Isis Pharmaceuticals Inc. said Friday it is discontinuing patientaccrual in Phase III trials of its antisense cytomegalovirus (CMV)retinitis drug because of adverse events that may or may not berelated to the compound, which is called ISIS 2922.

The Carlsbad, Calif., company plans to lower dosages and resume thetrials as soon as the new formulations are available. But the company,making its announcement just days after it was notified of the events,said early Friday it hadn't been in contact with the FDA and it wasunclear whether a protocol continuation would be OK'd or if a newtrial would be necessary.

Two trials are affected. One is a comparative study evaluating ISIS2922 in combination with ganciclovir against ganciclovir alone. Thatstudy involves patients whose CMV retinitis progressed while theywere being treated with ganciclovir or foscarnet. The other study isevaluating ISIS 2922 as a monotherapy in newly diagnosed patients.

The events seen in three to five of the 20 or so patients treated to dateis RPE (retinal pigmented epithelial) stippling, a spotting effect thatlooks like salt-and-pepper across the retina. It is a response to injuryrather than a primary injury, company officials said. A possible resultof RPE stippling is loss of peripheral vision.

"I think the implications are minimal," Stanley Crooke, Isis'chairman and CEO, said in a conference call Friday with analysts andmembers of the news media. "I think the response we're taking willtake care of the problems. We think it may cost us several months inthe ultimate submission of the NDA [new drug application]."

Isis initiated the Phase III trial of its lead drug in December. (SeeBioWorld Today, Dec. 15, 1994, P. 1.) About 200 patients wereexpected to be enrolled in the two studies. A third arm of the trial _involving those whose disease has progressed despite varioustreatments _ is being run in lieu of a compassionate-use study, saidJane Green, Isis' director of investor relations. That study isunaffected, she said.

Isis is collaborating on ISIS 2922 with Tokyo-based Eisai Co. Ltd.They are sharing development costs and plan to co-promote andmarket the drug.

Drug Targets Messenger RNA

The antisense compound acts by inhibiting the function of messengerRNA. The drug is designed to bind to certain sites on a particularmRNA of CMV.

In earlier Phase I/II studies involving severely ill patients, Isis testedfour dosages: 75 micrograms (mg), 150 mg, 300 mg and, in onepatient, 450 mg. That patient developed RPE stippling. In the PhaseIII studies, the dose being used was 300 mg.

Crooke said there were a number of possibilities about what causedRPE stippling in the few patients in the Phase III studies. It could bea response to ISIS 2922, a response to CMV retinitis, an effect of thevirus being killed, a result of multiple drugs, unrelated to thetreatment, or caused by some other source.

Crooke said there have been reports in the past week of a couple ofpatients who had RPE stippling. Thursday, the company got a reportof a patient who got RPE stippling after the first dose of ISIS 2922,Crooke said.

The company was having its annual meeting and an open house, andhad upcoming meetings scheduled with investment firms. So itdecided it was best to release the news, even though it was before thecompany had all the information regarding the cause of the events orwhat its next course of action will be.

Crooke said Isis intends to propose a protocol modification thatwould check the safety of dosages before a transition into acontinuation of the Phase III trial, with the same investigators. Fornow, Isis will recommend that investigators offer patients alternativetreatment.

CMV is a virus in the herpes family that normally doesn't causedisease. However, for those with AIDS or others with compromisedimmune systems, it can infect the retina, destroy retinal tissue andlead to blindness.

Stock Falls, But Doesn't Plummet

Isis' stock (NASDAQ:ISIP) fell 88 cents, or 9.6 percent Friday, toclose at $8.25 per share. The drop was not as significant as thatexperienced by other biotechnology companies who have had late-stage troubles with their lead products. That could be because Isis hashad a run of good news recently.

In March, Isis and Germany-based Boehringer IngelheimInternational GmbH entered a cell-adhesion collaboration worth up to$100 million to Isis. It involved the purchase of Isis stock at a heftypremium and access to a $40 million line of credit.

In February, Isis and Ciba-Geigy Ltd., of Basel, Switzerland,extended their research collaboration, bringing the term of theirantisense project to eight years, to September 1998. And in January,Isis and Human Genome Sciences Inc. _ a gene discovery companyin Rockville, Md. _ announced a collaboration in which they'll worktogether to discover antisense drugs, then find partners to fund theresearch. n

-- Jim Shrine

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