ROCKVILLE, Md. -- Betaseron, a beta interferon analog, got abig boost on Friday when the Peripheral and Central NervousSystem Drugs Advisory Committee of the FDA voted 7-2 torecommend approval of Chiron Corp. and Berlex LaboratoriesInc.'s product licensing application (PLA).
It would be the first new treatment for symptoms of multiplesclerosis (MS) in 20 years, succeeding cyclosporin, an immunesuppressant of questionable efficacy.
Berlex's unit in Richmond, Calif., developed the product,conducted trials and will market Betaseron (interferon beta-1b) in the U.S. if it is approved by the full FDA.
Auto immune demyelination in the central nervous systemcauses the symptoms of MS, which range from numbness andtingling to spasticity and motor disability in the limbs, andoccasionally incontinence, blindness or cognitive problems.
Though the course of the disease is extremely variable, looselyspeaking it takes two forms: an initial "relapsing-remitting"phase that can persist for a decade, in which symptoms strikesuddenly, lasting from a day to several weeks, and asubsequent chronic-progressive phase in which the patientmay become increasingly disabled over years, or even decades.
Clinical trials at centers in the U.S. and Canada examinedfrequency and severity of relapse-remission in patients onplacebo and on doses of 9 million and 45 million internationalunits of Betaseron. Overall, those on placebo averaged 1.27relapses per year, compared with 1.17 for the low-dose group,and 0.84 for the high-dose group. Thirty-one percent ofpatients on the high dose remained free of relapses for a year,compared with only 16 percent of those on placebo.
Donald Paty, chairman of neurology at the University of BritishColumbia and a pioneer in the use of magnetic resonanceimaging (MRI) to diagnose MS, said that patients on placebo,who had the highest relapse rate, also had the highest increasein lesion burden -- an 18 percent increase, while demyelinationactually declined by about 4 percent in those on the high dose.
Debate over approval turned on several issues. There was someargument over whether disability might be a more appropriateoutcome that relapse. "Exacerbation can be very debilitating,"Stephen Rheingold, vice president for research and medicalprograms for the National Multiple Sclerosis Society, toldBioWorld. Furthermore, the relapsing-remitting stage afflictstwo-thirds of the estimated 300,000 Americans who have MS.
Finally, controlling this might reduce severity of the later,chronic-progressive form, he said.
A second issue was the quality of double-blinding, which is avery difficult task in MS trials. Ultimately, committee membersagreed that researchers had taken every possible precaution.
A final issue was that FDA's decision would have to turn on onestudy instead of two. Nonetheless, several committee memberswere loath to set a different precedent. "People will look toyour evaluation of this data as to how you are likely to respondto future applications," warned Paul Leber, director of thedivision of neuropharmacological drug products in FDA's Centerfor Drug Evaluation and Research (CDER).
Certainly CDER has approved treatments for life-threateningdiseases where the endpoint is mortality on the basis of asingle study," said Janet Woodcock, director of the office oftherapeutics in FDA's Center for Biologics Evaluation andResearch. "CBER has approved a number of therapeutic agentsfor serious diseases on the basis of a single trial."
In the end, committee members were only moderatelyimpressed with the clinical data, but they were very impressedby the MRI data, and also very impressed that trends in thedata were consistent for all of the different endpoints, and ateach of the trial centers in the U.S. and Canada.
"With the MRI data, I felt it was extremely convincing," saidcommittee member Sid Gilman, chairman of neurology at theUniversity of Michigan, Ann Arbor.
Another committee member, Ira Shoulson, professor ofneurology, pharmacology and medicine at the University ofRochester School of Medicine, praised Berlex's analysis,documentation and presentation.
After the vote, Theresa Gerrard, acting director of the divisionof cytokine biology at CBER, said she expected a final decision"before summer." It would then take "some months" tocomplete scale-up from laboratory to commercial scale to getthe drug into the market, Jeffrey Latts, Berlex's vice presidentfor clinical research and development, told BioWorld.
Analyst Brandon Fradd of Montgomery Securities said thedecision was pretty much in line with expectations. "Mostpeople are very impressed with the MRI data," he said. "Thesafety profile is better than I expected."
Fradd said his estimates on Chiron's yearly earnings fromBetaseron could be "off by a substantial multiple." He hadestimated sales at $7 million in pretax earnings for Chiron nextyear using the price of about $3,000 per year per course oftherapy for Betaseron. But when you consider that alpha-interferon for treating hepatitis costs $5,000 for half a year,then $3,000 for Betaseron is "on the low side."
While Chiron's stock (NASDAQ:CHIR) rode a very busy roller-coaster for much of the day, with 2.7 million shares traded, thestock ended the day at $50.50, off $2.25 a share. Fradd said,however, that the stock was bouncing back in after-markettrading.
D. Gregory Brown, an analyst with Vector SecuritiesInternational, projected in January that Chiron's revenues fromBetaseron will reach $36 million in 1994 and will surpass $100million in '95. His model does not project '93 Betaseronrevenues.
Chiron of Emeryville, Calif., and its marketing partner, BerlexLaboratories Inc. of Cedar Knolls, N.J., the U.S. subsidiary ofSchering AG, filed a PLA on Betaseron last June for treatingrelapsing-remitting MS patients.
Berlex has three units: two in Wayne, N.J., and one in Richmond,Calif.
Wendy Neininger, Berlex's director of corporatecommunications, told BioWorld in December that the companyis planning clinical trials in patients with chronic progressiveMS this year.
-- David C. Holzman Washington Bureau
(c) 1997 American Health Consultants. All rights reserved.