Cover story
FDA approvals hit a 20-year high in 2017, with cancer and rare-disease drugs dominating the list of new medicines LISA M. JARVIS, C&EN CHICAGO
Trulance Parsabiv Emflaza Siliq Xermelo Kisqali Xadago Bavencio Symproic Zejula Dupixent Ocrevus 26
C&EN | CEN.ACS.ORG | JANUARY 22, 2018
Austedo Ingrezza Brineura Alunbrig Rydapt Tymlos Imfinzi Radicava Kevzara Baxdela Bevyxxa
Tremfya Nerlynx Vosevi Idhifa Mavyret Besponsa Vabomere Benznidazole Aliqopa Solosec Verzenio Calquence
Vyzulta Prevymis Fasenra Mepsevii Hemlibra Ozempic Xepi Rhopressa Macrilen Steglatro Giapreza
fter a dip in 2016, 2017 brought a two-decade peak in drug approvals. The U.S. Food & Drug Administration gave its green light to 46 new molecular entities, the highest number since 1996. Cancer treatments and drugs for rare diseases continued to command a hefty portion of approvals, and many benefited from an agency that seems motivated to streamline development for truly innovative medicines.
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C R E D I T: WI LL LU DW I G/C & EN / S H U TT E RSTOC K
In brief The pharmacopoeia grew nicely in 2017, with FDA drug approvals hitting a 20-year peak. Although some new drugs were retreads of older ones, several important breakthroughs—for science and for patients—arrived last year. Cancer and rare-disease drugs dominated the new drug list, thanks in part to FDA’s efforts to clear the path for truly innovative treatments. Read on for more about the 46 additions to the medicine cabinet.
Early on in 2017, it was clear the year would bring a bountiful crop of new medicines. By mid-June, FDA had given its nod to as many new molecules as were approved in all of 2016. The prior year’s meager output meant many big companies were in need of a rebound in productivity. And indeed, for some, 2017 was a salve. AstraZeneca, for example, had no approvals in 2016. It now has three new products in its portfolio: two cancer treatments and an asthma drug. Pfizer, which in 2016 had a lone approval that came only through a midyear acquisition, also scored three new products last year. However, it must share rights to two of them: the cancer immunotherapy Bavencio, which came to Pfizer in 2014 through a multi-billion-dollar deal with Germany’s Merck KGaA, and the diabetes treatment Steglatro, an internally developed drug that in 2013 Pfizer chose to codevelop with U.S.based Merck & Co. For others, the drought persisted. Although Bristol-Myers Squibb continued to expand the types of cancer that are treated with its existing immuno-oncology drugs, 2017 was the company’s second year in a row without a new product approval. The drug industry’s record-breaking productivity does come with caveats. Although FDA said 33% of the products it approved belonged to new classes of compounds, most drug industry watchers would consider several of them to be older drugs. For example, FDA’s list of firstin-class drugs includes Emflaza, a decades-old corticosteroid approved for the first time in the U.S. to treat Duchenne muscular dystrophy. A handful of other treatments either are similarly old drugs just now reaching the U.S. market or work against older protein targets now associated with new diseases. Cancer treatments continued to dominate the list, representing over a quarter
of all new molecules approved last year. However, many of the new oncology drugs are not especially unique and work by the same mechanism of action as already marketed drugs. The approval list included two more CDK4/6 inhibitors, two more PD-L1 inhibitors, and more compounds that block the proteins PARP, BTK, and ALK. The new cancer treatments were the primary beneficiaries of FDA’s efDespite ongoing scrutiny over fort to speed development health care costs, new oncology of potentially important treatments continue to carry new drugs. Of the 12 onhigh price tags. cology products approved, WHOLESALE nine had breakthrough DRUG NAME ACQUISITION COST therapy designation (BTD), a status introIdhifa $24,872/month duced in 2012. FDA has Imfinzi $15,000/month previously described BTD Rydapt $14,990/28 days as triggering an all-handsCalquence $14,259/month on-deck approach at the agency to ensure efficient Alunbrig $14,250/month and well-designed clinical Bavencio $13,000/month programs for drugs that Aliqopa $12,726/month are novel or address an underserved disease. Kisqali $10,950/28 days (600 mg dose) The program has been growing quickly. Overall, Verzenio $10,948/month 17 drugs approved in 2017 Nerlynx $10,500/month had BTD status. In 2015, Zejula $9,833/month for 200 mg/ which previously held day (recommended 300 the recent record for new mg/day dose) drug approvals, just 10 Sources: Companies, insurers products had the special status. Beyond cancer, anti-infectives and drugs for rare diseases were the other beneficiaries of breakthrough status. According to the Tufts Center for the Study of Drug Development, BTD is significantly shortening drug development timelines. The average time from Investigational New Drug Application— asking FDA to begin clinical trials—to approval letter was 65 months for the 17 BTD drugs approved in 2015 and 2016, compared with 110 months for drugs approved without the status.
The cost of cancer
JANUARY 22, 2018 | CEN.ACS.ORG | C&EN
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Bountiful year Cancer and rare-disease drugs scored the most approvals in 2017, and small molecules continued to be an important drug modality. DRUG NAME
ACTIVE INGREDIENT
APPLICANT
MODE OF ACTION
INDICATION
Chronic idiopathic constipation Secondary hyperparathyroidism in chronic kidney disease Duchenne muscular dystrophy ▮ Psoriasis Carcinoid syndrome diarrhea HR-positive/HER2-negative advanced or metastatic breast cancer ▲ Parkinson's disease Merkel cell carcinoma ▲ ● Opioid-induced constipation Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer ▲
Trulance
Plecanatide
Synergy Pharmaceuticals
Parsabiv
Etelcalcetide
Amgen
Emflaza Siliq Xermelo
Deflazacort Brodalumab Telotristat ethyl
Marathon Pharmaceuticals Valeant Pharmaceuticals Lexicon Pharmaceuticals
Guanylate cyclase-C agonist Calcium-sensing receptor modulator Corticosteroid prodrug IL-17RA antagonist Tryptophan hydroxylase inhibitor
1 Kisqali
Ribociclib
Novartis
CDK4/6 inhibitor
2 Xadago Bavencio Symproic
Safinamide Avelumab Naldemedine
Newron Pharmaceuticals Merck KGaA/Pfizer Purdue Pharma
Monoamine oxidase B inhibitor PD-L1 inhibitor Mu opioid receptor antagonist
3 Zejula
Niraparib
Tesaro
PARP inhibitor
Dupixent
Dupilumab
Ocrevus
Ocrelizumab
Sanofi/Regeneron Pharmaceuticals Roche
4 Austedo
Deutetrabenazine
Teva Pharmaceutical
Ingrezza
Valbenazine
Neurocrine Biosciences
Brineura 5 Alunbrig
Cerliponase alfa Brigatinib
BioMarin Pharmaceutical Takeda Pharmaceutical
6 Rydapt
Midostaurin
Novartis
Tymlos
Abaloparatide
Radius Health
Imfinzi Radicava
Durvalumab Edaravone
Kevzara
Sarilumab
Baxdela Bevyxxa
Delafloxacin Betrixaban
AstraZeneca Mitsubishi Tanabe Sanofi/Regeneron Pharmaceuticals Melinta Therapeutics Portola Pharmaceuticals
IL-4 and IL-13 inhibitor
Eczema ▲
CD20 binder Vesicular monoamine transporter 2 inhibitor Vesicular monoamine transporter 2 inhibitor Enzyme replacement therapy ALK inhibitor Multikinase inhibitor, including FLT3 and KIT Parathyroid hormone-related protein PD-L1 inhibitor Unknown
Multiple sclerosis ▲ Huntington's disease-associated chorea Tardive dyskinesia ▲ Batten disease ▲ ▮ ALK-positive non-small cell lung cancer
▲●
FLT3-positive acute myeloid leukemia ▲ Osteoporosis Urothelial carcinoma ▲ ● Amyotrophic lateral sclerosis
IL-6R inhibitor
Rheumatoid arthritis
Fluoroquinolone Factor Xa inhibitor
Skin infections Venous thromboembolism
Note: Drugs appear in order of approval during 2017. Source: FDA
HN N
N H
O
O
N
N
N
N
O
O
N(CH3)2
F
N H
H2N
O–
• –O
O
•H C 3
S
CF3
N
N
N H
7 28
• 2HCl
N
N N
N H
HO Idhifa (enasidenib) C&EN | CEN.ACS.ORG | JANUARY 22, 2018
3 Zejula (niraparib)
O
N N
+
NH2
N
Xadago (safinamide)
N
N
F3C
2
Kisqali (ribociclib)
NH2 N
O–
O
O
1
O
O
O
N OCH3
8
O
N
N H
NO2
N N
Aliqopa (copanlisib)
NH2
9
OH Solosec (secnidazole)
O– S
O •H O 2
KEY: ■ Small molecule ■ Peptide ■ Antibody ■ Enzyme ● Accelerated approval ▮ Priority review voucher earned DRUG NAME
Tremfya Nerlynx
ACTIVE INGREDIENT
APPLICANT
Guselkumab Neratinib maleate Sofosbuvir, velpatasvir, and voxilaprevir Enasidenib Glecaprevir and pibrentasvir Inotuzumab ozogamicin
MODE OF ACTION
INDICATION
IL-23 inhibitor EGFR, HER2, and HER4 inhibitor NS5B polymerase, NS5B, and Vosevi Gilead Sciences NS3/4A protease inhibitors 7 Idhifa Celgene IDH2 inhibitor NS3/4A protease and NS5A Mavyret AbbVie inhibitors CD22-binding antibody and Besponsa Pfizer cytotoxic antibiotic Carbapenem antibacterial and Meropenem and Vabomere The Medicines Co. non-β-lactam β-lactamase vaborbactam inhibitor Benznidazole Benznidazole Chemo Research Nitroimidazole antimicrobial 8 Aliqopa Copanlisib Bayer Pan-PI3K inhibitor 9 Solosec Secnidazole Symbiomix Therapeutics Nitroimidazole antimicrobial 10 Verzenio Abemaciclib Eli Lilly & Co. CDK4/6 inhibitor 11 Calquence Acalabrutinib AstraZeneca BTK inhibitor Latanoprostene bunod Metabolizes into two pressure12 Vyzulta Valeant Pharmaceuticals ophthalmic solution lowering moieties Cytomegalovirus DNA terminase 13 Prevymis Letermovir Merck & Co. complex inhibitor Fasenra Benralizumab AstraZeneca IL-5R α receptor binder Mepsevii Vestronidase alfa Ultragenyx Pharmaceutical Enzyme replacement therapy Hemlibra Emicizumab Roche Factor IX and X binder Ozempic Semaglutide Novo Nordisk GLP-1 receptor agonist Medimetriks Nonfluorinated quinolone Xepi Ozenoxacin Pharmaceuticals antibiotic Netarsudil ophthalmic Rhopressa Aerie Pharmaceuticals ρ-kinase inhibitor solution Macrilen Macimorelin acetate Aeterna Zentaris Ghrelin mimetic 14 Steglatro Ertugliflozin Merck & Co./Pfizer SGLT2 inhibitor Giapreza Angiotensin II La Jolla Pharmaceutical Synthetic human angiotensin II
Johnson & Johnson Puma Biotechnology
H3CO
CD3O N
CD3O
▲ FDA breakthrough status
■ Antibody-drug conjugate
N
H N
N
Psoriasis HER2-positive breast cancer Hepatitis C ▲ IDH2-positive acute myeloid leukemia Hepatitis C ▲ Acute lymphoblastic leukemia ▲ Complicated urinary tract infections Chagas disease ● ▮ Follicular lymphoma ● Bacterial vaginosis Breast cancer ▲ Mantle cell lymphoma ▲ ● Glaucoma/ocular hypertension Infection prevention after bone marrow transplant ▲ Severe asthma MPS VII (Sly syndrome) ▮ Hemophilia A ▲ Type 2 diabetes Impetigo Glaucoma/ocular hypertension Adult growth hormone deficiency Type 2 diabetes Hypotension in sepsis or critical illness
O H3C CH3 H P N
N
H N
Cl
O
4
N
N
N
O H
H3CN
5
Austedo (deutetrabenazine)
CH3O
Alunbrig (brigatinib) N
O
F
NH2
N N HN
N
N
N
N
N
CH3N
O
NH
F N
O
6 Rydapt (midostaurin) N
O N
N
10
Verzenio (abemaciclib)
11
Calquence (acalabrutinib) JANUARY 22, 2018 | CEN.ACS.ORG | C&EN
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O
2017 new drug approvals by the numbers
46
12
New molecular entities approved in 2017
Cancer drugs approved in 2017
4
22
Approved in 2016
Approved in 2016
63% 37% Drugs with “breakthrough therapy” status
Small molecules approved
$702,000 Annual price of treatment with BioMarin’s Brineura Sources: FDA, companies
Peak New drug approvals were the highest in 21 years. New molecular entities approved 50 40 30 20 10 0 2005 07
09
11
13
15
Source: FDA
30
C&EN | CEN.ACS.ORG | JANUARY 22, 2018
17
O
“I would say that’s pretty good confirmation that this is another FDA program that seems to be working,” says Christopher-Paul Milne, director of research at the Tufts center. “What has to come next is expansion into other therapeutic areas of need.” That shortened development time, which in theory should mean lower R&D costs for companies focused on oncology, is not translating into lower prices. All 12 oncology drugs approved last year featured six-figure annual wholesale acquisition costs, the company’s list price before any rebates or discounts. Although the biotech industry has been energized by the potential for new tech-
nologies and therapeutic OH O NO2 modalities to tackle difficult-to-treat diseases, OH small molecules continue to dominate FDA’s HO docket. Conventional, Vyzulta (latanoprostene bunod ophthalmic solution) chemically synthesized drugs represented alO most two-thirds of the new CF3 molecular entities approved last year. HO Still, compared with a decade ago, the OCH3 N new drug list last year featured a wider range of modalities, including peptides, N N enzyme replacement therapies for rare N F OCH3 diseases, and an antibody-drug conjugate. Industry insiders will notice that the tally of 46 does not include the two new Prevymis (letermovir) therapeutic modalities that garnered the biggest headlines in 2017. Missing are NoCl vartis’s Kymriah and Gilead Sciences’ Yescarta, both chimeric antigen receptor (CAR) T-cell therapies, a new class of drugs made by reengineerO OH ing a person’s own T cells to seek O and destroy cancer cells. Also absent O is Spark Therapeutics’ Luxturna, OH O OH N the first-ever approved gene therapy for a H OH genetic condition. Luxturna treats a rare O HO form of blindness. Steglatro (ertugliflozin) C&EN has long tracked FDA’s actions on new molecular entities, and these celdrugs, and he quickly acted: In December, lular treatments—the approval of which the agency released draft guidance to the agency called “historic”—fall outside clarify the clinical development for such that category. Overall, FDA gave the green light to a combined 56 new molecu- treatments. “When drugs successfully target these lar entities and biologic therapies. molecular mistakes to reverse the effects Similarly, the list does not capture of different diseases, we need a develanother groundbreaking approval that opment pathway that arrived in 2017. In May, allows the new drug to FDA green-lighted Merpursue approval in each ck & Co.’s cancer imof these novel settings on munotherapy Keytruda the basis of the molecular for use in anyone harmarker that the drug tarboring a specific genetic gets,” Gottlieb said when profile. the draft guidance was Keytruda had already released. been on the market for Even as the breadth of three years for a variety modalities and clinical of cancer types. But last pathways expands, the year the agency gave agency said that every drug the drug its first “tissue in 2017 was approved withagnostic” approval, in the review time frame meaning that a genetic required by law; many apmutation rather than plications actually got the the location of the cannod before the deadline. cer—lung or colon, for Looking ahead, the example—guides use of agency appears deterthe treatment. Soon after coming on —Christopher-Paul Milne, mined to continue partas FDA commissioner director of research, Tufts nering with companies on May 9, Scott GottliCenter for the Study of Drug to make the development eb signaled his intenDevelopment, speaking about process for innovation to ease the path for FDA’s breakthrough therapy tive drugs even more other tissue-agnostic designation efficient. ◾
12
13
14
“I would say that’s pretty good confirmation that this is another FDA program that seems to be working.”
