Johnson, Mark S. PharmD, BCPS
The FDA approved 39 new drugs and biologics in 2012—the largest number since 1996.1 Some of the notable approvals include 11 new cancer treatments, such as the HER2/neu receptor antagonist pertuzumab for HER2-positive metastatic breast cancer and the angiogenesis inhibitor ziv-aflibercept for advanced metastatic colorectal cancer.1 Other approved drugs include ivacaftor for patients with cystic fibrosis who have a certain type of gene mutation; the second oral multiple sclerosis (MS) drug teriflunomide, approved to treat relapsing forms of the disease; the antimycobacterial drug bedaquiline for pulmonary multidrug-resistant tuberculosis; the oral kinase inhibitor tofacitinib for moderate-to-severe rheumatoid arthritis; and the factor Xa inhibitor anticoagulant apixaban for stroke prevention in patients with nonvalvular atrial fibrillation.1 Also in 2012, many patents expired, causing an increase in generic drug manufacturing and approvals.1
The forecast for drug development and approval in 2013 and beyond is promising. Predictions for the future include a continuing focus on safety during the drug development process, a continuing development of oncology drugs, orphan drug development (drugs used to treat rare diseases), and increasing development of biologics and specialty drugs for specific populations through the use of pharmacogenomics.2 This article highlights the current top 10 drug trends in the United States. These trends include drugs that are unique based on mechanism of action or other properties when compared with drugs already on the U.S. market (based on a particular disease state) and those which are farthest along in phase III clinical trials or were very recently FDA approved as of the publication of this article. (See Table 1.)
New drugs for MS are needed to improve the efficacy and adverse reactions of currently available therapies.3 Dimethyl fumarate is an oral fumaric acid ester drug for the treatment of relapsing forms of MS.3 Fumaric acid esters have been used for the treatment of psoriasis in Europe, but have a high incidence of gastrointestinal (GI) adverse reactions. The proposed mechanisms of action for treating MS include anti-inflammatory effects and improving the cellular response to oxidative stress via nuclear factor E2-related factor 2.3
Of the clinical trials to date, one phase II and two phase III trials have been completed, along with an ongoing phase III long-term extension trial to evaluate safety and efficacy.3 The Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (DEFINE) and the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) trials compared dimethyl fumarate with a placebo. Based on these trials, dimethyl fumarate is superior to a placebo in reducing annualized relapse rates (44% versus 53%, respectively), and new lesions on magnetic resonance imaging at a dose of 240 mg two or three times daily at 2-years follow-up. Additionally, the DEFINE trial showed a reduction in disability progression.4
The most common adverse reactions observed with the use of this drug are flushing, GI problems (diarrhea, nausea, abdominal pain, and so on), and reduced lymphocyte count. The FDA approved the drug in March 2013 at a starting dose of 120 mg orally twice daily for 7 days, then increasing to 240 mg orally twice daily.4–6
It's estimated that 8.3% of the U.S. population has diabetes, and the incidence of type 2 diabetes is increasing worldwide.7 Many classes of drugs used to treat type 2 diabetes now exist; however, despite the vast array of treatment options, achieving appropriate glycemic levels can be difficult even with combination therapy because adverse reactions (weight gain, hypoglycemia, GI problems, pancreatitis, and others) can limit optimal disease management.8
Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that was recently approved by the FDA for the management of type 2 diabetes in adults.9 A similar drug, dapagliflozin, was recently rejected by the FDA due to increased risk of breast and bladder cancers.8 SGLT2 regulates glucose reabsorption in the kidney. Inhibition of SGLT2 results in increased urinary glucose excretion, lowered plasma glucose levels, and weight loss.8
Efficacy and safety data from nine clinical trials involving over 10,000 patients were submitted to the FDA. These studies have investigated the drug as monotherapy, and in combination therapy compared with placebo, glimepiride, and sitagliptin, in older patients and in patients with moderate renal impairment.9,10 In terms of efficacy, canagliflozin 100 mg P.O. daily and 300 mg P.O. daily resulted in hemoglobin A1C reductions from baseline of 0.62% to 0.91% and 0.74% to 1.16%.8,10 Fasting plasma glucose was reduced by 36 mg/dL to 43 mg/dL.10 Canagliflozin was less effective in patients with moderate renal impairment: A1C reductions were 0.38% to 0.47% with 100 mg P.O. daily and 300 mg P.O. daily, respectively.8,10 Canagliflozin also showed significant weight reductions (up to a 4.7% weight loss) in four studies, and significant reductions of systolic BP in two studies.8,10
The most common adverse reactions noted in phase III clinical trials included hypoglycemia (4.9% to 5.6%), osmotic dieresis and volume depletion (particularly in moderate renal impairment), increased urination, superficial genital fungal infections, and urinary tract infections.8,11 Major adverse cardiovascular reactions—defined as a composite endpoint consisting of the adjudicated events of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, and hospitalization for unstable angina—occurred in 18.9% of patients taking canagliflozin and in 20.5% of patients taking comparison drugs.8 Stroke risk was also increased with canagliflozin.8
Results from the ongoing Canagliflozin Cardiovascular Assessment Study trial will be available in 2015 to further investigate cardiovascular safety.9 The FDA is requiring postmarketing studies including bone safety, pediatrics, photosensitivity, pregnancy, pancreatitis, and severe hypersensitivity reactions.9
Another diabetes pipeline drug to watch for is dulaglutide, a once weekly glucagon-like peptide-1 analog.12 Dulaglutide is similar in weekly administration to exanatide extended-release and has shown to be noninferior to insulin glargine in efficacy. It's currently showing positive results in phase III trials.13
Between 50 and 70 million people suffer from a sleep-related disorder in the United States, one of the most common being insomnia.14 Many pharmacologic treatments currently exist to treat insomnia, all of which have varying degrees of efficacy along with many adverse reactions, including anterograde amnesia, next-day residual effects, and rebound insomnia.15,16
Suvorexant represents a new class of drugs for treating insomnia called orexin receptor antagonists. Orexins are chemical messengers in the hypothalamus that cause wakefulness and help keep the brain alert; blocking orexins may help patients fall asleep faster and stay asleep longer.16 Two phase III placebo-controlled trials were submitted to the FDA as part of the new drug application (NDA), and included over 2,000 patients with varying suvorexant doses (15 to 40 mg daily depending on age) over 3 months.17 Patients receiving suvorexant reported falling asleep 26 minutes (36 minutes observed) faster versus 17 minutes (27 minutes observed) with a placebo, and reported staying asleep 60 minutes longer (48 minutes observed) versus 40 minutes (25 minutes observed) with a placebo.13
The most common adverse reactions included sleepiness and headache, with no substantial differences noted when compared with the placebo for memory changes, attention, and motor speed the next morning.17
An increasing number of new cancer drugs have been approved in recent years and the pipeline for the future looks very promising, particularly for malignant melanoma, metastatic pancreatic cancer, multiple myeloma, and prostate cancer.2 Trends in new therapies have focused on drugs that target the cancer cells while better preserving normal cells and drugs that employ companion diagnostics that can better predict which patients will respond best to treatment.2
In February 2013, the FDA approved ado-trastuzumab emtansine for patients with HER2-positive, late-stage (metastatic) breast cancer under the FDA priority review program.18 The HER2 protein is overproduced in some breast cancers, increasing cancer cell growth and survival, and usually represents a more aggressive disease that's less responsive to hormonal therapy.18 Ado-trastuzumab emtansine is a “drug conjugate” of trastuzumab, linked to an antimitotic chemotherapy agent (DM1) that's “joined together with a stable linker” until it reaches cancer cells.18 Trastuzumab targets HER2 proteins on the cancer cell surface and then DM1 exerts its cytotoxic effect on cancer cells. It has the potential advantages of directly delivering chemotherapy to the cancer cells with fewer adverse reactions compared with older therapies.18
Approval was based on a clinical trial of 991 patients comparing ado-trastuzumab emtansine with lapatinib plus capecitabine. Results showed a greater median progression-free survival of 9.6 versus 6.4 months and a greater median overall survival of 30.9 months versus 25.1 months in patients who received ado-trastuzumab emtansine versus lapatinib plus capecitabine, respectively.18
The most common adverse reactions included nausea, fatigue, muscle/joint pain, thrombocytopenia, headache, constipation, and increased liver enzymes.18
Chronic hepatitis C virus (HCV) infection is a common liver disease affecting over 180 million individuals worldwide and around 3.2 million in the United States.19 Historically, peginterferon alfa-2a and ribavirin (RBV) have been the treatments of choice for HCV, but the recent addition of oral protease inhibitors has resulted in sustained virologic response rates of 60% to 80% in the HCV genotype 1 infection.19 Despite the improved response rates, effective therapies for chronic HCV across all genotypes and improved adverse reaction profiles are still needed.19,20 Various classes of drugs are in the pipeline, including NS5A inhibitors, NS3-4A inhibitors, nonnucleotides, and protease inhibitors.2
Sofosbuvir is an oral nucleotide (NUC) inhibitor of HCV polymerase being studied for HCV. Development of two other NUCs was recently stopped due to safety concerns.2 Sofosbuvir has undergone four phase III trials in various HCV genotypes. Results from the phase III studies show sofosbuvir oral therapy coupled with RBV resulted in sustained reductions in virologic response rates of 50% to 78% among HCV genotype 2 and 3 patients who are treatment-naive, treatment-experienced, and interferon-intolerant.21,22 Sixteen months of treatment was more effective than 12 weeks in patients infected with genotype 3 who were previously treated.21 Response rates were lower with genotype 3 infection than genotype 2, and lower with cirrhosis.21 The trials also showed a 90% reduction in virologic response rates in genotypes 1, 4, 5, and 6 in combination with RBV and pegylated interferon among patients who are treatment-naive.21,22 This drug has shown sustained virologic response rates when used with peginterferon alfa-2a and ribavirin, ribavirin with NS5A inhibitors, or as monotherapy.
The most common adverse reactions included headache, fatigue, insomnia, nausea, rash, and anemia.20 The manufacturer filed an NDA with the FDA in April 2013.23
Approximately 5.3 million Americans currently have Alzheimer disease (AD), and it's projected that this number will grow to 13.8 million by 2050.24 Although neuritic plaques and neurofibrillary tangles characterize AD, the exact etiology is unknown. Current therapies are used to treat cognitive symptoms, but they don't provide a cure for AD or slow the disease progression.25
Solanezumab is a monoclonal antibody under development that binds to amyloid-beta peptides after it's produced, allowing it to be cleared before it forms beta-amyloid plaques, the protein plaques found in patients with AD.26 Development of a similar compound, bapineuzumab, was recently stopped due to disappointing results. Interest in solanezumab has been tempered by the recent results of the two phase III trials, EXPanding alzhEimer's Disease InvestigaTIONs (EXPEDITION) 1 and 2, because the drug wasn't effective in meeting primary endpoints in mild-to-moderate AD. However, a secondary analysis of solanezumab revealed a significant slowing of cognitive decline in early-stage AD. Adverse reactions noted in the trials included angina and edema.
Solanezumab will now undergo two phase III studies (a federally funded study and manufacturer sponsored study) to test if AD can be prevented in at-risk older patients.26 The studies will enroll patients who don't have symptoms of dementia, but have brain plaque buildup.26
Osteoporosis is a very common condition that increases in prevalence with age, resulting in an increased fracture risk that can have serious consequences. Bisphosphonates, calcium, and vitamin D are the main drugs used to prevent and treat osteoporosis. Other drugs include estrogen agonists/antagonists raloxifene, calcitonin, denosumab, and teriparatide.27
Odanacatib is an antiresorptive drug created to treat osteoporosis with a new mechanism of action. Compared with other drugs, odanacatib selectively inhibits cathepsin K, a cysteine protease enzyme in osteoclasts that degrades bone proteins during bone resorption.28
A recent phase III clinical trial in over 16,000 postmenopausal women with osteoporosis was stopped early after the first planned interim analysis showed odanacatib was highly effective; it decreased fracture risk, increased bone mineral density, and improved markers of bone formation.28 Other phase II and smaller phase III trials have also shown positive results. The manufacturer is now conducting a blinded extension of the trial in approximately 8,200 women for additional safety and efficacy data. It's anticipated the manufacturer will file for FDA approval in 2014.29
Cardiovascular disease is the leading cause of death in the world.30 Drug development in this area over the past 10 years has been dynamic and robust, particularly with antiplatelet and anticoagulation drugs. However, the balance between efficacy and increased bleeding is real and can often limit the use of these drugs.31
Vorapaxar is a new class of antiplatelet drug that inhibits the actions of thrombin through antagonism of protease-activated receptors (PAR-1).32 Vorapaxar (2.5 mg) was compared with a placebo in a recent phase III trial of 26,449 patients with a history of MI, ischemic stroke, or peripheral arterial disease (PAD).32 Researchers determined that vorapaxar significantly reduced the risk of cardiovascular death and ischemic events. This study was stopped after 2 years because the risk of moderate-to-severe bleeding (including intracranial hemorrhage) was statistically increased in patients taking the drug.32
A subgroup analysis of 17,779 patients with a history of only MI showed the rate of cardiovascular death, MI, or stroke to be significantly reduced in the vorapaxar group compared with the placebo group.33 Additionally, in patients with PAD, rates of hospitalization for acute limb ischemia and peripheral artery revascularization were significantly lower.34 Vorapaxar was also associated with an increased risk of bleeding, but not intracranial bleeding.33 As a result, the manufacturer announced that it would seek approval of the drug in 2013 with a narrower indication of patients: those with a history of only MI.29
Cholesteryl ester transfer protein inhibitors
We'll also most likely see advances in hyperlipidemic drugs. These include the cholesteryl ester transfer protein (CETP) inhibitors, which normally transfer cholesterol from high-density lipoprotein cholesterol to very low-density or low-density lipoprotein cholesterol. Interest has been tempered by the recent discontinuation of the drug dalcetrapib (a phase III trial was canceled due to lack of efficacy) and past failure of torcetrapib (due to increased mortality with atorvastatin).2
Other CETP inhibitors in the pipeline include anacetrapib and evacetrapib. Monoclonal antibodies that are proprotein convertase subtilisin/kexin type 9 inhibitors are entering phase III trials, including alirocumab.2
Neuromuscular blocking agents, including rocuronium and vecuronium, are used as a part of anesthesia during surgery to induce muscle relaxation. Sugammadex, a modified gamma-cyclodextrin, is the first selective relaxant binding agent indicated to reverse the neuromuscular blockade of rocuronium or vecuronium during general anesthesia. The manufacturer submitted an NDA in 2008, but it was rejected by the FDA, citing the need for additional data on hypersensitivity (allergic) reactions and coagulation events. The NDA was resubmitted in January 2013.
Because sugammadex doesn't inhibit acetylcholinesterase (such as neostigmine or pyridostigmine) it should have less cardiovascular and autonomic adverse reactions. Sugammadex is currently approved in Europe and several other countries.35
Other drugs on the horizon
The following is a list of other medications that are currently in the pipeline undergoing promising phase III trials (or recently approved): riociguat for pulmonary arterial hypertension; ixekizumab for autoimmune disorders, including psoriasis and rheumatoid arthritis; fluticasone and vilanterol as a once-daily steroid/long-acting beta agonist for chronic obstructive pulmonary disease (FDA approved May 2013); and antibiotics, including radezolid (an oxazolidinone), solithromycin (a fluoroketolide), and ceftaroline/tazobactam (a cephalosporin/beta-lactamase inhibitor combination).2,36,37 Drug development and approval continues to be robust and dynamic.
Keeping abreast of drug trends is important for nurse managers in supporting and enabling nurses to be well informed and provide the most up-to-date drug therapy for their patients. So, be sure to keep an eye out for all of these drugs and more within coming months.
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10. Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013; 15:372–82.
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20. Papafragkakis H, Rao MS, Moehlen M, Dhillon S, Martin P. Depression and pegylated interferon-based hepatitis C treatment. International Int J Infereron Cytokine Mediator Res. 2012; 4:25–35.
21. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013; 368:(20):1867–77.
25. Slattum PW, Swerdlow RH, Hill AM. Alzheimer's disease. In: Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011; .
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32. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012; 366:(15):1404–1413.
33. Scirica BM, Bonaca MP, Braunwald E, et al. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2P-TIMI 50 trial. Lancet. 2012; 380:(9850):1317–1324.
34. Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in patients with peripheral artery disease: results from TRA2(P-TIMI 50. Circulation. 2013; 127:1522–29.