By and large, Gilead's latest Phase II results for its fixed-dose, four-drug "Quad" regimen for HIV and stand-alone data on its novel GS-9350 booster satisfied clinicians and analysts when it came to the commercially crucial tolerability test.

But there were a few disappointing findings in the mix, notably insufficient differentiation of the side effect profile between Gilead's GS-9350, which is included in the Quad co-formulation, and Abbott's rival Norvir (ritonavir), the only currently available booster for HIV therapy.

Positive safety and efficacy results for two small Phase II studies on Gilead's Quad pill and booster were presented by the Community Research Initiative of New England's Calvin Cohen at the Conference on Retroviruses and Opportunistic Infections in San Francisco on Feb. 17. The presentation of the full datasets followed a top-line release last month (¹ Also see "Gilead's Positive Phase II Data On Quad Pill For HIV Eases Analysts Concerns" - Pink Sheet, 6 January, 2010.).

The once-daily "Quad" tablet combines four Gilead compounds: the marketed Truvada (combining emtricitabine/tenofovir); GS-9350 (cobicistat), a novel agent that increases blood levels of certain HIV drugs; and elvitegravir, an investigational integrase inhibitor.

Gilead also has been studying cobicistat as a stand-alone boosting agent for other antiretroviral medications, such as Bristol's once-daily protease inhibitor Reyataz (atazanavir).

Gileads's future depends on the success of new compounds. Patents for Atripla , the company's three-drug combination (efavirenz/emtricitabine/tenofovir), Viread (tenofovir) and Truvada are due to expire from 2017 to 2021. These three drugs had combined sales of about $5.5 billion in 2009; Gilead's total sales were $7 billion.

Efficacy with existing HIV regimens is hard to beat, but there is much room for improvement when it comes to convenience, side-effect profile, adherence and avoidance of treatment resistance.

"Differentiation here will ultimately be important to Gilead's success moving market share from its current flagship Atripla to Quad, extending the life cycle of the HIV franchise beyond the 2017 to 2021 patent expiries, while simultaneously improving its economics," wrote Baird analyst Tom Russo in a Feb. 18 note.

Quad Pill Means Sweeter Dreams

In one study presented at the CROI meeting, the Quad pill's antiretroviral activity tested well against Atripla in 71 patients, as expected. At 24 weeks, the proportion of patients who achieved HIV RNA (viral load) less than 50 copies/mL was 90 percent in the Quad arm compared to 83 percent in the Atripla arm. It wasn't a statistically significant difference, but it did show non-inferiority.

"I think from an efficacy perspective they hit the nail on the head," said Daniel Kuritzkes, professor of medicine and director of AIDS research at Brigham and Women's Hospital in Boston.

"They did exactly what they needed to do and showed that the Quad was as effective as an Atripla-based regimen in suppressing viral replication," Kuritzkes said during a Feb. 18 J.P. Morgan call.

The Quad pill also had a much better overall side effect profile, and fewer CNS effects, which can be very problematic with Atripla treatment. About 10 percent on the Quad pill had CNS events, such as abnormal dreams and nightmares, versus 35 percent in the Atripla arm. In absolute terms, the numbers were small, reflecting the size of the study (five events for the Quad versus eight for Atripla). Discontinuation rates due to adverse events were comparable in both arms of the study.

However, the side-effect profile was not perfect. There were a few more cases of diarrhea and nausea in the Quad arm compared to the Atripla group. Specifically, there were four cases of diarrhea (eight percent of participants) compared to one case (four percent) for Atripla. There were also two cases of nausea (four percent) for the Quad pill, versus one in the Atripla group (four percent).

Ritonavir has been linked to gastrointestinal side effects, so the findings raise concerns about competitive positioning, as well as tolerability.

Also, as Kuritzkes pointed out, previously it had been thought that '9350 was very free of side effects, so expectations were high.

"I think it's important to remember that these are small numbers, we are talking about events that are occurring in literally a handful of patients," Kuritzkes said. "It could be that when they do a bigger study in Phase III this is all going to wash out and there will be nothing there. But it could also be that maybe this is really a lot like ritonavir and it turns out that there is only a modest improvement in tolerability."

There was some evidence of elevated serum creatinine, a measure of kidney function in the Quad study. But presenter Cohen highlighted very persuasive follow-up research in healthy volunteers showing that this was a laboratory effect and not a sign of a real kidney problem, said Bradley Hare, assistant clinical professor of medicine at the University of San Francisco and medical director of the UCSF Positive Health Program.

Nevertheless, clinicians at the CROI meeting were concerned about how they would be able to differentiate in practice between an inconsequential laboratory effect and a real underlying problem with the kidneys.

"There is still a little question mark about how that will affect use of the drug. It's not a big deal, just a footnote to pay attention to as the drug goes forward to larger studies," Hare said.

Phase III testing of the Quad pill is expected to start in the middle of this year.

Booster Results Also Raise Questions

Some arguably disappointing results also emerged in a second study presented by Cohen, comparing GS-9350 to Abbott's Norvir. In that trial, researchers compared GS-9350-boosted atazanavir to ritonavir-boosted atazanavir (each in combination with Truvada) in 79 patients.

Gilead's booster achieved non-inferiority to Norvir. But as Merriman Curhan Ford analyst Michael King pointed out in a Feb. 18 note, in the GS-9350 arm, there were a few more patients with Grade 2 to 4 effects on cholesterol and protein in the urine, a potential sign of kidney damage.

"The company stated that the median increase in cholesterol - HDL, LDL and triglycerides - is the same between the arms. These differences will need to be ironed out in larger studies, in our view," he said.

Rates of diarrhea and nausea were comparable for the two boosters.

The major downsides to using ritonavir as a booster have been GI and cholesterol problems, and the Gilead booster didn't really improve on either one of those effects, Hare said.

However, GS-9350 offers an important advantage - its lack of anti-HIV activity, meaning it doesn't act on the disease on its own.

"That sounds contrary but it is a good property," Hare said. "It's desirable when you want not to inhibit HIV, but to boost other drugs."

Ritonavir is a protease inhibitor on its own, with anti-HIV activity, but it has high levels of side effects at effective doses. Instead the drug has found a niche role for use at low doses as an add-on to boost the activity of other protease inhibitors. However, if the booster were to be used in a regimen that did not involve a protease inhibitor, the low level of activity could result in treatment resistance to protease inhibitors.

Overall, the side effect profiles of the booster and Quad pill appear to be within acceptable ranges, even though they fall short of ideal when it comes to offering advantages over Norvir, Hare said.

That's an outcome that has been appreciated by analysts tracking the drug. "Quad's differentiated profile, which will be key to commercial success, clearly began to emerge at CROI, and cobicistat came through intact in its own right," Baird's Russo concluded.

- Emily Hayes (² e.hayes@elsevier.com)

Gilead's HIV Quad Pill Passes Tolerability Test, But Not With A Straight "A"

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