Biotechnology Focus August/September 2017

INSIGHTS FOR THE LIFE SCIENCE INDUSTRY

AUGUST/SEPTEMBER 2017 VOLUME 20, NUMBER 4

A ERS RY IS IV

E SU

AN N

Anniversary

From preclinical to the market The search for commercial viability

INSIDE : Ontario’s Innovation Brokers BioNeutra - A rising star from Alberta Health Canada speaks out on biosimilars EY’s Canadian biotech outlook

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FEATURES

contents August/September 2017 – VOLUME 20 – NUMBER 4

10

Renovate to innovate: ICH GCP E6 Revision 2 and new clinical trial standards The updated Good Clinical Practice (GCP) guidelines bring major implications for all clinical development stakeholders worldwide (By Vatche Bartekian)

12 Helping clear the path to the market for healthcare innovators

10

A new approach which links Ontario-based health technology companies with opportunities, key players, and support (By the Innovation Brokers Team)

14 Clinical considerations for the authorization of biosimilar biologic drugs in Canada A summary of the pathway to authorization for biosimilars in Canada (By Bradley J. Scott)

18

Staying the course amid uncertainty – How Canadian biotech can turn industry trends to their advantage Global megatrends are shaping the industry in new and complex ways, and Canadian biotech companies should be planning ahead to ensure they’re equipped to thrive (By Mario Piccinin)

16 Biotechnology Focus 20th Anniversary Special We continue our celebration of Biotechnology Focus’ twentieth anniversary. This time, we look back at past issues from the years 2004 to 2006.

(By Shawn Lawrence)

IN EVERY ISSUE

30

The Last Word Canada’s scientists can individually compete with the best in the world. However, a key question is whether our healthcare institutions can compete globally in innovation?

(By Wayne Schnarr)

DEPARTMENTS 6

Research news

8

Business corner

28 Calendar of events www.biotechnologyfocus.ca

21 Innovator story: VitaFiber spells sweet success for Alberta biotech rising star BioNeutra’s bet on a natural prebiotic sweetener pays back big time (By Nestor Arellano)

24 Cas9 enzyme variant cuts down CRISPR off-targets A custom manufacturer of DNA and RNA oligonucleotides has launched a Cas9 enzyme variant which can drastically reduce off-target effects in CRISPR genome editing.

(By Nestor Arellano)

26 Breakthrough in regen therapy for Hemophilia A: HemAcure A consortium made up of several European universities and an Ontario-based biotech company reported they have achieved several breakthroughs in their work on a regenerative medicine therapy for treating Hemophilia A (By Nestor Arellano) August/September 2017 BIOTECHNOLOGY FOCUS 3

PUBLISHER’S note

PUBLISHER/ EDITOR-IN-CHIEF Editor CONTRIBUTING WRITERS

Terri Pavelic Nestor Arellano Shawn Lawrence

Wayne Schnarr Vatche Bartekian The Innovation Brokers Team Bradley J. Scott

The product development relay race In this issue of Biotechnology Focus, we are focusing on clinical trials and clearing the path from preclinical to the following phase of product development.

Vatche Bartekian, president of Vantage BioTrials, starts us off with an in-depth look at how the latest updates to the Good Clinical Practice (GCP) guidelines from the International Council for Harmonization will impact professionals and businesses in the biotech industry. Whether you work for a pharmaceutical, biotechnology, a research site, or a contract research organization, Vatche’s feature article, Renovate to innovate: ICH GCP E6 Revision 2 and new clinical trial standards, is a must read.

Earlier this year, Ontario’s Chief Health Innovation Strategist, William Charnetski, announced the launch of the Innovation Brokers program. The innovation brokers link Ontario-based health technology companies with opportunities, key players, and support, in order to bring their intellectual properties and research out of the lab and into the provincial health care system. Look for the article, Helping clear the path to the market for healthcare innovators, and find out how you or your company might be able to avail of this program.

Biosimilars are invaluable in the treatment of a wide range of diseases, and they have the potential to increase competition and decrease the substantial costs often associated with biologic treatment, says Bradley J. Scott. He is a senior clinical evaluator, for the Biologics and Genetic Therapies Directorate, Health Products and Food Branch at Health Canada. His piece, Clinical considerations for the authorization of biosimilar biologic drugs in Canada, is just what you need to read if you’re looking for a pathway to the authorization of your biosimilar in Canada.

Mario Piccinin, partner and Ontario Life Sciences leader for the private client services at EY, reports on the global megatrends shaping the biotechnology industry. Working with the data accumulated by EY through its Beyond borders: Biotechnology Report 2017, Mario gives us a snapshot of the key developments, technology breakthroughs, and issues biotech professionals need to keep an eye on in order to thrive in this ever changing environment.

If you’re looking for inspiration, look no further than our Innovator story for this issue. Biotechnology editor, Nestor Arellano, recently had an engaging conversation with Dr. Jianhua Zhu. Within a few years of arriving in Canada, this bioengineer was able to launch a blockbuster product which broke into the highly competitive health food and beverage market and generated $70 million in sales. Find out more in the story, VitaFiber spells sweet success for Alberta biotech rising star.

For our Last Word editorial, healthcare sector and market capitals consultant Wayne Schnarr takes a look at Canada’s healthcare infrastructure. Wayne looks at the numbers and what he sees makes him a bit skeptical. To find out why, read his piece: Can Canada’s healthcare infrastructure foster effective innovation?

Enjoy your read.

4 BIOTECHNOLOGY FOCUS August/September 2017

Mario Piccinin GRAPHIC DESIGNER CONTROLLER MARKETING MANAGER

Elena Pankova John R. Jones Mary Malofy

CIRCULATION DIRECTOR Mary Labao circulation@promotivemedia.ca Tel: 905-841-7389

EDITORIAL ADVISORY BOARD Christine Beyaert, Roche Canada; Pierre Bourassa, IRAP, Montréal; Murray McLaughlin, Sustainable Chemistry Alliance; Ulli Krull, UTM; John Kelly, KeliRo Company Inc.; Peter Pekos, Dalton Pharma Services; Robert Foldes, Viteava Pharmaceuticals Inc.; Gail Garland, OBIO; Barry Gee, CDRD; Bonnie Kuehl, Scientific Insights Consulting Group Inc.; Raphael Hofstein, MaRS Innovation; Roberto Bellini, Bellus Health; Peter van der Velden, Lumira Capital; Albert Friesen, Medicure Inc.; Ali Tehrani, Zymeworks Inc.; Dr. Jason Field, Life Sciences Ontario; Andrew Casey, BIOTECanada

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 Scientists use CRISPR to encode video in DNA

Using the gene editor CRISPR, Harvard scientists were able to save videos in DNA. In a study published in Nature, the team at the Wyss Institute for Biologically Inspired Engineering and Harvard Medical School (HMS) led by Wyss core faculty member George Church explained that the CRISPR system can encode information, such a digitized image, in living cells.

Their approach could lead to the creation of a record of a cell’s “molecular experiences” during development or when it is being attacked by viruses.

Church is the Robert Winthrop Professor of Genetics at Harvard Medical School and a Professor of Health Sciences and Technology at Harvard and MIT. Funding for the team’s research was provided by: The National Institute of Mental Health, the National Human Genome Research Institute, the Simons Foundation Autism Research Initiative, the National Institute of Neurological Disorders and Stroke, Paul G. Allen Frontiers Group, and the Wyss Institute. “…what we’re aiming to do in the grand sense basically is to encode information into living cells over time,” said Seth Shipman, a postdoctoral fellow who is working with Church and is the study’s first author.

“So we were able to write new information into the genome using the CRISPR adaptation system.”

Shipman said the team found out that they could “hijack the system” and make it take sequences that the team provides.

The researchers encoded five grayscale images into 104 DNA fragments per image. One image per day was introduced to the Escherichia coli bacterium.

First, they used static images. After that, they tried delivering moving images to the living bacteria.

Today, in order to get information from cells, scientists need to watch the cell or disrupt its operation. The approach developed

by Church’s team illustrates that it is possible to manipulate cells to record, in their natural environment, the changes that they are undergoing.

That data, Church said in an interview with the Harvard Gazette, can be recorded into a “synthetically created memory hotspot” in the cell’s genome. “…in a way we are getting ahead of the game by storing information in a bacterial population because the population has more storage…maybe a bacterium has room for four megabytes of information before it starts squeezing out the not native genome…if you have billions of cells you can now get millions of gigabytes,” said Church.

Positive data on Eloctate and Alprolix in treating hemophilia patients Global biotechnology company Bioverativ Inc., announced that clinical data from its leading extended half-life therapies Alprolix and Eloctate indicates that the medications improve joint health, bleeding, and the quality of life of hemophilia patients.

Alprolix [Coagulation Factor IX (Recombinant), Fc Fusion Protein] and Eloctate [Antihemophilic Factor (Recombinant), Fc Fusion Protein] are synthetic coagulation factors VIII and IX, for hemophilia A and B, respectively.

The data showed that hemophilia patients who were given Eloctate and Alprolix exhibited improved joint health scores and joint annualized bleed rates.

Meanwhile, Bioverativ Canada Inc. reported that it has received notices of compliance from Health Canada approving the transfer of marketing licenses for Eloctate and Alprolix from Biogen Canada Inc. to Bioverativ Canada Inc., following Bioverativ’s separation from Biogen.

Bioverativ was created as a spin-off from Biogen’s hemophilia business. It is an independent biotechnology company focused on the discovery, development, and commercialization of innovative therapies for hemophilia and other rare blood disorders.

Following the spin-off, effective February 1, 2017, Biogen was the marketing authorization holder of Eloctate and Alproxil in Canada until Health Canada approved the transfer of the marketing licenses to Bioverativ Canada Inc.

To see this story online visit http://biotechnologyfocus.ca/scientistsuse-crispr-to-encode-video-in-dna/

Ontario government funds disposable hep C diagnostic tool Faculty of Pharmacy. It’s a simple solution to At least one hundred million people in developing countries have contracted hepatitis C. Early detection is key to providing timely treatment for the deadly blood-borne liver infection. However, testing tools are often in low supply and expensive in many regions.

Researchers at the University of Toronto are developing a disposable “dipstick” type diagnostic tool which works like a home pregnancy test. The tool could one day help health workers around the world detect hepatitis C. By placing a drop of blood on the dipstick, people can find out if they have hepatitis C, said Professor Shana Kelley of the Leslie Dan 6 BIOTECHNOLOGY FOCUS August/September 2017

detecting a disease which, if left untreated, can cause long-term health consequences and even death.

Research on the disposable hep C diagnostic tool has received a $1.6 million grant from the Government of Ontario. It is one of the 62 projects at the University of Toronto which is being supported by the province, said Reza Moridi, Ontario’s minister of research, innovation, and science.

To see this story online visit http://biotechnologyfocus.ca/ontariogovernment-funds-disposable-hep-cdiagnostic-tool/

To see this story online visit http://biotechnologyfocus.ca/positivedata-on-eloctate-and-alprolix-in-treatinghemophilia-patients/

R&D news Stem-cell researchers find cause of relapse in acute myeloid leukemia

Rare therapy-resistant leukemia stem cells are responsible for causing relapse in acute myeloid leukemia (AML) patients, according to findings of a study conducted by Ontariobased researchers.

Prior to this, physicians never had any opportunity to identify AML patients up front, said Dr. John Dick, who led the team of leukemia researchers.

“Now we have the first step to identify these patients at the outset and during remission,” he said. “Our new findings add to that knowledge, and we hope that we will soon have a

new biomarker that will tell whether a patient will respond to standard chemotherapy, and then another to track patients in remission to identify those where treatment failed and the rare leukemia stem cells are coming back.”

Dick is a senior scienDr. John Dick tist at Princess Margaret Cancer Centre, University Health Network, and professor in the Department of Molecular Genetics, University of Toronto. He holds the Canada Research Chair in Stem Cell Biology and is Director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research.

This study was primarily undertaken by postdoctoral fellow Dr. Liran Shlush and scientific associate Dr. Amanda Mitchell.

Their findings, which were published in Nature, provide significant insights into cell types fated to relapse. It can help accelerate the quest for new upfront therapies.

Fundamental science research in Canada dropping: Report A shift in focus towards applied research is bringing about a growing decline in basic science research in Canada, according to a recent report based on a survey conducted by an international organization made up of young scientists.

The emphasis on applied research has resulted in reallocation of funding which has left “many accomplished researchers in Canada un-funded and Canada’s future as a global leader in innovation and discovery is at stake,” said the report, Restoring Canada’s Competitiveness in Fundamental Research: The View from the Bench. The report was published by the Global Young Academy, an organization of more than 200 scientists in the early stages of their careers.

The report covers the period between 2005 and 2015. It reveals the erosion of federal support for fundamental research in Canada’s major research councils: Losses of 36 per cent per researcher in natural sciences and engineering, and 31 per cent

per researcher in social sciences and humanities. The figures are similar for healthrelated fields.

The report leaders, Julia Baum; an associate professor of biology at the University of Victoria, Oded Hod; a professor at the Tel Aviv University who specializes in theoretical chemistry and nanomaterial science, and their team members gathered the perspective of over 1,300 members of the Canadian research community. They used an online survey to collect information for the report.

The research was funded by the Ontario Institute for Cancer Research, the Cancer Stem Cell Consortium via Genome Canada and the Ontario Genomics Institute, the Canadian Institutes of Health Research, the Canadian Cancer Society, the Terry Fox Foundation, the Canada Research Chair and The Princess Margaret Cancer Foundation.

Dick said the research conducted by the team represents the marriage of stem cell biology and genetics. These two areas have historically operated as separate camps.

The researchers set out to solve the mystery of AML relapse by analyzing paired patient samples of blood taken at the initial clinic visit and blood take post-treatment when disease recurred.

“This is a story that couldn’t have happened five years ago, but with the evolution of deep sequencing, we were able to use the technology at just the right time and harness it with what we’ve been working on for decades,” Dick said.

To see this story online visit http://biotechnologyfocus.ca/stem-cellresearchers-find-cause-of-relapse-inacute-myeloid-leukemia/

They found that the “dismantling” of funding for fundamental research has resulted in the decline of the proportion of researchers conducting fundamental research from 24 per cent in the period covering 2006 to 2010 to less than two per cent from 2011 to 2015.

The funding gap between fundamental research and applied research in Canada reached $535 million by 2015.

The researchers noted that Canada’s new Liberal government, in its 2016 federal budget, began to address this deficit by allocating $73 million to three granting councils.

Authors of the report suggested an additional investment towards fundamental research of $459 million to cover the outstanding funding gap.

Overall, 40 per cent of researchers substantially changed the focus of their research programs over the past decade, “most commonly away from fundamental research,” the report said.

To see this story online visit http://biotechnologyfocus.ca/fundamental-science-research-in-canada-dropping-report/ August/September 2017 BIOTECHNOLOGY FOCUS 7

BUSINESS corner

Clementia files for $115-M IPO to bankroll palovarotene trials

Montreal, QC – Clementia Pharmaceutical is seeking to raise $115 million in an initial public offering to finance clinical trials for a drug that could treat a disorder which turns muscles, tendons, and ligaments into bone.

The Montreal-based biotech firm, which is focused on treating bone diseases, had licensed Roche’s palovarotene drug.

Palovarotene is an oral retinoic acid receptor gamma agonist for the treatment of emphysema. Emphysema is characterized by the destruction of alveoli and alveolar ducts within the lungs.

Clementia aims to repurpose palovarotene to treat fibrodysplasia ossificans progressiva (FOP).

FOP is an ultra-rare bone formation disease. It causes muscle tissue and connective tissue such as tendons and ligaments to ossify. It forms bones outside the skeleton and constrains movement.

An estimated 3,000 people are affected by the disease worldwide. Of that number, 800 are known patients.

Clementia wants to bring palovarotene through two Phase 3 trials.

To see this story online visit http://biotechnologyfocus.ca/ clementia-files-for-115-m-ipo-tobankroll palovarotene-trials/

8 BIOTECHNOLOGY FOCUS August/September 2017

Purdue Pharma to market BioDelivery’s Belbuca in Canada

TORONTO, ON – Purdue Pharma (Canada) has secured the rights to the exclusive Canadian licensing, distribution, marketing and sale of BioDelivery Sciences International’s pain management medication, Belbuca.

Belbuca is a buprenorphine buccal film for the management of pain severe enough to require daily, around-the-clock, longterm opioid treatment, and for which alternative treatment options are inadequate.

It was recently approved by Health Canada for the management of severe pain.

The medication incorporates BDSI’s BioErodible MucoAdhesive (BEMA) drug delivery technology. According to the company, Belbuca is the first and only long-acting opioid that uses novel buccal film technol-

ogy to deliver buprenorphine for appropriate patients living with chronic pain.

Buprenorphine is an opioid used to treat opioid addiction, moderate acute pain, and moderate chronic pain. The combination buprenorphine/naloxone is also used for opioid addiction.

BDSI is using its novel and proprietary BEMA technology and other drug delivery technologies to develop and commercialize, either on its own or in partnership with third parties, new applications of proven therapies aimed at addressing important un-met medical needs.

In return for the licensing and distribution rights to Belbuca in Canada, BioDelivery Sciences is eligible to receive upfront and potential milestones of up to $4.5 million, as well as royalties on net sales.

The mother company of Purdue Pharma (Canada), Purdue Pharma L.P. of New York, is the maker of the pain pill OxyContin. It also makes medicines such as hydromorphone, fentanyl, codeine, and hydrocodone.

Canada’s opioid crisis can be traced to the introduction of OxyContin as a prescription painkiller some 20 years ago.

In May this year, Purdue Pharma agreed to pay $20 million to settle a class-action lawsuit involving as many as 2,000 Canadians who became addicted to physicianprescribed OxyContin.

To see this story online visit http://biotechnologyfocus.ca/ purdue-pharma-to-marketbiodeliverys-belbuca-in-canada/

BUSINESS corner

Evasc Neurovascular closes $10-M financing

Vancouver – Evasc Neurovascular Enterprises ULC has closed a $10 million Series A venture capital financing round, led by Yonghua Investment Management Co., Ltd. of Shanghai.

Several of Evasc’s existing investors also participated in the financing. Together with previous seed financing rounds, a total of $27 million has been raised for the development and commercialization of the eCLIPs System.

“We are excited to welcome Yonghua Capital to the Evasc team,” said Dr. Donald Ricci, president, and CEO of Evasc. “This new funding will allow us to accelerate our plans to transform the cerebral aneurysm repair industry, enabling a much higher level of patient care and successful treatment outcomes than is currently possible.”

Yonghua Capital is one of China’s most competitive private equity investors.

Evasc Neurovascular is a privately held medical device company focused on the development of disruptive endovascular treatments for cerebral aneurysms. eCLIPs is a patented endovascular device designed to treat 95 per cent of cerebral aneurysm cases and is currently targeted for use in challenging wide-neck bifurcations. eCLIPs has been in development since 2008.

The new funds will be used towards

achieving strategic milestones related to the eCLIPs Aneurysm Treatment System in the following key areas: • Expand use cases, to demonstrate efficacy • Flow disruption at bifurcations, to eliminate the need for embolization coils • Sidewall aneurysms, to broaden eCLIPs’ use to 95 per cent of cerebral aneurysms • Improve ease of use through updated design for simplified deployment as well as use in smaller catheters, to accelerate accessibility and adoption by interventionists • Clinical trials, regulatory approval, and continuation of the current EESIS trial and preparation for FDA IDE trial, to further demonstrate the efficacy of eCLIPs and gain approval for sale in the U.S.A. To see this story online visit http://biotechnologyfocus.ca/evascneurovascular-closes-10-m-financing/

Canadian pharma to reach $25-B by 2021

The Canadian pharmaceutical market is on track to grow from $22.6 billion in 2016 to around $25 billion four years from now, according to the latest report from research and consulting firm GlobalData.

The report also said that, in recent years, global pharma and biotechnology firms have ramped investments in aca-

demic industrial activities in Canada. Major pharmaceutical firms have also begun to conduct a significant number of the clinical trials in the country. Canada’s pharmaceutical industry is the 10th largest market with a share of two per cent of the global market.

In 2016, the value of the generic pharmaceutical market was $6.2 billion.

At that time, generic drugs accounted for

around 70 per cent of prescriptions in Canada, compared with 89 per cent in the US. However, generic drug sales account for only 22.4 per cent of the overall pharmaceutical market.

The use of generic medicines saved nearly $20 billion for the government in 2016.

GlobalData expects the market to continue to grow as the government promotes generics usage and as quality perception improves among patients.

Patented drugs accounted for 61.8 per cent of the total sales in 2015.

The medical device market in Canada was worth $8.7 billion in 2009. That figure grew to $11 billion in 2016. It is expected to grow at a CAGR of 4.2 per cent from $11.5 billion in 2017 to $13.5 billion in 2021.

“The main segments, ophthalmic devices, orthopedic devices, drug delivery devices, in vitro diagnostics, and healthcare IT will drive market growth,” the report said.

To see this story online visit https://biotechnologyfocus.ca/canadian-pharma-to-reach-25-b-by-2021/ August/September 2017 BIOTECHNOLOGY FOCUS 9

clinical trials

| By Vatche Bartekian

Renovate to innovate: ICH GCP E6 Revision 2 and new clinical trial standards

T

The second revision of the GCP guidelines reflects the drug development industry’s growing emphasis on risk-based quality management and monitoring

10 BIOTECHNOLOGY FOCUS August/September 2017

he updated Good Clinical Practice (GCP) guidelines from the International Council for Harmonization (ICH), known as ICH-GCP E6 (R2), have now been approved, and implementation has begun across the globe. This second revision of the GCP guidelines in over 20 years has already been adopted by Health Canada with an implementation target date of April 1, 2018.

If your organization – whether you work for a pharmaceutical, biotechnology, a research site, or a contract research organization – has not yet kept abreast of these changes to GCP guidelines, you need to begin today, as they bring major implications for all clinical development stakeholders worldwide.

ICH-GCP E6 (R2) reflects the drug development industry’s growing emphasis on riskbased quality management and monitoring.

This highlights the increasing complexity of clinical research and how the ongoing evolution and emergence of new technologies creates opportunities for realizing greater efficiencies in quality management.

The updated guidelines specifically de-

scribe quality management as a versatile process, with an emphasis on re-thinking protocol design to minimize its complexity, eliminating unnecessary procedures and refining data collection tools and methods.

Ultimately, it provides us with a key to better decision-making to ensure we focus on relevant activities, bringing about faster, less costly studies while maintaining high levels of quality and safety for trial participants. As an excerpt from E6 (R2) states: “When the original ICH E6(R1) text was prepared, clinical trials were performed in a largely paper-based process. Advances in use of electronic data recording and reporting facilitate implementation of other approaches.

For example, centralized monitoring can now offer a greater advantage, to a broader range of trials than is suggested in the original text.

Therefore, this guideline has been amended to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting while continuing to ensure human subject protection and reliability of trial results.”1 In essence, what ICH has done is force the drug development industry to take a hard look at itself after 20 years of complacency, and implement changes to systems and processes in order to achieve more innovative approaches to the whole life cycle of developing new therapies.

As Arkadi Kuhlmann, the chairman and CEO of ING Direct USA, wrote in the Ivey Business Journal in 2010, “For all the talk about the importance of innovation, very few companies have figured out how to make it happen in a sustained way. Many businesses come up with one big idea, but that’s not enough…. The key to long-term success is to make innovation happen continuously. That’s where companies fall down. Intentionally or not, they become complacent.”2 Most people think that innovation equates to new inventions, gadgets, or start-up businesses, however, true innovation is when we begin creating organizational cultures that continually renew, change and improve the way we work and live. By proposing the fol-

clinical trials

Table 1 where are the CHANGES in ich e6 (R2)?

Clinical trials of the future are already becoming smaller, faster, and involve fewer participants. lowing changes to GCP guidelines, ICH has given us not only an interesting challenge, but a wonderful opportunity to do better. Interestingly enough, and rightly so, ICH still leaves enough ambiguity and room for interpretation even within the new updates to E6. Most clinical research professionals would find this frustrating since we often demand straightforward answers to issues we might encounter while conducting research studies.

However, ICH has recognized the fact that leaving room for interpretation and providing more of a guide rather than a recipe book will foster out-of-the-box thinking. This also allows the new guidelines to have more flexibility in a fast-changing world of evolving technologies.

Again, many of us would probably be outright disappointed to see that after 20 years of no changes, ICH provides us updates that certainly clarify lots of contentious issues (such as use of e-records, certified copies, investigator oversight responsibilities, validation of computer systems, etc), yet still falls somewhat short of leaving zero doubt in other areas of

interest. One particular section of the new updates, number 5.0, Quality Management, shines a much-needed light on a topic that has, for many years, baffled even some of the most experienced of us all.

During one particular conference a year ago, the author probed audience members during a presentation on Quality by Design and asked, “What is your definition of Quality Management?”

Ten people raised their hands and provided 10 very different answers.

Indeed, ICH recognizes that “one-sizedoes-not-fit-all” when it comes to Quality Management (QM) systems, but provides a well-thought-out generalized roadmap for organizations to get started with setting-up a solid QM foundation that promotes principles of continuous process improvement strategies throughout the lifecycle of a clinical trial. This is when true innovation is achieved.

You cannot attain or even begin to claim that your organization is “innovative” without fostering a culture of innovation, and it all begins with hiring the right type of people. It starts at the interview process.

At Vantage BioTrials – an innovative Canadian CRO – they have learned to hire individuals that do not fit in a perfect mold.

The best people are often found in unusual places. For example, one of their clinical project managers with an M.BA and a history of entrepreneurial ventures proved to be

one of their most valuable team players, not to mention a marketing guru with effective patient-recruitment ideas; another employee, a highly-motivated drug discovery scientist with over 10 years of lab research experience became one of their most valued clinical monitors, who could easily discuss scientific concepts with principle investigators.

These are just some examples of how creating a diverse, engaged and open-minded workforce helps bring about the necessary cultural shift towards innovation. Vantage BioTrials also uses the diverse backgrounds and experiences of their staff in their protocol optimization process, where they carefully and meticulously scrutinize study designs, protocol procedures, and scientific concepts in order to realize best outcomes for their sponsor clients and ultimately remain compliant with ICH GCP E6 (R2).

Because of innovations that have increased the value and power of data in trials today, clinical trials of the future are already becoming smaller, faster, and involve fewer participants. With more patient involvement and input and continued progress in the areas of technology platforms, recruitment strategies, and building partnerships, we expect to see more responsive and flexible trial designs, making it possible for studies to make adjustments to protocols in response to trial data and refine and improve outcomes in the midst of a trial.

Reaching this ideal state and realizing all of the potential for future clinical trials requires more than just innovation amongst industry stakeholders, and we now finally see international policies aligning with industry efforts through ICH’s amended guidelines.

Ultimately, this is what is needed to get lifesaving treatments to patients; and in the drug development world, it is the only thing that should truly matter.

References 1. ICH Harmonized Guideline; Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6 (R2), Current Step 4 version dated 9 November 2016.

2. Ivey Business Journal; Reinventing Innovation, by Arkadi Kuhlmann, May/ June 2010 issue Vatche Bartekian is president of Vantage BioTrials Inc. To see this story online visit https://biotechnologyfocus.ca/renovateto-innovate-ich-gcp-e6-revision-2-and-newclinical-trial-standards/ August/September 2017 BIOTECHNOLOGY FOCUS 11

Healthcare

| By the Innovation Brokers Team

Helping clear the path to the market for

healthcare innovators A new approach which links Ontario-based health technology companies with opportunities, key players, and support

T

he path from idea to innovation adoption is traditionally not a straight line and can be hard to navigate. Ontario’s Innovation Brokers program aims to help innovators identify opportunities for support, refine their business models, land a validation test site in a research hospital, and navigate other challenges along their path to successful adoption.

12 BIOTECHNOLOGY FOCUS August/September 2017

Announced by Ministers Eric Hoskins and Reza Moridi in April 2017, the program is a new initiative of the Office of the Chief Health Innovation Strategist. “Our goal is to use the power of technology to deliver on the needs and goals of patients and the health system,” said William Charnetski, Ontario’s Chief Health Innovation Strategist. “The brokers provide a necessary link between those who need to work together to accelerate the spread of effective health innovations so as to benefit patients, the healthcare system, and Ontario’s economy.”

The mandate of the innovation brokers is to work with innovators and health service providers to bolster innovation across the province. This means helping remove barriers so that new innovative technologies and processes get into our health care system and to patients faster. The brokers also link growing Ontario-based health technology companies with opportunities, key players, and support.

The aim is to create and enhance the connections and collaboration that help ensure success. To achieve these goals, the brokers also work with health system partners to improve

access to sources of support, make it easier to identify test sites for gathering feedback from patients and clinicians, and offer guidance and mentorship in moving innovative ideas from development to adoption and diffusion in Ontario’s health system.

The first three brokers have distinct but complementary roles. For instance, Azimuth Health Group recently launched @3iOntario, a web service that provides weekly updates of opportunities that innovators and innovation champions can take advantage of to advance their best ideas for improving health and healthcare. The service also shares requests for comment on policy directions and recent publications related to health innovation. It focuses on health technology, including digital health solutions and medical devices.

“Large companies have dedicated staff who seek support for their research and development, commercialization, and growth; small ones rarely do,” said Jennifer Zelmer, president of Azimuth Health Group. “We’re already hearing from innovators who are taking advantage of opportunities that they learned about via @3iOntario to accelerate their work

Healthcare “Our goal is to use the power of technology to deliver on the needs and goals of patients and the health system. The brokers provide a necessary link between those who need to work together to accelerate the spread of effective health innovations so as to benefit patients, the healthcare system, and Ontario’s economy.” — William Charnetski, Ontario’s Chief Health Innovation Strategist on real-world solutions that improve health, care, and value.”

With expertise in clinical adoption of health technologies, Zelmer and her team will also be building innovation capacity within the health system by mentoring change agents on such topics as value-based procurement and understanding and delivering social return on investment.

“Ontario innovations – from electric wheelchairs to pacemakers – have had profound effects on health and healthcare world-wide,” noted Zelmer. “Looking ahead, scale and spread of effective innovations will continue to be key to improving patient outcomes and to the future sustainability of the health system. As brokers, we aim to work with partners across Ontario and beyond to accelerate this process.”

The second innovation broker is Martin Gurbin, vice-president and founder, Sunnybrook International. With strong international business expertise, he will be working with health technology innovators to define and communicate their value proposition to Ontario-based health service providers. Gurbin’s focus is on mentoring and guiding health tech innovators, large and small, on business strategy and health system navigation. Martin conducts half-day sessions with companies and offers deeper support and mentoring to a handful of ready-to-scale innovations. In his short time as innovation broker, Gurbin has connected numerous companies that have innovative, promising products and services directly to leaders within provider environments, with the aim of shortening sales cycles and achieving faster adoption.

“I’ve always been a believer that true discovery and spotting the potential for bona fide innovation occurs when you are working the interface of a wide range of disciplines, professionals, and institutions,” said Gurbin.

“Serving as an innovation broker is a rare opportunity to work at the interface of the entire health and life sciences industry. Even at this early stage, it feels like we are making a difference by helping companies to refine

their value proposition, to get noticed, and to translate their opportunities into a reality. The potential benefits for patients and the health system are what makes this work even more exciting.”

Future plans include building a network of Ontario healthcare providers, beyond the teaching hospitals, that are keen to serve as early receptors for health tech innovations.

“This is an incredible opportunity to help stimulate and drive the formation of networks that can become the receptors for new technologies that will impact health and wealth,” noted Gurbin.

On behalf of Ontario’s 23 research hospitals, the third innovation broker – the Council of Academic Hospitals of Ontario (CAHO) – is helping to clear the path to market by pulling innovation into Ontario’s health system.

They have already developed and shared a list of critical problems requiring innovative solutions to provide market intelligence on the needs of the health system. CAHO has also launched a service to connect innovators to Ontario’s 23 research hospitals to help find real-life validation test sites.

“As an innovation broker, we provide the industry with streamlined and simultaneous access to Ontario’s 23 research hospitals,” said Rena Menaker, director of policy and member relations and lead of CAHO’s Innovation Broker Task Force. “By knocking on one door, innovators have faster access to validation test sites and, in time, faster adoption into some of the most advanced hospitals in the province.”

Future plans include developing the ability to broker connections with hospitals that are ready to adopt specific innovations, working with them to develop implementation plans for efficient adoption, and building capacity for innovation adoption by creating standard procedures among CAHO hospitals that enable clarity, transparency, and timeliness for innovators.

“Through CAHO’s innovation broker role, we are building capacity to effectively pull innovations into CAHO hospitals, while providing industry with greater clarity and transpar-

ency on market needs, and on our processes and timelines,” said Menaker. “While already adding value for innovators today, this work is also laying the foundations to help clear the path to market for innovators tomorrow. As a result, it is our hope that industry will have a greater opportunity to build innovationfocused partnerships with CAHO hospitals and accelerate validation and adoption of innovations that meet the needs of patients in the future.”

The innovation brokers are supported by the Office of the Chief Health Innovation Strategist at the Ministry of Health and LongTerm Care. The office serves as a catalyst to help accelerate health technology commercialization efforts and works on behalf of health technology innovators to remove barriers and improve access to Ontario’s health care system. Its goal is to grow businesses and build a health innovation ecosystem. Specifically, the office aims to drive collaboration across the health care system to accelerate the adoption and diffusion of new innovative health technologies and processes to improve patient outcomes, add value to the system, and create jobs in Ontario.

To subscribe to the free @3iOntario weekly digest of opportunities available to health innovators and innovation champions in Ontario, visit http://www. azimuthhealthgroup.ca/3iOntario To learn more about CAHO’s role as an Innovation Broker, visit http:// cahohospitals.com/partnerships/ innovation-broker/ For general information about the Broker service, visit http://health.gov.on.ca/en/ pro/programs/ochis/innovation-brokers. aspx To see this story online visit www.biotechnologyfocus.ca/helping-clearthe-path-to-the-market-for-healthcareinnovators/ August/September 2017 BIOTECHNOLOGY FOCUS 13

Best Practices

| By Bradley J. Scott

Clinical considerations for the authorization of

biosimilar biologic drugs in Canada A summary of the pathway to authorization for biosimilars in Canada

14 BIOTECHNOLOGY FOCUS August/September 2017

B

iologic medicines have been invaluable in the treatment of diseases ranging from cancer to autoimmune disease. The expiry of patents for many successful biologic medicines has fostered a high degree of interest in the development of subsequent entry versions, known as biosimilar biologic drugs or, simply, biosimilars. Biosimilars have the potential to increase competition and decrease the substantial costs often associated with biologic treatment.

In 2013, data published regarding the number of biosimilars in development signaled a high level of activity in this area. For example, over 40 programs were reported to be underway for biosimilar versions to three of the most successful biologics: the TNF inhibitors known as Humira, Enbrel, and Remicade[1].

Since then, a number of biosimilars have been approved and have come to market in Canada. This article is intended to provide a summary of the pathway to authorization for biosimilars in Canada with a focus on clinical aspects as outlined within Health Canada’s

recently updated guidance document: Information and Submission Requirements for Biosimilar Biologic Drugs.[2] Biologics are structurally complex and more difficult to replicate than small molecule pharmaceuticals. This is partially due to their large size, in comparison to pharmaceuticals, but also due to their production, which is accomplished by harnessing the productive capabilities of living cells. Due to the complexity of both the product and the manufacturing process, it is not possible to make an exact copy of a biologic product, and therefore the regulations that specify the requirements for demonstrating that a generic small molecule drug is pharmaceutically equivalent to its reference product do not apply. To address this, and to provide a framework for the authorization of biosimilars, Health Canada has published guidance on the information required to support submissions for biosimilar biologic drugs.

Health Canada’s guidance, originally published in 2010 and revised in 2016, provides recommendations to guide sponsors through the development of a biosimilar. Importantly, a biosimilar submission must make reference to a product that is currently authorized for sale in Canada. It is acceptable for sponsors to compare to reference product sourced from another jurisdiction, so long as the product can be justified to be a reasonable surrogate for the product that is authorized in Canada.

Following the guidance should allow the sponsors of biosimilars to fulfill the requirements of the Food and Drugs Act and regulations that apply to all new drugs.

Importantly, the guidance emphasizes the need for extensive side-by-side chemistry and manufacturing comparisons. By laying the foundation for the demonstration of similarity, this extensive comparative characterization of critical quality attributes, including assessments of biological function, facilitates a reduced clinical data package.

Clinical components, discussed below, are required to address the residual uncertainty that exists due to the fact that minor differences will always exist between a biosimilar

Best Practices Biosimilars have the potential to increase competition and decrease the substantial costs often associated with biologic treatment.

and its reference biologic drug, and evidence should be provided that these differences are unlikely to impact clinical outcomes. When taken together, demonstrations of similarity in each of these aspects (chemistry and manufacturing, biological function, clinical outcomes) establish a scientific bridge that allows the biosimilar to draw on the established safety and efficacy of the reference. As follows, a biosimilar is eligible to seek authorization for each indication held by the Canadian version of the reference biologic drug with the expectation that clinical outcomes will not differ meaningfully, whether a patient receives the biosimilar or its reference.

In general, the clinical aspects recommended supporting a biosimilar submission include side-by-side investigations of pharmacokinetics/pharmacodynamics (PK/PD), safety and efficacy, and immunogenicity. In certain circumstances a side-by-side PD assessment may replace a comparative investigation of efficacy; however, this requires the existence of a PD marker that is reasonably predictive of efficacy. In either case, the safety of the biosimilar should be characterized. The purpose of these studies is to exclude clinically meaningful differences in PK/PD, safety, efficacy and immunogenicity that would refute the biosimilarity of the product.

Comparative PK/PD studies intended to support a biosimilar submission should be conducted in healthy volunteers, when appropriate, since this population is considered homogenous and is a sensitive model in which to detect product specific differences.

Some considerations should be taken into account when designing comparative PK studies to support a biosimilar submission. For example, biologics often have long half-lives, PK may be nonlinear and influenced by targetmediated drug disposition, and the presence of endogenous protein may interfere with detection methods. All of these factors may influence the type (e.g. cross-over vs. parallel group), size and duration of study that is necessary to provide evidence of similarity in PK. When possible, PD should be investigated within the comparative PK study; however, it is recognized that for many biologics, valid

PD markers do not exist. In the absence of a valid PD marker, evidence of similar efficacy is needed to establish that the biosimilar does not produce outcomes that are meaningfully different from the reference.

At least one well designed, randomized, controlled safety and efficacy study is usually recommended to support a biosimilar submission. In most cases, the efficacy of the biosimilar should be demonstrated to be statistically equivalent to the reference product, based on pre-defined margins. Margins should be established based on historical information available for the reference product and should exclude differences that would be considered clinically meaningful. The study population and study outcomes selected to compare the biosimilar and reference should be considered sufficiently sensitive to detect differences between products, should they exist. Factors that may affect the sensitivity of the clinical trial include the expected magnitude of effect (based on historical efficacy information for the reference), the homogeneity of the population, the use of concomitant medications, and the duration of treatment and follow-up. Sponsors are encouraged to demonstrate equivalent efficacy in the most sensitive setting possible as this provides the most robust demonstration of similarity. Safety assessments should be included in the study and should involve descriptive comparisons of adverse events occurring after the initiation of treatment. Observed safety signals should also be compared against the known safety profile of the reference product to determine whether new signals have been identified. It is recognized that this type of assessment will often be incapable of detecting differences in the incidence or severity of events that may be rare to begin with. Due to this, appropriate risk management plans and post-marketing surveillance are critical in strengthening the safety database for biosimilars. This approach to post-market monitoring is similar to that in place for all new biologic medicines.

Finally, immunogenicity is a key consideration in the development of biosimilars and should be explored within the comparative safety and efficacy study(ies). This is for

several reasons, chief among them being that the development of immunogenicity can have unwanted consequences ranging from severe adverse reactions to neutralization of the biologic, which can lead to reduced efficacy. Furthermore, the immune system is considered highly sensitive, with even minor molecular differences having the potential to elicit a significant immune response. Therefore, demonstrated similarity in the incidence, magnitude, and persistence of the immune response, observed in an appropriately sensitive population, provides additional evidence that the biosimilar and the reference can be expected to produce comparable outcomes.

Importantly, consideration must be given to the assay(s) used to assess the immunogenicity of the biosimilar and reference biologic drugs. These assays should be validated, sensitive and sufficiently drug-tolerant so as to allow for a robust assessment of immunogenicity.

In conclusion, Health Canada’s guidance on biosimilar biologic drugs specifies rigorous comparisons of chemistry and manufacturing attributes, nonclinical aspects, as well as clinical studies comparing the PK/PD, safety and efficacy, and immunogenicity of a biosimilar biologic drug to its reference. When taken as a whole, evidence of similarity in each of these aspects allows for a conclusion of biosimilarity, meaning that, in any given setting, the biosimilar is expected to produce clinical outcomes that are not meaningfully different from those expected with the reference biologic drug.

For more information regarding the development of biosimilar biologic drugs for the Canadian market, please consult the guidance document: Information and Submission Requirements for Biosimilar Biologic Drugs.

References 1. Rader RA. 2013. An Analysis of the US Biosimilars Development Pipeline and Likely Market Evolution. BioProc. Int. 11(6): S16 – 23.

2. Health Canada. 2016. Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

Bradley J. Scott, is a senior clinical evaluator, for the Biologics and Genetic Therapies Directorate, Health Products and Food Branch at Health Canada.

To see this story online visit https://biotechnologyfocus.ca/clinicalconsiderations-for-the-authorization-ofbiosimilar-biologic-drugs-in-canada/ August/September 2017 BIOTECHNOLOGY FOCUS 15

20th anniversary

| Compiled by Shawn Lawrence

Biotechnology 20th Anniversary Special: Years 7 to 9!

Biotechnology Focus in the years 2004 to 2006

We continue our celebration of Biotechnology Focus’ 20th anniversary with another look back at our past issues highlighting various moments in time that speak not just of then, but of today as well. This month we look back at past issues from the years 2004 to 2006, and while some issues are missing in our synopsis, you’ll see we’ve got most of the important ones covered.

January 2004

May 2004

Vol. 7, No. 1

Vol. 7, No. 5

Jeff Graham and his BLG team get things rolling with a look into the regulation of stem cell research in Canada. We also review the startup business landscape, and our technical piece this month delves into immunotherapeutic approaches to treat cancer. January was also the relaunch of our website www. bioscienceworld.ca.

February 2004 Vol. 7, No. 2

Our first executive edition of the year features the strong biotech bloodlines of the Bellini family with Dr. Francesco Bellini of Neurochem on the cover. A decade later, his son Roberto Bellini would follow in his footsteps. Other features from this issue include James Cahill’s advice piece on securing laboratory space, Richard Clark’s piece on the do’s and don’ts of joint ventures, and a review of the ethical, legal and social issues around Genomics research.

The featured executive for this issue was Biomira CEO Dr. Alex McPherson. The timing of this piece is auspicious as just one month later, Merck KGaA would pull away from its codevelopment deal for the Edmontonbased company’s cancer vaccine.

June 2004 Vol. 7, No. 6

In this issue we see growth in Canada’s strategic venture funds in the biotech space with government agencies and venture capital firms leading the charge.

Also, there is a spotlight piece on Canada’s research-related activities for treating spinal cord injuries.

Wrapping up the issue, our innovator for this issue is Michael May, then of Rimon Therapeutics. Of course, he’s better known today as the president and CEO of CCRM.

August 2004 Vol. 7, No. 8

January 2005 Vol. 8, No. 1

The top stories from this issue include: the ramifications of ineffective communications on drug development, new changes to the rules governing medical devices, coverage of Ernst & Young’s annual biotech report, and in our innovator Hot topics from this edition include spotlight, Dr. David Young’s company cellular assays gaining favour in Arius Research Inc. drug-discovery research, and tips for biotechs going into the clinic. We also September 2004 feature a profile piece on National SciVol. 7, No. 9 ence Advisor Arthur Carty.

In our next executive profile, we look at Leon Gosselin’s company Axcan Pharma, which today is a wholly owned subsidiary of Allergan plc. Next, we offer a real to-do list for sponsors looking to manage the contract manufacturing of biologic products. Closing things out, with MethylGene going public, we ponder the possibility of the IPO window opening in Canada.

2004

February 2005

May

Vol. 8

In R&D manu our fe rundo ings f on Jim peutic

June

Vol. 8

A gro in fro MaRS Disco first s focus that is See if who o

Vol. 8, No. 2

Our cover story featured then AnorMed president and CEO Michael Abrams, while inside, Kristine Archer reviews biopartnering trends, and John Curling discusses the challenges facing biopharmaceutical process development.

2004

2005

Biotechnology Focus in the years 2004 to 2006

2004 March 2004 Vol. 7, No. 3

In this issue, we spotlight research that is looking at bacteriophage as a means of combating bacterial infection, CIHR president Alan Berstein discusses Canada’s health research strategy, and we wrap this issue up with an innovator piece on Dr. K. Wayne Marshall of ChrondroGene Ltd.

April 2004 Vol. 7, No. 4

The theme this month is outsourcing, specifically looking at ways to successfully outsource dosageform development from proof of concept to commercialization. Also in the spotlight is the James Hogg iCAPTUR⁴E Centre for Cardiovascular and Pulmonary Research in Vancouver, BC. And while today we know Clarissa Desjardins as the president and CEO of Clementia Pharmaceuticals, her first successful biotech business venture was with the proteomics firm she launched, Caprion Pharmarceuticals Inc.

July 2004 Vol. 7, No. 7

Our cover story isn’t just big in our industry, but also made all the major news cycles. The piece highlights the ramifications of the Supreme Court’s ruling in Monsanto vs. (Percy) Schmeiser, and even today its impact on the patentability of genes and cells, the question of patent infringement, and specifically the issue of use of an invention by an innocent (unknowing) infringer is still debated. Briefly stated, the majority of the Court held that Monsanto Co’s patent relating to Roundup Ready® canola was valid and infringed upon by the farmer and his company.

16 BIOTECHNOLOGY FOCUS August/September 2017

October 2004 Vol. 7, No. 10

Bioinformatics comes of age in Canada, with the advent of Pile System, as well as the use of computer modeling to help predict a diabetic patient’s sensitivity to insulin. Also this month, the Canadian Light Source, the country’s first synchrotron, opens in Saskatoon, SK. Finally, in our innovator section we profile Dr. Simon Pimstone and his company Xenon Pharmaceuticals.

March 2005 Vol. 8, No. 3

Highlights from this edition includes a cover story on the importance of biomanufacturing, an innovator piece on one of the legends of Canada’s life science industry: Dr. Henry Friesen. Plus we review some cost saving IP strategies for small and new companies.

April 2005 Vol. 8, No. 4

Dubbed the BIO-IT issue, this issue covers new protein chip technologies and the variDecember 2004 ous ways that Vol. 7, No. 12 informatics In addition to a special “New Prodtools and ucts for 2005” showcase, the editorial databases help scientists understand lineup for this issue includes educaand manipulate biology. Also, the tion initiatives aimed to fill the skills NRC appoints Pierre Coulombe to gap in biotech, Cangene’s recombithe role of president and Dr. Jacquenant protein research, and the vital line Shan, then of CV Technologies role venture capital plays in support Inc., is our spotlighted innovator. of Canadian biotech firms.

July

Vol. 8

On th opini inside prote and w comp and i Terri resea Hosp Dr. A man

Aug Vol.

the g cove

ude

ps for e also al Sci-

20th anniversary We hope you enjoyed this retrospective look at Biotechnology Focus Years 7 to 9. Be sure to check back to see our next timeline piece for 2007 to 2011!

May 2005 Vol. 8, No. 5

In R&D news, Medicago’s first manufacturing plant opened, while our feature story lineup includes a rundown of Canadian biotech financings for 2005-06 and a profile piece on Jim Wright, former Lorus Therapeutics Inc’s president and CEO.

June 2005 Vol. 8, No. 6

A group of familiar faces stand in front of the soon to be opened MaRS building in Toronto’s Discovery District. This marks our first special Ontario life sciences focused issue, an annual tradition that is still going strong today!

See if you can pick out who’s who on the front page.

orMed ms, ws urling ioment.

des a bioce on fe sci. Plus tratees.

September 2005 Vol. 8, No. 9

Helga Long gets things started with her C-level skills piece “Top 10 attributes of the emerging biotech superstar.”

Under the heading of corporate governance we discuss when and where Canadian biotech companies should go public. And on the cover, Aeterna Zentaris Gilles Gagnon is this month’s featured executive.

October 2005 Vol. 8, No. 10

Stories in this Bio-IT themed issue include a piece on systems biology research in Canada, experimental design automation to solve the informatics bottleneck in drug R&D productivity, and best practices to manage and leverage scientific data. Also, on September 22nd, the MaRS Centre officially opened.

January 2006

September 2006

Vol. 9, No. 1

Vol. 9, No. 9

In Laying Down the Law, staff writer Amber Lepage-Monette looks into the current state of stem cell regulation in Canada, the U.K. and U.S. Next, Jacqueline Csonka-Peeren contributes a piece on emerging medical device technologies and Canada’s inventive output in this area. And our innovator this month is Steven Arless of CryoCathTechnologies.

The Ontario government passes the Transparent Drug System For Patient Act (Bill 102) and stakeholder sentiment is mixed. Pharmacogenomics and informationbased medicine is on the rise and with it, personalized medicine.

And Tony Cruz of Transition Therapeutics, dons our cover.

February 2006

October 2006

Yes, that is indeed a much younger David Allan gracing our cover. Back then, David was the founding chairman and CEO of YM Biosciences and the company was in the midst of celebrating a banner year of achievement. More than a decade later, David’s broad involvement with the biotechnology industry in Canada continues strong via his work serving on various boards and as a Principal at Cresswell Advisors. As for the company he helped launch, it was bought in 2012 in one of the industry’s biggest deals, by Californian-based heavyweight Gilead Sciences Inc. for approximately US$510 million.

Topics covered in this issue include: the importance of sample collection and handling methods in biomarker research, logistics as the weakest link in the clinical trial process, the Stiller Centre strives to change commercialization in Canada, and finally, the Canadian Intellectual Property Office attempts to stop the patenting of inventions directed to stem cells, organs and tissues.

Vol. 9, No. 2

2005

Vol. 9, No. 10

2006 2006

July 2005 Vol. 8, No. 7

On the cover, we conduct public opinion surveys on biotech, while inside we look at advances in proteomics, toxicity in clinical trials and we profile Dr. Michael Hayden’s company Aspreva Pharamaceuticals and its IPO. Finally, in her pub note, Terri Pavelic highlights the exciting research news out of Mount Sinai Hospital where researchers led by Dr. Andras Nagy develop two human embryonic stem cell lines.

August 2005 Vol. 8, No. 8

Hot topics this month include lab automation, biotech financings for special purpose entities, and in our Across Canada section we give an update on the global efforts underway to find a coveted vaccine to cure HIV.

November 2005

April 2006 Vol. 9, No. 4

November 2006

Vol. 8, No. 11

Kevin Giese of BioMS Medical Corp. graces the cover as our featured executive, while inside we recognize Canada’s rise as a protein maker via the Structural Genomics Consortium and the urgent need for federal dollars to commercialize university research.

This edition marks what is possibly our biggest publication to date, or is at least the issue that put us on the map. Why? Well, the jam-packed 48 pager was Ontario-focused and included articles on the Ministry of Research and Innovation, the province’s major investments in the sector, and its rich history of scientific breakthroughs and milestones, and presented the benefits of doing business here. And of course, we managed to land a coveted one-on-one interview with the then Premier of Ontario, Dalton McGuinty. We even convinced him to appear on our cover!

As part of our executive edition series, Bertrand F. Bolduc discusses the three Fs of entrepreneurship: “the faith in the project, the fun getting there, and the finance.”

Other feature stories include the diversification of DNA testing and the forensic value of mitochondrial DNA, and furnishing a foundation for vaccines with the latest in immune-diagnostics technologies.

December 2005 Vol. 8, No. 12

The interface of art and science takes centre stage in Andrea Bielecki’s Across Canada column.

Next, the scientist behind the Canadian Science Policy Conference Mehrdad Hairiri offers his insights into the applications of gene expression profiling. Rounding out the issue, Elizabeth Fowler and Carolyn Cardin of Bio-IT World provide key tips for sponsors working with contract labs.

Vol. 9, No. 11

August 2006

December 2006

Vol. 9, No. 8

In this issue we look at Prometic Biosciences’ UK endeavor, the role of Academebased HTS, and the Myelin Repair Foundation and MS research.

Vol. 9, No. 12

To close out 2006, we look at the positive impact foods with fibre have in maintaining the intestinal tract, as well as new genome screening technologies which identify colon cancer risk in patients. And our innovator this month is Carolyn Cross of Ondine Biopharma Corp.

August/September 2017 BIOTECHNOLOGY FOCUS 17

Megatrends

| By Mario Piccinin

Staying the course amid uncertainty How Canadian biotech firms can turn industry trends to their advantage

F

ast-paced change and shifting markets are the name of the game in the global biotechnology sector these days. From geopolitical complexities in Europe and the U.S., which are affecting capital markets, to funding challenges that continue to impact key institutions, to far-reaching digital disruption, powerful forces are at work. And they have serious implications for the industry, both globally and domestically. Add to the mix the unrelenting pace of technological change, and it’s a potent combination that is challenging traditional biotech models and driving Canadian biotech players to consider how best to navigate a successful course to growth.

But this is hardly a new situation for leaders in the Canadian life sciences sector. Amid similar challenges over the past several years – among them, market decline, payer pressure and U.S. election rhetoric, dwindling drug approvals and shrinking public R&D capital – biotech largely stayed the course and was able to deliver historically strong results on many fronts globally.

As examined in EY’s recent report, Beyond borders: Biotechnology Report 2017, this “steady hand” approach has merit, but only if it is coupled with a serious commitment to preparing for a very different future. After all, biotech development cycles are very long, a characteristic that can provide a measure of insulation from broader uncertainty. But these global megatrends are shaping the industry in new and complex ways, and Canadian companies should be planning ahead to ensure they’re equipped to thrive.

Digital disruption is here to stay Emerging technologies and a blurring of industry boundaries is causing disruption across the biotech value chain – and it’s a 18 BIOTECHNOLOGY FOCUS August/September 2017

The “steady hand” approach has merit, but only if it is coupled with a serious commitment to preparing for the future. disruption that goes far beyond the previous wave of digitization and adoption of enterprise-wide solutions.

Technology and wellness companies, as well as other non-traditional players with substantial consumer and patient data, are homing in on biopharmaceutical turf. What’s more, competitors like Apple are far ahead of many biotech firms in understanding consumer behavior, brand building and shortcycle innovation.

Traditional players will need to work with technology and data-management firms, as well as healthcare providers and payers, to unlock the insights that can drive innovation and new models. In turn, greater access to evolving technologies will allow the sector to leverage data, focus on patient outcomes and eventually move to “beyond the pill” solutions.

Smart leaders will recognize that these new sources of competition can also be new sources of partnership and external innovation.

Megatrends

More efficient R&D is a priority Meanwhile, biotech firms need to leverage and incorporate emerging technologies into R&D, or risk being supplanted by those who do. Globally, the sector poured record amounts of capital into R&D last year. In fact, growth in R&D expenses increased 12 per cent and outpaced revenue for the second straight year.

The reality is that current R&D costs are unsustainable, especially for larger pharmaceutical firms. Unless companies can reduce these expenses, return on investment will eventually drop to levels that threaten the sector’s viability.

Many have already taken steps to improve their R&D ROI by focusing on those therapy areas with the greatest revenue potential, such as oncology. While this makes some sense, it doesn’t address the underlying inefficiencies.

Ultimately, the more sustainable route will be to embrace digital advances such as artificial intelligence (AI) and machine learning, and to

The most successful organizations will be those that focus on long-term value creation… use creative business models across the R&D value chain to improve efficiencies.

AI is going mainstream When it comes to AI, it’s not a question of whether it will transform healthcare, but rather when. A key benefit of digitization is the discovery of innovative treatments and novel ways of providing personalized health care.

Given that AI allows us to access and analyze more data – and do it faster – than the human brain ever could in a lifetime, it is already having a tremendous impact on the entire drug discovery and development process.

AI is becoming so sophisticated that it is already improving traditional drug target selection and R&D methods. As certain chronic conditions continue to face a dwindling num-

ber of truly innovative treatment options, AI and other data-based tools are likely to drive more appropriate and targeted medication use. A growing number of firms are also using AI to generate viable drug targets and leads more quickly and inexpensively than traditional methods.

Another benefit will be AI’s potential to level the playing field, providing an advantage to smaller companies. As noted at an EY-led panel discussion that took place at this year’s BIO International Convention, “AI enables biopharma Davids to compete with incumbent Goliaths.” If biotech firms aren’t proactive in using AI to ask better questions that can lead to better products and services, nontraditional players will beat them to it.

PHASE I-III Drug Development PHASE IV Post-Market Studies

KNOW-HOW AND ACCURACY IN CLINICAL RESEARCH

MEDICAL DEVICE & DIAGNOSTICS

vantagebiotrials.com

August/September 2017 BIOTECHNOLOGY FOCUS 19

Megatrends

With China’s emerging venture ecosystem, there is a new generation of homegrown biotech competitors coming.

Mergers and acquisitions are reshaping the market In 2016, the sector enjoyed its third-best financing year ever, despite a drop in proceeds from initial public offerings and follow-on rounds. Deal-making remained active overall, and the industry’s largest players continue to look for assets that will augment their pipelines.

Investors seem increasingly concentrated in specialist markets, such as rare diseases and oncology. Both venture investment and the public market bets seem particularly focused on immune-oncology companies.

Looking ahead, the growth of the industry will be increasingly global. With China’s emerging venture ecosystem, there is a new generation of homegrown biotech competitors coming. These and other forms of competition will inevitably drive biopharma dealmaking even further. The promise of M&A will further boost investors’ outlook on the sector and their willingness to finance new drug discoveries and developments.

Across biotech, evidence shows that companies can no longer pursue only organic activities to meet digital needs because the pace of change from digital innovation is happening too quickly.

5 ways Canadian biotech leaders can be ready for what’s coming 20 BIOTECHNOLOGY FOCUS August/September 2017

1

Prioritize innovation and agility.

Innovation drives growth. Those who build an environment where it can flourish will be better equipped to lock onto new sources of growth. Cultivating agility will help your organization stay nimble to quickly capitalize on opportunities as they arise.

2

Tackle your talent crunch head on.

Ongoing digital disruption – including new technologies around AI, among others – will demand new skills and expertise.

Fostering high-performing talent in-house and looking beyond local borders to attract the best and brightest will help to address potential organizational gaps.

3

Engage with policy issues that affect your business.

Today’s environment of evolving public and regulatory policy may mean hiring government-relations employees early on to develop an effective strategy.

4

Keep an eye on your pipeline.

There are still plenty of biotech targets that can boost future prospects and augment assets.

5

Get to know the emerging markets.

New prospects can present a host of opportunities you hadn’t considered previously.

Amid these tectonic shifts at home and abroad, Canada’s biotech companies will be best served by a steady “stay the course” mindset that has one eye firmly focused on the future. The most successful organizations will be those that focus on long-term value creation, even as financial markets come and go, while remaining flexible enough to capture investor cash when it’s available, even if it’s at prices well below the peak of a year or two ago.

For those who stay nimble, these megatrends may be the very drivers of tomorrow’s growth and prosperity.

Mario Piccinin is a partner and Ontario Life Sciences leader for Private Client Services at EY.

To see this story online visit https://biotechnologyfocus.ca/staying-thecourse-amid-uncertainty-how-canadianbiotech-can-turn-industry-trends-to-theiradvantage/

Innovator

| By Nestor Arellano

VitaFiber spells sweet success for Alberta biotech rising star BioNeutra’s bet on a natural prebiotic sweetener pays back big time

B

utter is back in style – with a vengeance. Pea and hemp proteins are the de rigueur powders for smoothies. And forget about cutting carbs, it’s all about sugar detox these days.

The trillion-dollar health and wellness industry is a fickle field and its road to success is littered with failed ventures.

This is a fact not lost on Dr. Jinhua Zhu, a bioengineer from China who is the founder and president of one of Alberta’s fastest rising biotechnology companies making a name for itself in the lucrative health food and beverage market. Zhu’s BioNeutra North America Inc. made half a million dollars in sales each week in 2016. VitaFiber IMO, the

company’s starch-derived, prebiotic natural sweetener in syrup and powder form, generated $70 million in sales over the last four years.

How Zhu, 58, and his team managed to transform raw agricultural products easily found in Alberta into a commercially successful product is instructive for any biotech startup seeking to take their scientific research from the laboratory to the market place.

Zhu pointed out that while his company is 14-years-old, he actually began working on the idea behind VitaFiber 27 years ago.

“But all that time, I was very conscious that I needed to commercialize my research,” he said. “The scientific research is essential but it’s critical that you also know your market.”

August/September 2017 BIOTECHNOLOGY FOCUS 21

Innovator

The entrepreneur mindset It is a mindset that is not typically associated with scientists, but it was an idea that was inculcated into Zhu very early on in his career.

His grandparents were entrepreneurs in China.

When he was 18, Zhu entered university in 1978, a time when China was still re-organizing its university system following the Cultural Revolution. Competition to get in was stiff, but Zhu managed to get in and thrive.

Zhu earned a PhD in biochemistry and later, at the age of 30, he was appointed vice-dean of the Institute of Chemistry and Chemical

“You can’t imagine how many presentations I had to make to raise money. If you have passion, you can convince people of the merit of your idea. One university chairman said to me: ‘I realize I might never see my money again, but I believe in you.’ That was pretty humbling.”

— Dr. Jinhua Zhu

Engineering – a division of South China University of Technology. He was placed in charge of three departments and about 300 professors.

“Universities were called upon to play a key role in China’s drive towards industrialization, and I was eager to get involved,” he said.

“I helped my professors commercialize some of their research. I used the profits to reward the initiators while helping supplement the low pay the faculty received across the board.”

Zhu also did a stint in Japan’s Yokohama University. He came to Canada in 1998 after receiving an invitation from the University of Alberta to work in its chemical engineering department.

It didn’t take long for the new immigrant to realize that the challenges he encountered in China were also present in his new home.

Two years after arriving as a visiting professor, Zhu was hired – and laid off twice by two biotech companies that were struggling to stay afloat.

“At that time, it was common for companies to open and close, open and close,” he recalled. “These spinoffs were launched by university professors who had great ideas, but weren’t usually trained to run a business.” Many had no experience in raising the money needed by their businesses. Nor did they usually have any training in hiring or managing staff or how to market their products. “…often, they were poorly financed and before they knew it, they had given away the farm to survive. Today things have significantly improved,” Zhu said.

Starting BioNeutra Zhu himself had no money when he set out to build BioNeutra.

His wife, Dr. Jiangyan Qin, a QA/QC scientist at an Edmonton pharmaceutical company, knew the venture would require Zhu’s maximum effort and attention. She agreed to pitch in.

“My wife and I discussed the matter,” he said. “She agreed that she would pay for the mortgage, car and household expenses for six months to see if I could make a go of it.”

Then, Zhu approached family and colleagues. Alberta Agriculture and Forestry also agreed to provide $15,000 for a feasibility study if he could match the amount.

“You can’t imagine how many presentations I had to make to raise money. If you have passion, you can convince people of the merit of your idea,” said Zhu. “One university chairman said to me: ‘I realize I might never see my money again, but I believe in you.’ That was pretty humbling.”

Knowing your market Zhu had done his research.

Stats Canada was predicting that by 2019 more than 14 million Canadians would be considered overweight. Numerous studies already indicate that North Americans are suffering from digestive problems.

In the U.S. alone, statistics show that 42 million people suffer from constipation. Americans have spent $6.4 billion on laxatives over the past five years.

“In Canada, experts say our diet is fibre starved,” Zhu explained.

“On average, our daily fibre intake should be 38g for men and 25g for women. Instead, we are getting 15 to 18g per day.”

At the same time, the public was increasingly becoming averse to sugar and consumers were in search of an ideal alternative.

Zhu, however, did not want to simply introduce another lowcalorie, natural sweetener. He wanted to focus on something that provided additional health benefits.

22 BIOTECHNOLOGY FOCUS August/September 2017

Innovator

Today, BioNeutra sells VitaFiber to food manufacturers in the U.S. and Europe. The product is added to protein bars, ice cream, beverages, and confectionaries.

This was where the idea of creating VitaFiber, a starch-based, prebiotic sweetener, came from.

“We all know that fibre is something that helps us with regularity and cholesterol,” said Barry Charnay, VP/Business Development for BioNeutra. He noted numerous reports show that fibre claims on food packaging are on the rise and that consumers have been seeking out fibre-rich products and supplements.

It was also at this time, Charnay said, that the public was being educated through the media about the benefits of prebiotics.

From the start, Zhu said he was determined to make VitaFiber from naturally derived sources available locally in Alberta. For instance, potato, which is a source of starch, is abundant in the province.

VitaFiber is isomalto-oligosaccharide (IMO), a new category of health food ingredient which is known for its weight management properties. It is derived from cassava, corn, potato and other cereal crops.

BioNeutra uses a patented, highly controlled enzymatic process to transform starch molecules into branched-chain molecules made of four to seven units of glucose which contain a series of alpha-(1-6) bonds. The bonds are poorly digested by humans, so they deliver fewer calories while providing fibre-like benefits.

BioNeutra is a finalist in the company category for the 2017 ASTechs science and technology awards.

During the last two years, BioNeutra has been successful in selling a retail line of VitaFiber to consumers through Amazon and Shopify.

This year, BioNeutra will be slowly rolling out VitaFiber through select health stores and retailers.

To aspiring bio entrepreneurs, Zhu gives these pointers which he has learned over the years: • Be strategic in choosing your market and build on success.

• Keep tight control of your expenditures. Whether your revenues are small or great, it’s important to keep an eye on the bottom line.

• Pursue awards. They provide peer and media recognition.

• It’s a cliché, but surround yourself with smart people.

• If you’re passionate, prove it. If you’re a university professor with a project that can be commercialized, go for it; otherwise, it’s just pure research.

“Take a chance,” said Zhu. “And as you grow, display a healthy degree of skepticism regarding the many pitches that will come your way.”

To see this story online visit https://biotechnologyfocus.ca/vitafiber-spells-sweet-successfor-alberta-biotech-rising-star/

www.kalgene.com “KalGene is determined to develop therapeutics to treat Alzheimer’s.”

- Dr. T. Nathan Yoganathan, CEO, KalGene Pharmaceuticals Inc.

Early challenges One of Zhu’s first moves was to get the technology patented. Then, he needed to leap over the regulatory hurdles.

BioNeutra had to conduct multiple tests to prove that VitaFiber was safe and that it provided the benefits the company claimed it did.

The company spent $13 million to conduct a series of collaborative research projects with the U of A and then presented the findings of the studies and human clinical trials to Health Canada, the U.S. FDA and the European Food Safety Authority. It was only after this, that BioNeutra received the green light to sell VitaFiber in 30 countries.

Today, BioNeutra sells VitaFiber to food manufacturers in the U.S. and Europe. The product is added to protein bars, ice cream, beverages, and confectionaries.

By 2012, BioNeutra became profitable. The product has been featured in various media outlets, and Zhu was honoured by the Alberta Legislative Assembly for his business and scientific achievements.

The company manufactures VitaFiber in Indonesia and China and will be opening its own plant in Canada soon.

This year, Zhu is also a nominee for the innovation category and

KalGene Pharmaceuticals is developing a novel therapeutic molecule to treat Alzheimer’s disease. KalGene is collabo rating with NRC, McGill, the Montreal Neurological Institute and CIMTEC to advance the therapeutic development.

KalGene plans to initiate Phase 1 clinical trials in 2018.

For additional information on KalGene’s efforts to develop new treatments for Alzheimer’s disease, please contact nathan@kalgene.com

August/September 2017 BIOTECHNOLOGY FOCUS 23

genome

| By Nestor Arellano

Cas9 enzyme variant cuts down CRISPR off-targets On-target editing was just as good as wild-type Cas9 and off-target events were greatly reduced

T

he ability to modify the gene of an organism through CRISPR genome editing holds the promise of curing diseases such as cancer and leukemia. However, there are also growing concerns that the innovative gene editing technology could alter regions of the genome which researchers are not targeting.

A custom manufacturer of DNA and RNA oligonucleotides has launched a Cas9 enzyme variant which it said can drastically reduce off-target effects in CRISPR genome editing.

The Alt-R S.p. HiFi Cas9 Nuclease 3NLS enzyme developed by Integrated DNA Technologies (IDT) is a recombinant S. pyogenes Cas9 mutant that improves specificity while maintaining a high editing efficiency similar to wild-type Cas9.

The Cas9 enzyme variant is able to cut down on off-target effects without significant loss of on-target activity, according to IDT. Off-target gene editing could have serious consequences.

For example, genome editing could inadvertently disable a tumour-suppressor gene or activate a cancer-causing gene. There is also the possibility of an off-target effect where two different chromosomes are joined in a phenomenon called transloca-

tion. Translocation is the cause of chronic myeloid leukemia and other conditions.

The new enzyme has been tested at a number of prominent laboratories conducting translational research into various diseases.Results have exceeded all expectations, according to a press release from IDT. “We performed an unbiased evaluation of several versions of high-fidelity Cas9 enzyme in primary human stem cells,” said Dr. Matt Porteus from the Stanford University’s

TAble 1 IDT Cas9 enzyme

24 BIOTECHNOLOGY FOCUS August/September 2017

Division of Stem Cell Transplantation and Regenerative Medicine. “We have been very impressed with the characteristics of this new IDT enzyme.”

He said that unlike other versions, Alt-R S.p. HiFi Cas9 Nuclease 3NLS consistently achieved high on-target editing activity while having low off-target activity.

“Because of the retained excellent ontarget activity and improved specificity profile, we are excited to use this version in our future experiments focused on developing novel genome editing based therapies for severe diseases with unmet medical needs,” said Porteus.

In order to successfully provide a Cas9 mutant with radically reduced off-target effects while maintaining high on-target activity, IDT screened more than 250,000 mutants in two rounds of selection.

The resulting rigorously tested enzyme, Alt-R S.p. HiFi Cas9 Nuclease 3NLS, is further enhanced with three nuclear localization signals (NLS) for optimal migration to the target DNA. A few months ago, Dr. J. Keith Joung of Massachusetts General Hospital, showed some 150 experts from biotech industry and academia an example where CRISPR is supposed to edit the VEGFA gene on chromosome 6. VEGFA stimulates the production

genome

Cas9 gene editing

“The IDT high-fidelity Cas9 performed admirably in primary human hematopoietic stem cells. On-target editing was just as good as wild-type Cas9 and off-target events were greatly reduced.”

of blood vessels, including those used by cancerous tumors.

“Although each CRISPR has zero to a dozen or more ‘known’ off-target sites (where known means predicted by those web-based algorithms),” Joung said, “there can be as many as 150 ‘novel’ off-target sites, meaning scientists had no idea those errors were possible.”

Off-target effects occur because CRISPR has two parts. The RNA part targets the site in the genome specified by the RNA’s string of nucleotides. The enzyme cuts the genome at this site.

However, a genome can have more than one site where the same string of nucleotides appears.

The cutting enzyme of CRISPR does not stop at one cut. The enzyme “still has the energy to bind with an off-target site, so it can still cleave those sites,” said Joung.

Alternative to CRISPR genome editing IDT is not the only company interested in developing a solution to CRISPR Cas9 offtarget effects.

Before IDT’s release of its Cas9 enzyme variant, chemical and life sciences firm Mil-

liporeSigma reported that it developed an alternative to CRISPR genome editing.

The new technique, called proxy-CRISPR, provides researchers with more experimental options and rapid results that can help speed up drug development, according to Udit Batra, CEO of the company.

“With more flexible and easy-to-use genome editing technologies, there is greater potential in research, bioprocessing, and novel treatment modalities,” he said. “…

MilliporeSigma’s new technology is just one example of our commitment to solving challenges in the genome editing field, and we will continue to make CRISPR research a priority.”

Most natural CRISPR systems, found in bacteria, cannot work in human cells without significant re-engineering.

However, proxy-CRISPR provides a rapid and simple method to increase their usability without the laborious need to re-engineer native CRISPR proteins, according to Batra.

MilliporeSigma has filed several patent applications on the proxy-CRISPR technology.

Other scientists have expressed confidence in IDT’s Cas9 variant enzyme.

“The IDT high fidelity Cas9 performed admirably in primary human hematopoietic stem cells. On-target editing was just as good as wild-type Cas9 and off-target events were greatly reduced,” said Dr. Jacob Corn, director of the Innovative Genomics Initiative at the University of California Berkeley.

The typically preferred method of delivering genome editing reagents as RNP complexes do not eliminate the risk of off-target editing.

“Previous attempts to make improved specificity Cas9 mutants focused on plasmidbased methods, which greatly overexpress the Cas9 protein and maximize unwanted side effects,” said Mark Behlke, chief scientific officer at IDT. “To achieve reduced off-targeting in the face of sustained overexpression, this first generation of Cas9 variants relied on mutations that compromised activity, which in turn led to poor function when used in RNP format. IDT specifically developed a mutant that performs well when used with the lower levels of protein employed with RNP delivery, maximizing safety and further reducing unwanted side effects.”

To see this story online visit https://biotechnologyfocus.ca/idt-launchescas9-enzyme-which-cuts-down-crispr-offtargets/ August/September 2017 BIOTECHNOLOGY FOCUS 25

ful

Genome

Breakthrough in regen therapy for Hemophilia A: HemAcure

A

consortium made up of several European universities and an Ontariobased biotech company reported they have achieved several breakthroughs in their work on a regenerative medicine therapy to treat Hemophilia A. People with Hemophilia have prolonged abnormal bleeding as a result of trauma.

Hemophilia A, also called Factor VIII (FVIII) deficiency is the most common form of Hemophilia and is a genetic disorder caused by missing or defective FVIII, a blood clotting protein. Severe Hemophilia occurs in about 60 per cent of cases where the deficiency of FVIII is less than one per cent of normal blood concentration. While it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous change in the gene.

The therapy being developed by international scientific HemAcure Consortium is to treat severe Hemophilia A, with Sernova Corp.’s implanted Cell Pouch device transplanted with therapeutic cells. The cells are corrected to produce Factor VIII at a level sufficient to significantly reduce the side effects of the disease and improve patient quality of life.

The Cell Pouch system is a novel implantable and scalable medical device. It forms a natural environment in the body for the housing and long-term survival and function of therapeutic cells. These therapeutic cells release necessary proteins or hormones missing from the body to treat chronic diseases as an alternative to daily administration of drugs.

This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 667421. The EU Commission awarded the HemAcure consortium €5.6 million in next-stage funding of the Cell Pouch therapy.

The consortium members include the University Hospital Wuerzburg (Coordinating Institute), Germany; IMS - Integrierte Management, Heppenheim, Germany; Università del Piemonte Orientale “Amedeo Avogadro,” Novara, Italy; Loughborough University, Loughborough, United Kingdom; ARTTIC 26 BIOTECHNOLOGY FOCUS August/September 2017

• In combination, this work is in preparation for safety and efficacy studies of human Hemophilia corrected Factor VIII producing cells in the Cell Pouch in a preclinical model of Hemophilia.

International Management Services, Munich, Germany; and Sernova Corp., London, Ontario.

The following developments have been achieved by the consortium: • A reliable procedure has been implemented to isolate and maintain required endothelial cells from a sample of the patient’s blood.

• Using a novel gene correction process, the cells have been corrected and tuned to reliably produce the required Factor VIII to treat Hemophilia A. • The cells have been successfully scaled up to achieve the required therapeutic number, and cryopreserved for shipping and future transplant into the implanted Cell Pouch.

• A preliminary study confirmed survival of the Factor VIII corrected human cells injected into the Hemophilia model, achieving sustained therapeutic Factor VIII levels.

This preliminary work is being used to aid in dosing of these cells in the Cell Pouch.

• Safe Cell Pouch surgical implant and cell transplant procedures have been developed in the Hemophilia A model in preparation for use in Hemophilia patients.

• Development of Cell Pouch vascularized tissue chambers suitable for Factor VIII producing cell transplant has been demonstrated in the Hemophilia A model, expected to mimic the predicted findings in human patients.

“The international HemAcure Consortium team members are pleased with the ground breaking scientific advances achieved at this point and are on track for this regenerative medicine solution to advance into human clinical evaluation,” remarked Dr. Philip Toleikis, Sernova president and CEO. “Sernova’s Cell Pouch platform technologies are achieving important world-first milestones in both diabetes and now Hemophilia, two significant clinical indications which are being disrupted by its regenerative medicine approach aimed at significantly improving patient quality of life.”

“This is a strong validation of the Consortium’s dedication and teamwork and the importance of this regenerative medicine approach,” said Dr. Joris Braspenning, HemAcure program coordinator.

With Factor VIII corrected cells, studies are ongoing to optimize cell dosing within the Cell Pouch and for the study of safety and efficacy of Hemophilia corrected Factor VIII cells in the Hemophilia model.

These studies support the current extensive regulatory package already assembled for the Cell Pouch in anticipation of human clinical evaluation of the Cell Pouch with Hemophilia corrected Factor VIII producing cells. “…these fundamental advancements have set the stage for further optimization and implementation of cell production processes under controlled GMP conditions,” according to Martin Zierau, IMS member consortium team leader responsible for coordination of GMP processes.

To see this story online visit https://biotechnologyfocus.ca/breakthrougprogress-in-regen-therapy-for-hemophilia-ahemcure/

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| By Wayne Schnarr

LAST word

Can Canada’s healthcare infrastructure foster effective innovation?

F

unding for innovation and commercialization should be challenging and selective. Every Canadian university, research institute and healthcare company knows the funding sources.

Governments have maze-like, mysterious and political criteria.

For philanthropic donors, the key is access and the story.

Investors may need a tax incentive to increase their risk appetite.

However, the biggest R&D pool in the world is over US$150 billion annually by the combined pharma, biotech, device and diagnostics industries. Canada’s pitch to this R&D pool needs to show it has a track record of success, the people and the infrastructure to support healthcare innovation.

I agree that Canada’s scientists can individually compete with the best in the world. However, a key question is whether our healthcare institutions can compete globally in innovation. In the table below, there are some recent numbers on the two largest Canadian universities and three of their U.S. competitors – their complete financial statements are online and worth reviewing.

A fairer U.S. comparison from the student’s perspective might be with the state universities of California and New York, but the innovation competition in the U.S. is in universities like Harvard, M.I.T. and Stanford. Maybe Canada needs some smaller, focused, researchintensive universities or institutes (think the Perimeter Institute) – with looser or minimal ties to government, not trying to be all things to all students and can readily forge alliances with industry. My cynical perception of politics says this will never happen – but then again after 50 years, the Toronto Maple Leafs have real hopes, not hallucinations, of a Stanley Cup. Research spending at Canada’s top 40 research hospitals in F2015 was CAD$2.39 billion (source: researchinfosource.com). Do the research hospitals use the funding entirely for research activities or do they set aside even two per cent for innovation commercialization?

The F2016 research budget at the University of Texas M. D. Anderson

Cancer Center was US$681 million. Does the total cancer research funding at all of Canada’s hospitals even match the funding of the bestknown cancer research centre in the U.S.? Is there any cooperation or is it all-in competition between the Canadian cancer research centres?

In rough numbers, Canada probably has between two per cent and five per cent of the R&D and commercialization funding which is available in the U.S. Since Canada cannot compete on an absolute dollar basis, it must create critical mass in the areas where it can compete internationally.

The first step is to determine where Canada can compete internationally for the next 20 years. I don’t think that analysis can be done from inside our system – too much bias and inertia. The analysis needs to include many non-Canadians or ex-pats from academia, government and industry in other countries who will be minimally biased.

Once the focus areas have been identified, critical mass needs to be created and funded. The Networks of Centres of Excellence program is a promising approach, but average annual funding of $5 million for five years is insufficient. Most federal and provincial governments distribute programs as evenly as possible across their geographies – an approach which will keep local voters happy but is unlikely to create effective critical mass.

Are Canada’s innovation engines – its universities and hospital research institutes - properly structured for effective innovation?

Wayne Schnarr is a soon-to-be retired healthcare consultant who has spent 40 years in the healthcare sector and capital markets.

His final consulting work is with Bloom Burton Inc., writing blogs and as an industry advisor.

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Table 1 Toronto

B.C.

Harvard

M.I.T.

Stanford

(CAD$)

(CAD$)

(US$)

(US$)

(US$)

Students

78,000

63,000

22,000

11,000

16,000

Annual Expenses

$2.8 B

$2.3 B

$4.8 B

$3.3 B

$4.5 B

Expenses/Student

$36,000

$37,000

$218,000

$300,000

$281,000

Endowment Fund

$2.4 B

$1.5 B

$42.4 B

$13.2 B

$22.4 B

Endowment Fund Distributions

?

?

$1.7 B

$0.4 B

$1.1 B

30 BIOTECHNOLOGY FOCUS August/September 2017

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