The US Food and Drug Administration approved 41 new molecular entities in 2014, surpassing a recent high for the pharmaceutical industry. Will the industry be able to continue its surge in innovation? DCAT Value Chain Insights (VCI) takes an inside look. 

The new year is bringing renewed optimism in the pharmaceutical industry as the industry comes off a fruitful year in 2014 for new drug approvals. In 2014, the US Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) approved 41 new molecular entities (NMEs), surpassing the industry’s recent high of 39 NME approvals in 2012 and exceeding 2013’s total of 27 NME approvals. Although an uptick in the number of NME approvals is positive, it is important to evaluate the potential of last year’s crop of approvals and their position in the pharmaceutical market.  

NME approvals in 2014
The FDA’s CDER approved 41 NMEs in 2014, 30 new drug applications and 11 biologics license applications (BLAs) (see Table I), both recent highs in terms of overall NME approvals and the number of approvals of new biologics by CDER. In comparison, FDA’s CDER approved 27 NMEs in 2013 and 39 NMEs in 2012. From 2004 to 2012, CDER averaged 26 NME approvals per year, which was bolstered by approval levels in 2004 (36 NMEs approved), 2011 (30 NMEs approved), 2012 (39 NMEs approved) and 2013 (27 NMEs approved). The period of 2005 to 2010 was a slower period for NME approvals. In 2005, 20 NMEs were approved, 22 in 2006, 18 in 2007, 24 in 2008, 26 in 2009, and 21 in 2010. 

With regard to the mix between small molecules and biologics, the level of NME approvals by CDER increased in 2014. The 11 BLA NMEs approved in 2014 represent a high for NME approvals for biologics by CDER. In 2013, CDER approved only two BLA NMEs  and six NME BLAs in each of the following years: 2009, 2010, 2011, and 2012. The 11 NME BLA approvals in 2014 were: Amgen’s Blincyto (blinatumonmab) for treating a rare form of leukemia; AstraZeneca’s Myalept (metreleptin) for treating a rare form of high cholesterol; Biogen Idec’s Plegridy (peginterferon beta-1a) as a treatment for adults with relapsing multiple sclerosis; BioMarin Pharmaceutical’s Vimizim (elosulfase) for treating the rare disease, Mucopolysaccharidosis; Bristol-Myers Squibb’s Opdivo (nivolumab) for treating unresectable or advanced melanoma; two biologics by Eli Lilly, Trulicity (dulaglutide), a drug to treat Type 2 diabetes, and Cyramza (ramucirumab), a drug to treat patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma; GlaxoSmithKline’s (GSK) Tanzeum (albiglutide), a drug to treat Type 2 diabetes; Johnson & Johnson’s Janssen Biotech’s Sylvant (siltuximab), a drug to treat the rare disease, multicentric Castleman’s disease; Merck & Co’s Keytruda (pembrolizumab) for treating advanced melanoma; and Takeda’s Entyvio (vedolizumab), a drug to treat moderate-to-severe ulcerative colitis and severe Crohn’s disease in adults.  

Reflecting the level of innovation among NME approvals, nine of the NMEs approved by CDER in 2014 were granted breakthrough therapy designation, a relatively new classification by the FDA that is designed to encourage the development and approval of promising drugs. Authorized under the Food and Safety Administration Innovation Act of 2012, a breakthrough therapy is a drug intended alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition and for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If a drug is designated as a breakthrough therapy, the FDA will expedite the development and review of such a drug. In 2014, nine NMEs with breakthrough therapy status were approved by the FDA: AbbVie’s Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets co-packaged with dasabuvir tablets) for treating chronic hepatitis C infection (genotype 1); Amgen’s Blincyto (blinatumomab) for treating patients with Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia (B-cell ALL), an uncommon form of ALL; Boehringer Ingelheim’s Ofev (nintedanib) and Roche’s Esbriet (pirfenidone), both for treating idiopathic pulmonary fibrosis; Bristol-Myers Squib’s Opdivo (nivolumab) for treating unresectable or metastatic melanoma; Gilead Sciences’ Zydelig (idelalisib), a drug to treat three types of blood cancer; Gilead Sciences’ Harvoni (ledipasvir and sofosbuvir), a drug to treat chronic hepatitis C virus genotype 1 infection; Novartis’ Zykadia (certinib), a drug to treat a certain type of metastatic non-small cell lung cancer; and Merck & Co,’s Keytruda (pembrolizumab) for treating metastatic melanoma. 

Pharma company activity
Among the large pharmaceutical companies, AstraZeneca led all companies with four NME approvals in 2014, followed by Boehringer Ingelheim, Eli Lilly and Company, and Merck & Co., each which had three NME approvals in 2014. AstraZeneca received FDA approval for the following: Farxiga (dapaglifozin) for treating Type 2 diabetes; the orphan drug Myalept (metreleptin); Movantik (naloxegel), a drug to treat opiod-induced constipation in adults with chronic non-cancer pain; and Lynparza (olaparib) for treating advanced ovarian cancer. 

Farxiga was approved by the FDA in January 2014. It was approved in Europe, where it is marketed as Forxiga, in November 2012 and in Japan in March 2014. Farxiga was the second drug approved by the FDA in a new class of drugs to treat diabetes, sodium glucose cotransporter 2 (SGLT2) inhibitors. The first was Janssen Pharmaceuticals’ Invokana (canagliflozin), which was approved in 2013. As a SGLT2 inhibitor, Farxiga blocks the reabsorption of glucose by the kidney, increases glucose excretion, and lowers blood glucose levels. It is indicated as an adjunct to diet and exercise as a once-daily oral medication to improve glycemic control in adult patients with Type 2 diabetes mellitus as an add-on combination therapy or as monotherapy in metformin-intolerant patients. Myalept is a recombinant analog (laboratory-created form) of human leptin as a replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. A third SGLT inhibitor, Jardiance (empagliflozin), a drug a part of the diabetes alliance between Boehringer Ingelheim and Eli Lilly, was also approved in 2014.

AstraZeneca gained full rights to Farxiga as well as Myalept as part of its $2.7-billion acquisition of its diabetes alliance with Bristol-Myers Squibb, a deal which was completed in February 2014. The acquisition gave AstraZeneca ownership of the intellectual property and global rights for the development, manufacture, and commercialization of the diabetes business, which included Farxiga/Forxiga, Xigduo (dapaglifozin and metformin HCl extended release), Onglyza (saxagliptin), Komboglyze (saxagliptin and metformin HCl), Kombiglyze XR (saxagliptin and Byetta (exenatide), Bydureon (exenatide extended-release for injectable suspension), metreleptin, and Symlin (pramlintide acetate). In addition to the $2.7 billion, AstraZeneca also agreed to pay up to $1.4 billion in regulatory, launch, and sales payments, and various sales-related royalty payments up until 2025, $600 million of which related to the approval of Farxiga in the US. In addition, AstraZeneca may make payments of up to $225 million when certain assets are subsequently transferred. 

AstraZeneca received US and EU approval of Lynparza in December 2014. Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor that targets tumor DNA repair pathway deficiencies to preferentially kill cancer cells. It is the first PARP inhibitor to be approved for patients with germline BRCA-mutated advanced ovarian cancer as detected by an FDA approved companion diagnostic test, BRACAnalysis CDx, which detects the presence of mutations in the BRCA genes in blood samples from patients with ovarian cancer. The BRCA genes are involved with repairing damaged DNA and normally work to suppress tumor growth. Women with mutations resulting in defective BRCA genes are more likely to get ovarian cancer, and it is estimated that 10% to 15% of all ovarian cancer is associated with these hereditary BRCA mutations. BRACAnalysis CDx is manufactured by and performed at Salt Lake City, Utah-based Myriad Genetic Laboratories, Inc. Olaparib was approved under the FDA’s Accelerated Approval program based on existing objective response rate and duration of response data. Continued approval for this indication is contingent upon verification of clinical benefit in ongoing confirmatory Phase III trials. 

In 2014, Boehringer Ingelheim received FDA approval for Ofev (nintedanib) for treating idiopathic pulmonary fibrosis, Jardiance (empagliflozin) for treating Type 2 diabetes and part of the diabetes alliance that the company has with Eli Lilly, and Striverdi Respimat (olodaterol), a respiratory drug. Ofev is a small-molecule tyrosine kinase inhibitor that blocks multiple pathways that may be involved in the scarring of lung tissue. Nintedanib targets growth factor receptors involved in the mechanisms by which pulmonary fibrosis occurs. Most importantly, nintedanib inhibits the platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and the vascular endothelial growth factor receptor (VEGFR). The FDA granted Ofev fast track, priority review, orphan product, and breakthrough designations. Boehringer Ingelheim received FDA approval for Striverdi Respimat (olodaterol) inhalation spray to treat patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema that are experiencing airflow obstruction. Boehringer Ingelheim is also studying olodaterol as a possible future combination partner with Spiriva (tiotropium bromide inhalation powder), the company’s long-acting muscarinic antagonist treating COPD. 

As previously mentioned, Eli Lilly received approval for Trulicity (dulaglutide), a drug to treat Type 2 diabetes, and Cyramza (ramucirumab), a drug to treat patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma. In addition, Eli Lilly is partnered with Boehringer Ingelheim for Jardiance (empagliflozin), a drug for treating Type 2 diabetes, which also was approved in 2014 and which is part of the companies’ diabetes alliance.

Merck & Co. received FDA approval for Keytruda, Belsomra (suvorexant) for treating insomnia, and Zontivity (vorapaxar), an antiplatelet. Keytruda was the first FDA-approved drug that blocks a cellular pathway known as PD-1, which restricts the body’s immune system from attacking melanoma cells. Keytruda is intended for use following treatment with ipilimumab, a type of immunotherapy. For melanoma patients whose tumors express a gene mutation called BRAF V600, Keytruda is intended for use after treatment with ipilimumab and a BRAF inhibitor, a therapy that blocks activity of BRAF gene mutations. 

Belsomra is an orexin receptor antagonist and is the first approved drug of this type. Orexins are chemicals that are involved in regulating the sleep-wake cycle and play a role in keeping people awake. Belsomra alters the signaling action of orexin in the brain. The FDA recommended that Belsomra be classified by the US Drug Enforcement Administration as a scheduled product. Zontivity was the first drug approved in a new class of drugs called protease-activated receptor-1 (PAR-1) antagonists. It is designed to decrease the tendency of platelets to clump together to form a blood clot. By decreasing the formation of blood clots, Zontivity decreases the risk of heart attack and stroke. It was approved by the FDA to reduce the risk of heart attack, stroke, cardiovascular death, and the 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. 

Gilead Sciences had two NME approvals in 2014. Gilead Sciences received approval of its combination therapy, Harvoni (ledipasvir and sofosbuvir), for treating chronic hepatitis C virus genotype 1 infection and for Zydelig for treating three types of blood cancer. Harvoni was the first combination pill approved to treat chronic hepatitis C virus genotype 1 infection. It was also the first approved regimen that does not require administration with interferon or ribavirin, two FDA-approved drugs also used to treat chronic hepatitis C virus infection. Both drugs in Harvoni interfere with the enzymes needed by the hepatitis C virus to multiply. Sofosbuvir is a previously approved drug for treating chronic hepatitis C marketed under the brand name Sovaldi. Harvoni also contains a new drug called ledipasvir. Harvoni is one of several recently approved  drugs by the FDA to treat chronic hepatitis C virus infection. The FDA approved Olysio (simeprevir) in November 2013 and Sovaldi in December 2013. Sofosbuvir is Gilead’s top-selling drug. It had sales of $8.550 billion for the first nine months of 2014. It was approved by the FDA in December 2013 as the first all-oral interferon-free regimen for treating chronic hepatitis C. It was approved as a component of a combination antiviral treatment regimen. In December 2014, AbbVie received approval FDA approval for Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets co-packaged with dasabuvir tablets) for treating chronic hepatitis C virus genotype 1 infection, including patients with cirrhosis.

Gilead Sciences also received approval for Zydelig (idelalisib), which is indicated for treating three types of blood cancer. Zydelig was approved to treat patients whose chronic lymphocytic leukemia (CLL) has returned (relapsed) as well to two treat two other indications: relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma, another type of non-Hodgkin lymphoma. Other recent FDA approvals for treating CLL include Roche’s Gazyva (obinutuzumab) in November 2013, a new indication for Janssen Biotech/Pharmacyclics’ Imbruvica (ibrutinib) in February 2014, and a new use for GSK’s Arzerra (ofatumumab) in April 2014. Both Gazyva and Arzerra also received breakthrough therapy designation for this indication. 

Novartis had two NMEs approved in 2014. Novartis received approval for its drug, Zykadia (ceritinib), for treating a certain type of metastatic non-small cell lung cancer. Zykadia is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that blocks proteins that promote the development of cancerous cells. It is intended for patients with metastatic ALK-positive non-small cell lung cancer who were previously treated with crizotinib, the only other approved ALK tyrosine kinase inhibitor. Through its eye-care division, Alcon, Novartis also received approval for Xtoro (finafloxacin) for treating swimmer’s ear. 

AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Eisai (with Helsinn), GSK, Johnson & Johnson, Sanofi, and Takeda each had one NME approval in 2014. As previously mentioned, AbbVie received approval in December 2014 for its NME for treating chronic hepatitis C infection, competing most notably against Gilead Sciences in this market. AbbVie received approval FDA approval for Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets co-packaged with dasabuvir tablets) for treating chronic hepatitis C virus genotype 1 infection, including patients with cirrhosis. In other approvals, Bristol-Myers Squibb received FDA approval for its melanoma drug and PD-1 inhibitor, Opdivo (nivolumab), competing against Merck’s PD-1 therapy, Keytruda, also approved in 2014.

Amgen received FDA approval for Blincyto (blinatumonmab), a drug that engages the body’s T-cells, a type of white blood cell or lymphocyte, to destroy leukemia cells. The drug acts as a connector between a protein called CD19, which is found on the surface of most B-cell lymphoblasts, and CD3, a protein on T-cell lymphocytes. The FDA granted Blincyto breakthrough therapy designation, priority review, and orphan product designation. Helsinn’s Akynzeo is a fixed combination capsule comprised of two drugs. Oral palonosetron, approved in 2008, prevents nausea and vomiting during the acute phase (within the first 24 hours) after the start of cancer chemotherapy. Netupitant, a new drug, prevents nausea and vomiting during both the acute phase and delayed phase (from 25 to 120 hours) after the start of cancer chemotherapy. Akynzeo is distributed and marketed by Eisai under license from Helsinn Healthcare S.A. 

Biogen Idec received FDA approval for Plegridy (peginterferon beta-1a) as a treatment for adults with relapsing multiple sclerosis. Plegridy is dosed once every two weeks and is administered subcutaneously with the Plegridy Pen, a new ready-to-use autoinjector, or a prefilled syringe. Plegridy is interferon beta-1a that has been pegylated to extend its half-life to permit a less frequent dosing schedule. 

GSK received approval for its biologics, Tanzeum (albiglutide) for treating Type 1 diabetes. Albiglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is a biological product for treating Type 2 diabetes, administered once-weekly using an injector pen. It is a recombinant fusion protein comprised of two tandem copies of modified human GLP-1 genetically fused in tandem to human albumin.GLP-1 is an important incretin hormone that helps reduce blood glucose levels, but, in people with Type 2 diabetes, its production is often reduced or absent, according to a GSK press release. In gaining approval for Tanzeum, GSK will be competing against other GLP-1 agonists: AstraZeneca’s Byetta (exenatide injection) and Bydureon (exenatide extended-release injectable suspension), Novo Nordisk’s Victoza (liraglutide), and Sanofi’s Lyxumia (lixisenatide). Lyxumia was in-licensed by Sanofi from Zealand Pharma A/S and is also approved in Europe for the treatment of adults with Type 2 diabetes mellitus to achieve glycemic control in combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycemic control. Lyxumia is also approved in Mexico, Australia, Japan, and Brazil for the treatment of adults with Type 2 diabetes. Sanofi plans to resubmit its new drug application for lixisenatide in the United States in 2015 after completion of a cardiovascular outcomes study. 

As previously mentioned, Johnson & Johnson’s Janssen Biotech received approval for Sylvant (siltuximab), a drug to treat the rare disease, multicentric Castleman’s disease. Roche, through its acquisition of InterMune earlier in 2014, gained FDA approval for Esbriet (pirfenidone) for treating idiopathic pulmonary fibrosis. Esbriet acts on multiple pathways that may be involved in the scarring of lung tissue. it is believed to interfere with the production of transforming growth factor (TGF)-beta, a small protein in the body involved in how cells grow and tumor necrosis factor (TNF)-alpha, a small protein that is involved in inflammation. The FDA granted Esbriet fast track, priority review, orphan product, and breakthrough therapy designations.  

Sanofi, through its Genyzme subsidiary, gained FDA approval for Cerdelga (eliglustat) for the long-term treatment of adult patients with the Type I form of Gaucher disease, a rare genetic disorder. The drug also received orphan drug status from the FDA. The new oral drug was developed by Sanofi’s Genzyme subsidiary, which also developed Cerezyme (imiglucerase for injection), which is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease. Cerezyme posted 2013 sales of EUR 688 million ($913 million) and is one of several enzyme-replacement therapies by Sanofi to treat rare diseases. Others are: Myozyme/Lumizyme (alglucosidase alfa) to treat Pompe disease; Fabrazyme (agalsidase beta) to treat Fabry disease; and Aldurazyme (laronidase) to treat mucopolysaccharidosis Type I. 

In 2014,Takeda Pharmaceutical received approval for its NME, Entyvio (vedolizumab) injection, for treating adult patients with moderate-to- severe ulcerative colitis and adult patients with moderate-to-severe Crohn‘s disease. Entyvio is an integrin receptor antagonist. Integrin receptors are proteins expressed on the surface of certain cells. Integrin receptors function as bridges for cell-cell interactions. Entyvio blocks the interaction of a specific integrin receptor (expressed on circulating inflammatory cells) with a specific protein (expressed on cells in the interior wall of blood vessels), and thereby blocks the migration of those circulating inflammatory cells across those blood vessels and into areas of inflammation in the gastrointestinal tract. 

Also, in 2014, the FDA approved four QIDP-designated antibacterial drugs, a designation by the FDA for Qualified Infectious Disease Products (QIDPs), an incentive for developing multidrug-resistant antibiotics. Under the QIDP designation, the FDA provides priority review, and the drug can also receive fast-track designation at the sponsor’s request. At the time of approval, a product with QIDP designation may be eligible for an additional five years of marketing exclusivity with exclusive marketing rights without competing with a generic drug product. The first four QIDP-designated antibacterial drugs were approved by the FDA in 2014: Durata Therapeutics’ Dalvance (dalbavancin) in May 2014; Cubist Pharmaceuticals’ Sivextro (tedizolid phosphate) in June 2014; Cubist Pharmaceuticals Zerbaxa (ceftolozane/tazabactam) in December 2014; and The Medicines Company’s Orbactiv (oritavancin) in August 2014. Dalvance is intended to treat acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria such as Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains) and Streptococcus pyogenes. Actavis recently acquired Durata Therapeutics, and in December 2014, Merck & Co. agreed to acquire Cubist for $9.5 billion. Sivextro and Orbactiv are also approved to treat patients with ABSSSI caused by certain susceptible bacteria, including Staphylococcus aureus (including methicillin-resistant strains and methicillin-susceptible strains), various Streptococcus species, and Enterococcus faecalis. Zebrexa is indicated to treat adults with complicated intra-abdominal infections and complicated urinary tract infections.

Also in 2014, Chelsea Therapeutics, which was acquired by H. Lundbeck A/S for $658 million in June 2014, received approval for its orphan drug, Northera (droxidopa), for the treatment of neurogenic orthostatic hypotension (NOH). NOH is a rare, chronic drop in blood pressure upon standing that is associated with Parkinson’s disease, multiple-system atrophy, pure autonomic failure, dopamine beta hydroxylase deficiency, and non-diabetic autonomic neuropathy.