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FDA panel recommends Gilead's Quad for HIV - FDA Briefing Document attached, below are summary excerpts from the document at the bottom of this report
  FDA briefing document

Gilead briefing document

By David Morgan

WASHINGTON | Fri May 11, 2012 5:04pm

from Jules: QUAD is potent, its the first once daily single tablet integrase inhibitor, its boosted by cobicistat, a substitute made for ritonavir. In the 2 main phase 3 studies in absolute numbers it was at least as potent as Atripla and Reyataz. QUAD appears associated with renal side effects which the committee said is manageable in their panel discussions. These discussions were extensive in examining the data related to renal side effects and you can review the data in detail in the attached FDA briefing document. The FDA & Gilead will be providing a renal management algorithm for clinicians & patients to follow. This is the first fixed dose combination integrase inhibitor. Several years ago Merck launched raltegravir which was the first integrase inhibitor which is taken twice daily, its not boosted, with a clean side effects profile, and ViiV will be launching it's potent once daily integrase inhibitor dolutegravir very soon as its currently in global phase 3 studies, which will be also a once daily, not boosted, and in a fixed dose once daily combination with abacavir+3TC.

(Reuters) - A U.S. Food and Drug Administration panel of outside experts on Friday recommended the use of Gilead Sciences Inc's Quad pill for untreated HIV patients.

The FDA advisory committee voted 13-1 to endorse the four-drugs-in-one treatment, but members said there should be effective monitoring for potential kidney problems among patients and urged further research to determine the drug's safety profile for women, who have been under-represented in clinical research.

This is the first time the FDA has been asked to give marketing clearance to a fixed-dose combination containing two drugs that have not, individually, been reviewed and approved by the agency.

The panel's recommendation will now be taken into account by agency regulators, who are expected to decide on final approval for Quad by August 27.

An overwhelming number of the experts said they were satisfied with Gilead's demonstration of safety and efficacy.

But Dr. Michelle Estrella of Johns Hopkins University School of Medicine, the panel's lone 'no' vote, said data on potential renal problems and women's health was too limited to justify her approval.

"There are plenty of alternatives to Quad," she said. "There's no huge hurry in approving this drug before the outstanding studies are completed."

Gilead shares closed 1.2 percent higher at $51.84 after the committee voted.

Wall Street analysts said the panel's action was expected and predicted more good news for Gilead on the FDA front.

"Approval of the Quad is likely with renal monitoring. Renal monitoring is not a particular concern," J.P. Morgan analysts said in a note to investment clients. "We believe the Quad will further strengthen Gilead's market leading HIV business."

In fact, the new drug is seen as key to Gilead's continued dominance of the market for HIV drugs. Most of the company's current drug sales, which totaled $8.1 billion last year, come from Atripla, a once-daily pill that combines Truvada with Bristol-Myers Squibb's Sustiva. Truvada consists of Gilead's older HIV drugs Emtriva and Viread.

On Thursday, the panel also recommended Gilead's Truvada pill as the first-ever drug for use in preventing HIV infections.

Nearly 1.2 Americans are infected with the human immunodeficiency virus that causes AIDS and the HIV epidemic grows by 50,000 new cases each year, according to the U.S. Centers for Disease Control and Prevention.

Company research shows Quad to be 88% effective at suppressing HIV infection, surpassing 84% efficacy for Atripla. But data also indicated a disproportionate number of kidney problems among the hundreds of patients who participated in clinical trials.

The panel's approval recommendation is based primarily on the 48-week results of two similar Phase III clinical trials: Gilead studies 102 and 103. Both studies were non-inferiority studies comparing QUAD to standard regimens currently used to treat HIV: ongoing Study 102 compares the Quad to Atripla (efavirenz plus tenofovir and emtricitabine); ongoing Study 103 compares the Quad to ritonavir boosted Reyataz plus Truvada (tenofovir plus emtricitabine).

1,408 were randomized in 2 main studies 701 received Quad, 352 received Atripla and 355 received Norvir-boosted Reyataz plus Truvada. Participants in Study 102 were recruited in the United States, while 54% of those in Study 103 were from US.

After 48 weeks 87.6 percent of those receiving the Quad, compared with 84.1% of those receiving Atripla, had viral loads below 50 copies in Study 102, and in study 103, 89.5% in the Quad group, compared with 86.8 percent of those in the Norvir-boosted Reyataz group, had undetectable viral loads.

It combines the experimental integrase inhibitor elvitegravir with the boosting agent cobicistat and two older nucleotide reverse transcriptase inhibitors - emtricitabine and tenofovir.

If approved by the FDA, Gilead executives said Quad would provide HIV suffers with the first ever once-daily integrase inhibitor, a class of drug designed to block the spread of HIV by preventing the virus from binding with the DNA of host cells.

Advocates said the one-a-day regimen would encourage patients to adhere to the treatment with Quad, boosting the likelihood of high efficacy outside the clinical atmosphere.

But HIV activists who provided public testimony warned policymakers to be wary of new HIV drugs that provide only marginal improvements over current treatments but allow drug makers to charge significantly higher prices at a time when public assistance can be restricted by government budget constraints.

"Reduced access here in America is compelling AIDS activists to rethink the rules on drug pricing," said James Driscoll of the AIDS Healthcare Foundation, a Los Angeles-based nonprofit group that provides care for nearly 170,000 HIV and AIDS patients.

Gilead said it has yet to establish a price for Quad. Atripla currently costs about $20,000 a year.

WSJ: Gilead is hoping that the one-pill, once-daily Quad regimen will provide more convenience to HIV patients, many of whom now take multiple pills for treatment. Some analysts think it could become a blockbuster seller.

The FDA said clinical studies of the Quad showed it met study goals looking at effectiveness by reducing viral load in patients and said adverse events were similar among patients treated with the Quad compared to those being treated with other HIV drugs. However, the FDA said slightly more patients in the Quad study groups stopped the drug because of kidney-related side-effects compared to patients not receiving the drug.

Gilead submitted two clinical studies involving Quad. One 700-patient study compared it with Atripla, which combines three HIV medicines in a single, once-daily pill, as an initial therapy for HIV infection. Atripla is a combination of Gilead's Truvada with Bristol-Myers Squibb Co.'s (BMY) Sustiva. The study met its goal of showing both drugs were similar in treating HIV by suppressing the so-called viral load. The study found that 88% of Quad recipients had viral suppression 48 weeks after starting treatment, versus 84% of Atripla users.

Another study involving about 700 patients compared the Quad to patients taking Truvada in addition to another HIV drug, atazanavir/ritonavir and showed the Quad reduced viral load in 90% of patients after 48 weeks compared to 87% of patients being treated with the other drugs.

FDA Briefing Document Excerpts: document attached with full review by FDA

Renal Summary:

The disproportionate number of renal adverse events leading to study drug

discontinuation (including proximal tubulopathies) in the EVG/COBI/FTC/TDF group combined with a higher frequency of graded serum creatinine and urine protein abnormalities raise a question as to whether two discrete processes may be at work: a non-pathologic decrease in eGFR as the Applicant maintains and a bone fide increased risk of renal dysfunction. The difficulty arises in assessing for and rapidly discriminating between these two events, as a modest elevation in creatinine and modest decline in eGFR is anticipated with the use of EVG/COBI/FTC/TDF, but prolonged use in the setting of renal injury should be avoided.

The Applicant proposes the following renal safety measures with respect to the use of EVG/COBI/FTC/TDF: 1) assess CrCl before initiating treatment with

EVG/COBI/FTC/TDF and do not initiate treatment in patients with a CrCl < 70 mL/min; 2) discontinue EVG/COBI/FTC/TDF if the estimated CrCl declines below 50 mL/min; 3) perform routine monitoring of estimated CrCl and serum phosphorus in patients with renal impairment or at risk of renal impairment; 4) avoid administration of EVG/COBI/FTC/TDF with concurrent or recent use of nephrotoxic drugs.

General Summary:

In the two pivotal Phase 3 trials, EVG/COBI/FTC/TDF was shown to be non-inferior to the comparator groups with respect to efficacy. Rates of virologic failure were low in the EVG/COBI/FTC/TDF group and similar to rates demonstrated in the comparator groups.

The safety profile of EVG/COBI/FTC/TDF was generally acceptable. In the pivotal Phase 3 studies, there was a lower overall incidence of premature study drug discontinuation due to AEs in the EVG/COBI/FTC/TDF group compared to either control group. The overall incidence of any treatment-emergent AEs, moderate to severe AEs, and SAEs judged as related to study drug by the investigator was similar between groups. An apparent disproportionate number of renal AEs leading to study drug discontinuation (including proximal tubulopathy) occurred in the EVG/COBI/FTC/TDF group compared to the control groups. Also, women comprised only 10% of EVG/COBI/FTC/TDF subjects in the pooled Phase 3 studies. Given the relatively small percentage of women enrolled, our ability to identify potential safety signals in this population may be limited.

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