Isis Pharmaceuticals Inc. and Ciba-Geigy Ltd. finalized Wednesdayexpanded terms of their antisense collaboration dating to 1990. Thework from here on out will be dictated by the two lead anticancercompounds coming out of the research.

The new agreement finalizes terms of an expanded deal laid out lastSeptember that took the collaboration from the research stage intodevelopment of compounds that target protein kinase C-alpha (PKC-alpha) and c raf-kinase, specific signal transduction proteins frommulti-gene families that are implicated in proliferation ofmalignancies.

The collaborators decided to inhibit the PKC-alpha isotype fromamong the PKC family because of the promising anticancer activityseen in mouse models. Phase I studies have just begun of ISIS 3521,the lead compound in that program.

An investigational new drug application has been filed for the lead craf-kinase inhibitor, ISIS 5132, and trials are expected to get underway soon.

Rainer von Mielecki, head of pharma communications for Ciba-Geigy Ltd. in Basel, Switzerland, told BioWorld Today the idea is tointervene at different stages of the cascade of enzymes that transducethe signals in the cells. Clinical work will help show at what pointintervention is most effective for various cancers.

"We will also look into research and development of othercandidates," von Mielecki said. "We believe in the antisenseapproach and we're confident it will help us develop effective cancercompounds."

Antisense technology is aimed at inhibiting the function of messengerRNA and preventing the production of disease-causing proteins.

Phase I studies of both drugs will be conducted in patients with arange of advanced metastatic tumors. Cohorts of three patients willbe treated and followed for three to four weeks; another cohort givena higher dose of drug then will be treated and progressively higherdoses (from 0.15 to 2.5 mg/kg) will be used until a certain level oftoxicity is reached, said Dan Kisner, president and chief operatingofficer for Isis. He said data detailing safety and perhaps showingsome signs of tumor stabilization or shrinkage could be ready aroundthe end of the year.

The expanded collaboration calls for Ciba to fund development of thetwo compounds and others coming behind them. Isis, of Carlsbad,Calif., will conduct trials through Phase IIb and be eligible formilestones and royalties while retaining manufacturing rights.

The Phase I studies will be conducted at the Cancer Therapy andResearch Center in San Antonio. The plan is to take the drug fromthere into tumor-specific Phase IIb while at that time starting trials inEurope, Isis officials said last month when announcingcommencement of the studies. (See BioWorld Today, Sept. 18, 1995,p. 1, and Jan. 25, 1996, p. 1, for more on the collaboration andcompounds.)

Isis has received about $30 million in research funding since 1990and another $19.5 million in equity investments from Ciba, Kisnersaid.

"The magnitude of this deal to us is quite a bit larger than [the moneyreceived to date]," Kisner said, adding that Ciba's contribution likelywill exceed $100 million, including development costs, by the end ofPhase II. "This is really a substantial investment on their part in thesetwo antisense programs.

"These are the first two of what is anticipated to be a pipeline ofPKC- and raf-targeted compounds," Kisner said, adding that eachwould entail additional funding.

Ciba's von Mielecki said the signal transduction work with Isis is oneof at least four approaches being investigated for cancer. Othersinclude research into hormonal-dependent cancers, immune therapyand angiogenesis.

ISIS 3521 (also called CGP 64128A) was designed to specificallyinhibit PKC-alpha, an isotype in the PKC family. Animal studiesshowed the compound eradicated PKC-alpha mRNA expressionwithout affecting mRNA levels of other PKC isotypes. ISIS 5132 (orCGP 69846A) did the same to c raf-kinase when studied in threedifferent human tumor cells lines in cell culture.

Isis' stock (NASDAQ:ISIP) gained 88 cents Wednesday to close at$12.50. n

-- Jim Shrine

(c) 1997 American Health Consultants. All rights reserved.