In a landmark win for GlaxoSmithKline’s ViiV Healthcare and its ambition to reduce the number of medications HIV patients are taking—and beat rival Gilead Sciences along the way—the FDA has approved its complete two-drug regimen for newly diagnosed HIV patients.

Dovato, made up of two FDA-approved ingredients: Tivicay (dolutegravir, DTG) and Epivir (lamivudine, 3TC), has become the first two-drug regimen cleared for new (i.e., untreated) HIV patients.

The approval was based on results from the Gemini studies on 1,433 new HIV patients, which showed Dovato could match up to a three-drug regimen consisting of DTG and Gilead’s Truvada (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC) in its ability to suppress HIV viral load at week 48. The approval is good news for the U.K.-based pharma, but it's only the start: GSK will likely have some convincing to do if it wants to shift the treatment paradigm from traditional three-drug therapies to just two drugs, mainly over concerns of treatment resistance.

And the cost? Mindful of its rival, GSK is pricing Dovato at the list sticker of about $2,300 per month, a 25% discount to Gilead’s fast-growing three-drug regimen Biktarvy and in line with the price of each component, according to RBC Capital analyst Brian Abrahams.

"While on the surface this may seem negative [for Gilead], discounting for the regimen is unknown, and given our estimate that Biktarvy’s real-world [gross-to-net ratio] is around 50% anyway, this does not necessarily mean that Gilead will face any new pricing pressures for its HIV cocktails," Abrahams wrote in a Monday note to clients, adding that his team will keep an eye on formulary flexibility within Medicare.

Dovato’s approval comes with a boxed warning that cautions patients with both HIV and hepatitis B to consider other cocktails or add an additional antiviral medication as these patients have developed HBV mutations to 3TC and may have severe liver problems when they stop taking 3TC-containing drugs. That is a similar warning slapped on Biktarvy’s label, which warns of potential exacerbations of HBV post-Biktarvy treatment.

But in a safety problem unique to Dovato and all DTG-containing drugs, the FDA is alerting neural tube birth defects in babies born to women treated with DTG. Although the findings are preliminary, the FDA is asking patients to avoid use of Dovato at the time of conception through the first trimester of pregnancy.

One major concern among physicians, as industry watchers have noted, is that two-drug combos like Dovato won't be strong enough to keep the virus under control over the long term, and patients might develop resistance more easily because they only contain one nucleoside reverse transcriptase inhibitor rather than the two in current standard treatments.

So far, the two Gemini studies have yielded 48-week data. Within that time frame, six of 716 patients on Dovato had confirmed virologic failure—where the drug didn’t effectively suppress the virus—while four of 717 patients on the Tivicay-Truvada arm had that.

In 63 patients with base-line CD4+ cell count of less than 200, which means the patient’s immune system has been severely damaged and disease is in the late-stage of AIDS, investigators of the Gemini studies reported a notably low viral suppression rate of merely 79% on Dovato, versus over 90% across all other groups. While ViiV argued that most patients in that subgroup experienced virologic failures due to nontreatment-related factors and therefore are excluded from final analysis, RBC Capital’s Abrahams pointed to those data as evidence of "theoretical greater resistance risk in a real-world setting."

During an interview with FiercePharma on Tuesday, Dr. Kimberly Smith, head of ViiV's global research and medical strategy, called Abrahams' argument a "complete misinterpretation of the data." She contended that only one confirmed treatment-related virologic failure happened in that subgroup, and that the so-called "snapshot" failure was more about the fact that individuals who have low CD4 cell count often have more other challenges in their life. She also pointed out that the FDA doesn't limit Dovato's use in low CD4 count patients.

No treatment-emergent resistance occurred in the Gemini trials. But again, these are just one-year results that won’t likely quash skepticism over the possibility of treatment-related resistance in the long run.

GSK did have some long-term data for Juluca (DTG+rilpivirine), the first-ever two-drug therapy the FDA approved in late 2017 for patients already virally suppressed. And as data from the two studies, dubbed Sword, showed, virologic success was indeed on the decline and resistance cases were on the rise as patients were followed longer.

In the Sword program, viral suppression was achieved in 93% of patients who switched from their original three- or four-drug regimens to Juluca and stayed on it for a year. However, in patients who got Juluca from day 1 of the trial and were followed for 100 weeks, the rate dropped to 89% and then further to 84% at 148 weeks, according to data ViiV just unveiled last week.

Smith said the drop-off is common with any HIV therapy. "Most studies don't take individuals out to three years, so it's not that common to see data from week 148 as we've shown," she said. "We did that because we did want to demonstrate the durability of this regimen."

Confirmed virologic withdrawal cases across the early- and late-switch groups increased slightly from eight at 100 weeks to 11 at 148 weeks, and resistance to Johnson & Johnson’s rilpivirine, a non-nucleoside reverse transcriptase inhibitor, also grew from three patients to six.

Smith cautioned that there was not comparator after the first year, as the investigators were only following patients on two-drug regimens. In fact, according to Smith, in studies on three-drug regimens that included rilpivirine, the rate of resistance is higher than what researchers saw in the Juluca study. And despite the fact that most resistant patients on the Sword studies already had some evidence of resistance to NNRTI when they came into the study, they maintained viral suppression for a year or two. "We think the results from the Sword study actually are very reassuring for providers that this is a regimen that is holding up long term," she said.

Two-drug cocktails have posted some safety advantages. For example, the Juluca Sword studies showed improvements in kidney and bone density measures for patients switching away from a TDF-containing regimen. But TDF is known for those risks and is replaced by the safer tenofovir alafenamide (TAF) in Biktarvy, which is ViiV’s real competitor.

ViiV intends to follow the Gemini patients longer and will share the 96-week data later this year. Besides, it is looking at Dovato’s use as a switch option in suppressed patients. Specifically, the Tango study will examine those who switched from a TAF-based regimen.

Overall, GSK/ViiV hopes that with two-drug cocktails, HIV patients could take fewer medications and therefore experience fewer side effects and potential drug-drug interactions. And Dovato will be "the key growth driver going forward," ViiV Chairman David Redfern said on GSK's fourth-quarter earnings call in February. But it still has a long way to go. Juluca, in its first full year on the market, registered sales of £133 million ($174 million). In comparison, Biktarvy, which was just approved by the FDA last February, hauled in $551 million in Q4 in the U.S. alone.

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