Dimeric agent sidelined for at least two yearsThe monetary and clinical promises of Schering's Isovist 280 x-raycontrast agent have faded in a swirl of red ink and worry overwhether unexpected side-effects spell doom for this first productof a
The monetary and clinical promises of Schering's Isovist 280 x-raycontrast agent have faded in a swirl of red ink and worry overwhether unexpected side-effects spell doom for this first productof a new generation of dimer-based nonionic contrast agents.
Berlin-based Schering has formed a special working group toexamine the incidence, severity and causes of adverse reactionsthat led the company to announce on Sept. 29 the voluntarily withdrawalof Isovist 280 from sale in Germany, Japan and Austria (SCAN 10/11/95).
"We consider this action to be precautionary," saidDr. Hans Peter Niendorf, Schering AG's head of clinical developmentdiagnostics.
Niendorf estimated that it will take at least two years tofully reassess the risk profile of the intravascular contrastagent. The action does not affect Isovist 240 or Isovist 300 formyelography.
The recall was blamed for a 2% sales decline and an 18% declinein profitability at Schering AG for the nine months ending inSeptember, according to Dow Jones newswire. Before the withdrawal,Schering expected Isovist 280 sales would more than double to$140.5 million in 1996.
The Berlin-based company wrote off $109 million in the latestperiod to cover production expenses and customer returns of Isovist280, according to CFO Klaus Pohle. After tax and other adjustments,the final writeoff was $29.5 million.
Schering AG claims a 32% share of the $3.5 billion world contrastmedia market. Its diagnostics group, which manages its contrastbusiness, generated $567 million or 35% of Schering's total salesin the first half of 1995.
Allergy-like reactions. Although fewer than 1% of patientsadministered with Isovist 280 experienced a reaction, the peculiarnature of the side-effects led to a temporary suspension of sales,according to Niendorf. About 72% of the reported incidents weredelayed reactions occurring more than an hour after the agent'sadministration, he told SCAN.
About two-thirds of the delayed reactions involved allergy-likesymptoms including rashes, wheals, itching, angioedema or edemaof the eyelids, Niendorf said.
Most of these reactions were mild or moderate, he said. Seriousallergy-like reactions occurred in approximately one case in every10,000 administrations. The most serious cases required hospitalization.
Niendorf was encouraged that no deaths were reported due toan adverse drug reaction. He noted that studies examining theclinical experience of other agents documented death rates dueto adverse reactions of between one death for every 40,000 administrationsand one death for every 160,000 administration.
"Compared to these, we had a very good result," Niendorfsaid.
Schering's decision to withdraw Isovist 280 came after reviewingthe experience of the first 300,000 clinical administrations inJapan and Germany. Sales commenced in Japan and Germany in December1994 and January 1995, respectively. Schering began selling Isovist280 in Austria in September. In the U.S., phase-III clinical trialshad been completed under the aegis of Berlex, Schering's U.S.-basedsubsidiary, when the agent was recalled.
The monetary losses incurred from the product withdrawal arecompounded by Isovist 280's status as one of the first dimericisotonic agents introduced for broad radiological use. Similarcontrast media are close to commercial introduction. Nycomed,for example, awaits a Food and Drug Administration ruling on itsnew drug application (NDA) for Visipaque, another dimeric compound.Nycomed officials have decided to move forward with the Visipaqueprogram, citing encouraging clinical trials and differences inthe chemical composition of the two agents.
A dimer features chemical characteristics that scientists hopewill maintain the low incidence of severe adverse reactions arisingfrom the use of nonionic monomers while eliminating problems withpain and heat experienced with the first-generation of low-osmolaragents.
European and Japanese clinical trials showed that the population'sgeneral tolerance to contrast media was improved with Isovist280, according to Niendorf. Schering researchers have reason tobelieve from a retrospective analysis of accumulated data thatthe renal tolerance of the nonionic dimers will turn out to bebetter than the experience with nonionic monomers, he said.
Yet, the incidents that led to the recall of Isovist 280 haveraised fears that the source of the adverse reactions may springfrom the composition of the dimer itself.
"If the cause is with the concept of a dimer, then certainlywe would have to re-think further developments in that direction,"Niendorf said.