Gilead's Bictegravir Demonstrates Broad Non-Inferiority, But Will That Suffice?

Having lost market share in recent years to HIV regimens containing ViiV's Tivicay, will a showing of non-inferiority across four head-to-head Phase III studies give bictegravir the market edge Gilead seeks?

Gilead Sciences Inc. revealed success demonstrating non-inferiority in four Phase III trials testing its investigational integrase inhibitor bictegravir head-to-head against other HIV therapy regimens, but it remains unclear whether these findings will give the virology specialist an edge against ViiV Healthcare's Tivicay (dolutegravir).

The Foster City, Calif.-based firm reported May 30 that bictegravir met the standard for non-inferiority in studies using comparator regimens of ViiV's Triumeq (dolutegravir/lamivudine/abacavir) and of dolutegravir with Gilead's emtricitabine and tenofovir alafenamide (Gilead's Descovy) in treatment-naïve HIV-infected patients, as well as in switch studies with treatment-experienced patients receiving either dolutegravir plus existing antiviral agents or an approved protease inhibitor/nucleoside polymerase inhibitor combination. However, Gilead did not provide full data other than that the primary endpoints had been achieved, saying it planned to present full data later this year at conferences.

More Data To Come

In the two studies testing BIC/F/TAF against Triumeq and against Tivicay/F/TAF in treatment-naïve patients, the primary endpoint was proportion of patients achieving virologic control at 48 weeks. The data, however, are blinded out to 144 weeks so that Gilead can obtain a fuller sense of efficacy duration.

In the studies of treatment-experienced patients, one randomized patients either to stay with Triumeq or switch to BIC/F/TAF, while the other compared BIC/F/TAF with regimens containing Janssen Pharmaceuticals Inc.'s Prezista (darunavir) or Bristol-Myers Squibb Co.'s Reyataz (atazanavir) plus a backbone of either F/TAF or lamivudine and abacavir. The primary endpoint measured continued virologic suppression, requiring a margin of no more than 4% between existing therapy and the switch regimen.

Datamonitor Healthcare lead analyst Michael Haydock said the announcement might be met with relief by GlaxoSmithKline PLC – the primary stakeholder in ViiV, along with Pfizer Inc. and Shionogi & Co. Ltd. – because the bictegravir regimens did not demonstrate superiority to dolutegravir. In Phase II data presented this past February at the Conference on Retroviruses and Opportunistic Infections, Gilead showed that bictegravir monotherapy achieved a numerical advantage compared to dolutegravir monotherapy over 24 and 48 weeks, but the studies were not sufficiently powered for a claim of superiority. (Also see "Gilead's Bictegravir Data Could Mean Continued HIV Sector Dominance" - Scrip, 15 Feb, 2017.)

Gilead said it planned to file the three-drug regimen of bictegravir, emtricitabine and tenofovir alafenamide (BIC/F/TAF) for US approval before the end of the second quarter. Tenofovir alafenamide (TAF), a successor to tenofovir disoproxil fumarate (TDF), has anchored successful Gilead follow-on regimens (Genvoya, Odefsey and Descovy) for HIV that have yielded increased sales for the franchise. (Also see "Is Gilead Vulnerable to ViiV As It Nears End Of HIV R&D Activity?" - Scrip, 3 Nov, 2016.)

"The big danger to ViiV was that BIC/F/TAF would show superiority to the dolutegravir-based regimens," Haydock told Scrip. "[Triumeq and Tivicay] have been the main driving force of ViiV's HIV revenues and have helped it take market share from Gilead, so Gilead is developing BIC/F/TAF to try and recapture that market share."

In a May 30 note on the data announcement, William Blair & Co. analyst John Sonnier pointed out that Gilead held roughly a 90% market share for treatment-naïve HIV patients from 2011 to 2013, but that share dropped to 77% in 2014, the year Tivicay got approved, and 74% in 2015. Gilead rebounded a bit to 76% by the end of 2016 on the strength of the TAF-containing launches.

The investigational triple regimen that would eliminate the need for the pharmacokinetic boosting agent cobicistat, if approved, could give Gilead further help against ViiV, he said. "We believe the potential approval of [the] un-boosted triple regimen could also help the company more effectively fend off competition," Sonnier wrote.

Elvitegravir, included in existing Gilead HIV fixed-dose combo therapies Genvoya (elvitegravir/cobicistat/emtricitabine/TAF) and predecessor Stribild (elvitegravir/cobicistat/emtricitabine/TDF), requires a boosting agent. Even without superiority to dolutegravir, Haydock said Gilead should benefit because BIC/F/TAF would offer fewer drug/drug interaction complications than Stribild and Genvoya.

"Boosting agents are considered inconvenient (especially as the population ages) because they increase drug-drug interactions," Haydock explained. "So, if people are taking other medications (like elderly people tend to) then it means that doctors may have to consider dose reductions/swapping other medications."

The same day that Gilead unveiled the non-inferiority findings for bictegravir, Merck announced that FDA had approved a new formulation of its integrase inhibitor raltegravir, Isentress HD, that allows for once-daily dosing: a 1,200 mg dose comprised of two 600 mg tablets for combination therapy in treatment-naïve HIV patients or those who've achieved viral suppression with a regimen including Isentress dosed at 400 mg twice-daily.

Gilead Ahead Of Scheduling On Recouping Share?

In contrast to Haydock's view that the Gilead data might be good news for ViiV, Leerink Partners analyst Geoffrey Porges issued a note May 30 saying that the initial results are in line with expectations and put Gilead on track to begin recouping additional market share more quickly than Leerink had anticipated.

Porges predicted that Gilead will use one of the two priority review vouchers it currently has on hand to ensure a six-month FDA review of BIC/F/TAF, which would mean the product could reach market before the end of the year if the company achieves its goal of filing a new drug application (NDA) this quarter. (Also see "Gilead, With Two PRVs In Hand, Holds Options For Accelerating Late-Stage Pipeline" - Scrip, 21 Feb, 2017.)

While the bictegravir-containing regimen did not achieve superiority, he noted that it also apparently presents no liabilities for adverse events, safety signals or metabolic or hematologic safety concerns.

The full dataset, however, will need to be seen to be certain that BIC/F/TAF is "completely benign," Porges conceded, but Gilead said the regimen was well tolerated with no patient discontinuations in the four studies due to renal events. No patients randomized to bictegravir or dolutegravir-containing regimens developed treatment-emergent resistance either, the company stated.

Leerink is more bullish on BIC/F/TAF than industry consensus, Porges said, anticipating only $344m in 2018 sales based on prior expectations of a third quarter 2018 launch (compared to consensus projections of $865m that year), but it projects sales increasing to $5.9bn in 2022, compared to consensus estimates of $3.4bn. Leerink's peak sales estimate is $10.6bn, compared to consensus of $5.6bn. They forecast bictegravir will provide 20% of Gilead's total revenue and 30% of their global HIV revenue by 2022, "and this grows to 45% of Gilead's global HIV revenue at peak," Porges added.