West Coast Editor

With a rolling biologics license application with the FDA under way since April, BioMarin Pharmaceutical Inc. and Genzyme General disclosed detailed data from a six-month, double-blind Phase III trial of their enzyme replacement therapy Aldurazyme (laronidase), and preliminary six-month findings from an ongoing open-label extension study.

"Patients who have now been on the drug for 12 months have maintained [their benefits] or improved," said Jeremy Price, director of investor relations for Novato, Calif.-based BioMarin. "The longer they're on treatment, the better they do."

In March, a marketing authorization application also was submitted to the European Agency for the Evaluation of Medicinal Products to sell the drug in the European Union. Both filings were based on positive preliminary data from the Phase III study in 45 children. (See BioWorld Today, Nov. 5, 2001.)

The new data were presented Saturday at the International Symposium on Mucopolysaccharide and Related Diseases in Paris. BioMarin and Genzyme will submit the six-month interim extension study data to the U.S. FDA in the third quarter to complete their rolling BLA.

"We have not submitted the clinical section of the BLA yet," Price told BioWorld Today, adding that the FDA "likes to get each section all at once, so we've held off until we had the extension data, although we've already done all the work we need to do on the double-blind portion."

Aldurazyme is for mucopolysaccharidosis I, caused by a deficiency of the enzyme alpha-L-iduronidase leading to a buildup of complex carbohydrates in the lysosomes of cells. Symptoms can include impaired cardiac and pulmonary function, delayed physical development, skeletal and joint deformities and reduced endurance. Most patients die before reaching adulthood.

Detailed data show that, in the first six months of the Phase III trial, Aldurazyme patients gained a 5.3 percent mean increase in pulmonary function as measured by forced vital capacity (FVC, which is the total volume of air exhaled after a full inhalation) compared to patients treated with placebo (p=0.016), a change from the early data's finding (p=0.028). Patients also did better enduring a six-minute walk test, improving by a mean of 38.1 meters compared to placebo (p=0.066). Analysis that allowed for differences between patients showed statistical significance (p=0.039).

Eric Schmidt, analyst with S.G. Cowen Securities Corp. in New York, said the 0.066 result might be viewed as a blot on the BLA, although the profile otherwise is encouraging with regard to the main symptoms.

The reanalysis of walk-test data showed statistical significance, Schmidt allowed in a research note, but "we believe that the FDA is unlikely to view this reanalysis as more than an informative view of a subset of patients."

Price said he didn't want to "get into the tricky business of predicting how the FDA is going to respond to our data. It is true that the [0.066 p value] is the primary analysis for that endpoint. This alternative analysis will be looked at secondarily, and I think that's the point that Eric might be making."

But, Price said, the reanalysis is "more than interesting. When you have a disease that's so heterogeneous, with patients running the gamut, it's difficult to look at them all as the same type and analyze them that way."

What's more, he said, the alternative analysis was in the plan all along.

"We didn't just go backward and say, How can we get this to look statistically significant?'" he said. And Schmidt observed in his research note that, given the heterogeneity of the patient sample, it was "not entirely surprising" that the walk-test endpoint was missed.

In other good news from the Phase III double-blind study, livers of Aldurazyme patients reduced in size to a statistically significant degree (p=0.001), as did the urinary excretion of glycosaminoglycans.

A sleep study using the apnea-hypopnea index showed a positive trend (p=0.145) in the overall patient population, and one post-hoc subset analysis of 21 patients deemed to have clinically significant sleep apnea at baseline demonstrated a statistically significant improvement.

Two other secondary endpoints did not reach statistical significance: a health assessment questionnaire and shoulder range of motion.

The safety profile in the double-blind portion of the Phase III trial was comparable between the treatment group and the placebo group.

For the extension study, those previously on placebo were switched to Aldurazyme, and those who'd been on Aldurazyme continued to get their weekly infusions. Included in the extension study are the same two primary endpoints that were evaluated in the double-blind part of the Phase III trial: pulmonary function, as determined by FVC, and endurance, as measured by the walk test.

Patients on Aldurazyme in the double-blind portion who stayed on the drug in the extension study kept their FVC improvement, rising from their 5.3 percentage point mean increase to 5.9 percent. In the walk test, the same patients improved from a 19.7 meter mean increase in the six-minute walk test over the first six months to a 42.9 meter mean increase.

Other extension-study findings are in line with results in the Phase I trial and the double-blind portion of the Phase III trial - that is, statistically significant reductions in liver size and in the excretion of GAGS.

BioMarin's stock (NASDAQ:BMRN) closed Monday at $4.55, up 5 cents. Cambridge, Mass.-based Genzyme General's shares (NASDAQ:GENZ) ended the day at $19.26, up 32 cents.