FAMILY TIES

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By Amber Lepage-Monette

It’s all relative at Xenon Pharmaceuticals Inc. (Burnaby, BC). Or, perhaps more accurately, it’s all related.

Not only does this drug-development company deal with gene discovery to develop therapeutics, but historical, family connections exist for its co-founders as well.

For company president and CEO Dr. Simon Pimstone, PhD, becoming a third-generation South African physician was all in the family — following in the footsteps of both his late father and grandfather.

And even in coming to Canada, Pimstone could not escape his South African roots.

In 1994, during his move to begin a clinical research fellowship in cardiovascular genetics at the University of British Columbia (Vancouver, BC), Pimstone met with other researchers in his field to feel out the opportunities in Vancouver.

When he met with prominent genetics researcher Dr. Michael Hayden, PhD, the two discovered that not only had Hayden received his medical training at the University of Cape Town (Cape Town, South Africa), Pimstone’s alma mater, but also that Pimstone’s father had been Hayden’s teacher.

Juggling Act
Their shared research interests and historical connection paved the way for Hayden to offer Pimstone a job in his lab, where the two began collaborating on genetics projects. The pair’s most significant project, and the one that led to the establishment of Xenon, was the identification of a gene that regulates high-density lipoprotein (HDL) cholesterol — also known as “good” cholesterol — in humans.

That was a busy time for Pimstone. The clinical research fellowship he started in ’94 ended up becoming a PhD in cardiovascular genetics, which he received from the University of Amsterdam (Amsterdam, the Netherlands) in 1998. From 1997 to 2001, Pimstone had to complete an internal medicine residency, in essence redoing much of his post-medical training in order to comply with Canadian regulations. On top of all that, he and Hayden started Xenon in 1996 — though Pimstone says the company operated as a virtual shell doing contract research until 1999, when it received its first official financing.

“There was one stage where I was doing my PhD, my internal medicine residency, plus starting the company — it was crazy,” Pimstone says. “Each was more than one full-time job, so it was a busy time in my life.”

The HDL gene identification was what got Hayden and Pimstone moving toward commercialization.

“It made the front page of the Vancouver Sun, and it was big news in the scientific community,” Pimstone says. “That was really the precipitant for the company’s first financing.”

But their discovery wasn’t the only thing that helped launch Xenon into a true business. Timing, as always, was everything.

“It was a very exciting time in genetics, with the work that was being performed on sequencing of the human genome, and also the development of technologies, including computational platforms and bioinformatics,” Pimstone says. “And with these opportunities, there now existed a real opportunity to identify genetic mechanisms of disease more rapidly than ever before. And, that there would be a real push to translate those discoveries into new therapeutics by the industry.”

Gene Mining
Through academic collaborations, Xenon studies families and founder populations from Canada and around the world, including areas such as Quebec, Newfoundland, South Africa and the U.S. By studying these genetically homogeneous populations, Xenon has identified 17 functionally validated genes to date using comparative genomics.

“You can identify more readily when a gene is mutated that results in a disease, and that’s why the study of diseases in founder populations has been successful for many geneticists,” Pimstone says.

Not only does Xenon study multiple founder populations with the same disease, but it also takes part in what it calls “extreme genetics,” studying rare families that have extreme forms of a targeted disease. Additionally, the company looks at “opposite phenotypes” by studying families with phenotypes that are opposite of the disease in question.

The company then uses that information to develop novel therapeutics through traditional, small-molecule drug development.

“This holds the promise for the development of therapies that are far more specific, and we believe therefore would be more efficacious, with fewer side-effects because they are based on the fundamental molecular mechanism of that disease in humans,” Pimstone says.

In the last couple of years, Xenon has begun a transition, moving from a drug-discovery company to a clinical-development and commercialization company, a change that is most clearly highlighted by its recent name change from Xenon Genetics to Xenon Pharmaceuticals.

Pimstone says that Xenon sees this evolution occurring in two ways: both through partnerships with other pharmaceutical companies and by developing its own programs.

An excellent example is Xenon’s lead program in obesity, which is currently in preclinical development, and is expected to move into the clinic next year, Pimstone says.

The company recently signed a research, development and commercialization deal worth $157 million US with Novartis Pharma AG (Basel, Switzerland) for its SCD1 obesity program. Novartis has gained royalty-bearing, worldwide rights to products in the SCD1 program, though Xenon will retain an option to co-promote in certain territories. For the research portion of the deal, Novartis will fund Xenon researchers for a minimum of two years.

Leading Role
Though the company’s therapeutic programs are moving along positively now, there were, of course, hurdles in the early days of the company’s establishment, Pimstone says.

Despite Hayden’s background as founder of a previous gene therapy company, and Pimstone’s experience running a company that sold clothing to retailers in South Africa to pay for his university education, neither had formal financing or business development experience in biotech, Pimstone says. Frank Holler was hired as the company’s CEO, a post he held until last June. Holler remains on the board of directors.

Prior to joining Xenon, Holler had served as president, CEO and co-founder of ID Biomedical Corp. (Vancouver, BC) and was a founding director of Angiotech Pharmaceuticals Inc. (Vancouver, BC).

“I really consider Frank a co-founder in this company as well, as he really brought the early expertise neither Michael nor I had,” Pimstone says.

When the company first started out, Pimstone worked only part-time with Xenon. In 2001, he took over the roles of president and COO. When Holler stepped down as CEO last year, Pimstone took on that role, and now serves as the company’s president and CEO.

“My interest, really, was to have an opportunity to participate at a senior executive level in a biotech company like Xenon,” Pimstone says of his decision to take on the role of CEO. “And Frank Holler, as he transitioned out from his role, it seemed like a natural transition for me to be given the opportunity to take on the leadership of the company.”

Though working at a management level is very different than his previous medical and research training, Pimstone says his medical background turned out to be very relevant to his leadership position.

“You’re very used to dealing with people, you’re very comfortable with managing crises, managing stress,” he says.

“I think many physicians go into that career because of their natural bent toward people, and I think running a company is not that different in that regard.”

At Xenon, Pimstone says he is in a privileged position to be able to combine all of his interests: medical, research and business.

“I’m able to run a company, with great management colleagues and staff in the company, that is focused on delivering novel medicines to treat patients based on research that I deeply understand,” he says.

Hayden has chosen to remain in the role of CSO, and though his position isn’t quite as management-driven as Pimstone’s, Pimstone says they both contribute to all facets of the company. Both are still very involved in the research and the business sides of running the company, each as needed, he says.

“It’s not like this is a clear separation,” Pimstone explains. “There’s of course some overlap that we each have our respective focus, and there’s a great level of comfort in that we understand each other and the decisions we’ll make very, very well, having worked so closely with each other now for 10 years.”

That comfort is an important aspect of their relationship.

“Both Dr. Hayden and I know and understand each other so well, and we’ve worked together so well as a team, that we really, in most instances, represent the same voice,” Pimstone says.

In establishing Xenon, these co-founders were like-minded in what they wanted to achieve, as well.

“We needed to find a vehicle to apply the resources to identify these completely novel therapies that we hope and believe will transform medicine. And this, for us, was the true promise of molecular medicine,” Pimstone says. “(It) was one that we wanted to be part of. Both Michael and I, being physicians at heart and having spent years treating patients with different diseases, we felt that there was no greater privilege in being able to use our skills to translate these exciting discoveries into medicines that could cure and heal.”