something to say? Please send your comments/letters to biotechnology_focus@promotive.net

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