Entering the marketplace battle for HIV-1 share with a new fixed-dose pill is Viiv Healthcare Ltd., the joint venture between Glaxosmithkline plc and New York-based Pfizer Inc., which won the go-ahead from U.S. regulators last week for Triumeq.

The compound consists of Viiv's integrase strand transfer inhibitor dolutegravir, branded Tivicay, with the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine, both from London-based GSK and branded Ziagen and Epivir, respectively. Tivicay, the next-generation integrase inhibitor in HIV-1 that was developed in partnership with shareholder Shionogi & Co. Ltd., of Osaka, Japan, was approved in the U.S. about a year ago.

"I can tell you from having treated a whole lot of folks with HIV disease that the goal is to make it easy and tolerable for patients," said Kimberly Smith, head of R&D for Viiv, who has been an HIV clinician and researcher for 20 years. "The Holy Grail is that people have to be adherent, they have to be able to take their medicine every day."

As a single-dose regimen for HIV with an integrase inhibitor, Triumeq follows to the market Stribild for treatment-naïve patients, which garnered $539 million last year for Gilead Sciences Inc., of Foster City, Calif., the HIV leader that also sells blockbuster Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate). Stribild, Smith noted, "includes tenofovir, which they're trying to replace because it has issues with long-term tolerability, and it also has an integrase inhibitor that [unlike Tivicay] requires a boosting agent," which can lead to drug interactions and tolerability problems.

The U.S. clearance was based on results of trials that showed better results with Triumeq than with Atripla. Specifically, in a phase III noninferiority study with a pre-specified superiority analysis, more patients were deemed virally undetectable (HIV-1 RNA <50 copies/mL) in the dolutegravir and abacavir/lamivudine arm than in the Atripla arm, a difference that was statistically significant and driven by a higher rate of discontinuation due to adverse events in the Atripla arm.

Smith allowed that "the major uptick [in the trial] was for tolerability" but said "what we think we're bringing to the table" is a boost in efficacy as well. "We don't have to give up potency in order to have maximum tolerability," she told BioWorld Today. "The potency was similar, but ultimately what ends up being most important is efficacy based upon the combination of potency and tolerability." In late June, Europe's Committee on Human Medicinal Products issued a positive opinion on Triumeq.

Gilead, though, has more up its sleeve: the once-daily single tablet regimen containing tenofovir alafenamide (TAF), a more potent prodrug of the firm's hepatitis B drug Viread (tenofovir disoproxil fumarate) with "similar efficacy but less long-term kidney damage and bone mineral density [BMD] loss," noted RBC Capital Markets analyst Michael Yee. "Also, its much smaller size makes it amenable to 'co-formulate' with protease inhibitors, so Truvada [emtricitabine/tenofovir, Gilead Sciences Inc.] can be combined with Prezista [darunavir, Johnson & Johnson] and make what is a two-pill regimen now into a one-pill simple regimen," Yee wrote in a research report. "We are confident, over the long run, [that] most developed nations won't be 'splitting up pills' and ruining compliance, so we model a 20 percent erosion post 2019, vs. consensus which is 25-50 percent erosion expectation after [a generic version of Viread] launches in 2018." Truvada was approved in 2004 and cleared two years ago for use in preventing HIV in high-risk individuals. (See BioWorld Today, July 17, 2012.)

"Investors have been highly focused on hepatitis C [virus, HCV] but we remind investors that GILD's HIV franchise is also a $10 billion-plus giant, and we think the tail is longer than investors are currently modeling," wrote Yee.

TIVICAY FAST OUT OF THE GATE

At the Interscience Conference on Antimicrobial Agents and Chemotherapy in Denver last September, Gilead offered 48-week results from a phase II study (Study 102) evaluating TAF in the treatment of HIV-1. At 48 weeks, a regimen of elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/TAF 10 mg was found to be similar to Stribild (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), based on the percentage of patients with HIV RNA levels less than 50 copies/mL, and was associated with more favorable renal and bone safety markers. Phase III TAF data are due next month "and we want to see noninferior/similar efficacy and statistically significant lower kidney damage," along with less BMD loss, wrote RBC's Yee.

London-based Viiv, with potential new blockbuster Triumeq, is still busy in the space, too. In June, the firm inked a deal with Janssen R&D Ireland Ltd., of Cork (part of Johnson & Johnson) to develop and commercialize a combination of Tivicay and Janssen's non-nucleoside (nuc) reverse transcriptase inhibitor rilpivirine (Edurant) for yet another single-tablet therapy that could bring fewer side effects.

The two well-tolerated compounds "we hope will work very well together as a maintenance regimen," Smith said. "We basically just want people to have many different opportunities to use dolutegravir, which we think is one of the best drugs out there," she added.

"It's not just in HCV – big pharma continues to try to chip away at Gilead's dominance in HIV as well," Wells Fargo analyst Brian Abrahams pointed out, calling the Janssen deal "relevant for Gilead because this type of regimen would represent a 'nuc-sparing' approach. Conceptually, the idea is that as patients live longer on HIV therapy, such regimens could reduce some of the long-term toxicities associated with nucs," as Gilead is doing with TAF.

"Nuc-sparing cocktails have been tried for several years, with somewhat mixed results, and there is limited evidence such NRTI-free regimens could maintain adequate virological suppression in patients switched from a nuc-containing regimen," Abrahams wrote in a research report. "We believe it is unlikely to ultimately show benefits as strong as HIV regimens using a nuc backbone, such as Gilead's Atripla and Stribild." Just the same, dolutegravir boasts "a particularly high barrier to resistance, which could give this combo better odds, and should such a cocktail show strong benefits, it could be an important threat to Gilead's HIV franchise," in Abrahams' view.

Meanwhile, Tivicay seems to be doing well. Jefferies analyst Naomi Kumagai, reporting on prescription trends in the week that ended Aug. 8, found new scripts for Tivicay at 1,892 (compared to 1,675 in the week before) and "takeoff looks stronger compared with Stribild, which was launched a year ahead of Tivicay," with new scripts reaching 3,246, vs. 3,093 in the previous week.