BioWorld Today Columnist

I got a "heads up" recently about a scientific tiff in Blood, the American Society of Hematology journal. One title talked about the "Superior Effects of High Dose Enzyme Replacement Therapy (ERT) in Type 1" Gaucher's disease, and the other included the words "Low Dose Therapy Trumps High Dose Therapy Again."

The long-standing argument about Gaucher's ERT dosing is smack in the midst of the emotional debate over how much innovation is worth - in returns to shareholders, in lives improved and saved. Genzyme Corp.'s new ERT Myozyme, approved for another debilitating orphan disease, has patient advocates aghast, though not surprised, at the anticipated $280,000 annual cost.

Genzyme, ImClone and Genentech sell life-saving therapies that convert fatal disease into chronic, treatable illness with huge dose-dependent price tags averaging more than $100,000 per year (up to $520,000 for some adult Gaucher's patients). The Wall Street Journal reported that ImClone, partner Bristol-Myers Squibb and Genentech are contemplating annual price caps and other cost-containment measures for their pricey cancer drugs before the government decides to step in.

The Low Dose Theory

Genzyme's orphan strategy has generated jealousy among its biopharma brethren for a decade. A worldwide patient population of 4,500, some of whom get their drug through charities and other Genzyme-supported efforts, generated Cerezyme 2005 sales of $932 million - very close to that blockbuster $1 billion to which all aspire.

Genzyme's other orphan product, aimed at 1,700 Fabry's disease patients, brought in $305 million last year. Genzyme's total 2005 revenue was $2.7 billion, with net earnings of $441.5 million, gross margins of 78 percent, and a $14 billion market cap.

It sounds like a slam-dunk, but the orphan strategy requires much intestinal fortitude of the company and its investors. It took a decade of struggle to reach that first year of revenue ($94 million in 1992, with gross margins of 40 percent).

The argument over dosing started in the 1980s when Genzyme designed the single pivotal trial of its first ERT, Ceredase. It could afford to produce material for only 12 patients, dosed 60 units/kg body weight every two weeks, and used historical controls. Genzyme hoped the large dose would increase the probability of success - it would not get another chance.

Ernest Beutler is a champion of lower doses. His team at City of Hope started in the 1970s with placental enzyme, targeted by encapsulation in red blood cells. Low-dose Ceredase testing began in 1990 because he couldn't afford enough drug to give patients the full recommended dose. Beutler and his team, now at Scripps Research Institute, evaluated one-fourth the recommended dose, three times weekly instead of every two weeks.

Beutler reported patient response to the lower dose, and set off on a multi-decade crusade to get the cost of treatment down while maintaining that important clinical response. In various publications, he and others reported meta-analyses showing that increased enzyme dose did not produce any additional clinical effect in patients.

Carla Hollak said the most important finding in the recent Blood article by de Fost, Hollak, et al., is "showing superiority of a higher dose on two disease parameters." While important, there is controversy over the clinical relevance of those markers. Beutler is quick to point out that the paper also confirmed no dose effect on the most widely used clinical responses. Hollak's view: The only clear conclusion in that very challenging, diverse patient population is that each patient needs to be evaluated and dosed on an individual basis to maximize clinical benefit and minimize cost.

Walking The Tightrope

Genzyme has shown orphan drugs are an attractive profit center and make a huge difference to patients. Genzyme's chairman and CEO, Henri Termeer, speaks eloquently about the incredibly long, hard path to creating Cerezyme. He makes it very clear that Genzyme's dual goals are to maximize benefit to patients who lacked previous treatments, and to maximize benefit to the company and its shareholders. The income from orphan drugs has fueled Genzyme's evolution into a very sustainable company developing other important drugs.

But that hefty price tag for rDNA Cerezyme, unchanged from when the drug was extracted painfully from placenta, plus the newly registered Myozyme, make Genzyme a target for angry patients and activists.

Termeer said, "These products are worthwhile because they change a very serious disease in a very significant way, and thus the market will support it. Health care cost arguments come up in settings where in fact we are not able to treat effectively - in cancers, Alzheimer's, etc., where the drugs are making incremental benefits.

"These therapies are expensive, and society has the right to ask questions. We explained for 15 years how the cost came about - we provide global access to these products and charge the same price worldwide, or provide it free. Genzyme has not shied away from the debate. We invited in the federal Office of Technology Assessment and journalists, and I testified at federal investigations. If you are not willing to have these open discussions, this will be a very tough business."

Beutler and Pompé patient advocate Randall House both give Genzyme kudos for having the guts to stick it out and get critical medicines to the marketplace. House, cofounder of the Acid Maltase Deficiency Association and parent of a daughter receiving 40 mg/kg Myozyme, says Genzyme has an excellent reimbursement staff, has set up a charitable medical access program and has guaranteed that existing patients can stay on the therapy for life. He still worries about that $1 million cap on his insurance plan, with $380,000 already spent.

In doctor's offices, the dosing debate continues. Beutler said at least one of his patients has been approached by a Genzyme sales rep about moving to high-dose Cerezyme. Bo Piela, spokesman for Genzyme, said the company has always asked doctors to find the correct dose for each patient and has never advocated for the high vs. low dose.

With the NIH announcement of a five-year, $71 million orphan disease clinical program, more companies may be considering following the Genzyme model. Just be ready to weather the inevitable storm.

Robbins-Roth, Ph.D., founding partner of BioVenture Consultants, can be reached at Her opinions are her own and do not necessarily reflect those of BioWorld Today.

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