Bio Business March April 2016

reGional profile

new jersey maintains tradition of biopharma innovation 9

law

how cEta will affect tpp 22

analoGueS & inhibitorS dr. daniel drucker’s research leads to new diabetes drugs 25

march/april 2016

championing the Business of Biotechnology in canada

eye damaGe

anxiety & depression

diabetes

new treatments promise to combat devastatinG disease

hiGh blood pressure

heart disease & stroKe

nerve damaGe Kidney damaGe

celiac disease eatinG disorders canadian publications mail product—agreement 40063567

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inside

feature

Diabetes Deadlock

Innovative diabetes treatments, even a cure, are on the horizon, but are pharmaceutical companies willing to take a chance on them?

Growing in the Garden State

9

Known as the medicine chest of the world, New Jersey’s life sciences sector has the advantages of location, a skilled labour force and some creative incentive programs.

Championing the Business of Biotechnology in Canada

How CETA Will Affect TPP

22

The lawyers at Gowling WLG are back to give us their legal opinion on the CanadaEuropean Union Comprehensive Economic and Trade Agreement (CETA) and how it might impact the Trans-Pacific Partnership Treaty (TPP).

standard Do the flip!

to read about the role exercise is playing in diabetes research.

Editor’s note 5 canadian news 6 worldwide news 7 moments in time 25

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eDitor’s notE

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theresa rogers trogers@jesmar.com

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Mike forbes mforbes@jesmar.com

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knowlEdGE is powEr k

atie* was first diagnosed with breast cancer at age 50 in 2004. She underwent chemo and a mastectomy. She was diagnosed with breast cancer for a second time in 2014. Again, she underwent chemo and a mastectomy.

Because the first cancer had been a rare type, came at a young age, and the pathology was positive for the HER2 gene, the subject of genetic testing came up with the second diagnosis. Katie was receptive. “Knowledge is power,” she said, but appointments with genetic counsellors were hard to come by. Katie’s oldest daughter was uncomfortable with the idea and told her mom she was worried a positive connection with either or both the BRCA 1 or BRCA2 genes would hurt Katie in terms of buying and using health and life insurance. Katie dismissed those concerns, instead focused on the idea that she had to know what had caused the cancer so that her two daughters, sister, niece, and granddaughter would all be aware of their own risks and able to manage them accordingly.

Two years passed and Katie underwent an elective hysterectomy to allay her fears of cervical cancer. Finally, she received a call for an appointment. At exactly this time, her daughter’s cautiousness about receiving the genetic testing were being confirmed in the media. The Globe and Mail reported that results could not only be used against the person who had been tested, but against family members as well.

“Canada is the only country in the G7 that does not have a law in place to protect people from discrimination based on their genetics,” the author wrote. “Considering that there are more than 33,485 genetic tests available, and counting, the lack of protection affects everyone. Medical science is unlocking a database of life-saving information, but Canadians face a major barrier to obtaining that information.”

Again, Katie’s daughter pleaded with her mother not to take the test, saying all of the family members already knew enough to know their risk was elevated. None of them were planning any preventive surgeries like Katie’s hysterectomy or Angelina Jolie’s double mastectomy. And Katie had already undergone all of the surgeries she could to reduce her own risks of any related cancers occurring.

This is a huge issue as we look to unlock more genetic mysteries and use them to personalize medical treatments. This is why, in 2013, Bill S-201, Genetic No-Discrimination Act, was introduced. It is now with the Standing Senate Committee on Human Rights. If passed, the bill will make it illegal to compel a person to take a genetic test or to disclose the results of the testing.

Sadly, the Bill didn’t come soon enough to help this family. Katie cancelled her appointment and was told four people had cancelled in two days.

Knowledge is not always power, it seems. Or in Theresa Rogers these cases, power for whom? execUtiVe eDitor

Bio Business is a proud member of BiotEcanada and life sciences ontario publisher of laB BusinEss magazine Bio BusinEss magazine Printed in Canada

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oN twitter at @biolabmag oN the web at www.biobusinessmag.com oN facebook at /biolabmag

*Name has been changed to protect the innocent.

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championing the Business of Biotechnology in canada

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canadian news

Government Funds Genomic Tech Projects

Minister of Science Kirsty Duncan has announced $4.2 million in federal investment for four new projects that will use genomic technologies. The University of Alberta is collaborating with DowAgroSciences to enhance the commercial use of canola oil and meal. The University of Manitoba is partnering with Winnipeg-based Composites Innovation Centre to develop and test a vehicle prototype using a novel biocomposite made of flax fibre and binding resin. The University of Toronto is partnering with Trillium Therapeutics Inc. to realize the commercial potential of a novel therapeutic that fights cancer. The Université Laval is partnering with GenePOC Inc. to develop a new instrument that can rapidly diagnose infections at the point-of-care.

Alberta Company Sets up Biorefinery in Edmonton

Settlement sets Precedent for Genetic Testing

CHEO, Ottawa’s children’s hospital, has reached a settlement of its legal challenge with Transgenomic, the owner of five gene patents related to the potentially deadly Long QT syndrome. Transgenomic has agreed to provide CHEO and all other Canadian public sector hospitals and laboratories the right to test Canadians for Long QT syndrome on a not-for-profit basis. “This agreement will act as a model for public access to future gene patents, so that Canadian hospitals are empowered to provide access to cuttingedge genetic tests,” says Nathaniel Lipkus, a lawyer at Osler, Hoskin & Harcourt LLP. Lipkus and Sana Halwani, a lawyer at Gilbert’s LLP, represented CHEO as pro bono counsel in this case.

bio business m a r c h /a p r i l 2 0 1 6

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International Bacteriophage Study Underway

Université Laval microbiologist Sylvain Moineau will oversee the Canadian component of an international study aimed at understanding the role of bacteriophages (viruses that attack only bacteria) in the development of chronic inflammatory diseases. Increasingly compelling data indicates the composition of intestinal microbiota during childhood plays a key role in the development of chronic inflammatory diseases such as asthma, allergies and Crohn’s disease. The study will look at how bacteriophages affect the composition of intestinal microbiota.

Shannon Phillips, Alberta’s Minister of Environment and Parks, answers reporters’ questions at a recent news conference in the SBI biorefinery.

SBI BioEnergy (SBI), with funding from Alberta Innovates Bio The company uses a proprietary catalyst Solutions (AI Bio), is establishing a biorefinery in Edmonton that instead of hydrogen in its processing. It will convert non-food canola oil uses no water or chemicals and generates and waste fats into renewable no waste. In addition, the process is transportation fuels that can continuous rather than producing fuel replace or blend with conventional in batches, so further efficiencies are fuels. Using SBI’s catalytic processing technology, the process achieved. SBI is able to produce renewable creates no emissions, generates no diesel, gasoline and jet fuel. waste and costs less than other alternative fuel technologies.

The company uses a proprietary catalyst instead of hydrogen in its processing. It uses no water or chemicals and generates no waste. In addition, the process is continuous rather than producing fuel in batches, so further efficiencies are achieved. SBI is able to produce renewable diesel, gasoline and jet fuel.

“This is new technology, invented in Alberta. It comes at the right time in the right place and the market is huge,” says SBI President and CEO Dr. Inder Pal Singh, a chemist who founded the company. Alberta is currently importing 300 million litres per year of renewable diesel, primarily from overseas, to blend with conventional fuel, he notes.

In addition to AI Bio funding, SBI has received about $460,000 in support from Alberta Innovates Technology Futures. SBI has built a demonstration refinery capable of producing up to 10 million litres of renewable fuel per year. The company’s goal is to build a full-scale commercial biorefinery in the next several months that will produce up to 240 million litres per year by 2018. SBI hopes to start producing renewable fuel by the end of 2016.

worldwide news

A study of the molecular mechanism behind the rare genetic disease, Jacobsen syndrome, may have implications for autism.

Researchers at the University of California, San Diego School of Medicine and collaborators at the University of Tokyo, developed a mouse model of the disease that exhibit autism-like social behaviours. About half of children born with Jacobsen syndrome experience social and behavioural issues consistent with autism spectrum disorders.

The study, published March 16 in Nature Communications, demonstrated that the anti-anxiety clonazepam reduces autistic features in Jacobsen syndrome mice.

“While this study focused on mice with a specific type of genetic mutation that led to autism-like symptoms, these findings could lead to a better understanding of the molecular mechanisms underlying other autism spectrum disorders,” says study co-author Paul Grossfeld, a clinical professor The research was inspired by Robyn (here with her mother), the first patient with Jacobsen syndrome that the research of pediatrics at UC San Diego team learned also displays autism-like symptoms.

School of Medicine and pediatric cardiologist at Rady Children’s Hospital-San Diego.

Researchers at the University of California, Jacobsen syndrome is a rare San Diego School of Medicine and genetic disorder in which a child collaborators at the University of Tokyo, is born missing a portion of one developed a mouse model of the disease copy of chromosome 11. This gene loss leads to multiple clinical that exhibit autism-like social behaviours. challenges, such as congenital About half of children born with heart disease, intellectual disability, Jacobsen syndrome experience social and developmental and behavioural behavioural issues consistent with autism problems, slow growth and failure spectrum disorders. to thrive.

Previous research by Grossfeld and his colleagues suggested that PX-RICS might be the missing chromosome 11 gene that leads to autism in children with Jacobsen syndrome. His collaborators in Tokyo found that mice lacking the PX-RICS gene were also deficient in GABAAR, a protein crucial for normal neuron function. That observation inspired the researchers to test clonazepam, a commonly used anti-anxiety drug that works by boosting GABAAR.

Australian Scientists Discover New Ways of Finding Platinum

Until now, finding new deposits of platinum group metals was becoming increasingly difficult due to a limited understanding of the processes that affected the way they were cycled through surface environments.

Australian scientists, led by the University of Adelaide in South Australia, have linked specialized bacterial communities found in biofilms on the grains of platinum group minerals at three separate locations around the world. “This research reveals the key role of bacteria in these processes,” says lead researcher Dr. Frank Reith. “This improved bio geochemical understanding is not only important from a scientific perspective but we hope will also lead to new and better ways of exploring for these metals.”

International Partnership will Fund Arthritis Research

A Canada-Netherlands international partnership, between the Canadian Institutes of Health Research (CIHR), Reumafonds (Dutch Arthritis Foundation), and ZonMw (Dutch national organisation for health research and healthcare innovation), will fund health research in personalized treatment of debilitating inflammatory musculoskeletal diseases (such as rheumatoid arthritis, lupus, and psoriatic diseases). The partnership will also involve the creation of a network that gives researchers the opportunity to expand and strengthen their research data and resources, and stimulate collaboration among international scientists.

Japanese Researchers Develop Parkinson’s Model

Neurological disease research, such as on Parkinson’s disease, relies on animal models and immortalized neural cell lines because the central nervous system of patients is not accessible for invasive examination.

Researchers in Japan report that cultured neural stem cells could provide an alternative that is closer to the biology of the patient in question. A collaboration of researchers at universities and institutions in Japan have developed a novel protocol to culture neural stem cells derived from readily available T cell-derived human induced pluripotent stem cells (iPSCs) and demonstrated the potential efficacy of this less invasive alternative.

w w w. b i o b u s i n e s s m ag .co m

Anti-Anxiety Drug Possible Treatment for Autism

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regional profile

Growing

in the

Garden State

By hermione wilson

T

he Garden State is known for being at the heart of a large concentration of government bodies and business centres, but when it comes to the life sciences, New Jersey has proven to be much more than a middle child to cities like New York, Washington D.C., and Philadelphia. Known as the “medicine chest” of the world, New Jersey is fertile ground for biotechnology and pharmaceutical companies looking to move from proof of concept to production.

New Jersey was the birthplace of healthcare company Johnson & Johnson in 1886 and it has since become a lodestone for big bio business. The state is now home to more than 400 biotechnology companies and 14 of the world’s largest biopharmaceutical companies are headquartered there including Merck, Celgene and oncology research leader Bristol-Myers Squibb.

The state is an ideal location when it comes to the commercialization phase of a company’s development, says Michele Brown, President and CEO of Choose New Jersey. “We know that a company like Radius Health that is in an earlier point in its development has engaged in research opportunities in Boston, and some research opportunities in Pennsylvania, and yet they’re looking hard at the state of New Jersey as they move now into commercialization,” Brown says.

“We have a very long tradition of innovation and drug development,” says Debbie Hart, President and CEO of BioNJ. Because of the state’s rich life science history, there is a large pool of biotech talent companies can tap into, she says. “New Jersey has more scientists and engineers than anywhere else in the world.”

It helps that New Jersey has more than 50 higher education institutions, many of them – like Rutgers University and Princeton – among the highest-ranked schools in the U.S. “All of them are doing cutting-edge research in the life sciences,” Brown says.

Rutgers University in particular has engaged in collaborative agreements with

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Here’s why big pharma has put down roots in New Jersey

9

regional profile

researchers in the private and public sectors around the world. The school is also home to the Institute of Infinite Biologics, the world’s largest universitybased cell and DNA repository.

“We’ve done some research on the facilities that are engaged in research in our state devoted to the life sciences and more than a million square-feet of facility space is engaged at this moment in time in research in the biological and health sciences field,” Brown says.

Geographically, New Jersey is particularly well-placed for biotech and pharmaceutical companies. The state is close to important government institutions like the FDA and the National Institutes of Health (NIH) which are just a train ride away in Washington D.C., and Wall Street and the New York Stock Exchange are across the river. Because the state is fairly small, it is simple to “travel the state from one end to the other in a business day and

Hard at work at Rutgers University’s RUCDR Infinite Biologics in New Brunswick (top right), New Jersey (bottom right), and Ferring Pharmaceuticals’ facilities in Bridgewater, New Jersey (middle). Photo Credit: Choose New Jersey

bio business m a r c h /a p r i l 2 0 1 6

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The state is now home to more than 400 biotechnology companies and 14 of the world’s largest biopharmaceutical companies.

regional profile

be back in your own bed at night,” Hart says. “You can get from top to bottom in an hour-and-a-half.”

Not only does New Jersey have location and talent going for it, the state has a government that is supportive of life science business and incentive programs that encourage growth in the sector.

“Tufts [Center for the Study of Drug Development] estimates that it takes $2.6 billion to bring a drug to market,” Hart says. Most never make it and it takes 10 to 15 years, so that means generating a lot of cash. It’s a constant challenge for our companies to be out there and raising money.”

Both Brown and Hart gush about New Jersey’s Technology Business Tax Certificate Transfer Program, popularly known as the NOL program, because it allows companies to sell their net operating losses for cash.

“They sell them to a big, profitable company who is a New Jersey taxpayer and that taxpayer can buy them on a discount and apply them on their own tax return and get the savings of that tax payment,” Hart says. “It gives the biotech company an infusion of cash from the sale of their losses and they’re not giving up any ownership, any stock as a result of making that sale.”

It was Hart’s organization, BioNJ, that came up with the idea in the mid-90s as a way of adding value to their losses. It was one of the first programs of its kind, Hart says, and it has gone a long way to encouraging businesses to relocate to the state.

“It allows companies that are working toward commercialization, that haven’t turned a profit yet, to take their accounting losses for the year and sell them to the state government for cash,” Brown says. “It gives nondilutive financing to these early-stage companies that they can then use as operating revenue.”

The NOL program transaction can bring in anywhere from a couple $100,000 to $7 million, the largest incentive awarded to date, Hart says.

The foyer of Celgene Corporation’s headquarters in Summit, New Jersey. Photo Credit: Celgene

That comes to about $60 million a year, Brown says. Another incentive program the New Jersey state government offers, the Angel Investor Tax Credit program, generates $10 million a year and gives investors tax credit against their state income taxes equal to 10 per cent of an investment they make in an early-stage life science or biotech company, Brown says.

Both she and Hart credit the NOL incentive program as Celgene’s saving grace.

In 1998, the biopharma company, which has been headquartered in New Jersey since the 1980s, had “35 employees and six weeks of cash, but some pretty promising technology,” Hart says.

The company took advantage of the NOL program and managed to make a comeback by bringing back the drug thalidomide, notorious for causing catastrophic birth defects in the 1960s, and achieving FDA approval. Celgene went back to the drawing board with thalidomide and discovered that the compound was effective in treating blood cancers. “It was sort of the founding drug approval for the company,” Hart says.

Today Celgene has more than 7,000 employees worldwide and operations in about 60 countries, as well as key research facilities throughout the U.S. and in Spain.

“We have 50 unique compounds, the majority of them having different mechanisms

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Not only does New Jersey have location and talent going for it, the state has a government that is supportive of life science business and incentive programs that encourage growth in the sector.

11

reGioNal profile

and actions that are addressing unmet medical needs in close to 100 indications in the area of cancer and immunoinflammatory type diseases,” says Brian Gill, Vice President of Corporate Affairs.

Not only is New Jersey an ideal place for companies looking to move toward commercialization, with its incentive programs and ready workforce, it is a welcoming place for early-stage companies as well.

The state government funds several co-working locations across the state in urban areas where there is a lot of start-up activity, and the stateowned Commercialization Center for Innovative Technologies (CCIT) provides biotech start-ups with the facilities and the technical support they need to grow their business.

“When a small company moves into our centre, they get not only belowmarket rent, but they also get technical expert assistance by executives in residence that can help them through their projects as the move toward commercialization,” Brown says. Her company, Choose New Jersey, also holds Founders and Funders events to put those companies in contact with payers and venture capitalists.

“Everything is happening in New Jersey,” Gill says. “New Jersey represents the epicentre of the world when it comes to life sciences and is well represented in medical centres, in academia, as well as medical innovators like Celgene that are helping to change the course of human health.” BB

Bio BusinEss m a r c h /a p r i l 2 0 1 6

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top: rUcDr infinite biologics at rutgers University. Photo credit: choose New Jersey bottom: celgene corporation in summit, New Jersey. Photo credit: choose New Jersey

new Jersey Facts 400+ biotech companies

14 of the 20 world’s larGest biopharmaceutical companies $87 billion economic output linked to the biopharmaceutical sector 3,100 life science establishments

more than 50% of 2015 new fda drug approvals came from companies with a nj footprint 70,991 jobs in the biopharmaceutical sector, and an additional 251,058 jobs indirectly linked to the industry 22,000 liFe sciences Graduates annually from 63 colleges and universities, including 13 teaching hospitals and 3 medical schools

BioTalent Canada has granted over

$4 Million in wage subsidies

What can we do for you? visit www.biotalent.ca to find out

feature story

anxiety & depression

Diabetes

Deadlock Innovative Canadian research may find a cure, but is big pharma buying?

high blood pressure

nerve damage Type 2, is often characterized by a constant monitoring of blood glucose levels and insulin injections. In some severe cases, pancreatic islet cell transplantation can lead to long-term insulin independence, but it also requires the recipient to take immunosuppressants for the rest of their life.

celiac disease

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The treatment of diabetes, be it Type 1 or

15

feature storY

diabetes: A disease in which the

body’s ability to produce or respond to the hormone insulin is impaired, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose in the blood.

By hermione wilson

A

bio business m a r c h /a p r i l 2 0 1 6

16

n estimated one in 10 deaths of Canadian adults is diabetesrelated, according to Diabetes in Canada, a 2011 report from the Public Health Agency of Canada. The condition comes with a host of complications, including cardiovascular disease, chronic kidney disease and non-traumatic lower limb amputation due to diabetic neuropathy and peripheral vascular disease. There is no cure.

The news, however, is not all dire. Promising treatments and biotechnological innovations have emerged in recent years that hold out hope of a more lasting solution for those suffering with the condition. And of course, there is the search for the ultimate cure, a search that organizations like JDRF Canada (formerly known as the Juvenile Diabetes Research Foundation) are dedicated to funding.

The search for a cure A cure for Type 1 diabetes would require two things, says Dr. Robert Goldstein, Senior Advisor to JDRF Canadian Clinical Trial Network (CCTN). “You have to stop the pathologic autoimmune response and you have to replace or restore insulinsecreting cells.”

Type 1 diabetes involves a faulty immune response where the insulin-secreting beta cells in the pancreas are attacked and destroyed. Science has figured out how to suppress the immune

response, but only by suppressing the whole system. Once the autoimmune attack is halted, the race is on to protect the remaining beta cells and even stimulate the growth of new beta cells to replace those lost.

“The research is very exciting in Type 1 diabetes because we have successful samples of all of these things in animal studies and now the race is on to transfer and translate those into human studies,” Goldstein says. “The problem is... the results in the best animal models don’t always translate and the proof of concept trials often fail. Studying 30 humans is much more expensive than studying 30 mice and you can only do so many studies.”

Along with the expense, there is the difficulty of establishing the safety of treatments targeted to young diabetes sufferers. Most studies recruit participants over 18 years of age, but most people with Type 1 diabetes are diagnosed in childhood or early adolescence, long before the age of 18.

This may explain why the pharmaceutical industry has been hesitant to wade into diabetes drug development, despite the large potential market.

“There’s probably less funding across the board in the area of taking the basic research findings to the clinic,” says Goldstein. “In the earliest stages it’s a high-risk gamble and drug companies these days are, shall we say, risk-averse.

They’ll invest in something that has better data early and cheaper, and a foundation like the [JDRF] helps to fill that gap by funding some of the more innovative high-risk research at that point in the translation process [from animal studies to human clinical trials].”

Researchers at the Institut de recherches cliniques de Montréal (IRCM) are looking to improve the way Type 1 diabetics monitor their blood sugar. Dr. Rémi Rabasa-Lhoret, Director of the Metabolic Diseases research unit at IRCM, and his colleagues are testing

feature story

Dr. Timothy Kieffer (right) and his colleagues at UBC’s Diabetes Research Group are part of a global effort to convert differentiated stem cells into pancreatic beta cells.

Photo Credit: Martin Dee

a fully automated external continuous glucose monitoring device that also administers insulin to the wearer as needed, also known as an artificial pancreas.

“We take advantage of existing [insulin] pumps and existing continuous glucose monitoring systems, and we take control of the pump,” RabasaLhoret says. He describes the device like a home climate control system that monitors the temperature in the house and then heats or cools it depending on programmed specifications. The system analyzes the wearer’s glucose profile and takes control of the insulin pump to maintain a target glucose value.

Other teams around the world have more advanced versions of the artificial pancreas platform, Rabasa-Lhoret says, but the IRCM platform is unique in that it combines both insulin and glucagon.

“Glucagon is doing roughly the opposite of what insulin is doing,” Rabasa-Lhoret

says. “While insulin is bringing glucose down, [glucagon] is bringing glucose up.”

He compares the insulin-only artificial pancreas to driving a car with only an accelerator. Adding glucagon into the mix to counteract hypoglycemia is like adding brakes.

“The glucagon seems to be more interesting, but it’s also more expensive, it makes the system more complex, and we could raise some safety issues unknown until now because no one has been exposed to repeated doses of glucagon long-term,” Rabasa-Lhoret says. “Cost, complexity, and potential safety need to be weighed against the probable benefits.”

Staging a beta cell comeback Another area of diabetes research that has seen progress is the use of stem cells to encourage the growth of insulinsecreting beta cells. The lack of beta cells in the pancreas is a problem for

both Type 1 and late-stage Type 2 diabetes patients.

When insulin injections are not sufficient to control glucose levels, islet cell transplantation can be an effective alternative.

However, the islet cells are obtained from deceased donors and are therefore in short supply.

With the stem cell approach, the problem of a limited supply of beta cells is eliminated, says Dr. Timothy Kieffer, leader of the University of British Columbia’s Diabetes Research Group.

“We could make enough in one lab to treat everybody in the world,” he says.

Kieffer and his colleagues are part of a global effort to find the best way to convert differentiated stem cells into pancreatic beta cells and then protect them once they are introduced into the body of a diabetic. To get around the body’s destructive immune response, he and his fellow researchers are working on a way to transplant encapsulated differentiated stem cells just under the skin.

The encapsulation device would act like a teabag, Kieffer says. “The membranes will allow the nutrients to get inside where the [beta] cells are, and the glucose to get in, and the hormone insulin from the cells to get out through the membrane, but the immune cells that may want to destroy the cells within don’t have access.”

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Diabetes comes with a host of complications, including cardiovascular disease, chronic kidney disease and non-traumatic lower limb amputation.

There is no cure.

17

feature storY

Whether or not this will be a one-time procedure and long-term solution has yet to be determined in clinical trials.

Meanwhile, at the Ottawa Hospital Research Institute, Dr. Michael Rudnicki and his graduate students have been doing some interesting animal studies in the area of regenerative medicine. They have identified a protein called periostin that seems to be an important factor in pancreatic regeneration.

“We asked whether, if we injected periostin protein into a pancreas, we could stimulate a regenerative response, and indeed that’s what we found,” Rudnicki says.

During a long-term safety study the research team gave repetitive doses of periostin to knock out mice that lacked the protein. After six weeks of injecting periostin into the gut cavities of the mice and then aging the mice for six months, the researchers observed that the mice were leaner, had improved gluco-regulatory features and more pancreatic islets.

“What we’re pursuing right now, with JDRF support, is we’re testing periostin on human islets to ask whether they stimulate their function, stimulate their expansion, stimulate their engraftment and so on,” Rudnicki says. A possible application of the periostin protein would

Dr. Robert Goldstein, Senior Advisor, Juvenile Diabetes Research Foundation’s Canadian Clinical Trial Network

Dr. Timothy Kieffer, leader of UBC’s Diabetes Research Group Photo Credit: Martin Dee

bio business m a r c h /a p r i l 2 0 1 6

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Dr. Rémi Rabasa-Lhoret, Director, Metabolic Diseases Research Unit, IRCM

Dr. Michael Rudnicki, Senior Scientist and Director of the Regenerative Medicine Program and the Sprott Centre for Stem Cell Research, Ottawa Health Research Institute Photo Credit: The Ottawa Hospital

Roll Film In high school, Harry Gandhi worked at a diabetes clinic. “Monitoring [the condition] continuously was such a big factor,” he says. “It’s basically the next best thing to preventing the disease.”

As a student in the University of Waterloo’s Biotechnology and Economics program, Gandhi and a group of his friends started working on a contact lens that would act as a continuous glucose monitoring sensor. The project became the basis of Medella Health, a biotech company Gandhi co-founded.

Medella Health’s glucose monitor analyzes tear film, the liquid layer on the eye that bathes the cornea, in much the same way glucose levels are monitored in the blood. In fact, Gandhi says, tear film is essentially like a diluted version of the blood “minus all the crap.” “[Tear film has] no white blood cells, no red blood cells, no platelets, and that makes detection very easy,” he says.

The idea is that, instead of pricking fingers several times a day or wearing an interstitial glucose measuring devices connected to sensors placed just below the surface of the skin, a diabetic could pop in a contact lens in order to monitor blood sugar continuously throughout the day. The contact lens would connect via Bluetooth-like technology to a device worn close to the face, perhaps on a necklace or a clip, which would in turn connect to an app on their mobile phone that would analyze the data generated.

“If your glucose is jumping too high and we’re noticing that trend, or if it’s dropping too low and we think you’re going into hypoglycaemic [shock], it will create an early warning system,” Gandhi says.

Glucose levels will not be the only health indicator the contact lens will be able to monitor.

“In the future, we’re going to be able to monitor things like proteins, hormones, or small molecules that are indicative of your health,” Gandhi says. “We see diabetes just as a starting point, but really we want this to be a complete preventative data gathering system.”

feature story

be in conjunction with the Edmonton Protocol, a technique for delivering donor pancreatic islets to a patient with diabetes.

Rudnicki would also like to explore whether periostin would be helpful in the stem cell work Kieffer and his research group are doing, by augmenting the differentiation protocol. “Periostin would be a protein that enhances these process; it might increase the efficacy of these existing therapies,” he says.

Stopping MACE In a field that is racing to find a way to stop diabetes’ destructive autoimmune response and replace insulin-producing beta cells, Calgary-based biotech company Resverlogix is more concerned with the long-term complications that come with the condition.

“The problem with the industry right now is that they’re very glucosecentric... and quite frankly they’ve kind of plateaued on successes,” says

Don McCaffrey, President and CEO of Resverlogix. The biotech has carved a niche for itself by focusing instead on reducing major adverse cardiac events, or MACE, in diabetic patients.

Resverlogix’s drug, Apebetalone, which is currently in a phase three clinical trial, is being tested as a treatment for the reduction of MACE events in patients with Type 2 diabetes, with the secondary effect of reducing MACE events in patients with chronic kidney disease. Previous trials have shown a relative risk reduction of MACE by as much as 77 per cent.

For the FDA, it seems to be more important for diabetes drugs to reduce glucose than MACE events like death, heart attacks and strokes, McCaffrey says. “The FDA updated guidance from around 2008 shows that if you can show a glucose reduction of just a few per cent, but you don’t increase MACE by more than 30 per cent, that is a registerable drug,” he says. However, reducing MACE

At the Heart of Diabetes 3.4 million

people affected in Canada*

Diabetes is responsible for

1/10 deaths in Canada*

estimated cost of diabetes in canada is

14 billion*

68%

*Canadian Diabetes Association Statistics ** Heart Disease and Stroke Statistics – 2016 Update A Report From the American Heart Association.

Differentiated human stem cells following transplant. Image Credit:Tim Kieffer

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die from heart disease**

19

feature storY Type 1 diabetes involves a faulty immune response where the insulinsecreting beta cells in the pancreas are attacked and destroyed.

77% MACE RATE (%)

fewer MACE in diabetic patients

is a priority for Resverlogix and although they could go after a glucose reduction target as well, they chose not to.

The most important target for a drug company is not so much FDA or Health Canada approval, it is securing the approval of payer groups, McCaffrey says. That means having the support of government bodies in Canada, and insurance companies and health care groups in the U.S. “If a drug is approved by the FDA and payer groups just don’t believe in it, or it costs too much, the payer group is not going to do anything,” McCaffrey says. "It doesn’t matter what the FDA said.” BB

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Placedo Patient

RVX-208 Patient

RVX-208 Diabetic Patient

Major Adverse Cardiac Events (MACE) = death, myocardial infarction, hospitalization for acute coronary syndrome or heart failure.

Source: Johansson et al. Eur Heart J (2014) 35 (suppl 1): 513-850.

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“Celebrating 20 Years”

law

HOW MIGHT

CETA AFFECT TPP? By scott fostEr and patrick cashin

i

n the January/February 2016 edition of Bio Business, the opportunities that the Trans-Pacific Partnership Treaty (TPP), if ratified, might provide to biotech-related industries in Canada were described. Our analysis also included a brief discussion of the impact that the Canada-European Union Comprehensive Economic and Trade Agreement (“CETA”) might have on implementation of the provisions of the TPP. On February 29, 2016, almost immediately after the earlier article was published, the federal government announced that a legal review of the English text of CETA was complete and the text of the final agreement was published. International Trade Minister Chrystia Freeland has said she hopes that CETA will be ratified later this year and come into force in 2017.

We have reviewed the final legal text of CETA and can provide the following updates to the earlier article. We will also briefly describe some other provisions of CETA that are likely to be of interest to biotech-related industries in Canada.

PATENT TERM RESTORATION FOR PHARMACEUTICAL PRODUCTS

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As described in the earlier article, for patents covering pharmaceutical products, patent terms can be extended where “unreasonable curtailment” of the patent term occurs during the marketing approval process. A similar principle applies in Europe. The objective is to provide additional patent protection to permit the patentee to recover some of the expensive research and development costs.

Under the final legal text of CETA, the maximum additional period of protection is to be between two and five years. The Canadian government has publicly suggested that it intends to set the maximum time available at two years. In contrast, in Europe the maximum extension allowed to innovators is five years. It therefore appears that there is to be a significant difference in the period of protection available in Europe and Canada. The TPP does not state how long the delay must be before a patent is entitled to a term extension. In comparison, CETA appears to require a minimum regulatory delay of five years between the filing of a patent and granting of marketing approval to qualify for patent term restoration. This would be harmonious with the Supplementary Protection Certificate regime currently in force in Europe.

PATENT LINKAGE MECHANISMS

A company may not market a medicine, drug or biologic in Canada until that product has been approved by the issuance of a Notice of Compliance (“NOC”) under the Food and Drug Regulations.

For the innovator, this requires the submission of a New Drug Submission containing data on the safety and efficacy of the product; including the results of clinical trials which can cost (particularly when combined with the costs of drug discovery) hundreds of millions of dollars.

law

in proceedings under the regulations, should the innovator be unsuccessful and the generic’s drug approval submission be considered approvable, the minister of health is mandated to issue a noc.

COUNTERFEIT GOODS

CETA also includes several obligations aimed at curtailing trade in counterfeit goods; including enhanced border enforcement rights and more severe remedies and penalties.

These provisions will be useful to help stem the flow into Canada of counterfeit products such as pharmaceuticals, veterinary products and agricultural tools and products.

Canada has already implemented the enhanced border measures when it passed the Combating Counterfeit Products Act amending the Copyright Act, the Trade-marks Act and the Customs Act to provide the Canada Border Services Agency

GEOGRAPHICAL INDICATIONS

A geographical indication (“GI”) is currently defined in the Trade-marks Act as an indication that identifies the wine or spirit as originating in the territory, region or locality of a member of the World Trade Organization, where a quality, reputation or other characteristic of the wine or spirit is essentially attributable to its geographical origin. Under CETA, Canada will provide protection for over 173 additional terms covering various agricultural products and foodstuffs.

Examples include “prosciutto di parma” and “parmigiano reggiano”. CETA requires Canada to set up a means for rights holders to block unauthorised parties from using protected GIs and to allow rights holders to block registration by third parties of marks that are protected as GIs. A number of exceptions listed in Part A of Annex 20-A of CETA allow for different uses of certain GI-protected terms. The impact of such protection is potentially quite broad. In 2015, the Toronto Star reported that the Italian trade commissioner to Canada estimated that Canada buys $3.6 billion dollars’ worth of “fake” Italian foods yearly. Blocking use of protected terms should result in a decrease of such “fake” imports.

CONCLUSION

It is likely that as a result of the ratification of CETA, some aspects of Canada’s intellectual property laws and systems will need to change. Innovative companies in particular can expect to see enhanced protections for innovative drugs, with substantial changes in the litigation process. BB

Scott Foster is Partner, Gowling WLG in Vancouver and Patrick Cashin is Associate, Ottawa.

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In contrast, a generic drug manufacturer seeking to market a generic product only needs to file an Abbreviated New Drug Submission (“ANDS”) and establish that its product is bioequivalent to an approved drug. In this manner, it is not necessary for the generic company to invest in the expensive and extensive clinical studies.

When filing an ANDS, the generic must also address any patents listed against the innovative drug before the Minister of Health will grant an NOC. Under the Patented Medicines (Notice of Compliance) Regulations (the “Regulations”), the generic company sends a Notice of Allegation to the innovator and thereafter the innovator may commence an application under the Regulations to prohibit the Minister of Health from granting an NOC to the generic. The Regulations thus establish a link between the granting of an NOC and the patent system to summarily prevent any potential drug approvals that would also be considered an infringement of a valid patent.

In proceedings under the Regulations, should the innovator be unsuccessful and the generic’s drug approval submission be considered approvable, the Minister of Health is mandated to issue a NOC. Under such circumstances, any appeal by the innovator is considered moot as the generic company is already approved. The innovator’s only recourse is therefore to commence a patent infringement action in the courts.

The lack of an effective appeal mechanism for innovators would appear to be ameliorated by CETA, which would require that “all litigants [be] afforded equivalent and effective rights of appeal” in linkage proceedings. Thus, CETA, which aims to allow the innovator a right of appeal, will most likely require amendments to the Regulations.

and rights holders with tools to help limit the flow of counterfeit goods in or out of Canada. These provisions came into force on January 1, 2015, and are commonly referred to as the Request for Assistance Program. The Copyright Act was also amended by the Combating Counterfeit Products Act to contain provisions that criminalize the possession, sale or distribution of infringing works.

New Prohibitions also apply to those importing products which violate trade-mark rights, and these prohibitions have been incorporated into the Trademarks Act. Persons found to contravene these provisions are subject to fines of up to $1 million and imprisonment for up to five years.

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MoMeNts iN time

analoGues and inhibitors

d

r. Daniel Drucker received a 2011 CIHR/CMAJ Top Achievements in Health Research Award and was made an Officer of the Order of Canada in 2015 for conducting research that led to the development of two new classes of drugs for Type 2 diabetes. A Senior Investigator at the Lunenfeld-Tanenbaum Research Institute, Drucker studies hormones produced in the pancreas, digestive tract and brain. His laboratory researched ways to mimic the functions of the hormone GLP-1 which is made by cells in the intestine and tells the pancreas to release insulin after a meal and stop releasing glucagon, therefore lowering blood glucose.

His research led to the development of GLP-1 analogue treatments and DPP4 inhibitors, meaning they blocked the DPP4 protein from removing GLP-1 from the body. Drucker’s research has led to the creation of drugs such as liraglutide (Victoza), exenatide (Byetta) and sitagliptin (Januvia). BB

www.diabetes.ca/research/progress-in-research

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Photo credit: Mount sinai Hospital, sinai Health system

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