One encouraging trend that we’re seeing in pharma is record-breaking numbers of new molecular entities (NMEs) and other drugs that are approved by the FDA. For instance, the number of NMEs approved by the Center for Drug Evaluation and Research (CDER) was at an all-time high in 2018, with 59 novel drugs destined for pharmacy shelves and refrigerators. This total beat out the previous record of 53 approvals in 1996, and bested even the 46 drugs approved in 2017. The CDER is the epicenter of innovation at the FDA. Every year, the CDER approves two kinds of drugs. The first are NMEs and new therapeutic biologics. The rest are drugs that are similar to ones already on the market. If you equate importance with novelty, then the NMEs will be of interest. Since it’s nearly the end of the decade, let’s take a year-by-year look at some of the biggest FDA drug approvals—including NMEs—that have made waves over the past 10 years. 2010: Denosumab (Prolia) Treatment for osteoporosis is a long-term commitment, and as such, these drugs need to be safe. In 2010, the FDA approved denosumab for the treatment of osteoporosis in men and women. Like the Energizer Bunny, this drug was still going strong several years out, per the results of a study published in Lancet. Results led the authors to conclude: “Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in [bone mineral density] without plateau.” Of note, denosumab is a human monoclonal antibody that binds to RANKL, an apoptosis regulator gene. By binding to RANKL, it stops the activation of the RANK receptor, located on the surface of osteoclasts, thus impacting their survival and function. In other words, the drug decreases bone resorption and increases bone mass via effects on osteoclasts. 2011: Gabapentin (Gralise, Horizant, Neurontin) Although gabapentin had been on the market for years as an approved treatment for seizures, it was first approved for the treatment of pain (post-herpetic neuralgia) in 2011. This new indication dramatically expanded options for chronic, neuropathic pain sufferers. Gabapentin was conceived to mimic the actions of GABA, but it does not bind to GABA receptors. Instead, its mechanism may include the inhibition of alpha 2-delta subunit of voltage-gated calcium channels. Gabapentin has proven to be a boon for Abbott and is one of the most prescribed drugs in the United States. Fortunately, the adverse effects of gabapentin are lower than those of opioids, but like opioids, gabapentin—and pregabalin (Lyrica) for that matter—can be misused. 2012: Tofacitinib (Xeljanz) The FDA approved tofacitinib for the treatment of rheumatoid arthritis in 2012, and then in 2016 approved tofacitinib citrate as the first and only once-daily oral Janus kinase (JAK) inhibitor treatment for rheumatoid arthritis. Tofacitinib is a targeted small molecule that inhibits JAK, thus moderating cytokines important in immune and inflammatory processes. Cytokines play an important role in the disease progression of rheumatoid arthritis. In recent years, tofacitinib has proven so successful in clinical trials that its use has been expanded to other indications, including ulcerative colitis. An expert commentary on the drug in the Expert Review of Clinical Immunology states: “The efficacy of tofacitinib monotherapy has garnered much attention and has been initiated in a large number of patients. However, combination therapy with [methotrexate] is necessary in order to achieve the maximum effect...There has been no new safety signal although venous thrombotic events (VTEs) have been raised and would require long-term follow-up. Increased events of herpes zoster were observed and the use of a subunit vaccination is expected to become an effective tool for prevention.” 2013: Canagliflozin (Invokana) Some drugs are important not because of their benefit, but rather because of their potential danger. Canagliflozin is a sodium-glucose cotransporter 2 inhibitor responsible for decreasing blood sugar levels, albuminuria, and body weight, albuminuria, and blood pressure levels in patients with type 2 diabetes. In 2016, however, the FDA issued a safety warning for canagliflozin regarding an increased risk of amputation, which was twice as high in those treated with the drug compared with those taking placebo. In 2019, this safety alert was elevated to a black-box warning. 2014: PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) Nivolumab and pembrolizumab were the first programmed death 1 (PD-1) inhibitors approved for those with unresectable or metastatic melanoma and disease progression after treatment with ipilimumab. These immune checkpoint inhibitors prevent binding to programmed death ligand 1 (PD-L1). By preventing the complexing of PD-1 and PD-L1, T cells are free to kill cancer cells. Although concerns exist about the accuracy of the PD-L1 assays used to select patients for anti-PD1/PD-L1 treatments, the treatments themselves have proven remarkably impressive in their results in scary cancers with typically guarded prognoses, such as non-small cell lung cancer and triple-negative breast cancer. 2015: Sugammadex (Bridion) This first-in-class drug was approved in 2015 to reverse neuromuscular blockade secondary to rocuronium bromide and vecuronium bromide in adults receiving anesthesia. Sugammadex blocks neuromuscular-blocking agents—most importantly, rocuronium and vecuronium. The sugammadex-rocuronium/vecuronium complexes rapidly reverse neuromuscular blockade compared with anticholinesterase inhibitors. Anesthesiologists use many drugs every day, such as local anesthetics, opioids, intravenous anesthetics, and neuromuscular-blocking drugs and their antagonists. Paradoxical muscle weakness, nausea, vomiting, bronchoconstriction, and bradyarrhythmias secondary to the administration of antagonists of neuromuscular-blocking drugs (ie, acetylcholinesterase inhibitors) are rare occurrences, but comprise a medical emergency. One situation where sugammadex excels is the reversal of rocuronium neuromuscular blockade during a difficult intubation. Administration of the drug leads to spontaneous ventilation. 2016: Venetoclax (Venclexta) Chronic lymphocytic leukemia (CLL) patients with a 17p deletion lack part of the chromosome that inhibits cancer growth. For these patients—about 10% of those with CLL and 20% of those with relapsed CLL—the FDA approved venetoclax in 2016. Venetoclax is the first FDA-approved treatment targeting the B-cell lymphoma 2 (BCL-2) protein, which is responsible for cancer growth and is overexpressed in patients with CLL. In 2018, indications for treatment with venetoclax were broadened to include all patients with CLL—regardless of chromosome status—who failed at least one previous treatment. On May 15, 2019, venetoclax in combination with obinutuzumab—a monoclonal antibody targeting CD20—was FDA approved as first-line therapy in patients with CLL or small lymphocytic lymphoma (SLL). This approval made history as the second non-chemotherapy first-line treatment for the treatment of CLL. 2017: Dupilumab (Dupixent) Eczema, or atopic dermatitis, affects 15%-20% of children and 1%-3% of adults. This chronic, relapsing inflammatory skin condition results in dry, itchy skin. The symptoms wax and wane, with flare-ups interfering with quality of life. The FDA approved injectable dupilumab for adults with moderate-to-severe atopic dermatitis refractory to topical prescription therapies. Dupilumab is a first-in-class drug and can be combined with steroids. Dupilumab combats inflammation by inhibiting interleukin (IL)-4 and IL-3 signaling and cytokine-reduced responses, which results in decreased release of proinflammatory cytokines/chemokines and IgE. A review article from Pharmacy and Therapeutics touted the benefits of the drug, stating: “Dupilumab is the only FDA-approved medication for moderate-to-severe atopic dermatitis that is administered weekly. This may greatly increase patient compliance, and thus improve symptoms. Dupilumab treatment was not only associated with improvement in skin lesions, but also with rapid reductions in pruritus and other symptoms that place a burden on patients with atopic dermatitis.” 2018: Cannabidiol oral solution (Epidiolex) There’s nothing new about cannabis, which folks have been smoking for at least 2,500 years. But in 2018, the FDA approved the first derivative of this Schedule I drug—cannabidiol (CBD) oral solution—for the treatment of certain rare, severe forms of epilepsy. Of note, this preparation contains CBD and not THC, which is the psychoactive component of marijuana. Then-FDA commissioner Scott Gottlieb, MD, provided comment on the importance of this approval: “This approval serves as a reminder that advancing sound development programs that properly evaluate active ingredients contained in marijuana can lead to important medical therapies. And, the FDA is committed to this kind of careful scientific research and drug development. Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA’s drug approval process, is the most appropriate way to bring marijuana-derived treatments to patients.” He added: “We’ll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products. But, at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims. Marketing unapproved products, with uncertain dosages and formulations can keep patients from accessing appropriate, recognized therapies to treat serious and even fatal diseases.” 2019: Lefamulin (Xenleta) The countervailing force to antibiotic resistance is innovation in the form of new antibiotics. Unfortunately, while antibiotic resistance is cresting, the pipeline for new antibiotics is drying up. Any new antibiotic, therefore, is big news. In 2019, the FDA approved lefamulin as a new treatment for community-acquired pneumonia. Any mention of a new antibiotic raises curiosity about its mechanism of action. Lefamulin is a systemic pleuromutilin antibacterial. It inhibits bacterial protein synthesis by interfering with the A- and P-sites of the peptidyl transferase center in domain V of the 23s rRNA of the 50S subunit. Put another way, the drug disrupts the correct positioning of bacterial tRNA. Lefamulin is bactericidal against Mycoplasma pneumoniae, Streptococcus pneumoniae, and Haemophilus influenzae. It is also bacteriostatic against Streptococcus pyogenes and Staphylococcus aureus. The past 10 years have been a banner decade for the advancement of medicine, but there’s still more to look forward to in the pipeline for 2020. Here’s to even more research & development in the coming year. Source
