Conventional wisdom says that two is better than one. By that logic, combining two or more active ingredients which have the same goal should translate into automatic synergy.
That's true for the most part when it comes to fixed-dose combinations (FDCs) of two or more active pharmaceutical ingredients (APIs). But in order to ensure that FDCs are effective and safe—meaning no harmful pharmacokinetic or pharmacodynamic interactions between the APIs—the FDA has set up a rigorous and well-defined submission and approval process for the combos.
New FDC approvals
This month alone, the FDA has approved four new FDCs, all designed to address a specific medical need or improve upon currently available therapies. Gilead’s Harvoni (ledipasvir/sofosbuvir) for treatment of hepatitis C genotype 1 costs $95,000 per 12-week treatment, but is associated with a higher level of complete cure in more patients than sofosbuvir alone.
Akynzeo (netupitant/palonosetron), co-developed and marketed by the Helsinn Group and Esai, is an FDC intended for use in patients with chemotherapy-induced nausea and vomiting (CINV). It combines two antiemetics with different modes of action. Whereas netupitant is designed to address CINV during the acute phase, palonosetron has been proven clinically to decrease CINV during the extended phase—25 to 120 hours after chemotherapy. Then, in the middle of the month, Pfizer’s Embeda (morphine/naltrexone) was approved as a medication for round-the-clock management of severe pain.
And just this morning, the FDA approved AstraZeneca's Xigduo XR, a once-daily oral tablet for the treatment of type 2 diabetes in adults that is the first-ever once-daily FDC of an SGLT2 inhibitor (Farxiga/dapagliflozin) and metformin to win U.S. approval.
That doesn't even take earlier approved FDCs into account. For instance, in September, the FDA approved Contrave (buproprion/naltrexone), which was developed as a treatment for obesity by Orexigen. And in August, Invokamet became the first FDA-approved FDC to combine an SGLT inhibitor (in this case Invokana/canagliflozin—the number one newly prescribed non-insulin medication for patients with type 2 diabetes), with metformin.
A long tradition of fixed-dose combos
These new FDCs build on a long tradition of combining synergistic drugs; however, there is a notable evolution in FDC drug development trends. Old standbys in this category include the combination of analgesics, especially opioid analgesics, with other types of painkillers. But more recently, the focus has been on combining opioids with active ingredients that deter abuse, such as Embeda (morphine/naltrexone). Other well-validated FDC categories include progestin and estradiol; antihypertensives and diuretics; anithistamines and pseudoephedrine; antidiabetics and metformin; steroids and bronchodilators or anticholinergics; and various combinations of antiretroviral drugs for the treatment of HIV.
At face value, it might seem that combining approved or clinically vetted drugs is easier than developing a drug from scratch. But gaining approval for an FDC is actually more challenging in many ways than gaining approval for a single-entity product—at least in the U.S., which requires significant efforts beyong basic formulation development and toxicology, safety, and efficacy studies. These requirements include assessing the basic toxicology of the interaction between more than one API; ensuring stability; evaluating the efficacy and safety of the combined active ingredients; and conducting dose-ranging studies to determine the best ratios of the constituent ingredients.
The long list of criteria needed to submit an FDC to the FDA may be one reason that 99% of approved FDCs include at least one previously FDA-approved product. Furthermore, because of rigorous regulations that require interaction studies between all of the APIs in an FDC, there are very few FDCs with more than two APIs. In fact, out of the 131 FDCs developed between 1990 and 2013, only 12 were comprised of three APIs, and only two were comprised of four APIs.
A study published in the Journal of the American College of Cardiology last month found that using a "polypill" or FDC secondary prevention strategy in patients who had experienced a heart attack was significantly more effective than asking patients to take multiple pills. The researchers found that, over a nine-month period, 50.8% of polypill patients were adherent compared with 41% of patients taking multiple pills (P=0.019). Numerous studies have shown that adherence increases alongside the use of FDCs regardless of the therapeutic area. The implications of this are positive not only for patient health and long-term outcomes, but also for profitability.
FDCs received another boost earlier this month when the FDA announced that, as of October 10, all approved FDCs will automatically have five years of marketing exclusivity. Previously, only FDCs that had two new chemical entities (NCEs) had five years of exclusivity, while those with only one NCE had three years of exclusivity.
There are clearly unmet medical needs that could be better treated with effective FDCs. Now it’s up to innovative companies to lead the way with R&D that embraces the challenges associated with research, development, and submission of these products.