Superiority just out of reach for Gilead's Quad

Gilead Sciences’ final pivotal trial of its Quad HIV pill was not the home run some investors had hoped for, but the infectious diseases specialist was safely on base. The combination regimen showed itself non-inferior to Truvada, and with fewer patients discontinuing because of adverse events observers now expect regulatory approval to come next year.

As the California group released little data beyond headline numbers, final judgement on its commercial outlook will have to wait until detailed safety data are released at a medical meeting early next year. Without clear differentiation on efficacy from Truvada and Atripla, it may take a stellar performance on safety to persuade large numbers of HIV patients to switch from already effective drugs, leaving new patients as its chief market.

Better on safety

The 48-week trial of Quad against Truvada plus Rayataz boosted by Norvir found that similar percentages of patients in both study arms achieved the primary endpoint of undetectable viral load, or fewer than 50 copies of HIV RNA per millilitre of blood – 90% for Quad and 87% for Truvada. As with a similar pivotal trial against Atripla, the results of which were released last month, Quad proved itself statistically no better than the comparator drug, disappointing some who expected it to be superior (Close but no cigar yet for Gilead’s Quad, August 16, 2011).

Gilead did release a little more information on safety this time: discontinuation rates were higher in the Truvada arm at 5.1%, compared with 3.1% for Quad. Elevated bilirubin levels in control-arm patients drove the difference in the dropout rate, company executives said.

Based on the results, the company has accelerated its regulatory timetable and now expects to submit an application to the FDA by the end of 2011, rather than in the first quarter of 2012. It will also seek a priority review of six months, although with a surfeit of HIV medications and an unclear efficacy advantage, analysts reckon a 10-month standard review is more likely.

Assuming no wrinkles in the regulatory pathway, Quad could be approved by the end of 2012 and launched in early 2013; analysts are suggesting that a finding of non-inferiority will be sufficient for approval.

Investors gave a warmer response to the latest trial – shares were up 1% to $40.62 in early trade today.

Switching drugs

A successful launch for the Quad is an essential bulwark for Gilead to defend its HIV franchise, which is estimated to account for 85% of its sales in 2011, according to EvaluatePharma forecasts. The Quad pill is forecast as its biggest growth driver between now and 2016, and will account for $920m in sales in that year.

Current top seller Atripla will continue as a major contributor over the 2010-2016 period, bringing in a forecast $3.14bn in 2016. Yet its sales have more or less peaked as annual growth will be 1% over the 2010-2016 period; moreover, generics are mounting significant challenges to the drug's patents which causes uncertainty although most analysts predict exclusivity until at least 2017.

Gilead currently pays out more than $1bn a year in partnership revenues to Bristol-Myers Squibb as the New York group developed and holds the rights to Sustiva, a component drug in Atripla. Thus Gilead has several incentives to shift its marketing efforts away from the Sustiva-containing compound.

Truvada is forecast to be a bigger contributor to sales growth, but has also reached the gentler grade of its sales ramp with annual growth of 3% a year.

The commercial question will be how persuasive the data is for HIV specialists and patients; those patients well controlled on Truvada may not wish to switch in the absence of side effects.

Based on a survey of high prescribers, analysts from UBS write that 13-15% of patients on dual nucleoside reverse transcriptase inhibitor therapy switch each year, a rate that the physicians surveyed believe will grow because of a desire for better-tolerated agents. UBS estimates Quad sales of more than $2bn in 2016. However, with a consensus forecast less than half that, it is clearly not a view shared by all.

There seems to be little doubt that the Quad will receive the regulators’ nod, and indeed a less-than-flawless approval pathway would probably be viewed negatively. But Gilead still needs to prove that existing HIV patients will be willing to switch – the data could still surprise, but it clearly has its work cut out.

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