You can read part 1 of this series, Diving into the future of fixed-dose combos, here.
The FDA has published guidance to support the submission process for companies developing fixed-dose combinations (FDCs) for the treatment of HIV patients. According to this guidance, “FDCs are essential for the treatment of HIV/AIDS…They are consistent with the goal of HIV therapy—to maximally and durably suppress virus to allow the recovery of the immune system and reduce the emergence of HIV resistance.”
However, the FDA has also stated that there are some antiretrovirals that should not be combined due to overlapping toxicities and potential viral antagonisms. Numerous studies show that FDCs improve adherence and reduce costs, but those factors don’t make an extremely time-consuming and complex development and approval process any less challenging.
Nonetheless, according to Sean Dalziel, Managing Director and Co-founder of Actera Pharmaceuticals, a formulation innovation company specializing in FDCs, "Now that drug development companies receive five years of marketing exclusivity for newly approved NCEs, even where first registered in the context of an FDC, companies can invert their sequence of FDC lifecycle development without an exclusivity penalty."
"Instead of developing single agent products one at a time over a period of years, and then combining them into an FDC later in the product lifecycle, a company (or collaborating companies) can strategically develop an FDC for the NCE’s initial product launch," Dalziel continues. "Further, where the FDC is used in the pivotal clinical studies, the primary efficacy and safety database is based on that combination product, thereby eliminating the requirement, costs, complexities, and technical risks of bioequivalence studies between an FDC and its respective single agents."
Gilead leads the way
There are very few companies that have successfully developed 3-in-1 combinations because of the long development timeline and the strenuous regulatory process involved. This is one reason why the introduction of Gilead’s 3-in-1 treatment for HIV/AIDS, Atripla (efavirenz/emtricitabane/tenofovir), was hailed as a breakthrough when it was approved in July 2006.
The FDA called the development of Atripla “a landmark achievement,” citing its efficacy and ability to increase adherence and simplify complex HIV treatment regimens. As the first single-tablet regimen (STR), Atripla has been a significant performer in the HIV/AIDS market, grossing $3.65 billion in revenues last year.
Mark Menning, Managing Director and Co-founder of Actera Pharmaceuticals, was an FDC formulation scientist involved in the Atripla and subsequent STR development programs for HIV at Gilead. "Atripla was a challenging development process because of the difficulty to achieve bioequivalence to Sustiva (efavirenz)," he told BioPharma Dive in an interview.
"When developing FDCs, there are a lot of challenges, both chemically and physically. We worked through those and once we were able to demonstrate bioequivalence, we moved quickly towards approval.”
As the company that introduced the concept of STR treatment, Gilead is considered a leader in FDC development. It has developed a total of three STRs for HIV, including a four-drug FDC—one of only two 4-in-1 FDCs approved between 1990 and 2013. In August 2011, Gilead launched Complera (emtricitabane/rilpivirine/tenofovir) for treatment-naive patients with no more than 100,000 copies/mL of viral load in their bodies. Then, in August 2012, Gilead introduced Stribild (elvitegravir/cobicstat/tenofovir/emtricitabane) for treatment of HIV patients who have never been treated before, regardless of their viral load.
Both drugs have done well, but Stribild has been the more successful of the two. Despite the fact that Stribild is targeted towards treatment-naive patients, it is quickly moving towards blockbuster status. The drug had $539.2 million in sales in 2013, with analysts projecting annual sales of $3.5 billion by 2018.
The triumph of Triumeq
In August, Triumeq (abacavir/dolutegravir/lamivudine) was approved by the FDA, becoming the fourth STR for the treatment of HIV. Triumeq was developed by a specialty company, Viiv Healthcare, formed when Pfizer and GSK joined forces for the purpose of developing HIV therapeutics.
Experts say that dolutegravir, a relatively new product, is the real game-changer because of its favorable pharmacokinetics and significant activity against resistant strains of HIV. It is also part of a powerful class of antivirals—integrase strand transfer inhibitors—that were introduced in 2007. Many experts feel that, because of its long half-life and high degree of antiviral activity, dolutegravir works especially well as a constituent part of an FDC. It is also indicated for both treatment-naive and treatment-experienced patients.
The whole point of developing FDCs is to upgrade the standard of care by creating treatment options that are either more effective, more convenient, safer—or ideally all three. In fact, Triumeq is the most recent FDA-approved single-table regimen (STR) and does not contain tenofovir, which is linked with bone and kidney problems in some patients.
Dolutegravir is linked with very few cases of drug resistance and drug-drug interactions and widely perceived as the next step in the evolution of more convenient and effective HIV treatment options. In phase III clinical studies comparing Atripla and Triumeq, Triumeq was associated with a shorter median time to viral suppression, greater increases in CD4 cell counts, and a greater proportion of patients who achieve a viral load below 50 copies/mL.
When adherence matters most
Non-adherence is a major area of concern in HIV therapeutics since it increases the risk of viral mutations, leading to cross-resistance to medication and rendering many treatment options ineffective. Even worse, transmission of resistant strains of HIV means that even treatment-naive patients may be difficult to treat because of multi-drug resistant HIV.
But studies show that ease of use can make patients with HIV more adherent. In a study of 1,727 HIV-positive women published in the Journal of Acquired Immune Deficiency Syndrome, the percentage of women using STRs increased from 6% in 2006 to 27% in 2013. During the same period, the level of adherence increased from 78% to 85% thanks to the simplified treatment regimen.
Development of FDCs, especially in virology, is not simply a matter of throwing various drugs together. It is a complex process that involves multi-drug and multi-target synergistic activities related to immune function, resistance, and virologic suppression over time. Scientists involved in developing HIV therapeutics are always trying to stay one step ahead of the virus, while companies dedicated to developing these therapies are well positioned to reap the rewards for what has become a chronic disease that requires lifelong treatment.
Learning the lessons of HIV drug development
Citing the "cultural shift" that has taken place since the FDA changed the rules surrounding FDCs and marketing exclusivity, Menning and Dalziel say they are excited about the future of FDC drug development. In fact, they see an opportunity to change the standard of care in oncology by considering the drug tolerability needs of patients.
"We see an untapped area in FDC development in oncology in which a targeted agent or other chemotherapy drug can be combined with supportive care drugs, such as an anti-emetic, to reduce the gastrointestinal toxicities, improving quality of life, and potentially increasing maximum tolerable dose," Dalziel explains.
FDC drug development is evolving rapidly as the industry gains experience in manufacturing them and ushering them through the review process. The laws have changed towards a more favorable marketing climate. And finally, it is clear that FDCs are more than a way to improve adherence—though that will always be a prominent consideration. FDCs can shift the standard of care towards a more tolerable, patient-friendly, value-oriented approach to treatment, and in the final analysis, that approach to development bodes well for companies, payers, and most importantly, patients.