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A review of this year's crop of the new molecular entities and new biologics license applications approved by FDA thus far in 2013.
As 2013 nears a close, how has the pharmaceutical industry fared in new drug approvals? Through Nov. 14, 2013, the Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) had approved 24 new molecular entities (NMEs) and biologics license application (BLAs) (1). Although the end-of-the-year activity of FDA typically results in additional approvals, it is unlikely that the industry will match in 2013 the 39 NMEs and BLAs approved by FDA in 2012, which was a recent high. This year’s crop of NMEs and BLAs, however, show several interesting developments: the approval of two new breakthrough therapies, a new designation by FDA to accelerate approval for drugs with high unmet medical need; three drug approvals with companion diagnostics; and an approval of an antibody drug conjugate (ADC).
On a company basis, thus far in 2013, the winners in the race for NMEs and BLA approvals by FDA’s CDER are Bayer Healthcare, GlaxoSmithKline (GSK), Johnson & Johnson, Roche and Takeda, each with two or more new drug approvals (see Table I). GSK led the pack with three NME approvals: Breo Ellipta (fluticasone furoate and vilanterol trifenatate), Mekinist (trametinib dimethyl sulfoxide), and Tafinlar (dabrafenib mesylate). Breo Ellipta is a combination of fluticasone furoate, an inhaled corticosteroid, and vilanterol, a long-acting beta2-adrenergic agonist, used to treat airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease. GSK also received FDA approval for two drugs to treat metastatic melanoma: Mekinist, a kinase inhibitor for treating unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test, and Tafinlar, also a kinase inhibitor indicated for treating unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. In 2010, GSK formed a collaboration with the molecular diagnostics company bioMerieux to develop a companion diagnostic test to detect BRAF V600 (V600E and V600K) gene mutations found in several cancers, including melanoma. bioMerieux received FDA premarket approval of its companion diagnostic, THxID-BRAF, in May 2013.
Table I: Approvals of new molecular entities (NMEs) and biologic license applications (BLAs) in 2013 by FDA’s Center for Drug Evaluation and Research.*
Proprietary name (active ingredient)
Opsumit (macitentan); NME
Adempas (riociguat); NME
Xofigo (radium RA-223 dichloride); NME
Tecfidera (dimethyl fumarate); NME
Capsule, delayed release/oral
Gilotrif (afatinib dimaleate); NME
Pomalyst (pomalidomide); NME
Vizamyl (flutemetamol F-18); NME
Tafinlar (dabrafenib mesylate); NME
Mekinist (trametinib dimethyl sulfoxide); NME
Breo Ellipta (fluticasone furoate; vilanterol trifenatate); NME
Dotarem (gadoterate meglumine); NME
Janssen Biotech and Pharmacyclics
Imbruvica (ibrutinib); NME
Invokana (canagliflozin): NME
Lymphoseek Kit (technetium Tc-99m tilmanocept); NME
Duavee (bazedoxifene acetate; estrogens, conjugated); new combination
Gazyva (obinutuzumab); BLA
Kadcyla (ado-trastuzumab emtansine); BLA
Kynamro (mipomersen sodium); NME
Osphena (ospemifene); NME
Aptiom (eslicarbazepine acetate); NME
Brintellix (vortioxetine hydrobromide); NME
Nesina (alogliptin benzoate); NME
Luzu (luliconazole); NME
Tivicay (dolutegravir sodium); NME
* Source: FDA’s Center for Drug Evaluation. FDA approvals as of Nov. 14, 2013 (Reference 1).
• Bayer Healthcare formed an agreement in September 2009 with Algeta ASA (Oslo, Norway) for the development and commercialization of Xofigo.
• Janssen Biotech and Janssen Pharmaceuticals are part of Johnson & Johnson. Janssen Biotech and Pharmacyclics are partnered for Imbruvica. Janssen Pharmaceuticals has rights to Invokana through a license agreement with Mitsubishi Tanabe Pharma.
• Roche Glycart AG, a wholly owned, independent research unit of Roche, discovered Gazyva. In the US, Gazyva is part of a collaboration between Genentech and Biogen Idec.
• Roche licenses technology for Kadcyla under an agreement with ImmunoGen.
• Sanofi’s subsidiary, Genzyme, partnered with ISIS Pharmaceuticals and Genzyme for the development of Kynamro.
• Sunovion Pharmaceuticals is an indirect, wholly owned US subsidiary of Dainippon Sumitomo Pharma.
• Takeda Pharmaceutical and H. Lundbeck A/S formed a strategic alliance for Brintellix in September 2007 under a broader alliance for several compounds in Lundbeck’s pipeline for the treatment of mood and anxiety disorders. The companies plan to copromote Brintellix in the US.
• Valeant Pharmaceuticals acquired Medicis Pharmaceutical in 2012. Luzu (luliconazole) has been approved in Japan since 2005.
• ViiV Healthcare is an independent pharmaceutical company focused on HIV established in 2009 by GlaxoSmithKline and Pfizer. Shionogi joined as a 10% shareholder in 2012.
Through its bio/pharmaceutical units, Janssen Biotech and Janssen Pharmaceuticals, Johnson & Johnson had two NMEs approved in 2013. Janssen Biotech partnered with the biopharmaceutical company Pharmacyclics for Imbruvica (ibrutinib), a kinase inhibitor for treating mantle-cell lymphoma (MCL), a rare type of blood cancer. Imbruvica is the second drug with breakthrough-therapy designation to receive FDA approval; Roche’s Gazyva (obinutuzumab), a drug to treat chronic lymphocytic leukemia (CLL), also approved in 2013, was the first. The Food and Drug Administration Safety and Innovation Act, passed in July 2012, gave FDA the ability to designate a drug as a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicated the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. In addition to Imbruvica, there are two other FDA-approved drugs to treat MCL: Velcade (bortezomib) by Millennium Pharmaceuticals, the oncology company of Takeda Pharmaceuticals, and Celgene’s Revlimid (lenalidomide) (2).
J&J’s second NME approval was for Invokana (canagliflozin), a sodium-glucose cotransporter 2 (SGLT2) inhibitor for treating Type 2 diabetes. Invokana is the first drug in a new class of SGLT2 inhibitors to be approved in the United States. Forxiga (dapagliflozin), developed by Bristol-Myers Squibb and AstraZeneca and also a SGLT2 inhibitor, was approved by the European Medicines Agency in November 2012. The companies submitted a new drug application for Foriziga to FDA in July 2013.
Roche had two new BLAs approved by FDA thus far in 2013: Gazyva (obinutuzumab) and Kadcyla (ado-trastuzumab emtansine). Gazyva is a humanized anti-CD20 monoclonal antibody (mAb) of the IgG1 subclass for treating CLL. It is produced by mammalian cell (Chinese hamster ovary [CHO]) suspension culture (3). Kadcyla is a HER2-targeted ADC, which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable thioether linker MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate). Emtansine refers to the MCC-DM1 complex. Trastuzumab is a well-characterized recombinant mAb produced by mammalian CHO cells, and the small-molecule components (DM1 and MCC) are produced by chemical synthesis (4). Kadcyla is the first Roche ADC approved by FDA.
Takeda scored with two NME approvals thus far in 2013: Brintellix (vortioxetine hydrobromide) and Nesina (alogliptin benzoate). Brintellix, for treating major depressive disorder, was developed with H. Lundbeck. Nesina is a dipeptidyl peptidase-4 inhibitor designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) for treating Type 2 diabetes.
Bayer had two NMEs approved by FDA thus far in 2013: Adempas (riociguat) and Xofigo (radium RA-223 dichloride). Adempas is a soluble guanylate cyclase stimulator to treat two forms of pulmonary hypertension. Xofigo is an alpha particle-emitting radioactive therapeutic agent for treating castration-resistant prostate cancer, symptomatic bone metastases, and no-known visceral metastatic disease. In 2009, Bayer partnered with Algeta for the development and commercialization of Xofigo.
Other large companies earned FDA approvals in 2013. Biogen Idec received FDA approval for its oral multiple-sclerosis drug Tecfidera (dimethyl fumarate). Boehringer Ingelheim received FDA approval for Gilotrif (afatinib dimaleate), a kinase inhibitor for treating metastatic nonsmall-cell lung cancer with common epidermal growth factor receptor mutations as detected by an FDA-approved test. Sanofi received approval for Kynamro (mipomersen sodium), a synthetic phosphorothioate oligonucleotide sodium salt (20 nucleotides in length) to treat homozygous familial hypercholesterolemia, a rare type of high cholesterol (5).
ViiV Healthcare, an independent joint pharmaceutical company focused on HIV treatments formed by Pfizer, GSK, and Shionogi, received approval for Tivicay (dolutegravir sodium), an integrase inhibitor indicated for use in combination with other antiretroviral agents for treating HIV-1 in adults and children aged 12 years and older weighing at least 40 kg. Tivicay is the first new treatment delivered by
ViiV Healthcare, which was established in November 2009 by GSK and Pfizer. Shionogi joined as a 10% shareholder in October 2012. Shionogi also received approval for Osphena (ospemifene) for treating moderate to severe dyspareunia. Pfizer received approval of a its combination therapy, Duavee (conjugated estrogens/bazedoxifene), for treating vasomotor symptoms associated with menopause and preventing postmenopausal osteoporosis.
1. FDA, “New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products of 2013” www.fda.gov/drugs/developmentapprovalprocess/druginnovation/default.htm, accessed 19 Nov. 2013.
2. FDA, “FDA Approves Imbruvica for Rare Blood Cancer,” Press Release, 13 Nov. 2013.
3. FDA, “Label for Gazyva,” www.accessdata.fda.gov/drugsatfda_docs/label/2013/125486s000lbl.pdf, accessed 15 Nov. 2013.
4. FDA, “Label for Kadcyla,” www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf, accessed 15 Nov. 2013.
5. FDA, “Label for Kynamro,” www.accessdata.fda.gov/drugsatfda_docs/label/2013/203568s000lbl.pdf, accessed 15 Nov. 2013.