The outlook for HIV drug development

The HIV market is shifting towards integrase inhibitor-based single-tablet regimens – but emerging markets such as Brazil and China are hesitant to pay the cost.

Since the first anti-HIV drug Retrovir (zidovudine) was approved in 1987, the field of antiretroviral therapy (ART) has undergone dramatic changes. In the beginning, many of the available treatment options were associated with severe side effects and an uncertain short- and long-term prognosis.

Modern ART regimens are very successful in achieving low viral loads and restoring immunological function in the vast majority of patients and, as a result, the life expectancy of HIV patients now matches that of the general population if appropriate treatment is initiated in time. Today, HIV is most commonly treated with a cocktail of drugs containing two nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent, which is usually a protease inhibitor (PI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or an integrase inhibitor (INI).

Two major trends

Currently, there are two key trends shaping the HIV market space, driven by both patient and physician demand.

The first is a move towards INI-based therapies, which are becoming increasingly popular due to their favourable efficacy, tolerability and, in the case of ViiV's Tivicay (dolutegravir), a high barrier to resistance. In 2007, Merck's Isentress (realtegravir) was the first INI to be approved and, while it is still highly regarded by physicians for its tolerability and efficacy, the drug requires twice-per-day dosing and is losing patient share to newer, once-daily INI drugs.

The second trend is a shift towards simplified regimens, particularly single-tablet regimens (STRs), in which all constituent drugs of an ART regimen are combined within a single tablet. Such STRs are administered once per day and make it easier for patients to adhere to their anti-HIV regimen. This is important, as strict adherence is required to suppress viral replication and prevent the development of drug resistances.

"There are a number of novel products that address both the shift towards integrase inhibitors and treatment simplification"

Drug developers have recognised the demand for simplified treatment options and additional INIs, and with the launch of Gilead's Stribild (elvitegravir/cobicistat/emtricitabine/TDF) in 2013, the first INI-based STR became available.

While Stribild has become a popular drug, particularly in the US, it has certain clinical disadvantages that have limited its success. First, it contains a pharmacokinetic enhancer, and thus carries the risk for drug-drug interactions usually associated with boosted PIs. Furthermore, it contains tenofovir disoproxil fumarate (TDF), which is associated with renal and bone toxicity.

Based on these attributes, Stribild is expected to reach its peak annual sales of $1.3 billion in the seven major markets (7MM), comprising the US, Japan, France, Germany, Spain, Italy and UK, in 2015 and then gradually lose market share. The drug's projected loss of market share from 2015 is also due to the introduction of two novel INI-based STRs.

The first of these, ViiV's Triumeq (dolutegravir/abacavir/lamivudine), was approved in the US and 5EU in 2014 and in Japan in 2015. Importantly, it was the first regimen to demonstrate superior virologic efficacy over Gilead's NNRTI-based Atripla (efavirenz/emtricitabine/TDF), which is currently the best-selling STR. This superiority was mostly due to the better tolerability of the Triumeq regimen, resulting in lower dropout rates than in the Atripla arm.

Triumeq has a few clinical disadvantages, one of them being the risk of potentially fatal hypersensitivity to abacavir, a component of Triumeq. As a result, all patients must be screened for the presence of a genetic marker for abacavir hypersensitivity, HLA-B*5701, prior to administering Triumeq.

Furthermore, there is still some concern about potential cardiovascular risk associated with abacavir use. Several studies have assessed this topic and, while no clear conclusions can be drawn, recently interviewed experts have stated that, if there is a risk, it is not very high. Nevertheless, it is unlikely that Triumeq will be used by patients who have cardiovascular risk factors. Despite these concerns, its superior efficacy in clinical studies, as well as its good tolerability profile, will win Triumeq one of the highest market shares in the HIV therapeutics market.

The second novel INI-based STR, Gilead's Quad 2 (elvitegravir/cobicistat/emtricitabine/TAF), has a similar formulation to Stribild, except that it contains tenofovir alafenamide fumarate (TAF) instead of TDF. Both TAF and TDF are prodrugs of tenofovir, which are converted to their active form by metabolic processes.

"TAF is advantageous because it requires a 30-fold lower dose to achieve the same virological effect as TDF"

TAF is advantageous because it requires a 30-fold lower dose to achieve the same virological effect as TDF and, as a result, Quad 2 showed improved renal and bone tolerability compared with Stribild in phase III studies. It is estimated that Quad 2 will launch in the US in 2015 and in the 5EU and Japan in 2016.

Impact of novel INI-based STRs on the 7MM

In the 7MM, INI-based STRs will see rapid uptake, and this will be most pronounced in the US, where the patient share of such drugs is expected to explode from 4 per cent in 2013 to 42 per cent in 2023.

By 2023, the best-selling INI-based STR in the US will be Triumeq, and this success will be driven by the drug's superior efficacy and good tolerability.

While Gilead's Quad 2 will benefit from patient and physician familiarity with its predecessor, Stribild, and from improved tolerability, the drug shares Stribild's disadvantage of containing a pharmacokinetic enhancer and is also expected to be more expensive than ViiV's competitor product.

Generics set to dominate in Brazil and China

Both Brazil and China offer universal free access to ART for all patients and, in order to curb the financial burden of this, governments in both countries are employing a number of cost-saving strategies, such as the aggressive promotion of generic ART drugs, pricing negotiations with pharma companies, and the threat of compulsory licensing.

Due to an increase in the use of generic antiretrovirals from 2013–2023, headlined by the anticipated launch of generic versions of the NNRTI-based STRs Atripla and Complera (rilpivirine/emtricitabine/TDF), the success of novel INI-based STRs in Brazil and China is expected to be modest.

Instead of adopting novel, costly, STRs, governments will probably focus on combining key components of these drugs, such as Triumeq's INI component, Tivicay, with low-cost generic ART drugs, and restrict their use to special patient populations who are resistant to less expensive, older treatments.

Outlook

Besides the shift towards INI-based STRs, a number of other factors will also affect HIV therapeutics sales in the nine major markets of the US, Japan, France, Germany, Spain, Italy, UK, Brazil and China, which topped $14 billion in 2013, according to our analysis. These include an increasing number of people living with HIV who are treated with ART and the expiration of patents protecting key ART drugs. Based on these considerations, it is likely that HIV therapeutics in these countries will experience modest sales growth from 2013–2023.

It will be interesting to see how the uptake of novel INI drugs will develop in the face of increasing generic competition over the coming years.

About the author:

Moritz Herrmann, PhD, is an Infectious Diseases Analyst at research and consulting firm GlobalData, where he uses his expertise to write business intelligence reports on topics within the infectious diseases market. Recent projects have included a forecast analysis of HIV therapeutics sales as well as an ongoing analysis of respiratory syncytial virus (RSV) therapy and prophylaxis.

Prior to joining GlobalData, Moritz conducted his doctoral research at the Wellcome Trust/CRUK Gurdon Institute, investigating the role of histone lysine demethylases in gene regulation. He holds a BSc in Biochemistry from the University of Aberdeen and a PhD in Genetics from the University of Cambridge. Email: pr@globaldata.com; www.healthcare.globaldata.com