Synergen Inc. will conduct another Phase III trial before askingFDA to approve its anti-infective, Antril, Chief Executive OfficerJon Saxe said Tuesday.
In February, when Synergen announced disappointingpreliminary results from its first Phase III Antril trial, Saxesaid the company planned to discuss with regulatory agenciesin the U.S., Canada and Europe submitting a product licenseapplication in the third quarter.
On Tuesday, Saxe spoke on a conference call after results fromthe Boulder, Colo., company's first Phase III trial werepresented at the 13th International Symposium on IntensiveCare and Emergency Medicine in Brussels, Belgium.
Data presented by Charles Fisher Jr. of the Department ofPulmonary and Critical Care Medicine, the Cleveland ClinicFoundation and Case Western Reserve University showed thatalthough there was no significant difference in survival timesamong treatment groups in all patients, in two-thirds ofpatients with the highest predicted risk of mortality, thosetreated with a high dose of Antril had a 22 percent reduction inmortality compared to placebo. The level of significance wasp=0.032.
Synergen's stock (NASDAQ:SYGN) closed at $11.38 a share onTuesday, down $1.75.
"Clearly the stock market's in a 'show-me' mode withSynergen," said Jeff Casdin of Oppenheimer & Co. "I think whatthey had to say was not more disappointing than what theysaid earlier, but maybe the fact that they had nothing to say onthe upside was a disappointment to some."
A large short-interest segment selling off the stock at the firstsign of news Tuesday may have fueled the drop, noted JimMcCamant, publisher of the Medical Technology Stock Letter, aswell as institutional investors clearing the stock from theirbooks before the end of the quarter. McCamant considers thedrug potentially valuable and the stock attractive since it isselling well below book value of about $14 a share.
Synergen spokesman Michael Durand of the Porter/Novellipublic relations firm in New York helped arrange a satellitevideo hook-up broadcast from Brussels to New York andBoulder. He said the bright spot revealed Tuesday was a"powerful new diagnostic tool" for predicting which patientsmight benefit from treatment with Antril, an antagonist to theimmune cascade mediator interleukin 1.
Based on patients' APACHE (acute physiology and chronichealth evaluation) scores, underlying disease, age, past medicalhistory and other risk factors, a mathematical algorithm wasdeveloped to predict a given patient's chances of survival.According to Durand, the new tool holds the potential to"change the landscape of treating sepsis."
"The risk prediction method used in this study was developedby APACHE Medical Systems specifically to predict mortality inpatients with sepsis and uses information that can readily bedetermined prior to treatment," said Synergen's Saxe.
A priori patient identification has been one of the toughestchallenges facing companies developing drugs for sepsis. Tocombat a deadly disease that runs its course in roughly 72hours, physicians must be able to quickly and accuratelyidentify patients who would benefit from a particular therapyat the bedside.
Edmund Debler, who follows the company from the researchhouse Mehta & Isaly, said that the predictive model is positive."They have made some major strides in isolating somesubgroups and understanding the progression of the disease,"Debler said. "It can be very useful in the study of the diseaseand in clinical diagnosis and treatment."
Industry observer Carol Hall of BioVenture View was intriguedby the notion of using a computer software model to predictwhich patients would be most suited for inclusion in the nextPhase III trial. The concept of using hand-held computerscombined with the algorithm software to assess risk was raisedby Fisher on Tuesday, but Synergen has not specified how itwould utilize the risk prediction model in the next Phase IIItrial.
Hall's colleague at BioVenture, Cynthia Robbins-Roth, had somefundamental concerns with the Antril data, risk predictionmodels aside. "The real question here is, why isn't thiscompound, which intervenes at the level of the cytokinecascade and theoretically mediates immune response, morehelpful earlier in the disease?" she said.
"Biologically speaking, it doesn't make complete sense thatAntril only works in very sick patients."
The company will file for Antril approval in Europe in the thirdquarter of this year, Saxe said. This strategy did not win overanalysts, however.
"Cytogen Corp. fell on their face in Europe with their imagingagent," noted analyst Robert Peterson of Hanifen, Imhoff Inc. inDenver. "You need a pretty big marketing force."
David Webber of Alex. Brown & Sons will not project approvalin Europe before approval in the U.S., which he now estimatescould be either in late 1995 or early 1996. "Odds are, this drugworks and will be approved," he said, pointing to a reasonablylarge, accessible subgroup that may benefit from Antriltreatment.
Kenneth Collins, Synergen's chief financial officer, expects thecompany to finish the year with $150 million in cash.
"The bottom line," Webber added, "is positive for the product.But there are still questions about the size of the market andthe volume that will go to the competition because of the real,but modest benefit (of Antril) and the uncertainty of timing forapproval."
Competing companies, in fact, will concentrate on enrollingsicker patients in clinical trials that may capitalize on theopening created by Antril's slower progress.
In six Phase III trials over "five long years," said PatrickScannon, Xoma Corp.'s vice chairman for scientific and medicalaffairs, the general implication has been that potentialtreatments work in patients who are severely ill. Xoma ofBerkeley, Calif., is designing a new Phase III trial for its anti-endotoxin E5, and has started a Phase I trial for BPI, anotherpotential sepsis treatment. "The field is really open," Scannonsaid, "to those people who can really find and identify patientswho have severe sepsis."
Immunex Corp. of Seattle has a Phase II trial of two fusedsoluble TNF receptors in sepsis. The product is intended tomodulate the central mediator of sepsis, said Mary McConnon,the company's communications manager. The company also hasa Phase I trial of a soluble receptor for interleukin 1.
Cortech Inc. of Denver, Incyte Corp. of Palo Alto, Calif., andChiron Corp. of Emeryville, Calif., have also been working onsepsis therapeutics.
"Maybe the door's open a little wider now for another drug tobe better," Debler concluded. A Phase II trial of Antril hadfueled hopes by showing up to 64 percent fewer deaths inpatients treated with Antril.
"What we have is less effective than we originally thought,"Debler said, "which will be useful, but hopefully for all ofmankind another drug will come along and replace this one."
-- Nancy Garcia Associate Editor
(c) 1997 American Health Consultants. All rights reserved.