2013 New Drug Launches PDF

Drugs of Today 2014, 50(1): 51-100
copyright 2014 Prous science, s.a.u. or its licensors. all rights reserved.
ccc: 1699-3993/2014
DoI: 10.1358/dot.2014.50.1.2116673
REVIEW
ThE YEaRs NEW DRugs & BIologIcs,

2013: PaRT I
A.I. Graul, E. Cruces and M. Stringer
Thomson Reuters, Barcelona, spain
CONTENTS
summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
agents for analgesia & anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Psychopharmacological drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Neurologic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Respiratory drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
cardiovascular drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Renalurologic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
hematologic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Endocrine drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Dermatologic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
gastrointestinal agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
anti-infective therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Therapy of musculoskeletal & connective tissue diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Immunomodulators & agents for immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Treatment of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
ophthalmic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Metabolic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Treatment of poisoning & drug dependency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Dental agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Diagnostic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Correspondence: a.I. graul, Thomson Reuters, Barcelona, spain. E-mail: ann.graul@thomsonreuters.com.

51
ThE YEaRs NEW DRugs & BIologIcs 2013
A.I. Graul et al.
SUMMARY
This article provides a comprehensive overview of the 56
new drugs and biologics introduced for the first time in
2013, the largest number in at least a decade. This includes
20 new orphan drugs and 10 first-in-class agents, as well
as the first three products bearing the FDAs new
Breakthrough Therapy Designation. The review also covers
30 important new line extensions, encompassing new indications, new formulations and new combinations of previously marketed agents. In addition to this bumper crop of
new launches, another 19 products were approved for the
first time during the year but not yet launched by the close
of this article; these new products are also discussed.
agents, defined as drugs with a new and unique mechanism of action. also launched this year were 30 important new line extensions (new indications, new formulations or new combinations of previously marketed drugs
and biologics).
The most active therapeutic group for new drugs and
biologics in 2013 was oncolytic drugs, with 12 new drugs
and biologics reaching the market to treat patients with
cancer, followed by immunologic agents and metabolic
drugs, with 11 and 7 products, respectively (see Table I).
INTRODUCTION
Twenty of the new products and line extensions introduced in 2013 have orphan drug status, also a much
higher number than previous years, reflecting the recent
upsurge of R&D investment in this area. In another exciting new development, the first three products bearing
the FDas new Breakthrough Therapy Designation were
approved for marketing by the agency.
The year 2013 witnessed the first launches of 56 new

drugs and biologics, the highest number in at least a
decade (see Table I). This includes 10 first-in-class
as shown in Figure 1, the united states was by far the

most important market for new drugs, with 42 global
first launches in 2013 taking place in that country. Japan
Key words: New drug launches New biologics New

approvals line extensions orphan drugs
Table I. Drugs & biologics introductions by therapeutic category, 2003-2013.

Therapeutics
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
central nervous system
Respiratory
cardiovascular
Renalurologic
hematologic
gastrointestinal
Endocrine drugs
Dermatologic
anti-infective
antiarthritic
Immunologic
17
11
cancer
10
12
ophthalmic
Metabolic drugs
Poisoning & drug abuse
Dental
Diagnostic agents
Total
29
26
42
41
30
33
51
29
36
36
56
52
ThoMsoN REuTERs Drugs of Today 2014, 50(1)
A.I. Graul et al.
agency (DEa) schedule II drug. Zogenix plans to launch

it during the first quarter of 2014.
usa
Japan
Eu
India
canada
argentina
Figure 1. Distribution of new launches in 2013 by country.
followed with 5, while India debuted in this listing with 4

new launches.
In addition to this bumper crop of new launches, another 19 products were approved for the first time during the
year but not yet launched by the close of this article; this
number includes both new drugs and biologics, as well
as important new line extensions.
The information in this review and the accompanying
tables was compiled from company communications,
Thomson Reuters Drug News and the Thomson Reuters
IntegritysM and Thomson Reuters cortellis drug databases.
AGENTS FOR ANALGESIA & ANESTHESIA
The long-acting opioid analgesic hydrocodone bitartrate (Zohydro ER; Zogenix) was approved for the first
time last year in the u.s., where it is indicated for the
management of pain severe enough to require daily,
around-the-clock, long-term opioid treatment and for
which alternative treatment options are inadequate.
Zohydro ER is the first extended-release hydrocodone
therapy that is formulated without acetaminophen.
acetaminophen overdose is a leading cause of acute liver
failure in the u.s., and 63% of unintentional acetaminophen overdoses are attributed to the use of hydrocodoneacetaminophen combination products such as Vicodin.
Zohydro uses alkermes patented spheroidal oral Drug
absorption system (soDas) drug delivery technology.
The product will be classified as a Drug Enforcement
In March, the u.K.s Medicines and healthcare products

Regulatory agency (MhRa) approved horizon Pharmas
Duexis (ibuprofen/famotidine) for the symptomatic
treatment of osteoarthritis, rheumatoid arthritis and
ankylosing spondylitis in patients who require regular
treatment with high-dose ibuprofen administered three
times a day and who are at risk of developing nonsteroidal anti-inflammatory drug (NsaID)-associated
gastric and/or duodenal ulcers. horizon Pharma is seeking a commercial partner or partners for Duexis in the
u.K. and the rest of Europe. Duexis, a proprietary singletablet combination of the NsaID ibuprofen and the histamine h2 receptor antagonist famotidine, is indicated in
the u.s. for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the risk
of developing upper gastrointestinal ulcers in patients
who are taking ibuprofen for those indications. The u.K.
approval was the first worldwide to include the new indication of ankylosing spondylitis.
NuPathes Zecuity, an iontophoretic transdermal system for delivery of the 5-hT1B/1D receptor agonist sumatriptan, was approved last year in the u.s. for the acute
treatment of migraine with or without aura in adults.
Zecuity is a single-use, battery-powered patch that is
applied to the upper arm or thigh during a migraine.
Following application and with a press of a button,
Zecuity initiates transdermal delivery, bypassing the
gastrointestinal tract. Throughout the 4-hour dosing
period, the microprocessor within Zecuity continuously
monitors skin resistance and adjusts drug delivery
accordingly to ensure delivery of 6.5 mg of sumatriptan,
with minimal patient-to-patient variability. The product
provides relief of both migraine headache pain and
migraine-related nausea. NuPathe is currently seeking
partnerships to maximize the commercial potential of
Zecuity, and has delayed product launch until the identification of said commercial partner.
PSYCHOPHARMACOLOGICAL DRUGS
a new treatment for major depressive disorder (MDD)
was approved in the u.s. in July 2013: Pierre Fabre and
Forests levomilnacipran (Fetzima), a once-daily serotonin and norepinephrine reuptake inhibitor (sNRI) and
the active isomer of the marketed antidepressant milnacipran. The NDa was supported by three double-blind
phase III studies including two fixed-dose studies, and
one flexible-dose study that compared levomilnacipran
53
to placebo in adults with MDD. combined, these studies

included a total of more than 1,600 adult patients who
received a once-daily dose of either levomilnacipran (40,
80 or 120 mg) or placebo. In each study, the primary
endpoint was change from baseline to endpoint in the
Montgomery-sberg Depression Rating scale total
score and the secondary endpoint was change from
baseline to endpoint in the sheehan Disability scale
total score. In all three studies, statistically significant
improvement was seen for the levomilnacipran group
compared with placebo on both the primary and secondary endpoints. The product was launched in the u.s.,
its first market, in December 2013.
The serotonergic agent vortioxetine (Brintellix;
lundbeck/Takeda) was approved by the u.s. Food and
Drug administration (FDa) in september 2013 for the
treatment of MDD. Vortioxetine inhibits serotonin reuptake and acts as a 5-hT1a receptor agonist, 5-hT1B partial
agonist and 5-hT3, 5-hT1D and 5-hT7 receptor antagonist. This multifaceted profile results in the modulation
of neurotransmission in several systems, including predominantly serotonin, but conceivably also the norepinephrine, dopamine, histamine, acetylcholine, gaBa
and glutamate systems. The relative contribution of each
individual mechanism of action has not been established. Vortioxetine is the first antidepressant with this
combination of pharmacodynamic activities. In october,
the committee for Medicinal Products for human use
(chMP) under the European Medicines agency (EMa)
adopted a positive opinion and recommended European
marketing authorization of vortioxetine for MDD. The
drug was made available in December, although a formal launch is planned for January 2014.
In June 2013, sunovion Pharmaceuticals received FDa
approval of lurasidone hydrochloride (latuda) for two
new indications: as monotherapy and as adjunctive therapy with either lithium or valproate, both to treat adult
patients with major depressive episodes associated with
bipolar I disorder. approval of the new indications was
supported by two 6-week, double-blind, randomized,
placebo-controlled trials, PREVaIl 2 (monotherapy) and
PREVaIl 1 (adjunctive therapy; respective clinicalTrials.
gov Identifiers NcT00868699 and NcT00868452).
lurasidone is an atypical antipsychotic that has been
marketed since 2011 for the treatment of schizophrenia.
It was introduced for the new indication in late July.
adasuve, a new formulation of the typical antipsychotic loxapine succinate formulated using the staccato
inhalation system, was launched for the first time in
54
A.I. Graul et al.
germany last July following approval by the European

commission in February. In Europe, it is indicated for the
rapid control of mild to moderate agitation in adult
patients with schizophrenia or bipolar disorder. The marketing authorization requires that patients receive regular treatment immediately after control of acute agitation symptoms, and that the drug be administered only
in a hospital setting under the supervision of a healthcare professional. adasuve was previously approved in
the u.s. in 2012, as announced in last years edition of
this article, but has not yet been launched in that country. alexza is responsible for manufacture and marketing
of the product, which is distributed by Ferrer. loxapine
succinate is a typical antipsychotic that was first
launched in 1975 by Watson Pharmaceuticals in a capsule formulation for the treatment of psychosis.
NEUROLOGIC DRUGS
In the first quarter of 2013, Biogen Idec obtained FDa
approval for dimethyl fumarate (Tecfidera), indicated
as a first-line treatment for people with relapsing forms
of multiple sclerosis (Ms). Dimethyl fumarate is an orally administered immunomodulating and neuroprotective agent that provides a new approach to the treatment of Ms via activation of the Nrf2 pathway, although
its exact mechanism of action is not fully understood.
The Nrf2 pathway provides a way for cells in the body to
defend themselves against inflammation and oxidative
stress caused by conditions such as Ms (Fig. 2). Dimethyl
fumarate has been clinically proven to significantly
reduce important measures of disease activity, including
relapses and development of brain lesions, as well as to
slow disability progression over time, while demonstrating a favorable safety and tolerability profile. Biogen Idec
launched the drug just days after approval.
In september, the European commission approved the
humanized anti-cD52 monoclonal antibody alemtuzumab (lemtrada; genzyme) for the treatment of
adult patients with relapsingremitting Ms with active
disease defined by clinical or imaging features. The
approval was supported by the caRE-Ms I and caREMs II trials, in which alemtuzumab was significantly
more effective than interferon -1a at reducing annualized relapse rates. This is a new indication for alemtuzumab, which has been marketed by Bayer healthcare
Pharmaceuticals since 2004 for the treatment of chronic lymphocytic leukemia. genzyme holds the worldwide
rights to alemtuzumab and has primary responsibility
for its development and commercialization in Ms.
A.I. Graul et al.
Figure 2. Dimethyl fumarate is a second-generation fumarate derivative that is orally available and exhibits immunomodulatory
properties. It has recently been shown to promote neuroprotection by upregulating antioxidative responses through the activation
of nuclear factor, erythroid-derived 2, -like 2 (Nrf2), an effect that is believed to be independent of its immunomodulatory and
radiosensitizing mechanisms. Its function as an Nrf2 activator is expected to have utility in treating relapsing-remitting multiple
sclerosis.
Istradefylline (Nouriast), a first-in-class antiparkinsonian agent from Kyowa hakko Kirin, was approved for the
first time worldwide last March in Japan. Istradefylline is
a selective adenosine a2a receptor antagonist with a
mechanism of action that is clearly distinct from that of
other antiparkinsonians, most of which act on dopamine
receptors (Fig. 3). adenosine a2a receptors are located in
the basal ganglia, a region of the brain involved in motor
control that is frequently degenerated or abnormal in
Parkinsons disease (PD). In clinical trials conducted in
Japan, istradefylline improved wearing-off phenomena
and was well tolerated in levodopa-treated PD patients.
The drug is indicated for use in combination with levodopa-containing products, to treat wearing-off phenomena. It was launched in Japan in May.
The tricyclic antidepressant clomipramine hydrochloride (anafranil), which has been marketed since the
1960s for the treatment of anxiety and depression, was

approved and launched last year for the first time in
Japan for a new indication: treatment of cataplexy in
patients with narcolepsy. This is the first time that a regulatory body has officially approved clomipramine for
this use, although it has long been prescribed off-label
for patients with cataplexy, and in fact alfresa filed the
application for this indication based on evidence in the
public domain. Japan has the worlds highest prevalence
of narcolepsy: 1 in 600 inhabitants, according to the
Narcolepsy Network.
RESPIRATORY DRUGS
Breo Ellipta (glaxosmithKline[gsK]/Theravance), a
fixed-dose combination product incorporating the
inhaled corticosteroid fluticasone propionate and
vilanterol, a long-acting 2-adrenoceptor agonist
(laBa), was approved last year for the first time in the
55
A.I. Graul et al.
Figure 3. The loss of dopamine input into the neostriatum is a key characteristic of Parkinsons disease (PD). although dopamine
replacement therapy using dopamine precursors assuages motor symptoms, their extended use may result in diminished efficacy
and debilitating dyskinesia. an alternative approach is the implementation of nondopaminergic therapy, which entails the modulation of adenosine receptors. adenosine, a neuromodulator, facilitates responses to dopamine and neurotransmitters of motor function/cognition. adenosine a2a receptors are heavily populated within the striatum and directly associated with dopamine D2 receptors, with which they share a reciprocal function, i.e. a2a receptor activation blocks D2 receptor signaling. The suppression of a2a
receptor activity by antagonists such as istradefylline is therefore expected to heighten dopamine-mediated responses in PD.
u.s. for the treatment of chronic obstructive pulmonary

disease (coPD). It is indicated in the u.s. as an inhaled
long-term, once-daily maintenance treatment of airflow
obstruction in patients with coPD, including chronic
bronchitis and/or emphysema. It is also indicated to
reduce exacerbations of coPD in patients with a history
of exacerbations. Data supporting the approval included
findings from a program of nonclinical studies, 52 clinical pharmacology studies in 1,406 patients and 11 clinical
studies in 7,851 patients with coPD. There were four primary coPD studies: two 6-month lung function studies
and two 1-year replicate exacerbation studies. Breo
Ellipta was launched in the u.s., its first coPD market, in
october 2013. The same combination product was also
approved last year in Japan, where it is known as Relvar
Ellipta, for a different respiratory indication: the treat56
ment of bronchial asthma in adults and adolescents

aged 12 years and older in cases where concurrent use of
an inhaled corticosteroid and a long-acting 2-adrenoceptor agonist is required. The product was developed
using a dry powder formulation technology for inhalation products licensed by gsK from skyePharma. In
November, Relvar Ellipta was approved in the E.u. for
both indications: asthma and coPD.
another new combination product for coPD ultibro
(glycopyrronium bromide/indacaterol) was also
approved last september in both the European union
and Japan. ultibro is a first-in-class combination product
containing the laBa indacaterol and the long-acting
muscarinic antagonist (laMa) glycopyrronium bromide,
and is formulated as inhalation capsules for use with the
Breezhaler device. Dual bronchodilation with ultibro is
A.I. Graul et al.
expected to set a new standard of care in coPD, according to product codevelopers Novartis and sosei. coPD is
a progressive disease affecting up to 10% of adults
across Europe and is projected to be the third leading
cause of death by 2020. In addition, 5.3 million patients
are currently living with coPD in Japan. The first product
launches took place in germany and the Netherlands,
with launch in Japan following shortly thereafter.
Olodaterol hydrochloride (striverdi Respimat), a new
long-acting 2-adrenoceptor agonist from Boehringer
Ingelheim, was approved last year in several countries
including Russia, canada, Denmark, Iceland and the
u.K. The laBa was developed as a fast-acting and longlasting bronchodilator for once-daily maintenance treatment of airflow obstruction in patients with coPD,
including chronic bronchitis and emphysema.
Lucinactant (surfaxin; Discovery laboratories), a
humanized, engineered version of natural human lung
surfactant, was launched for the first time in the u.s. in
November 2013. lucinactant is indicated for the prevention of respiratory distress syndrome (RDs) in premature
infants at high risk for RDs. It is the first FDa-approved
synthetic, peptide-containing surfactant and the only
alternative to animal-derived surfactants available in
the u.s.
CARDIOVASCULAR DRUGS
over the course of 2013, partners Bristol-Myers squibb
and Pfizer began rolling out the coagulation factor Xa
inhibitor apixaban (Eliquis) in markets worldwide for a
new indication: the prevention of stroke and systemic
embolism in patients with nonvalvular atrial fibrillation.
The first country in which launch took place was the u.s.
in January 2013, followed later in the year by the u.K. and
Japan. apixaban was first launched in 2011 for the prevention of venous thromboembolic events in adults who have
undergone elective hip or knee replacement surgery.
also in 2013, a new treatment option became available
to Japanese patients with mild to moderate essential
hypertension: Bisono Tape, a once-daily transdermal
patch formulation of the established 1-adrenoceptor
antagonist bisoprolol. Bisono Tape is the first
transdermal patch formulation of a -blocker to reach
the market anywhere in the world. It was codeveloped by
Toa Eiyao and Nitto Denko, and is marketed and distributed by astellas.
shionogis Irtra, a fixed-dose combination antihypertensive agent, was also approved and launched last year
for the first time in Japan. Irtra contains the angiotensin

aT1 receptor antagonist irbesartan and trichlormethiazide, a diuretic, in a single tablet. The combination of a
renin-angiotensin blocker and a low-dose diuretic is recommended in Japanese guidelines for hypertension
therapy, due to their synergistic antihypertensive activity
and favorable side effect profile.
another irbesartan-containing fixed-dose combination
reached its first market last year in Korea: hanmi and
sanofis Robelito, containing irbesartan and atorvastatin calcium, a widely marketed statin. Robelito is indicated to reduce the risk of heart disease in patients with
hypertension and hyperlipidemia who are already prescribed the two active drugs, and was developed to simplify treatment regimens.
The endothelin ETa/ETB antagonist macitentan
(opsumit; actelion) was approved and launched last
year for the first time in the u.s. for the treatment of
adults with pulmonary arterial hypertension (Pah, Who
group I), to delay disease progression. The product carries a boxed warning alerting patients and healthcare
professionals that it should not be used in pregnant
women because it can harm the developing fetus. The
efficacy of macitentan was established in the pivotal
study sERaPhIN (clinicalTrials.gov Identifier
NcT00660179), a randomized, controlled trial involving
742 patients with Pah with predominantly Who functional class II-III symptoms treated for an average of 2
years. In october 2013, the EMas committee for
Medicinal Products for human use issued a positive
opinion on the use of macitentan in Pah.
chronic thromboembolic pulmonary hypertension
(cTEPh) is a progressive and life-threatening type of
pulmonary hypertension in which thromboembolic
occlusion of pulmonary vessels gradually leads to
increased blood pressure in the pulmonary arteries,
resulting in an overload of the right heart. last year the
first-in-class soluble guanylate cyclase stimulator riociguat (adempas; Bayer) was approved and launched
in canada, becoming the first drug ever to obtain regulatory approval for this rare disease (Fig. 4). cTEPh
affects up to several thousand patients in canada. Prior
to the introduction of riociguat, there were no proven
pharmacotherapeutic alternatives for patients with inoperable or persistent cTEPh.
RENALUROLOGIC DRUGS
Vesomni, a new fixed-dose combination product from
astellas incorporating the 1-adrenoceptor antagonist
57
A.I. Graul et al.
Figure 4. Riociguat (also known as BaY-63-2521) is an oral soluble guanylate cyclase (sgc) activator that is expected to be useful
for treating pulmonary arterial hypertension (Pah). By stimulating sgc, the compound promotes the catalyzing of cyclic guanosine
monophosphate (cgMP). Increased cgMP levels result in the inhibition of calcium channels and decreased intracellular calcium
release. activation of cgMP-mediated protein kinase and myosin light chain protein, involved in muscle cell relaxation and vasodilatation, leads to blood vessel dilation, the diminution of blood pressure and the modulation of tissue-protective effects. Thus, gc
activators may be effective in the treatment of Pah and associated disorders such as chronic thromboembolic pulmonary
hypertension.
tamsulosin hydrochloride and solifenacin succinate,

an antimuscarinic, was approved for the first time in May
in the Netherlands and was launched there in september. Vesomni is indicated for the treatment of moderate
to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with
benign prostatic hyperplasia in men who are not adequately responding to treatment with monotherapy. The
Netherlands will act as Reference Member state for further registration of the product throughout Europe.
In November, Plethora solutions holdings received marketing authorization from the European commission
forPrilocaine Lidocaine Plethora (PsD-502), a topical
spray incorporating two local anesthetics, indicated for
the treatment of primary premature ejaculation. The
treatment was associated with significant improvement
58
in the primary measures of intravaginal ejaculation

latency time, control and satisfaction in two pivotal, double-blind, placebo-controlled, phase III studies. It was
also well accepted by subjects in over 23,000 exposures.
Filing with the FDa is anticipated for early 2014, and the
first European launch is expected later in the year.
In December 2013, the u.s. FDa approved the first pharmacotherapeutic agent ever for the treatment of
Peyronies disease: collagenase Clostridium histolyticum (Xiaflex; auxilium), indicated for the treatment of adult men with Peyronies disease with a palpable plaque and curvature deformity of at least 30
degrees at the start of therapy. The safety and efficacy of
Xiaflex were evaluated in the randomized, double-blind,
placebo-controlled phase III IMPREss I and II studies in
subjects with Peyronies disease. Men with the disorder
A.I. Graul et al.
were randomized to receive a maximum of four treatment cycles at 6-week intervals of Xiaflex or placebo
administered by intralesional injection. Men randomized
to the active treatment showed a mean 34% improvement in penile curvature, as compared to 18.2%
improvement in those randomized to placebo. symptom
bother scores also improved to a significantly greater
extent with Xiaflex as compared to placebo (2.8 3.8
vs. 1.8 3.5, respectively). Xiaflex was previously
approved by the FDa in 2010 for the treatment of
Dupuytrens contracture. auxilium immediately began
commercializing the product for this new indication.
In patients with reduced renal function, phosphorus is
not sufficiently excreted into the urine via the kidneys
and accumulates in the body, which can lead to hyperphosphatemia. Persistent hyperphosphatemia causes
secondary hyperparathyroidism and even nephrogenic
osteopathy characterized by bone pain and a tendency
for bone fracture. additionally, phosphorus binds to calcium to form calcium phosphate, which in turn causes
calcinosis on vascular walls, heart, lungs and other internal organs, as well as periarticular areas. Because this
represents an increased risk for cardiovascular disease,
the management of serum phosphate levels in patients
with renal disease is of paramount importance. This goal
became easier last year with the approval of two new
products developed specifically for this purpose.
Mitsubishi Tanabe Pharmas colestilan (BindRen), a
non-absorbed anion exchange resin and phosphate
binder, was approved by the European commission in
February and launched in its first markets germany
and austria in april. colestilan is indicated for the
treatment of hyperphosphatemia in adult patients with
chronic kidney disease (cKD) stage 5 receiving
hemodialysis or peritoneal dialysis. This is a new indication for colestilan, which has been marketed in Japan (as
cholebine) since 1999 for the treatment of hypercholesterolemia.
The iron-based phosphate binder sucroferric oxyhydroxide (Velphoro; Vifor Pharma) was approved by the
FDa in November 2013 for the control of serum phosphorus levels in patients with cKD on dialysis. The
approval was based on a pivotal phase III study which
met both its primary and secondary endpoints. The
study demonstrated that Velphoro successfully controls
hyperphosphatemia with fewer pills (average of 3.3/day)
as compared to sevelamer carbonate, the current standard of care. Velphoro will be launched in the u.s. by
Fresenius in 2014. The product is also under regulatory
review in Europe, switzerland and singapore, where

decisions are expected in the first half of 2014.
HEMATOLOGIC AGENTS
The FDa approved Baxters Rixubis (nonacog gamma,
coagulation factor IX [recombinant]) in June, indicated
for routine prophylactic treatment, control of bleeding
episodes and perioperative management in adults with
hemophilia B. Rixubis is the first new recombinant coagulation factor IX (rFIX) approved for hemophilia B in
more than 15 years and is the only rFIX indicated for both
routine prophylaxis and control of bleeding episodes in
the u.s. for adult patients living with this chronic condition. The approval was based on a phase I/III study
demonstrating that twice-weekly prophylactic treatment
with Rixubis for 6 months achieved a median annualized
bleed rate of 2.0 with 43% of patients experiencing no
bleeds (clinicalTrials.gov Identifier NcT01174446).
Baxter launched the product in the u.s. and Puerto Rico
in october, and shortly thereafter filed for marketing
approval in the European union.
Turoctocog alfa (NovoEight), a recombinant coagulation factor VIII product from Novo Nordisk, was approved
last year by the u.s. FDa for use in adults and children
with hemophilia a. It is indicated for the control and prevention of bleeding, perioperative management, and
routine prophylaxis to prevent or reduce the frequency of
bleeding episodes. awaiting the expiration of existing
patents, Novo Nordisk plans to launch turoctocog alfa in
the u.s. shortly after april 2015. last year the product
also received a positive opinion from the European
Medicines agencys committee for Medicinal Products
for human use.
ENDOCRINE DRUGS
The sodium/glucose cotransporter (sglT), which exists
on the chorionic membrane of the intestine and the kidney, actively transports glucose by coupling with Na+.
The inhibition of renal sglTs leads to suppression of
tubular glucose reabsorption and the excretion of excess
plasma glucose into urine, thereby eliminating hyperglycemia. In persons with diabetes and/or obesity, glucose and energy loss through excretion is advantageous,
as this action can reduce hyperglycemia and glucoserelated osmotic dehydration of cells. Both low-affinity
(sglT2) and high-affinity (sglT1) forms have been studied for this indication, although sglT2 inhibitors in particular are held to be especially promising for the treatment of type 2 diabetes. The first sglT2 inhibitor,
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dapagliflozin, was launched in Europe in 2012 and last

year the second compound in this important new class of
diabetic drugs reached the market: Janssens Invokana
(canagliflozin) was approved by the FDa in March for
the treatment of adults with type 2 diabetes.
canagliflozin is the first sglT2 inhibitor to achieve marketing approval in the u.s., where it has been available
since april 2013.
a new incretin mimetic, the glP-1 receptor agonist
lixisenatide (lyxumia), was approved by the European
commission in February 2013 for use in the 27 member
countries of the E.u. as well as Norway, Iceland and
liechtenstein. It was launched in the u.K., its first market, later in the first quarter. lixisenatide was developed
by sanofi under license from Zealand Pharma. It is indicated for the treatment of adults with type 2 diabetes in
order to achieve glycemic control in combination with
oral glucose-lowering medicinal products and/or basal
insulin when these, together with diet and exercise, do
not provide adequate glycemic control.
Takedas Kazano, a novel fixed-dose combination therapy incorporating the dipeptidyl peptidase 4 (DPP IV)
inhibitor alogliptin benzoate and metformin
hydrochloride, a biguanide insulin sensitizer, was
launched for the first time last year in the u.s. Kazano is
indicated as an adjunct to diet and exercise, to improve
glycemic control in adults with type 2 diabetes mellitus.
The safety and efficacy of the product were demonstrated in 4 clinical trials involving more than 2,500 patients
with type 2 diabetes.
The novel insulin analogue insulin degludec (Tresiba),
a once-daily basal insulin from Novo Nordisk, was
launched last March for the first time in Denmark and
just a few days later in Japan. The new long-acting
insulin is designed for once-daily dosing and has been
shown to lower blood glucose levels, while offering less
risk of hypoglycemia especially at night compared
with insulin glargine. The product is indicated for use as
monotherapy and as part of a combination therapy
for the treatment of type 1 and type 2 diabetes in
adults. Novo Nordisk supplies insulin degludec in its
FlexTouch prefilled disposable pen. It has also been
approved in Mexico.
Two new products reached the market last year and a
third was approved that will help to ease the transition
through menopause for the growing global population
of aging women. The first, ospemifene (osphena;
shionogi), is a selective estrogen receptor modulator
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(sERM) that was approved and launched in the u.s. for

the treatment of moderate to severe dyspareunia, a
symptom of vulvar and vaginal atrophy (VVa), due to
menopause. More than half of u.s. women will experience VVa at some point during their postmenopausal
life, although the vast majority of them do not receive
treatment. ospemifene is the first and only oral alternative to vaginal or oral steroidal estrogens for women with
dyspareunia due to menopause. Its safety and effectiveness were established in 3 clinical studies of 1,889 postmenopausal women with symptoms of VVa. after 12
weeks of treatment, results from the first two trials
showed a statistically significant improvement of dyspareunia in ospemifene-treated women compared with
those receiving placebo. Results from the third study
support the products long-term safety in treating dyspareunia. osphena carries a boxed warning alerting
women and healthcare professionals that the drug,
which acts like estrogen on vaginal tissues, can stimulate
the lining of the uterus and cause it to thicken. Women
should see their healthcare professional if they experience any unusual bleeding as it may be a sign of
endometrial cancer or a condition that can lead to it. The
boxed warning also states the incidence rates of thrombotic and hemorrhagic strokes (0.72 and 1.45 per thousand women, respectively) and the incidence rate of
deep vein thrombosis (1.45 per thousand women). These
rates are considered to represent low risks in contrast to
the increased risks of stroke and deep vein thrombosis
seen with estrogen-alone therapy. however, ospemifene
should be prescribed for the shortest duration consistent
with treatment goals and risks for the individual woman.
shionogi obtained exclusive global marketing rights to
the sERM under a license agreement signed with
QuatRx Pharmaceuticals in 2010.
Brisdelle, a new low-dose formulation of the selective
serotonin reuptake inhibitor (ssRI) paroxetine mesilate,
was approved and launched last year in the u.s. as the
first nonhormonal therapy for vasomotor symptoms
(VMs) associated with menopause. The product was
developed by Noven Pharmaceuticals to treat hot flashes
and night sweats associated with menopause. Many
women are unable or unwilling to take hormone therapy
to treat VMs, often leaving symptoms untreated. In phase
II and III studies enrolling a total of 1,276 women with VMs
associated with menopause, treatment with paroxetine
mesilate for 24 weeks led to reductions in the frequency
and severity of moderate to severe hot flashes, with a
favorable safety profile. Paroxetine mesilate has been
marketed since 2001 for the treatment of depression.
A.I. Graul et al.
In october, Pfizers fixed-dose combination product

Duavee (conjugated estrogens/bazedoxifene) was
approved in the u.s. It is indicated, in women with a
uterus, for the treatment of moderate to severe vasomotor symptoms associated with menopause and for the
prevention of postmenopausal osteoporosis. Duavee is
the first FDa-approved medication that contains an
estrogen in combination with a sERM, bazedoxifene.
The sERM component reduces the risk of endometrial
hyperplasia that can occur with the estrogen component. Duavee was originally developed at Wyeth (now
Pfizer), and was subject to a joint research, discovery and
development agreement signed with ligand in
september 1994. Pfizer plans to introduce Duavee in
February 2014.
DERMATOLOGIC DRUGS
In august 2013, the FDa approved galdermas Mirvaso
(brimonidine tartrate), the first topical treatment
specifically developed and indicated for the treatment of
facial erythema of rosacea. Erythema (redness) is a common symptom of rosacea, but until now there were no
approved drugs to treat it. applied once daily, Mirvaso
works quickly to reduce the redness of rosacea and lasts
for up to 12 hours. Brimonidine, an 2-adrenoceptor agonist and vasoconstrictor, has been marketed for many
years as an ocular formulation for the treatment of glaucoma and ocular hypertension. galderma launched
Mirvaso in september.
also in august, Biocon launched alzumab (itolizumab), a first-in-class humanized monoclonal antibody
directed against the T-cell differentiation antigen cD6, in
India. cD6 is a pan T-cell marker involved in costimulation, adhesion and maturation of T cells, which play a
leading role in autoimmune disease (Fig. 5). By binding
to cD6, itolizumab downregulates T-cell activation,
decreases the synthesis of proinflammatory cytokines
and may reduce T-cell infiltration at sites of inflammation. Based on the results of a 52-week phase III trial
conducted in India, itolizumab was approved by the
Drugs controller general of India for the treatment of
moderate to severe chronic plaque psoriasis.
GASTROINTESTINAL AGENTS
The gastroprokinetic agent acotiamide hydrochloride
hydrate (acofide), a peripheral acetylcholinesterase
(achE) inhibitor, was approved and launched last year
for the first time in Japan, where it is indicated for the
treatment of functional dyspepsia. acetylcholine is an
important neurotransmitter for regulating gastrointestinal motility. By blocking achE and inhibiting the degradation of acetylcholine, acotiamide improves impaired
gastrointestinal motility and delayed gastric emptying,
and thus improves symptoms of functional dyspepsia
such as postprandial fullness, upper abdominal bloating
and early satiation. acotiamide is the first agent
approved for use in patients with functional dyspepsia
diagnosed according to Rome III diagnostic criteria. The
product was discovered by Zeria and was licensed exclusively to astellas for codevelopment and marketing.
Janssen Biotechs golimumab (simponi) was approved
and launched last year in the united states for a new
indication: the treatment of moderately to severely active
ulcerative colitis in adults who have demonstrated corticosteroid dependence or who have had an inadequate
response to or failed to tolerate oral aminosalicylates,
oral corticosteroids, azathioprine or 6-mercaptopurine.
In addition, the drug is also indicated to induce clinical
remission and achieve and sustain clinical remission in
induction responders. golimumab is a human monoclonal antibody that targets and neutralizes excess TNF-.
It is also approved for use with methotrexate for the
treatment of moderately to severely active rheumatoid
arthritis, active psoriatic arthritis alone or with
methotrexate, and active ankylosing spondylitis.
The u.s. was the site of the first launch last year of
Fulyzaq (crofelemer) delayed-release tablets, approved by the FDa for the symptomatic relief of noninfectious diarrhea in patients with hIV/aIDs on antiretroviral therapy (aRT). crofelemer is derived on a
sustainable basis from the Croton lechleri plant. It is
believed to improve hIV-associated diarrhea via a dual
mechanism of action, i.e., inhibition of both the cystic
fibrosis transmembrane conductance regulator (cFTR)
and the calcium-activated chloride channel (cacc),
resulting in reduced chloride ion secretion into the gastrointestinal lumen. FDa approval was based on a randomized, double-blind, placebo-controlled (1-month)
and placebo-free (5-month), multicenter study in 374
hIV-positive patients on aRT, with a history of diarrhea
for 1 month or more (clinicalTrials.gov Identifier
NcT00547898). The primary efficacy endpoint was the
proportion of patients experiencing two watery bowel
movements or less per week during at least 2 of the 4
weeks of the placebo-controlled phase of the study.
Patients who received concomitant antidiarrheal medications or opiates were counted as clinical nonresponders. Data demonstrated that a significantly larger pro61
A.I. Graul et al.
Figure 5. Itolizumab is a humanized Igg1 immunosuppressive monoclonal antibody that selectively inhibits the cell surface receptor cD6 and is predicted to be useful in the therapeutic intervention of chronic plaque psoriasis. The antibody binds to cD6, which
in turn binds to its ligand cD166, resulting in the suppression of T-cell activation and reduced proinflammatory cytokine production.
It may additionally offset T-cell infiltration at sites of inflammation.
portion of patients taking crofelemer 125 mg twice daily

experienced a clinical response compared with patients
in the placebo group. In addition, statistically significant
reductions from baseline to the end of the double-blind
period were also observed for the number of watery
bowel movements per day and daily stool consistency
score among patients taking crofelemer compared with
placebo. Furthermore, the crofelemer treatment effect
for clinical response (125 mg twice daily vs. placebo) was
similar in subgroup analyses based on duration of diarrhea, baseline number of daily watery bowel movements, use of protease inhibitors and cD4 cell count.
The most common adverse reactions in the study were
respiratory tract infection, bronchitis, cough, flatulence
and increased bilirubin. crofelemer did not influence the
efficacy or safety of the patients hIV medications. The
drug is distributed in the u.s. by salix Pharmaceuticals
under license from Napo Pharmaceuticals.
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NPs Pharmaceuticals teduglutide [rDNA origin]

(gattex) was launched for the first time last year in the
u.s. as a treatment for adult patients with short bowel
syndrome (sBs). Teduglutide has orphan drug status for
the indication of sBs. This highly disabling condition
typically develops following surgical resection of the
bowel due to crohns disease, ischemia or other conditions, and can lead to serious life-threatening complications. Patients with sBs often suffer from malnutrition,
severe diarrhea, dehydration, fatigue, osteopenia and
weight loss due to the reduced intestinal capacity to
absorb nutrients, water and electrolytes. Teduglutide is a
recombinant analogue of human glucagon-like peptide
2 (glP-2), a naturally occurring protein involved in the
rehabilitation of the intestinal lining.
last summer, Entera health launched its oral serumderived bovine immunoglobulin protein isolate
EnteraGam, a prescription medical food product.
A.I. Graul et al.
Enteragam is indicated for the clinical dietary management of enteropathy under medical supervision for
patients who, because of therapeutic or chronic medical
needs, have limited or impaired capacity to ingest,
digest, absorb or metabolize ordinary foodstuffs or certain nutrients, or who have chronic loose or frequent
stools (e.g., diarrhea-predominant irritable bowel syndrome [IBs-D]), and in patients with chronic loose or frequent stools who are infected with hIV. Enteragam, a
serum-derived bovine immunoglobulin/protein isolate
(sBI), has been shown in clinical studies in diverse disorders to improve gastrointestinal nutrient absorption, as
well as manage immune function and mucosal barrier
function in the intestine.
ANTI-INFECTIVE THERAPY
In august the FDa approved ViiV healthcares Tivicay
(dolutegravir) for use in combination with other antiretroviral agents for the treatment of hIV-1 in adults and
children aged 12 years and older, weighing at least 40
kg. Dolutegravir is an integrase inhibitor that blocks hIV
replication by preventing the viral DNa from integrating
into the genetic material of human immune cells. The
approval was supported by data from 4 pivotal phase III
trials enrolling 2,557 adults with hIV, 2 of which
(sPRINg-2 and sINglE; clinicalTrials.gov Identifiers
NcT01227824 and NcT01231516) included treatmentnaive patients. The sPRINg-2 trial compared a oncedaily dolutegravir-based regimen to twice-daily raltegravir, while sINglE evaluated once-daily dolutegravir
and abacavir/lamivudine compared to once-daily
atripla (efavirenz/emtricitabine/tenofovir disoproxil
fumarate). another trial, called saIlINg (clinicalTrials.gov
Identifier NcT01263015) compared a once-daily dolutegravir-based regimen to twice-daily raltegravir in treatment-experienced patients who had not previously been
treated with an integrase inhibitor. Finally, the fourth
trial, which was called VIKINg-3 (clinicalTrials.gov
Identifier NcT01328041), assessed the effectiveness of
twice-daily dolutegravir on viral load in treatment-experienced patients with resistance to multiple classes of
hIV medicines, including resistance to integrase
inhibitors. Dolutegravir was launched in the u.s. shortly
after approval. In october, ViiV filed marketing applications in the u.s. and E.u. for a single-tablet formulation
incorporating dolutegravir, abacavir and lamivudine.
another hIV integrase inhibitor, gileads elvitegravir
(Vitekta), was approved in the E.u. in November. It is
indicated for the treatment of hIV-1 infection in adults
without known mutations associated with resistance to

elvitegravir, as part of hIV treatment regimens that
include a ritonavir-boosted protease inhibitor. In clinical
trials, elvitegravir was effective in suppressing hIV
among patients with drug-resistant strains of hIV. gilead
is currently working with regulatory authorities throughout the European union to bring Vitekta to patients as
quickly as possible. Elvitegravir is also a component of
gileads stribild (elvitegravir 150 mg/cobicistat 150
mg/emtricitabine 200 mg/tenofovir disoproxil fumarate
300 mg), a once-daily single tablet regimen for hIV that
was approved in the united states in august 2012 for
treatment-naive adults and by the European
commission in May 2013 for adults who are treatmentnaive or who have no known mutations associated with
resistance to any of the three antiretroviral agents contained in the combination product.
During the third quarter, gilead received marketing
authorization from theEuropean commissionfor oncedaily cobicistat (Tybost), a cytochrome P450 3a4
inhibitor and pharmacokinetic enhancer that increases
blood levels of certain hIV medicines. Tybost is indicated
as a boosting agent for the hIV protease inhibitors
atazanavir 300 mg once daily and darunavir 800 mg
once daily as part of antiretroviral combination therapy
in adults with hIV-1 infection. This approval allows for the
marketing of Tybost in all 28 countries of theEuropean
union. like elvitegravir, cobicistat was approved in 2012
as a component of the combination product stribild;
however, it was not approved as a single agent until
2013. In the u.s., gilead submitted an NDa to the FDa
for cobicistat as a single agent in June 2012 and received
a complete Response letter in april 2013. The company
is currently working on resubmitting the application to
the FDa.
Simeprevir is an Ns3/4a protease inhibitor jointly developed by Janssen and Medivir for the treatment of genotype 1 and 4 chronic hepatitis c in adult patients with
compensated liver disease, including all stages of liver
fibrosis. simeprevir works by blocking the protease
enzyme that enables the hepatitis c virus (hcV) to replicate in host cells. last september it was approved for the
first time in Japan. The following month, the FDas
antiviral Drugs advisory committee voted 19 to 0 to recommend approval of simeprevir, administered once daily
with pegylated interferon and ribavirin, for the treatment
of genotype 1 chronic hepatitis c in adult patients with
compensated liver disease, including cirrhosis. In
November, it was approved in both the u.s. and canada,
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and in December the product was launched in its first

markets: Japan (as sovriad) and the u.s. (as olysio).
hepatitis replicase, the RNa-dependent RNa polymerase encoded by Ns5B, is essential for hcV replication. This enzyme synthesizes viral RNa using an RNa
template, a virus-specific biochemical activity that has
not been observed in mammalian cells (Fig. 6). The
Ns5B enzyme is targeted by both nucleoside inhibitors,
which bind to the active catalytic site, and by nonnucleoside inhibitors, which bind to one of several allosteric
binding sites on the hcV polymerase. In December 2013,
the u.s. FDa approved sofosbuvir (sovaldi; gilead), a
first-in-class nucleoside analogue Ns5B inhibitor, indicated for the treatment of hcV infection as a component
of a combination antiviral treatment regimen. sofosbuvir
can be used in combination with ribavirin or peginterferon alfa/ribavirin, but should not be used as monotherapy. The product, which has FDa Breakthrough Therapy
Designation, was launched in the u.s. in December.
A.I. Graul et al.
Tuberculosis (TB) is a major public health concern

around the world, particularly due to the emergence in
recent years of multidrug-resistant (MDR) strains. Thus
the development of several new classes of antituberculosis drugs has been regarded with great interest and
has begun to bear fruit. In the last days of 2012, the u.s.
FDa granted accelerated approval to Janssen
Therapeutics for bedaquiline (sirturo), indicated as
part of combination therapy, to treat adults (18 years or
older) with MDR-TB when other alternatives are not
available. Bedaquiline, the first new TB drug in 40 years,
is the first targeted inhibitor of proton-translocating aTP
synthetase (F0F1 aTPase), the enzyme required by
Mycobacterium tuberculosis to replicate and spread
through the body (Fig. 7). Janssen launched bedaquiline
in the u.s., its first market, in april 2013. In June, the
World health organization (Who) issued interim policy
guidance on the use of bedaquiline in the treatment of
MDR-TB. The interim guidance was developed using lim-
Figure 6. sofosbuvir, a chirally pure isomeric form of PsI-7851, acts as an RNa-directed RNa polymerase (Ns5B) inhibitor and is
expected to be useful for treating chronic hepatitis c virus (hcV) infection. It functions by suppressing the RNa polymerase that hcV
utilizes to facilitate the replication of its RNa. The drug has demonstrated efficacy in subjects with hcV genotype 1, 2, 3 or 4 infection and hepatocellular carcinoma (awaiting liver transplantation), as well as those with hcV/hIV-1 co-infection.
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ited evidence available from clinical trials; the FDas

accelerated approval of the drug was based on two
phase IIb trials. The guideline thus lists five conditions
that must be in place if bedaquiline is used in combination therapy to treat adults with MDR-TB: effective treatment and monitoring; proper patient inclusion (caution
is required when bedaquiline is used in people aged 65
and over and in adults with hIV); informed consent;
adherence to Who recommendations on MDR-TB treatment regimens; and active pharmacovigilance and management of adverse events. The Who strongly recommended the acceleration of phase III trials to generate a
more comprehensive evidence base to inform future policy on bedaquiline. The organization will review, revise or
update the interim guidance as additional information
on efficacy and safety becomes available.
In December 2012, the u.s. FDa approved the first
anthrax antitoxin, raxibacumab, indicated for the treatment of adult and pediatric patients with inhalational
anthrax due to Bacillus anthracis in combination with

appropriate antibacterial drugs and for the prophylaxis
of inhalational anthrax when alternative therapies are
not available or are not appropriate. Raxibacumab is a
monoclonal antibody that neutralizes toxins produced
by B. anthracis that can cause massive and irreversible
tissue injury and death (Fig. 8). Raxibacumab is the first
monoclonal antibody approved under the FDas animal
Efficacy Rule. In this case, because inhalational anthrax
is a rare and lethal disease, it was not possible to conduct adequate efficacy trials in humans, and the agents
effectiveness was therefore demonstrated in one study in
monkeys and three studies in rabbits. The safety of raxibacumab was evaluated in 326 healthy human volunteers. Raxibacumab was developed by human genome
sciences (hgs) in conjunction with the u.s. Department
of health and human services Biomedical advanced
Research and Development authority. hgs was
acquired by gsK in august 2012, and gsK began mar-
Figure 7. Bedaquiline (also designated TMc-207) is a diarylquinoline that acts as a mycobacterial F0-F1 aTP synthase inhibitor and
is reported to be effective against both drug-susceptible and multidrug-resistant strains of Mycobacterium tuberculosis. The enzyme
aTP synthase is essential for aTP synthesis and energy metabolism. Inhibition of the enzyme is expected to result in the depletion
of aTP, which consequently diminishes the chances of pathogen survival. Bedaquiline is thus expected to be a potent treatment
option for tuberculosis.
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keting the monoclonal antibody to the u.s. government

in 2013. In september, gsK announced a new contract
with the u.s. government, under which gsK will provide
60,000 doses to the national stockpile over a period of 4
years.
last year the triazole antifungal agent efinaconazole
(Jublia; Valeant) was approved for the first time in
canada, where it is indicated for the treatment of mild to
moderate onychomycosis. This common and destructive
fungal nail infection is unusually difficult to treat. oral
treatments are limited by drug interactions and numerous safety concerns, including the potential for acute
liver injury. laser treatments only improve the appearance of the nail. Pivotal international studies of efinaconazole were conducted in 1,655 subjects with onychomycosis, including subjects in canada. For the
pivotal studies, the primary endpoint was complete cure
at week 52, which required that the target nail show no
A.I. Graul et al.
clinical involvement and no evidence of fungus present

by both Koh testing and a negative fungal culture. In
study 1, 17.8% of subjects treated with efinaconazole
were completely cured, compared to only 3.3% of subjects treated with vehicle. In study 2, 15.2% of subjects
treated with efinaconazolewere completely cured, compared to only 5.5% of subjects treated with vehicle.
Valeant has not yet set a launch date for the product.
THERAPY OF MUSCULOSKELETAL & CONNECTIVE
TISSUE DISEASES
The anti-interleukin-1 (Il-1) human monoclonal antibody canakinumab (Ilaris; Novartis), marketed since
2009 for the treatment of cryopyrin-associated periodic
syndromes, was approved and launched last year for two
new indications. In March it was approved in the E.u. for
the treatment of adult patients with frequent gouty
arthritis attacks in whom NsaIDs and colchicine are con-
Figure 8. Raxibacumab is a human monoclonal antibody that is directed against the Bacillus anthracis protective antigen component (Pac) and is thus predicted to have utility in the therapeutic intervention of anthrax infection. The antibody acts by preventing
the Pac from binding to cell surfaces, thereby blocking the fatal entry of anthrax toxins into cells. In several animal models, the drug
has demonstrated effectiveness in protecting against death induced by anthrax spore inhalation.
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A.I. Graul et al.
traindicated, are not tolerated, or do not provide adequate response, and in whom repeated courses of corticosteroids are not appropriate. It was rolled out for this
indication in germany and greece later in the year. In the
month of May, canakinumab was approved in the u.s.
for the treatment of active systemic juvenile idiopathic
arthritis (sJIa) in patients aged 2 years and older.
canakinumab became available for u.s. patients with
sJIa during the second quarter.
In september, the FDa approved ucBs cimzia
(certolizumab pegol) for the treatment of adult
patients with active psoriatic arthritis. The approval was
based on data from the RaPID-Psa study, an ongoing,
multicenter, randomized, double-blind, placebocontrolled phase III trial designed to evaluate the
efficacy and safety of certolizumab pegol in 409 patients
with active and progressive adult-onset psoriatic
arthritis (clinicalTrials.gov Identifier NcT01087788).
ucB immediately began marketing certolizumab in the
u.s. for the psoriatic arthritis indication. shortly thereafter, the company also obtained FDa approval for
another new indication for certolizumab pegol: the treatment of adults with active ankylosing spondylitis. In
october, the European commission approved the
product for the treatment of adult patients with severe
active axial spondyloarthritis, comprising adults with
severe active ankylosing spondylitis who have had an
inadequate response to or are intolerant to NsaIDs and
adults with severe active axial spondyloarthritis without
radiographic evidence of ankylosing spondyloarthritis
but with objective signs of inflammation by elevated
cRP and/or MRI, who have had an inadequate response
to or are intolerant to NsaIDs. In addition to these three
new indications, cimzia has been available since 2008
for the treatment of crohns disease and since 2009 for
rheumatoid arthritis.
In June 2013, the FDa approved a new indication for
denosumab (amgens Xgeva) for the treatment of
adults and skeletally mature adolescents with giant cell
tumor of bone (gcTB) that is unresectable or where surgical resection is likely to result in severe morbidity.
gcTB is a rare and usually noncancerous tumor that
destroys normal bone as it grows, resulting in pain, limited range of motion and bone fractures. approval of
denosumab, following a priority review, was based on
encouraging results from 2 open-label trials that
enrolled a total of 305 patients with gcTB that was
either recurrent, unresectable, or for which planned surgery was likely to result in severe morbidity. The overall
objective response rate of the 187 patients evaluated was

25%. The estimated median time to response was 3
months. In the 47 patients with an objective response,
51% (24/47) had a duration of response of at least 8
months. Three patients experienced disease progression
following an objective response. The safety profile of
denosumab in patients with gcTB was similar to that
reported in studies of patients with bone metastases,
and also appeared to be similar in skeletally mature adolescents and adults. safety data was evaluated in 304
patients with gcTB who received at least 1 dose of denosumab. of these patients, 145 were treated for at least 1
year. The most common adverse reactions were arthralgia, headache, nausea, back pain, fatigue and pain in the
extremity. The most common serious adverse reactions
were osteonecrosis of the jaw and osteomyelitis. Xgeva,
a monoclonal antibody that binds to TNF ligand superfamily member 11 (RaNKl), has orphan drug designation
for gcTB; amgen began marketing it for the new indication immediately upon receipt of approval. Denosumab
has been available for several years for the treatment of
skeletal-related events in patients with bone metastases
from solid tumors.
IMMUNOMODULATORS & AGENTS FOR
IMMUNIZATION
In late 2012, the FDa approved swedish orphan
Biovitrum (sobi)s Kineret (anakinra) for the treatment
of children and adults with neonatal-onset multisystem
inflammatory disease (NoMID), the most severe form of
cryopyrin-associated periodic syndromes (caPs). This
was the first approval allowing the use of the product in
children. Kineret was approved under an orphan drug
designation and an FDa priority review. anakinra is a
recombinant form of the Il-1 receptor antagonist protein
that blocks the biological activity of Il-1 by binding to Il1 receptor type 1. anakinra was discovered and developed by amgen, and has been approved for the reduction of signs and symptoms of rheumatoid arthritis in
adults since 2001. In 2013, sobi acquired the product
from amgen for development and commercialization
worldwide. sobi began marketing anakinra for the new
indication during the second quarter of 2013.
In February, Biotest Pharmaceuticals announced the
u.s. launch of Bivigam (immune globulin intravenous
[human]) 10% liquid. Bivigam is a sugar-free, glycine
stabilized intravenous immune globulin approved by the
FDa for use in patients with primary humoral immunodeficiency. This includes, but is not limited to, the
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humoral immune defect in common variable immunodeficiency (cVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-aldrich syndrome and severe combined immunodeficiencies.
In May, the European commission granted Baxter marketing authorization in all E.u. member states for the use
of HyQvia (hyQ, Ighy, solution for subcutaneous use) as
a replacement therapy for adult patients with primary
and secondary immunodeficiencies. The product is a
new combination incorporating human normal immunoglobulin (Igsc, 10%) and recombinant human hyaluronidase, which facilitates the dispersion and absorption of
the Igsc. The application was based on results from a
prospective, open-label, non-controlled, multicenter
phase III trial (clinicalTrials.gov Identifier NcT00814320)
that evaluated the safety and effectiveness of hyQvia in
the prevention of acute serious bacterial infections, and
the pharmacokinetic parameters compared to immunoglobulin administered intravenously. The rate of validated acute serious bacterial infections in the study was
0.025 per patient per year, which is below the required
efficacy threshold of 1.0. In the tolerability assessment of
hyQvia, the most frequently reported adverse reactions
were infusion site reactions, headache, fatigue and
pyrexia. Baxter launched hyQvia in germany, its first
market, in July 2013.
2013 was an active year for vaccines, with five new
influenza vaccines reaching the market and the first
approval worldwide of the first vaccine for MenB disease,
in addition to other new immunizing agents.
In the area of influenza vaccines, the novelty was the
introduction for the first time in 2013 of quadrivalent vaccines. Influenza vaccines have traditionally employed
two influenza a strains plus one of two possible influenza B strains. In 2012, the u.s. FDa approved the first
quadrivalent influenza vaccine, FluMist Quadrivalent
(MedImmune), which contains both B strains and was
designed to take the guesswork out of the B component.
This and three other new quadrivalent vaccines
(glaxosmithKlines Fluarix Quadrivalent and
FluLaval Quadrivalent and sanofi Pasteurs Fluzone
Quadrivalent) were all launched in the u.s. in time for
the 2013-2014 flu season. In December 2013, the
MedImmune intranasal vaccine was approved in the E.u.
as FluenzTM Tetra. It will replace the Fluenz trivalent vaccine from the 2014-2015 flu season onwards.
another drawback of traditional influenza vaccines is
their method of production, which involves the genera68
A.I. Graul et al.
tion of viral strains in embryonated chicken eggs. This

technology is complex, antiquated and inefficient, and is
plagued with various drawbacks, most significantly the
time required to produce sufficient amounts of the vaccine. In January, the u.s. FDa approved Flublok
(Protein sciences), the first trivalent influenza vaccine
made using an insect virus (baculovirus) expression system and recombinant DNa technology. This novel vaccine does not use the influenza virus or eggs in its production. Flublok was launched in the u.s. in February
2013.
Jenvac, a Vero cell-derived purified inactivated Japanese encephalitis (JE) vaccine from Bharat Biotech, was
launched last year in India. The vaccine is based on a JE
strain isolated in Kolar, Karnataka during the early 1980s
that is purified and inactivated using the companys
advanced bioreactor technology. In clinical trials, Jenvac
showed superior safety and immunogenicity as compared to the live sa14-14-2 vaccine. In addition to reducing disease burden, Jenvac will decrease Indias reliance
on imported JE vaccines. approximately 50,000 cases of
JE are reported each year in asia although the disease
is known to be vastly underreported, making it the
leading cause of viral encephalitis in the region.
another new vaccine from Bharat Biotech, the typhoid
conjugate vaccine Typbar-TcV, was also approved and
launched last year in India. The fourth-generation vaccine was designed to overcome two important limitations of previous vaccines: the lack of long-term protection and efficacy in children under the age of 2 years. In
studies involving approximately 1,200 healthy volunteers, Tpybar-TcV induced seroconversion in 98% of
infants aged 6-24 months and in 99% of children aged
2-15 years; it also induced seroconversion in 92% of
those aged 15-45 years. seroconversion was defined as a
four-fold increase in serum Igg responses. The vaccine
was safe and well tolerated in all age groups tested.
Typhoid fever causes between 250,000 and 600,000
deaths and more than 20 million illnesses each year.
according to the Who, 90% of these deaths occur in
asia, mainly in children under 5 years of age.
Meningococcal disease is a leading cause of bacterial
meningitis. Five main groups of meningococcal bacteria
(a, B, c, W-135 and Y) cause the majority of all cases
around the world. In the past, vaccines were available to
help protect against a, c, W-135 and Y, but not against
disease caused by meningococcal B (MenB) bacteria.
MenB is a potentially deadly disease which is easily misdiagnosed and can kill within 24 hours of onset. about 1
A.I. Graul et al.
in 10 of those who contract the disease will die despite

appropriate treatment. The approval of Novartiss
Bexsero (meningococcal group B vaccine [rDNA,
component, adsorbed]) in the E.u. in January 2013 and
in australia in august thus represents a significant
development. The vaccine is indicated for active immunization against invasive disease caused by Neisseria
meningitidis serogroup B strains and can be used in
infants as young as 2 months. Novartis launched
Bexsero in the u.K., germany and Ireland during the
fourth quarter of 2013.
also approved and launched last year was
glaxosmithKlines Menhibrix (meningococcal groups
C and Y and Haemophilus b tetanus toxoid conjugate
vaccine). The conjugate vaccine was approved by the
u.s. FDa for use in children aged 6 weeks through 18
months, to protect against invasive disease caused by N.
meningitidis serogroups c and Y and Haemophilus
influenzae type b. N. meningitidis serogroups B, c and Y
are responsible for most cases of meningitis in the u.s.
hexyon, a new combination DTaP-IPV-Hib-HepB vaccine from sanofi Pasteur, was approved in the E.u. in
april 2013 and launched in germany, its first market, in
July. The vaccine is indicated for primary and booster
vaccination of infants from 6 weeks of age against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and
invasive infections caused by H. influenzae type b. It is the
first and only fully liquid, ready-to-use, 6-in-1 pediatric
vaccine, reducing the number of injections and vaccination visits required for appropriate immunization of
infants.
In august, the European commission granted marketing
authorization for Bavarian Nordics third-generation
smallpox vaccine Imvanex, indicated for active immunization against smallpox disease for the general adult
population, including people with weakened immune
systems (people diagnosed with hIV or atopic dermatitis). The authorization includes all 27 European union
member states, as well as Iceland, liechtenstein and
Norway. The vaccine was also approved (as Imvamune)
in canada in November. In the u.s., the smallpox vaccine
is being developed and supplied for emergency use to
the u.s. strategic National stockpile under a contract
with the u.s. government.
TREATMENT OF CANCER
Trastuzumab emtansine (Kadcyla; Roche), a novel
antibodydrug conjugate incorporating the anti-hER2
antibody trastuzumab and the antimitotic agent DM1

joined together via a stable linker, was approved by the
FDa in February 2013 and launched later that quarter.
Trastuzumab emtansine is indicated as a single agent for
the treatment of patients with hER2-positive metastatic
breast cancer who previously received trastuzumab and
a taxane, separately or in combination. Patients should
have either received prior therapy for metastatic disease,
or developed disease recurrence during or within 6
months of completing adjuvant therapy. The antibody
drug conjugate was approved in september in Japan,
where it will be marketed by chugai, for the treatment of
receptor tyrosine-protein kinase erbB-2 (hER2)-positive
inoperable or recurrent breast cancer. It was also
approved in November by the European commission,
indicated as a single agent for the treatment of adults
with hER2-positive, unresectable locally advanced or
metastatic breast cancer who previously received
trastuzumab and a taxane, separately or in combination.
The Raf kinase B inhibitor dabrafenib mesilate (Tafinlar;
glaxosmithKline) was approved by the u.s. FDa in May
2013 for the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600E
mutation as detected by an FDa-approved test. on the
same day, the FDa also approved the mitogen-activated
protein (MaP) kinase kinase (MEK1/MEK2) inhibitor
trametinib dimethyl sulfoxide (Mekinist; glaxosmithKline) for the treatment of adult patients with
unresectable or metastatic melanoma with BRAF V600E
and V600K mutations as detected by an FDa-approved
test. The FDa also granted premarket approval for
bioMrieuxs companion diagnostic ThxID-BRaF,
which is able to determine whether a patient has either
of these mutations in the BRAF gene. among patients
with metastatic melanoma, approximately half have a
BRAF mutation; of those with BRAF V600 mutations,
approximately 85% have V600E and approximately 10%
have V600K mutations. Tafinlar and Mekinist were
launched by gsK shortly after approval.
In July 2013, the u.s. FDa approved Boehringer
Ingelheims afatinib (gilotrif) as a first-line treatment
for patients with metastatic non-small cell lung cancer
(Nsclc) with common epidermal growth factor receptor
(EGFR) mutations as detected by an FDa-approved test.
Boehringer Ingelheim worked in collaboration with
Qiagen to develop the companion diagnostic test,
therascreen EGFR RgQ PcR Kit. among patients with
Nsclc, between 10 and 15% of caucasians and approximately 40% of asians have EGFR mutations. The two
69
most common mutations, Del19 and l858R, account for

90% of all EGFR mutations in Nsclc. afatinib is an orally active kinase inhibitor that is designed to bind and irreversibly inhibit EgFR (c-ErbB-1), hER2 (c-ErbB-2) and
c-ErbB-4 receptors. Its efficacy was demonstrated in the
luX-lung 3 trial, one of the largest phase III trials ever
conducted in the setting of first-line EGFR mutationpositive, locally advanced or metastatic Nsclc. among
patients treated with afatinib in this study, the median
progression-free survival was 11.1 months, versus 6.9
months for those treated with pemetrexed and cisplatin.
among afatinib-treated patients who had the most common EGFR mutations (Del19 and l858R), median progression-free survival was 13.6 months. afatinib was
launched in the u.s., where it has orphan drug status for
the approved indication, in september 2013.
another targeted therapeutic also reached its first
market last year: Exelixiss cabozantinib S-malate
(cometriq), launched in the u.s. in January. The drug is
an inhibitor of multiple receptor tyrosine kinases, including Ret, Met, VEgFR-1, -2 and -3, Trk-B, FlT-3, aXl and
TIE-2, which are involved in both normal cellular function and pathological processes such as oncogenesis,
metastasis, angiogenesis and maintenance of the tumor
microenvironment. It is indicated for the treatment of
progressive, metastatic medullary thyroid cancer, and
has orphan drug status for this indication.
In December 2012, the multikinase inhibitor ponatinib
(Iclusig; ariad Pharmaceuticals) was approved by the
FDa. It is indicated for the treatment of adult patients
with chronic, accelerated or blast phase Philadelphia
chromosome-positive (Ph+) chronic myelogenous leukemia (cMl) that is resistant or intolerant to prior tyrosine
kinase inhibitor (TKI) therapy. Ponatinib was also
approved for the treatment of Ph+ acute lymphoblastic
leukemia (all) that is resistant or intolerant to prior TKI
therapy. Ponatinib has orphan drug status for both indications, and was launched in the u.s., its first market, in
January 2013. however later in the year, on the basis of
increasingly frequent postmarketing reports of serious
and life-threatening blood clots and severe narrowing of
blood vessels in patients treated with the drug, the FDa
requested that ariad suspend marketing of ponatinib.
The company complied with this request and is now
working with the agency to resume marketing of the
drug, pending updates to the products prescribing information and implementation of a risk mitigation strategy.
The antimitotic agent sphingosomal vincristine
(Marqibo; spectrum Pharmaceuticals) was launched
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A.I. Graul et al.
for the first time last september, more than a year after
receipt of marketing approval. Discovered and developed by Talon Therapeutics, Marqibo was approved in
the u.s. in august 2012 for the treatment of adult
patients with Philadelphia chromosome-negative (Ph)
all in second or greater relapse or whose disease has
progressed following two or more antileukemia therapies. Talon and its product portfolio were acquired by
spectrum Pharmaceuticals in July 2013; spectrum
launched Marqibo shortly thereafter.
Obinutuzumab is a new monoclonal antibody designed
to bind to cD20, a protein found only on B cells. It
attacks targeted cells both directly and by working in
conjunction with the bodys immune system. on the
basis of the significance of positive progression-free survival results in phase III trials and the seriousness and
life-threatening nature of the disease it is designed to
treat, the FDa granted obinutuzumab Breakthrough
Therapy Designation in May 2013 and priority review status in July. In November 2013, obinutuzumab (gazyva;
Roche) was approved and launched in the u.s., indicated in combination with chlorambucil chemotherapy for
the treatment of patients with previously untreated
chronic lymphocytic leukemia (cll). obinutuzumab was
the first medicine to be approved with the FDas
Breakthrough Therapy Designation.
In February 2013, the u.s. FDa approved celgenes
pomalidomide (Pomalyst) for the treatment of multiple myeloma in patients who have received at least two
prior therapies, including lenalidomide and bortezomib,
and have demonstrated disease progression on or within 60 days of completion of the last therapy. supporting
the approval were the results of MM-002, a randomized,
open-label phase II study evaluating pomalidomide plus
low-dose dexamethasone versus pomalidomide alone in
patients with relapsed multiple myeloma who were
refractory to their last myeloma therapy and had
received lenalidomide and bortezomib. of the 221
patients who were evaluable for response, 29.2%
achieved a partial response or better in the pomalidomide plus low-dose dexamethasone arm compared to
7.4% in the pomalidomide alone arm. The overall
response rate was based on responses assessed by the
Independent Review adjudication committee based on
the European group for Blood and Marrow Transplantation criteria. The median duration of response for
patients in the pomalidomide plus low-dose dexamethasone arm was 7.4 months, while the median had not
yet been reached for the pomalidomide alone arm at the
A.I. Graul et al.
time of approval. a total of 219 patients were evaluable

for safety. The most common grade 3 or 4 adverse reactions (15%) in the pomalidomide plus low-dose dexamethasone arm versus pomalidomide alone, respectively,
were neutropenia (38 and 47%), anemia (21 and 22%),
thrombocytopenia (19 and 22%) and pneumonia (23 and
16%). Pomalidomide is an immunomodulatory derivative
of thalidomide (IMiD) and is contraindicated in pregnancy. It is only available through the Pomalyst Risk
Evaluation and Mitigation strategy (REMs) program. It
was launched in the u.s. later in the first quarter, and
was approved by the European commission in august.
Bruton tyrosine kinase (BTK) is a key signaling molecule
of the B-cell receptor signaling complex that plays an
important role in the survival of malignant B cells (Fig. 9).
The BTK inhibitor ibrutinib (Imbruvica) was approved
and launched in the u.s. in 2013 for the treatment of
mantle cell lymphoma (Mcl). The approval of ibrutinib

was based on the favorable overall response rate (oRR)
and duration of response (DoR) seen in the phase II
study PcYc-1104, which enrolled 111 patients with
relapsed or refractory Mcl. The efficacy results of this
study demonstrated a 65.8% oRR, with 17% of patients
achieving a complete response and 49% achieving a
partial response. The median DoR was 17.5 months.
Ibrutinib was discovered by Pharmacyclics and was
licensed to Janssen in 2011 for codevelopment and
comarketing worldwide. like obinutuzumab, ibrutinib
has Breakthrough Therapy Designation from the FDa; it
also has orphan drug status for the indication of Mcl.
In May 2013, algeta and development and marketing
partner Bayer schering Pharma launched radium Ra
223 dichloride (Xofigo) in the u.s. The agent is a radiopharmaceutical incorporating the alpha particle-emit-
Figure 9. Ibrutinib functions as an orally available, selective and covalent inhibitor of the enzyme Tyrosine-protein kinase BTK
(Bruton tyrosine kinase), which plays an essential role in B-cell maturation and mast cell activation, and is indicated for use in treating B-cell malignancies such as small lymphocytic lymphoma, diffuse large B-cell lymphoma and relapsed or refractory mantle cell
lymphoma. BTK is characterized by a Ph domain that selectively binds to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which
results in the phosphorylation of phospholipase c. This leads to the hydrolysis of PIP2 into inositol triphosphate (IP3) and diacylglycerol (Dag), two second messengers that regulate certain downstream proteins during B-cell signaling.
71
ting isotope radium 223, and is approved by the FDa for

the treatment of patients with castration-resistant
prostate cancer, symptomatic bone metastases and no
known visceral metastatic disease. It is the first and only
alpha particle-emitting radioactive therapeutic agent
approved by the agency that has demonstrated improvement in overall survival and delay in time to first symptomatic skeletal event compared to placebo. Bone
metastases are particularly prevalent among men with
prostate cancer, affecting up to 90% of these patients,
and have a significant negative impact on mortality and
quality of life.
Racotumomab (Vaxira), an antiganglioside, anti-idiotypic antibody-based cancer vaccine from REcoMBIo,
was launched for the first time last year in argentina. It is
indicated for the treatment of advanced-stage Nsclc in
patients undergoing chemotherapy and radiotherapy or
in patients who have not responded to first-line therapy.
Racotumomab has also been approved in cuba. The
vaccine has been licensed in 25 countries on the
american and asian continents under the name Vaxira,
with Elea laboratories having the exclusive right to sell it
in argentina and Eurofarma having the exclusive license
in Brazil, as well as semi-exclusive rights in the rest of
the south american continent. Innogene Kalbiotech has
the license to market the drug in Korea, Taiwan and
India, as well as in Brunei, cambodia, Indonesia, laos,
Malaysia, Myanmar, singapore, Thailand and the
Philippines. REcoMBIo holds the license in the rest of
the american and asian countries, as well as in Europe.
The vaccine has shown significant results in the clinical
setting, where it tripled the 2-year survival rate among
patients receiving treatment. Racotumomab could provide an alternative treatment for lung cancer patients, as
it implies less toxicity and side effects compared to conventional cancer therapies, and it also holds the potential to be studied and applied to other tumor types that
have the same target.
OPHTHALMIC DRUGS
simbrinza (brinzolamide/brimonidine tartrate), a
fixed-dose combination product for the treatment of
glaucoma, was approved and launched for the first time
last year in the u.s. The product was developed by alcon,
the global eye care division of Novartis, and is indicated
for the reduction of elevated intraocular pressure in
patients with primary open-angle glaucoma or ocular
hypertension. simbrinza is the only fixed-dose combina72
A.I. Graul et al.
tion therapy for glaucoma in the u.s. that does not

include a -blocker. Its active components are brinzolamide, a carbonic anhydrase inhibitor, and brimonidine
tartrate, an 2-adrenoceptor agonist.
another combination product for glaucoma, santens
TaPcoM (tafluprost/timolol maleate), was approved
last year in Japan for the treatment of glaucoma and
ocular hypertension. Tafluprost is a prostaglandin F2
analogue that promotes the outflow of aqueous humor,
and timolol is a -adrenoceptor blocker that inhibits the
production of aqueous humor.
Iluvien (fluocinolone acetonide intravitreal implant in
applicator) is a sustained-release intravitreal implant
developed by alimera sciences under license from
psivida to treat vision impairment associated with
chronic diabetic macular edema considered insufficiently responsive to available therapies. Each implant provides a therapeutic effect of up to 36 months by delivering sustained submicrogram levels of fluocinolone
acetonide. It is injected in the back of the patients eye to
a position that takes advantage of the eyes natural fluid
dynamics. The applicator employs a 25-gauge needle,
which allows for a self-sealing wound. Iluvien was
launched for the first time last april in the u.K., and was
introduced later in the year in germany; it is also
approved in several other European countries. an NDa
continues under review in the u.s., where the FDa has
issued a complete response letter expressing concerns
regarding the benefit-to-risk and safety profiles of
Iluvien, and has indicated that results from a new clinical
trial will need to be submitted.
In the early days of January 2013, Thrombogenics
announced the u.s. launch of ocriplasmin (Jetrea) for
the treatment of symptomatic vitreomacular adhesion
(VMa). symptomatic VMa is a progressive sight-threatening condition that, when untreated, frequently leads
to retinal distortion, further deterioration in vision and
irreversible damage to eyesight. ocriplasmin, administered by intravitreal injection to the affected eye, is a
selective proteolytic enzyme that cleaves fibronectin,
laminin and collagen, three major components of the
vitreoretinal interface that play an important role in
VMa.
cystinosis is a genetic lysosomal storage disease that
affects approximately 300 children and young adults in
the u.s. and some 2,000 people worldwide. It causes
cystine crystals to build up in various organs of the body,
including the corneas, kidneys, liver, pancreas, muscles,
A.I. Graul et al.
brain and white blood cells. The accumulation of cystine

crystals in the cornea can lead to a range of ocular complications, including squinting, foreign body sensation,
change in visual acuity, corneal haziness and photophobia. sigma-Tau Pharmaceuticals, a part of the sigmaTau group Rare Disease Franchise, launched cystaran
(cysteamine ophthalmic solution) last May in the u.s.,
where it is indicated for the treatment of corneal cystine
crystal accumulation in patients with cystinosis. sigmaTau developed the cystine-depleting agent in partnership with the National Institutes of health and in cooperation with the cystinosis Foundation, the cystinosis
Research Foundation and the cystinosis Research
Network. The FDa approved cysteamine in october
2012, having previously granted it orphan drug designation.
METABOLIC DRUGS
amarin launched Vascepa (icosapent ethyl ester) in
the u.s. in January 2013, indicated to treat severe
hypertriglyceridemia (triglyceride 500 mg/dl). The
ultrapure omega-3 fatty acid product, comprising not
less than 96% EPa (ethyl eicosapentaenoic acid) in a 1-g
capsule, was approved by the FDa in July 2012. In published controlled trials, Vascepa significantly reduced
triglyceride levels without elevating lDl cholesterol levels, while displaying a tolerability and safety profile similar to that of placebo. later in the year, amarin filed a
supplemental NDa for Vascepa for use as an adjunct to
diet in the treatment of adult patients with high
triglycerides (Tg 200 mg/dl and < 500 mg/dl) with
mixed dyslipidemia and coronary heart disease (chD) or
a chD risk equivalent (the aNchoR indication). however, an FDa advisory committee recently voted against
the approval of this new indication.
Merck & co.s liptruzet (ezetimibe/atorvastatin) was
approved and launched last year in the u.s. for the treatment of elevated lDl cholesterol in patients with primary or mixed hyperlipidemia as adjunctive therapy to
diet when diet alone is not enough. The product is also
indicated for the reduction of elevated total cholesterol
and lDl cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipidlowering treatments or if such treatments are unavailable. In a multicenter, double-blind, placebo-controlled
study in which 628 patients with hyperlipidemia were
treated for up to 12 weeks, the combination drug lowered
lDl cholesterol across all doses by more than 50%.
Pooled across doses, the combination of ezetimibe and
atorvastatin reduced lDl cholesterol by a mean 56%

compared with 44% for all atorvastatin doses pooled.
Based on this and other clinical studies, the combination
tablet has been shown to be bioequivalent to coadministration of corresponding doses of ezetimibe and atorvastatin.
another statin-containing combination product,
abbotts cholib (fenofibrate/simvastatin), was approved by the European commission in august 2013.
cholib is indicated as adjunctive therapy to diet and
exercise in high cardiovascular risk adult patients with
mixed dyslipidemia to reduce triglycerides and increase
hDl cholesterol levels when lDl cholesterol levels are
adequately controlled with the corresponding dose of
simvastatin monotherapy.
In June, Zydus reported that saroglitazar (lipaglyn), a
novel peroxisome proliferator-activated receptor (PPaR)
agonist indicated for the treatment of diabetic dyslipidemia or hypertriglyceridemia in type 2 diabetes not
controlled by statins alone, had been approved for marketing in India. The NDa for saroglitazar was based on a
comprehensive clinical development program spanning
8 years. Results from the first phase III program of
saroglitazar, using pioglitazone as a comparator drug in
patients with diabetes, showed that at a dose of 4 mg,
the agent led to a reduction in triglycerides and in lDl
cholesterol, and an increase in hDl cholesterol, as well
as a reduction in fasting plasma glucose and glycosylated hemoglobin (hba1c). More than 80% of all diabetic
patients are believed to have dyslipidemia a potential
market of up to 300 million patients worldwide. saroglitazar was launched in India during the third quarter.
homozygous familial hypercholesterolemia (hoFh) is a
serious, rare genetic disease that impairs the function of
the receptor responsible for removing lDl cholesterol
from the body. a loss of lDl receptor function results in
extreme elevation of blood cholesterol levels. Patients
with the disorder often develop premature and progressive atherosclerosis. While heterozygous Fh is relatively
common, occurring in 1 in 300-500 individuals worldwide, hoFh is much more rare, occurring in only 1 per
million (source: Fh Foundation). In 2013, two new products developed to treat this disorder both fist-in-class
agents reached the market for the first time.
In January the microsomal triglyceride transfer protein
(MTTP) inhibitor lomitapide (Juxtapid; aegerion) was
launched in the u.s., where it is indicated as an adjunct
to low-fat diet and other lipid-lowering treatments,
73
including lDl apheresis where available, to reduce lDl

cholesterol, total cholesterol, apolipoprotein B and nonhDl cholesterol in patients with hoFh (Fig. 10). The
approval of lomitapide was based on a pivotal phase III
study that evaluated the safety and effectiveness of the
drug in reducing lDl cholesterol levels in 29 adult
patients with hoFh (clinicalTrials.gov Identifier
NcT00730236). When added to baseline lipid-lowering
therapy, lomitapide significantly lowered lDl cholesterol levels from 336 mg/dl to 190 mg/dl, a decrease of
approximately 40%. Because of the risk of liver toxicity,
the product carries a black box warning and is available
only through a Risk Evaluation and Mitigation strategy
(REMs) program. In august, the European commission
granted approval to lomitapide (known there as
lojuxta) as an adjunct to low-fat diet and other lipidlowering medicinal products, with or without lDl
A.I. Graul et al.
apheresis, in adult patients with hoFh. lomitapide has

orphan drug status for this indication in the u.s. as well
as Japan.
The second drug for hoFh, mipomersen sodium
(Kynamro), was approved and launched in the u.s.
during the first quarter. Mipomersen is an antisense
oligonucleotide that blocks the production of apolipoprotein B-100, the protein that provides the structural
core for atherogenic particles such as lDl (Fig. 11). It is
approved as an adjunct to lipid-lowering medications
and diet to reduce lDl cholesterol, apolipoprotein B,
total cholesterol and non-hDl cholesterol in patients
with hoFh. approval was based on the largest clinical
trial conducted to date in the hoFh patient population.
The randomized, double-blind, placebo-controlled, multicenter trial enrolled 51 patients aged 12-53 years,
including 7 patients aged 12-16 years, who were main-
Figure 10. lomitapide acts as a microsomal triglyceride transfer protein (MTTP) inhibitor and is useful as a treatment option for
lipoprotein disorders such as homozygous familial hypercholesterolemia. MTTP promotes the formation and secretion in the liver of
very low-density lipoprotein (VlDl) cholesterol. Therefore, inhibiting MTTP results in a reduction of cholesterol and triglyceride
blood levels by limiting the production of lipoproteins from the intestine and liver. This mechanism of action, together with an ability to suppress apolipoprotein B-containing lipoproteins from both intestinal and hepatic sources, marks mTTP inhibitors such as
lomitapide as potential monotherapy for reducing lDl cholesterol as well as triglycerides.
74
A.I. Graul et al.
taining a regimen of maximally tolerated lipid-lowering

medications. Treatment with mipomersen further
reduced lDl cholesterol levels by an average of 113
mg/dl, or 25%, from a treated baseline of 439 mg/dl,
and also reduced all measured endpoints for atherogenic particles. safety data were based on pooled results
from 4 randomized, double-blind, placebo-controlled
phase III trials with a total of 390 patients, of whom 261
patients received mipomersen and 129 patients received
placebo for a median treatment duration of 25 weeks.
Data showed that 18% of patients on mipomersen and
2% of patients on placebo discontinued treatment due
to adverse reactions. The most common adverse reactions in patients treated with mipomersen that led to
treatment discontinuation and occurred at a rate greater
than placebo were injection-site reactions (5.0%), alanine aminotransferase (alT) increase (3.4%), flu-like
symptoms (2.7%), aspartate aminotransferase (asT)
increase (2.3%) and abnormal liver function test (1.5%).
No clinically relevant pharmacokinetic interactions were
reported between mipomersen and warfarin, or between
mipomersen and simvastatin or ezetimibe. Kynamro carries a boxed warning citing the risk of hepatic toxicity.
The product was discovered by Isis Pharmaceuticals and
was licensed to genzyme for development and commercialization. It has orphan drug status for the hoFh indication.
In June 2012, the FDa approved the selective 5-hT2c
receptor agonist lorcaserin hydrochloride (Belviq;
arena), the first prescription weight loss treatment
Figure 11. Mipomersen sodium is a second-generation antisense oligonucleotide which is indicated for use in treating conditions
such as homozygous familial hypercholesterolemia. Mipomersen sodium selectively targets apolipoprotein B (apoB), a protein crucial to the synthesis and transport of lDl and VlDl cholesterol, which are both implicated in the development of cardiovascular disease. Mipomersen sodium is a synthetic phosphorothioate oligonucleotide sodium salt with five 2-O-methoxyethyl modifications
(2-MoE) at the 2 position of the ribose on both 3 and 5 ends. The 10 central 2-deoxynucleotides serve as the site for RNase hmediated mRNa degradation. The drug selectively targets apoB by hybridizing within the coding region of apoB-100 mRNa. Its
potential for lowering cholesterol and triglyceride levels is thus expected to be of use in the prevention and management of cardiovascular disease and lipoprotein disorders.
75
approved in the u.s. in 13 years. specifically, the product

is indicated for use in addition to diet and exercise in
adults who are obese (BMI 30 kg/m2) or who are
overweight (BMI 27 kg/m2) and have at least one
weight-related condition, such as hypertension, type 2
diabetes or dyslipidemia. The safety and efficacy of lorcaserin were evaluated in 3 randomized, placebo-controlled trials that included nearly 8,000 patients who
were obese or overweight, with and without type 2 diabetes, treated for 52-104 weeks. Following receipt of
DEa scheduling in May 2013, lorcaserin was launched in
the u.s. in June. Eisai is responsible for marketing and
distribution of lorcaserin, which is manufactured by
arena at its facility in switzerland.
another antiobesity agent was approved last year for the
first time in Japan: the triacylglycerol lipase inhibitor
cetilistat (oblean). like the marketed drug orlistat,
cetilistat inhibits the activity of lipase, a lipolytic enzyme
secreted by the digestive tract and pancreas, and blocks
the absorption of fat from the gut. This results in
decreased body weight, reduced visceral fat and
improved parameters related to lifestyle disease.
cetilistat is the first therapy that controls lipid absorption approved in Japan for the treatment of obesity with
complications. The drug was discovered by alizyme.
Norgine acquired all rights to cetilistat in october 2009.
Takeda has held development and commercialization
rights in Japan since 2003.
The xanthine oxidase inhibitor topiroxostat was
approved and launched last year in Japan for the treatment of gout and hyperuricemia. Topiroxostat was codeveloped by sanwa Kagaku Kenkyusho and Fuji Yakuhin;
the former markets the product under the name
uriadec and the latter under the name Topiloric.
Xanthine oxidase inhibitors block the production of uric
acid by selectively and reversibly suppressing xanthine
oxidoreductase within the purine metabolic pathway.
congenital lipodystrophy is a rare and life-threatening
disorder characterized by a lack of the subcutaneous fat
tissue required for normal metabolic functions, and is
highly correlated to metabolic abnormalities, such as
severe diabetes, hypertriglyceridemia, hepatic steatosis
and steatohepatitis (also known as fatty liver disease).
last year metreleptin (recombinant human oB protein),
the first drug developed specifically to treat congenital
lipodystrophy, was launched for the first time in Japan,
where it has orphan drug status. shionogi developed
metreleptin for the Japanese market under license from
amylin, a subsidiary of Bristol-Myers squibb. The prod76
A.I. Graul et al.
uct was approved by the Japanese Ministry of health,

labour and Welfare in March and was launched in July.
In the u.s., Bristol-Myers squibb is codeveloping
metreleptin through its diabetes alliance with
astraZeneca and the product has priority review status.
In December, an FDa advisory committee voted 11-1 in
favor of approving metreleptin for the treatment of pediatric and adult patients with generalized lipodystrophy.
urea cycle disorders (ucDs) are a collection of inherited
metabolic disorders characterized by high levels of systemic ammonia, a potential neurotoxin. ammonia is produced via normal protein ingestion; the body normally
detoxifies it by converting it, through a series of enzymatic steps, to urea, which is secreted in urine. Throughout
their lives, patients with ucDs may experience recurrent
hyperammonemic crises in which ammonia levels rise,
and can develop complications ranging from nausea,
vomiting and headache, to coma and death. last year
the FDa approved hyperion Therapeutics Ravicti (glycerol phenylbutyrate), a nitrogen-binding agent indicated for the chronic management of ucDs in patients aged
2 and older whose disease cannot be managed by
dietary protein restriction and/or amino acid supplementation alone. Ravicti must be used with dietary protein
restriction and in some cases dietary supplements (e.g.,
essential amino acids, arginine, citrulline, protein-free
calorie supplements). glycerol phenylbutyrate has
orphan drug status for this indication in the u.s.
last year the European commission granted a marketing authorization, valid throughout the European union,
for cholic acid (orphacol; laboratoires cTRs). The product, which has orphan drug status, is indicated as a
treatment for inborn errors in primary bile acid synthesis
due to 3-hydroxy-5-c27-steroid oxidoreductase
deficiency or 4-3-oxosteroid-5-reductase deficiency in
infants, children and adolescents aged 1 month to 18
years and in adults. This product was approved by way of
a simplified procedure that is applicable, inter alia, to
orphan medical products for which the applicant is able
to demonstrate that the active substance has been in
well-established medicinal use within the E.u. for at
least 10 years, with recognized efficacy and an acceptable level of safety. The European commission in 2011
refused to grant approval for orphacol; however, in July
2013 the European general court annulled that decision, paving the way for the september approval of
orphacol by the E.c.
Zeria Pharmaceutical launched Phosribbon combination granule (INKP-102; monobasic sodium phosphate
A.I. Graul et al.
monohydrate/dibasic sodium phosphate anhydrous), an

oral agent for hypophosphatemia, last March in Japan,
becoming the first oral phosphate to reach the market in
that country. Phosribbon is usually used for the treatment of hypophosphatemia in combination with an activated vitamin D agent. Zeria developed this agent following requests from the Review committee on
unapproved Drugs and Indications with high Medical
Needs. Phosribbon has orphan drug status in Japan for
this indication. It has been marketed since 2001 as a
purgative agent for colon cleansing prior to colonoscopy.
TREATMENT OF POISONING & DRUG DEPENDENCY
The European commission approved selincro (nalmefene; BioTie Therapies/lundbeck) in February 2013, indicated for the reduction of alcohol consumption in adult
patients with alcohol dependence. It was launched in its
first European markets (Norway, Finland, Poland and the
Baltic countries) in april. Nalmefene has been developed
for use on an as needed basis, with one tablet taken
each day when the patient feels a risk of drinking.
lundbeck intends to provide the drug as part of a novel
treatment concept that includes continuous psychosocial support focused on the reduction of alcohol consumption and treatment adherence. The marketing
authorization applies to all 27 E.u. member states and is
based on the results from 3 pivotal, randomized, doubleblind, placebo-controlled trials that evaluated the efficacy and safety of nalmefene in approximately 2,000
patients with alcohol dependence. In these trials, the
drug was shown to be effective in reducing alcohol consumption in patients with a high drinking risk level.
specifically, subjects treated with nalmefene showed a
40% reduction in total alcohol consumption within the
first month and an approximately 60% reduction after 6
months. a unique dual-acting opioid system modulator,
nalmefene acts on the brains motivational system,
which is dysregulated in patients with alcohol dependence. under the new European approval, the product is
indicated for the reduction of alcohol consumption in
adult patients with alcohol dependence who have a high
drinking risk level, defined as over 60 g/day for men and
over 40 g/day for women, without physical withdrawal
symptoms and who do not require immediate detoxification. This is a new indication for nalmefene, which was
first launched by Baker Norton in 1995 for the treatment
of opioid overdose.
In March 2013, the u.s. FDa approved cangenes Bat
(botulism antitoxin [equine] heptavalent [A, B, C, D,
E, F, G]) for the treatment of patients showing signs of
botulism following documented or suspected exposure

to botulinum neurotoxin subtypes a, B, c, D, E, F or g.
The antitoxin, which has orphan drug designation from
the FDa, is derived from horse plasma and contains a
mixture of antibody fragments that neutralize all of the
seven botulinum nerve toxin serotypes known to cause
botulism. It was developed with support from the
Biomedical advanced Research and Development
authority within the u.s. Department of health and
human services office of the assistant secretary for
Preparedness and Response, and will be maintained in
the strategic National stockpile and distributed through
the centers for Disease control and Prevention (cDc)
Drug service. Due to its extreme potency and potential
lethality, botulinum toxin has been identified in the u.s.
as one of the highest priority bioterrorism threats. The
effectiveness of the product was studied under the FDas
animal Rule, which permits demonstration of efficacy in
appropriate animal models when it is not feasible or ethical to conduct efficacy studies in humans. These results
provided substantial evidence that the antitoxin is reasonably likely to benefit humans with botulism. The safety of the product was tested in 40 healthy human volunteers and also monitored in 228 patients who received
the antitoxin experimentally under a botulism treatment
program administered by the cDc. cangene began
shipping Bat to the u.s. strategic National stockpile
during the second quarter.
DENTAL AGENTS
gintuit (allogeneic cultured keratinocytes and fibroblasts in bovine collagen), a novel wound-healing
agent developed by organogenesis, was launched for
the first time last year in the u.s. for the treatment of
mucogingival conditions in adults. The product is a
bilayered structure composed of an upper cornified layer
formed by allogeneic human keratinocytes and a lower
layer formed by bovine-derived collagen, human extracellular proteins and allogeneic human dermal fibroblasts. It is supplied as a cellular sheet that is applied to
a surgically created vascular wound bed. While the specific way in which gintuit increases keratinized tissue has
not been identified, studies have demonstrated that the
cell-based product secretes human growth factors and
other proteins that are known to be involved in wound
repair and regeneration.
DIAGNOSTIC AGENTS
In october, the u.s. FDa approved gE healthcares
Vizamyl (flutemetamol F18 injection), a radioactive
77
diagnostic agent indicated for positron emission tomography (PET) imaging of the brain to estimate amyloid
neuritic plaque density in adult patients with cognitive
impairment who are being evaluated for alzheimers disease or other causes of cognitive decline. Vizamyl is an
adjunct to other diagnostic evaluations. Vizamyl is the
only PET imaging tracer for detection of amyloid
approved by the FDa for visual interpretation of color
images rather than black and white assessment, and will
be commercially available in 2014.
Navidea Biopharmaceuticals launched lymphoseek
(technetium Tc 99m tilmanocept) injection last year in
the u.s. for use in lymphatic mapping procedures that
are performed to help in the diagnostic evaluation of
potential cancer spread in patients with breast cancer
and melanoma. as part of Navideas u.s. distribution
partnership, cardinal health is responsible for the sale
and distribution of the product to healthcare professionals through its existing network of nuclear pharmacies.
Technetium Tc 99m tilmanocept is a novel, receptor-targeted, small-molecule radiopharmaceutical designed to
identify the lymph nodes that drain from a primary
tumor, which have the highest probability of harboring
cancer. Navidea plans to continue developing the product into other solid tumor areas that may include head
and neck cancer, prostate cancer, thyroid cancer,
lung/bronchus cancer, colorectal cancer and others.
A.I. Graul et al.
In December, the u.s. FDa granted 510(k) approval for

C4-ECAM (sirius; c4 Imaging), a novel positive-signal
MRI marker developed for the localization of radioactive
seeds used in brachytherapy of prostate cancer. The
sirius MRI Marker consists of a 5.5-mm sealed, biocompatible polymer capsule containing c4, a unique MRI
agent. The capsules are implanted as brachytherapy
seed spacers that facilitate the anatomical localization
of seeds using a single post-implant MRI procedure,
eliminating the need for computed tomography in the
assessment of prostate brachytherapy.
Table II presents an overview of all new drugs and biologics launched in 2013, including line extensions (new
indications, new combinations and important new formulations of previously marketed drugs). Products in
this table are listed in alphabetical order.
Table III summarizes the estimated market size for
selected products introduced last year.
DISCLOSURES
The authors state no conflicts of interest.
78
alogliptin benzoate/metformin hydrochloride*,

tablets, 12.5 mg/500 mg & 12.5 mg/1000 mg
alogliptin/metformin hcl
anakinra, prefilled syringe, 0.67 ml (100 mg) anakin- Treatment of children and adults with neonatal-onset
ra in solution for s.c. injection
multisystem inflammatory disease (NoMID)**
Bisoprolol fumarate, transdermal patch***, 4 & 8 mg
Botulism antitoxin (equine), heptavalent, 20- and

Treatment of symptomatic botulism following documented
50-ml vials containing no less than 4,500 units (u)
or suspected exposure to botulinum neurotoxin subtypes a,
for serotype a antitoxin, 3,300 u for serotype B anti- B, c, D, E, F or g in adults and pediatric patients
toxin, 3,000 u for serotype c antitoxin, 600 u for
serotype D antitoxin, 5,100 u for serotype E antitoxin,
3,000 u for serotype F antitoxin, and 600 u for
serotype g antitoxin
organogenesis
Takeda
swedish orphan
BioVitrum
Bristol-Myers
squibb/Pfizer
Janssen Therapeutics
Toa Eiyo; marketed and

distributed by astellas
cangene
galderma
Kazano (us)
Kineret (us)
Eliquis (us)
sirturo (us)
Bisono Tape (JP)
BaT (us)
Mirvaso (us)
Brimonidine tartrate, topical gel, 0.33%
Bedaquiline, tablets, 100 mg
apixaban, tablets, 2.5 & 5 mg
allogeneic cultured keratinocytes and fibroblasts in

bovine collagen, cellular sheet for oral application.
approximately 4 million cells are initially used to
manufacture the product
Continued
Topical treatment of persistent (nontransient) facial

erythema of rosacea in adults 18 years of age or older**
Mild to moderate essential hypertension
as part of combination therapy, to treat adults (18 years or

older) with multidrugresistant pulmonary tuberculosis (TB)
when other alternatives are not available
Prevention of stroke and systemic embolism in patients with

nonvalvular atrial fibrillation**
as an adjunct to diet and exercise, to improve glycemic

control in adults with type 2 diabetes
For topical (nonsubmerged) application to a surgically

created vascular wound bed in the treatment of
mucogingival conditions in adults
First-line treatment of patients with metastatic non-small

cell lung cancer (Nsclc) whose tumors have epidermal
growth factor receptor (EGFR) exon 19 deletions or exon 21
(l858R) substitution mutations as detected by an FDaapproved test
gintuit (us)
afatinib, tablets, 20, 30 & 40 mg
Boehringer Ingelheim
giotrif (us)
Treatment of functional dyspepsia
acotiamide hydrochloride hydrate, tablets, 100 mg
Zeria; codeveloped and

comarketed by astellas
acofide (JP)
Indication
active ingredient2
company
Trade name (country)1
Table II. New product intros 2013.
A.I. Graul et al.

79
80
Treatment of adult patients with frequent gouty arthritis

attacks (at least 3 attacks in the previous 12 months) in whom
nonsteroidal anti-inflammatory drugs (NsaIDs) and colchicine
are contraindicated, are not tolerated, or do not provide an
adequate response, and in whom repeated courses of corticosteroids are not appropriate**
Treatment of active systemic juvenile idiopathic arthritis

(sJIa) in patients aged 2 years and older**
as an adjunct to diet and exercise, to improve glycemic

control in adults with type 2 diabetes
Treatment of progressive, metastatic medullary thyroid cancer
Reduction of intraocular pressure in patients with primary

open-angle glaucoma or ocular hypertension
Indication
Treatment of cataplexy in patients with narcolepsy**
clomipramine hydrochloride, tablets, 10 & 25 mg
coagulation factor IX (recombinant), lyophilized pow- antihemophilic factor indicated for:

der in single-use vials containing nominally 250, 500, control and prevention of bleeding episodes in adults with
1000, 2000 or 3000 Iu
hemophilia B
Perioperative management in adults with hemophilia B
Routine prophylaxis to prevent or prevent or reduce the
frequency of bleeding episodes in adults with hemophilia B
alfresa Pharma
Baxter
anafranil (JP)
Rixubis (us, PR)
Continued
Ttreatment of adult patients with severe active axial spondyloarthritis, comprising adults with severe active ankylosing spondylitis
who have had an inadequate response to or are intolerant to
nonsteroidal anti-inflammatory drugs (NsaIDs) and adults
with severe active axial spondyloarthritis without radiographic
evidence of ankylosing spondyloarthritis but with objective
signs of inflammation by elevated cRP and/or MRI, who have
had an inadequate response to or are intolerant to NsaIDs**
certolizumab pegol, lyophilized powder in single-use Treatment of adult patients with active psoriatic arthritis**
vials, 200 mg, for reconstitution with 1 ml sterile water
for injection single-use prefilled syringes, 200 mg/ml
Treatment of adults with active akylosing spondylitis**
canakinumab, single-use vials containing lyophilized

powder, 180 mg, for reconstitution and s.c. injection
canagliflozin, tablets, 100 & 300 mg
cabozantinib s-malate, capsules 20 & 80 mg
Brinzolamide/brimonidine tartrate*, ocular suspension in multidose bottle, brinzolamide (1.0%) and brimonidine tartrate (0.2%)
active ingredient2
cimzia (Eu)
cimzia (us)
cimzia (us)
ucB
Novartis
Ilaris (us)
Ilaris (DE, gR)
Exelixis
Janssen Therapeutics
Invokana (us)
alcon (Novartis)
simbrinza (us)
cometriq (us)
company
Table II. (Cont.) New product intros 2013.

A.I. Graul et al.
collagenase Clostridium histolyticum, single-use vials

containing sterilized, lyophilized powder, 0.9 mg, for
reconstitution with supplied sterile diluent
crofelemer, delayed-release tablets, 125 mg
Dabrafenib mesilate, capsules, 50 & 75 mg
Denosumab, single-use vials, 120 mg/1.7 ml for s.c.

injection
Dimethyl fumarate, delayed-release capsules, 120 & 240 mg Treatment of patients with relapsing forms of multiple sclerosis
Dolutegravir, tablets, 50 mg
auxilium
salix; licensed from

Napo
sigma-Tau
glaxosmithKline
amgen
Biogen Idec
ViiV healthcare
sanofi Pasteur
Merck & co.
Xiaflex (us)
Fulyzaq (us)
cystaran (us)
Tafinlar (us)
Xgeva (us)
Tecfidera (us)
Tivicay (us)
hexyon (DE)
liptruzet (us)
Ezetimibe/atorvastatin*, tablets, 10 mg/10 mg,

10 mg/20 mg, 10 mg/40 mg & 10 mg/80 mg
DTaP-IPV-hib-hepB vaccine, vials and prefilled

syringes, 0.5 ml
Continued
as adjunctive therapy to diet, to:

Reduce elevated total-c, lDl-c, apo B, Tg and non-hDl-c,
and to increase hDl-c in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed
hyperlipidemia
Reduce elevated total-c and lDl-c in patients with
homozygous familial hypercholesterolemia (hoFh), as an
adjunct to other lipid-lowering treatments
Primary and booster vaccination of infants from 6 weeks of

age against diphtheria, tetanus, pertussis, hepatitis B,
poliomyelitis and invasive infections caused by Haemophilus
influenzae type b
In combination with other antiretroviral agents, for the treatment of hIV-1 infection in adults and children aged 12 years
and older and weighing at least 40 kg
Treatment of adults and skeletally mature adolescents with

giant cell tumor of bone (gcTB) that is unresectable or
where surgical resection is likely to result in severe morbidity**
Treatment of adult patients with unresectable or metastatic

melanoma with BRAF V600E mutation as detected by an
FDa-approved test
cysteamine hydrochloride, sterile ophthalmic solution Treatment of corneal cystine crystal accumulation in
containing 6.5 mg/ml of cysteamine hydrochloride
patients with cystinosis**
equivalent to 4.4 mg/ml of cysteamine (0.44%)***
symptomatic relief of noninfectious diarrhea in adult

patients with hIV/aIDs on antiretroviral therapy
Treatment of adult men with Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees
at the start of therapy**
Treatment of hyperphosphatemia in adult patients with

chronic kidney diseasestage 5 receiving hemodialysis or
peritoneal dialysis**
colestilan, film-coated tablets, 1 g; oral granules, 2 &

3g
Mitsubishi Tanabe
Pharma/NextPharma
Indication
BindRen (DE, aT)
active ingredient2
company
A.I. Graul et al.

81
82
Fluticasone furoate/vilanterol*, dry powder inhaler,

100 g fluticasone furoate/25 g vilanterol
glycerol phenylbutyrate, oral liquid, 1.1 g/ml
human normal immunoglobulin/recombinant human Replacement therapy in adults ( 18 years) in primary

hyaluronidase*, solution for infusion for subcutaneous immunodeficiency syndromes and in myeloma or chronic
lymphocytic leukemia with severe secondary hypogammause, 100 mg/ml
globulinemia and recurrent infections
Ibrutinib, capsules, 140 mg
glaxosmithKline/
Theravance
hyperion Therapeutics
Novartis/sosei
Janssen Biotech
Baxter/halozyme
Therapeutics
Pharmacyclics/Janssen
Breo Ellipta (us)
Ravicti (us)
ultibro Breezhaler
(DE, Nl)
simponi (us)
hyQvia (DE)
Imbruvica (us)
Relief of symptoms caused by airway obstruction in patients

with chronic obstructive pulmonary disease (coPD)
Immune globin intravenous [human], liquid solution Treatment of patients with primary humoral
containing 10% Igg (100 mg/ml) for i.v. infusion (5 g immunodeficiency. This includes, but is not limited to, the
in 50 ml solution & 10 g in 100 ml solution)
humoral immune defect in common variable
immunodeficiency (cVID), X-linked agammaglobulinemia,
congenital agammaglobulinemia, Wiskott-aldrich syndrome,
and severe combined immunodeficiencies
Biotest Pharmaceuticals
glaxosmithKline
Bivigam (us)
Fluarix Quadrivalent
(us)
Continued
Influenza virus vaccine, quadrivalent, suspension for active immunization of children (3 years and older) and
i.m. injection supplied in 0.5-ml single-dose prefilled adults to help prevent disease caused by seasonal influenza
syringes
(flu) virus subtypes a and type B contained in the vaccine
Icosapent ethyl, capsules, 1 g
amarin
Vascepa (us)
as an adjunct to diet, to reduce triglyceride (Tg) levels in

adults with severe (Tg 50 mg/dl) hypertriglyceridemia**
Treatment of patients with mantle cell lymphoma who have

received at least one prior therapy
golimumab, single-dose prefilled smartJect

Treatment of moderately to severely active ulcerative colitis
autoinjector, 50 mg/0.5 ml & 100 mg/1 ml single- in adult patients who have demonstrated corticosteroid
dose prefilled syringe, 50 mg/0.5 ml & 100 mg/1 ml dependence or who have had an inadequate response to or
failed to tolerate oral aminosalicylates, oral corticosteroids,
azathioprine, or 6-mercaptopurine**
glycopyrronium bromide/indacaterol*, inhalation

capsules, 50 g glycopyrronium/110 g indacaterol,
for administration using the Breezhaler device
chronic management of urea cycle disorders in patients 2

years of age and older
long-term, once-daily maintenance treatment of airflow

obstruction in patients with chronic obstructive pulmonary
disease (coPD), including chronic bronchitis and/or emphysema
Fluocinolone acetonide, sustained-release intravitreal Treatment of vision impairment associated with chronic
implant in applicator, 190 g***
diabetic macular edema considered insufficiently responsive
to available therapies**
alimera sciences;
licensed from psivida
Indication
Iluvien (gB)
active ingredient2
company

A.I. Graul et al.
company
glaxosmithKline
MedImmune
(astraZeneca)
sanofi Pasteur
Protein sciences
Zeria
Novo Nordisk
hanmi/sanofi
shionogi
Kyowa hakko Kirin
Biocon
Bharat Biotech
Flulaval Quadrivalent
(us)
FluMist Quadrivalent
(us)
Fluzone Quadrivalent
(us)
FluBlok (us)
Phosribbon (JP)
Tresiba (DK)
Robelito (KR)
Irtra (JP)
Nouriast (JP)
alzumab (IN)
Jenvac (IN)
active immunization for the prevention of influenza disease

caused by influenza a subtype viruses and type B viruses contained in the vaccine
Indication
Prevention of seasonal influenza in people 18 to 49 years

of age
Reduction of the risk of heart disease in patients with hypertension and hyperlipidemia who are prescribed both irbesartan and atorvastatin
once-daily basal insulin for the treatment of type 1 and 2

diabetes in adults
Japanese encephalitis vaccine, purified inactivated,

single-dose (2 ml) and multidose (3 ml) glass vials
and 1-ml glass syringe, each containing purified
inactivated Japanese encephalitis virus protein, 5.0
g per 0.5-ml dose
Itolizumab, vials, 5 ml containing 25 mg itolizumab
Istradefylline, tablets, 20 mg
Continued
active immunization against Japanese encephalitis infection
Treatment of patients with active moderate to severe chronic

plaque psoriasis who are candidates for systemic therapy
Improvement of wearing-off phenomena in patients with

Parkinson's disease on concomitant treatment with levodopacontaining products
Irbesartan/trichlormethiazide*, tablets, 100 mg/1 mg Treatment of hypertension

& 200 mg/1 mg
Irbesartan/atorvastatin calcium*, tablets, 150 mg/10

mg & 150 mg/20 mg
Insulin degludec, cartridge containing solution for

injection (100 units/ml; prefilled pen (100 units/ml
& 200 units/ml)
INKP-102, granules, containing 330 mg of monobasic Treatment of hypophosphatemia**

sodium phosphate monohydrate and 119 mg of dibasic sodium phosphate anhydrous
Influenza virus vaccine, trivalent, sterile solution in

single-dose vials, 0.5 ml for i.m. injection
Influenza virus vaccine, quadrivalent, prefilled single- active immunization for the prevention of influenza disease
dose syringe, 0.25 & 0.50 ml single-dose vials, 0.5 caused by influenza a subtype viruses and type B viruses conml for i.m. administration
tained in the vaccine
Influenza virus vaccine live, quadrivalent, nasal spray active immunization for the prevention of influenza disease
in single-dose (0.2 ml) intranasal sprayer
caused by influenza a subtype viruses and type B viruses contained in the vaccine
Influenza virus vaccine, quadrivalent, suspension for

i.m. injection, 5-ml multidose vials containing ten
0.5-ml doses
active ingredient2
A.I. Graul et al.

83
84
Novartis
Discovery laboratories
surfaxin (us)
Bexsero (gB, DE, IE)
alexza; marketed by
Ferrer
adasuve (DE)
actelion
arena; marketed and

distributed by Eisai
Belviq (us)
opsumit (us)
aegerion
Juxtapid (us)
sunovion
sanofi; licensed from

Zealand Pharma
lyxumia (gB)
latuda (us)
levomilnacipran hydrochloride, extended-release

capsules, 20, 40, 80 & 120 mg
Forest/Pierre Fabre
Fetzima (us)
Treatment of major depressive disorder in adults
Indication
Treatment of adults with pulmonary arterial hypertension

(Who group I) to delay disease progression
Macitentan, tablets, 10 mg
Continued
Meningococcal group B vaccine [rDNa, component,

active immunization against invasive disease caused by
adsorbed], prefilled syringe containing suspension for Neisseria meningitidis serogroup-B strains
injection, 0.5 ml
as monotherapy or adjunctive therapy with either lithium or

valproate, both to treat adult patients with major depressive
episodes associated with bipolar I disorder (bipolar depression)**
lurasidone hydrochloride, tablets, 20, 40, 80 &

120 mg
Prevention of respiratory distress syndrome (RDs) in premature infants at high risk for RDs
For rapid control of mild to moderate agitation in adult

patients with schizophrenia or bipolar disorder**
loxapine succinate, inhalation powder, 10 mg***

lucinactant, intratracheal suspension, 8.5 ml, in
glass vial. Each ml contains 30 mg phospholipids
(22.50 mg dipalmitoylphosphatidylcholine and 7.50
mg palmitoyloleoyl-phosphatidylglycerol, sodium
salt), 4.05 mg palmitic acid, and 0.862 mg sinapultide
as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an
initial body mass index of
30 kg/m2 or greater (obese) or
27 kg/m2 or greater (overweight) in the presence of at least
one weight-related comorbid condition (e.g., hypertension,
dyslipidemia, type 2 diabetes)
as an adjunct to a low-fat diet and other lipid-lowering treatments, including lDl apheresis where available, to reduce
lDl cholesterol (lDl-c), total cholesterol (Tc), apolipoprotein B (apo B) and non-hDl cholesterol in patients with
familial hypercholesterolemia
lorcaserin hydrochloride, tablets, 10 mg
lomitapide, capsules, 5, 10 & 20 mg
lixasenatide, prefilled pen containing solution for s.c. For the treatment of adults with type 2 diabetes to achieve
injection, 10 & 20 g
glycemic control in combination with oral glucose-lowering
medicinal products and/or basal insulin when these, together
with diet and exercise, do not provide adequate glycemic
control
active ingredient2
company

A.I. Graul et al.
Metreleptin, vials for s.c. injection, 11.25 mg
genzyme; licensed from Mipomersen sodium, single-use vials containing 1 ml as an addition to lipid-lowering medications and diet, to
of a 200 mg/ml solution single-use prefilled syringes treat patients with homozygous familial hypercholesIsis Pharmaceuticals
containing 1 ml of a 200 mg/ml solution
terolemia (hoFh)
Nalmefene, film-coated tablets, 18 mg
obinutuzumab, single-use vials, 1000 mg/40 ml for

i.v. infusion
shionogi; licensed from

amylin
BioTie
Therapies/lundbeck
Roche; codeveloped by
genentech and Biogen
Idec
Thrombogenics
shionogi
Noven
celgene
(JP)
Kynamro (us)
selincro (Eu)
gazyva (us)
Jetrea (us)
osphena (us)
Brisdelle (us)
Pomalyst (us)
Treatment of multiple myeloma in patients who have

received at least two prior therapies including lenalidomide
and bortezomib and have demonstrated disease progression
on or within 60 days of completion of the last therapy
Pomalidomide, capsules, 4 mg
Continued
Treatment of moderate to severe vasomotor symptoms associated with menopause**
Treatment of moderate to severe dyspareunia, a symptom of

vulvar and vaginal atrophy, due to menopause
Paroxetine mesilate, capsules, 7.5 mg
ospemifene, tablets, 60 mg
ocriplasmin, single-use glass vials containing 0.5 mg Treatment of symptomatic vitreomacular adhesion
in 0.2 ml solution for intravitreal injection (2.5 mg/ml)
In combination with chlorambucil, for the treatment of

patients with previously untreated chronic lymphocytic
leukemia
Reduction of alcohol consumption in adult patients with

alcohol dependence who have a high drinking risk level ( >
60 g/day for men, > 40 g/day for women) without physical
withdrawal symptoms and who do not require immediate
detoxification**
Treatment of congenital lipodystrophy
active immunization to prevent invasive disease caused by

Neisseria meningitidis serogroups c and Y and Haemophilus
influenzae type b in children 6 weeks of age through 18
months of age
Meningococcal groups c and Y and Haemophilus b

tetanus toxoid conjugate vaccine, lyophilized powder
in single-use vials for reconstitution in saline. Each
0.5-ml dose contains 5 g purified N. meningitidis c
capsular polysaccharide, 5 g purified N. meningitidis
Y capsular polysaccharide, and 2.5 g of purified
Haemophilus b capsular polysaccharide
glaxosmithKline
Menhibrix (us)
Indication
company
active ingredient2
Table II. (Cont.) New product intros 2013
A.I. Graul et al.

85
86
Bayer
adempas (ca)
Entera health
glaxosmithKline
(us)
Enteragam (us)
algeta; developed and

marketed by Bayer
schering Pharma
Xofigo (us)
Zydus
Recombio
Vaxira (aR)
lipaglyn (IN)
Ponatinib, tablets, 45 mg
ariad Pharmaceuticals
Iclusig (us)
Treatment of advanced stage non-small cell lung cancer in

patients undergoing chemotherapy and radiotherapy treatment
or in patients who have not responded to first-line therapy
Treatment of adult patients with chronic, accelerated or blast

phase chronic myeloid leukemia (cMl) that is resistant or
intolerant to prior tyrosine kinase inhibitor (TKI) therapy or
Philadelphia chromosome-positive acute lymphoblastic
leukemia (Ph+ all) that is resistant or intolerant to prior TKI
therapy****
Indication
clinical dietary management of enteropathy under medical

supervision for patients who, because of therapeutic or
chronic medical needs, have limited or impaired capacity to
ingest, digest, absorb or metabolize ordinary foodstuffs or
certain nutrients, or who have chronic loose or frequent
stools (e.g., diarrhea-predominant irritable bowel syndrome
[IBs-D]) and in patients with chronic loose or frequent stools
who are infected with hIV
serum-derived bovine immunoglobulin/protein isolate (sBI), powder for reconstitution, 5 g sBI/packet
Continued
Treatment of hypertriglyceridemia in type 2 diabetic patients

not controlled by statins alone
For the management of inoperable chronic thromboembolic

pulmonary hypertension (cTEPh, Who group 4) and of persistent or recurrent cTEPh after surgical treatment in adult
patients ( 18 years of age) with Who functional class II or III
pulmonary hypertension
Treatment of adult and pediatric patients with inhalational

anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs and for prophylaxis of inhalational
anthrax when alternative therapies are not available or are
not appropriate
saroglitazar, tablets, 4 mg
Riociguat, film-coated tablets, 0.5, 1.0, 1.5, 2.0 &

2.5 mg
Raxibacumab, single-use vials containing 1700

mg/34 ml (50 mg/ml) solution for i.v. infusion
Radium Ra 223 dichloride, single-use vials at a con- Treatment of patients with castration-resistant prostate
centration of 1,000 kBq/ml (27 microcurie/ml) at the cancer, symptomatic bone metastases and no known visceral
reference date with a total radioactivity of 6,000
metastatic disease
kBq/vial (162 microcurie/vial) at the reference date
Racotumomab, vials, 1 ml containing 1 mg racotumumab for intradermal injection
active ingredient2
company

A.I. Graul et al.
sphingosomal vincristine, kit consisting of vial containing vincristine sulfate injection, usP 5 mg/5 ml,
vial containing sphingomyelin/cholesterol liposome
injection, 103 mg/ml, and vial containing sodium
phosphate injection 355 mg/25 ml. after preparation, each single-use vial of Marqibo contains
5 mg/31 ml (0.16 mg/ml) vincristine sulfate
Technetium Tc 99m tilmanocept, kit for preparation

of lymphoseek containing five tilmanocept powder
vials each containing 250 g tilmanocept and five
Diluent for lymphoseek vials containing 4.5 ml of
sterile buffered saline. after radiolabeling with technetium Tc 99m and dilution, lymphoseek contains
approximately 92.5 MBq (2.5 mci) and 250 g of
technetium Tc 99m tilmanocept in 0.5 ml to 5 ml
total volume. For subcutaneous, intradermal or peritumoral injection
Teduglutide [rDNa origin], powder in vials, 5 mg, and Treatment for adult patients with short bowel syndrome
solvent, 0.5 ml in prefilled syringe, for reconstitution
(5 mg/0.5 ml) and s.c. injection
spectrum
Pharmaceuticals
astellas
Navidea
Biopharmaceuticals;
sold and distributed by
cardinal health
NPs Pharmaceuticals
Marqibo (us)
Vesomni (Nl)
lymphoseek (us)
gattex (us)
Tamsulosin hydrochloride/solifenacin succinate*,

modified-release tablet, 0.4 mg tamsulosin/6 mg
solifenacin
sofosbuvir, tablets, 400 mg
gilead
sovriad (JP)
sovaldi (us)
Continued
Indicated for lymphatic mapping with a hand-held gamma

counter to assist in the localization of lymph nodes draining a
primary tumor site in patients with breast cancer or
melanoma
Treatment of moderate to severe storage symptoms (urgency,

increased micturition frequency) and voiding symptoms
associated with benign prostatic hyperplasia (BPh) in men
who are not adequately responding to treatment with
monotherapy
Treatment of adult patients with Philadelphia chromosome

negative (Ph) acute lymphoblastic leukemia (all) in second
or greater relapse or whose disease has progressed following
two or more antileukemia therapies
Treatment of chronic hepatitis c virus infection as a component of a combination antiviral treatment regimen
For use in combination with pegylated interferon (PEg-IFN)

and ribavirin for the treatment of genotype 1 chronic hepatitis
c virus (hcV) patients who are treatment-naive, prior nonresponders or relapsed following treatment with PEg-IFN with
or without ribavirin
simeprevir, capsules, 100 mg (JP) and capsules, 150

mg (us)
Janssen licensed from

Medivir
Indication
olysio (us)
active ingredient2
company
A.I. Graul et al.

87
88
Vortioxetine, tablets, 5, 10 & 20 mg
Roche
Bharat Biotech
lundbeck; codeveloped
and comarketed by
Takeda
Kadcyla (us)
Typbar-TcV (IN)
Brintellix (us)
2Products
Treatment of adult patients with unresectable or metastatic

melanoma with BRAF V600E and V600K mutations as
detected by an FDa-approved test
Treatment of gout and hyperuricemia
Indication
Treatment of major depressive disorder in adults
Prevention of typhoid disease in adults and infants aged > 6

months to 45 years
Trastuzumab emtansine, lyophilized powder in single- as a single agent, for the treatment of patients with hER2positive, metastatic breast cancer who previously received
use vials containing 100 mg/vial or 160 mg/vial
trastuzumab and a taxane, separately or in combination.
Patients should have either received prior therapy for
metastatic disease, or developed disease recurrence during
or within 6 months of completing adjuvant therapy
country codes are the abbreviations used by the World Intellectual Property organization.
are ordered alphabetically by active ingredient.
*New combination.
**New indication.
***New formulation.
****Marketing temporarily suspended.
Typhoid conjugate vaccine, prefilled syringes,

25 g/dose in 0.5 ml
glaxosmithKline;
licensed from Japan
Tobacco
Mekinist (us)
Trametinib dimethyl sulfoxide, tablets, 0.5, 1 & 2 mg
sanwa Kagaku
Topiroxostat, tablets, 20, 40 & 60 mg
Kenkyusho/Fuji Yakuhin
uriadec (JP)
Topiloric (JP)
active ingredient2
company

A.I. Graul et al.
A.I. Graul et al.
Chemical structures of NCEs launched in 2013
O
H3C
H3C
N
H
CH3
H
N
N
O
OH
N
H3C
3.H2O
CH3
.HCl
CH3
acotiamide hydrochloride hydrate
CH3
N
Br
N
H3C
CH3
HO
O
Bedaquiline
afatinib
H
N
H
N
O
H3C
Cl
N
CH3
H3C
HN
HN
CH3
. HO
OH
O
OH
cabozantinib S-malate
H3C
CH3
O
HO
HO
CH3
N
H3C
S
S
OH
OH
F
H
N
O
N
N
canagliflozin
.CH3SO3H
NH2
Dabrafenib mesilate
89
A.I. Graul et al.
New launches - structure list for TYND 2013
CH3
O
H3C
OH
H
N
O
O
N
H
Dimethyl fumarate
CH3
Dolutegravir
O
O
O
O
O
NH2
glycerol phenylbutyrate
N
N
N
O
H3C
N
O
CH3
N
N
CH3
CH3
CH2
O
H3C
Ibrutinib
Istradefylline
NH2
.HCl
N
CH3
CH3
levomilnacipran hydrochloride
F
F
N
NH
N
H
lomitapide
90
A.I. Graul et al.
H3C
N
H
Br
NH
N
NH
.HCl
Cl
H3C
lorcaserin hydrochloride
OH
ospemifene
NH
NH2
Pomalidomide
N
N
CH3
H3C
H2N
NH2
H3C
Br
Macitentan
Cl
CH3
Riociguat
H
N
N
F
Ponatinib
91
A.I. Graul et al.
CH3
CH3
H3C
CH3
N
N
O
O
CH3
S
O
CH3
OH
CH3
H
N
H3C
saroglitazar
N
H
simeprevir
O
HN
O
CH3
H3C
O
CH3
HO
Topiroxostat
F
HN
N
O
N
N
CH3
CH3
.
O
H3C
CH3
O
N
H
CH3
Trametinib dimethyl sulfoxide
92
CN
CH3
sofosbuvir
N
N
P
O
N
H O
H
N
CH3
CH3
.HBr
N
H
Vortioxetine hydrobromido
company
ucB
Biocon
sanofi/Zealand
Pharma
Takeda
Janssen
Therapeutics
Product name
(trade name)
certolizumab
pegol (cimzia)
Itolizumab
(alzumab)
lixasenatide
(lyxumia)
alogliptin benzoate/metformin
hydrochloride
(Kazano)
canagliflozin
(Invokana)
Treatment of with type 2

diabetes
Treatment of plaque psoriasis
Treatment of active psoriatic

arthritis
Indication
1,293
387
1,956
lantus Degludec/Tresiba
Invokana Tenelia Nesina
onglyza/Kombiglyze
galvus/Eucreas
glucophage/Metgluco
Victoza humulin
Januvia/glactiv Welchol
Novolog/NovoRapid/Novo
mix Basen actos
Tradjenta/Trajenta
Janumet Forxiga
NovoNorm/Prandin/Prandi
Met/NovoMet/ surepost
glumetza cycloset liovel
amaryl Byetta
Fastic/starsis glufast
Bydureon glucobay
Juvicor/Xelezor Diastobol
humira
Neoral/sandimmune
Diprolene/ Rinderon
Enbrel Remicade
Fumaderm allelock
Elocon/Fulmeta centocor
Tazorac/Zorac
humira/humira Pen
Remicade stelara simponi
Enbrel lodotra cimzia
Drug's estimated competitors trade

sales 2018
names
(million, usD)
Table III. Estimated market size for selected new drugs and biologics and new line extensions launched in 2013.
29,932
30,057
32,123
32,790
Continued
40,024
41,316
31,311
35,013
competitors'
competitors'
estimated sales 2013 estimated sales 2018
(million, usD)
(million, usD)
A.I. Graul et al.

93
94
ViiV healthcare
Dolutegravir
(Tivicay)
hanmi/sanofi
Irbesartan/
atorvastatin
calcium (Robelito)
shionogi
Janssen Biotech
golimumab
(simponi)
Irbesartan/
trichlormethiazide
(Irtra)
company
Product name
(trade name)
Treatment of hIV-1 infection
Treatment of hypertension
Reduction of the risk of

heart disease in patients
with hypertension and
hyperlipidemia
Treatment of ulcerative
colitis
Indication
1,573
Isentress Edurant Trizivir

Reyataz Viread Prezista
complera/Eviplera stribild
Truvada crixivan/strocin
Intelence Kaletra Fuzeon
Zerit/Zerit XR Norvir
Emtriva atripla combivir
Viracept selzentry Epivir
lexiva Telzir agenerase
Epzicom/Kivexa Videx
Zestril cleviprex
olmetec/Benitec/Benicar
Micardis atacand/Parapres
Diovan/co-Diovan unisia
azilva coreg IR/coreg cR
calblock caduet cardura
Norvasc/amlodin concor
Tanatril Bystolic aimix
aprovel/av alide Inspra
Detantol Tenormin coniel
Exforge luprac
cozaar/hyzaar
seloken/Toprol Xl Tritace
Vasotec/Vaseretic Tekturna
Monopril Tribenzor/sevikar
hcT lotrel azor/sevikar
acequin
Delzicol humira Prograf

Remicade asacol
Budenofalk
ultesa/uceris/cortiment
Pentasa salofalk
lialda/Mezavant colazal
2,945
Drug's estimated competitors trade names

sales 2018
(million, usD)
Table III. (Cont.) Estimated market size for selected new drugs and biologics and new line extensions launched in 2013.
17,701
20,208
23,614
Continued
15,256
12,032
28,100
competitors'
competitors'
(million, usD)
(million, usD)

A.I. Graul et al.
Forest/Pierre Fabre
lundbeck/Takeda
glaxosmithKline/
Theravance
levomilnacipran
hydrochloride
(Fetzima)
Vortioxetine
(Brintellix)
Fluticasone
furoate/vilanterol
(Breo Ellipta)
Treatment of type 1 and 2

diabetes in adults
Novo Nordisk
Insulin degludec
(Tresiba)
Prevention of stroke and

systemic embolism in
patients with nonvalvular
atrial fibrillation
Treatment of primary or
mixed hyperlipidemia and
homozygous familial hypercholesterolemia (hoFh)
Bristol-Myers
squibb/Pfizer
apixaban (Eliquis)
Treatment of patients with

relapsing forms of multiple
sclerosis
Treatment of chronic
obstructive pulmonary
disease (coPD)
Treatment of major
depressive disorder
Indication
Ezetimibe/atorvas- Merck & co.

tatin (liptruzet)
Biogen Idec
Dimethyl fumarate
(Tecfidera)
glycopyrronium
Novartis/sosei
bromide/indacaterol
(ultibro Breezhaler)
company
Product name
(trade name)
1,085
18
2,318
5,007
870
2,219
274
14,757
13,611
humulin
Novolog/NovoRapid/
Novomix lantus
14,950
15,293
15,850
17,265
Continued
15,369
5,412
10,342
26,967
12,776
4,335
competitors'
competitors'
(million, usD)
(million, usD)
lipitor Welchol livazo

Zocor Zetia Kynamro
crestor Vytorin Niaspan
Mevacor lescol
argatrovan lipitor crestor

Radicut Xarelto Novastan
Fragmin arixtra coumadin
lovenox angiomax
Fraxiparine axanum
gilenya copaxone Tysabri

Fampyra/ampyra avonex
aubagio Betaferon Rebif
Extavia
alvesco symbicort
Turbuhaler Relovair
Xopenex lodotra Flutiform
Pulmicort Dulera Foradil
seretide/ advair Ventolin
serevent
Prozac
cipralex/Emtact/lexapro
Zoloft cymbalta
Effexor/Effexor XR Pristiq
abilify seroxat/Paxil Viibryd
Wellbrutin Xl/Zyban
Remeron

sales 2018
(million, usD)
A.I. Graul et al.

95
96
genzyme/Isis
Pharmaceuticals
Recombio
sunovion
celgene
actelion
Bayer
Mipomersen
sodium (Kynamro)
Racotumomab
(Vaxira)
lurasidone
hydrochloride
(latuda)
Pomalidomide
(Pomalyst)
Macitentan
(opsumit)
Riociguat
(adempas)
Treatment of symptomatic
vitreomacular adhesion
ocriplasmin
(Jetrea)
Thrombogenics
Treatment of Ph acute lymphoblastic leukemia (all)
sphingosomal vin- spectrum

cristine (Marqibo) Pharmaceuticals
488
1,159
241
Management of chronic
thromboembolic pulmonary
hypertension
Treatment of pulmonary
arterial hypertension
1,473
Treatment of major depressive episodes associated

with bipolar I disorder
(bipolar depression)
Treatment of multiple
myeloma
175
748
Eylea lucentis Macugen
sprycel gleevec/glivec
Erwinaze/Erwinase clolar/
Evoltra
Tasigna sprycel
gleevec/glivec
adcirca Revatio adempas

Tracleer letairis Ventavis
Remodulin Veletri Tyvaso
Kyprolis Treanda Velcade

Thalomid Revlimid
sumiferon Doxil/caely
seroquel IR/XR Zyprexa

abilify Tegretol carbatrol
lamictal geodon
Taxol gemzar avastin

abraxane Tarceva Xalkori
Taxotere Paraplatin Iressa
lojuxta lipitor Zetia

Kynamro crestor Vytorin
lescol/lochol

sales 2018
(million, usD)
Treatment of advanced
stage non-small cell lung
cancer (Nsclc)
Treatment of homozygous
familial hypercholesterolemia (hoFh)
Indication
Treatment of chronic
myeloid leukemia (cMl) or
Ph+ acute lymphoblastic
leukemia (Ph+ all)
ariad
Pharmaceuticals
aegerion
lomitapide
(Juxtapid)
Ponatinib (Iclusig)
company
Product name
(trade name)
5,822
6,064
7,161
8,059
8,336
9,754
10,696
13,391
competitors' estimated sales 2013

(million, usD)
Continued
9,160
3,393
5,300
5,818
10,633
2,728
13,248
5,931
competitors' estimated sales 2018

(million, usD)

A.I. Graul et al.
Treatment of hER2-positive
metastatic breast cancer
Roche
gilead
Janssen/Medivir
Boehringer
Ingelheim
Trastuzumab
emtansine
(Kadcyla)
sofosbuvir
(sovaldi)
simeprevir
(sovriad, olysio)
afatinib (giotrif)
Ibrutinib
(Imbruvica)
amarin
Zydus
Biotest
Pharmaceuticals
Mitsubishi Tanabe
Treatment of hyperphosphaPharma/NextPharma temia in chronic kidney disease
Icosapent ethyl
(Vascepa)
saroglitazar
(lipaglyn)
Immune globin
intravenous
[human] (Bivigam)
colestilan
(BindRen)
Treatment of primary
humoral immunodeficiency
Treatment of hypertriglyceridemia
443
Fosrenol Renvela/Renagel
gammagard
Niaspan Mevalotin Mecavor

atozet
Juvicor/Xelezor/Tesozor
lovaza Vascepal/Miraxion
Neupro Trerief Madopar

azilect Permax
stalevo/comtess/comtan
Requip sinemet apokyn
Kyowa hakko Kirin
Istradefylline
(Nouriast)
Improvement of wearing-off
phenomena in patients with
Parkinson's disease
coagulation factor IX
deficiency (hemophilia B)
Baxter
coagulation factor
IX (recombinant)
(Rixubis)
Treanda Velcade Torisel

BeneFIX Novoseven
3,677

mantle cell lymphoma
Pharmacyclics/
Janssen
Xalkori gemzar alimta

Iressa
Incivek Rebetol olysio

Pegasys Victrelis uRso
copegus sumiferon PegIntron
Taxol gemzar
afinitor/certican abraxane
halaven Taxotere Tykerb
Ixempra Faslodex arimidex
29
260
6,762
2,826

sales 2018
(million, usD)
Treatment of metastatic nonsmall cell lung cancer (Nsclc)
Treatment of hepatitis c
virus infection
Indication
company
Product name
(trade name)
1,417
1,635
1,968
2,275
2,484
3,455
Continued
855
998
1,571
2,548
1,259
4,062
1,506
3,860
3,813
7,987
4,917
competitors'
competitors'
(million, usD)
(million, usD)
A.I. Graul et al.

97
98
company
Influenza virus
glaxosmithKline
vaccine, quadrivalent
(Flulaval)
Influenza virus
sanofi Pasteur
(Fluzone)
active immunization against

invasive disease caused by
Neisseria meningitidis
serogroup-B strains
active immunization to
prevent invasive disease
caused by Neisseria meningitidis serogroups c and Y and
Haemophilus influenzae type
b
Meningococcal
Novartis
group B vaccine
[rDNa, component,
adsorbed]
(Bexsero)
glaxosmithKline
Toa Eiyo/astellas
Pharma
Meningococcal
groups c and Y
and haemophilus
b tetanus toxoid
conjugate vaccine
(Menhibrix)
Bisoprolol (Bisono
Tape)
Treatment of essential
hypertension
Treatment of active systemic

juvenile idiopathic arthritis
(sJIa) and gouty arthritis
Novartis
canakinumab
(Ilaris)
260
800
377
Influenza virus
vaccine (FluBlok)
Influenza virus
glaxosmithKline
(Fluarix)
300
herbesser Plendil adalat

Verelan
Merrem/Meropen ocephin
Menveo ceftin/Zinacef
uloric colcrys arcoxia
Rapiacta/PeramiFlu
Tamiflu Fluvirin Fluviral
Relenza

sales 2018
(million, usD)
Prevention of influenza (a
and B)
Indication
Protein sciences
Influenza virus
MedImmune
vaccine live (FluMist (astraZeneca)
Quadrivalent)
Product name
(trade name)
Table III. (cont.) Estimated market size for selected new drugs and biologics and new line extensions launched in 2013.
1,180
1,214
1,294
1,092
912
Continued
1,109
1,168
912
competitors'
competitors'
(million, usD)
(million, usD)

A.I. Graul et al.
Treatment of moderate to
severe dyspareunia due to
menopause
Topical treatment of persistent

facial erythema of rosacea
Treatment of short bowel

syndrome
alfresa Pharma
shionogi
galderma
NPs
Pharmaceuticals
sanwa Kagaku
Treatment of gout and
Kenkyusho/Fuji Yakuhin hyperuricemia
arena/Eisai
alcon (Novartis)
swedish orphan
BioVitrum
clomipramine
hydrochloride
(anafranil)
ospemifene
(osphena)
Brimonidine
tartrate (Mirvaso)
Teduglutide
(gattex)
Topiroxostat
(uriadec, Topiloric)
lorcaserin hydrochloride (Belviq)
Brinzolamide/
brimonidine
tartrate (simbrinza)
anakinra (Kineret)
Treatment of neonatal-onset
multisystem inflammatory
disease (NoMID)
Reduction of intraocular
pressure in patients with
primary open-angle glaucoma
or ocular hypertension
Weight management
Treatment of cataplexy in
patients with narcolepsy
glaxosmithKline
Raxibacumab
(abthrax)
Treatment of inhalational
anthrax due to Bacillus
anthracis
glaxosmithKline
Dabrafenib
mesilate (Tafinlar)
Treatment of BRAF-mutated
metastatic melanoma
Trametinib dimethyl glaxosmithKline/

sulfoxide (Mekinist) Japan Tobacco
Indication
Treatment of moderate to
severe vasomotor symptoms
associated with menopause
company
Noven
Paroxetine
mesilate (Brisdelle)
Product name
(trade name)
436
582
502
666
167
115
Ilaris
376
336
775
Continued
258
262
182
313
206
1,289
317
406
565
567
553
2,178
962
835
965
competitors'
estimated sales 2018
(million, usD)
1,063
competitors'
estimated sales 2013
(million, usD)
Tapros Rescula
Xenical Qsymia
uloric
saizen / serostim
allelock Fulmeta
activella Estrace
Xyrem
levaquin/Floxin ozex
Doryx cipro/ciprobay
Yervoy
Premarin

sales 2018
(million, usD)
A.I. Graul et al.

99
100
Roche/genentech/
Biogen Idec
algeta/Bayer
schering Pharma
obinutuzumab
(gazyva)
Radium Ra 223
dichloride (Xofigo)
68
symptomatic relief of noninfectious diarrhea in adult

patients with hIV/aIDs on
antiretroviral therapy
crofelemer
(Fulyzaq)
source: Thomson Reuters cortellisTM and Thomson Reuters IntegritysM, December 2013.
salix/Napo
136
140
Treatment of congenital
lipodystrophy
chronic management of urea

cycle disorders
shionogi licensed
from amylin
Metreleptin
(leptin)
243
280
937
Treatment of functional
dyspepsia
Treatment of Peyronie's
disease

castration-resistant prostate
cancer with symptomatic bone
metastases
1,189
3,803
301
350
caprelsa
Enablex
selincro campral

sales 2018
(million, usD)
glycerol phenylbu- hyperion

tyrate (Ravicti)
Therapeutics
Zeria/astellas
Pharma
acotiamide
hydrochloride
hydrate (acofide)
collagenase
auxilium
Clostridium
histolyticum (Xiaflex)
Treatment of giant cell tumor

of bone
amgen
Denosumab
(Xgeva)

previously untreated chronic
lymphocytic leukemia
Treatment of progressive, metastatic medullary thyroid cancer
cabozantinib
Exelixis
S-malate (cometriq)
Reduction of alcohol consumption in adult patients

with alcohol dependence
Treatment of moderate to severe

storage symptoms (urgency,
increased micturition frequency)
and voiding symptoms associated
with benign prostatic hyperplasia
BioTie Therapies/
lundbeck
Nalmefene
(selincro)
Indication
Tamsulosin
astellas
hydrochloride/
solifenacin
succinate (Vesomni)
company
Product name
(trade name)
49
73
82
156
23
361
competitors'
competitors'
(million, usD)
(million, usD)

A.I. Graul et al.

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Drugs of Today 2014, 50(1): 51-100

ThE YEaRs NEW DRugs & BIologIcs,

Correspondence: a.I. graul, Thomson Reuters, Barcelona, spain. E-mail: ann.graul@thomsonreuters.com.

ThE YEaRs NEW DRugs & BIologIcs 2013

A.I. Graul et al.

The year 2013 witnessed the first launches of 56 new

as shown in Figure 1, the united states was by far the

Key words: New drug launches New biologics New

Table I. Drugs & biologics introductions by therapeutic category, 2003-2013.

central nervous system

Poisoning & drug abuse

ThoMsoN REuTERs Drugs of Today 2014, 50(1)

A.I. Graul et al.

ThE YEaRs NEW DRugs & BIologIcs 2013

agency (DEa) schedule II drug. Zogenix plans to launch

Figure 1. Distribution of new launches in 2013 by country.

followed with 5, while India debuted in this listing with 4

In March, the u.K.s Medicines and healthcare products

ThE YEaRs NEW DRugs & BIologIcs 2013

to placebo in adults with MDD. combined, these studies

A.I. Graul et al.

germany last July following approval by the European

A.I. Graul et al.

ThE YEaRs NEW DRugs & BIologIcs 2013

1960s for the treatment of anxiety and depression, was

ThE YEaRs NEW DRugs & BIologIcs 2013

A.I. Graul et al.

u.s. for the treatment of chronic obstructive pulmonary

ment of bronchial asthma in adults and adolescents

A.I. Graul et al.

ThE YEaRs NEW DRugs & BIologIcs 2013

for the first time in Japan. Irtra contains the angiotensin

ThE YEaRs NEW DRugs & BIologIcs 2013

A.I. Graul et al.

tamsulosin hydrochloride and solifenacin succinate,

in the primary measures of intravaginal ejaculation

A.I. Graul et al.

ThE YEaRs NEW DRugs & BIologIcs 2013

review in Europe, switzerland and singapore, where

ThE YEaRs NEW DRugs & BIologIcs 2013

dapagliflozin, was launched in Europe in 2012 and last

A.I. Graul et al.

(sERM) that was approved and launched in the u.s. for

A.I. Graul et al.

In october, Pfizers fixed-dose combination product

ThE YEaRs NEW DRugs & BIologIcs 2013

ThE YEaRs NEW DRugs & BIologIcs 2013

A.I. Graul et al.

portion of patients taking crofelemer 125 mg twice daily

NPs Pharmaceuticals teduglutide [rDNA origin]

A.I. Graul et al.

ThE YEaRs NEW DRugs & BIologIcs 2013

without known mutations associated with resistance to

ThE YEaRs NEW DRugs & BIologIcs 2013

and in December the product was launched in its first

A.I. Graul et al.

Tuberculosis (TB) is a major public health concern

ThoMsoN REuTERs Drugs of Today 2014, 50(1)

A.I. Graul et al.

ited evidence available from clinical trials; the FDas

ThE YEaRs NEW DRugs & BIologIcs 2013

anthrax due to Bacillus anthracis in combination with