Tracking Small-Molecule MuscleBy
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.