Therapy focus – Plugging new molecules into the HIV combinations

With hepatitis C therapies in their 15th minute of fame, Gilead Sciences’ investors are looking to the group’s core HIV drugs as its primary growth driver. The California-based group has the mightiest franchise in this space, and thanks to replacement of older molecules with newer ones, sales of that franchise are forecast to grow by almost 50% between 2015 and 2022.

While previously important players like Bristol-Myers Squibb, Johnson & Johnson and Abbvie have largely retired, Glaxosmithkline remains a rival to Gilead – the UK group’s triplet Triumeq is expected to have the biggest sales in 2022 (see table below). Along with Glaxo, Merck & Co is working on partial-generic combinations that could compete on price against Gilead’s all-branded strategy, raising the risk that payers will play hardball in HIV.

Gilead’s big shift has been replacement of tenofovir disoproxil, part of the Stribild, Complera, Truvada and Atripla combination pills, with tenofovir alafenamide. The latter is a prodrug that is associated with lower rates of renal and bone effects, and is in the fast-growing Descovy doublet and Odefsey triplet and the Genvoya quad. With the sun setting on hep C drugs like Harvoni, Genvoya is now forecast to be Gilead’s biggest seller in 2022.

Glaxo, meanwhile, has advanced dolutegravir as its HIV flagship, taking a place as a monotherapy, Tivicay, and Triumeq, a triplet. In addition to those two products, Glaxo is developing two doublet combinations of dolutegravir with older drugs – Johnson & Johnson’s Edurant and its own off-patent Epivir – that could give Gilead a run for its money (Gilead and Glaxo’s HIV battle intensifies, February 14, 2017). 

The dolutegravir-Edurant combo has already reported positive data from the Sword phase III programme and could hit the market in 2018.

And then there were two – the evolving HIV market
Total annual HIV sales ($m)
2015 2016 2017 2018 2019 2020 2021 2022
Gilead Sciences 10,271 12,096 12,906 13,290 13,824 14,990 15,381 15,282
Glaxosmithkline 3,553 4,763 5,110 5,851 6,441 6,911 7,402 7,860
Merck & Co 1,573 1,437 1,380 1,336 1,321 1,314 1,287 1,238
Johnson & Johnson 2,483 2,569 2,574 2,243 2,119 2,078 2,060 1,939
Bristol-Myers Squibb 1,299 1,047 882 474 338 264 223 162
Abbvie 933 691 562 455 375 315 272 237
Source: EvaluatePharma

Glaxo’s Tivicay plus Epivir is in the phase III Gemini 1 and 2 trials due to read out in 2018, and Leerink analyst Geoffrey Porges believes it could reach the market in 2019. A long-acting injectable version of dolutegravir called cabotegravir is in phase III and could be on the market in 2019 or 2020.

Unlike the integrase inhibitor in Gilead’s combination, elvitegravir, dolutegravir does not require the assistance of ritonavir to boost blood concentrations of HIV-fighting drugs. This fact has motivated Gilead to push through a new molecule in bictegravir, to be combined with tenofovir alafenamide and emtricitabine (bictegravir/F/TAF), which also does not require a metabolic booster. The bictegravir triplet is the only one of the clinical-stage combinations from any manufacturer for which the sellside has ascribed sales – $3.7bn in 2016.

Branded-generic combo

A branded-generic combination should offer Glaxo the opportunity to present payers with a lower-price offering with competitive efficacy. This could put some pressure on Genvoya, which cost the US Medicaid programme about $31,000 per patient in 2016.

This is probably on the mind of executives at Merck & Co, who have put doravirine, a non-nuclease reverse transcriptase inhibitor, into phase III trials in combination with either generic Epivir or Gilead’s tenofovir disoproxil; the latter is marketed as a monotherapy under the name Viread, and is scheduled to lose patent protection in December 2017.

Meanwhile, a comparison of the doravirine/Epivir/Viread combination against Atripla is due to report data very soon.

Mr Porges writes that this combination “would offer an improved version of Gilead’s Atripla with less of the liabilities associated with the efavirenz (Sustiva) component,” which include neuropsychiatric side effects.

Moreover, he writes that it could be priced at half as much as the bictegravir combination. Indeed the four branded-generic combos of Glaxo and Merck could all beat bictegravir on cost if Gilead chooses to price its next HIV combination equal to Genvoya.

Gilead played the villain in the hep C drama when it set a list price for Sovaldi and Harvoni at more than $1,000 a day, although an independent assessment has shown that those drugs cost less than $20,000 per quality adjusted life year gained. Should these new combinations from Glaxo and Merck generate positive data, Gilead may need equally persuasive data to take to payers.

Drug Trial Setting Primary completion ID
Bictegravir/F/TAF GS-US-380-1489  vs Triumeq in treatment naïve patients May 2017 NCT02607930
Dolutegravir plus rilpivirine Sword-1 switching from another antiretroviral regimen Reported February 2017 NCT02429791
Sword-2 switching from another antiretroviral regimen Reported February 2017 NCT02422797
Dolutegravir plus lamivudine Gemini 1 vs dolutegravir plus Truvada in treatment naïve patients April 2018 NCT02831673
Gemini 2 vs dolutegravir plus Truvada in treatment naïve patients April 2018 NCT02831764
Doravirine/Epivir/Viread 1439A-021  vs Atripla in treatment naïve patients March 2017 NCT02403674

To contact the writer of this story email Jonathan Gardner in Virginia at jonathang-us@epvantage.com or follow @ByJonGardner on Twitter

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