How a U of A spinoff company beat the odds to create a new kind of cancer treatment

A University of Alberta spinoff company is looking to raise millions of dollars from investors in a bid to further test its promising anti-cancer drug through Phase 2 human trials. 

Pacylex Pharmaceuticals was formed in 2012 by three U of A staff members. The company was recently named 2024 Company of the Year by BioAlberta. The intervening 12 years tell a story of teamwork and community support that have moved a treatment first envisioned in a U of A lab steadily toward becoming a commercially available drug to help cancer patients around the world. 

“We want to let people — donors, investors and other investigators — know that it is possible to do translational research in Alberta, that you can go from the idea, the results in the lab, and translate that into a medicine that can be used by patients,” says company co-founder Luc Berthiaume, professor in the Department of Cell Biology, member of the Cancer Research Institute of Northern Alberta and chief scientific officer of Pacylex.

Pacylex is the first in the world to develop a new class of drugs — N-myristoyltransferase inhibitors — that preferentially kill cancer cells. 

The company’s lead drug candidate, zelenirstat, delivered orally as a once-a-day pill, has completed Phase 1 trials in Canada, and has been shown to be sufficiently safe to continue clinical development with evidence of potential efficacy against blood and solid tumour cancers. 

The odds are against any new drug getting to this stage, according to co-founder John Mackey, professor emeritus of oncology, founder of the Alberta Pre-Phase 1 Cancer Program and chief medical officer of Pacylex.

“Bringing new ideas to the clinic is not easy,” Mackey points out. “It’s time-consuming, it’s difficult, it requires a team that includes good scientists, willing patients and clinicians who are devoted to advancing their field. And there was a community of donors and investors that made it possible to do this for a small U of A spinout company.

“It was very much a team effort.”

Pacylex has been supported over the years by Brent Saik’s World’s Longest Games charities, the Alberta Cancer Foundation, the Cure Cancer Foundation, Alberta Innovates and the National Research Council of Canada Industrial Research Assistance Program.

“I did not expect it to take this long, but this time frame is on trend for pharmaceutical startups,” says co-founder Ryan Heit, who was a research assistant for Berthiaume when the company first formed and is now vice-president of operations.

Heit coins a phrase when he sums up Pacylex’s current position: “It’s fraught with potential.”

Uncovering cancer’s weakness

Myristoylation is a natural process that attaches a fatty acid (myristate) to proteins in cells. It’s a necessary step for building growth signalling pathways, regulating metabolism and other biological processes, but it can lead to the development of cancerous tumours when it doesn’t work properly. The Pacylex treatment capitalizes on an unexpected weakness in that process that was uncovered at the U of A. 

Erwan Beauchamp, now director of discovery biology at Pacylex, was a postdoctoral fellow in the Berthiaume lab after doing his PhD in France on the role of myristoylation in nutrition. Beauchamp was testing blood cancer samples — partly because they were easier to acquire from patients than solid tumour samples — looking for potential defects in the two key enzymes known to be essential to myristoylation, NMT-1 and NMT-2. 

“The dogma at the time was that those enzymes were overexpressed in cancers, but when I looked at the hematological samples of leukemia and lymphoma, I found that NMT-2 was missing,” remembers Beauchamp. “Because these results were a surprise, I knew Luc would tell me to redo the analysis. You have to show that the science is reproducible.” 

By the time he showed Berthiaume his results, Beauchamp had already repeated the experiment three times, just to be sure. “That was the moment when we thought, ‘OK, something is different and we can work on that.’”

The concept was simple: Take advantage of that important weakness in the cancer cell caused by the missing enzyme, target the other enzyme to disrupt the tumour’s signalling system and metabolism, and stop the growth while sparing normal cells. 

Berthiaume reached out to the University of Dundee in Scotland, where researchers had identified compounds with myristoylation-inhibiting capabilities. Though they were originally intended to treat African sleeping sickness, Berthiaume thought some of the NMT inhibitory compounds could also have cancer-fighting properties. After demonstrating this was correct, the team purchased licenses for 503 related compounds, focusing their initial efforts on one compound that seemed to hold the most promise — DDD84681, which became Pacylex’s first drug, PCLX-001.

Heit, another young scientist in Berthiaume’s lab at the time, was also working on his MBA. His ability to straddle the worlds of science and business provided a critical bridge that led to the formation of the company. Heit introduced the cell biologist with the big idea — Luc Berthiaume — to the cancer clinical trials expert who could help develop its potential impact for patients — John Mackey — and Pacylex was born. Beauchamp returned to France to take on an assistant professor job at his alma mater but would return two years later, drawn back by the opportunity to push the boundaries of his field with Pacylex.

Working together, Berthiaume, Mackey, Heit and their newly recruited CEO, Michael Weickert, connected the company with critical angel investors from the community, who also saw the urgent gap this new drug could fill. After years of work on cell lines, patient blood samples and animals with cancer, the team was ready to begin Phase 1 clinical trials in humans by 2020. At that point, the drug was renamed zelenirstat under the World Health Organization’s drug naming protocol.

The Phase 1 clinical trial in Edmonton, Toronto, Vancouver and Montreal was conducted on 42 patients with both solid tumours and blood cancers. Most had only months to live and were no longer receiving any benefit from conventional, approved treatments, so they were willing to enrol in a clinical trial. Results showed the drug can be administered safely without significant side-effects and zeroed in on the most effective dose for the next round of trials. There were hopeful signs of efficacy, which are not always seen in Phase 1 trials. One patient received the drug for a year and a half, and several took it for six months or more. 

“I’m very hopeful because there are patients at the Cross Cancer Institute who did better with this treatment than they did with three or four other lines of treatment,” says Beauchamp. “We are helping those patients who had no other alternative and so it feels great.” 

Second mechanism of action revealed

Research to understand why the drug works continues in Berthiaume’s cell biology laboratory at the U of A. A recent discovery surprised even Berthiaume, who has been the driving force behind the science from the beginning. In a recent paper, the team reports on a second mechanism of action, beyond the interference with cell growth signalling processes, that makes the drug so effective. 

“In that study, we show that the drug prevents the cells from efficiently using their mitochondria to produce energy, a process that requires oxygen,” explains Berthiaume. “So basically we’re not only telling the cells to die with our drug, we’re also suffocating them by preventing their use of oxygen.”

Another paper published last spring includes a list of 54 genes in tumours that are most sensitive to myristoylation inhibition, essentially providing a personalized signature to predict how well the drug would likely work on individual tumours. Once validated in humans, a test measuring those 54 genes in tumours could help identify patients who stand to benefit the most from the treatment.

The lab’s new sensitivity signature shows that the most aggressive cancers that are likely to respond to zelenirstat are lymphoma and acute myeloid leukemia (AML), a blood cancer with a five-year survival rate of less than 30 per cent. Thanks to a grant from the U.S. Department of Defense, AML patients at MD Anderson Cancer Center in Houston, Texas, will be enrolled in a new Phase 1 trial of zelenirstat.

“AML is a hugely unmet medical need,” says Mackey. “Unlike some other cancers where you can have five or six or even 10 or 15 approved drugs, for AML patients there are very few drugs after the first-line cocktail fails, so there’s a dire need for new treatments.”

The hope is that if zelenirstat shows the expected cancer-killing results, it could receive accelerated approval for distribution to AML patients in the U.S., and then eventually in Canada and globally.

Competition inspires innovation

They say that imitation is the sincerest form of flattery. A competitor has arrived on the scene for Pacylex. Myricx Bio, based in London, England, is also raising funds for trials of its own myristoylation-inhibiting treatment using the latest technology in delivering cancer drugs — antibody drug conjugates (ADCs). ADCs deliver their payload drugs directly to a specific target such as a tumour. 

Using different compounds than those owned by Pacylex, Myricx Bio drugs have not yet been tested in humans, meaning Pacylex has about a three-year lead. Still, the British competitor has managed to raise more than US$100 million from backers such as Eli Lilly, Novo Holdings, Sofinnova, Brandon Capital partners and the National Bank of England. 

Rather than viewing the new competition as a threat, the Pacylex principals welcome the newcomer. For one thing, it validates their approach of using myristoylation inhibition as a cancer treatment, a fact that may give investors more confidence. Breaking completely new ground can be scary, even for venture capitalists. It’s also demonstrated there may be advantages to ADC development for Pacylex. 

“People think of competition as a threat, but in our case, competition opened the door to an area that we were not pursuing,” says Pacylex CEO Michael Weickert, who was hired for his 30-plus years in the drug development business. 

“We were not doing ADCs because our compound is safe enough to use without putting it on an antibody,” Weickert explains. “We figure Myricx’s compound might be too toxic to use on its own, so they put it on an ADC and got good preliminary pre-clinical results on solid tumours with this strategy. That tells us that if we put our compound on an ADC, we will also likely be very effective against solid tumour cancers.” 

Knocking on doors

It is now Weickert’s top priority to knock on every door he can think of looking for backing for Phase 2 and Phase 3 trials for zelenirstat. He says it will take at least $100 million to develop a commercially ready product, assuming the drug passes all the tests of safely treating cancers and providing better outcomes for patients than existing treatments. Weickert is travelling across Canada and the U.S. to meet with philanthropic families, pharmaceutical companies and venture capitalists, asking them to help support the next step in Pacylex’s grand project. 

“Our safety profile is relatively benign compared with most chemotherapeutic drugs,” he told NPR’s BioTech Nation. “We kill lots of different types of cancers because we hit multiple different cancer processes simultaneously. Most other drugs are hitting one process at one target, with one specific action.” 

Mark Huson, professor in the Department of Finance and the Dianne and Irving Kipnes Chair in Finance and Development, has served as an adviser to Pacylex from its early days and has been on its board since 2020. An expert in venture capital, Huson is also academic director for the Creative Destruction Lab-Rockies at Calgary’s Haskayne School of Business. Huson notes that the outlook for pharmaceutical fundraising is not rosy at the moment, thanks to everything from geopolitical uncertainty to the relatively high interest rates that can be earned by putting money in safer investments. 

“A great idea is a great idea,” Huson points out. “A great idea with capital is a company.” 

The Phase 1 trials were financed with about $20 million, so this ask is exponentially greater. But it’s not as risky as earlier investments because of the promise shown by the drug in Phase 1. As all the team members will tell you, the results just keep getting stronger, so they are bullish that Pacylex will find the funds and get through the critical next steps of Phase 2 clinical trials. 

“The point is we need to get this drug into people, and that takes time and it takes resources,” says Mackey. “The more resources you have, the less time it takes and the more people we can help more quickly. We’re thrilled that we’re in the position where we are looking to expand the development of zelenirstat, and we’ll do so aggressively depending on the amount of money we have.”

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