Pharmaprojects: track pharma R&D, Citeline
By Ian Lloyd
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For World AIDS Day, we look at current and upcoming novel single tablet regimens (STRs) for HIV treatment. STR’s primary advantage is that they simplify treatment and this leads to greater patient adherence, lower resistance emergence and overall improved outcomes over more traditional cocktails of antiretroviral drugs.
With the launch and widespread uptake of Gilead Sciences’ Atripla in 2006, the future of HIV treatments appeared to be firmly cemented as STRs, which are forecast to increase their combined market share from 30.8% in 2013 to 49.1% in 2022. Its strongest uptake was with treatment naive patients who make up slightly under half of all HIV patients in the US and EU. Global sales of Atripla in 2014 alone were $US 3.47 billion (out of a global market of just over $14 billion annually), giving it just under a quarter of the total market.
All STRs currently available are based off a backbone of two nucleotide reverse transcriptase inhibitors (NRTI) combined with a third component; Atripla being the classic example with a combination of emtricitabine/efavirenz/tenofovir disoproxil fumarate.
Eviplera (emtricitabine/rilpivirine/tenofovir disoproxil) and Stribild (emtricitabine/elvitegravir/tenofovir disoproxil) are Gilead’s newer entries to the STR market. Launched in 2011 and 2012 respectively, they are best considered as incremental improvements over the Atripla formula as both retain the emtricitabine and tenofovir disoproxil (TDF) components. Both aim to avoid the CNS-related side effects associated with efavirenz with the replacements of rilpivirine (Eviplera) and elvitegravir (Stribild). Stribild also includes the pharmacoenhancer cobicistat, a liver enzyme inhibitor used to increase absorption of elvitegravir. Ritonavir was previously the only option for pharmacoenhancers until Gilead developed cobicistat. Since Gilead replaced efavirenz with elvitegravir and ritonavir with cobicistat, Stribild consists of all Gilead compounds. With these two candidates as well as its ongoing Atripla sales, Gilead retains their prominent position in the STR market. (Table 1)
ViiV Healthcare recently entered the STR market in 2014 with Triumeq (abacavir/dolutegravir/lamivudine), which has a superior side effect profile to Atripla and is expected to increase its market share over the coming years. As such, Triumeq should place ViiV Healthcare as one of the leading companies in HIV treatment and in competition with Gilead for the STR market. (Table 1)
STR Clinical Pipeline
Likewise to currently marketed STRs, Gilead remains the major player with multiple combinations under development. Most notably, pipeline combinations include their nucleotide reverse transcriptase inhibitor tenofovir alafenamide (TAF). (Table 2) TAF has demonstrated in phase III trials an improved renal and bone safety profile as well as high antiviral efficacy at a dose 10 times lower than Gilead’s tenofovir disoproxil fumarate, which is used in their current STRs. Gilead is also inclined to promote TAF use over TDF as the patent protection for TDF is set to expire in July 2017.
First and closest to launch is Genvoya, which consists of emtricitabine/elvitegravir/tenofovir alafenamide + cobicistat. The European Commission and the FDA have granted marketing authorization in November 2015, and the STR will likely be marketed as a replacement for Gilead’s Stribild regimen. Second is Gilead’s yet unnamed emtricitabine/rilpivirine/tenofovir alafenamide STR that has been submitted to the FDA and EU CHMP. Like Genvoya, it is an incremental improvement over an already launched product (Eviplera) using TAF to replace TDF. Approval is likely in 2016.
Gilead previously had a third TAF-based STR under development containing emtricitabine/darunavir/tenofovir alafenamide with cobicistat, however, Gilead transferred the rights to this combination to Janssen Pharmaceuticals (J&J). The combination is currently undergoing phase III trials.
Merck & Co are also developing a direct competitor to Atripla named MK-1439A using Merck’s a non-nucleoside reverse transcriptase inhibitor doravirine (MK-1439). This STR also contains lamivudine and TDF, and is currently undergoing phase III trials.
ViiV Healthcare is represented in the STR pipeline by its efforts to develop a maintenance regimen in collaboration with Janssen of dolutegravir/rilpivirine. This phase III compound is unique in attempting to achieve continued viral suppression of already virally suppressed patients with a two drug regimen rather than three drugs, unlike all the other STRs.
Finally Teva Pharmaceuticals is developing three different fixed dose combinations for HIV treatment that are currently beginning phase I trials or undergoing IND filings in the US. However, due to the early stage of development it is uncertain whether these are STRs or other fixed dose combinations to be used with additional antivirals.
2016 is expected to be a very busy year for STRs with launch expected for Gilead’s Genvoya and approval for its emtricitabine/rilpivirine/tenofovir alafenamide combination, while ViiV Healthcare’s Triumeq battles for market share against the four Gilead STRs that will be available.
 Sax PE, Meyers JL, Mugavero M, Davis KL (2012) Adherence to Antiretroviral Treatment and Correlation with Risk of Hospitalization among Commercially Insured HIV Patients in the United States. PLoS ONE 7(2): e31591.
 Datamonitor Healthcare HIV Forecast.
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