The Year In New Drugs - ACS Publications

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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

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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

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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.

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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.

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1 Ibrance (palbociclib) O

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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

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MODE OF ACTION

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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

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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

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Praxbind

Idarucizumab

Boehringer Ingelheim

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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

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Cobimetinib

Genentech

Melanoma

MEK inhibitor ▮ ●

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Osimertinib

AstraZeneca

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Johnson & Johnson

Multiple myeloma

Anti-CD38 antibody ▮ ▲ ●⧫

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Takeda Pharmaceutical

Multiple myeloma

Proteasome inhibitor ▮ ●

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Kanuma

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Alexion Pharmaceuticals

Lysosomal acid lipase deficiency

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Alecensa

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10 Cotellic (cobimetinib)

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AstraZeneca

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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

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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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