Small Molecules Still Leading in New Drug Approvals

By Patricia Van Arnum - DCAT Editorial Director

February 6, 2019

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)
15% biologics (6 NMEs)
Plus 2 NME radioactive diagnostic imaging agents**

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.