No harm, no foul

Isis Pharmaceuticals Inc. last week closed the books on an incident of data manipulation by a researcher at partner Novartis that, fortunately, caused no lasting harm to either patients or the company. In a letter to Nature Medicine, the company reported that the doses of ISIS 5132 required to achieve anti-tumor activity in human tumor xenograft models are 10-20 mg/kg, not the 0.6 mg/kg originally reported by the Novartis researcher. The higher dose still falls within a treatment window below the maximum tolerated dose, ISIP said.

The problem with preclinical work conducted from about 1993-95 came to light last year after Novartis (Basel, Switzerland) discovered that one of its researchers had manipulated data related to three of ISIP's antisense cancer compounds: ISIS 3521, ISIS 5132, and ISIS 2503 ( see BioCentury Extra, March 17, 1998). "The harm that was done, while substantial, was not lethal," said Stanley Crooke, chairman and CEO of ISIP (Carlsbad, Calif.). "About two years before the exposure, we had some trouble reproducing Novartis' data. That there was a difference was not a surprise - human tumor xenograft data is fairly variable. But the potency was significantly different. This led to an internal investigation at Novartis." Crooke said that due to differences in body mass and physiology, doses in animals do not correlate to those in humans. Thus a 10-20 mg/kg dose in animals may be approximated to a 3-5 mg/kg dose in humans. "In the clinic we have had significant activity in tumors in doses of 0.5 to 5 mg/kg," said Crooke. "We've gone up to 30 mg/kg with no adverse events." ISIS 5132, 3521 and 2503 are phosphorothioate antisense oligodeoxynucleotides targeted against C-raf kinase, kinase C-alpha and Ha-raf, respectively. In spite of the data manipulation, the clinical progress of the agents has not been delayed. ISIS 5132 and 3521 are in Phase II testing to treat solid tumors and ISIP anticipates starting Phase III trials before year end. ISIS 2503 has completed Phase I testing and the company plans to begin Phase II studies in the first half of 1999.- Steve Edelson ...