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FDA approves treatments for new diseases and drugs that operate by new mechanisms.
With respect to FDA approval of new medicines, 2014 has been another strong year for the pharmaceutical industry. The agency’s Center for Drug Evaluation and Research (CDER) approved a total of 34 new medicines (as of the end of October 2014): 22 new molecular entities (NMEs) and 12 biologics license applications (BLAs) (see Table I) (1). In 2013, the total number of approvals for the entire year was 27, while in 2012 the number reached 39, which was unusually high compared to the numbers of approvals over the previous 10 years (2). Not only were a high number of new medicines approved in 2014, there were numerous examples of first-ever approvals for the treatment of certain diseases and new classes of drugs that treat diseases via new routes. Treatments were also approved under new designations.
Hetlioz (tasimelteon, Vanda Pharmaceuticals), a melatonin receptor agonist, was the first treatment approved by FDA for non-24-hour sleep-wake disorder, a chronic circadian rhythm (body clock) disorder that causes problems with the timing of sleep that occurs almost exclusively in people who suffer complete blindness (3). Vimizim (elosulfase alfa) from BioMarin Pharmaceutical is the first FDA-approved treatment for mucopolysaccharidosis type IVA (Morquio A syndrome), a rare, autosomal recessive lysosomal storage disease caused by a deficiency in N -acetylgalactosamine-6-sulfate sulfatase (GALNS). Vimizim is intended to replace the missing GALNS enzyme involved in an important metabolic pathway. Absence of this enzyme leads to problems with bone development, growth, and mobility (4). Myalept (metreleptin for injection), developed by Amylin Pharmaceuticals, which was acquired by AstraZeneca, is an orphan drug and the first treatment approved by FDA for patients with congenital or acquired generalised lipodystrophy (5). Sylvant (siltuximab, Janssen Biotech) is another drug approved as a first treatment for a rare disease--multicentric Castleman’s disease, a rare disorder that causes an abnormal overgrowth of immune cells in lymph nodes and related tissues in the body. Administered as an injection, Sylvant works by blocking a protein that stimulates abnormal growth of immune cells (6).
Novel mechanisms of action
Several of the drugs approved by FDA also fall into new classes of drugs. Three of the most noteworthy are manufactured by Merck & Co. Zontivity (vorapaxar) tablets reduce the risk of heart attack, stroke, cardiovascular death, and need for procedures to restore the blood flow to the heart in patients with a previous heart attack or blockages in the arteries to the legs. It is the first protease-activated receptor-1 antagonist and is designed to decrease the tendency of platelets to clump together to form a blood clot (7). Belsomra (suvorexant) for insomnia is the first FDA-approved orexin receptor antagonist, which alters the signaling of orexin in the brain. Orexins are involved in regulating the sleep-wake cycle (8). Keytruda (pembrolizumab) was approved for the treatment of patients with advanced or unresectable melanoma who are no longer responding to other drugs. It is the first approved drug that blocks the programmed death-1 (PD-1) cellular pathway, which restricts the body’s immune system from attacking melanoma cells. Keytruda was also designated a breakthrough therapy and an orphan product and received priority review (9).
Harvoni (ledipasvir and sofosbuvir) from Gilead Sciences is the first combination treatment (pill) for chronic hepatitis C virus (HCV) genotype 1 infection. It is also the first approved regimen that does not require administration with interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection. Both drugs in Harvoni interfere with the enzymes needed by HCV to multiply. Harvoni was designated a breakthrough therapy (10).
In addition, 2014 saw the first approved antibiotic drugs--Dalvance (dalbavancin, Durata Therapeutics), Sivextro (tedizolid, Cubist Pharmaceuticals), and Orbactiv (oritavancin, The Medicines Company)--designated as qualified infectious disease products (QIDPs) under the Generating Antibiotic Incentives Now title of the FDA Safety and Innovation Act (FDASIA) (11). Vimizin was also the first drug to receive the Rare Pediatric Disease Priority Review Voucher, a provision that aims to encourage the development of new drugs and biologics for the prevention and treatment of rare pediatric diseases (4).
For only the second year, FDA was able to classify new NMEs and BLAs as breakthrough therapies, which are drugs with preliminary clinical evidence demonstrating that they may have substantial improvement on at least one clinically significant endpoint over available therapies. While in 2013 just three approved drugs were designated as breakthrough therapies, to date in 2014, six have already been approved: Zykadia (ceritinib, Novartis), Zydelig (idelalisib, Gilead Sciences), Keytruda, Harvoni, Ofev (nintedanib, Boehringer Ingelheim Pharmaceuticals), and Esbriet (pirfenidone, InterMune). Zykadia was approved for patients with a certain type of late-stage (metastatic) non-small cell lung cancer (12), and Zydelig was approved for patients with relapsed chronic lymphocytic leukemia, elapsed follicular B-cell non-Hodgkin lymphoma, and relapsed small lymphocytic lymphoma (13). Both Ofev and Esbriet were approved for the treatment of idiopathic pulmonary fibrosis, which is a serious, chronic condition in which the lungs become progressively scarred over time (14). Four additional supplemental submissions also received breakthrough therapy designations (15).
In addition to the breakthrough designation, FDA also has several other designations designed to expedite the review of NMEs and BLAs. These include fast track, orphan product (for rare diseases), and priority review designations. Drugs can receive multiple designations. Up to Oct. 29, 2014, seven approved drugs had fast-track status, nine were designated as orphan products, and 12 underwent priority review (1).
Looking at companies that received the most approvals, two have come out on top as of Oct. 29, 2014. Boehringer Ingelheim and Merck & Co. each received approvals for two NMEs and one BLA. Boehringer Ingelheim received approvals for Ofev, Jardiance (empagliflozin) for improvement of glycemic control in adults with type 2 diabetes, and Striverdi Respimat (olodaterol), a biologic drug for the treatment of chronic obstructive pulmonary disease (1). Merck’s winners included Zontivity, Belsomra, and Keytruda as described above. AstraZeneca, Eli Lilly, and Gilead Sciences were also successful with two approvals each: Gilead for one BLA and one NME (Harvoni and Zydelig, respectively); Eli Lilly for two BLAs, Cyramza (ramucirumab) for the treatment of stomach cancer and Trulicity (dulaglutide) for the treatment of adults with type 2 diabetes; and AstraZeneca for two NMEs, Farxiga (dapaglifozin) to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes and Movantik (naloxegol) to treat opioid-induced constipation in adults with chronic non-cancer pain (1). Through its acquisition of the diabetes alliance assets of Bristol Myers Squibb, including Amylin Pharmaceuticals, AstraZeneca also acquired Myalept.
1. FDA, “New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products of 2014,” www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm20025676.htm, accessed Oct. 29, 2014.
2. FDA, “Novel New Drugs 2013 Summary,” www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM381803.pdf, accessed Oct. 29, 2014.
3. FDA, “FDA Approves Hetlioz: first treatment for non-24 hour sleep-wake disorder,” Press Release, Jan. 31, 2014.
4. FDA, “FDA approves Vimizim to treat rare congenital enzyme disorder,” Press Release, Feb. 14, 2014.
5. AstraZeneca, “US FDA approves orphan drug Myalept (metrleptin for injection),” Press Release, Feb. 25, 2014.
6. FDA, “FDA approves Sylvant for rare Castleman’s disease,” Press Release, April 23, 2014.
7. FDA, “FDA approves Zontivity to reduce the risk of heart attacks and stroke in high-risk patients,” Press Release, May 8, 2014
8. FDA, “FDA approves new type of sleep drug, Belsomra,” Press Release, Aug. 13, 2014.
9. FDA, “FDA approves Keytruda for advanced melanoma,” Press Release, Sept. 4, 2014.
10. FDA, “FDA approves first combination pill to treat hepatitis C,” Press Release, Oct. 10, 2014.
11. FDA, “FDA approves Orbactiv to treat skin infections,” Press Release, Aug. 5, 2014.
12. FDA, “FDA approves Zykadia for late-stage lung cancer,” Press Release, April 29, 2014.
13. FDA, “FDA approves Zydelig for three types of blood cancers,” Press Release, July 23, 2014.
14. FDA, “FDA approves Esbriet to treat idiopathic pulmonary fibrosis,” Press release, Oct. 15, 2014.
15. FDA, “CY 2014 Breakthrough Therapy Calendar Year Approvals,” www.fda.gov/downloads/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/UCM380724.pdf, accessed Oct. 29, 2014.