Cancer Drug Ingenuity – New Source, New Drug, New Issue

A small Canadian firm’s journey from independent, successful startup to struggle for subsistence

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BY DEBORAH KOMLOS

Brigitte Kiecken and her colleagues were greeted by more than a pleasant whiff of the forest when they introduced a local plant to their lab: an unanticipated whirlwind of both exciting and unsettling events ensued.

President and chief administrator of St. Catharines, Ont.-based Biolyse Pharma Corp., Kiecken, along with her team, had then been functioning as Pelagique Laboratory, a privately run firm begun 25 years ago on the Gaspé coast in Port Daniel, Que. The company had found a niche to fill and decided to channel its efforts into developing purified concentrates from naturally based extracts. Specialized chromatography technologies were devised and aside from pursuing ongoing research projects, Pelagique was also contracted for environmental analyses and consulting work.


It was around 1988 when Kiecken and associates read about the U.S. National Cancer Institute’s (NCI) plea to find an alternative to the Pacific or Western yew tree (Taxus brevifolia Nutt.) as a source of the promising anti-cancer compound paclitaxel (See inset, p.18). Excessive harvesting of the Pacific yew, the bark of which is used to derive the compound, was fast depleting this natural resource. In contrast, the related Canada or Eastern yew bush (T. canadensis Marsh.) was — and still is — abundant and practically growing in Pelagique’s backyard (Fig. 1). “We went out, got our little clipping, did some extraction and then asked NCI to send us a standard and compared it, and we were happily surprised,” Brigitte Kiecken says.

A Discovery Cascade

Not only had the team derived paclitaxel from a new source of yew, they were the first to discover that this compound could be extracted from the needles of that species. Already having the appropriate setup and instrumentation were also encouraging reasons to venture forth with this new discovery. Biolyse Pharma Corp. was born in 1988.

“It sort of invaded our whole existence; it took us over more than by choice,” Kiecken says of the turn of events.

Biolyse’s paclitaxel business started by selling the drug substance — a white crystalline powder — to R&D labs of multinational companies. Early on, Kiecken says her team realized that more stability was to be found in selling the ready-to-inject paclitaxel product rather than the “active pharmaceutical ingredient” (API).

The company’s steady focus, she says, was to develop a means of efficiently producing a paclitaxel drug at a reasonable cost. Familiar with New York-based Bristol-Myers Squibb Co. (BMS), which produces the anti-cancer, paclitaxel-containing drug Taxol®, the Biolyse group first attempted in 1994 to enter the formulated-product market as a generic of Taxol®. BMS was, at the time, the only firm selling its ready-to-inject paclitaxel product, as it had signed an exclusive R&D agreement with NCI in 1991 and then gained approval to market the drug the following year. The company currently holds three patents in relation to Taxol®.

It was also nine years ago that Kiecken et al. had their first taste of the outside forces that were to challenge Biolyse’s advancement to market. BMS sued Biolyse, preventing it from using the name Taxol on the basis that the Biolyse drug contains paclitaxel from a different natural source and is processed by a different manufacturing protocol than that of the BMS product.

Concurrence by the Therapeutic Products Directorate of Health Canada on the novel botanical source of Biolyse’s product meant that a submission based on pharmaceutical equivalence with another drug was unacceptable. Thus, the firm was required to initiate preclinical and clinical trials to demonstrate drug safety and efficacy. The studies involved hospitals and cancer treatment centres in Ontario and Quebec, and focused on advanced breast cancer unresponsive to usual treatments and locally advanced non-small-cell lung cancer.

Broaching the Market

Following five years of testing, Biolyse moved to St. Catharines in 1999. The firm submitted a New Drug Submission in 2000 for its drug Paclitaxel for Injection in 6-mg/mL strength. Under the Food and Drug Regulations, selling of a drug in Canada is only permitted once the Minister of Health issues a Notice of Compliance (NOC) for the new drug. The requirements of the Patented Medicines (Notice of Compliance) Regulations must also be satisfied. Biolyse was issued its NOC on Sept. 20, 2001.

It has been a long, difficult and expensive road, Kiecken admits, involving an investment of approximately $1 million per year over the last 12 years, including the $5-million production facility.

The firm’s collection procedure involves a renewable resource, Kiecken says, as only eight-inch cuttings are taken from the branch tips and re-growth occurs within two years. Although Biolyse’s process methodology could use more automation, she says her firm is able to produce a consistent product.

Contemplating Biolyse’s triumphs thus far, Kiecken says there was an advantage to beginning small and building up.

“I think that having been a small company right from the start, it has made us survivors. You have to fight right from the start to stay in business.” For one, the reality of limited resources forced the group to discover for itself how to store, dry and pulverize its material.

Kiecken believes that a mistake made by many individuals who attempt to build a new company is to overspend. In this regard, having been located in a remote area was also beneficial, she says. “You learn how to get around problems, and not always depending on huge amounts of money to do it. Instead of calling in the service guy, you just have to figure it out yourself, and just to save in the long run, to make it to the next year.”

Meanwhile, impediments to Biolyse’s success have surfaced.

Regressive Forces

In late November of last year, BMS again took the St. Catharines firm to court. The drug giant argued that BMS ought to have been notified before Health Canada granted Biolyse approval to sell Paclitaxel for Injection, on the grounds that the API in Biolyse’s medication is identical to that of Taxol.

The dispute at hand concerns the interpretation of subsection 5(1.1) of the Patented Medicines (Notice of Compliance) Regulations that was added in 1999. The section requires patents to be addressed where a manufacturer is producing a drug with the same medicine, via the same administration route and in comparable strength and dosage as a drug that is on the Patent Register.

Justice Edmond P. Blanchard quashed Biolyse’s NOC based on the conclusion that subsection 5(1.1) did apply, and the Minister of Health erred in issuing Biolyse its NOC without first requiring the firm to serve BMS a Notice of Allegation (NOA).

Providing a much-needed lifeline, Biolyse requested and was granted a stay, which will last until the case is heard in the Federal Court of Appeal.

Despite having initially received acceptance of Paclitaxel for Injection as a new drug — which required taking the longer, costlier route of conducting clinical trials — Kiecken says it’s very disappointing that Biolyse has had to address the current situation as if its medication were a generic, and consequently, has had to file the NOA.

As a Canadian-developed drug, Biolyse’s product is a rarity, says Bob Reichert, PhD, a member of the Expert Committee on Plant Products and employed with the Industrial Research Assistance Program of the National Research Council of Canada. For example, he says, during the last 10 years, only six new molecular entities have been discovered in Canada and commercialized: Vioxx® and Singulair® (Merck Frosst Canada & Co.), Visudyne® (QLT Inc.), Epivir® or 3TC (Shire BioChem Inc.), Levulan® PDT (DUSA Pharmaceuticals Inc.), and Diab II™ (Biotech Holdings Ltd.).

“The Romanow report was criticized for suggesting a $15-billion health-care program without suggesting ways of paying for it,” Reichert says. “Romanow’s program could, in part, be paid for by the creation of many Biolyse-type companies in Canada that would reduce drug costs, generate employment and increase the tax base at the same time.”

Conviction and Perseverance

Kiecken says that while a natural fear exists of what will happen next, she maintains her steadfast hope and enthusiasm. “It (Paclitaxel for Injection) is currently considered one of the best oncology drugs and its accessibility should not be hindered.”

At an estimated maximum capacity of 75 kilograms of API per year, Biolyse’s production facility is in an excellent position to serve the Canadian market, which Kiecken says currently requires approximately six to 10 kilograms of paclitaxel per year.

The Biolyse team is persisting, she says, driven by a desire to see the availability of its medication increase and thus benefit more people. Ideally, this could happen by maintaining its concentration on the company’s science without having to funnel substantial time, energy and funds into legal proceedings along the way.

“It has been an exciting project,” Kiecken says. “I’m much happier in the lab than in the courtroom, that’s for sure.”