The Year of Results

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By Amber Lepage-Monette

In chairman and CEO David Allan’s eyes, YM BioSciences Inc.’s (Mississauga, ON) time has come.
Allan says the company, which was created in 1994 specifically to translate university research into commercial products, has never gotten its due. “YM has been plagued by (an) absence of recognition,” he says.
But he doesn’t expect that to be the case for much longer.
2006 is shaping up to be a busy year for the company, which is expecting to initiate, enrol patients, or obtain results for at least four clinical trials over the next twelve months.

From the Beginning
For Allan, one of the main reasons behind YM’s life in the shadows is its origins.
YM BioSciences licensed its first few products from the University of Havana (Havana, Cuba) — one of which, nimotuzumab (TheraCIM h-R3), the company still has.
Despite the fact that its lead drug hails from Canada, and that it never specifically set out to focus on Cuban products, the company can’t seem to shake that story.
“Do you think anybody ever asks me about whether I go to Winnipeg?” Allan says. “Never.
“The tragedy of the Cuban connection is the fact that it’s exotic, and the fact that it has this history, and the fact that there’s this embargo from the United States (that) gets in the way of the science,” Allan says.
“The YM model had nothing to do with Cuba,” he explains. “The YM model had to do with good science. It just happened that we found some in Cuba.”
YM’s business model is a simple one: no basic research. Though this may seem obvious and even commonplace now, Allan says that wasn’t the case in when YM was getting started.
“Years ago when I founded this company, analysts would say to me, ‘But that’s not a real company, that’s not a real business because you’re not doing anything’,” he says.
Despite what naysayers thought, Allan stuck to his no-research guns. Given the failure rate in the early stages of drug development, it seemed like an obvious choice.
“Basic research is a very dumb business,” Allan says. “It’s very important to society, but it’s a very poor odds-on business.”
Not only are the often-cited numbers of potential drugs actually making it to the market in the range of one in every tens of thousands, basic research is a large battle ground Allan says he didn’t want to face.
The amount of money spent each year by research institutes and councils such as the Canadian Institutes of Health Research (Ottawa, ON), the Natural Sciences and Engineering Council of Canada (Ottawa, ON), the U.S. National Institutes of Health and the Medical Research Council (London, U.K.) is too high to compete with, he says.
“The NIH (spends) $28 billion a year, $6 billion of which is on basic research in cancer alone. So here we have $6 billion a year spent at Stanford, Harvard, Yale, you name it, and I’m supposed to go up against that with a small biotech company with three or four people sticking unknown molecules into rats and mice,” Allan says. “I don’t think so.”
Though their business plan eliminates the early-stage risk, getting a product to market can still be a long and tedious road. The company continues to face challenges when deciding which candidate to license in.
“It’s actually an impossible process,” Allan says of selecting a potential success. “I mean, if it weren’t, then everybody would get it right. But the fact of the matter is that nobody gets it right. Nobody.”
Luck is an incredibly big part of the equation, Allan says — but when luck doesn’t come through, he puts his money on diversification.
“Nobody buys one stock. We don’t invest in one drug,” he says.
Diversifying not only broadens the company’s portfolio, but in an indication such as cancer, it just makes sense. Cancer, Allan says, is not one disease, but 200 diseases that can never be treated with a single approach.
Another bonus that comes with licensing versus basic research is objectivity.
“Because we’re not married to anything — it’s not ours, we didn’t invent it — our job is to make it work, and to see whether it works, and if it doesn’t, we give it back,” Allan says.

Unbelievable
Quite coincidentally, YM ended up licensing in its lead drug, tesmilifene, because someone else gave it back.
The drug — discovered at the University of Manitoba (U of M) (Winnipeg , MB) and originally licensed by Bristol-Myers Squibb Co. (New York, NY) — had undergone a Phase III trial in metastatic and recurrent breast cancer run by the National Cancer Institute of Canada (Toronto, ON).
The trial was considered to have failed because tesmilifene did not meet its primary end point — which was difference in response rate and progression-free survival — and Bristol returned the licence to U of M. YM licensed the drug in January 2000.
Bristol looked at the response rates and returned the drug before the trial was complete, Allan explains.
By the time it was completed, the results showed that, despite there being no difference in response or progression-free survival rates between tesmilifene and the currently accepted treatment, there was a difference in overall survival rates for some of the women in the trial.
Of the two arms — chemotherapy alone, and chemotherapy in combination with tesmilifene — women in the combination arm lived 50 per cent longer than women in the chemotherapy-alone group.
Despite this good news, Allan says the results were a bit too difficult for some to swallow.
“Here you had twice as good (results) with a drug that had been returned by a major pharmaceutical company — so surely they must have known something that these guys don’t — and picked up by a private company in a town called Mississauga, ” he says. “We either had to have made it up, or it must have been a fluke or there must have been some other reason other than the drug for that benefit.
“The trial was perceived to have been a failed trial because it failed its primary end point,” Allan says. “As it turns out, the drug didn’t fail. It was the wrong primary end point.”
The company now knows that tesmilifene works by knocking out multiple drug-resistant cells, allowing chemotherapy to target cancers that it would not otherwise affect. Multiple drug-resistant cells correlate with what are known as aggressive clones, which comprise a small part of a tumour mass.
Killing the aggressive clones does not greatly affect tumour size, which accounts for why the original end point did not prove successful. However, aggressive clones correlate with rapidly progressing disease. With this knowledge in hand, YM now knows that tesmilifene only benefits women with rapidly progressing cancer.
The company currently has tesmilifene in a pivotal trial — for which they received a special protocol assessment from the U.S. Food and Drug Administration (FDA) — that is focused on survival benefit.
The FDA has allowed YM to conduct sequential analysis, which allows the company to assess results and submit them at various points in the trial, instead of waiting until its conclusion.
“So what they’re saying is that they will permit the drug to be approved on smaller numbers if the benefit’s larger,” Allan says.
The company expects to submit the preliminary results to the FDA this summer.

Busy Times Ahead
And that’s just one trial the company is involved in.
Nimotuzumab, the drug originally licenced from the University of Havana, is currently in a Phase II trial for metastatic pancreatic cancer, as well as an ongoing phamacodynamic study, and has completed Phase II trials in head and neck cancer, and pediatric brain cancer. A pivotal study in pediatric brain cancer is expected to begin early this year.
The company also started a Phase IIb trial at the beginning of December for its fentanyl-delivery product, AeroLEF™, which it received as a result of its acquisition of Delex Therapeutics Inc. in May 2005.
YM is also collaborating with Sanofi-Aventis (Paris, France) on a combination Phase II trial for Sanofi’s breast cancer drug, Taxotere® with tesmilifene.
With all of this activity, it’s no wonder YM earned a place in the Ottawa Life Sciences Council’s (Ottawa, ON) Top 10 at last November’s BioNorth conference — receiving honours in the Emerging and Late Stage category.
For Allan, it means finally getting some of that well-deserved recognition.
“I think it’s really important,” he says.
“I understand why we would be greeted with some doubt in the Canadian community,” he goes on to explain. “We had a unique model, we had things that people had never seen before . . . and a major pharmaceutical company returned a drug that YM picked up.”
Allan knows, however, that he isn’t just tooting his own horn, and that the coming year will bring others around.
“Ultimately the data will be the data,” he says. “And so much of it is coming very soon.”