Earlier this month, powerhouse Genzyme Corp. disclosed its launch of Phase III trials with the toxin binder tolevamer for patients with Clostridium difficile-associated diarrhea - a compound that derives from the same platform that yielded Renagel, the phosphate binder approved for end-stage renal disease that pulled in $364 million in revenue last year, up 29 percent over 2003.
While the news about tolevamer proved worthy of headlines, Renagel (sevelamer hydrochloride) has been more a focus of interest lately, as the competition between phosphate binders heats up.
The latest player on the field is Fosrenol (lanthanum carbonate), from Shire Pharmaceuticals Group plc, approved by the FDA in October - a move that triggered an $18 million licensing payment to AnorMed Inc., per their agreement.
Fosrenol looks strong. Data reported the same month at the American Society of Nephrology meeting showed treatment for up to five years caused no deterioration in bone health.
There's also PhosLo (calcium acetate), from Nabi Biopharmaceuticals Inc., acquired in the summer of 2003 from Braintree Laboratories Inc. for $90 million in cash and 1.5 million shares of stock.
Phosphate binders also made news earlier this year when Spectrum Pharmaceuticals Inc. bought worldwide exclusive rights to RenaZorb, which consists of two second-generation phosphate-binding agents based (like Fosrenol) on lanthanum, from Altair Nanotechnologies Inc., potentially for hyperphosphatemia. Spectrum provided Altair with an up-front payment of 100,000 shares of restricted common stock and made an equity investment of $200,000 for 38,314 shares of Altair common stock.
"Once the FDA approved Fosrenol, that's when I started opening my eyes," said Rajesh Shrotriya, president and CEO of Spectrum.
Because of its potency, RenaZorb (though still preclinical), could become the lowest-in-class dosage - maybe one tablet per meal - and with smaller tablets, Spectrum said in March. An investigational new drug application is expected within the next 12 to 15 months.
When kidneys fail, excess phosphate can't be excreted, and the body makes too much parathyroid hormone, which skews the calcium-phosphate balance even worse. Phosphate binders help pass extra phosphate out of the body in the stool, thus reducing the amount in the blood.
The newer binders (not based on calcium or aluminum, which can lead to unhealthy buildups of those minerals) are the ones that have physicians and patients most excited. And investors have been watching Fosrenol.
Lanthanum also is a naturally occurring metal, found mostly in China and used industrially in water treatment, Shrotriya noted. "The FDA was very concerned about [metal] absorption, and made Shire do all kinds of safety studies," he told BioWorld Financial Watch. Trials found minuscule amounts were absorbed, "and even then the FDA wanted long-term safety trials."
Then mighty Genzyme, it first seemed, might have some cause to worry - albeit not about the development pipeline. Along with tolevamer, the firm has Myozyme (alglucosidase alfa) for Pompe disease. A bid for European approval has been filed and Genzyme expects to submit an application to the FDA around the middle of the year.
Label expansion efforts are ongoing at Genzyme, too. Pivotal trials with Synvisc (hylan G-F 20) for pain due to hip osteoarthritis are under way. Synvisc is approved for osteoarthritis knee pain, and sold only $15 million in the fourth quarter, compared with $26 million during the period a year ago, but the drop was due to an inventory reduction by Wyeth ahead of Genzyme's buy-back of sales and marketing rights for Synvisc in the U.S. and five European countries. That transaction closed in January.
And of course for Genzyme there's the well-known marketed lineup - flagships Ceredase/Cerezyme, plus Renagel, Synvisc, Campath, Thyrogen, Thymoglobulin, Campath, Aldurazyme, Fabrazyme and Clolar. Genzyme's annual revenues grew 39 percent from $1.6 billion in 2003 to $2.2 billion in 2004.
One cloud over Genzyme remains in the form of Fabrazyme (agalsidase beta) competition overseas from Transkaryotic Therapies Inc.'s Replagal (agalsidase alfa). The U.S. battle between the pair of companies ended in January 2004 when the FDA gave its nod to Genzyme's product and TKT, which had gained marketing clearance in 27 countries, gave up on selling the drug for Fabry's disease in the U.S.
At the start of 2005, the combatants were involved in a different war, that time over therapies for Gaucher's disease. The battle in Israel, where patents were filed, concerns intellectual property surrounding TKT's GA-GCB (glucocerebrosidase). Genzyme says its Israeli patent covers novel culture processes that have been critical in enabling the company to produce Cerezyme (imiglucerase) for Gaucher's, and the company accuses TKT of importing into Israel and using the GA-GCB product made by those protected processes.
It's a skirmish, like the one over the Fabry's therapies, likely to drag on and cost money. Of more immediate concern is the Fosrenol threat to Renagel from Shire, which has some observers buzzing. But maybe they'll buzz less now.
New data fielded in March by BioTrends Research group, based on a survey of about 75 practicing nephrologists and renal dietitians, indicated Fosrenol is leveling out. A report on the BioTrends findings by Robert W. Baird & Co. finds "growing dissatisfaction" with Fosrenol after only four months on the market.
"It has to," Shrotriya said. "You should see the size of the pills. They're big pills, and patients have to chew them before food every day at every meal for the rest of their lives."
One of the reasons for the Fosrenol plateau cited by Baird is the cost-benefit ratio. Fosrenol's label calls for one or two tablets per meal, but respondents polled by BioTrends said patients often require more. Doctors might also be taking a closer look at the fine print. On the labels, Renagel's phosphorous-lowering capability is said to surpass that of Fosrenol, despite earlier excitement about the latter as a new and apparently better drug, the Baird report said.
Already, the discontinuation rate for Fosrenol has hit 9 percent to 11 percent, and Baird still feels comfortable with its revenue estimate of $422 million for Renagel.
Compliance, though, is a challenge not only for Fosrenol, Shrotriya said, and Renagel has other problems.
"It's a polymer that binds to certain nutrients in the gut and is hyperacidic," and may require antacid and vitamin supplements, he said. "These patients, I'm told by physicians, end up taking a lot of tablets."
Shrotriya said he didn't want to "make any tall claims" yet for Renazorb, but pointed out that the drug in vitro binds more phosphate than Fosrenol - which already has carved a niche for lanthanum compounds.
"The market worldwide could be over a billion dollars, and there are not many drugs," he said.