GAITHERSBURG, Md. _ The FDA's Oncologic Drugs AdvisoryCommittee (ODAC) voted 6-to-2 on Friday to recommend approvalof Guilford Pharmaceuticals Inc.'s Gliadel as an adjunct to surgery inpatients with recurrent glioblastoma multiforme, the most commonand aggressive form of primary brain cancer. The recommendationfor use of Gliadel as a second-line therapy against a single type ofglioma fell short of the company's application, which soughtapproval for use as an adjunct to surgery in all malignant gliomapatients.

As ODAC debated the quality of the clinical data supporting its newdrug application (NDA), Guilford announced an agreement grantingRhone-Poulenc Rorer Inc. (RPR) worldwide marketing rights (exceptScandinavia) to Gliadel. Under the terms of the agreement,Collegeville, Pa.-based RPR will pay Guilford $7.5 million in cashand will purchase $7.5 million in equity at a 15 percent premium toFriday's close of $27.88 per share (roughly 233,936 shares at a priceof $32.06 per share). In addition, RPR will extend a $7.5 million lineof credit to Baltimore-based Guilford and will pay up to $60 millionin milestone payments, $7.5 million of which will be in equity.Guilford will manufacture Gliadel and receive royalties on productsales.

According to Guilford's president and CEO, Craig Smith, if the FDAfollows ODAC's recommendation and approves Gliadel for recurrentmalignant glioblastoma multiforme, his company will get a $20million milestone payment from RPR in cash. That total is $15million less than Guilford would have gotten if they had obtainedFDA approval for first-line therapy of malignant gliomas (the first-line milestone payment, if made, will consist of $7.5 million equityand $7.5 million cash).

"Obviously the labeling is more restrictive than we applied for butnevertheless we think that this will be an important new treatment forpatients with recurrent malignant glioma," Smith said after theODAC vote. "Of course we anticipated that this [the restrictedindication] might occur and we have in place plans to pursue thebroader indication." Current standard first-line therapy consists ofsurgery followed by radiation therapy and/or systemic chemotherapy.

Guilford Stock Suffers

Wall Street appeared to give more weight to the gloomy news of thesecond-line therapy indication than the cheery news of the RPRagreement. After reaching a high of $37.75 per share after the RPRdeal was announced, Guilford stock (NASDAQ:GLFD) shed $6.88per share on Friday, a 20 percent drop in value.

According to the National Center for Health Statistics, approximately20,000 surgical procedures for brain tumors are performed annuallyin the U.S. Guilford's own market research indicates that about12,000 of those procedures are primary (first-line) therapy and about8,000 represent secondary therapy (re-operation to remove recurrenttumors). Based on these figures, ODAC's formal labelingrecommendation more than halved the number of patients eligible toreceive Gliadel.

Gliadel is a biodegradable polyanhydride polymer wafer that releasesthe cancer chemotherapeutic drug carmustine after implantation at thesite of brain tumor removal, a procedure known as surgicalresectioning. Flat, off-white discs about the size of a dime, Gliadelwafers erode in the brain much like a bar of soap. Surgeonsimplanted an average of eight wafers per patient in clinical trials ofthe drug and, Smith said, one treatment with Gliadel wafers willlikely cost between $7,000 and $8,000 per patient.

Gliadel has been granted orphan drug designation for all patients withmalignant glioma and has been available to patients free of chargesince October 1995 under a Treatment Investigational New Drugapplication approved by the FDA.

Matthew Geller, a biotechnology analyst with Oppenheimer & Co. inNew York, one of the underwriters of Guilford's most recent publicoffering last March, told BioWorld Today he was surprised by thepanel's action. "The restrictive labeling will slow uptake of theproduct," he predicted.

ODAC panel members were sharply critical at times of the clinicaldata that formed the basis of the Gliadel NDA, submitted on Feb. 7,1996. Data were presented from two Phase III double-blind,randomized, placebo-controlled studies. One study (designated 8802)enrolled 222 patients with recurrent malignant glioma who failedprior conventional therapy. The primary efficacy endpoint was six-month survival _ 60 percent of Gliadel-treated patients were alive atthat time point vs. 47 percent of patients in the placebo group.However, the finding was not statistically significant (p-value =0.06).

Guilford scientists did not design or conduct study 8802, which wasinitiated in 1988 by scientists at Baltimore-based NovaPharmaceuticals Inc., which subsequently merged with MountainView, Calif.-based Scios Inc. in 1992.

A second clinical trial (designated 0190), conducted at four sites inFinland and Norway, enrolled 32 newly diagnosed malignant gliomapatients. In those patients, Gliadel or placebo wafers were implantedduring the first surgery. Survival rates at one year (the primaryefficacy endpoint) were 63 percent with Gliadel, compared to only 19percent with placebo _ in this case, the finding was statisticallysignificant (p-value = 0.03).

Gliadel Won Lukewarm Support From ODAC Members

But ODAC members ruled that the 0190 study was not an "adequateand well-controlled study" because it was stopped early due to lackof drug supply and thus was too small to provide firm evidence. Thestudy was designed to enroll a total of 100 patients but got lost in theshuffle of the Scios Nova merger. The new company droppeddevelopment of Gliadel for strategic reasons, leaving study 0190 andits patients in the lurch. Gliadel was resuscitated by Smith and hiscolleagues at Guilford in late 1993 but it was too late to manufacturesufficient quantities of drug to continue the study. Since then,Guilford has built and obtained FDA approval for a manufacturingplant.

On Friday, Guilford paid the price for Scios Nova's strategic decisionwhen it saw Gliadel's potential market shrink dramatically eventhough logic, intuition and 0190 study data suggest that the drug maywork well for newly diagnosed patients. The termination of the studyalso was challenged on ethical grounds.

"One could argue that it's immoral to start a trial with an insufficientsupply of drug," charged Paul Bunn, ODAC's chairman and directorof the University of Colorado Cancer Center, in Denver. Later, Bunnvoted for approval of Gliadel as a second-line agent but said the drug"certainly is at the bottom of my threshold" for approval.

Other contentious issues at Friday's meeting included confusion overthe statistical significance of Gliadel's efficacy. The drug workedbest in a subgroup of patients, those with glioblastoma multiforme,and appeared to have no effect whatsoever on patients with othertypes of tumors, such as anaplastic astrocytomas. However, since thevast majority of brain tumors are of the glioblastoma multiformevariety, the subgroup turned out to be the majority of patients in thiscase. That is why the panel voted to restrict its approvalrecommendation only to glioblastoma multiforme patients. n

-- Lisa Piercey Special To BioWorld Today

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