You don't need much, but you better have some or else.
The subject is enzymes, replacement therapy for which has been in the forefront in June, with big player Genzyme General Corp. and partner BioMarin Pharmaceuticals Inc. making headlines (good news), as well as competitor Oxford GlycoSciences plc (bad news).
Genzyme, of course, is known for its already-marketed treatments for Gaucher's disease, Cerezyme (recombinant glucocerebrosidase) and Ceredase, the natural version of the enzyme, derived from human placenta. Although Genzyme lowered its overall guidance for 2002, causing the firm's stock to dip more than 20 percent, Genzyme raised its 2002 guidance for Cerezyme (also known as imiglucerase) from between $580 million and $600 million to between $600 million and $610 million. In fiscal 2001, sales of Cerezyme hit about $570 million.
And let's not forget Genzyme's Fabrazyme (agalsidase beta) for another enzyme deficiency disorder, Fabry's disease. On the market in Europe, Fabrazyme has been the subject of litigation with Transkaryotic Therapies Inc., which has a potentially competing candidate for the ailment, Replagal (agalsidase alfa), also sold in Europe.
In December, TKT said a federal judge dismissed patent litigation brought against TKT by Genzyme, which is expected to appeal. The FDA has yet to decide its part of the situation, and both are orphan drugs.
"Whoever wins that game gets seven years of exclusivity, which is always nice," said Yaron Werber, analyst with SG Cowen, estimating Genzyme is "on track to do $630 million in sales from Cerezyme and Fabrazyme this year," or about 57 percent of total sales for 2002.
Might the FDA approve both, as some analysts have speculated?
"It's tough to tell," Werber said. "[Genzyme and TKT] filed a few weeks apart, but the FDA is unlikely to make a decision before they have a commissioner." Similar situations have arisen, though, in which the FDA didn't hesitate to make the tough call, he noted.
"In the past, they've been sued [on orphan drug cases] and they won every case," Werber said. "Replagal certainly shows a better safety profile than Fabrazyme, and TKT has shown hard clinical data," he added. "Genzyme hasn't yet; they've only shown surrogate markers. Genzyme is now doing a randomized, double-blind placebo-controlled trial. They're calling it a Phase IV study, and they say they don't need to file with it."
In other recent developments, Oxford GlycoSciences got knocked out of the competitive arena for Gaucher's disease, or at least knocked aside. A non-approvable letter from the FDA for OGS's glucosyltransferase inhibitor, Vevesca, landed on the company's desk, with the agency saying more studies would be required before it makes a decision.
"We thought that, at best, they might be able to treat patients who failed Cerezyme, or perhaps [OGS' drug could be used] earlier in the disease course, before you go on Cerezyme, or for patients who want to take holidays from Cerezyme," Werber told BioWorld Financial Watch. "That was a lot of hypothesis, and the data never supported any of it."
OGS said it would be meeting with the FDA to determine the exact concerns and how to proceed. The agency said only, in a prepared statement, that OGS failed to provide sufficient evidence to support its claims that Vevesca is safe and efficacious.
Meanwhile, European regulators expected to hand down their decision on Cerezyme overseas by the third quarter, and Genzyme has more in the works.
In April, the company's joint venture with Pharming Group NV, called Genzyme-Pharming Alliance LLC, started a Phase II/III trial in Europe and the U.S. of recombinant alpha glucosidase in infants with Pompe's disease, another enzyme deficiency disorder. Alpha glucosidase breaks down glycogen for conversion to glucose. Without it, glycogen builds up, damaging the skeleton, heart and lungs, and (in its infantile form) usually causing death by heart failure in the first year of life.
And it was only a year ago that Genzyme acquired Novazyme Pharmaceuticals Inc. for $137.5 million in stock, thereby acquiring its early stage candidate, NZ-1001, for Pompe's disease.
"[Novazyme] had a technology that allows them to make the protein look more 'human' when they put the sugars on it, and they had the Pompe's pipeline," Werber said.
At center stage of late, though, was Aldurazyme (laronidase), the treatment for another wicked enzyme disorder called mucopolysaccharidosis I, or MPS I, which is caused by a deficiency of the enzyme alpha-L-iduronidase. The culprit again is buildup of unwanted complex carbohydrates in the lysosomes of cells. Symptoms include impaired cardiac and pulmonary function, delayed physical development, skeletal and joint deformities and reduced endurance. Most patients die before they reach adulthood.
Genzyme and BioMarin have had a rolling biologics license application in the FDA's hands since April, and last week offered details from a six-month, double-blind Phase III trial of Aldurazyme, and preliminary six-month findings from an ongoing open-label extension study.
A marketing authorization application based on strong preliminary results from the Phase III trial in 45 children was submitted several months ago to the European Agency for the Evaluation of Medicinal Products to sell the drug in the European Union.
With the new disclosures, there was plenty of cause for satisfaction. Although one endpoint was missed statistically significant improvement in a six-minute walk test patients did noticeably better in that department and in several others, notably pulmonary function.
Clinicians measured pulmonary function by testing forced vital capacity (FVC), the total volume of air exhaled after a full inhalation. In Aldurazyme patients compared to those treated with placebo, the improvement recorded by the detailed Phase III data was even greater than in the preliminary findings: p=0.016 as compared to p=0.028.
Not only that, but livers of Aldurazyme patients came down in size, as did glycosaminoglycans (GAGS, indicative of the carbohydrate buildup) in their urine. A sleep study using the apnea-hypopnea index showed a positive trend (p=0.145) in the overall patient population, too, as did one post-hoc subset analysis of 21 patients deemed to have clinically significant sleep apnea at baseline.
A pair of secondary endpoints was missed results from a health assessment questionnaire and shoulder range of motion but the findings provided encouragement for the company and for analysts, especially given what both noted is the heterogeneity of MPS I patients.
The extension study (with the same two primary endpoints) switched placebo patients to Aldurazyme, and the patients who had been getting the drug stayed on their weekly infusions. Those 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 over the first six months to a 42.9-meter mean increase.
Not bad. As for the liver size and GAGS excretion, results from the extension study were in line with the Phase III trial (and a Phase I study). BioMarin and Genzyme plan to complete their rolling BLA in the third quarter.
Also, at the International Symposium on Mucopolysaccharide and Related Diseases and the Scientific Lysosomal Storage Disorders Congress in Paris, where the MPS I data were disclosed, BioMarin offered favorable results from Phase I trials with another drug against a fatal disorder in the same realm as MPS I.
The drug is Aryplase (recombinant human N-acetylgalactosamine 4-sulfatase, or arylsulfatase B), and the disorder is MPS VI, also known as Maroteaux-Lamy syndrome. BioMarin provided findings from the 24-week, open-label extension part of the Phase I study, showing the drug reduced GAGS and was safe. A Phase II trial in 10 patients began in March.
Although the patient population is low, the stakes in potentially deadly enzyme deficiency disorders are high, Werber said.
Treatments with Replagal and Fabrazyme, he said, run about $170,000 per patient per year, "and Cerezyme is just north of that. But they're all going to be around the same."
A patient population that is smaller in more ways than one makes clinical trials hard to design and endpoints difficult to decide upon, not to mention hit, Werber said.
All of the enzyme replacements "show an ability to reduce liver size and GAGS excretion, but some of these [other] endpoints are very much effort dependent," he said. "It's not just that you measure someone's creatinine and blood pressure. The patients have to decide how hard they're going to try to walk or blow into a tube, and these are kids."
As companies vie for clinical success, for market position, and for the FDA's favorable regard, the field of enzyme replacement is likely to get even more contentious, Werber said.
Genzyme nemesis TKT, it turns out, owns the Aldurazyme patent, which it licensed from an Australian university, he said. "Genzyme and BioMarin believe there is prior art here that may invalidate the patent," Werber said.
"This could be resolved, if they decide to do a royalty [arrangement]," he allowed. "We don't think TKT is going to try to keep Aldurazyme off the market. You don't want to keep something off the market that's going to keep people from expiring."
So far, there's no legal paperwork but this means little, Werber said.
"You're not going to sue anybody until they file," he said. "Once [Genzyme and BioMarin] file, there could be a potential for negotiations," a phrase that Werber acknowledges is euphemistic for another probable legal war.
"I think they will want to test this in court," he said.