WASHINGTON _ The FDA's Oncologic Drugs AdvisoryCommittee (ODAC) voted unanimously with one abstention onTuesday to recommend approval of Liposome Technology Inc.'s(LTI) DOX-SL as a second line therapy for AIDS-related Kaposi'ssarcoma under the FDA's accelerated approval program.
If the FDA follows ODAC's recommendation, DOX-SL could bemarketed to treat a subset of Kaposi's sarcoma patients _ those whohave failed combination chemotherapy due to disease progression orintolerable toxicities. Approximately 20,000 people in the U.S. sufferfrom Kaposi's sarcoma, the most commonly diagnosed malignancyin HIV-infected individuals.
Accelerated approval is a special, conditional category of FDAlicensure reserved for drugs that demonstrate efficacy against"surrogate markers," or indirect measures, of a life-threateningillness as opposed to demonstrating an impact on hard clinicalendpoints, such as survival.
The "condition" attached to accelerated approval is that confirmatoryproof of the drug's safety and efficacy must be demonstrated in post-marketing (Phase IV) studies. In the case of DOX-SL, ODACmembers concluded that the drug shows activity in shrinking andflattening the painful and disfiguring lesions associated withKaposi's sarcoma but were unsure whether lesion-shrinkagetranslated into a net clinical benefit for DOX-SL-treated patients.
The Next Best Thing
"Accelerated approval is the next best thing you can get to fullapproval," Nicolaos Arvanitidis, LTI's chairman and CEO, toldBioWorld. "It allows you to get the drug to market and to work withthe FDA on Phase IV trials in which you provide answers toquestions unanswered by the current data base."
If approved, DOX-SL would be the first liposomal formulation of adrug to reach the U.S. market. Based on LTI's so-called Stealthtechnology, DOX-SL consists of the widely prescribed cancer drugdoxorubicin hydrochloride encased in liposomes.
DOX-SL squeaked by after hours of intense debate about the poorquality of LTI's clinical data. ODAC members were sharply criticalof the unblinded, single arm study, known as LTI-30-12, whichformed the basis of LTI's new drug application (NDA). For thatreason, they voted unanimously with one abstention against"unconditional" (or regular) approval of DOX-SL. "It was not ablowout victory," conceded Arvanitidis.
"Frankly, we've all been appalled by what we've heard today," saidODAC chairman and oncologist Charles Schiffer after the finalDOX-SL vote. "We've acted on imperfect data with a hint ofefficacy and a burst of sympathy and that has caused meconsiderable discomfort."
LTI's data on the 77 patients it deemed evaluable in LTI-30-12showed that 34 percent experienced a "partial response" to DOX-SL,in terms of reductions in lesion size, lesion-associated edema andlesion thickness. A different method of assessing response rates,which was based on a clinical investigator's "global" assessment of apatient's illness, showed that 43 percent of patients experiencedpartial responses to DOX-SL therapy.
However, the FDA's analysis concluded that far fewer patients wereactually evaluable _ for a variety of reasons, including protocolviolations (such as not meeting the entry criteria of the trial) _ thanthe company did. Even so, The FDA's estimate of partial responsesto DOX-SL, as measured by lesions, was 48 percent (a higherresponse rate than the company's but in fewer patients, 42 instead of77). The FDA calculated that 27 percent of patients achieved apartial response based on investigators' assessments.
"No matter how the data were analyzed, you got response rates thatwere north of 30 percent," said Arvanitidis.
Ambivalence Reflected In Vote
But the depth of ODAC's ambivalence about LTI's study wasreflected in the voting on whether LTI-30-12 constituted an"adequate, well-controlled investigation." Five members said yes,five said no and one abstained. Legally, the FDA cannot approve adrug for any purpose unless the data are deemed adequate and wellcontrolled.
Robert Temple, director of the Office of Drug Evaluation I at FDA'sCenter for Drug Evaluation and Research (CDER), told BioWorldthat the committee's split vote would be interpreted to mean thatLTI-30-12 "was a well-controlled trial for purposes of assessingtumor [lesion] response," but not for proving "meaningfuleffectiveness." Such an interpretation would leave the door open forthe FDA to grant DOX-SL accelerated approval status.
One big problem with LTI-30-12 was the potential for biasintroduced by the unblinded nature of the study, according to ODACmembers. Numerous AIDS patients who testified before the start ofTuesday's meeting argued passionately for approval of DOX-SL,noting that lesion shrinkage is important to a patient's quality of lifewhether or not it alleviates disease.
But George Omura, ODAC member and professor of medicine at theUniversity of Alabama at Birmingham, noted that patients' intensesupport of DOX-SL cast doubt over the data. "There's clearly atremendous amount of interest in this agent," said Omura. "We havevery motivated patients who are anxious to be treated and anxious torespond combined with doctors who are anxious to help theirpatients get better. Compounding the problem is the use of somesubjective measures of benefit. We have to ask, does this open thedoor for patient and investigator bias?"
Tuesday's accelerated approval recommendation came at a criticaltime for LTI, which reported having $17 million in cash as of Sept.30, 1994. With current burn rates of $5 to $6 million per quarter,LTI's chief financial officer Peter Leigh said the company cansurvive only until mid-1995 without a fresh infusion of money.
LTI's stock (NASDAQ:LTIZ) has climbed nearly 41 percent inrecent weeks, from $6.44 per share at the beginning of the year to$9.06 on Monday. Trading was halted by NASDAQ on Tuesday toallow for wide dissemination and market digestion of ODAC'sdecision.
"The stock rise was largely due to expectations of a favorable FDAadvisory panel ruling and this was generally regarded as favorable,"said Arvanitidis. "You don't get a unanimous recommendation foraccelerated approval unless people believe the drug has a beneficialeffect in patients and they want to make it available as quickly aspossible." He added that LTI is "in a much better situation to raisecash than it was a day ago."
DOX-SL is also being studied as first line therapy for Kaposi'ssarcoma, a potentially larger market than second line therapy. OnePhase III trial is complete and results are now under analysis while asecond Phase III trial should be completed soon. Arvanitidis said LTIplans to file an NDA for the new indication by mid-year. Since LTIowns all worldwide marketing rights for DOX-SL, he said thecompany was in a good position to go shopping for a marketingpartner for the drug. n
-- Lisa Piercey Washington Editor
(c) 1997 American Health Consultants. All rights reserved.