COVER STORY
THE YEAR IN NEW DRUGS Speedier development and regulatory action in the U.S. contributed to a PEAK IN PRODUCT APPROVALS in 2015
Savaysa Cosentyx Natpara Ibrance Lenvima Farydak Avycaz Cresemba Unituxin Cholbam Corlanor Kybella Viberzi
LISA M. JARVIS, C&EN CHICAGO
Xuriden Vraylar Lonsurf Tresiba Aristada Praxbind Veltassa Yondelis Strensiq Nucala Genvoya
Kengreal Orkambi Entresto Rexulti Praluent Odomzo Daklinza Addyi Repatha Varubi CEN.ACS.ORG
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Cotellic Tagrisso Darzalex Ninlaro Portrazza Empliciti Kanuma Alecensa Bridion Uptravi Zurampic
F
OR THE SECOND YEAR in a row, new drug approvals in
the U.S. arrived at a blistering pace. Forty-five new products received the Food & Drug Administration’s green light in 2015, making it the most productive year for the pharmaceutical industry since 1996. But unlike in 2014, when the quality of the therapies was as impressive as the quantity, few products approved in 2015 stood out as major breakthroughs. Rather, many of the new drugs were notable more for their breathtaking price tags and how swiftly they moved to the market than for their ability to transform lives. The bounty of new drugs in 2015 included more biologics than in the previous two years: A third of the drugs approved were antibodies, peptides, or enzymes compared with about a quarter in 2014. The year’s class included fewer novel mechanisms of action—36% of approvals compared with 42% in 2014. Although big innovations were in short supply in 2015, the nearly two-decade peak in approvals buoyed spirits in the industry. Twenty years after the sequencing of the human genome promised a new way to cure disease, “it really feels like we’re in a period and will continue to be in a period where breakthroughs are turning into new medicines,” says Glen Giovannetti, global life sciences leader at Ernst & Young. Aside from the sheer number, the most notable feature of last year’s approval list might be the speed with which the drugs reached the market. FDA granted one or more forms of expedited review—which include priority review, accelerated approval, and orphan drug status—to 60% of the drugs approved in 2015. At the same time, more New Drug Applications are getting FDA’s rubber stamp on their first try. Last year 39 drugs, or 87%, were approved in the first cycle—meaning the agency did not ask companies for more information that would extend the review time. In 2010, just 56% of new drugs were approved in the first cycle. FDA attributes the improved success rate to factors such as better interactions with companies early in the development process, fewer me-too drugs, more targeted therapies, and more drugs for rare disease in which greater risk is tolerated. That so many drugs were approved— and so many made it through the regulatory gantlet on their first try—is important affirmation of a changing attitude at FDA, Giovannetti says. Given that companies’ relationships with the agency once seemed
adversarial, “the impression that regulators are interested in getting good drugs to patients is positive,” he adds. One of the biggest recent changes at FDA was the introduction in 2012 of “breakthrough therapy designation.” Companies developing drugs that FDA considers to be truly innovative—ones with a new mechanism of action or that address a disease that currently lacks treatment options—receive extra guidance from agency staffers early in the development process.
SURGE New drug approvals have risen sharply in recent years.
BREAKTHROUGH STATUS has proven
New molecular entities approved 50 40 30 20 10 0 2005 07
09
11
13
15
SOURCE: FDA
Companies and industry watchers are now trying to gauge how much time breakthrough status can shave from the lengthy drug development process. Between 2002 and 2013, it took an average of 7.5 years for a drug to go from Investigational New Drug Application—a request for FDA’s permission to start human studies—to regulatory approval, according to the Tufts Center for the Study of Drug Development. By comparison, the 11 drugs with breakthrough status approved in 2013 and 2014 took an average of 5.2 years to go from application to market. And the three drugs out of those 11 that had the status CEN.ACS.ORG
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plus a second expedited status sailed to market in just 4.3 years. The data set is small, stresses Christopher Milne, director of research at the Tufts center, but so far the time saved with breakthrough status—potentially more than three years—is huge. Tufts is waiting for a larger cohort of drugs approved with the designation before doing a complete analysis. One reason it’s hard to draw definitive conclusions about the impact of the breakthrough designation is that many drugs lingered in the pipeline before companies got extra guidance from FDA. Of the 10 products with breakthrough status that were approved in 2015, six had already been in the clinic for at least four years before the special designation was introduced. But the four companies that received the status early on in a drug’s development clearly benefited from closer FDA guidance. For example, Boehringer Ingelheim’s Praxbind, an antibody fragment that reverses the activity of the company’s blood thinner Pradaxa, went into the clinic in 2012, was granted the status in 2014, and won approval a year later.
FEBRUARY 1, 2016
particularly helpful for cancer drugs. AstraZeneca’s Tagrisso, which treats lung cancer driven by a specific mutation, is an example of how the status can help a compound reach the market at breakneck pace. AstraZeneca chemists first synthesized the drug’s active ingredient in June 2011, and it was chosen as a lead candidate in 2012. FDA approved the drug in November 2015, just 2.5 years after the first patient received it in a clinical trial. Similarly, Genentech’s Alecensa, which also targets a specific driver of lung cancer, was discovered in 2008, entered the clinic in 2010, and was approved five years later. Both Tagrisso and Alecensa also were granted “accelerated approval,” which is a way to put important treatments on the market with limited data—with the proviso that their efficacy is proved in a postapproval study. For the many drugs with expedited approval routes, the time saved can translate into lower development costs and potentially a longer period of patent exclusivity in which they face little or no competition. As such, some companies are willing to pay princely sums to get their drugs onto the market faster. Last year brought the first real sense of how the market might shake out for priority review vouchers (PRVs), an
COVER STORY
NEW PEAK New drug approvals in the U.S. reached a nearly 20-year high, but innovation was in short supply.
O N N
N
HN
O
N
N N H
1 Ibrance (palbociclib) O
O NH
F F
O
N
DRUG NAME
ACTIVE INGREDIENT
Savaysa
Edoxaban
Daiichi Sankyo
APPLICANT
Anticoagulant
Factor Xa inhibitor
Cosentyx
Secukinumab
Novartis
Psoriasis
IL17A antagonist ⧫
Natpara
Parathyroid hormone
NPS Pharmaceuticalsa
Low calcium levels in hypoparathyroidism
Parathyroid hormone replacement ▮
1 Ibrance
Palbociclib
Pfizer
Metastatic breast cancer
CDK inhibitor ▲ ● ⧫
Lenvima
Lenvatinib
Eisai
Thyroid cancer
VEGF, FGFR, PDGFR, KIT, RET inhibitor ▮ ●
2 Farydak
Panobinostat
Novartis
Multiple myeloma
HDAC inhibitor ▮ ●
Avycaz
Ceftazidimeavibactam
Forest Laboratories
Antibiotic
Bacterial cell-wall synthesis inhibitor/nonβ-lactam β-lactamase inhibitor ●
Cresemba
Isavuconazonium sulfate
Astellas
Antifungal
Prodrug of lanosterol 14 α-demethylase inhibitor ▮●
Unituxin
Dinutuximab
United Therapeutics
Children with neuroblastoma
Ganglioside GD2 binding ▮ ●⧫★
Cholbam
Cholic acid
Asklepion Pharmaceuticalsa
Bile acid synthesis disorders
Unknown ▮ ● ★
3 Corlanor
Ivabradine
Amgen
Heart failure
HCN channel inhibitor ● ⧫
Kybella
Deoxycholic acid
Kythera Biopharmaceuticalsa
Reduce chin fat
Fat cell lysis
Viberzi
Eluxadoline
Forest Laboratoriesa
Irritable bowel syndrome
µ-Opioid receptor agonist and δ-opioid receptor antagonist ●
Kengreal
Cangrelor
The Medicines Co.
Anticoagulant
P2Y12 inhibitor
4 Orkambi
Lumacaftor/ ivacaftor
Vertex Pharmaceuticals
Cystic fibrosis
CFTR corrector/CFTR modulator ▮ ▲ ● ⧫
5 Entresto
Sacubitril/ valsartan
Novartis
Heart failure
Neprilysin inhibitor/ angiotensin receptor blocker ● ⧫
Rexulti
Brexpiprazole
Lundbeck/Otsuka
Schizophrenia
D2 dopamine partial agonist
Praluent
Alirocumab
Sanofi/Regeneron
High cholesterol
PCSK9 inhibitor ⧫
Odomzo
Sonidegib
Novartis
Basal cell carcinoma
SMO inhibitor
6 Daklinza
Daclatasvir
Bristol-Myers Squibb
Hepatitis C
NS5A inhibitor ●
7 Addyi
Flibanserin
Sprout Pharmaceuticalsa
Low libido in women
5-HT1A receptor agonist ⧫
Repatha
Evolocumab
Amgen
High cholesterol
PCSK9 inhibitor ▮
Varubi
Rolapitant
Tesaro
Chemotherapy-induced nausea
Substance P/NK-1 receptor antagonist
a
O
Lumacaftor
OH H N
N H O
OH
INDICATION
MODE OF ACTION
O
Ivacaftor
4 Orkambi
O O
OH
N H
O
O
Sacubitril O OH N O H N N N
O
N H
N
H N
H3CO N
OH
Valsartan
5 Entresto
O
N H
H3CO
2 Farydak (panobinostat) CEN.ACS.ORG
14
N
OCH3
CH3
OCH3
3 Corlanor (ivabradine) FEBRUARY 1, 2016
KEY: ■ Small molecule ■ Antibody fragment ■ Peptide ■ Antibody ■ Enzyme ▮ Orphan drug ▲ FDA breakthrough status ● FDA priority review ⧫ Novel mode of action DRUG NAME
ACTIVE INGREDIENT
APPLICANT
INDICATION
★ Priority review voucher earned
MODE OF ACTION
Uridine replacement ▮ ▲ ●⧫★
8 Xuriden
Uridine triacetate
Wellstat Therapeutics
Hereditary orotic aciduria
Vraylar
Cariprazine
Allergan/Gedeon Richter
Schizophrenia
D2 and D3 receptor partial agonist
Lonsurf
Trifluridine/tipiracil Taiho Onoclogy
Colon cancer
Cytotoxin/thymidine phosphorylase inhibitor
Tresiba
Insulin degludec
Novo Nordisk
Diabetes
Insulin
Aristada
Aripiprazole lauroxil
Alkermes
Schizophrenia
Unknown Dabigatran reversal agent ▮ ▲● ⧫
O HN
N N
7 Addyi (flibanserin)
Praxbind
Idarucizumab
Boehringer Ingelheim
Veltassa
Patiromer
Relypsa
Hyperkalemia
Potassium binding agent
9 Yondelis
Trabectedin
PharmaMar/Johnson & Johnson
Soft-tissue sarcoma
DNA binding agent ●
Strensiq
Asfotase alfa
Alexion Pharmaceuticals
Juvenile-onset hypophosphatasia
TNSALP enzyme replacement ▮ ▲ ● ⧫ ★
Nucala
Mepolizumab
GlaxoSmithKline
Asthma
Interleukin-5 antagonist ⧫
Genvoya
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide
Gilead Sciences
10 Cotellic
Cobimetinib
Genentech
Melanoma
MEK inhibitor ▮ ●
11 Tagrisso
Osimertinib
AstraZeneca
EGFR T790M mutationpositive lung cancer
EGFR inhibitor ▮ ▲ ●
Darzalex
Daratumumab
Johnson & Johnson
Multiple myeloma
Anti-CD38 antibody ▮ ▲ ●⧫
Ninlaro
Ixazomib
Takeda Pharmaceutical
Multiple myeloma
Proteasome inhibitor ▮ ●
Portrazza
Necitumumab
Eli Lilly & Co.
Lung cancer
EGFR inhibitor ▮
Empliciti
Elotuzumab
Bristol-Myers Squibb/ AbbVie
Multiple myeloma
SLAMF7 targeted ▮ ▲ ● ⧫
Kanuma
Sebelipase alfa
Alexion Pharmaceuticals
Lysosomal acid lipase deficiency
Lysosomal acid lipase replacement ▮ ▲ ● ⧫ ★
Alecensa
Alectinib
Genentech/Roche
ALK-positive lung cancer
ALK fusion inhibitor ▮ ▲ ●
NH
H3CO
O S OH
O O
OH
9 Yondelis (trabectedin) HO
HIV
Antivirals
O F
H N
CH3 N
Uptravi
Selexipag
Actelion Pharmaceuticals
Pulmonary arterial hypertension
Prostacyclin receptor agonist ▮
O O O
N
S O
O NaO2C
O
N
OH
HO
OH
HO
O
OCH3
O
S
O O
8 Xuriden (uridine triacetate)
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FEBRUARY 1, 2016
CO2Na O S O
HO OH HO OH OH HO O O
O
CEN.ACS.ORG
HO OH OH HO HO OH
CO2Na
O
O
O HN
N
6 Daklinza (daclatasvir)
O
O
O
N
N H
S
O
O
S
O
O
CO2Na
CO2Na
NH
N
OCH3
S
O
H N
CH3
N H
11 Tagrisso (osimertinib)
NaO2C
O
CH3
N
Urate transporter inhibitor
a Applicant was acquired SOURCE: FDA
O
N
N N
Anesthesia reversal
CH3
NH
O
Merck & Co.
Hyperuricemia
F
10 Cotellic (cobimetinib)
Sugammadex
AstraZeneca
N H
N
F
12 Bridion
H N
CH3
N N
Selective relaxant binding agent ● ⧫
H3CO
OCH3
O HO
O
I
Lesinurad
CF3
HO
Reversal of anticoagulant efects of BI's Pradaxa
Zurampic
N
NaO2C
O
NaO2C S
12 Bridion (sugammadex)
S
COVER STORY
incentive for firms to com2015 NEW DRUG APPROVALS BY THE NUMBERS mercialize drugs for rare pediatric or tropical diseases. New Biologics Breakthrough Drugs with Cancer The voucher, which is transa molecular a novel approved: therapies treatments ferable, can be submitted entities mechanism approved: approved: alongside a New Drug Application to shave four months approved: of action: off its regulatory review. In 2014, BioMarin Pharmaceutical sold the first PRV to Sanofi and Regeneron PharApproved Drugs that are maceuticals for $68 million. One-year supply of Alexion’s Kanuma: for rare diseases: The partners used the vouch- in 2014: er to get their cholesterollowering treatment Praluent onto the market last year one a FDA-granted status for drugs that treat serious conditions or are a significant advance over existing medicines. SOURCES: FDA, companies month before a competing drug from Amgen. Of the five vouchers earned last year, for $245 million. AstraZeneca paid an unapproved in 2015 is more than $100,000 three were sold, and for much higher disclosed sum to buy the third 2015 PRV per year; drugs with breakthrough designaprices. AbbVie shelled out $350 million for from Wellstat Therapeutics, which won tion accounted for eight of those 12 highthe voucher United Therapeutics received approval for Xuriden, a treatment for a rare ticket treatments. Moreover, several other upon the approval of Unituxin, an antibody metabolic disorder that has been reported products must be taken in combination to treat children with neuroblastoma. in approximately 20 patients worldwide. with expensive drugs, easily bringing the Rare disease firm Retrophin, meanwhile, Drugs might be getting to patients combined annual cost of treatment into sold its voucher for Cholbam, a treatment faster, but they aren’t getting any cheaper. the six figures. for bile acid synthesis disorders, to Sanofi The list price for a dozen of the products Overall, the research firm Datamonitor
45 10
16
41 $310,000
CEN.ACS.ORG
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~29% ~47%
Residential School on Medicinal Chemistry R and Biology in Drug Discovery June 5-10, 2016 Wyndham Hotel, Florham Park, NJ Healthcare forecasts that more than a dozen of the 2015 class of new drugs will become blockbusters, topping $1 billion in annual sales. Most of the expensive products treat small patient populations—either people with rare diseases or people whose cancer is driven by a highly specific molecular mutation. In 2015, nearly half the drugs approved were for “orphan” diseases for which the patient population is fewer than 200,000 people, a definition that encompasses some types of cancer. Companies rationalize that narrow markets are only commercially viable if they can charge enough to recoup their research costs and make a profit. But as patients, doctors, insurers, and politicians call more loudly for lower drug prices, they are asking pointed questions about the value of some of those new drugs.
This graduate level course concentrates on the fundamentals that are useful in drug discovery spanning initial target assay evaluation through clinical development. Several case histories of recent successful drug development programs will also be presented. The five-day program covers: Principles of Med Chem Chemoinformatics Lead ID & Optimization Epigenetics Fragment-based Drug Design Structure-based Drug Design Drug-like Properties Protein-Protein Interactions Molecular Modeling
CANCER DRUGS have come under particular scrutiny. At least
eight of the ones approved in 2015 carry a six-figure list price. The shining example of a transformative cancer drug has long been Novartis’s Gleevec, which addresses a specific subset of chronic myelogenous leukemia patients. Gleevec works so well
William Greenlee, Vincent Gullo and Ronald Doll Co-organizers
For more information and application forms: www.drew.edu/resmed e-mail:
[email protected] phone: 973/408-3787; fax: 973/408-3504
STICKER SHOCK New drugs for cancer and rare diseases came with hefty list prices DRUG NAME
INDICATION
DMPK Toxicophores GPCRs Kinase Inhibitors Ion Channels Enzyme Inhibitors Bioisoteres Preclinical Toxicology Clinical Development
ANNUAL PRICE
Kanuma
LAL deficiency
$310,000
Strensiq
Juvenile-onset hypophosphatasia
$285,000
Orkambi
Cystic fibrosis
$259,000
Uptravi
Pulmonary arterial hypertension
$160,000–170,000
Tagrisso
Lung cancer
$153,000a
Alecensa
ALK-positive lung cancer
$150,000a
Empliciti
Multiple myeloma
$140,000b
Portrazza
Lung cancer
$137,000a
Farydak
Multiple myeloma
$119,000a
Ibrance
Metastatic breast cancer
$118,200
Ninlaro
Multiple myeloma
$113,000a
Darzalex
Multiple myeloma
$110,000
a Based on announced monthly or four-week pricing. b For first year of treatment. NOTE: Blue indicates a cancer drug; yellow indicates a rare drug treatment. SOURCES: Companies, patient groups
that it has added years to patients’ lives, notes Bernard Munos, founder of the InnoThink Center for Research in Biomedical Innovation. But Munos also points out that Gleevec is the exception rather than the rule in cancer treatments. Many products add months, not years, to survival rates. “It’s better than we had before, but in the grand scheme of things, it’s not all that great,” he says. Patients are becoming more sensitive to the relationship between the cost of a drug and its benefits as insurance providers raise copays. “I think that realization is going to sink in as patients are being made more cost-aware,” Munos says. It’s a realization that will surely impact the drugs of the class of 2016. ◾ CEN.ACS.ORG
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