Tracking Small-Molecule Muscle

By Patricia Van Arnum - DCAT Editorial Director

February 7, 2018

Small molecules remain the dominant modality in pharmaceuticals based on approvals of new molecular entities (NMEs), but biologics continue to make inroads. So what do the numbers show?

Small molecules accounted for nearly three-fourths of NME approvals in 2017, more than the nearly two-thirds share of small-molecule NME approvals in 2016. DCAT Value Chain Insights looks inside the numbers.

Small molecules versus biologics

The US Food and Drug Administration ‘s (FDA) Center for Drug Evaluation and Research approved 46 new molecular entities in 2017, substantially higher than the 22 NMEs (20 new drugs and two new diagnostic/imaging agents) approved in 2016. The uptick in NME approvals in 2017 resumes an upward trajectory beginning in 2011 (with the exception of 2013) for NME approvals with 30 NMEs approved in 2011 and 39 in 2012. The exception was in 2013, which had a decline to 27 NMEs, but levels jumped again to 41 NMEs approved in 2014 and in 2015 when 45 NMEs were approved.

In looking at the 46 NME approvals by FDA’s CDER (see Table I), 34 or 74% were small molecules and 12 or 26% were biologics. The nearly quarter of NME approvals that were biologics were slightly down from recent product mixes for NME approvals. In 2016, 32% of the NME approvals were biologics, and in 2015 and 2014, 27% of NME approvals were biologics (see Table II at end of article).

Also in 2017, FDA’s Center for Biologics Evaluation and Research (CBER) approved two cell-based gene therapies. Novartis' Kymriah (tisagenlecleucel), a chimeric antigen receptor T-cell (CAR-T) therapy, was approved in August 2017, marking the first CAR-T therapy approved by the FDA. The therapy was approved for treating certain pediatric and young adult patients with a form of acute lymphoblastic leukemia. Each dose of Kymriah is a customized treatment created using an individual patient’s own T-cells, a type of white blood cell known as a lymphocyte. The patient’s T-cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains a specific protein (a chimeric antigen receptor or CAR) that directs the T-cells to target and kill leukemia cells that have a specific antigen (CD19) on the surface. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

A second CAR-T therapy was approved by FDA’s CBER in October 2017 with the approval of Gilead Sciences’ Yescarta (axicabtagene ciloleucel) for treating patients with large-B-cell lymphomas whose cancer has progressed after receiving at least two prior treatment regimens. Kite Pharma, the developer of Yescarta, was acquired by Gilead Sciences in October 2017 for $11.9 billion.

Table I: Small Molecule and Biologics New Molecular Entities Approved by the US Food and Drug Administration’s Center for Drug Evaluation and Research, 2010 to 2017.
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 agent**
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)

*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 .

*****In 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.

 

Big Pharma and small molecules

Among the large pharmaceutical companies, Merck & Co. and Novartis led with small-molecule NME approvals with each having two small-molecule approvals in 2017 (see Table II at end of article). Merck & Co. received approval for Prevymis (letermovir), a drug to prevent infection after bone-marrow transplant, and Steglatro (ertugliflozin), a drug for treating Type II diabetes and co-developed with Pfizer. Novartis received approval for Kisqali (ribociclib), a drug to treat advanced breast cancer, and Rydapt (midostaurin) for treating acute myeloid leukemia in patients with a specific genetic mutation. Novartis’ Kisqali is slated by some analyst with potential blockbuster status. It is a highly selective CDK4/CDK6 inhibitor, which was approved by the FDA for treating HR-positive, HER2-negative first-line breast cancer. The drug will compete with Pfizer’s CDK4/6 inhibitor, Ibrance (palbociclib), a strong competitor and earlier market entry that was launched in early 2015. Forecasts for 2021 for the drug are nearly $1.3 billion, according to a 2017 analysis by Clarivate Analytics.

Nine large pharmaceutical companies had one small-molecule NME approval in 2017. AbbVie received approval in 2017 for its small-molecule combination therapy, Mavyret (glecaprevir and pibrentasvir) for treating chronic hepatitis C virus (HCV) genotypes 1-6 (see Table II at the end of the article). Gilead Sciences also had a drug combination approved for treating HCV with the approval of Vosevi (sofosbuvir, velpatasvir, and voxilaprevir) for treating HCV genotypes 1-6.

Several of the large phama companies received FDA approval for small molecules for treating cancer. AstraZeneca received approval for Calquence (acalabrutinib), a drug for treating mantle-cell lymphoma, a rare form of cancer (see Table II at the end of the article ). Bayer received approval for Aliqopa (copanlisib) for treating relapsed follicular lymphoma. Eli Lilly and Company received approval for Verzenio (abemaciclib) for treating advanced or metastatic breast cancer. Through its acquisition of Ariad Pharmaceuticals in 2017, Takeda Pharmaceutical received FDA approval for Alunbrig (brigatinib) for treating anaplastic lymphoma kinase positive metastatic non-small cell lung cancer.

In addition, other large pharma companies had small-molecule NME approvals in 2017 for various other therapeutic areas. Amgen received FDA approval for Parsabiv (etelcalcetide), a drug for treating secondary hyperparathyroidism in adult patients with chronic kidney disease on hemodialysis (see Table II at the end of the article). Novo Nordisk’s Ozempic (semaglutide) was approved for glycemic control. Teva Pharmaceutical Industries’ Austedo (deutetrabenazine) was approved for treating chorea associated with Huntington’s disease.

Some other small-molecule approvals in 2017 included Celgene’s Idhifa (enasidenib) for treating elapsed or refractory acute myeloid leukemia in patients with a specific genetic mutation and Lupin’s Solosec (secnidazole) for treating bacterial vaginosis (see Table II at the end of the article).

Innovation and small molecules

Of the 46 NMEs approved in 2017, CDER identified that 15 of them or roughly one-third were first-in-class drugs, which refer to drugs with mechanisms of action different from those of existing drugs. Of the 15 first-in-class NMEs approved in 2017, nine were small molecules, with three from large pharmaceutical companies. The first-in-class NMEs approved from larger pharmaceutical companies in 2017 were: Celgene’s Idhifa (enasidenib) for treating elapsed or refractory acute myeloid leukemia in patients with a specific genetic mutation; Merck & Co.’s Prevymis (letermovir), a drug to prevent infection after bone-marrow transplant; Mitsubishi Tanabe Pharma America’s Radicava (edaravone), a drug for treating amyotrophic lateral sclerosis (i.e., Lou Gehrig’s disease); and Novartis’ Rydapt (midostaurin) for treating acute myeloid leukemia in patients with a specific genetic mutation.

The first-in-class NMEs approved from smaller pharmaceutical companies in 2017 were: PTC Therapeutics’ Emflaza (deflazacort) for treating Duchenne muscular dystrophy, a rare disease characterized by progressive muscle degeneration and weakness; La Jolla Pharmaceuticals’ Giapreza (angiotensin II) for increase blood pressure in adults with septic or other distributive shock; Aeterna Zentaris’ Macrilen (macimorelin) for diagnosis of adult growth hormone deficiency; Aerie Pharmaceuticals’ Rhopressa (netarsudil) for treating glaucoma or ocular hypertension; and Lexicon Pharmaceuticals’ Xermelo (telotristat ethyl) for treating Carcinoid syndrome diarrhea. 

Table II: Approvals of Small Molecules as New Molecular Entities (New Drug Applications (NDAs) in 2017 by the US Food and Drug Administration’s Center for Drug Evaluation and Research.
Company Brand name (active ingredient); application type Indication
AbbVie Mavyret (glecaprevir and pibrentasvir); NDA Chronic hepatitis C virus genotypes 1-6 without cirrhosis or with mild cirrhosis
Aerie Pharmaceuticals Rhopressa (netarsudil); NDA Glaucoma or ocular hypertension
Aeterna Zentaris Macrilen (macimorelin acetate); NDA Diagnosis of adult growth hormone deficiency
Amgen Parsabiv (etelcalcetide); NDA Secondary hyperparathyroidism in adult patients with chronic kidney disease on hemodialysis
AstraZeneca Calquence (acalabrutinib); NDA Mantle-cell lymphoma
Bayer Aliqopa (copanlisib); NDA Relapsed follicular lymphoma
Celgene Idhifa (enasidenib); NDA Relapsed or refractory acute myeloid leukemia in patients with a specific genetic mutation
Chemo Research benznidazole; NDA Chagas disease
Eli Lilly and Company Verzenio (abemaciclib); NDA Certain advanced or metastatic breast cancers
Ferrer Internacional Xepi (ozenoxacin); NDA Impetigo (i.e., skin sores)
Gilead Sciences Vosevi (sofosbuvir, velpatasvir, and voxilaprevir); NDA Chronic hepatitis C virus, genotypes 1-6 without cirrhosis or with mild cirrhosis
La Jolla Pharmaceutical Company Giapreza (angiotensin II); NDA Increase blood pressure in adults with septic or other distributive shock
Lexicon Pharmaceuticals Xermelo (telotristat ethyl); NDA Carcinoid syndrome diarrhea
Lupin Solosec (secnidazole); NDA Bacterial vaginosis
Melinta Therapeutics Baxdela (delafloxacin); NDA Acute bacterial skin infections
Merck & Co. Prevymis (letermovir); NDA To prevent infection after bone marrow transplant
Merck & Co. and Pfizer Steglatro (ertugliflozin); NDA Glycemic control in adults with Type 2 diabetes mellitus
Mitsubishi Tanabe Pharma America Radicava (edaravone); NDA Amyotrophic lateral sclerosis (Lou Gehrig’s disease)
Neurocrine Biosciences Ingrezza (valbenazine); NDA Tardive dyskinesia
Novartis Kisqali (ribociclib); NDA Hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
Novartis Rydapt (midostaurin); NDA Acute myeloid leukemia in patients with a specific genetic mutation, FLT3, in combination with chemotherapy
Novo Nordisk Ozempic (semaglutide); NDA Glycemic control
Portola Pharmaceuticals Bevyxxa (betrixaban); NDA Prophylaxis of venous thromboembolism
PTC Therapeutics Emflaza (deflazacort); NDA Duchenne muscular dystrophy
Puma Biotechnology Nerlynx (neratinib); NDA Extended adjuvant treatment of early-stage, HER2-positive breast cancer
Radius Health Tymlos (abaloparatide); NDA Osteoporosis
Shionogi Symproic (naldemedine); NDA Opioid-induced constipation in adult patients with chronic non-cancer pain
Synergy Pharmaceuticals Trulance (plecanatide); NDA Chronic idiopathic constipation
Takeda Pharmaceutical Alunbrig (brigatinib); NDA Anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer
Tesaro Zejula (niraparib); NDA Epithelial ovarian, fallopian tube or primary peritoneal cancer
Teva Pharmaceuticals Austedo (deutetrabenazine); NDA Chorea associated with Huntington’s disease
The Medicines Company Vabomere (meropenem and vaborbactam); NDA Complicated urinary tract infections
US World Meds Xadago (safinamide); NDA An add-on treatment for patients with Parkinson’s disease
Valeant Pharmaceuticals Vyzulta (latanoprostene bunod ophthalmic solution); NDA Intraocular pressure in patients with open-angle glaucoma or ocular hypertension

Lupin acquired Symbiomix, the developer of Solosec (secnidazole), in October 2017.

PTC Therapeutic acquired rights to Emflaza (deflazacort) for the treatment of Duchenne muscular dystrophy in the US from Marathon Pharmaceuticals in April 2017.

Takeda acquired Ariad Pharmaceuticals in February 2017.

The Medicines Company acquired Rempex Pharmaceuticals in 2013.

US WorldMed is partnered with Zambon, which is partnered with Newron Pharmaceuticals by which Zambon has the rights to develop and commercialize Xadago (safinamide) globally, excluding Japan and other key territories where Meiji Seika has the rights to develop and commercialize the compound. The rights to develop and commercialize Xadago in the US have been granted to US WorldMeds by Zambon.

Source: US Food and Drug Administration's Center for Drug Evaluation and Research and company information.