Amazing Journey

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By Patricia Nicholson

After a decade-long journey, the destination is coming into view for Pieter Cullis, PhD.

Cullis is founder, senior vice-president of Research and chief scientific officer of Inex Pharmaceuticals Corp., a Burnaby, B.C.-based company that is nearing the end of the long clinical trial process for its anticancer therapeutic Onco TCS.

Cullis founded Inex Pharmaceuticals in 1992 to commercialize the research he was doing at the University of British Columbia (UBC) (Vancouver, BC) on lipid-based carriers, or liposomes, for drug delivery.

“It was really the drive to make sure that these things that we developed in the laboratory were actually going to be used thera-peutically that drove me,” Cullis says of the impetus to go from lab to startup. “A good way to get something that you really believe in all the way through to the clinical setting is to be part of that commercialization process.”

Special Delivery

Onco TCS is the lead product in Inex Pharmaceuticals’ Targeted Chemotherapy platform, which combines approved cancer chemotherapeutics with the company’s proprietary drug-delivery technology, Transmembrane Carrier System (TCS).

“In essence what we’ve done is encapsulated the drug vincristine in a liposomal system,” Cullis says. Vincristine is a widely used, off-patent chemotherapy drug. “The liposomes are very small entities. They’re one one-hundreth the size of a red blood cell, and as a result they can get pretty much everywhere. Vincristine, the free drug, will get removed very quickly from the circulation. But when it’s encapsulated in the liposome it will circulate around with a much longer half-life.”

Cullis explains that the staying power and small size of the carrier system, combined with the liposomes’ tendency to accumulate around the leaky vasculature associated with tumour sites, means that the drug will preferentially partition at those sites. He adds that vincristine is a cell-cycle-specific drug, so retaining it at a tumour site for a longer period helps ensure that it will hit the sensitive part of a cell’s cycle — in this case, mitosis and cytokinesis.

Building a platform approach stemming from its TCS technology has several advantages for Inex Pharmaceuticals. Among these, Cullis says, is the ability to use the same manufacturing approach for several different liposomal drugs.

“But the more profound advantage is the active ingredients that you have inside the liposome,” Cullis says. “In other words, the drug that you’re encapsulating has already been used clinically . . . So it’s quite a familiar agent in terms of the possible dangers and the possible utility of the drug . . . It’s also useful in terms of doctors themselves, because they all tend to view these formulations as being improved versions of something they’re quite familiar with.”

Inex Pharmaceuticals is now in the final phases of preparation for filing a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for Onco TCS in the treatment of relapsed lymphoma.

“We’re getting close. The whole company is totally energized to get this filing done at the moment,” Cullis says.

The pivotal Phase II/III clinical trial that provided the data for the NDA was completed last fall. Inex Pharmaceuticals intends to file with the FDA late in the third quarter or early in the fourth quarter of 2003.

“It’s quite amazing,” Cullis says of the current corporate atmosphere, where a large percentage of the company’s approximately 190 employees are now focused on the NDA for Onco TCS.

“One hundred and sixty people working in total unison trying to get one massive document out the door is really an education for me, that’s for sure, because I never conceived that it would be that much work to get a drug through to being clinically accepted,” he says. “As a scientist, one tends to think that if you can cure a few animals, well gee, from here on it’s very straightforward. Well that’s absolutely not the case. It’s an amazing journey that one has to go on after that.”

Switching Sciences

Cullis began working in biochemistry only after he had developed expertise in another science. When he graduated with a PhD in physics from UBC, Cullis says he already knew he didn’t want to continue in that area. There were a number of reasons for this, but he says one of the most compelling was that the grass looked greener in other fields.

“The opportunities in the life sciences seemed inherently much more exciting, even though I didn’t know anything about biology or biochemistry or even some of the basic organic chemistry that’s required to understand some of these things,” he says. “So I decided that one way or another I was going to break out of the physics environment.”

Cullis applied to what was then known as the Canadian Medical Research Council (now the Canadian Institutes of Health Research (Ottawa, ON)) for a post-doctoral fellowship in the biochemistry department at Oxford University (Oxford, UK).

“I was as amazed as anyone when I actually won that, because I’d never been in a biochemistry department before I got there to do my post-doctoral work. The reason that I managed to make that switch was because my physics research was utilizing a technique known as magnetic resonance,” he says. “It’s a very useful technique in chemistry, but particularly in biochemistry or biology because one can use it to understand quite directly some of the molecular processes that are going on in living systems. So that was my entrée — I was an expert in the technique, and then I got more interested in some of the applications than the technique itself as time went on.”

Physics’ loss was life sciences’ gain, and following his fellowship at Oxford and a stint in Utrecht, Holland, Cullis made his way home to Vancouver, where he joined UBC as an assistant professor in 1979. Since that time, Cullis has won various accolades, including the 1991 B.C. Science Council Gold Medal for Health Sciences, the Alec D. Bangham, MD, FRS Achievement Award in 2000 and the B.C. Biotech Innovation and Achievement Award in 2002.

The trip back to the city where he was brought up was quite deliberate. While still at Oxford, Cullis was invited to apply for a position in Omaha, Neb.

“I went to look at a map and I realized this place was almost equidistant between the Pacific Ocean and the Atlantic Ocean. And the thought of actually living that far from the sea was something that didn’t exactly appeal to me,” he says. “I thought, gee, maybe I’d better start thinking about where it is I want to go as well as what it is I want to do. So I made an effort to get back to Vancouver, and luckily that worked out.”

Luckily in many ways, because in addition to great scenery and strong academics, UBC is known for the excellence of its technology transfer division, the University-Industry Liaison Office (UILO).

“The biotech industry in Vancouver is quite strong, especially when you think of it on a per capita basis,” Cullis says. “And that is very largely due to the efforts of the UILO, and the help that it will give to academic investigators in their quest to see the applications of their research realized. It has been very helpful to me as well as other people.”

Team Spirit

Cullis still splits his time 50-50 between UBC and Inex Pharmaceuticals. The dual roles complement each other, he says, because the basic research done in his UBC lab has similar directions as the applied research done at Inex Pharmaceuticals. But combining roles has other advantages as well.

“One of the really enjoyable parts of business as opposed to academia is the need to work in the business environment with more of a team approach,” Cullis says. “Academia as a whole is a bunch of rather separate enterprises led by individual faculty members, and so there isn’t that overall team spirit that one can be part of in a company.”

Building — and keeping — a winning team is something that Cullis says Inex Pharmaceuticals has accomplished admirably.

“I’ve been particularly lucky in that regard,” he says, adding that many of the original people that were involved in the early development of the company’s technology have stayed with Inex Pharmaceuticals.

“That’s one of the major strengths of Inex: I think in the area of liposome technology in general, we can lay claim to be certainly well up there — if not leading the world — in this regard. So that’s been a challenge that we’ve met really successfully: keeping a core of people together that have very considerable expertise in this area. And then building on that with getting the right sort of management team in place that can fulfil the other functions, whether they’re on the management side or whether they’re on the business development side, the clinical side, et cetera.”

Cullis says some of the biggest challenges in bringing Onco TCS this far have been the classic hurdles faced by all biotech companies.

“The really huge challenge is the sheer amount of money that it takes to get a drug through to having the potential of being approved. We’ve raised over $100 million since 1992, and a good proportion of that — the lion’s share — has gone toward the development of Onco TCS,” Cullis says. “Obviously in order to raise that level of money the investors have to be reasonably confident that there’s at least some potential of a good return. So in many ways I have found that a very challenging sort of process: playing on that interface between the science and also the very commercial considerations of investment.”

Cullis has met that challenge by knowing his priorities and his strengths.

“The main thing is to realize one’s limitations. If you try to do all of these things it becomes impossible, and one of the things that I don’t want to let go of is the science side or the research side of the organization. I think, for example, in order to be a CEO that one in essence has to be a full-time CEO. You can’t say you’re going to be a scientist part of the time and a CEO the rest of the time,” he says. “Aside from anything else, that’s not my background. So the challenge there is to develop a company in which all the complementary people with complementary expertise are present, and also people that you enjoy working with as a team.”

After navigating the obstacle course of clinical trials, Cullis and his team are now focused on reaching the finish line for Onco TCS.

“It’s a really exciting time,” Cullis says. “Not just for me but also for all the rest of the company, because there’s a tremendous number of people here who have devoted a very significant part of their lives to try to get this drug through the regulatory and clinical process.”