GAITHERSBURG, Md. _ An FDA advisory panel on Wednesdayunanimously recommended the agency approve Abbott Laboratories'ritonavir for treatment of patients with advanced AIDS, but itwithheld broader approval until the company confirms with a newstudy that the drug helps patients who are early in the course ofdisease.
If the agency accepts the Antiviral Drugs Advisory Committee'srecommendation _ as it usually does _ ritonavir would joinHoffman-La Roche Inc.'s Invirase (saquinavir), which was approvedfor use in December, as a mainstay in HIV treatment _ but for anarrow class of patients. (See BioWorld Today, Special NewsBulletin, Dec. 7, 1995.)
That approval would be based on one study that ritonavir candramatically inhibit viral reproduction and lengthen survival inadvanced patients. A second study, looking at patients earlier in thecourse of the disease was less convincing.
Indeed, it suggested that treatment with ritonavir alone was moreeffective than combination therapy in early AIDS _ a finding thatcontradicts vast experience with other drugs.
Also, the drug has a narrow therapeutic range. If the dosage fallsbelow 600 mg every 12 hours, treatment would breed drug resistance.At 700 milligrams, the drug becomes toxic.
The committee took a second vote and ruled 8-to-1 with oneabstention to require that Abbott prepare a new protocol for treatmentof these patients and apply to the FDA again, but this time under theagency's rules for accelerated approval.
Andre Pernet, president of Abbott's antiviral division, told committeemembers that the company would work with the FDA to carry out along-term study on patients early in the course of their disease.
John Leonard, of Abbott's antiviral ventures division, which is basedin Abbott Park, Ill., however, told the FDA advisory panel that thedeath rate among ritonavir-treated patients with advanced AIDS was40 percent lower than among patients taking placebo.
When ritonavir was taken in combination with two other drugs, hesaid, patients experienced "a sustained suppression of HIV-RNAactivity, an increase of CD5 cell counts and was well tolerated."
A double-blind, placebo controlled study of ritonavir's effectivenessin patients with advanced AIDS _ involving 1,090 patients, dividedroughly in half between drug and placebo groups _ yieldedpromising results. In the ritonavir group, after six months oftreatment, 31 of the 543 patients died, compared with 52 of 547 inthe placebo group.
The primary side effects were nausea and vomiting. Some patientsalso experienced tingling. For the most part, in patients taking therecommended dosage, the side effects were temporary, lasting just acouple of weeks and rarely causing patients to discontinue theirtreatment.
Lab tests showed that patients taking ritonavir also experiencedincreases in their levels of platelets, white cell counts, neutrophils andmonocytes.
Apart from saquinavir, all of the previously approved AIDS drugs arenucleoside analogues, which interfere with HIV's gene replicationcycle. Protease inhibitors attack the virus later in its life cycle byblocking the action of an enzyme that virus particles employ tofashion a coating from the membrane of an infected cell.
A One-Two Punch
The FDA approved saquinavir at a low dosage for use in combinationwith the older class of nucleoside analogues, because research trialshave shown that combination treatments were more effective thaneither class of drug given by itself. Researchers say that, if ritonavir isapproved, the two drugs together would constitute a potent one-twopunch.
Ritonavir slows the metabolism of saquinavir, which means the drugcirculates in the blood at higher levels and for longer periods thanwhen saquinavir is given alone. That means doctors could prescribelower doses than the 1,200 mg that's required when saquinavir isgiven alone, said Thomas Quinn, a committee member and professorof medicine at Johns Hopkins University School of Medicine, inBaltimore.
Leonard said that given together, the two drugs, "may represent abarrier the virus will be unable to overcome."
But the evidence in support of the application was not ironclad.
Patients, community activists and physicians _ as well as severalmembers of the advisory committee and its consultants _ cited ahost of unanswered questions. Among them, is an absence of long-term data on safety; the drug's potential for provoking HIV resistanceto protease inhibitors and spreading that resistance nationwide; andthe absence of trials involving pregnant women, infants and children_ which effectively will deprive them of the latest treatmentsbecause of the lack of data.
Lingering Doubts Were Voiced
Douglas Mayers, head of the HIV drugs and gene therapy for WalterReed Army Institute of Research, in Rockville, Md., and a consultantto the committee, said: "I don't know if this drug is safe after sixmonths. I don't know what the resistance profile is. I don't knowabout the long-term toxicity of this drug. No one will be taking thedrug for six months, most people will be taking it for two or threeyears. There's also a narrow window of toxicity with this drug. AndI'm not sure the Phase IV trials the company has put forth is going toanswer these questions in a meaningful way."
Judith Feinburg, associate professor of clinical medicine at theUniversity of Cincinnati, Ohio, and a committee member, said shewas very concerned about the "minefield of potential druginteractions" with this drug.
Arthur Ammann, chairman of the Pediatric AIDS Foundation, ofNovato Calif., speaking as a member of the public, called on thecommittee to recommend approval of ritonavir for adults, but tomake that contingent upon the development of a post-approval timeline to be submitted to FDA in March detailing studies on pregnantwomen, newborns and infants with AIDS.
Ammann called upon the committee to "join with me in trying tomake ritonavir the very last drug for a serious or life-threateningcondition that is withheld from infants and children solely because ofthe collective neglect of the manufacturer and FDA."
Ronald Baker, a consultant to the FDA's Antiviral Drugs AdvisoryCommittee and editor of the San Francisco-based Bulletin ofExperimental Treatments for AIDS, called for widespread patienteducation on how to use the drug most effectively, to minimize thepossibility of promoting resistance and the risk of drug interactions. n
-- Steve Sternberg Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.