From: Pipeline Report
INTRODUCTION
As a global community of people living with HIV, our needs from the antiretroviral (ARV) pipeline have changed considerably over the last 20 years.
Antiretroviral treatment (ART), particularly for people starting treatment, is increasingly effective, safe, and easier to take. ART now involves fewer pills and doses, with several combinations combined in a single daily pill. This may have raised the bar for drug research and development, with only those compounds with clear advantages progressing to clinical trials, but by definition, this has always been the case. Just as importantly, technological and scientific advances should enable companies to continue to design even better and more effective drugs.
Although current treatments are largely manageable, side effects continue to be a concern, especially when combination therapy will be taken for decades. Drug interactions are complex, even with some recently approved drugs. This is increasingly significant given the greater rates of complications and polypharmacy as we grow older. Drug interactions are also important because of the increasing role played by non-HIV specialists in HIV management, especially primary care providers. The strictness required to maintain longterm adherence continues; most once-daily combinations still involve being taken every 24 hours rather than “any time,” and many drugs still must be taken with food.
Critically for 2015 – and annually going forward – manufacturers need to market new drugs at prices that are not just competitive but affordable. This is particularly true given the results from the Strategic Timing of Antiretroviral Treatment (START) study, which support starting HIV therapy regardless of baseline CD4 count.1,2 The DSMB interim analysis, demonstrating a 53% reduction in the risk of developing serious illness or death in the early-treatment group (95% CI: 0.32–0.68, P < 0.001) compared with those in the deferred group, is expected to change ARV treatment guidelines in high-, middle-, and low-income countries. Overnight, this will substantially increase the number of people who will be eligible for treatment and the budgets required to meet this need.
The use of generic versions of widely used ARVs in high-income countries warrants a specific focus. Although they are bioequivalent, generics are technically new formulations. The dramatically lower prices in some countries have the potential to further widen the difference between standards of care for people who are rich or well insured compared with those dependent on public health providers. With nearly all health systems under pressure to save costs, certainly in Europe, this will bring a new dynamic to HIV management.
However, at least in the United States, launch prices continue to spiral upward – directly related to the wholesale acquisition cost established for a previously approved drug, irrespective of the active pharmaceutical ingredient (API) or the potential for high-volume sales – and annual (and sometime twiceyearly) price increases far exceed all medical consumer price index categories.
It is significant that the U.S. Department of Health and Human Service’s Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents 2015 update relegated Atripla to an alternative option. Although efavirenz is in now off patent in some countries in Europe, the U.S. patent has been extended to 2017, for reasons that are unclear.
Whether guideline recommendations alone will be sufficient to shift the majority of new prescriptions to one of the four integrase-based combinations or to darunavir/ritonavir plus tenofovir disoproxil fumarate (TDF)/ emtricitabine (FTC) is also unclear. Similar discussions are likely to occur when TDF, which has been a preferred regimen component since U.S. approval in 2001, comes off patent in 2017. A new prodrug of tenofovir, tenofovir alafenamide fumarate (TAF), is covered later in this report to discuss whether it brings important clinical advantages for some or all patients or whether it is merely a way to extend patent exclusivity
Even fixed-dose combinations (FDCs), clearly popular for anyone taking treatment, are undergoing more rigorous scrutiny, including whether, in the absence of evidence showing clinical benefits, the common-sense advantages of reduced pill count will be sufficient to justify continued access at higher prices than for matched generics. Also, for the first time, branded drugs are being co-formulated with generics for high-income markets.
Against this background, the antiretroviral pipeline in 2015 is surprisingly encouraging. It features compounds in phase II/III development that might bring important improvements for treatment. These include Gilead Science’s TAF, ViiV Healthcare’s cabotegravir (in oral and long-acting injection formulations), and Janssen’s long-acting rilpivirine formulation. Of particular interest for the important group of people with resistance to current drugs, Bristol-Myers Squibb (BMS) has an attachment inhibitor, fostemsavir, and a maturation inhibitor, BMS-955176, and Merck is progressing with the non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine.
