2013 New Drug Launches.pdf

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Drugs of Today 2014, 50(1): 51-100Copyright © 2014 Prous Science, S.A.U. or its licensors. All rights reserved.

CCC: 1699-3993/2014

DOI: 10.1358/dot.2014.50.1.2116673

CONTENTS

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Agents for analgesia & anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Psychopharmacological drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Neurologic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54Respiratory drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55Cardiovascular drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57Renal–urologic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Hematologic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Endocrine drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Dermatologic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61Gastrointestinal agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61Anti-infective therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63Therapy of musculoskeletal & connective tissue diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Immunomodulators & agents for immunization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67Treatment of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Ophthalmic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72Metabolic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73Treatment of poisoning & drug dependency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77Dental agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77Diagnostic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Correspondence: A.I. Graul, Thomson Reuters, Barcelona, Spain. E-mail: [email protected].

REVIEW

THE YEAR’S NEW DRUGS & BIOLOGICS,2013: PART I

A.I. Graul, E. Cruces and M. Stringer

Thomson Reuters, Barcelona, Spain


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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 FDA’s new

Breakthrough Therapy Designation. The review also covers

30 important new line extensions, encompassing new indi-

cations, new formulations and new combinations of previ-

ously 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.

Key words: New drug launches – New biologics – New

approvals – Line extensions – Orphan drugs

INTRODUCTION

The year 2013 witnessed the first launches of 56 newdrugs and biologics, the highest number in at least a

decade (see Table I). This includes 10 first-in-class

agents, defined as drugs with a new and unique mecha-nism of action. Also launched this year were 30 impor-

tant new line extensions (new indications, new formula-tions or new combinations of previously marketed drugs

and biologics).

The most active therapeutic group for new drugs andbiologics in 2013 was oncolytic drugs, with 12 new drugsand biologics reaching the market to treat patients withcancer, followed by immunologic agents and metabolic

drugs, with 11 and 7 products, respectively (see Table I).

Twenty of the new products and line extensions intro-

duced in 2013 have orphan drug status, also a muchhigher number than previous years, reflecting the recentupsurge of R&D investment in this area. In another excit-

ing new development, the first three products bearingthe FDA’s new Breakthrough Therapy Designation wereapproved for marketing by the agency.

As shown in Figure 1, the United States was by far themost important market for new drugs, with 42 globalfirst launches in 2013 taking place in that country. Japan

THE YEAR’S NEW DRUGS & BIOLOGICS 2013 A.I. Graul et al.

52 THOMSON REUTERS – Drugs of Today 2014, 50(1)

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 3 6 6 1 3 4 7 4 5 2 4

Respiratory 3 0 1 0 2 2 2 1 1 2 1

Cardiovascular 1 0 2 2 2 2 1 1 1 1 2

Renal–urologic 3 2 3 3 1 2 2 0 2 1 0

Hematologic 1 1 1 0 2 6 3 1 3 2 1

Gastrointestinal 0 0 1 2 1 3 1 1 0 1 4

Endocrine drugs 1 2 3 3 2 0 3 2 1 4 4

Dermatologic 2 0 0 0 0 2 1 0 1 2 1

Anti-infective 5 1 6 2 5 3 1 2 6 0 5

Antiarthritic 1 0 0 1 0 1 3 0 1 2 0

Immunologic 2 2 6 9 4 3 17 5 4 5 11

Cancer 3 7 6 7 5 1 6 7 7 10 12

Ophthalmic 0 0 2 2 0 1 1 1 2 0 1

Metabolic drugs 4 2 1 7 2 2 3 4 2 2 7

Poisoning & drug abuse 0 0 1 1 0 0 0 0 0 1 1

Dental 0 0 1 0 0 0 0 0 0 0 1

Diagnostic agents 0 3 2 1 1 1 0 0 0 1 1

Total 29 26 42 41 30 33 51 29 36 36 56


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followed with 5, while India debuted in this listing with 4new launches.

In addition to this bumper crop of new launches, anoth-er 19 products were approved for the first time during theyear but not yet launched by the close of this article; thisnumber includes both new drugs and biologics, as wellas important new line extensions.

The information in this review and the accompanyingtables was compiled from company communications,Thomson Reuters Drug News and the Thomson ReutersIntegritySM and Thomson Reuters Cortellis™ drug data-bases.

AGENTS FOR ANALGESIA & ANESTHESIA

The long-acting opioid analgesic hydrocodone bitar-

trate (Zohydro™ ER; Zogenix) was approved for the firsttime last year in the U.S., where it is indicated for themanagement of pain severe enough to require daily,around-the-clock, long-term opioid treatment and forwhich alternative treatment options are inadequate.Zohydro ER is the first extended-release hydrocodonetherapy that is formulated without acetaminophen.

Acetaminophen overdose is a leading cause of acute liverfailure in the U.S., and 63% of unintentional acetamino-phen overdoses are attributed to the use of hydrocodone-acetaminophen combination products such as Vicodin®.

Zohydro uses Alkermes’ patented Spheroidal Oral DrugAbsorption System (SODAS®) drug delivery technology.The product will be classified as a Drug Enforcement

Agency (DEA) Schedule II drug. Zogenix plans to launchit during the first quarter of 2014.

In March, the U.K.’s Medicines and Healthcare productsRegulatory Agency (MHRA) approved Horizon Pharma’sDuexis® (ibuprofen/famotidine) for the symptomatictreatment of osteoarthritis, rheumatoid arthritis andankylosing spondylitis in patients who require regulartreatment with high-dose ibuprofen administered threetimes a day and who are at risk of developing non-steroidal anti-inflammatory drug (NSAID)-associatedgastric and/or duodenal ulcers. Horizon Pharma is seek-ing a commercial partner or partners for Duexis in theU.K. and the rest of Europe. Duexis, a proprietary single-tablet combination of the NSAID ibuprofen and the his-tamine H

2receptor antagonist famotidine, is indicated in

the U.S. for the relief of signs and symptoms of rheuma-toid arthritis and osteoarthritis and to decrease the riskof developing upper gastrointestinal ulcers in patientswho are taking ibuprofen for those indications. The U.K.approval was the first worldwide to include the new indi-cation of ankylosing spondylitis.

NuPathe’s Zecuity™, an iontophoretic transdermal sys-tem for delivery of the 5-HT

1B/1Dreceptor agonist suma-

triptan, was approved last year in the U.S. for the acutetreatment of migraine with or without aura in adults.

Zecuity is a single-use, battery-powered patch that isapplied to the upper arm or thigh during a migraine.Following application and with a press of a button,Zecuity initiates transdermal delivery, bypassing thegastrointestinal tract. Throughout the 4-hour dosingperiod, the microprocessor within Zecuity continuouslymonitors skin resistance and adjusts drug deliveryaccordingly to ensure delivery of 6.5 mg of sumatriptan,with minimal patient-to-patient variability. The productprovides relief of both migraine headache pain andmigraine-related nausea. NuPathe is currently seeking

partnerships to maximize the commercial potential ofZecuity, and has delayed product launch until the identi-fication 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 andForest’s levomilnacipran (Fetzima™), a once-daily sero-tonin and norepinephrine reuptake inhibitor (SNRI) andthe active isomer of the marketed antidepressant mil-

nacipran. The NDA was supported by three double-blindphase III studies including two fixed-dose studies, andone flexible-dose study that compared levomilnacipran

A.I. Graul et al. THE YEAR’S NEW DRUGS & BIOLOGICS 2013

53THOMSON REUTERS – Drugs of Today 2014, 50(1)

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

USA

India

Japan

Canada

EU

Argentina


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to placebo in adults with MDD. Combined, these studiesincluded a total of more than 1,600 adult patients whoreceived 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 theMontgomery-Åsberg Depression Rating Scale totalscore and the secondary endpoint was change frombaseline to endpoint in the Sheehan Disability Scaletotal score. In all three studies, statistically significantimprovement was seen for the levomilnacipran groupcompared with placebo on both the primary and sec-ondary 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 andDrug Administration (FDA) in September 2013 for thetreatment of MDD. Vortioxetine inhibits serotonin reup-take and acts as a 5-HT

1Areceptor agonist, 5-HT

1Bpartial

agonist and 5-HT3, 5-HT1D and 5-HT7 receptor antago-nist. This multifaceted profile results in the modulationof neurotransmission in several systems, including pre-dominantly serotonin, but conceivably also the norepi-nephrine, dopamine, histamine, acetylcholine, GABAand glutamate systems. The relative contribution of eachindividual mechanism of action has not been estab-

lished. Vortioxetine is the first antidepressant with thiscombination 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 Europeanmarketing authorization of vortioxetine for MDD. Thedrug was made available in December, although a for-mal launch is planned for January 2014.

In June 2013, Sunovion Pharmaceuticals received FDAapproval of lurasidone hydrochloride (Latuda®) for twonew indications: as monotherapy and as adjunctive ther-

apy with either lithium or valproate, both to treat adultpatients with major depressive episodes associated withbipolar I disorder. Approval of the new indications wassupported by two 6-week, double-blind, randomized,placebo-controlled trials, PREVAIL 2 (monotherapy) andPREVAIL 1 (adjunctive therapy; respective ClinicalTrials.gov Identifiers NCT00868699 and NCT00868452).Lurasidone is an atypical antipsychotic that has beenmarketed since 2011 for the treatment of schizophrenia.It was introduced for the new indication in late July.

Adasuve®, a new formulation of the typical antipsychot-ic loxapine succinate formulated using the Staccato®inhalation system, was launched for the first time in

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 adultpatients with schizophrenia or bipolar disorder. The mar-

keting authorization requires that patients receive regu-lar treatment immediately after control of acute agita-

tion symptoms, and that the drug be administered only

in a hospital setting under the supervision of a health-care professional. Adasuve was previously approved in

the U.S. in 2012, as announced in last year’s edition of

this article, but has not yet been launched in that coun-

try. Alexza is responsible for manufacture and marketingof the product, which is distributed by Ferrer. Loxapine

succinate is a typical antipsychotic that was first

launched in 1975 by Watson Pharmaceuticals in a cap-

sule formulation for the treatment of psychosis.

NEUROLOGIC DRUGS

In the first quarter of 2013, Biogen Idec obtained FDAapproval for dimethyl fumarate (Tecfidera™), indicated

as a first-line treatment for people with relapsing forms

of multiple sclerosis (MS). Dimethyl fumarate is an oral-

ly administered immunomodulating and neuroprotec-

tive agent that provides a new approach to the treat-ment 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 oxidativestress 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 toslow disability progression over time, while demonstrat-

ing a favorable safety and tolerability profile. Biogen Idec

launched the drug just days after approval.

In September, the European Commission approved thehumanized anti-CD52 monoclonal antibody alem-

tuzumab (Lemtrada™; Genzyme) for the treatment ofadult patients with relapsing–remitting MS with active

disease defined by clinical or imaging features. The

approval was supported by the CARE-MS I and CARE-

MS II trials, in which alemtuzumab was significantly

more effective than interferon β-1a at reducing annual-ized relapse rates. This is a new indication for alem-

tuzumab, which has been marketed by Bayer HealthCare

Pharmaceuticals since 2004 for the treatment of chron-

ic lymphocytic leukemia. Genzyme holds the worldwiderights to alemtuzumab and has primary responsibility

for its development and commercialization in MS.




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Istradefylline (Nouriast®), a first-in-class antiparkinson-

ian 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 ofother 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

Parkinson’s 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 levo-

dopa-containing products, to treat wearing-off phenom-

ena. It was launched in Japan in May.

The tricyclic antidepressant clomipramine hydrochlo-

ride (Anafranil®), which has been marketed since the

1960s for the treatment of anxiety and depression, wasapproved and launched last year for the first time inJapan for a new indication: treatment of cataplexy inpatients with narcolepsy. This is the first time that a reg-ulatory body has officially approved clomipramine forthis use, although it has long been prescribed off-labelfor patients with cataplexy, and in fact Alfresa filed theapplication for this indication based on evidence in thepublic domain. Japan has the world’s highest prevalenceof narcolepsy: 1 in 600 inhabitants, according to theNarcolepsy Network.

RESPIRATORY DRUGS

Breo™ Ellipta™ (GlaxoSmithKline[GSK]/Theravance), afixed-dose combination product incorporating the

inhaled corticosteroid fluticasone propionate and vilanterol , a long-acting β

2-adrenoceptor agonist

(LABA), was approved last year for the first time in the



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 activationof nuclear factor, erythroid-derived 2, -like 2 (Nrf2), an effect that is believed to be independent of its immunomodulatory andradiosensitizing mechanisms. Its function as an Nrf2 activator is expected to have utility in treating relapsing-remitting multiple

sclerosis.


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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 airflowobstruction 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 clini-

cal pharmacology studies in 1,406 patients and 11 clinical

studies in 7,851 patients with COPD. There were four pri-

mary 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 alsoapproved last year in Japan, where it is known as Relvar™

Ellipta™, for a different respiratory indication: the treat-

ment of bronchial asthma in adults and adolescentsaged 12 years and older in cases where concurrent use ofan inhaled corticosteroid and a long-acting β

2-adreno-

ceptor agonist is required. The product was developedusing a dry powder formulation technology for inhala-tion products licensed by GSK from SkyePharma. InNovember, Relvar Ellipta was approved in the E.U. forboth indications: asthma and COPD.

Another new combination product for COPD —Ultibro®(glycopyrronium bromide/indacaterol)— was alsoapproved last September in both the European Unionand Japan. Ultibro is a first-in-class combination productcontaining the LABA indacaterol and the long-acting

muscarinic antagonist (LAMA) glycopyrronium bromide,and is formulated as inhalation capsules for use with theBreezhaler® device. Dual bronchodilation with Ultibro is



Figure 3. The loss of dopamine input into the neostriatum is a key characteristic of Parkinson’s disease (PD). Although dopamine

replacement therapy using dopamine precursors assuages motor symptoms, their extended use may result in diminished efficacyand debilitating dyskinesia. An alternative approach is the implementation of nondopaminergic therapy, which entails the modula-

tion of adenosine receptors. Adenosine, a neuromodulator, facilitates responses to dopamine and neurotransmitters of motor func-tion/cognition. Adenosine A

2Areceptors are heavily populated within the striatum and directly associated with dopamine D

2recep-

tors, 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.


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expected to set a new standard of care in COPD, accord-

ing to product codevelopers Novartis and Sosei. COPD isa 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 patientsare currently living with COPD in Japan. The first productlaunches took place in Germany and the Netherlands,with launch in Japan following shortly thereafter.

Olodaterol hydrochloride (Striverdi® Respimat®), a newlong-acting β

2-adrenoceptor agonist from Boehringer

Ingelheim, was approved last year in several countriesincluding Russia, Canada, Denmark, Iceland and theU.K. The LABA was developed as a fast-acting and long-lasting bronchodilator for once-daily maintenance treat-ment of airflow obstruction in patients with COPD,including chronic bronchitis and emphysema.

Lucinactant (Surfaxin®; Discovery Laboratories), ahumanized, engineered version of natural human lungsurfactant, was launched for the first time in the U.S. inNovember 2013. Lucinactant is indicated for the preven-tion of respiratory distress syndrome (RDS) in prematureinfants at high risk for RDS. It is the first FDA-approvedsynthetic, peptide-containing surfactant and the onlyalternative to animal-derived surfactants available inthe U.S.

CARDIOVASCULAR DRUGS

Over the course of 2013, partners Bristol-Myers Squibband Pfizer began rolling out the coagulation factor Xainhibitor apixaban (Eliquis®) in markets worldwide for anew indication: the prevention of stroke and systemicembolism 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. andJapan. Apixaban was first launched in 2011 for the preven-

tion of venous thromboembolic events in adults who haveundergone elective hip or knee replacement surgery.

Also in 2013, a new treatment option became availableto Japanese patients with mild to moderate essentialhypertension: Bisono® Tape, a once-daily transdermalpatch formulation of the established β

1-adrenoceptor

antagonist bisoprolol. Bisono Tape is the firsttransdermal patch formulation of a β-blocker to reachthe market anywhere in the world. It was codeveloped byToa Eiyao and Nitto Denko, and is marketed and distrib-uted by Astellas.

Shionogi’s Irtra®, a fixed-dose combination antihyper-tensive agent, was also approved and launched last year

for the first time in Japan. Irtra contains the angiotensinAT

1receptor antagonist irbesartan and trichlormethi-

azide, a diuretic, in a single tablet. The combination of arenin-angiotensin blocker and a low-dose diuretic is rec-

ommended in Japanese guidelines for hypertensiontherapy, due to their synergistic antihypertensive activityand favorable side effect profile.

Another irbesartan-containing fixed-dose combinationreached its first market last year in Korea: Hanmi andSanofi’s Robelito, containing irbesartan and atorvas-tatin calcium, a widely marketed statin. Robelito is indi-cated to reduce the risk of heart disease in patients withhypertension and hyperlipidemia who are already pre-scribed the two active drugs, and was developed to sim-plify treatment regimens.

The endothelin ETA/ET

Bantagonist macitentan

(Opsumit®; Actelion) was approved and launched lastyear for the first time in the U.S. for the treatment ofadults with pulmonary arterial hypertension (PAH, WHOgroup I), to delay disease progression. The product car-ries a boxed warning alerting patients and healthcareprofessionals that it should not be used in pregnantwomen because it can harm the developing fetus. Theefficacy of macitentan was established in the pivotalstudy SERAPHIN (ClinicalTrials.gov Identifier

NCT00660179), a randomized, controlled trial involving742 patients with PAH with predominantly WHO func-tional class II-III symptoms treated for an average of 2years. In October 2013, the EMA’s Committee forMedicinal Products for Human Use issued a positiveopinion on the use of macitentan in PAH.

Chronic thromboembolic pulmonary hypertension(CTEPH) is a progressive and life-threatening type ofpulmonary hypertension in which thromboembolicocclusion of pulmonary vessels gradually leads toincreased blood pressure in the pulmonary arteries,resulting in an overload of the right heart. Last year thefirst-in-class soluble guanylate cyclase stimulator rio-ciguat (Adempas®; Bayer) was approved and launchedin Canada, becoming the first drug ever to obtain regu-latory approval for this rare disease (Fig. 4). CTEPHaffects up to several thousand patients in Canada. Priorto the introduction of riociguat, there were no provenpharmacotherapeutic alternatives for patients with inop-erable or persistent CTEPH.

RENAL–UROLOGIC DRUGSVesomni™, a new fixed-dose combination product fromAstellas incorporating the α

1-adrenoceptor antagonist




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tamsulosin hydrochloride and solifenacin succinate,

an antimuscarinic, was approved for the first time in May

in the Netherlands and was launched there in Septem-

ber. Vesomni is indicated for the treatment of moderateto severe storage symptoms (urgency, increased micturi-

tion frequency) and voiding symptoms associated with

benign prostatic hyperplasia in men who are not ade-

quately responding to treatment with monotherapy. The

Netherlands will act as Reference Member State for fur-

ther registration of the product throughout Europe.

In November, Plethora Solutions Holdings received mar-

keting authorization from the European Commission

for Prilocaine Lidocaine Plethora (PSD-502), a topical

spray incorporating two local anesthetics, indicated forthe treatment of primary premature ejaculation. The

treatment was associated with significant improvement

in the primary measures of intravaginal ejaculation

latency time, control and satisfaction in two pivotal, dou-

ble-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 phar-

macotherapeutic agent ever for the treatment of

Peyronie’s disease: collagenase Clostridium his-

tolyticum (Xiaflex®; Auxilium), indicated for the treat-

ment of adult men with Peyronie’s disease with a palpa-

ble 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 Peyronie’s disease. Men with the disorder



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 guanosinemonophosphate (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 vasodi-

latation, leads to blood vessel dilation, the diminution of blood pressure and the modulation of tissue-protective effects. Thus, GCactivators may be effective in the treatment of PAH and associated disorders such as chronic thromboembolic pulmonary

hypertension.


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were randomized to receive a maximum of four treat-ment cycles at 6-week intervals of Xiaflex or placeboadministered by intralesional injection. Men randomizedto the active treatment showed a mean 34% improve-

ment in penile curvature, as compared to 18.2%improvement in those randomized to placebo. Symptombother scores also improved to a significantly greaterextent with Xiaflex as compared to placebo (–2.8 ± 3.8vs. –1.8 ± 3.5, respectively). Xiaflex was previouslyapproved by the FDA in 2010 for the treatment ofDupuytren’s contracture. Auxilium immediately begancommercializing the product for this new indication.

In patients with reduced renal function, phosphorus isnot sufficiently excreted into the urine via the kidneysand accumulates in the body, which can lead to hyper-

phosphatemia. Persistent hyperphosphatemia causessecondary hyperparathyroidism and even nephrogenicosteopathy characterized by bone pain and a tendency

for bone fracture. Additionally, phosphorus binds to cal-cium to form calcium phosphate, which in turn causescalcinosis on vascular walls, heart, lungs and other inter-

nal organs, as well as periarticular areas. Because thisrepresents 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 newproducts developed specifically for this purpose.

Mitsubishi Tanabe Pharma’s colestilan (BindRen®), anon-absorbed anion exchange resin and phosphate

binder, was approved by the European Commission inFebruary and launched in its first markets —Germanyand Austria— in April. Colestilan is indicated for the

treatment of hyperphosphatemia in adult patients withchronic kidney disease (CKD) stage 5 receivinghemodialysis or peritoneal dialysis. This is a new indica-

tion for colestilan, which has been marketed in Japan (as

Cholebine®) since 1999 for the treatment of hypercho-lesterolemia.

The iron-based phosphate binder sucroferric oxyhy-droxide (Velphoro®; Vifor Pharma) was approved by the

FDA in November 2013 for the control of serum phos-phorus levels in patients with CKD on dialysis. Theapproval was based on a pivotal phase III study which

met both its primary and secondary endpoints. Thestudy demonstrated that Velphoro successfully controlshyperphosphatemia with fewer pills (average of 3.3/day)

as compared to sevelamer carbonate, the current stan-dard of care. Velphoro will be launched in the U.S. byFresenius in 2014. The product is also under regulatory

review in Europe, Switzerland and Singapore, wheredecisions are expected in the first half of 2014.

HEMATOLOGIC AGENTS

The FDA approved Baxter’s Rixubis (nonacog gamma,coagulation factor IX [recombinant]) in June, indicatedfor routine prophylactic treatment, control of bleedingepisodes and perioperative management in adults withhemophilia B. Rixubis is the first new recombinant coag-ulation factor IX (rFIX) approved for hemophilia B inmore than 15 years and is the only rFIX indicated for bothroutine prophylaxis and control of bleeding episodes inthe U.S. for adult patients living with this chronic condi-tion. The approval was based on a phase I/III study

demonstrating that twice-weekly prophylactic treatmentwith Rixubis for 6 months achieved a median annualizedbleed rate of 2.0 with 43% of patients experiencing nobleeds (ClinicalTrials.gov Identifier NCT01174446).Baxter launched the product in the U.S. and Puerto Ricoin October, and shortly thereafter filed for marketingapproval in the European Union.

Turoctocog alfa (NovoEight®), a recombinant coagula-tion factor VIII product from Novo Nordisk, was approvedlast year by the U.S. FDA for use in adults and childrenwith hemophilia A. It is indicated for the control and pre-

vention of bleeding, perioperative management, androutine prophylaxis to prevent or reduce the frequency ofbleeding episodes. Awaiting the expiration of existingpatents, Novo Nordisk plans to launch turoctocog alfa inthe U.S. shortly after April 2015. Last year the productalso received a positive opinion from the EuropeanMedicines Agency’s Committee for Medicinal Productsfor Human Use.

ENDOCRINE DRUGS

The sodium/glucose cotransporter (SGLT), which existson the chorionic membrane of the intestine and the kid-ney, actively transports glucose by coupling with Na+.The inhibition of renal SGLTs leads to suppression oftubular glucose reabsorption and the excretion of excessplasma glucose into urine, thereby eliminating hyper-glycemia. In persons with diabetes and/or obesity, glu-cose and energy loss through excretion is advantageous,as this action can reduce hyperglycemia and glucose-related osmotic dehydration of cells. Both low-affinity(SGLT2) and high-affinity (SGLT1) forms have been stud-

ied for this indication, although SGLT2 inhibitors in par-ticular are held to be especially promising for the treat-ment 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: Janssen’s 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 mar-

keting approval in the U.S., where it has been available

since April 2013.

A new incretin mimetic, the GLP-1 receptor agonistlixisenatide (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 mar-

ket, later in the first quarter. Lixisenatide was developed

by Sanofi under license from Zealand Pharma. It is indi-cated 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.

Takeda’s Kazano®, a novel fixed-dose combination ther-

apy 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 demonstrat-

ed 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 lessrisk 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 populationof aging women. The first, ospemifene (Osphena®;

Shionogi), is a selective estrogen receptor modulator

(SERM) that was approved and launched in the U.S. forthe treatment of moderate to severe dyspareunia, asymptom of vulvar and vaginal atrophy (VVA), due tomenopause. More than half of U.S. women will experi-

ence VVA at some point during their postmenopausallife, although the vast majority of them do not receivetreatment. Ospemifene is the first and only oral alterna-tive to vaginal or oral steroidal estrogens for women withdyspareunia due to menopause. Its safety and effective-ness were established in 3 clinical studies of 1,889 post-menopausal women with symptoms of VVA. After 12weeks of treatment, results from the first two trialsshowed a statistically significant improvement of dys-pareunia in ospemifene-treated women compared withthose receiving placebo. Results from the third study

support the product’s long-term safety in treating dys-pareunia. Osphena carries a boxed warning alertingwomen and healthcare professionals that the drug,which acts like estrogen on vaginal tissues, can stimulatethe lining of the uterus and cause it to thicken. Womenshould see their healthcare professional if they experi-ence any unusual bleeding as it may be a sign ofendometrial cancer or a condition that can lead to it. Theboxed warning also states the incidence rates of throm-botic and hemorrhagic strokes (0.72 and 1.45 per thou-sand women, respectively) and the incidence rate of

deep vein thrombosis (1.45 per thousand women). Theserates are considered to represent low risks in contrast tothe increased risks of stroke and deep vein thrombosisseen with estrogen-alone therapy. However, ospemifeneshould be prescribed for the shortest duration consistentwith treatment goals and risks for the individual woman.Shionogi obtained exclusive global marketing rights tothe SERM under a license agreement signed withQuatRx 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 thefirst nonhormonal therapy for vasomotor symptoms(VMS) associated with menopause. The product wasdeveloped by Noven Pharmaceuticals to treat hot flashesand night sweats associated with menopause. Manywomen are unable or unwilling to take hormone therapyto treat VMS, often leaving symptoms untreated. In phaseII and III studies enrolling a total of 1,276 women with VMSassociated with menopause, treatment with paroxetinemesilate for 24 weeks led to reductions in the frequency

and severity of moderate to severe hot flashes, with afavorable safety profile. Paroxetine mesilate has beenmarketed since 2001 for the treatment of depression.




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In October, Pfizer’s fixed-dose combination productDuavee™ (conjugated estrogens/bazedoxifene) wasapproved in the U.S. It is indicated, in women with auterus, for the treatment of moderate to severe vasomo-

tor symptoms associated with menopause and for theprevention of postmenopausal osteoporosis. Duavee isthe first FDA-approved medication that contains anestrogen in combination with a SERM, bazedoxifene.The SERM component reduces the risk of endometrialhyperplasia that can occur with the estrogen compo-nent. Duavee was originally developed at Wyeth (nowPfizer), and was subject to a joint research, discovery anddevelopment agreement signed with Ligand inSeptember 1994. Pfizer plans to introduce Duavee inFebruary 2014.

DERMATOLOGIC DRUGS

In August 2013, the FDA approved Galderma’s Mirvaso®(brimonidine tartrate), the first topical treatmentspecifically developed and indicated for the treatment offacial erythema of rosacea. Erythema (redness) is a com-mon symptom of rosacea, but until now there were noapproved drugs to treat it. Applied once daily, Mirvasoworks quickly to reduce the redness of rosacea and lastsfor up to 12 hours. Brimonidine, an α

2-adrenoceptor ago-

nist and vasoconstrictor, has been marketed for manyyears as an ocular formulation for the treatment of glau-coma and ocular hypertension. Galderma launchedMirvaso in September.

Also in August, Biocon launched Alzumab™ (itolizu-mab), a first-in-class humanized monoclonal antibodydirected against the T-cell differentiation antigen CD6, inIndia. CD6 is a pan T-cell marker involved in costimula-tion, adhesion and maturation of T cells, which play aleading role in autoimmune disease (Fig. 5). By bindingto CD6, itolizumab downregulates T-cell activation,

decreases the synthesis of proinflammatory cytokinesand may reduce T-cell infiltration at sites of inflamma-tion. Based on the results of a 52-week phase III trialconducted in India, itolizumab was approved by theDrugs Controller General of India for the treatment ofmoderate to severe chronic plaque psoriasis.

GASTROINTESTINAL AGENTS

The gastroprokinetic agent acotiamide hydrochloridehydrate (Acofide®), a peripheral acetylcholinesterase

(AChE) inhibitor, was approved and launched last yearfor the first time in Japan, where it is indicated for thetreatment of functional dyspepsia. Acetylcholine is an

important neurotransmitter for regulating gastrointesti-

nal motility. By blocking AChE and inhibiting the degra-

dation of acetylcholine, acotiamide improves impaired

gastrointestinal motility and delayed gastric emptying,

and thus improves symptoms of functional dyspepsiasuch 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 exclu-

sively to Astellas for codevelopment and marketing.

Janssen Biotech’s 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 corti-costeroid 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 mono-

clonal antibody that targets and neutralizes excess TNF-α.

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, ap-

proved by the FDA for the symptomatic relief of non-

infectious diarrhea in patients with HIV/AIDS on anti-

retroviral 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 gas-

trointestinal lumen. FDA approval was based on a ran-

domized, 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 med-ications or opiates were counted as clinical nonrespon-

ders. Data demonstrated that a significantly larger pro-




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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 consistencyscore 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 diar-

rhea, baseline number of daily watery bowel move-

ments, 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. Thedrug is distributed in the U.S. by Salix Pharmaceuticals

under license from Napo Pharmaceuticals.

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 thebowel due to Crohn’s disease, ischemia or other condi-

tions, and can lead to serious life-threatening complica-

tions. 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 serum-derived bovine immunoglobulin protein isolate

EnteraGam™, a prescription medical food product.



Figure 5. Itolizumab is a humanized IgG1 immunosuppressive monoclonal antibody that selectively inhibits the cell surface recep-

tor CD6 and is predicted to be useful in the therapeutic intervention of chronic plaque psoriasis. The antibody binds to CD6, whichin 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.


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EnteraGam is indicated for the clinical dietary manage-

ment of enteropathy under medical supervision for

patients who, because of therapeutic or chronic medicalneeds, have limited or impaired capacity to ingest,

digest, absorb or metabolize ordinary foodstuffs or cer-tain nutrients, or who have chronic loose or frequent

stools (e.g., diarrhea-predominant irritable bowel syn-drome [IBS-D]), and in patients with chronic loose or fre-

quent stools who are infected with HIV. EnteraGam, a

serum-derived bovine immunoglobulin/protein isolate

(SBI), has been shown in clinical studies in diverse disor-

ders to improve gastrointestinal nutrient absorption, aswell as manage immune function and mucosal barrier

function in the intestine.

ANTI-INFECTIVE THERAPY

In August the FDA approved ViiV Healthcare’s Tivicay®

(dolutegravir) for use in combination with other anti-

retroviral agents for the treatment of HIV-1 in adults andchildren 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. Theapproval 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 IdentifiersNCT01227824 and NCT01231516) included treatment-

naive patients. The SPRING-2 trial compared a once-daily dolutegravir-based regimen to twice-daily ralte-

gravir, while SINGLE evaluated once-daily dolutegravir

and abacavir/lamivudine compared to once-daily

Atripla® (efavirenz/emtricitabine/tenofovir disoproxilfumarate). Another trial, called SAILING (ClinicalTrials.gov

Identifier NCT01263015) compared a once-daily dolute-

gravir-based regimen to twice-daily raltegravir in treat-

ment-experienced patients who had not previously been

treated with an integrase inhibitor. Finally, the fourthtrial, which was called VIKING-3 (ClinicalTrials.gov

Identifier NCT01328041), assessed the effectiveness of

twice-daily dolutegravir on viral load in treatment-expe-

rienced patients with resistance to multiple classes ofHIV medicines, including resistance to integrase

inhibitors. Dolutegravir was launched in the U.S. shortly

after approval. In October, ViiV filed marketing applica-

tions in the U.S. and E.U. for a single-tablet formulationincorporating dolutegravir, abacavir and lamivudine.

Another HIV integrase inhibitor, Gilead’s 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. Gileadis currently working with regulatory authorities through-

out the European Union to bring Vitekta to patients as

quickly as possible. Elvitegravir is also a component of

Gilead’s 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 treatment-

naive or who have no known mutations associated with

resistance to any of the three antiretroviral agents con-tained in the combination product.

During the third quarter, Gilead received marketing

authorization from the European Commission for once-

daily 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 themarketing of Tybost in all 28 countries of the European

Union. Like elvitegravir, cobicistat was approved in 2012as 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 devel-oped by Janssen and Medivir for the treatment of geno-

type 1 and 4 chronic hepatitis C in adult patients with

compensated liver disease, including all stages of liverfibrosis. Simeprevir works by blocking the protease

enzyme that enables the hepatitis C virus (HCV) to repli-

cate in host cells. Last September it was approved for the

first time in Japan. The following month, the FDA’s

Antiviral Drugs Advisory Committee voted 19 to 0 to rec-

ommend approval of simeprevir, administered once daily

with pegylated interferon and ribavirin, for the treatment

of genotype 1 chronic hepatitis C in adult patients withcompensated 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 firstmarkets: Japan (as Sovriad®) and the U.S. (as Olysio™).

Hepatitis replicase, the RNA-dependent RNA poly-merase encoded by NS5B, is essential for HCV replica-tion. This enzyme synthesizes viral RNA using an RNAtemplate, a virus-specific biochemical activity that hasnot been observed in mammalian cells (Fig. 6). TheNS5B enzyme is targeted by both nucleoside inhibitors,which bind to the active catalytic site, and by nonnucleo-side inhibitors, which bind to one of several allostericbinding sites on the HCV polymerase. In December 2013,the U.S. FDA approved sofosbuvir (Sovaldi™; Gilead), afirst-in-class nucleoside analogue NS5B inhibitor, indi-cated for the treatment of HCV infection as a componentof a combination antiviral treatment regimen. Sofosbuvircan be used in combination with ribavirin or peginterfer-on alfa/ribavirin, but should not be used as monothera-py. The product, which has FDA Breakthrough TherapyDesignation, was launched in the U.S. in December.

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 antitubercu-

losis drugs has been regarded with great interest andhas 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 (F0F

1ATPase), 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 isexpected 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 infec-

tion 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 FDA’saccelerated approval of the drug was based on twophase IIb trials. The guideline thus lists five conditionsthat must be in place if bedaquiline is used in combina-

tion therapy to treat adults with MDR-TB: effective treat-ment and monitoring; proper patient inclusion (cautionis required when bedaquiline is used in people aged 65and over and in adults with HIV); informed consent;adherence to WHO recommendations on MDR-TB treat-ment regimens; and active pharmacovigilance and man-agement of adverse events. The WHO strongly recom-mended the acceleration of phase III trials to generate amore comprehensive evidence base to inform future pol-icy on bedaquiline. The organization will review, revise orupdate the interim guidance as additional information

on efficacy and safety becomes available.

In December 2012, the U.S. FDA approved the firstanthrax antitoxin, raxibacumab, indicated for the treat-ment 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 producedby B. anthracis that can cause massive and irreversible

tissue injury and death (Fig. 8). Raxibacumab is the first

monoclonal antibody approved under the FDA’s Animal

Efficacy Rule. In this case, because inhalational anthrax

is a rare and lethal disease, it was not possible to con-

duct adequate efficacy trials in humans, and the agent’s

effectiveness was therefore demonstrated in one study in

monkeys and three studies in rabbits. The safety of rax-

ibacumab was evaluated in 326 healthy human volun-

teers. 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-F

1ATP 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 depletionof 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 numer-

ous safety concerns, including the potential for acute

liver injury. Laser treatments only improve the appear-

ance of the nail. Pivotal international studies of efina-

conazole were conducted in 1,655 subjects with ony-chomycosis, 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

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 sub-

jects treated with vehicle. In Study 2, 15.2% of subjectstreated with efinaconazole were completely cured, com-

pared 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-1β (IL-1β) human monoclonal anti-

body canakinumab (Ilaris®; Novartis), marketed since

2009 for the treatment of cryopyrin-associated periodic

syndromes, was approved and launched last year for twonew 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 compo-nent (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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traindicated, are not tolerated, or do not provide ade-

quate response, and in whom repeated courses of corti-

costeroids 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 UCB’s 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, placebo-

controlled phase III trial designed to evaluate theefficacy 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 there-

after, the company also obtained FDA approval for

another new indication for certolizumab pegol: the treat-

ment 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 withsevere 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 Crohn’s disease and since 2009 for

rheumatoid arthritis.

In June 2013, the FDA approved a new indication fordenosumab (Amgen’s Xgeva®) for the treatment ofadults and skeletally mature adolescents with giant cell

tumor of bone (GCTB) that is unresectable or where sur-

gical 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, lim-

ited 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 waseither recurrent, unresectable, or for which planned sur-

gery 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 progressionfollowing 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 ado-

lescents and adults. Safety data was evaluated in 304

patients with GCTB who received at least 1 dose of deno-

sumab. Of these patients, 145 were treated for at least 1year. The most common adverse reactions were arthral-

gia, 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 super-

family member 11 (RANKL), has orphan drug designation

for GCTB; Amgen began marketing it for the new indica-

tion immediately upon receipt of approval. Denosumabhas been available for several years for the treatment of

skeletal-related events in patients with bone metastases

from solid tumors.

IMMUNOMODULATORS & AGENTS FOR

IMMUNIZATIONIn late 2012, the FDA approved Swedish Orphan

Biovitrum (Sobi)’s Kineret® (anakinra) for the treatmentof 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 inchildren. 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 IL-

1 receptor type 1. Anakinra was discovered and devel-oped by Amgen, and has been approved for the reduc-

tion of signs and symptoms of rheumatoid arthritis in

adults since 2001. In 2013, Sobi acquired the product

from Amgen for development and commercializationworldwide. 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 theFDA for use in patients with primary humoral immuno-

deficiency. This includes, but is not limited to, the




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humoral immune defect in common variable immunod-

eficiency (CVID), X-linked agammaglobulinemia, con-

genital agammaglobulinemia, Wiskott-Aldrich syn-

drome and severe combined immunodeficiencies.

In May, the European Commission granted Baxter mar-

keting 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 immuno-

globulin (IGSC, 10%) and recombinant human hyaluroni-

dase, 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 immuno-

globulin administered intravenously. The rate of validat-

ed 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 vac-

cines. Influenza vaccines have traditionally employed

two influenza A strains plus one of two possible influen-

za 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

(GlaxoSmithKline’s Fluarix® Quadrivalent andFluLaval® Quadrivalent and Sanofi Pasteur’s 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 vac-

cine from the 2014-2015 flu season onwards.

Another drawback of traditional influenza vaccines is

their method of production, which involves the genera-

tion of viral strains in embryonated chicken eggs. Thistechnology is complex, antiquated and inefficient, and isplagued with various drawbacks, most significantly thetime required to produce sufficient amounts of the vac-

cine. In January, the U.S. FDA approved Flublok®(Protein Sciences), the first trivalent influenza vaccinemade using an insect virus (baculovirus) expression sys-tem and recombinant DNA technology. This novel vac-cine does not use the influenza virus or eggs in its pro-duction. Flublok was launched in the U.S. in February2013.

Jenvac™, a Vero cell-derived purified inactivated Japa-nese encephalitis (JE) vaccine from Bharat Biotech, waslaunched last year in India. The vaccine is based on a JEstrain isolated in Kolar, Karnataka during the early 1980sthat is purified and inactivated using the company’sadvanced bioreactor technology. In clinical trials, Jenvacshowed superior safety and immunogenicity as com-pared to the live SA14-14-2 vaccine. In addition to reduc-ing disease burden, Jenvac will decrease India’s relianceon imported JE vaccines. Approximately 50,000 cases ofJE are reported each year in Asia —although the diseaseis known to be vastly underreported—, making it theleading cause of viral encephalitis in the region.

Another new vaccine from Bharat Biotech, the typhoid

conjugate vaccine Typbar-TCV™, was also approved andlaunched last year in India. The fourth-generation vac-cine was designed to overcome two important limita-tions of previous vaccines: the lack of long-term protec-tion and efficacy in children under the age of 2 years. Instudies involving approximately 1,200 healthy volun-teers, Tpybar-TCV induced seroconversion in 98% ofinfants aged 6-24 months and in 99% of children aged2-15 years; it also induced seroconversion in 92% ofthose aged 15-45 years. Seroconversion was defined as afour-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 600,000deaths and more than 20 million illnesses each year.According to the WHO, 90% of these deaths occur inAsia, mainly in children under 5 years of age.

Meningococcal disease is a leading cause of bacterialmeningitis. Five main groups of meningococcal bacteria(A, B, C, W-135 and Y) cause the majority of all casesaround the world. In the past, vaccines were available tohelp 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 mis-diagnosed and can kill within 24 hours of onset. About 1




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in 10 of those who contract the disease will die despite

appropriate treatment. The approval of Novartis’s

Bexsero® (meningococcal group B vaccine [rDNA,component, adsorbed]) in the E.U. in January 2013 and

in Australia in August thus represents a significantdevelopment. The vaccine is indicated for active immu-

nization against invasive disease caused by Neisseriameningitidis serogroup B strains and can be used in

infants as young as 2 months. Novartis launchedBexsero in the U.K., Germany and Ireland during the

fourth quarter of 2013.

Also approved and launched last year was

GlaxoSmithKline’s MenHibrix® (meningococcal groups

C and Y and Haemophilus b tetanus toxoid conjugate

vaccine). The conjugate vaccine was approved by theU.S. FDA for use in children aged 6 weeks through 18months, 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 vac-

cine 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 boostervaccination of infants from 6 weeks of age against diph-

theria, 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 vaccina-tion visits required for appropriate immunization of

infants.

In August, the European Commission granted marketing

authorization for Bavarian Nordic’s third-generation

smallpox vaccine Imvanex®, indicated for active immu-

nization against smallpox disease for the general adult

population, including people with weakened immunesystems (people diagnosed with HIV or atopic dermati-tis). 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 tothe U.S. Strategic National Stockpile under a contract

with the U.S. Government.

TREATMENT OF CANCERTrastuzumab emtansine (Kadcyla™; Roche), a novel

antibody–drug 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 metastaticbreast 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 adultswith HER2-positive, unresectable locally advanced ormetastatic 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 unre-

sectable 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) inhibitortrametinib dimethyl sulfoxide (Mekinist™; Glaxo-

SmithKline) for the treatment of adult patients withunresectable or metastatic melanoma with BRAF V600E

and V600K mutations as detected by an FDA-approved

test. The FDA also granted premarket approval for

bioMérieux’s 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 BoehringerIngelheim’s 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 withNSCLC, between 10 and 15% of Caucasians and approx-

imately 40% of Asians have EGFR mutations. The two




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most common mutations, Del19 and L858R, account for90% of all EGFR mutations in NSCLC. Afatinib is an oral-ly active kinase inhibitor that is designed to bind and irre-versibly inhibit EGFR (c-ErbB-1), HER2 (c-ErbB-2) and

c-ErbB-4 receptors. Its efficacy was demonstrated in theLUX-Lung 3 trial, one of the largest phase III trials everconducted in the setting of first-line EGFR mutation-positive, locally advanced or metastatic NSCLC. Amongpatients treated with afatinib in this study, the medianprogression-free survival was 11.1 months, versus 6.9months for those treated with pemetrexed and cisplatin.Among afatinib-treated patients who had the most com-mon EGFR mutations (Del19 and L858R), median pro-gression-free survival was 13.6 months. Afatinib waslaunched in the U.S., where it has orphan drug status for

the approved indication, in September 2013.

Another targeted therapeutic also reached its firstmarket last year: Exelixis’s cabozantinib S -malate(Cometriq™), launched in the U.S. in January. The drug isan inhibitor of multiple receptor tyrosine kinases, includ-ing Ret, Met, VEGFR-1, -2 and -3, Trk-B, FLT-3, AXL andTIE-2, which are involved in both normal cellular func-tion and pathological processes such as oncogenesis,metastasis, angiogenesis and maintenance of the tumormicroenvironment. It is indicated for the treatment of

progressive, metastatic medullary thyroid cancer, andhas orphan drug status for this indication.

In December 2012, the multikinase inhibitor ponatinib(Iclusig™; Ariad Pharmaceuticals) was approved by theFDA. It is indicated for the treatment of adult patientswith chronic, accelerated or blast phase Philadelphiachromosome-positive (Ph+) chronic myelogenous leuke-mia (CML) that is resistant or intolerant to prior tyrosinekinase inhibitor (TKI) therapy. Ponatinib was alsoapproved for the treatment of Ph+ acute lymphoblasticleukemia (ALL) that is resistant or intolerant to prior TKI

therapy. Ponatinib has orphan drug status for both indi-cations, and was launched in the U.S., its first market, inJanuary 2013. However later in the year, on the basis ofincreasingly frequent postmarketing reports of seriousand life-threatening blood clots and severe narrowing ofblood vessels in patients treated with the drug, the FDArequested that Ariad suspend marketing of ponatinib.The company complied with this request and is nowworking with the agency to resume marketing of thedrug, pending updates to the product’s prescribing infor-mation and implementation of a risk mitigation strategy.

The antimitotic agent sphingosomal vincristine(Marqibo®; Spectrum Pharmaceuticals) was launched

for the first time last September, more than a year after

receipt of marketing approval. Discovered and devel-

oped 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 thera-

pies. 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 body’s immune system. On the

basis of the significance of positive progression-free sur-vival 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 sta-

tus in July. In November 2013, obinutuzumab (Gazyva™;

Roche) was approved and launched in the U.S., indicat-

ed 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 FDA’s

Breakthrough Therapy Designation.

In February 2013, the U.S. FDA approved Celgene’s

pomalidomide (Pomalyst®) for the treatment of multi-

ple myeloma in patients who have received at least two

prior therapies, including lenalidomide and bortezomib,

and have demonstrated disease progression on or with-

in 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 wererefractory 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 pomalido-

mide 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 Transplanta-

tion criteria. The median duration of response for

patients in the pomalidomide plus low-dose dexam-ethasone arm was 7.4 months, while the median had not

yet been reached for the pomalidomide alone arm at the




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time of approval. A total of 219 patients were evaluablefor safety. The most common grade 3 or 4 adverse reac-

tions (15%) in the pomalidomide plus low-dose dexam-ethasone 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 derivativeof thalidomide (IMiD) and is contraindicated in pregnan-cy. It is only available through the Pomalyst Risk

Evaluation and Mitigation Strategy (REMS) program. Itwas launched in the U.S. later in the first quarter, andwas approved by the European Commission in August.

Bruton tyrosine kinase (BTK) is a key signaling moleculeof 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 approvedand launched in the U.S. in 2013 for the treatment of

mantle cell lymphoma (MCL). The approval of ibrutinibwas based on the favorable overall response rate (ORR)and duration of response (DOR) seen in the phase IIstudy PCYC-1104, which enrolled 111 patients with

relapsed or refractory MCL. The efficacy results of thisstudy demonstrated a 65.8% ORR, with 17% of patientsachieving a complete response and 49% achieving apartial response. The median DOR was 17.5 months.Ibrutinib was discovered by Pharmacyclics and waslicensed to Janssen in 2011 for codevelopment andcomarketing worldwide. Like obinutuzumab, ibrutinibhas Breakthrough Therapy Designation from the FDA; italso 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 radio-

pharmaceutical incorporating the alpha particle-emit-


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