Quad PDUFA is Nigh; Approval Likely for Next HIV Blockbuster

By Jennifer Boggs
Managing Editor

A robust second quarter, approval of HIV drug Truvada (emtricitabine/tenofovir disoproxil fumarate) for prophylactic use and competitor setbacks that could add to its lead in the race for an all-oral hepatitis C virus regimen all contributed to an impressive summer for Gilead Sciences Inc.

But that string of good news has been a mere diversion for followers of the company's stock, who have kept their eyes trained on the expected FDA nod four-drug HIV tablet Quad. (See BioWorld Today, July 17, 2012, July 27, 2012, Aug. 3, 2012, and Aug. 17, 2012.)

The future of Gilead's HIV franchise rests largely on Quad, which is aimed at bolstering the HIV portfolio ahead of patent expiries, set to start in 2018. The top-selling franchise brought Gilead $7.05 billion in revenue for 2011, with 96 percent of that coming from Atripla, Truvada and Viread.

Analysts are expecting a clean approval by the Aug. 27 PDUFA date. Quad, which combines the ingredients of Truvada plus elvitegravir and boosting agent cobicistat, got a 13-1 vote in its favor during a May Antiviral Drugs Advisory Committee meeting and, in an unusual move by the International AIDS Society-USA, was included in the IAS-USA guidelines released during the AIDS 2012 meeting in Washington last month.

Those guidelines are updated every two years, but rarely include drugs that have yet to gain FDA approval.

Quad would follow on the heels of Gilead's other single-tablet regimens – Atripla, which combines Truvada plus Bristol-Myers Squibb Co.'s Sustiva (efavirenz), and Complera, which combines Truvada plus Johnson & Johnson's Edurant (rilpivirine) – but would be the first single-tablet drug co-formulated with an integrase inhibitor.

Designed to block the action of viral enzyme integrase, which inserts the viral genome into the DNA of a host cell, integrase inhibitors work by stopping that integration in the retroviral replication process, thereby preventing the spread of the virus. Merck & Co. Inc.'s Isentress (raltegravir) has become a staple in HIV therapy since its approval in 2007. It recorded $1.4 billion in sales for 2011 . But that drug has never been co-formulated into a single-drug regimen.

In addition to its Quad application, Gilead also is seeking approval of elvitegravir as a drug in its own right. A separate new drug application (NDA) also is under review for the cobicistat boosting agent, which will compete with marketed boosting agent ritonavir.

The Quad NDA is based on 48-week data from two Phase III noninferiority studies, one pitting Quad against Gilead's own Atripla and one testing the drug against atazanvir/ritonavir plus Truvada in HIV-1-infected antiretroviral-naïve adults. In the first study, 88 percent of Quad patients achieved viral load reduction vs. 84 percent of patients on Atripla. The second study had Quad demonstrating an impressive 90 percent viral load reduction, compared to 87 percent in the atazanvir/ritonavir/Truvada arm. (See BioWorld Today, Aug. 16, 2011, and Sept. 21, 2011.)

Its more convenient dosing should allow Quad to steal a portion of the Isentress market. Deutsche Bank analyst Robyn Karnauskas pointed out that there are roughly 20,000 patients taking Isentress as a first-line therapy, "which is low-hanging fruit for Quad," she wrote in a research note.

While consensus estimates are projecting a modest launch for Quad, which Gilead has said it is ready to roll out as soon as approved, Karnauskas is anticipating a stronger start, pointing to the Foster City, Calif.-based firm's track record in HIV drug launches. Atripla, for example, nearly reached blockbuster status in its second year on the market.

Complera, nicknamed "Btripla," has been slower to ramp up sales, but that drug had been intended to serve as a bridge between Atripla and Quad approval. (See BioWorld Today, Aug. 12, 2011.)

Deutsche Bank is modeling Quad sales of $85 million in 2012 and $746 million in 2013, well above consensus projections of $45 million and $400 million, respectively.

The Pricing Controversy

Of course, it all depends on pricing, and that likely will prove the biggest area of controversy for Quad. Gilead, which has yet to disclose its pricing strategy, already has come under fire from Congress to reduce the cost. In a letter to the company's chairman and CEO, John Martin, 13 House members last week claimed that an anticipated price tag in the range of $26,000 to $34,000 per patient per year could cause a funding crisis for state-run AIDS Drug Assistance Programs. (See BioWorld Today, Aug. 16, 2012.)

Quad is expected to be priced at a premium to Atripla, which was priced at $21 ,000. Complera came in at a 4 percent premium to Atripla. But Karnauskas has predicted a price range of $26,000 to $29,000 based on comments from Gilead management.

All told, analysts have predicted that Quad could end up generating as much as $4 billion per year, though more conservative estimates have pegged the drug's potential to be limited by the fact that it showed only noninferiority to Atripla – rather than superiority – which could put it at a disadvantage when generic Atripla hits the market in 2018.

There's also potential competition from GSK572 (dolutegravir), a next-generation integrase inhibitor from GlaxoSmithKline plc and Shionogi & Co. Ltd. That drug demonstrated superiority to Atripla last month, with statistical significance driven primarily by discontinuations in the Atripla arm due to adverse events, though analysts have pointed to potential cardiovascular risks seen in an earlier epidemiological study of one of the drug’s components. (See BioWorld Today, July 12, 2012.)

Gilead also expects a first quarter 2013 approval for Quad in the European Union.