Small Molecules Still Leading in New Drug ApprovalsBy
Small molecules accounted for 42, or 71%, of the 59 new molecule entities (NMEs) approved by the FDA in 2018, continuing a recent trend in which small molecules have accounted for roughly three-quarters of NME approvals. Which small-molecules and companies contributed to the NME Class of 2018?
Small molecules leading the NME pack
In 2018, the US Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) approved a record-high 59 new molecular entities (NMEs), surpassing the previous record of 53 NME approvals in 1996 and the 46 NMEs approved in 2017. Small molecules dominated in NME approvals in 2018 with 42 (71% of NME approvals) compared to 17 biologic-based NME approvals (29% of NME approvals), which included one antibody drug conjugate (ADC) (see Table I at end of article; NDA approval denotes small molecule).
This product mix in 2018 is consistent with NME approvals in 2017 and with recent years with the exception of 2016. In 2017, small-molecule NME approvals accounted for 74% of new drug approvals (see Table II at end of article) and biologics 26%. Between 2010 and 2015, small molecules accounted for between 71% and 81% of NME approvals. The exception was in 2016, when a lower number of NME approvals occurred with 22 NME approvals, which included 13 small-molecule NME approvals or 59%.
Big Pharma and small molecules
Of the 42 small-molecule NME approvals in 2018, 18 or 43% were from the large pharmaceutical companies, and 57% of small-molecule approvals in 2018 were from small to mid-sized companies (see Table I at end of article; NDA approval denotes small molecule).
Among the large pharmaceutical companies, Pfizer led with four NME approvals in 2018, all of which were small molecules. These were: Daurismo (glasdegib) for treating newly diagnosed acute myeloid leukemia (AML) in adult patients; Lorbrena (loratinib) for treating patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; Talzenna (talazoparib) for treating locally advanced or metastatic breast cancer patients with a germline BRCA mutation; and Vizimpro (dacomitinib) for treating metastatic non-small-cell lung cancer.
Fourteen of the large pharmaceutical companies each had one small-molecule NME approval in 2018.
AbbVie received approval for Orilissa (elagolix sodium) for treating moderate-to-severe pain associated with endometriosis. Allergan got the FDA nod for Seysara (sarecycline) for treating inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients nine years of age and older. Astellas received approval for Xospata (gilteritinib) for treating relapsed or refractory acute myeloid leukemia, and AstraZeneca received approval for Lokelma (sodium zirconium cyclosilicate) for treating hyperkalemia (high potassium levels). Eli Lilly and Company got the FDA nod for Olumiant (baricitinib) for treating moderately to severely active rheumatoid arthritis. Also, through its pending $8-billion acquisition of Loxo Oncology, Lilly will gain another small-molecule NME approval from 2018, Vitrakvi (larotrectinib), an anti-cancer drug.
Gilead Sciences received approval for a fixed-dose combination HIV drug, Biktarvy (bictegravir, embitcitabine, and tenofovir alafenamide), and GlaxoSmithKline received approval for Krintafel (tafenoquine), an anti-malaria drug. Johnson & Johnson’s Janssen Pharmaceutical got the FDA nod for Erleada (apalutamid) for treating non-metastatic, castration-resistant prostate cancer. Merck & Co. also gained approval of an HIV drug, Pifeltro (doravirine).
Mylan, although largely a generic-drug company, did get a NME approval in 2018, for its small-molecule, Yupelri (revefenacin) for treating chronic obstructive pulmonary disease (COPD). Novartis, through its acquisition of Advanced Accelerator Applications in 2018, received approval for the radiopharmaceutical, Lutathera (lutetium Lu 177 dotatate) for treating gastroenteropancreatic neuroendocrine tumors, a type of cancer that affects the pancreas or gastrointestinal tract.
Shire, which was acquired by Takeda in January 2019, received approval for Motegrity (prucalopride) for treating idiopathic constipation. Shionogi received approval for Mulpleta (lusutrombopag) for treating thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure, and Roche’s Genentech received approval for Xofluza (baloxavir marboxil), an antiviral medicine.
|Table I: Approvals of New Molecular Entities, New Drug Applications (NDAs) and Original Biologics License Applications (BLAs) by the US Food and Drug Administration’s Center in 2018.|
|Company||Brand name (active ingredient); application type||Indication|
|AbbVie||Orilissa (elagolix sodium); NDA||Moderate-to-severe pain associated with endometriosis|
|Advanced Accelerator Applications (Novartis company)||Lutathera (lutetium Lu 177 dotatate); NDA||Gastroenteropancreatic neuroendocrine tumors, a type of cancer that affects the pancreas or gastrointestinal tract|
|Achaogen||Zemdri (plazomicin); NDA||Adults with complicated urinary tract infections|
|Agios Pharmaceuticals||Tibsovo (ivosidenib); NDA||Relapsed or refractory acute myeloid leukemia|
|AkaRx||Doptelet (avatrombopag); NDA||Low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure|
|Akcea Therapeutics||Tegsedi (inotersen); NDA||Polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults|
|Alexion Pharmaceuticalstd>||Ultomiris (ravulizumab); BLA||Paroxysmal nocturnal hemoglobinuria|
|Almirall/Allergan||Seysara (sarecycline); NDA||Inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older|
|Alnylam Pharmaceuticals||Onpattro (patisiran); NDA||Polyneuropathy of hereditary transthyretin-mediated amyloidosis in adult patients|
|Amgen||Aimovig (erenumab-aooe); BLA||Preventive treatment of migraines in adults|
|Amicus Therapeutics||Galafold (migalastat); NDA||Adults with Fabry disease|
|Array BioPharma||Braftovi (encorafenib); NDA||Unresectable or metastatic melanoma|
|Array BioPharma||Mektovi (binimetinib); NDA||Unresectable or metastatic melanoma|
|Astellas||Xospata (gilteritinib); NDA||Lapsed or refractory acute myeloid leukemia (AML)|
|AstraZeneca||Lokelma (sodium zirconium cyclosilicate); NDA||Hyperkalemia (high potassium levels)|
|AstraZeneca||Lumoxiti (moxetumomab pasudotox-tdf; BLA||Relapsed or refractory hairy cell leukemia|
|Biocodex SA||Diacomit (stiripentol); NDA||Seizures associated with Dravet syndrome in patients 2 years of age and older taking clobazam|
|BioMarin Pharmaceutical||Palynziq (pegvaliase-pqpz); BLA||Phenylketonuria (inherited disorder that increases the levels of phenylalanine in the blood)|
|Catalyst Pharmaceuticals||Firdapse (amifampridine); NDA||Lambert-Eaton myasthenic syndrome (LEMS) in adults|
|Cosmo Technologies||Aemcolo (rifamycin; NDA||Travelers’ diarrhea|
|Dompe Farmaceutici||Oxervate (cenegermin-bkbj); BLA||Neurotrophic keratitis|
|Dyax Corp.||Takhzyro (lanadelumab); BLA||Types I and II hereditary angioedema|
|Eli Lilly and Company||Emgality (galcanezumab-gnlm); BLA||For the preventive treatment of migraines in adults|
|Eli Lilly and Company||Olumiant (baricitinib); NDA||Moderately to severely active rheumatoid arthritis|
|Fresenius Kabi||Omegaven (fish oil triglycerides); NDA||A source of calories and fatty acids in pediatric patients with parenteral nutrition-associated cholestasis|
|Gilead Sciences||Biktarvy (bictegravir, embitcitabine, and tenofovir alafenamide); NDA||HIV-1 infection in adults who have no antiretroviral treatment history or to replace the current antiretroviral regimen|
|GlaxoSmithKline||Krintafel (tafenoquine); NDA||Radical cure (prevention of relapse) of Plasmodium vivax malaria|
|GW Research||Epidiolex (cannabidiol); NDA||Seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome|
|Helsinn Healthcare||Akynzeo (fosnetupitant and palonosetron); NDA||To prevent acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy|
|Ionis Pharmaceuticals||Tegsedi (inotersen); NDA||Polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults|
|Janssen Pharmaceutical (Johnson & Johnson)||Erleada (apalutamid); NDA||Non-metastatic, castration-resistant prostate cancer|
|Kyowa Kirin||Poteligeo (mogamulizumab-kpkc); BLA||Two rare types of non-Hodgkin lymphoma|
|Leadiant Biosciences||Revcovi (elapegademase-lvlr); BLA||Adenosine deaminase-severe combined immunodeficiency (ADA-SCID)|
|Loxo Oncology||Vitrakvi (larotrectinib); NDA||Patients whose cancers have a specific genetic feature (biomarker)|
|Medicines Development for Global Health||Moxidectin (moxidectin); NDA||Onchocerciasis due to Onchocerca volvulus in patients aged 12 years and older|
|Merck & Co.||Pifeltro (doravirine); NDA||HIV-1 infection in adult patients|
|Merck & Co. and Sun Pharmaceutical||Ilumya (tildrakizumab); BLA||Adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy|
|Mylan||Yupelri (revefenacin); NDA||Chronic obstructive pulmonary disease (COPD)|
|Novoimmune||Gamifant (emapalumab-lzsg) BLA||Primary hemophagocytic lymphohistiocytosis|
|Paratek Pharmaceuticals||Nuzyra (omadacycline); NDA||Community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections|
|Pfizer||Daurismo (glasdegib); NDA||Newly-diagnosed acute myeloid leukemia (AML) in adult patient|
|Pfizer||Lorbrena (loratinib); NDA||Patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer|
|Pfizer||Talzenna (talazoparib); NDA||Locally advanced or metastatic breast cancer patients with a germline BRCA mutation|
|Pfizer||Vizimpro (dacomitinib); NDA||Metastatic non-small-cell lung cancer|
|Regeneron Pharmaceuticals||Libtayo (cemiplimab-rwlc); BLA||Cutaneous squamous cell carcinoma|
|Rigel Pharmaceuticals||Tavalisse (fostamatinib); NDA||Thrombocytopenia (low blood platelet count) in adult patients with persistent or chronic immune thrombocytopenia|
|Servier||Asparlas (calaspargase pegol-mknl); BLA||Acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years old|
|Shionogi||Mulpleta (lusutrombopag); NDA||Thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure|
|Siga Technologies||Tpoxx(tecovirimat); NDA||Smallpox|
|Stemline Therapeutics||Elzonris (tagraxofusp-erzs); BLA||Blastic plasmacytoid dendritic cell neoplasm (BPDCN)|
|Roche’s Genentech||Xofluza (baloxavir marboxil); NDA||Acute uncomplicated influenza in patients who have been symptomatic for no more than 48 hours.|
|Takeda/Shire||Motegrity (prucalopride); NDA||Idiopathic constipation|
|TaiMed Biologics USA||Trogarzo (ibalizumab-uiyk); BLA||HIV|
|Tetraphase Pharmaceuticals||Xerava (eravacycline); NDA||Complicated intra-abdominal infections in patients 18 years of age and older|
|Teva Pharmaceutical Industries||Ajovy (fremanezumab-vfrm); BLA||For the preventive treatment of migraines in adults|
|TherapeuticsMD||Annovera (segesterone acetate and ethinyl estradiol vaginal system); NDA||New vaginal ring used to prevent pregnancy for an entire year|
|Verastem||Copiktra (duvelisib); NDA||Relapsed or refractory chronic lymphocytic leukemia, small lymphocytic lymphoma and follicular lymphoma|
|Ultragenyx Pharmaceutical||Crysvita (burosumab-twza); BLA||To treat adults and children ages 1 year and older with x-linked hypophosphatemia, a rare, inherited form of rickets|
|US WorldMeds||Lucemyra (lofexidine); NDA||Non-opioid treatment for management of opioid withdrawal symptoms in adults|
|Vertex Pharmaceuticals||Symdeko (tezacaftor and ivacaftor); NDA||Cystic fibrosis in patients age 12 years and older|
Novartis acquired Advanced Accelerator Applications in January 2018.
Paratek Pharmaceuticals has exclusively licensed US development and commercialization rights of Seysara for the treatment of acne to Allergan, which has assigned such rights to Almirall SA. Paratek retains development and commercialization rights in the rest of the world.
In August 2015, Amgen entered into a global collaboration with Novartis to jointly develop and commercialize treatments in the fields of migraine and Alzheimer’s disease. The collaboration focuses on investigational Amgen drugs in the migraine field, including Aimovig. In April 2017, the collaboration was expanded to include co-commercialization of Aimovig in the US. For the migraine program, Amgen retains exclusive rights in Japan, and Novartis has exclusive rights in Europe, Canada, and rest of the world.
Array BioPharma has exclusive rights to Braftovi (encorafenib) and Mektovi (binimetinib) in the US and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including in Europe, Asia, and Latin America.
Eli Lilly and Company agreed to acquire Loxo Oncology in 2018.
Shire was acquired by Takeda in January 2018.
Sun Pharmaceutical Industries Ltd.’s wholly owned subsidiary licensed worldwide rights to Ilumya (tildrakizumab) from a subsidiary of Merck & Co., Inc. in 2014. Funded by a Sun Pharma subsidiary, Merck & Co., Inc. was responsible for the completion of Phase-III trials and submission of a biologics license application to the US Food and Drug Administration (FDA) as well as manufacturing finished goods to support Sun Pharma’s initial product launch. Sun Pharma is responsible for all post-approval regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing, and commercialization of the approved product. Sun Pharma is also responsible for all regulatory, pharmacovigilance, post approval studies, manufacturing, and commercialization of approved products for all non-U.S. markets. Merck & Co is eligible to receive milestone payments and royalties on sales of Ilumya.
Source: US Food and Drug Administration’s Center for Drug Evaluation and Research and company information.
|Table II: Small Molecule and Biologics New Molecular Entities Approved by the US Food and Drug Administration’s Center for Drug Evaluation and Research, 2010 to 2018.|
|Year||Number of New Molecular Entities (NMEs) Approved||Percentage relative to total NME approvals and number of small molecules and biologics approved as NMEs|
|2010||21 NMEs approved||71% small molecules (15 NMEs)
29% biologics (6 NMEs)
|2011||30 NMEs approved||77% small molecules (23 NMEs)
20% biologics (6 NMEs)
Plus 1 NME radioactive diagnostic imaging agent*
|2012||39 NMEs approved||
79% small molecules (31 NMEs)
|2013||27 NMEs approved||81% small molecules (22 NMEs)
11% biologics (3 NMEs)
Plus 2 NME radioactive imaging agents***
|2014||41 NMEs approved||71% small molecules (29 NMEs)
27% biologics (11 NMEs)
Plus 1 NME radioactive diagnostic imaging agent****
|2015||45 NMEs approved||71% small molecules (32 NMEs) and 1 insulin analog NME approved as a new drug application*****
27% biologics (12 NMEs)
|2016||22 NMEs approved||59% small molecules (13 NMEs)
32% biologics (7 NMEs)
Plus 2 NME radioactive diagnostic imaging agents******
|2017||46 NMEs approved||74% small molecules (34 NMEs)
26% biologics (12 NMEs)
|2018||59 NMEs approved||71% small molecules (42 NMEs)
29% biologics (17 NMEs)
In 2011, 23 small-molecule drugs and 1 radioactive diagnostic imaging were approved as new drug applications (NDAs).
In 2012, 31 small-molecule drugs and 2 radioactive diagnostic imaging agents were approved as NDAs.
In 2013, 22 small-molecule drugs and 2 radioactive diagnostic imaging agents were approved as NDAs.
In 2014, 29 small-molecule drugs and 1 radioactive diagnostic imaging agent were approved as NDAs .
n 2015, 32 small-molecule drugs were approved as NDAs and one insulin analog, Novo Nordisk’s Tresiba (insulin degludec injection), a long-acting basal human insulin analog produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification was approved as a NDA, not as a biologics license application.
In 2016, 13 small-molecule drugs and 2 diagnostic imaging agents were approved as NDAs.
Source: US Food and Drug Administration’s Center for Drug Evaluation and Research and company information.