FDA approves new single tablet ARV from Gilead but ViiV Healthcare sues

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The US Food and Drug Administration (FDA) has approved Biktarvy, Gilead Sciences’ new single tablet antiretroviral regimen containing the HIV integrase inhibitor bictegravir, which was highly effective and well tolerated in clinical trials. Biktarvy is the first fixed-dose combination pill to include bictegravir, which does not require pharmacokinetic boosting, unlike Gilead’s earlier integrase inhibitor elvitegravir (Vitekta, also in the Stribild and Genvoya combinations). This avoids the drug-drug interactions that can occur with the boosters ritonavir or cobicistat, which can affect the way many drugs are processed in the liver.

Bictegravir is combined with two nucleoside/nucleotide reverse transcriptase inhibitors: emtricitabine and tenofovir alafenamide (TAF), the new kidney- and bone-friendly formulation of tenofovir.

Biktarvy is indicated both for adults starting HIV treatment for the first time and for people on treatment with an undetectable viral load who wish to switch to a new regimen that might be more convenient or better tolerated. Biktarvy is a single pill taken once daily with no food requirements, and it is the smallest three-drug tablet on the market containing an integrase inhibitor, according to Gilead.

The other existing integrase inhibitor-based single-tablet regimens are ViiV Healthcare’s Triumeq (dolutegravir/abacavir/lamivudine) and the two-drug Juluca (dolutegravir/rilpivirine). Triumeq requires testing for the HLA-B*5701 genetic variation, which increases the risk of hypersensitivity to abacavir. Juluca was approved by the FDA in November but is not yet approved by the European Medicines Agency.

FDA approval of Biktarvy was based on data from four ongoing phase 3 clinical trials. Two studies compared bictegravir versus dolutegravir in triple regimens for previously untreated people, using either separate tablets (Study 1490) or single-tablet combination pills (Study 1489). They found that bictegravir was non-inferior to dolutegravir, with around 90% of study participants achieving viral suppression at 48 weeks using either regimen.

Two other studies evaluated bictegravir in people who were virally suppressed on their current treatment. Study 1878 showed that people who switched from a boosted protease inhibitor to Biktarvy were as likely to maintain an undetectable viral load as those who stayed on their existing regimen – again around 90% in both arms. Results from Study 1844 will be presented at an upcoming conference, Gilead said.

These studies showed that Biktarvy was generally safe and well tolerated. The most common adverse events were headache and diarrhoea.

Because it contains TAF instead of the older tenofovir disoproxil fumarate (TDF), Biktarvy is less likely to cause bone loss or kidney problems. Nonetheless, kidney function should be tested before starting Biktarvy and monitored regularly. No dosage adjustment of Biktarvy is necessary for people with an estimated creatinine clearance of 30 ml/min or greater, the cut-off for moderate (stage 3) chronic kidney disease, according to Gilead. Across the four trials, no participants developed proximal renal tubulopathy or Fanconi syndrome and no one discontinued treatment due to kidney-related side-effects.

People considering Biktarvy should be tested for hepatitis B virus (HBV) infection before starting because the TAF component is active against HBV as well as HIV, and stopping treatment could result in hepatitis flare-ups.

Biktarvy is currently being evaluated in a women-only trial and in a study of children and adolescents, Gilead said.

“In clinical trials through 48 weeks, no patients taking the regimen of bictegravir plus [emtricitabine]/TAF developed treatment-emergent resistance, results that were observed both in people new to therapy and those who were virologically suppressed and chose to switch regimens,” Dr Paul Sax of Brigham and Women’s Hospital in Boston said. “In addition, the clinical data show that the regimen’s antiviral efficacy, tolerability profile and limited drug interactions offer an effective new treatment option for a range of people living with HIV.”

 

Meanwhile, rival ViiV Healthcare, a joint venture majority-owned by GlaxoSmithKline Plc with Pfizer Inc and Shionogi Ltd, quickly filed a lawsuit alleging that Gilead was infringing patents on ViiV’s dolutegravir, a component of the venture’s triple-drug HIV treatment Triumeq, reports Reuters Health. Viiv is seeking “financial redress,” but is not asking for an injunction against sales of Biktarvy, according to Glaxo spokesperson Sarah Spencer.

Gilead is quoted in the report as saying, however, that it remained “steadfast in our opinion that Biktarvy does not infringe ViiV’s US patent, and that the court challenge did not affect the US availability of the drug. “We believe that a modest royalty could be possible far down the road if Gilead were to lose” the patent case, Jefferies analyst Michael Yee said in a research note.

The report says Wall Street analysts, on average, forecast Biktarvy sales of around $1bn this year, rising to a peak of nearly $5bn annually by 2024.

Dolutegravir, sold under the brand name Tivicay and as a component of Triumeq, is a key growth driver for Glaxo, posting fiscal 2017 sales of nearly $5.6bn.

The Gilead drug’s wholesale price, about $36,000 a year, is in line with current therapies, according to Guggenheim Securities.

The report says the global market for HIV drugs could reach as high as $40bn a year by 2021, according to pharmaceutical data company Quintiles IMS Institute, now known as IQVIA.

ViiV said it would seek to prove that Biktarvy infringed ViiV’s US and Canadian patents covering dolutegravir and many other compounds that include dolutegravir’s unique chemical scaffold. The US case was filed in the US District Court for the District of Delaware and the Canadian case in the Canadian Federal Court in Toronto.

 

BioWorld Today reports that Tivicay was approved by the FDA in 2013 to treat treatment-naïve and previously treated HIV-infected adults, including those treated with other integrase strand transfer inhibitors. The drug also was approved to treat individuals 12 and older weighing at least 40 kg (approximately 88 pounds) who are treatment-naïve or previously treated but without integrase strand transfer inhibitors.

At the time, analysts suggested Tivicay represented the first legitimate competitor to the formidable HIV franchise crafted by Gilead, including the four-drug, single-tablet Stribild, approved in 2012, which combines the ingredients of Truvada (emtricitabine/tenofovir disoproxil fumarate) plus elvitegravir and boosting agent cobicistat. On a head-to-head basis, Tivicay achieved that goal, recording 2017 sales of $1.954bn, GSK reported recently, compared to $1.053bn in 2017 for Stribild. The consensus 2022 forecast for Tivicay is $3.358bn in sales, according to Cortellis Competitive Intelligence, while the same-year sales forecast for Stribild is just $790.9m. A year later, the FDA approved Viiv’s fixed-dose combination, Triumeq, which included Tivicay along with the nucleoside reverse transcriptase inhibitors abacavir (Ziagen) and lamivudine (Epivir), GSK legacy drugs.

The report says Gilead has continued to add weapons to its HIV arsenal, as well, and Biktarvy’s approval set off a new round of enthusiastic expectations. The drug’s approval came a day after Gilead reported fourth-quarter 2017 product sales of $5.8bn vs $7.2bn for the same period in 2016 and full-year sales of $25.7bn vs $30bn in 2016.

The report says Gilead spokesperson Ryan McKeel confirmed the drug’s US wholesale acquisition cost (WAC) for a 30-tablet bottle at $2,945.65, or $35,839 for 12 months of therapy, at parity with the current price of the company’s Genvoya, which was the first FDA-approved tenofovir alafenamide (TAF)-based regimen, combining elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg and TAF 10 mg. Gilead plans to begin shipping the product to wholesalers this week.

“Viiv’s patent challenge does not impact our ability to make Biktarvy available to patients in the US, and we remain steadfast in our opinion that Biktarvy does not infringe Viiv’s US patent,” McKeel is quoted in the report as saying.

In a quick take, the report says Cowen and Co’s Phil Nadeau laid bare the foundation of GSK’s concern. Biktarvy priced at only a modest premium to Triumeq, which has a WAC of $2,805.20 for 30 days, he pointed out. Although a black box warning was included on Biktarvy’s label for acute exacerbations of hepatitis B, the same is true for Genvoya, Triumeq and other HIV single-tablet regimens.

But, unlike Gilead’s boosted integrase inhibitor elvitegravir (part of Genvoya and Stribild), “dolutegravir is a true once-per-day molecule,” Nadeau pointed out. Until now, prescribers have been forced to choose between a single-tablet regimen that lacked a best-in-class agent (dolutegravir or TAF) or a combination therapy that included Descovy (F/TAF) with Tivicay, he maintained.

“Our consultants have been clear that if bictegravir is merely ‘just as good’ as dolutegravir in terms of both efficacy and safety, then Biktarvy will become their clear first choice regimen,” Nadeau wrote. “In fact, under this scenario our consultants report they will have ‘no need’ for Tivicay or Triumeq and would rapidly shift prescribing toward B/F/TAF.”

With phase III data suggesting that Biktarvy’s efficacy, safety and tolerability achieved those thresholds, “we think that Gilead is poised to recapture share in the HIV market now that Biktarvy is approved,” he added. “As Tivicay and Triumeq are currently at an approximate $4bn annual revenue run rate, should Gilead capture even 25 percent of their patient share it would drive meaningful incremental revenue for GILD’s HIV franchise, which we project will have $14.8bn in revenue in 2018.”

Biktarvy “should help set the stage for long-term growth and sustainability of GILD’s core HIV franchise,” RBC Capital Markets analyst Brian Abrahams agreed following the drug’s approval. Sales of the once-daily medicine arrived with a clean label, he said, estimating peak sales of $4.8bn in 2025. “We expect a solid initial launch,” Abrahams wrote, “though perhaps not quite as rapid as TAF-based regimens, which had safety impetus to switch.” Overall, the drug’s “multiple best-in-class attributes” could make Biktarvy “a gold standard HIV regimen” for treatment-naïve patients.

Abrahams saw little reason to change his outlook after the patent lawsuit was filed, an event he predicted prior to Biktarvy’s approval. “Over the past several months, we have discussed extensively the possibility of GSK/Viiv initiating a lawsuit against GILD for potential bictegravir patent infringement of broad dolutegravir (intellectual property),” he wrote in a first glance. “Overall, we see low stock impact to GILD, as this issue had been identified previously and was coming onto investors’ radars.” He called a preliminary injunction blocking Biktarvy’s launch “extremely unlikely” and predicted that Gilead “has a good likelihood of ultimately prevailing,” should the issue go to trial. A worst-case scenario, Abrahams said, “would likely be a single-digit royalty to GSK/Viiv until 2026+.”

Although GSK alleges that Gilead observed dolutegravir chemical structure during the 2010 Conference on Retroviruses and Opportunistic Infections and copied the drug, “the fact that GILD did not file its own patent application until nearly three years later, along with the key structural dissimilarities, leads us to believe that GILD invested a substantial amount of time inventing a novel, patentably distinct and non-infringing compound,” he added.

Abrahams ticked off key differences between the undeniably similar chemical structures of bictegravir and dolutegravir, which he said included Di- vs. tri-fluorination, R- vs. S-chirality and substituted-ring features. He added that “one important feature of (bictegravir), the carbocycle on the substituted ring, may not be covered by GSK’s ‘385 patent – providing GILD an opportunity to argue non-infringement.” Resolution of the case could take two to four years, he suggested.

The report says Evercore ISI analyst Umer Raffat also dug into the legal weeds, writing that, “At the most basic level, as much as there is remarkable structural similarity between GILD’s bictegravir vs GSK’s dolutegravir, GILD’s chemical structure does NOT include a bridged ring – and that’s the crux of this case.”

GSK’s US Patent No 8,129,385 is fairly broad, “with Markush-type claims which theoretically cover hundreds of structures,” Raffat pointed out. But despite GSK’s legal protest, the bridged ring in Gilead’s structure is not captured among the possible combinations of substituents specified in GSK’s patent, he said. Even if the trifluoroaryl in bictegravir’s structure was captured by the Markush claims in GSK’s ‘385 patent – a prospect Raffat deemed likely – the bridge aspect would take precedent, making infringement moot.

Other analysts generally reached the same conclusions on the legal wrangling. Jefferies Group LLC analyst Michael Yee maintained that the lawsuit did not change the thesis for Gilead “and should not impact any of the bull case.” Although a modest royalty “could be possible far down the road,” Yee noted that such arrangements typically end in settlements or single-digit royalties. An injunction, he added, “would be a very high hurdle to overcome,” suggesting “the financial implications, in our opinion, are minor.”

The report says Biktarvy is also under review by the EMA, which validated the application in the EU in July 2017.

Aidsmap material
Gilead press release
Reuters Health report
BioWorld Today report


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