Prospects for the upcoming Phase III trials of the once-daily integrase inhibitor S/GSK1349572 from the Big Pharma joint venture ViiV are looking good following the release of positive Phase II data at the International AIDS Society meeting in Vienna.

The '572 compound is one of the first novel agents backed by ViiV Healthcare, a relatively new joint venture between GlaxoSmithKline and Pfizer geared specifically for HIV and AIDS (Also see "GSK And Pfizer Join Forces In New HIV-Focused Venture" - Pink Sheet, 3 November, 2009.).

Developed jointly by GSK and the Japanese pharma Shionogi, '572 is being positioned as a once-daily integrase inhibitor that does not need a "booster." Boosting, commonly with a low dose of ritonavir, is used to enhance effects of HIV medications but adds to the side effect burden and creates greater risk for treatment resistance.

The '572 compound is being targeted at both treatment-naïve patients and those who are treatment-experienced and resistant. During a late-breaker session at the IAS meeting in Vienna on July 22, investigators presented positive results from the partially-blinded, dose-ranging SPRING-1 study of 205 treatment-naïve patients, in which the drug proved safe and efficacious. On July 19, positive results for treatment-experienced and resistant patients were reported at the conference.

With the release of the Phase II studies, Shionogi and ViiV announced the drug is now Phase III-ready, with trials set to get under way this year. Details about the design of the trials, dose and formulations are not available. ViiV did confirm that the program will kick off in the fourth quarter.

Wanted: Once-daily Integrase Inhibitors

Integrase inhibitors now represent the most promising new class in HIV, particularly after the recent late-stage failure of Merck-Schering's CCR5 inhibitor vicriviroc, Bradley Hare, medical director of the UCSF Positive Health Program, commented. Merck-Schering announced the discontinuation of vicriviroc on July 14, following the release of disappointing Phase III results earlier this year.

Merck's twice-daily integrase inhibitor Isentress (raltegravir) is currently the only approved drug in the class. Enjoying its first-to-market status, Isentress garnered about $750 million in sales for 2009, up from $360 million the previous year.

The class got another boost from new IAS-USA guidelines, which for the first time included raltegravir as a front-line option, echoing new guidelines from the U.S. Department of Health and Human Services (Also see "Merck's Isentress Gets Boost From Guidelines Calling For Earlier HIV Treatment" - Pink Sheet, 19 July, 2010.). Isentress was the fifth best-selling HIV drug in 2009, in a market worth about $14.3 billion, according to figures from EvaluatePharma. By 2016, it will take the number three spot with about $2.2 billion in sales in a market of $20.2 billion, the firm estimates.

There are advantages to using Isentress in first-line therapy but the twice-daily dosing is a disadvantage, Hare commented. There is strong interest in a once-daily Isentress, which is in development, but due to the drug's unique pharmacokinetic profile, the feasibility of a once-daily version has been unclear, he said. As with other HIV meds, resistance to Isentress is also an issue, so more treatment options are needed - it would be good to have a range of integrase inhibitors with different resistance profiles, Hare added.

Gilead is testing a novel once-daily integrase inhibitor, elvitegravir, in combination with Abbott's booster Norvir (ritonavir) (Also see "Gilead: Near-Term Drug Filings Planned, But HIV Pressure Persists" - Pink Sheet, 21 July, 2010.). Gilead is also developing the once-daily "Quad" tablet, which combines elvitegravir with three other Gilead compounds: emtricitabine and tenofovir disoproxil ( Truvada ), and the novel booster GS-9350 (cobicistat) (Also see "Gilead's HIV Quad Pill Passes Tolerability Test, But Not With A Straight "A"" - Pink Sheet, 1 March, 2010.).

But analysts following Gilead say that following the release of the new data at the IAS meeting, ViiV's '572 appears to have an edge over elvitegravir and suggest that Gilead might now be open to partnering with ViiV to produce a fixed combination that would include Truvada and '572. Another option is a co-formulation of '572 with ViiV's own Epzicom (abacavir sulfate/lamivudine).

"As a potent, well tolerated (so far) once-daily integrase inhibitor, the biggest question is what GSK/PFE (ViiV) have to co-formulate with '572," to create its own one-pill, once-daily, fixed-dose combination option, Leerink Swann's Joshua Schimmer observed in a July 23 note.

Schimmer sees "significant limitations" for a combination with ViiV's in-house Epzicom, however, because of the perceptions of cardiovascular risk with the abacavir/lamivudine product.

Phase II Results Are Encouraging

So far, the development picture looks good for '572 on its own. At the AIDS meeting, investigators shared results from a 16-week analysis of SPRING-1, the ongoing dose-ranging study in patients resistant to raltegravir. The trial compares three doses of '572 (10 mg, 25 mg or 50 mg) to a 600 mg dose of efavirenz with either tenofovir/emtricitabine or abacavir/lamivudine in 205 treatment-naïve patients. After 16 weeks of treatment, from 90 percent to 96 percent of patients on '572 - depending on the dose - achieved viral suppression.

The test drug also appeared to be faster-acting, with 66 percent of patients achieving suppression after four weeks, versus 18 percent in the efavirenz arm. Investigators reported one virologic failure in the patients on '572 and one in those on efavirenz combinations.

ViiV/Shionogi reported that the integrase inhibitor was also generally well-tolerated, with no moderate to severe effects. Drug-related adverse events were actually more common in those on efavirenz (18 percent compared to only 6 percent for '572).

Gastrointestinal side effects were reported in 4 percent of patients on efavirenz and 2 percent of those on '572. Less commonly reported events for '572 were psychiatric effects (6 percent) and rash (4 percent).

In the small VIKING Phase IIb open-label, single-arm study also released at the AIDS meeting, the drug showed its value in treatment-experienced patients. That trial assessed a 50 mg dose of '572 as a monotherapy followed by combination use with background therapy in 27 HIV patients who had failed raltegravir and were resistant to at least three antiretrovirals.

After 11 days of treatment, most had a positive antiviral response. The study also assessed response based on various pathways for raltegravir resistance. Viral response was reported in all patients (16) with N155H, Y143H or Q148 single mutant pathways, three of four with Q148 plus one secondary mutation, and two subjects with other mutations. None of the subjects with Q148 plus two or more secondary mutations showed antiviral response.

As with SPRING-1, the drug was well-tolerated, with adverse events of diarrhea (three patients) and insomnia (also three patients).

The '572 data are encouraging but further research is needed to see if they will bear out in larger numbers of patients, Hare commented.

The data were impressive because the drug showed substantial residual activity even in patients with clinical and genotypic resistance to raltegravir, Bernstein analyst Geoffrey Porges explained in a July 19 note detailing competitive threats to Gilead.

"The data suggest GSK '572 may have a higher genetic barrier to resistance than raltegravir. Given the nature of the respective resistance profiles, it is possible that GSK's drug could ultimately be preferred over both Gilead and Merck's integrase inhibitors," the analyst observed.

The results also suggest that '572 is active even when another integrase inhibitor has been used as part of an up-front regimen, he noted.

Based on ViiV's plans to start Phase III this year, the '572 drug represents a threat to Gilead's HIV franchise prospects, the analyst concluded.

Gilead has been enjoying a relatively uncontested position at the top of the HIV market, but the new play from Big Pharma in the form of ViiV is a concerted effort to increase foothold in the space. Gilead initially sounded unfazed by the new entry (Also see "Gilead President Thinks Firm Is Safe From Pfizer/GSK HIV Joint Venture - For Now" - Pink Sheet, 22 April, 2009.), but the company is acting more defensively a year later (Also see "Gilead: Near-Term Drug Filings Planned, But HIV Pressure Persists" - Pink Sheet, 21 July, 2010.).

Data for ViiV's backup, the next-generation integrase inhibitor GSK 1265744, which were also presented at the AIDS meeting, also look encouraging, Porges noted: "With GSK now having multiple shots on goal in the integrase inhibitor class, both showing substantial residual activity in a resistant patient population, the company appears to be in a strong position to go head-to-head with Merck's and Gilead's integrase inhibitors in the future."

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

ViiV Preps Once-Daily Integrase Inhibitor '572 For Phase III

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