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THE YEAR’S NEW DRUGS & BIOLOGICS - 2009

Comprehensive annual review of the 51 new medicines and vaccines that reached their first markets in 2009, with a look at the new trends and novel mechanisms of action, as well as predictions for the new drugs and biologics that will make it to market in 2010. This report is published annually in the Thomson Reuters’ journal Drug News & Perspectives and draws on insights and information from Prous Science Integrity®.

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Prous Science Integrity® Integrated drug discovery and development portal Prous Science Integrity® integrates biological, chemical and pharmacological data on more than 315,000 compounds with demonstrated biological activity, plus tens of thousands of synthesis intermediates, and over 135,000 patent family records. Updated every day, its wealth of information forms a complete, flexible resource that can drive knowledge creation, target missioncritical milestones, and support faster, strategic decisions earlier in the discovery pipeline. Designed, populated, refined and supported entirely by pharmaceutical scientists and experts, Integrity provides a unique knowledge solution designed to empower your discovery activities right where you need it most — at the bench. To find out more, go to: go.thomsonreuters.com/integrity

Drug News Perspect 23(1), January/February 2010

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THE YEAR'S NEW DRUGS & BIOLOGICS — 2009

by Ann I. Graul, Lisa Sorbera, Patricia Pina, Montse Tell, Elisabet Cruces, Esmeralda Rosa, Mark Stringer, Rosa Castañer and Laura Revel Now in its 22nd edition, the annual series “The Year’s New Drugs & Biologics” provides the opportunity to present from both a historical and a research perspective those molecular entities and biological drugs that were launched or approved in various countries for the first time during the past year. Information on these drugs is provided to serve as a guide to the most recent developments in drug therapy, highlighting newgeneration compounds with therapeutic gains over existing drugs and new therapeutic entities arising from innovative approaches to drug research. According to our records, 51 new chemical entities and biologics for therapeutic use reached their first markets in 2009, the largest number in the last decade. Another 12 new products were approved for the first time in 2009 but were not launched before year-end. Following a growing tendency in recent years, 24 line extensions (new formulations, new indications and/or new combinations of previously marketed products) were introduced last year, accounting for 32% of the products considered in this review. During the past year, “Immunomodulators and Agents for Immunization” was the most active therapeutic group in terms of new chemical entities launched for the first time (Table I), with 17 market introductions, many of them new vaccines for the 2009 H1N1

influenza. The U.S. was again the most active single market for new products, with a total of 24 new launches in 2009, constituting almost 50% of the total of new introductions for the year. The European Union followed close behind, with 18 new launches (Fig. 1). The information in this review was compiled from company communications and the Thomson Reuters database Prous Science Integrity®. Products are grouped by therapeutic category and mechanism of action according to the classification scheme followed in Prous Integrity®, a unique database integrating biological, chemical and pharmacological data on more than 300,000 active compounds, tens of thousands of synthesis schemes and over 130,000 patent family records. NEW DRUGS & BIOLOGICS BY THERAPEUTIC GROUP Agents for analgesia & anesthesia In June 2009, Ortho-McNeil-Janssen launched the novel analgesic agent tapentadol hydrochloride (Nucynta™), a new centrally acting oral analgesic developed under a collaborative agreement with Gruenenthal, for the first time in the U.S. The compound, a dual µ opioid receptor agonist and norepinephrine reuptake inhibitor, was approved by the FDA for the relief of moderate to severe acute pain in adults aged 18 years or older. The approval was based on phase III studies in patients with various acute pain conditions, all of whom achieved significant pain relief with tapentadol as compared to placebo. The U.S. Drug Enforcement Agency has placed tapentadol into Schedule II of the Controlled Substances Act.

This year, 51 new products, including new chemical entities and biologics for therapeutic use, reached their first markets.

SUMMARY This annual article presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2009, 51 new medicines and vaccines reached their first markets. Line extensions (new indications, new formulations and new combinations of previously marketed products) accounted for more than 30% of the new products launched in 2009. In addition to providing an overview of all drugs and biologics launched or approved for the first time ever in the previous year, this article will also review in further depth the first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an analysis of the discovery and development periods for the year's new products; and a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines. We also provide a brief glimpse at selected drugs and biologics which could reach their first markets in the foreseeable future.

The FDA approved King’s Embeda™ (morphine sulfate/naltrexone hydrochloride) extended-release capsules for oral use in August 2009; the product was launched the following month. Embeda is a long-acting Schedule II opioid analgesic for the management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of Correspondence: A.I. Graul, [email protected]

Copyright © 2010 Prous Science, S.A.U. or its licensors. All rights reserved. CCC: 0214-0934/2010. DOI: 10.1358/dnp.2010.23.1.1440373

1

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Drug News Perspect 23(1), January/February 2010

Table I. Drugs and biologics introductions by therapeutic category, 1999–2009 Therapeutics

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Anti-infective

7

4

5

5

5

1

6

2

5

3

1

Antineoplastic

6

3

4

5

3

7

6

7

5

1

6

Central nervous system

3

7

4

5

3

6

6

1

3

4

7

Cardiovascular

3

4

2

3

1

0

2

2

2

2

1

Hematologic

3

0

2

1

1

1

1

0

2

6

3

Endocrine drugs

9

6

3

0

1

2

3

3

2

0

3

Metabolic drugs

1

2

4

5

4

2

1

7

2

2

3

Antiarthritic

2

1

1

2

1

0

0

1

0

1

3

Pulmonary & antiallergy

3

3

3

2

3

0

1

0

2

2

2

Dermatologic

0

1

1

2

2

0

0

0

0

2

1

Immunologic

5

6

0

0

2

2

6

9

4

3

17

Ophthalmic

1

0

2

0

0

0

2

2

0

1

1

Gastrointestinal

0

7

2

2

0

0

1

2

1

3

1

Renal–urologic

1

0

0

0

3

2

3

3

1

2

2

Poisoning & drug abuse

0

0

1

1

0

0

1

1

0

0

0

Dental

0

0

0

0

0

0

1

0

0

0

0

Contrast agents

2

2

2

2

Total 46 46 36 35 Based on information from Prous Science Integrity®

0

3

2

1

1

1

0

29

26

42

41

30

33

51

reversing both the subjective and analgesic effects of the opioid, thereby deterring abuse. The FDA approval was based on data from 12 clinical studies, including phase III data demonstrating efficacy and safety.

Figure 1. Geographic distribution of new products first launched in 2009. (Source: Prous Science Integrity®).

time. Embeda capsules contain extendedrelease morphine pellets, each with a sequestered core of naltrexone. The formulation is designed to work such that if taken as directed, the morphine would relieve pain while the sequestered naltrexone would pass through the body with no observed clinical effect. However, if the capsules are crushed or chewed, the naltrexone is released and absorbed with the morphine, 2

NeurogesX’s Qutenza™, a transdermal patch formulation delivering the vanilloid VR1 receptor agonist capsaicin, was approved last year in the E.U. and U.S. for different indications. In the E.U., where approval was granted in May, the product is indicated for the treatment of peripheral neuropathic pain in nondiabetic adults, either alone or in combination with other medicinal products for pain. In the U.S., approval is for the management of neuropathic pain associated with postherpetic neuralgia. Qutenza works by targeting certain pain nerves in the area of skin where pain is being experienced. The patch, which is applied by a physician, provides up to 12 weeks of pain relief following a single 1-hour treatment. Qutenza will be launched in 2010 in the E.U., where it will be marketed by Astellas, and the U.S., where it has orphan drug status. Although other capsaicinbased analgesic products are available in several countries, this is the first long-acting transdermal patch formulation.

In mid-November, Eisai announced the availability in the U.S. of fospropofol disodium (Lusedra™), an intravenous sedative– hypnotic agent indicated for monitored anesthesia care (MAC) sedation in adult patients undergoing diagnostic or therapeutic procedures. The product is a proprietary water-soluble prodrug of propofol that, after i.v. injection, is converted by alkaline phosphatase enzymes in the body to the active drug. In the approval, the FDA required that Lusedra be used only by personnel trained in the administration of general anesthesia and that all patients should be continuously monitored during sedation and through the recovery process. Lusedra is designated as a Schedule IV drug. Novalar Pharmaceuticals last year launched OraVerse™, a new formulation of the αadrenoceptor antagonist and vasodilating agent phentolamine mesylate, in the U.S. where it is indicated for use in reversing dental anesthesia. More than 300 million cartridges of local dental anesthetic are sold each year in the U.S. alone. Although widely used, dental anesthesia frequently results in unnecessary and lingering numbness and associated functional deficits. OraVerse is the first pharmaceutical agent indicated for the reversal of soft tissue anesthesia and the associated functional deficits resulting from a local dental anesthetic containing a vasoconstrictor, accelerating the return to normal sensation and function.

CH3 HO

CH3

N

.HCl

CH3

CH3

Tapentadol hydrochloride

O P O CH3 H3C

O

O

Na

O

Na

+ +

CH 3 CH3

Fospropofol disodium Agents for analgesia & anesthesia A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

Psychopharmacologic drugs Bupropion is a proven effective antidepressant therapy which provides acute relief of the symptoms of depression and low relapse rates over 1 year. The drug, a dopamine reuptake inhibitor, has been marketed as the hydrochloride salt since 1989. Last year, exactly two decades later, Biovail and sanofi-aventis introduced Aplenzin™ (bupropion hydrobromide), a new salt of bupropion that requires just one tablet per day. Aplenzin is indicated for the treatment of major depressive disorder in adults aged 18 years and older. Lilly’s Symbyax®, a fixed-dose combination of olanzapine and fluoxetine hydrochloride, was approved and launched last year in the U.S. for a new indication: the acute treatment of treatment-resistant depression (major depressive disorder in adults who do not respond to two separate trials of different antidepressants of adequate dose and duration in the same episode). Symbyax has been marketed since 2004 for the treatment of depressive episodes associated with bipolar disorder. The product incorporates an atypical antipsychotic (olanzapine) and a selective serotonin reuptake inhibitor (fluoxetine). The therapeutic options for schizophrenia improved significantly last year, with four new products approved or launched for the first time. The atypical antipsychotic asenapine maleate (Saphris®; ScheringPlough, now merged with Merck & Co.), a dual serotonin 5-HT2 receptor antagonist and dopamine D1/D2 receptor antagonist, was approved and launched in the U.S. for two related indications. It is indicated for the acute treatment of schizophrenia in adults, as well as for the treatment of manic or mixed episodes associated with bipolar I

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disorder, with or without psychotic features, also in adults. Asenapine is also under regulatory review in Europe, where it will have the trade name Sycrest®. Vanda Pharmaceuticals received approval in May 2009 from the U.S. FDA to market iloperidone (Fanapt™), another atypical antipsychotic acting via 5-HT2 and dopamine D2 receptor antagonism. Iloperidone is indicated for the acute treatment of adult patients with schizophrenia. The approval was supported by two placebo-controlled phase III clinical studies in schizophrenia patients treated for 4 or 6 weeks with iloperidone; the study drug was shown to be superior in controlling schizophrenia as compared to placebo or comparator drugs (ziprasidone and risperidone, respectively). Later in the year the company announced a marketing agreement with Novartis, under which Novartis will be responsible for marketing and commercialization of iloperidone in the U.S. and Canada; U.S. launch of iloperidone was planned for January 2010. The U.S. antipsychotic market is approximately $14 billion, according to Vanda. Lilly’s Zypadhera™ (olanzapine pamoate), a long-acting injection formulation of the established antipsychotic agent olanzapine (Zyprexa®), was launched for the first time last year, indicated for the maintenance treatment of adult patients with schizophrenia sufficiently stabilized during acute treatment with oral olanzapine. The World Federation of Societies of Biological Psychiatry guidelines state that poor or partial treatment compliance is a major problem in the long-term treatment of schizophrenia. Depot formulations should be considered as a treatment option when a patient expresses preference for said treatment due to convenience, or when it is

O Cl O Cl

H N CH3

CH3 CH3 CH3

Bupropion hydrobromide Psychopharmacologic drugs A.I. Graul et al. pp.

H .HBr

H

CO2H

.

N CH3

Asenapine maleate

CO 2H

determined that a depot formulation would assist in compliance. The pamoate salt formulation enables the sustained delivery of olanzapine for up to 4 weeks. Zypadhera was first introduced in Norway in March, but was also launched over the course of 2009 in several other European countries, including Germany, Ireland, Finland, the Netherlands and Denmark, as well as in New Zealand and Australia (where it is marketed as Zyprexa® Relprevv™). The product was approved by the U.S. FDA in midDecember; the Zyprexa Relprevv name will also be used in the United States. Paliperidone palmitate (Invega® Sustenna™), an extended-release injectable suspension form of the atypical antipsychotic paliperidone, was approved by the U.S. FDA and launched last year by Janssen. Indicated for the acute and maintenance treatment of schizophrenia in adults, Invega Sustenna is the first once-monthly, longacting, injectable atypical antipsychotic approved in the U.S. for this use. Attention deficit hyperactivity disorder (ADHD) is a prevalent disorder worldwide, affecting 5.3% of children globally, albeit with large variability. In the U.S., approximately 4.4 million children between the ages of 4 and 17 years have been diagnosed with ADHD at some time in their lives, according to the Centers for Disease Control and Prevention (CDC). Last year saw the approval and launch of a new therapeutic option for children and adolescents with ADHD in the U.S.: Shire’s Intuniv™ (guanfacine hydrochloride). Guanfacine is a selective α2A-adrenoceptor agonist that has been marketed for several decades as an antihypertensive agent. Stimulation of postsynaptic α2A-adrenoceptors in the prefrontal cortex is thought to improve working memory, attention regulation and behavioral inhibition, reduce susceptibility to distraction and enhance impulse control. Unlike previous ADHD therapeutics, which act as stimulants and thus are scheduled medicines, guanfacine is not a controlled substance and has no known potential for abuse or dependence. Formulated as an extended-release tablet, Intuniv is administered just once daily. Neurologic drugs Eslicarbazepine acetate (Zebinix®), a novel antiepileptic developed by Bial-Portela, was approved for the first time last year in the 3

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Drug News Perspect 23(1), January/February 2010

O CH 3

O

O

O

+

S

NH2 N O

NH2

Eslicarbazepine acetate

Armodafinil

In June, Cephalon launched Nuvigil® (armodafinil) tablets [C-IV], a longer-lasting single-isomer formulation of the CNS stimulant modafinil; in the U.S. Nuvigil is indicated to improve wakefulness throughout the day for patients who struggle with excessive sleepiness associated with treated obstructive sleep apnea, shift work sleep disorder and narcolepsy. Cephalon has also filed for approval of armodafinil in the U.S. for the treatment of excessive sleepiness associated with jet lag disorder due to eastbound travel; the FDA has extended the action date for the sNDA, previously set at December 29, 2009, to March 29, 2010.

Autism and autism spectrum disorders (ASDs) are a set of complex, behaviorally defined neurodevelopmental disorders characterized by three core features: deficits in social interaction, impaired communication and repetitive, restricted or stereotyped interests and/or patterns of behavior. Irritability is a common characteristic in children with ASD, and may be manifested as aggressiveness toward others, deliberate self-injurious behaviors, temper tantrums, aggression and quickly changing moods. Behavioral problems such as irritability can be a source of impairment or distress to individuals with ASD, as well as their families. Last November, the atypical antipsychotic agent aripiprazole (Abilify®; BristolMyers Squibb/Otsuka) was approved and launched in the U.S. for the treatment of irritability associated with autistic disorder in pediatric patients aged 6-17 years. This is a new indication for the drug, a 5-HT2A receptor antagonist/5-HT1A receptor partial agonist/dopamine D2 receptor partial agonist that has been marketed since 2002 for various psychiatric disorders including schizophrenia, major depression and bipolar disorder. Another atypical antipsychotic, risperidone, was approved by the FDA for this same indication in 2006. The U.S. market for this class of drugs is significant: according to a report released by the CDC in December 2009, 1 in 110 U.S. children has an autism spectrum disorder (1).

The dual norepinephrine/serotonin reuptake inhibitor milnacipran hydrochloride (Savella™), marketed for many years as an antidepressant, was approved and launched last year in the U.S. for the treatment of fibromyalgia. Milnacipran, the third drug to reach the market in as many years for this previously untreatable disorder, was developed by Cypress Bioscience under license from originator Pierre Fabre for the fibromyalgia indication. It is copromoted and comarketed by Forest. In a phase III study, results of which were presented in October at the American College of

Respiratory drugs Intranasal corticosteroids are gaining in popularity as first-line therapies for allergic rhinitis, particularly in patients with moderate to severe symptoms or in those with perennial allergic rhinitis with predominantly nasal symptoms. Intranasal corticosteroids address the process of allergic inflammation that contributes to the latestage symptom of nasal congestion. When used prophylactically, they can also prevent the early-phase response to allergens. Overall, inhaled corticosteroids effectively

Neurologic drugs

European Union and launched in Germany and Austria, where it is marketed, promoted and distributed by Eisai. Eslicarbazepine acetate is a novel voltage-gated sodium channel blocker that specifically targets the inactivated state of the ion channel, preventing its return to the active state and thereby reducing repetitive firing. It is indicated for the treatment of partial-onset seizures, the most common type of epilepsy. The established antiepileptic drug zonisamide (Trerief®; Dainippon Sumitomo Pharma), a sodium channel blocker and Ttype calcium channel blocker, was approved and launched last year in Japan for a new indication: the treatment of Parkinson’s disease (PD) in combination with levodopa. The development of zonisamide for this new indication was based on the serendipitous observation of alleviation of PD symptoms in a patient treated with the compound for comorbid epilepsy. Based on this finding, the company began developing zonisamide for PD in 2001. Benefits observed in clinical trials included improvements in movement ability and activities of daily living, especially in patients with advanced PD whose symptoms did not improve on dopaminergic therapies. The dopamine D2/D3 receptor agonist rotigotine (Neupro®; UCB), marketed for some years as a treatment for PD, was launched last year in the U.K. and Germany, its first markets, for the new indication of restless legs syndrome (RLS). The European marketing application was supported by results of two fixed-dose, randomized, double-blind, placebo-controlled efficacy and safety studies that evaluated rotigotine for the treatment of moderate to severe idiopathic RLS in almost 1,000 patients from the E.U. and U.S. over 6 months. The efficacy of rotigotine (0.5-3 mg/24 h) was evaluated by using 4

Rheumatology annual meeting, milnacipran treatment was associated with clinically meaningful improvements in pain, physical function and global patient assessment as compared to treatment with placebo. Fibromyalgia is a chronic condition characterized by widespread pain and decreased physical function, afflicting as many as six million people in the United States.

the International Restless Legs Severity Scale (IRLS). Additionally, the change in the severity of illness was evaluated by monitoring the Clinical Global Impressions (CGI) Item 1 scores. In both studies, rotigotine (2 mg/24 h and 3 mg/24 h) was shown to produce a statistically significant and clinically relevant improvement in the IRLS sum scores and a reduction in the CGI-1 score compared to placebo, with sustained improvement observed throughout the 6-month maintenance phase. The European Commission approved the supplementary application in 2008.

A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

HO

ment of arterial hypertension. Valturna, which combines the ARB valsartan and the direct renin inhibitor aliskiren in a single pill, is the first therapy to target two points within the renin–angiotensin–aldosterone system. It is indicated for the treatment of high blood pressure in patients not adequately controlled on aliskiren or ARB monotherapy, and as initial therapy in patients who are likely to require multiple drugs to achieve their blood pressure goals. Novartis began marketing the product in October.

CH3

N H

N H

DRUGLINE

CH 3

CO2H

CO2H

O

OH

Indacaterol maleate Respiratory drugs

relieve sneezing, itching, rhinorrhea and congestion, and a meta-analysis of clinical studies concluded that they are more effective than antihistamines for controlling rhinitis. Last year, Nippon Shinyaku received marketing approval for and launched the novel intranasal corticosteroid dexamethasone cipecilate (Erizas®) in Japan. This is the first once-daily nasal spray corticosteroid for allergic rhinitis to be made available in Japan. On November 30, the long-acting β2adrenoceptor agonist indacaterol maleate (Onbrez® Breezhaler®; Novartis) was approved for marketing in the European Union, where it is indicated for the oncedaily maintenance bronchodilator treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD). Indacaterol is the first and only treatment to demonstrate in clinical studies both 24-hour bronchodilatation and a rapid onset of action (within 5 minutes of inhalation). Additionally, it is the first new inhaled compound in 7 years to be made available for the treatment of COPD in the E.U., where as many as 82 million patients have the condition. The first product launch took place in Germany in December. Aztreonam lysinate (Cayston®) is a proprietary formulation of aztreonam developed by Gilead for inhalation administration. In 2009, the product was approved in the E.U. and Canada for the control of chronic pulmonary infections caused by Pseudomonas aeruginosa in patients with cystic fibrosis. An FDA advisory committee has also recommended approval of the drug for this indication in the U.S., where the target review date is February 13, 2010. The compound, delivered by the Altera® Nebulizer System (developed specifically for this product by PARI Pharma), is a single-ringed β-lactam antibiA.I. Graul et al. pp.

otic that has activity against a broad spectrum of Gram-negative bacteria. Gilead said that Cayston would be launched in the first E.U. countries in 2010. Cardiovascular drugs In recent years, an increasing number of new combination antihypertensive therapies have reached the market, all designed to simplify treatment regimens and improve patient compliance. Last year, Novartis received FDA approval for one such product: Exforge HCT®, a combination antihypertensive therapy incorporating the calcium channel blocker amlodipine, the angiotensin receptor blocker (ARB) valsartan and the diuretic hydrochlorothiazide in a single tablet taken once daily. Exforge HCT is the first antihypertensive medication to incorporate three different drugs in a single pill. It was approved by the FDA in late April and was launched in early June. The combination was later approved in the E.U., where it will bear the trade names Exforge HCT, Dafiro HCT and Imprida HCT. In September, the U.S. FDA issued the first approval worldwide for Valturna® (aliskiren fumarate/valsartan), another combination product developed by Novartis for the treat-

Boehringer Ingelheim’s Twynsta® (telmisartan/amlodipine besylate), a third combination product for the treatment of hypertension, was approved and launched in the U.S. during the autumn of 2009. In clinical studies supporting the approval, Twynsta was shown to deliver powerful blood pressure reductions of up to 40/29 mmHg, with a 24hour blood pressure response rate of up to 98% in hypertensive patients at risk of cardiovascular events, including patients with type 2 diabetes, elderly and obese patients. Twynsta has been filed for approval in the E.U. and Japan, and is on schedule to be submitted in other markets worldwide. The class III antiarrhythmic agent dronedarone hydrochloride (Multaq®; sanofiaventis) was approved and launched for the first time last year in the U.S. Dronedarone is indicated for reducing the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors who are in sinus rhythm or who will be cardioverted. The FDA approval was based on results of the randomized, double-blind, multinational ATHENA study, which evaluated the effect of dronedarone on cardiovascular hospital-

CH3 CH3

N

O O H 3C O

H N

.HCl

S O O

CH 3

Dronedarone hydrochloride Cardiovascular drugs 5

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Drug News Perspect 23(1), January/February 2010

ization or death in patients with AF at moderate to high risk, finding a significant 24% reduction in risk with dronedarone as compared to placebo. Later in the year, dronedarone was also approved in Canada and the E.U. In May 2009, the U.S. FDA approved United Therapeutics’ application to market the phosphodiesterase PDE5 inhibitor tadalafil (Adcirca™) for the treatment of pulmonary arterial hypertension (PAH; WHO group I). This approval encompasses patients with multiple forms of PAH, including etiologies such as idiopathic and familial PAH, as well as that associated with scleroderma and congenital heart disease. The company inlicensed the rights to develop, market, promote and commercialize the drug from Lilly; the latter has successfully marketed tadalafil (Cialis®) since 2003 for the treatment of erectile dysfunction. Tadalafil was launched in August for this new indication, for which it has orphan drug designation in the U.S. Later in the year, tadalafil was also approved and launched for the new indication in Japan, and approved in the European Union. Another new treatment for PAH was also approved and launched for the first time last year in the U.S.: United Therapeutics’ Tyvaso™ (treprostinil inhalation solution). Until now, the prostaglandin analogue has only been available in injectable (subcutaneous and intravenous) formulations. The efficacy of this new formulation was demonstrated in the 12-week, randomized, doubleblind, placebo-controlled TRIUMPH-1 clinical trial, in which patients taking Tyvaso in 4 daily inhalation sessions achieved a 20meter improvement in the 6-minute walking distance over those taking placebo. In conjunction with the Tyvaso approval, United Therapeutics has agreed to postmarketing commitments to modify certain aspects of the Tyvaso Inhalation System, perform a usability analysis and collect pharmacokinetic data to verify expected dosing with the modified device. The company reports that modifications to the inhalation system are well under way, and that the modified device is more patient-friendly. Renal–urologic drugs Gelnique™, a novel gel formulation of the muscarinic antagonist oxybutynin chloride developed by Watson, was approved and 6

H N

H3C

H 3C

O

O

N

CH3

CH3 O

.HCl

N

Cl HO

Tolvaptan

Dapoxetine hydrochloride

Renal–urologic drugs

launched during the year 2009 in the U.S. Indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency, Gelnique is active in both men and women, but will be marketed specifically for female patients. It is the first and only topical gel formulation available for this indication. The clear, quick-drying and fragrance-free gel is applied once daily to the thigh, abdomen, upper arm or shoulder, providing continuous delivery of the proven anticholinergic agent oxybutynin over a 24-hour period. Administration by the transdermal route has several advantages, particularly avoidance of first-pass metabolism, which may be linked to the well-known side effects of oxybutynin, such as dry mouth and constipation. In May 2009, the FDA approved Otsuka’s tolvaptan (Samsca™), an orally active and selective vasopressin V2 receptor antagonist, for the treatment of patients with clinically significant hypervolemic and euvolemic hyponatremia, including heart failure, cirrhosis and the syndrome of inappropriate antidiuretic hormone (SIADH). The FDA approval, as well as that received in the E.U. just months later, was based on results from the SALT-1 and SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatraemia) trial program, which showed that once-daily oral tolvaptan was effective in increasing serum sodium concentrations in patients with SIADH. Tolvaptan was launched by Otsuka in the U.S. in June. In February 2009, Janssen-Cilag’s dapoxetine hydrochloride (Priligy™) received marketing authorization in Finland and Sweden for the on-demand treatment of premature ejaculation in men 18-64 years of age. These

approvals followed the positive outcome of a decentralized marketing authorization procedure in seven European Union countries: Sweden, Austria, Finland, Germany, Spain, Italy and Portugal. The procedure was finalized in December 2008, and Finland and Sweden were the first countries worldwide to grant marketing authorization for the product, as well as the first countries in which it was launched. Serotonin is believed to play a central role in the timing of ejaculation. Dapoxetine is a unique, short-acting, selective serotonin reuptake inhibitor and is taken only when needed. Dapoxetine’s efficacy and safety were evaluated in a program of placebo-controlled phase III clinical trials conducted by Johnson & Johnson and involving more than 6,000 men with premature ejaculation and their partners, the largest studies ever conducted for this indication. Hematologic agents The P2Y12 (P2T) antagonist prasugrel (Efient®) was approved for the first time last February in the European Union, and was launched by Lilly in the U.K. in March and in Germany in April. The E.U. marketing authorization was for the prevention of atherothrombotic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Prasugrel works by blocking the P2Y12 purinoceptor on the surface of blood platelets, thereby preventing platelet aggregation and clotting. In a large phase III trial, prasugrel was superior to clopidogrel in reducing the risk of suffering major cardiovascular events in ACS patients undergoing PCI. Daiichi Sankyo and Lilly codeveloped the antiplatelet agent, which was discovered A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

O S

O

O

N

CH3

F

Prasugrel Hematoloic agents

by Daiichi Sankyo and Ube. Prasugrel was approved and launched later in the year in the U.S. as EffientTM, where it is indicated for the secondary prevention of thrombotic cardiovascular complications in patients with a recent ischemic stroke or with ACS, who are being managed with PCI; and for the reduction of secondary complications, including death, recurrent myocardial infarction, recurrent stroke and rehospitalization for severe angina. Following priority review, the plasminogen activator inhibitor tranexamic acid (Lysteda™; Xanodyne Pharmaceuticals) was approved by the U.S. FDA in November 2009 for the treatment of cyclic heavy menstrual bleeding, or menorrhagia. Lysteda is an orally active, modified-release formulation of tranexamic acid; an injectable formulation (Cyklokapron) has been marketed since 1986 for the treatment of patients with hemophilia. Lysteda is the first nonhormonal treatment option for menorrhagia, which affects approximately 10% of women of reproductive age in the U.S. An abnormally high rate of clot breakdown (fibrinolysis) in the uterus has been associated with heavy menstrual bleeding. As an antifibrinolytic, Lysteda works to reduce this excessive activity, thereby helping to support one of the important natural mechanisms by which menstrual blood flow normally stops each month. The results of pivotal, placebo-controlled phase III studies of Lysteda demonstrated that the drug significantly reduced mean monthly menstrual blood loss compared with baseline (pretreatment) blood loss. Biotest AG’s coagulation factor IX (Haemonine®) was launched in Germany in February 2009. It is indicated for the acute treatment and prevention of type B hemophilia, the rarer of the two types of this blood disorder. Haemonine was approved for marketing in A.I. Graul et al. pp.

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the European Union in late 2008; Germany was the first country in which it was introduced. Haemonine replaces another product that was previously marketed by Biotest within the framework of a licensing agreement. AMAG Pharmaceuticals’ ferumoxytol (Feraheme™), a new iron replacement therapy, was approved and launched for the first time last year in the United States. Ferumoxytol, which is administered by intravenous injection, is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). Iron deficiency anemia is a significant problem in this patient group. In all three phase III pivotal safety and efficacy studies evaluating ferumoxytol in patients with CKD and iron deficiency anemia, the study drug had a significantly greater effect in terms of increasing hemoglobin levels from baseline on day 35 after the first dose as compared to oral iron. Ferumoxytol is composed of superparamagnetic iron oxide particles with a proprietary semisynthetic carbohydrate coating; it has greater bioavailability than oral iron and is associated with fewer side effects. Gastrointestinal drugs The proton pump inhibitor (PPI) dexlansoprazole (Kapidex™; Takeda) was approved and launched last year in the U.S., where it is indicated for the treatment of heartburn associated with symptomatic nonerosive gastroesophageal reflux disease and for the healing of erosive esophagitis and maintenance of healed erosive esophagitis. Although various PPIs are already available, dexlansoprazole stands out as the first PPI with a Dual Delayed Release™ formulation designed to provide two separate releases of medication. Kapidex capsules contain two types of enteric-coated granules resulting in a concentration–time profile with two distinct peaks: the first occurring 1-2 hours

CH3

F F F

N

O

S N

O

Dexlansoprazole Gastrointestinal drugs

N H

after administration, and the second within 4-5 hours. Kapidex can therefore be taken just once daily, regardless of when food is consumed. Prucalopride, a selective, high-affinity serotonin 5-HT4 receptor agonist developed by Movetis, was approved in the E.U. in October 2009 for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Women account for 80-85% of all patients presenting to a doctor with symptoms of constipation. Movetis intends to market prucalopride (as Resolor®) by itself in certain European markets, including Germany, the U.K., France and the Benelux. Where necessary, Movetis will seek to broker partnerships to maximize the sales of Resolor in certain other European territories. It is expected that the first launch of prucalopride will be in Germany in the first quarter of 2010. Endocrine drugs Following approval by the European Commission in July 2009, the human glucagon-like peptide 1 (GLP-1) receptor agonist and incretin mimetic liraglutide (Victoza®; Novo Nordisk) was launched for the first time in the U.K. shortly thereafter. Liraglutide is the first once-daily GLP-1 analogue developed and approved for the treatment of type 2 diabetes, and only the second drug with this mechanism to reach the market; the first, exenatide (Byetta®; Amylin/Lilly), was introduced in 2005. In clinical studies involving more than 6,500 type 2 diabetes patients, treatment with liraglutide led to significant reductions in blood glucose levels, as well as weight loss, with a low associated risk of hypoglycemia. Regulatory applications have also been filed in the U.S. and Japan. A new dipeptidyl peptidase 4 (DPP IV) inhibitor was approved and launched in the U.S. last year: Bristol-Myers Squibb’s saxagliptin (Onglyza™), becoming the third member of this relatively new class of antidiabetic drugs to cross the finish line. Saxagliptin, which can be used as monotherapy or in combination with other antidiabetic drugs, is indicated in the U.S. as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes. In the E.U., where the European Commission granted marketing authorization in October for saxagliptin, it is indicated 7

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Drug News Perspect 23(1), January/February 2010

NC

H

His

Ser

Ala

Ser

Glu

Gly

Val

Thr

Asp

Ser

Phe

N O

OH NH2

Thr

Saxagliptin Tyr

Leu

Glu

Gly

Gln

Ala CH 3

O H N

CH3

H3C

N H

N

O

CH 3

CH 3

O

CH3

O O Ala

OH Ile

H

Phe

Glu

N H

O Trp

Leu

Val

Arg

Ala

O H

O

Gly

Arg

Gly OH

Ulipristal acetate

Liraglutide Endocrine drugs

for improving glycemic control in adults with type 2 diabetes in combination with metformin, a sulfonylurea or a thiazolidinedione. Bristol-Myers Squibb codeveloped the DPP IV inhibitor with AstraZeneca under the auspices of an antidiabetic drug collaboration signed in January 2007. In June 2008, the FDA approved Novo Nordisk’s PrandiMet™ (repaglinide/metformin hydrochloride), a fixed-dose combination of the fast-acting secretagogue repaglinide and the insulin sensitizer metformin, for the treatment of type 2 diabetes. The FDA approval was based on data demonstrating that PrandiMet 1 mg/500 mg and 2 mg/500 mg resulted in similar bioequivalence to coadministration of corresponding doses of repaglinide and metformin hydrochloride as individual tablets. Under a previously announced agreement, Sciele Pharma (now a subsidiary of Shionogi) has exclusive rights to market PrandiMet to physicians in the U.S. Launch took place in February 2009. Ulipristal acetate (ellaOne®; HRA Pharma), a selective progesterone receptor modulator (SPRM), was granted marketing approval in the European Union in May 2009. The first product launches took place in the U.K., Germany and France on October 1st. Ulipristal is indicated for emergency contraception within 120 hours (5 days) of unprotected sexual intercourse or contraceptive 8

failure. It is the first representative of a new therapeutic class, the SPRMs, in addition to being the first molecule specifically designed and developed for use as an oral emergency contraceptive. Clinical trials involving more than 4,000 women confirmed its efficacy in reducing the number of pregnancies versus those expected in the absence of emergency contraception. Unlike previous levonorgestrel-based emergency contraceptives, ulipristal acetate maintains efficacy for 5 days after unprotected intercourse. Its safety and tolerability profiles have been shown to be similar to those of levonorgestrel. Dermatologic drugs The κ opioid receptor agonist nalfurafine hydrochloride (Remitch®) was approved and launched last year for the first time in Japan. Nalfurafine is indicated for the improvement of pruritus in hemodialysis patients who have not responded to conventional treatment. Hemodialysis-related uremic pruritus is characterized by severe systemic itching without inflammation of the skin. Its cause has not been elucidated, and it often does not respond to treatment by conventional antipruritic drugs, such as antihistamines. Nalfurafine was codeveloped by Toray, Japan Tobacco and Torii Pharmaceuticals; it is manufactured and marketed by Toray. It has orphan drug status in Japan for the approved indication.

N OH .HCl

O

HO

O

O

N CH 3

Nalfurafine hydrochloride Dermatologic drugs

Hereditary angioedema (HAE) is an uncommon hereditary disorder that can cause sudden and severe episodes of acute, often painful inflammation that may affect any external or mucosal surface, including the face, arms, legs, hands, feet, genitalia, digestive track and airways. HAE is caused by low or dysfunctional levels of C1 esterase inhibitor (C1-INH), a naturally occurring molecule that inhibits plasma kallikrein and other serine proteases in the blood. The selective and reversible plasma kallikrein inhibitor ecallantide (Kalbitor®; Dyax) was approved by the U.S. FDA in December 2009 for the treatment of acute attacks of HAE in patients aged 16 years and older. The approval of ecallantide was based on the results of two placebo-controlled phase III clinical studies known as EDEMA3 and EDEMA4, in which treatment with the drug was associated with improvements in Mean A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

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Symptom Complex Severity (MSCS) scores and Treatment Outcome Scores (TOS), two disease-specific outcome endpoints developed by Dyax. Kalbitor is the first subcutaneous treatment for HAE approved in the U.S.; this route of administration makes it appropriate for treatment of acute attacks, regardless of anatomic location. Because of a risk of anaphylaxis associated with the treatment, Dyax worked with the FDA to establish a Risk Evaluation and Mitigation Strategy (REMS) program. The product will be launched during the first quarter of 2010, according to the company.

Following FDA approval in September, the once-daily injectable lipoglycopeptide antibiotic telavancin hydrochloride (Vibativ™) was launched for the first time in the U.S. in November 2009. The drug, which was also approved by Health Canada in October, was approved by the FDA for the treatment of adult patients with complicated skin and skin structure infections caused by susceptible Gram-positive bacteria, including Staphylococcus aureus, both methicillinresistant (MRSA) and methicillin-susceptible (MSSA) strains, as well as Streptococcus pyogenes, Streptococcus agalactiae, StreptoA.I. Graul et al. pp.

HN

O

HO

CH3

CH3 HO

O O

O

OH CH3

Cl O

Cl

O

HO

OH .HCl O

O

O

H N

N H

O

HN

HO

Anti-infective therapy Last summer, the U.S. FDA approved Medivir’s Lipsovir® (acyclovir/hydrocortisone) for the early treatment of recurrent herpes labialis to reduce the likelihood of ulcerative cold sores and to shorten lesion healing time. Treatment is approved for adults and children 12 years or older. In October, the European regulatory authorities approved Medivir’s marketing authorization for the combination product in 14 European countries for the treatment of early signs and symptoms of recurrent herpes labialis, to reduce the progression of cold sore episodes to ulcerative lesions in immunocompetent adults and adolescents (12 years of age and older). The trademark for the product in Europe will be Xerclear™. The Swedish Medical Products Agency issued a final statement of opinion in late December, stating that Xerclear will be released in Sweden in two formats: 5-g tubes available by prescription only, and a 2-g tube that will be available over the counter. Medivir reports that the former will be launched in the first quarter of 2010, and the latter will be available in the second quarter.

H N

OH

N H

O NH2

O

HO

P O

N H

OH

H N

CH3 CH3

CH3

O

HO HO

O

H N

OH

N H

Telavancin hydrochloride

Dermatologic drugs

coccus anginosus and vancomycin-susceptible strains of Enterococcus faecalis. Telavancin was discovered by Theravance in a research program dedicated to finding new antibiotics for serious infections due to S. aureus and other Gram-positive bacteria, including MRSA. The compound has a dual mechanism of action, both inhibiting bacterial cell wall synthesis and disrupting bacterial cell membrane function. Vibativ is marketed by Astellas. Nifurtimox/eflornithine hydrochloride combination therapy (NECT), a new treatment for human African trypanosomiasis (HAT, or sleeping sickness), was first made available in Africa through the World Health Organization (WHO) in September 2009. Developed by the Drugs for Neglected Diseases Initiative (DNDi) and its partners, the combination therapy consists of a simplified coadministration of oral nifurtimox and injectable eflornithine. It reduces the total number of intravenous eflornithine infusions from 56 to 14 and shortens hospitalization from 14 days to 10, as well as being significantly less costly than prior treatments. The development of the combination therapy is the result of a 6-year collaborative partnership coordinated by DNDi. The drugs were donated by sanofi-aventis and Bayer Schering Pharma. HAT is a lifethreatening parasitic disease that is endem-

ic in 36 countries, most of which lie in subSaharan Africa. According to the WHO, there are between 50,000 and 70,000 new cases of HAT each year, resulting in 48,000 deaths. WHO has included NECT in the Essential Medicines List as a treatment for stage 2 (advanced stage) HAT. Therapy of musculoskeletal & connective tissue diseases The year 2009 also saw the approval and launch of the anti-TNF-α antibody certolizumab pegol (Cimzia®; UCB) for the treatment of rheumatoid arthritis, an important new indication for this product, which was previously available for the treatment of Crohn’s disease. In the U.S., the first country to approve the rheumatoid arthritis indication, launch took place in May, immediately upon receipt of the FDA decision. Later in the year, approvals for the rheumatoid arthritis indication were received in Canada and the E.U. Golimumab (Simponi™), another anti-TNF-α monoclonal antibody (mAb), was also approved and launched last year in the U.S. and Canada for the treatment of rheumatoid arthritis in adult patients with moderately to severely active disease. In addition, golimumab is also indicated for the treatment of psoriatic arthritis and ankylosing spondylitis. It is marketed in the U.S. by 9

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Centocor Ortho Biotech and in Canada by Schering-Plough (now Merck & Co.), Later in the year, golimumab was approved in the European Union, also for the three indications of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Regular readers of this publication will recall that in 2008 the U.S. FDA approved rilonacept (Arcalyst™; Regeneron), the first treatment ever for cryopyrin-associated periodic syndrome (CAPS) disorders. Just a year later, in June 2009, the agency approved canakinumab (Ilaris®; Novartis), another drug for this group of extremely rare autoinflammatory disorders. Like its predecessor, canakinumab is indicated for the treatment of two forms of CAPS: familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). Symptoms of these rare disorders include joint pain, rash or skin lesions, fever and chills, eye redness or eye pain, and fatigue in both children and adults. MWS is furthermore associated with more severe inflammation and may lead to hearing loss or deafness, as well as amyloidosis. Unlike rilonacept, canakinumab is approved for use in patients as young as 4 years of age. This novel first-in-class therapeutic, which is administered just once every 8 weeks, acts by targeting and blocking interleukin-1β (IL-1β), which is overexpressed in CAPS and is involved in inflammation. There are approximately 300 CAPS sufferers in the U.S., where the product was launched in August. Canakinumab has orphan drug status for this indication in the U.S., as well as in the E.U. and Australia. In late July 2009, the U.S. FDA approved Colcrys™ (colchicine, USP) for the treatment of patients with familial Mediterranean fever (FMF). Colchicine is a complex compound derived from the dried seeds of Colchicum autumnale, also known as autumn crocus or meadow saffron. Colcrys, manufactured by URL Pharma, is the only single-ingredient colchicine approved by the FDA, and has orphan drug status for the FMF indication. It was launched later in the year. Familial Mediterranean fever belongs to a group of disorders known as the hereditary periodic fever syndromes. It is characterized by recurrent bouts of fever and peritonitis; other symptoms may include pleuritis, skin lesions, arthritis and, in rare cases, pericarditis. This hereditary disorder is most common in individuals of Mediterranean 10

Drug News Perspect 23(1), January/February 2010

heritage (Sephardic Jews, North African Arabs, Turks, Greeks, Italians and Armenians), although it may affect any ethnic group. The mechanism(s) of action by which colchicine exerts its beneficial effects in FMF is unclear. However, according to the FDAapproved product insert, it may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes, which mediates the activation of IL-1β. In addition, colchicine disrupts cytoskeletal functions by inhibiting β-tubulin polymerization into microtubules. In October 2009, TiGenix received approval from the European Commission to commercialize ChondroCelect® as an Advanced Therapy Medicinal Product in the 27 countries of the E.U., as well as Iceland, Lichtenstein and Norway. ChondroCelect is a cell-based medicinal product consisting of chondrocytes (cartilage-forming cells) that are taken from a healthy region of the patient’s cartilage, grown outside the body, and then reimplanted during an autologous chondrocyte implantation surgical procedure. Cartilage defects of the knee are very common and the spontaneous healing capacity of cartilage is limited. Currently, roughly two million cases of articular cartilage defects of the knee are diagnosed worldwide every year. TiGenix estimates that in Europe and the United States around 130,000 patients are eligible for treatment with cartilage regeneration products such as ChondroCelect. Advanced therapy medicinal products (ATMPs) are medicinal products for human use, and are based on gene therapy, somatic cell therapy or tissue engineering. They offer groundbreaking new treatment opportunities for diseases and injuries of the human body. The regulatory framework for ATMPs is established by Regulation (EC) No. 1394/2007 on ATMPs, which is designed to ensure the free movement of these medicines within the European Union, to facilitate their access to the E.U. market, and to foster the competitiveness of European pharmaceutical companies in the field, while guaranteeing the highest level of health protection for patients. ChondroCelect was the first ATMP to be approved under this regulation, as well as the first centrally approved cell-based product in Europe. The company began rolling out the product in November, and the first patients began receiving ChondroCelect in Germany before year-end.

Immunomodulators & agents for immunization Hepatitis B immune globulin (HBIG) has been used for nearly a decade to provide passive immunity to hepatitis B infection, for postexposure prophylaxis of newborn infants of hepatitis B surface antigen (HBsAg)-positive mothers and in individuals exposed to hepatitis B virus (HBV) or to HBsAg-positive materials in the healthcare setting. Immunoglobulin may also be used for postexposure prophylaxis after sexual exposure, or in the setting of liver transplantation (2). Antibodies specific to HBsAg, which are present in HBIG, combine with HBsAg and neutralize HBV so that its pathogenic properties are inhibited. In September 2009, Grifols launched Niuliva®, its human anti-hepatitis B immunoglobulin for intravenous administration, in Spain and Italy. Niuliva is approved for the prevention of HBV reinfection after liver transplantation for hepatitis B-induced liver failure during the maintenance phase in nonreplicator patients, and for the immunoprophylaxis of hepatitis B. The production of influenza vaccines in embryonated chicken eggs is a technology dating back to the 1950s. In the last decade, the pharma/biotech industry has dedicated significant resources to the development of newer, more efficient vaccine production methods that would overcome the many drawbacks of traditional methodology. Last year, a new cell-based seasonal influenza vaccine codeveloped by Solvay and Petrovax was approved in Russia. The vaccine, known as Grippol® Neo, is a seasonal influenza subunit vaccine based on influenza antigens produced by Solvay in its cell-based facility and incorporating Petrovax’s proprietary adjuvant polyoxidonium. The new preservative-free vaccine is then formulated in Petrovax’s facility near Moscow. The company began producing the first commercial batches of Grippol Neo in autumn 2009; the vaccine was launched in November. In February 2009, Sanofi Pasteur announced the approval in the European Union of a new seasonal influenza vaccine (split virion, inactivated), Intanza®/IDflu®. The vaccine is administered by intradermal microinjection, representing a significant improvement for patients in terms of convenience, ease of administration and patient acceptance, and potentially leading to better immunization rates in Europe. In spite of this promising profile, Intanza/IDflu was not launched for the 2009/2010 flu season, primarily A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

because the company’s resources were soon redirected to the development of a different influenza vaccine, as we shall now see. The global 2009 H1N1 influenza pandemic placed new and unprecedented demands on the biopharmaceutical industry during the past year, with the rapid emergence and spread of a new virus necessitating an equally rapid and coordinated response from the WHO, national health authorities and vaccine developers. The need for a human swine flu vaccine became clear soon after the first cases were registered in April. WHO Director-General Dr. Margaret Chan and United Nations Secretary-General Ban Ki-moon met on May 19, 2009 with more than 30 vaccine manufacturers from developing and developed countries. Industry representatives affirmed their cooperation in making vaccine supplies available to developing countries. In late May, the WHO and CDC provided samples of the seed virus (A/California/7/2009(H1N1)pdm) to pharma companies so that they could develop H1N1 vaccines. On September 15, the FDA approved the first four H1N1 vaccines worldwide; regulatory authorities worldwide –including Australia, China and the European Union– have since licensed other pandemic vaccines*. Mass vaccination campaigns began in most countries in October and November (3). Among the H1N1 vaccines approved for marketing in the U.S. during 2009 are those developed by Sanofi Pasteur, CSL and Novartis, all of which are injectable vaccines incorporating virus produced in embryonated chicken eggs, and a live attenuated intranasal vaccine developed by MedImmune. As specified by the FDA, none of the influenza A (H1N1) 2009 monovalent vaccines bear a trade name in that country, although some –such as the CSL vaccine, known as Panvax® H1N1 in Australia– do have trade names elsewhere. All four companies began shipping their vaccines almost immediately. A fifth H1N1 vaccine manufactured by ID Biomedical (a subsidiary of GlaxoSmithKline) was approved by the FDA in mid-November; GlaxoSmithKline expects to begin shipping the vaccine in early 2010. *Other H1N1 vaccines are known to have been approved for use in national vaccine campaigns in several other countries, although complete data were not available at the time this article went to press and therefore could not be included. A.I. Graul et al. pp.

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Other H1N1 vaccines that were rushed to market in various countries last year include the adjuvanted egg-based vaccine Focetria (A/H1N1) (Novartis) and the adjuvanted split influenza vaccine Pandemrix™ (H1N1) (GlaxoSmithKline), both approved and shipped to national governments in the E.U.; the adjuvanted cell culture-based vaccine Celtura® (Novartis), approved in Germany and Switzerland, and launched in Switzerland; the nonadjuvanted inactivated vaccine Panenza® from Sanofi Pasteur, approved and shipped to national authorities in France; the split-virion vaccine PANFLU.1 (Sinovac Biotech), approved and incorporated into national vaccination programs in China; and the whole-virion vaccine Fluval P (Omnivest), containing virus propagated in Vero cells, which was approved and is being distributed in Hungary. In some cases, such as that of Pandemrix and Focetria, the rapid development of a new vaccine was facilitated by the earlier development and regulatory approval of “prepandemic” vaccines (4). In a related development, Baxter International received European marketing approval in March 2009 for the pandemic influenza mock-up vaccine Celvapan®, based on an inactivated H5N1 strain manufactured in Vero cells. In October, the European Commission granted marketing authorization for Celvapan H1N1 pandemic influenza A (H1N1) vaccine, which was developed using Baxter’s Vero cell technology based on the previously approved mock-up vaccine. Celvapan H1N1 is the first cell culture-based and nonadjuvanted pandemic influenza vaccine to receive marketing authorization in the European Union. National public health authorities that have agreements with Baxter to receive Celvapan H1N1 pandemic vaccine include those in the U.K., Ireland, Germany, France, Austria and New Zealand; Baxter continues to deliver vaccine to national public health authorities that have agreements with the company. Japanese encephalitis is a mosquito-borne arbovirus infection with seasonal distribution. It is endemic in parts of China, India, the Republic of Korea, Japan, the Russian Federation, islands in the Torres Strait of Australia, Nepal, Thailand, Vietnam, Cambodia, the Lao People’s Democratic Republic, the Philippines, Taiwan, Indonesia, Malaysia and Sri Lanka. Japanese encephalitis virus belongs to the Flaviviridae family, genus Flavivirus. It is transmitted to

humans by a mosquito that has previously bitten an infected animal, such as pigs. Although some patients have only mild or no symptoms, the disease can be serious and even fatal in up to 30% of cases. Last year, two new vaccines were introduced for the prevention of Japanese encephalitis: Biken’s Jebik V® (Japanese encephalitis (Beijing strain) vaccine, dry-cell cultured), approved and marketed in Japan by Takeda and Mitsubishi Tanabe; and Intercell’s Jespect® (Japanese encephalitis vaccine, inactivated, adsorbed), approved and launched in Australia, where it is marketed by CSL, and in the U.S., France and Germany, where it is marketed by Novartis (as Ixiaro®). The latter has orphan drug status in the European Union. Pneumococcal disease is the leading cause of vaccine-preventable death worldwide in children younger than 5 years of age, and is estimated to cause up to one million pediatric deaths each year. Prevenar 13 (pneumococcal conjugate vaccine 13 valent [diphtheria CRM197 protein]), developed by Wyeth Lederle Vaccines (now Pfizer), was approved for the first time in Chile last July, indicated in that country for active immunization of children aged 6 weeks through 5 years for the prevention of invasive pneumococcal disease, as well as pneumonia and otitis media caused by 13 pneumococcal serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. The vaccine also received favorable recommendations from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) in September and from an FDA advisory committee in November; European approval followed in December, and the first launch worldwide of the vaccine took place in Germany in December. Prevenar, the company’s 7-valent pneumococcal conjugate vaccine, is currently registered in more than 100 countries and available in 97. Once Prevenar 13 is commercially available in a particular country, Prevenar 13 will replace Prevenar after a period of transition. A different pneumococcal conjugate vaccine –GlaxoSmithKline’s Synflorix™ (pneumococcal conjugate vaccine [nontypeable Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates], adsorbed)– was approved last year in the European Union and was launched for the first time in the Czech Republic. This particular 10-valent vaccine is active against 11

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pneumococcal disease caused by serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F, and is indicated for use in children aged 6 weeks through 2 years of age. Treatment of cancer In March 2009, Ferring launched degarelix acetate (Firmagon®), a gonadotrophinreleasing hormone (GnRH) receptor antagonist indicated for the treatment of patients with advanced prostate cancer. Degarelix is the first new treatment for prostate cancer to be launched in the U.S. in several years, as well as Ferring’s first global product launch. Also during 2009, marketing approval was granted in the E.U. In October, the Japanese Ministry of Health, Labour and Welfare granted manufacturing and marketing approval to Dainippon Sumitomo Pharma for Miripla® (miriplatin hydrate), its anticancer platinum complex for the treatment of hepatocellular carcinoma. The drug is first suspended in the Miripla® suspension vehicle, approved in Japan in August 2009, and then administered through the hepatic artery. Clinical studies confirmed satisfactory antitumor effects of the agent after initial treatment of patients with hepatocellular carcinoma, and also in patients who relapsed after treatments such as hepatic resection. The company has announced that Miripla® will be launched in Japan in January 2010. Allos Therapeutics announced last year the U.S. approval and launch of the company’s first product: pralatrexate (Folotyn™), a dihydrofolate reductase inhibitor approved for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Pralatrexate is the first and only drug approved by the FDA for this indication and represents a new treatment option for patients with relapsed or refractory PTCL, a group of aggressive blood cancers with poor prognosis and few treatment options. The product has orphan drug status in the U.S. and the E.U. for several indications, including T-cell lymphoma. The mTOR (mammalian target of rapamycin) inhibitor everolimus (Afinitor®; Novartis) was approved and launched last year in the U.S. for a new indication: the treatment of advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Unlike sunitinib and sorafenib, which are multiple kinase inhibitors, 12

Drug News Perspect 23(1), January/February 2010

everolimus selectively blocks mTOR, a protein in cancer cells that acts as a central regulator of tumor cell division, blood vessel growth and cell metabolism. Based on its potential to fulfill an unmet medical need, the FDA granted priority review status to everolimus in 2008. Later in 2009, Afinitor was approved in the E.U., where it has orphan drug status for this new indication, and was subsequently launched in the U.K. Everolimus has been marketed since 2004 (as Certican®) as an immunosuppressive agent for the prevention of rejection episodes following heart or kidney transplantation. The angiogenesis inhibitor pazopanib hydrochloride (Votrient™; GlaxoSmithKline), an orally active vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, was approved in the U.S. in October 2009 and was launched soon thereafter. It is indicated for the treatment of patients with advanced renal cell carcinoma, a type of cancer that was diagnosed in approximately 49,000 people in America in 2009 and caused approximately 11,000 deaths. Histone deacetylase (HD) inhibitors are emerging as a promising new class of targeted oncolytic drugs. Histone deacetylases alter chromatin structure and affect transcriptional regulation. Dysregulation of chromatin deacetylation is associated with cancer and inflammatory diseases. Inhibitors of HD act by inducing apoptotic cell death in cancer cells but not in normal cells, which are comparatively resistant to the apoptosis-inducing effects of these agents. In 2006, vorinostat (Zolinza™; Merck & Co.) became the first HD inhibitor to obtain regulatory authorization worldwide; it was approved by the FDA for the treatment of cutaneous T-cell lymphoma (CTCL) (5). Last year, the second HD inhibitor was approved in the U.S. for the same indication: Gloucester Pharmaceuticals’ romidepsin (Istodax®). In clinical studies, romidepsin therapy was associated with a 34-35% objective response rate, with a median duration of response of approximately 11-15 months and a mean time to first response of 2 months. Romidepsin will be launched in 2010. In April, the European Commission authorized Fresenius Biotech’s marketing application for Removab® (catumaxomab), a tri-

functional bispecific antibody against human epithelial cell adhesion molecule (Ep-CAM) and human CD3, for the treatment of malignant ascites. Malignant ascites, the accumulation of peritoneal fluid in the abdominal cavity, is most common in ovarian, pancreatic and gastric cancers, with an incidence of 20-50% of all cases. The condition is caused by abdominal spread of the cancer cells and is associated with poor prognosis. It was previously treatable only by paracentesis (puncture and drainage). The approval of catumaxomab was based on results of a large international pivotal phase II/III study, which demonstrated a statistically significant improvement in the primary endpoint of puncture-free survival. Patients receiving catumaxomab had a fourfold increase in puncture-free survival over therapy with paracentesis alone. Catumaxomab is a first-in-class product in several respects: it is the first approved treatment for malignant ascites; the first approved bispecific, trifunctional antibody; and the only approved antibody targeting the tumor antigen Ep-CAM. Fresenius began marketing the product in Germany shortly after approval. In October, the anti-CD20 human mAb ofatumumab (Arzerra™) received accelerated approval from the U.S. FDA for the treatment of chronic lymphocytic leukemia (CLL) that is refractory to fludarabine and alemtuzumab. Ofatumumab is an mAb that causes the body’s immune response to fight against normal and cancerous B cells. It attaches to the small and large loop epitopes on the CD20 molecule, which is found on the surface of B cells. Approval was based on results from a pivotal study in which 42% of patients with CLL who were refractory to both fludarabine and alemtuzumab responded to treatment with the mAb. These patients had a median duration of response of 6.5 months. As a condition of the accelerated approval, the companies will conduct further studies of ofatumumab in CLL patients to confirm that the addition of the mAb to standard chemotherapy delays disease progression. Ofatumumab was discovered by Genmab; it was codeveloped with and is marketed by GlaxoSmithKline. The latter began marketing the product in November. In March 2009, the European Commission formally granted a centralized marketing A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

DRUGLINE

authorization for IDM Pharma’s Mepact® (mifamurtide, L-MTP-PE) for the treatment of patients with nonmetastatic resectable osteosarcoma. The centralized marketing authorization allows mifamurtide to be marketed in the 27 member states of the European Union, as well as in Iceland, Lichtenstein and Norway. The approval was based on a phase III trial, a National Cancer Institute (NCI)-funded cooperative group study conducted by the Children’s Oncology Group, enrolling approximately 800 patients. Results demonstrated that the addition of mifamurtide to chemotherapy resulted in an approximately 30% decrease in the risk of death, with 78% of patients surviving through the sixth year of follow-up after treatment. Mifamurtide has orphan

ple myeloma (MM). By blocking CXCR4, a specific cellular receptor, plerixafor triggers the rapid movement of stem cells out of the bone marrow and into circulating blood, where they can be collected for use in stem cell transplant. The current standard of care for stimulating the mobilization of stem cells from the bone marrow is G-CSF alone. In clinical studies, plerixafor plus G-CSF rapidly increased the number of peripheral blood stem cells capable of engraftment, thereby increasing the proportion of patients reaching a peripheral blood stem cell target. In pivotal studies, 59% of patients treated with plerixafor plus G-CSF collected the target number of at least five million stem cells/kg body weight in four or fewer apheresis sessions, compared to just

drug status in the E.U. for this indication. IDM was acquired by Takeda later in the year; the drug will be marketed by Takeda Pharmaceuticals Europe, with first launches expected to take place early in 2010. Plerixafor hydrochloride (Mozobil™; Genzyme), a first-in-class small-molecule antagonist of the chemokine CXCR4 receptor, was launched early last year in the U.S. for use in certain cancer patients. The product, which has orphan drug status, is indicated for use in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the bloodstream for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multi-

O HN

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O N

O NH CH3

O H3C

H N

N H

O N H

H N

N H

O

O

CH3 H N

O

O H N

O

OH

O

O

CH3

O

O H N

NH

Cl O

.CH3CO2H

NH2

N H

N

N H

CH3 CH3

NH2

Degarelix acetate O

O

CH 3

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S

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.HCl

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Pazopanib hydrochloride

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Pralatrexate

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.8HCl .2H 2O

Plerixafor Treatment of cancer A.I. Graul et al. pp.

13

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Drug News Perspect 23(1), January/February 2010

20% of patients receiving placebo. In addition to the obvious benefits for patients requiring stem cell transplant, the use of plerixafor may also offer economic benefits to transplant centers, as fewer apheresis days are needed to mobilize the necessary number of stem cells. Later in the year, plerixafor was approved in the E.U. and launched in the U.K., where it is indicated to enhance mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma or MM. Ophthlamic drugs Bausch & Lomb’s topical ophthalmic antibacterial agent besifloxacin hydrochloride (Besivance™) was approved and launched last year in the U.S., where it is indicated for the treatment of bacterial conjunctivitis. Besifloxacin treats a wide range of ocular pathogens, including those that most commonly cause bacterial conjunctivitis. It is the first fluoroquinolone developed specifically for ophthalmic use, and is the first and only ophthalmic fluoroquinolone with no previous systemic use. The product is copromoted by Bausch & Lomb and Pfizer sales forces. The histamine H1 receptor antagonist bepotastine besilate (Bepreve™), developed by ISTA Pharmaceuticals as a topical eyedrop formulation for the treatment of ocular itching associated with allergic conjunctivitis, was approved and launched last year in the U.S., the first market for this new formulation/new indication. Bepotastine has been marketed since 2000 for the systemic treatment of allergic rhinitis and urticaria/pruritus. In 2006, ISTA in-licensed North American rights to develop an eyedrop formulation of bepotastine from Senju, which had previously obtained global rights to ocular formulations from product originator Tanabe Seiyaku.

O

OH N

N Cl

Besifloxacin hydrochloride Ophthalmic drugs 14

Ozurdex™ (dexamethasone intravitreal implant), a biodegradable, injectable steroid implant developed by Allergan, was approved for marketing by the U.S. FDA in June 2009. It is indicated for the treatment of macular edema following branch retinal vein occlusion or central retinal vein occlusion, which account for significant vision loss in patients over 40 years of age. Ozurdex is a first-of-its-kind therapy that is administered by intravitreal injection and delivers the potent corticosteroid dexamethasone via the company’s proprietary Novadur™ solid polymer delivery system. The product was launched in the U.S. in September. The prostaglandin analogue bimatoprost (Latisse®), which has been marketed by Allergan since 2001 for the treatment of glaucoma, was launched last year for an entirely new indication: the treatment of hypotrichosis of eyelashes. Patients with this medical aesthetic condition have inadequate or not enough eyelashes. The new indication was discovered serendipitously, upon the observation that patients using bimatoprost to treat open-angle glaucoma experienced eyelash growth as a side effect. In subsequent clinical studies, Allergan demonstrated that the once-daily application of bimatoprost led to improved eyelash length, thickness and darkness, together with a favorable safety profile.

O

F H2N

Azarga® (brinzolamide/timolol maleate; Alcon), a fixed-dose combination product for the treatment of glaucoma, was launched for the first time in early 2009 in Germany. Like arterial hypertension, ocular hypertension is often difficult to control with only one drug, necessitating the use of combination drug therapy. The development of fixed-dose combination products facilitates therapy, thereby increasing patient adherence to treatment regimens and potentially lowering costs. Azarga is indicated for the treatment of elevated intraocular pressure associated with open-angle glaucoma or ocular hypertension.

.HCl

Metabolic drugs In June 2009, Merck & Co. announced the first launch worldwide of Tredaptive™ (nicotinic acid/laropiprant), a fixed-dose combination product for lowering blood cholesterol, in Ireland. Tredaptive is indicated for the treatment of dyslipidemia, particularly in patients with combined mixed dyslipid-

emia (characterized by elevated levels of LDL cholesterol and triglycerides and low HDL cholesterol) and in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial). Tredaptive should be used in patients in combination with statins, when the cholesterol-lowering effects of statin monotherapy are inadequate; the product can be used as monotherapy only in patients in whom statins are considered inappropriate or not tolerated. Nicotinic acid is a lipid-modifying agent and laropiprant is a potent, selective antagonist of the prostanoid DP1 receptor. Nicotinic acid reduces plasma levels of VLDL cholesterol and LDL cholesterol, apolipoprotein B (apo B), triglycerides, total cholesterol and lipoprotein a (Lp(a)), and elevates levels of HDL cholesterol and apolipoprotein A-I (apo A-I). Laropiprant suppresses PGD2-mediated flushing, a side effect frequently associated with administration of nicotinic acid. Laropiprant has no effect on lipid levels, nor does it interfere with the effects of nicotinic acid on lipids. Selective estrogen receptor modulators (SERMs), sometimes referred to as “designer estrogens”, provide the benefits of estrogen without its adverse effects on reproductive organs due to their tissue-specific activity. The first compound from the SERM class to reach the market was raloxifene (Evista®; Lilly), which was launched in early 1998 for the prevention of postmenopausal osteoporosis, and a year later for its treatment. Since the launch of raloxifene, no further SERMs had achieved regulatory approval in any country until last year, when two SERMs were approved, both indicated for the treatment of osteoporosis in postmenopausal women. The first, Pfizer/ Ligand’s lasofoxifene tartrate (Fablyn®), was authorized for marketing in the E.U. in late March. The second, Wyeth/Ligand’s bazedoxifene acetate (Conbriza®), was approved by the same regulatory body just one month later. Neither has yet been launched. Pfizer and Wyeth merged during 2009, an event that will presumably have an impact on marketing decisions regarding these products. Also in the area of osteoporosis, the bone resorption inhibitor minodronic acid hydrate was approved and introduced last year in Japan, bringing the total number of bisphosphonates marketed for this indication to seven. There are an estimated 10 million A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

DRUGLINE

N

CH3

N

H3C

O P P O

OH

OH

O

O

.H2O

S NC

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OH N

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Febuxostat

Minodronic acid hydrate Metabolic drugs

current and potential osteoporosis sufferers in Japan, a number that is expected to continue growing due to the country’s aging population. Minodronic acid is the first drug to show a significant effect in preventing bone fractures as compared to placebo in a Japanese patient population. Minodronic acid was codeveloped by Astellas and Ono, who are marketing the drug as Bonoteo® and Recalbon®, respectively. The Augment™ Bone Graft (GEM-OS1), a novel implantable biologic developed by BioMimetic Therapeutics, was approved in Canada in November 2009. Augment is a completely synthetic grafting system for bone regeneration and is composed of a purified recombinant growth factor, recombinant human platelet-derived growth factor (rhPDGF-BB), and a synthetic calcium phosphate matrix, β-tricalcium phosphate

(β-TCP). rhPDGF-BB provides the biological stimulus for tissue repair by stimulating the recruitment and proliferation of new boneforming cells and blood vessels, while β-TCP provides the framework for new bone growth to occur. Augment is approved as an alternative to the use of autograft in midfoot, hindfoot and ankle fusion indications. In clinical studies conducted in Canada, a 90% clinical success rate was observed with Augment, while avoiding the morbidity and extra operating room time associated with autograft harvest. Augment Bone Graft was launched in Canada, its first market worldwide, in December. It is distributed by Joint Solutions Alliance. The xanthine oxidase inhibitor febuxostat, developed by Teijin, was first approved in the E.U. in May 2008 and subsequently in the U.S. in February 2009. A month later, in

March 2009, Teijin’s U.S. marketing partner Takeda launched the product in that country under the trade name Uloric®. Febuxostat is indicated in the U.S. for the chronic management of hyperuricemia in gout, and represents the first major new treatment for this condition in more than 40 years. In October 2009, Teijin Pharma announced that a sublicense agreement for febuxostat had been signed by Ipsen, the European licensee of the drug, and Menarini. Under the terms of the new agreement, Menarini will handle sales of the agent in Europe, including Russia, under the brand name Adenuric®, with commercial launch planned in early 2010. The ceramide glucosyltransferase inhibitor miglustat (Zavesca®; Actelion) was approved last year in the E.U. and launched for the first time in France for a new indication: treatment of progressive neurological manifestations in adult patients and pediatric patients with Niemann-Pick type C disease. Miglustat is the first treatment for this rare and devastating neurological disorder, symptoms of which are caused by the storage of glycosphingolipids in certain cells of the body, including the brain. Treatment with the drug was shown in clinical studies to provide clinically relevant benefits on neurological disease progression in patients with the disorder. Miglustat was previously approved in 2003 for the treatment of Gaucher’s disease, another lysosomal storage disorder.

Table II. New product intros – 2009 Trade name (country)1

Company

Active ingredient2

Indication

Valturna® (US)

Novartis

Aliskirin fumarate/valsartan***, tablets, 160 mg/160 mg & 300 mg/320 mg aliskirin/ valsartan

Treatment of high blood pressure in patients not adequately controlled on aliskirin or angiotensin receptor blocker monotherapy, and as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals

Exforge HCT® (US)

Novartis

Amlodipine/valsartan/hydrochlorothiazide***, Treatment of hypertension film-coated tablets containing amlodipine besylate equivalent to 5 mg or 10 mg of amlodipine free base with valsartan 160 mg or 320 mg and hydrochlorothiazide 12.5 mg or 25 mg, providing for the following available combinations: 5/160/12.5 mg, 10/160/12.5 mg, 5/160/25 mg, 10/160/25 mg & 10/320/25 mg

Abilify® (US)

Bristol-Myers Squibb/Otsuka

Aripiprazole, tablets, 2, 5, 10, 15, 20 & 30 mg; Treatment of irritability associated with autistic orally disintegrating tablets, 10 & 15 mg; oral disorder** solution, 1 mg/mL Continued

A.I. Graul et al. pp.

15

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Drug News Perspect 23(1), January/February 2010

Table II. Cont. New product intros – 2009 Trade name (country)1

Company

Active ingredient2

Indication

Nuvigil™ (US)

Cephalon

Armodafinil, tablets, 50, 150 & 250 mg

To improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome, narcolepsy and work shift sleep disorder

Saphris® (US)

Schering-Plough

Asenapine maleate, sublingual tablets, fastdissolving, equiv. to 5 & 10 mg asenapine

Acute treatment of schizophrenia in adults; acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults

Bepreve™ (US)

ISTA Pharmaceuticals; licensed from Senju

Bepotastine besilate, ophthalmic solution*, 1.5%

Treatment of itching associated with signs and symptoms of allergic conjunctivitis**

Besivance™ (US)

Bausch & Lomb/Pizer

Besifloxacin hydrochloride, ophthalmic suspension, 0.6%

Treatment of bacterial conjunctivitis

Latisse™ (US)

Allergan

Bimatoprost, ophthalmic solution, 0.03%

Treatment of hypotrichosis of eyelashes, to increase their growth including length, thickness and darkness**

Azarga® (DE)

Alcon

Brinzolamide/timolol maleate***, eyedrops, suspension, 1 mL containing 10 mg brinzolamide and 5 mg timolol (as timolol maleate)

Decrease of intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient IOP reduction

Aplenzin™ (US)

Biovail/sanofi-aventis

Bupropion hydrobromide, tablets, extended- Treatment of major depressive disorder in adults release*, once-daily, 174, 348 & 522 mg aged 18 years and older

Ilaris® (US)

Novartis

Canakinumab, single-use vials containing sterile, preservative-free lyophilized powder containing 180 mg canakinumab for reconstitution with 1 mL Sterile Water for Injection in a 150 mg/mL solution, for s.c. injection

Treatment of cryopyrin-associated periodic syndromes (CAPS) in adults and children 4 years of age and older including: familial cold autoinflammatory syndrome and Muckle-Wells syndrome (orphan drug)

Removab® (DE)

TRION Pharma/Fresenius

Catumaxomab, concentrate for solution for i.p. infusion, 10 µg/0.1 mL & 50 µg/0.5 mL, corresponding to 0.1 mg/mL

Intraperitoneal treatment of malignant ascites in patients with Ep-CAM-positive carcinomas where standard therapy is not available or no longer feasible

Cimzia® (US)

UCB

Certolizumab pegol, vials, lyophilized powder for reconstitution for s.c. administration, 200 mg; single-use prefilled syringe, 200 mg/1 mL for s.c. administration

Treatment of adults with moderately to severely active rheumatoid arthritis**

ChondroCelect® (DE)

TiGenix

Characterized viable autologous cartilage cells expanded ex vivo expressing specific marker proteins, vials, 4 million autologous human cartilage cells in 0.4 mL cell suspension, corresponding to a concentration of 10,000 cells/µL

Repair of single symptomatic cartilage defects of the femoral condyle of the knee (International Cartilage Repair Society [ICRS] grade III or IV) in adults

Haemonine® (DE)

Biotest AG

Coagulation factor IX, powder in vials, 250, 500 & 1000 IU for reconstitution in Water for Injection

Acute treatment and prevention of type B hemophilia

Colcrys™ (US)

URL Pharma

Colchicine, USP, tablets, 0.6 mg

Treatment of familial Mediterranean fever in adults and children 4 years and older**

Priligy™ (FI, SE)

Janssen-Cilag

Dapoxetine hydrochloride, tablets, 30 & 60 mg

On-demand treatment of premature ejaculation in men 18-64 years of age

Firmagon® (US)

Ferring

Degarelix acetate, powder for s.c. injection Treatment of patients with advanced prostate in vials containing degarelix acetate equiv. to cancer 80 & 120 mg degarelix, to be reconstituted with Sterile Water for Injection, USP Continued

16

A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

DRUGLINE

Table II. Cont. New product intros – 2009 Trade name (country)1

Company

Active ingredient2

Indication

Ozurdex™ (US)

Allergan

Dexamethasone, intravitreal implant* containing 0.7 mg dexamethasone in the Novadur™ solid polymer drug delivery system, composed of poly(D,L-lactide-co-glycolide) PLGA intravitreal polymer matrix that slowly degrades to lactic acid and glycolic acid

Treatment of macular edema following branch retinal vein occlusion or central retinal vein occlusion

Erizas® (JP)

Nippon Shinyaku

Dexamethasone cipecilate, dry powder for nasal spray in capsules, 400 µg

Treatment of allergic rhinitis

Kapidex™ (US)

Takeda

Dexlansoprazole, delayed-release capsules, 30 & 60 mg

Treatment of heartburn associated with symptomatic nonerosive gastroesophageal reflux disease, healing of erosive esophagitis and maintenance of healed erosive esophagitis

Multaq® (US)

sanofi-aventis

Dronedarone hydrochloride, tablets, equiv. to 400 mg dronedarone

To reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age > 70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥ 50 mm or left ventricular ejection fraction [LVEF] < 40%), who are in sinus rhythm or who will be cardioverted

Zebinix® (DE, AT)

Bial-Portela; marketed by Eisai

Eslicarbazepine acetate, tablets, 800 mg

Adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization

Afinitor® (US)

Novartis

Everolimus, tablets, 5 & 10 mg

Treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib**

Uloric® (US)

Takeda; licensed from Teijin

Febuxostat, tablets, 40 & 80 mg

Chronic management of hyperuricemia in patients with gout

Feraheme™ (US)

AMAG Pharmaceuticals

Ferumoxytol, single-use vials, 510 mg/ 17 mL for i.v. injection

Treatment of iron deficiency anemia in adult patients with chronic kidney disease

Lusedra™ (US)

Eisai

Fospropofol disodium, single-use vials containing aqueous solution for i.v. injection, 35 mg/mL (total of 1,050 mg/30 mL) fospropofol disodium

For monitored anesthesia care sedation in adult patients undergoing diagnostic or therapeutic procedures

Augment™ Bone Graft (CA)

BioMimetic Therapeutics; distributed by Joint Solutions Alliance

GEM-OS1, one sterile tray containing a vial filled with rhPDGF-BB solution (3 mL, 0.3 mg/mL) and disposable syringe and needle; another one containing a sealed cup filled with dry β-TCP granules. To be combined in entirety, mixed and applied to the surgical site

As an alternative to the use of autograft in foot and ankle fusion procedures that require supplemental graft material, including tibiotalar, talocalcaneal, talonavicular, calcaneocuboid, tarsometatarsal, naviculocuneiform, metatarsophalangeal and interphalangeal fusions

Simponi™ (US, CA)

Centocor Ortho Biotech; codeveloped and marketed by Schering-Plough

Golimumab, single-use SmartJect™ autoinjector or single-dose prefilled syringe containing 50 mg golimumab/0.5 mL, for once-monthly s.c. injection

In combination with methotrexate (MTX), for reducing signs and symptoms in adult patients with moderately to severely active rheumatoid arthritis; reducing signs and symptoms in adult patients with moderately to severely active psoriatic arthritis, alone or in combination with MTX; and reducing signs and symptoms in adult patients with active ankylosing spondylitis who have had an inadequate response to conventional therapies Continued

A.I. Graul et al. pp.

17

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Drug News Perspect 23(1), January/February 2010

Table II. Cont. New product intros – 2009 Trade name (country)1

Company

Active ingredient2

Indication

Intuniv™ (US)

Shire

Guanfacine hydrochloride, extended-release tablets, 1, 2, 3 & 4 mg

Treatment of attention deficit hyperactivity disorder in children and adolescents aged 6-17 years**

Niuliva® (ES, IT)

Grifols

Human anti-hepatitis B immunoglobulin, solution for infusion in prefilled syringes and vials, 250 IU/mL

Prevention of hepatitis B virus reinfection after liver transplantation for hepatitis B-induced liver failure during the maintenance phase in nonreplicator patients; immunoprophylaxis of hepatitis B

Onbrez® Breezhaler® (DE)

Novartis

Indacaterol maleate, powder for inhalation in Maintenance bronchodilator treatment of hard capsules, equiv. to 150 & 300 µg airflow obstruction in adult patients with chronic indacaterol, for administration with the obstructive pulmonary disease accompanying single-dose inhalation device

PANFLU.1 (CN)

Sinovac Biotech

Influenza A (H1N1) vaccine, vials, 15 µg

Active immunization against influenza H1N1 in subjects aged 3-60 years on a single-shot vaccination schedule

(US)

Sanofi Pasteur

Influenza A (H1N1) 2009 monovalent vaccine, prefilled syringe, 0.25 & 0.5 mL; single-dose vials, 0.5 mL; multidose vials, 5 mL, for i.m. injection

Active immunization of persons 6 months of age and older against influenza disease caused by pandemic (H1N1) 2009 virus

Panenza® (FR)

Sanofi Pasteur

Influenza A (H1N1) 2009 monovalent vaccine, suspension in multidose vials, 5 mL, for i.m. injection

Active immunization of persons 6 months of age and older against influenza disease caused by pandemic (H1N1) 2009 virus

Pandemrix™ (H1N1) (EU)

GlaxoSmithKline

Influenza A (H1N1) vaccine, two multidose 2.5-mL vials. Suspension: split influenza virus, inactivated, containing antigen (propagated in eggs) equivalent to: A/California/7/2009 (H1N1)v-like strain (X-179A) 3.75 µg hemagglutinin. Emulsion: AS03 adjuvant composed of squalene (10.69 mg), DL-α-tocopherol (11.86 mg) and polysorbate 80 (4.86 mg). Mixing 1 vial of suspension with 1 vial of emulsion will yield 10 doses of vaccine (5 mL), for i.m. injection

Active immunization against pandemic influenza in adults and children from 6 months of age

(US)

CSL

Influenza A (H1N1) 2009 monovalent vaccine, Active immunization to prevent influenza prefilled syringe, 0.5 mL; multidose vials, disease caused by the influenza A (H1N1) virus, in 5 & 10 mL, for i.m. injection adults, adolescents and children 10 years of age and older

Panvax® H1N1 (AU) (US)

MedImmune

Influenza A (H1N1) 2009 monovalent vaccine Active immunization of persons 2-49 years of live, intranasal, suspension in prefilled single- age against influenza disease caused by dose intranasal sprayer, 0.2 mL pandemic (H1N1) 2009 virus

(US)

Novartis

Influenza A (H1N1) 2009 monovalent vaccine, sterile suspension for i.m. injection in prefilled syringe, 0.5 mL, and multidose vials, 5 mL

Focetria (A/H1N1) (EU)

Novartis

Influenza A (H1N1) 2009 monovalent vaccine, Active immunization of persons 6 months of age adjuvanted, suspension in 0.5-mL prefilled and older against influenza disease caused by syringe, 0.5-mL dose and 5-mL multidose pandemic (H1N1) 2009 virus vials containing 7.5 µg of hemagglutinin and neuraminidase of A/California/7/2009 (H1N1)v like strain (X-179A) plus MF59C.1 adjuvant

Active immunization of persons 4 years of age and older against influenza disease caused by pandemic (H1N1) 2009 virus

Continued 18

A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

DRUGLINE

Table II. Cont. New product intros – 2009 Trade name (country)1

Company

Active ingredient2

Celtura® (CH)

Novartis

Influenza A (H1N1) 2009 monovalent vaccine, Active immunization in persons 6 months of age adjuvanted, single-dose prefilled syringes and older against influenza disease caused by containing 3.75 µg antigen and 0.125 mL of the novel pandemic A(H1N1) influenza virus MF59

Fluval P (HU)

Omnivest

Influenza A (H1N1) 2009 monovalent vaccine, Active immunization against H1N1 influenza in inactivated, adjuvanted, suspension in adults, including pregnant women, and children single-dose prefilled syringes, 0.5 mL older than 6 months of age

Celvapan H1N1 (EU)

Baxter

Influenza A (H1N1) 2009 monovalent vaccine, Active immunization of persons 6 months of age inactivated, multidose vials, 5 mL (containing and older against influenza disease caused by 10 0.5-mL doses) pandemic (H1N1) 2009 virus

Jebik V® (JP)

Biken; distributed by Takeda and Mitsubishi Tanabe

Japanese encephalitis (Beijing strain) vaccine, dry-cell cultured, solvent solution in single-use bottles, 0.7 mL

Prophylaxis against Japanese encephalitis

Jespect® (AU)

Intercell; distributed and marketed by CSL

Japanese encephalitis vaccine, inactivated, adsorbed, sterile suspension for i.m. injection in a prefilled syringe, 0.5 mL

Active immunization against Japanese encephalitis virus (orphan drug in E.U.)

Ixiaro® (US, FR, DE)

Intercell; distributed and marketed by Novartis

Victoza® (GB)

Novo Nordisk

Liraglutide, prefilled pen (3 mL) containing Treatment of type 2 diabetes in adults 6 mg/mL liraglutide solution for s.c. injection

Zavesca® (FR)

Actelion

Miglustat, capsules, 100 mg

Treatment of progressive neurological manifestations in adult patients and pediatric patients with Niemann-Pick type C disease**

Savella™ (US)

Forest/Cypress Bioscience

Milnacipran hydrochloride, tablets, 12.5, 25, 50 & 100 mg

Management of fibromyalgia**

Bonoteo® (JP)

Astellas

Minodronic acid hydrate, tablets, 1 mg

Treatment of osteoporosis

Recalbon® (JP)

Ono

Embeda™ (US)

King Pharmaceuticals

Morphine sulfate/naltrexone hydrochloride***, extended-release capsules containing morphine sulfate and sequestered naltrexone hydrochloride, 20 mg/0.8 mg, 30 mg/1.2 mg & 50 mg/2 mg

Management of moderate to severe pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time

Remitch® (JP)

Toray; codeveloped with Japan Tobacco and Torii

Nalfurafine hydrochloride, capsules, 2.5 µg

Improvement of pruritus in hemodialysis patients (orphan drug)

Tredaptive™ (IE)

Merck & Co.

Nicotinic acid/laropiprant***, modifiedrelease tablets, 1 g nicotinic acid/20 mg laropiprant

Treatment of dyslipidemia, particularly in patients with combined mixed dyslipidemia (characterized by elevated levels of LDL cholesterol and triglycerides and low HDL cholesterol) and in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial)

NECT (Africa)

Drugs for Neglected Diseases Initiative

Nifurtimox/eflornithine hydrochloride***, eflornithine supplied in 100-mL glass bottles containing 200 mg/mL for i.v. infusion; nifurtimox supplied as tablets, 120 mg

Treatment of stage 2 (advanced stage) human African trypanosomiasis ”sleeping sickness”)

Arzerra™ (US)

Genmab; codeveloped with and marketed by GlaxoSmithKline

Ofatumumab, single-use vials, 100 mg/ 5 mL, for i.v. infusion

Treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab

Indication

Continued A.I. Graul et al. pp.

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Drug News Perspect 23(1), January/February 2010

Table II. Cont. New product intros – 2009 Trade name (country)1

Company

Active ingredient2

Indication

Symbyax® (US)

Lilly

Olanzapine/fluoxetine hydrochloride, capsules, 3 mg/25 mg, 6 mg/25 mg, 6 mg/ 50 mg, 12 mg/25 mg & 12 mg/50 mg (mg equiv. olanzapine/mg equiv. fluoxetine)

Acute treatment of treatment-resistant depression**

Zypadhera™ (NO)

Lilly

Olanzapine pamoate, powder and solvent for prolonged release suspension for i.m. injection, containing olanzapine pamoate monohydrate equiv. to 210, 300 & 405 mg olanzapine for a final concentration of 150 mg/mL

Maintenance treatment of adult patients with schizophrenia sufficiently stabilized during acute treatment with oral olanzapine

Gelnique™ (US)

Watson

Oxybutynin chloride, gel, 10% in 1-g unit dose sachets*

Treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency in women

Invega® Sustenna™ (US) Johnson & Johnson

Paliperidone palmitate, extended-release injectable suspension in prefilled syringes, 39, 78, 117, 156 & 234 mg, for i.m. injection

Acute and maintenance treatment of schizophrenia in adults

Votrient™ (US)

GlaxoSmithKline

Pazopanib hydrochloride, tablets, 216.7 & 433.4 mg equiv. to 200 & 400 mg pazopanib

Treatment of patients with advanced renal cell carcinoma

OraVerse™ (US)

Novalar Pharmaceuticals

Phentolamine mesilate, dental cartridges containing solution for injection, 0.4 mg/ 1.7 mL

Reversal of soft tissue anesthesia and the associated functional deficits resulting from an oral submucosal injection of local anesthetic containing a vasoconstrictor**

Mozobil™ (US)

Genzyme

Plerixafor, single-use vials containing 1.2 mL of a 20 mg/mL solution

In combination with G-CSF, to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma and multiple myeloma (orphan drug)

Prevenar 13® (DE)

Wyeth Lederle Vaccines (Pfizer)

Pneumococcal conjugate vaccine 13 valent (diphtheria CRM197 protein), suspension in prefilled syringes, 0.5 mL for i.m. injection containing CRM197-conjugated pneumococcal polysaccharides, 2.2 µg of each serotype 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F and 4.4 µg of serotype 6B (approx. 28 µg) and adsorbed on aluminium phosphate

Active immunization for the prevention of invasive disease, pneumonia and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks to 5 years of age

Synflorix™ (CZ)

GlaxoSmithKline Biologicals

Pneumococcal conjugate vaccine (nontypeable Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates) adsorbed, suspension for i.m. injection, 0.5 mL

Active immunization against invasive disease and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks to 2 years of age

Folotyn™ (US)

Allos Therapeutics

Pralatrexate, solution for i.v. injection in Treatment of patients with relapsed or refractory single-use vials, 20 mg/1 mL & 40 mg/2 mL peripheral T-cell lymphoma (orphan drug)

Efient® (GB)

Daiichi Sankyo/Ube; codeveloped with and marketed by Lilly

Prasugrel, film-coated tablets, 5 & 10 mg

Coadministered with acetylsalicylic acid, for the prevention of atherothrombotic events in patients with acute coronary syndrome (i.e., unstable angina, non-S-T segment elevation myocardial infarction [UA/NSTEMI] or S-T segment elevation myocardial infarction [STEMI]) undergoing primary or delayed percutaneous coronary intervention Continued

20

A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

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Table II. Cont. New product intros – 2009 Trade name (country)1

Company

Active ingredient2

Indication

PrandiMet™ (US)

Novo Nordisk; marketed by Sciele

Repaglinide/metformin hydrochloride***, tablets, 1 mg/500 mg & 2 mg/500 mg

As an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes who are already treated with a meglitinide (such as Prandin®) and metformin or who have inadequate glycemic control on meglitinide alone or metformin alone

Neupro® (DE, GB)

UCB

Rotigotine, transdermal patch, 1 mg/24 h, 2 mg/24 h, 3 mg/24 h, 4 mg/24 h, 6 mg/ 24 h & 8 mg/24 h. Each patch contains 0.45 mg/cm2 rotigotine

Symptomatic treatment of moderate to severe idiopathic restless legs syndrome in adults**

Onglyza™ (US)

Bristol-Myers Squibb/ AstraZeneca

Saxagliptin, tablets, 2.5 & 5 mg

As an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes

Grippol® Neo (RU)

Solvay/Petrovax

Seasonal influenza subunit vaccine, trivalent, cell-based, single-dose prefilled syringe, 0.5 mL

Active immunization against seasonal influenza in adults 18 years of age and older

Adcirca™ (US)

United Therapeutics; licensed from Lilly

Tadalafil, tablets, 20 mg

Treatment of pulmonary arterial hypertension (WHO group I) to improve exercise ability** (orphan drug)

Nucynta™ (US)

Ortho-McNeil-Janssen

Tapentadol hydrochloride, tablets, immediate-release, equiv. to 50, 75 and 100 mg tapentadol

Relief of moderate to severe acute pain in adults 18 years of age or older

Vibativ™ (US)

Theravance/Astellas

Telavancin hydrochloride, single-dose vials, Treatment of adult patients with complicated equiv. to 250 & 750 mg telavancin free base, skin and skin structure infections caused by for i.v. injection susceptible Gram-positive bacteria

Twynsta® (US)

Boehringer Ingelheim

Telmisartan/amlodipine besylate***, tablets, telmisartan 40 mg and amlodipine besylate equiv. to 5 or 10 mg amlodipine (40/5 mg & 40/10 mg), or telmisartan 80 mg and amlodipine besylate equiv. to 5 or 10 mg amlodipine (80/5 mg & 80/10 mg)

Treatment of hypertension, alone or in combination with other antihypertensive agents; may be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals

Samsca™ (US)

Otsuka

Tolvaptan, tablets, 15 & 30 mg

Treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium < 125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH)

Tyvaso™ (US)

United Therapeutics

Treprostinil, solution for oral inhalation in ampules*, 174 mg (0.6 mg/mL), for administration using the Tyvaso Inhalation System

To increase walk distance in patients with WHO group I pulmonary arterial hypertension and NYHA class III symptoms**

ellaOne® (DE, FR, GB)

HRA Pharma

Ulipristal acetate, tablets, 30 mg

Emergency contraception within 120 hours of unprotected sexual intercourse or contraceptive failure

Trerief® (JP)

Dainippon Sumitomo Pharma Zonisamide, tablets, 25 mg

Treatment of Parkinson’s disease (second-line), in combination with levodopa**

1Country

codes are the abbreviations used by the World Intellectual Property Organization. Products are ordered alphabetically by active ingredient. *New formulation; **New indication; ***New combination. 2

A.I. Graul et al. pp.

21

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Drug News Perspect 23(1), January/February 2010

POSTSCRIPT TO “THE YEAR’S NEW DRUGS & BIOLOGICS – 2008” At least two of the drugs reported as being approved in last year’s edition of this article were in fact launched by year-end, although we were unable to obtain confirmation of launch before the journal went to print. Late 2008 saw the launch of GlaxoSmithKline’s eltrombopag olamine (Promacta®), the first small-molecule thrombopoietin receptor (TPO-R) agonist. Another TPO-R agonist, romiplostim (Nplate™; Amgen), was also launched during 2008 and was reported here as first-in-class (4). Eltrombopag received accelerated FDA approval for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have an insufficient response to corticosteroids, immunoglobulins or splenectomy. As a small molecule, eltrombopag is administered as an oral tablet formulation. Approval was supported by the largest database of randomized clinical trial information on investigational therapies for chronic ITP patients. The indication is based on data from two pivotal studies in the short-term treatment and one long-term treatment study of patients with chronic ITP. Eltrombopag has orphan drug status in the U.S. for the approved indication. In late 2009, GlaxoSmithKline received a positive opinion from the CHMP for eltrombopag olamine (Revolade®) for the oral treatment of thrombocytopenia in adults with ITP. In mid-December 2008, Health Canada approved ustekinumab (Stelara™), a new treatment option for adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. The first-in-class product is a human mAb targeting the proinflammatory cytokines IL-12 and IL-23. In addition to its unique mechanism of action, ustekinumab

CH 3

FIRST-IN-CLASS TARGETS – 2009 More than 100 years of history of traditional medicinal chemistry, mainly involving either serendipitous discovery or the empirical screening of a vast number of potentially bioactive compounds, has produced a surprisingly low yield of useful therapeutic agents. In an effort to improve the efficacy of pharmaceutical R&D, and aided by the Human Genome Project, current lead discovery efforts are increasingly directed first to the identification of previously unknown and promising new targets for therapeutic intervention, followed by the rational development of specially designed drugs or biologics directed to said target (6). Five of the new products discussed in this article introduce novel mechanisms of action in the current therapeutic arsenal. The targets upon which these medicines act to exert their therapeutic effect are described in detail below. In addition to the figures shown here, subscribers to Prous Science Integrity® (http://integrity.prous. com) will soon be able to access animated figures depicting these mechanisms of action in greater detail. Ustekinumab is a fully human mAb targeting IL-12 and IL-23 that was launched at the

O N

N H3C

has an attractive dosing regimen: following starter doses at weeks 0 and 4, it is selfinjected just once every 12 weeks. In pivotal phase III clinical studies, approximately twothirds of adults receiving ustekinumab achieved at least 75% improvement in psoriasis (PASI 75) within the first 12-week course of treatment. Ustekinumab was developed by Centocor, a Johnson & Johnson company, and is marketed in Canada by Janssen-Ortho, which launched the product in late December 2008. In early 2009, ustekinumab was approved in the E.U. and launched in Germany and the U.K.; later in the year it was approved in the U.S.

N

N H

OH OH

O H3C

Eltrombopag olamine

22

.2 HO

NH2

end of 2008 for the treatment of moderate to severe plaque psoriasis. IL-12 is a heterodimeric cytokine that promotes cellmediated immunity by facilitating type 1 helper T-lymphocyte (Th1) responses, including the production of interferon gamma by both T cells and natural killer (NK) cells, potentiating the lytic activity of NK cells and boosting specific cytolytic Tlymphocyte responses. Overproduction of this inflammatory cytokine may be involved in several autoimmune diseases, including psoriasis, insulitis, type 1 diabetes, inflammatory bowel disease (IBD), rheumatoid arthritis and multiple sclerosis. Thus, antagonism of IL-12 may be beneficial in the treatment of Th1-related autoimmune or immunological disorders (7-9) (Fig. 2). IL-23 is a heterodimeric cytokine composed of a unique p19 subunit and the p40 subunit component of IL-12. It is secreted by activated dendritic cells (DCs) and macrophages and binds to memory T cells, NK cells, macrophages and DCs. This cytokine is suspected to be involved in the activation and maintenance of the Th17 subset of inflammatory T cells. The heterodimeric receptors for both IL-12 and IL-23 share a component, IL-12Rβ, with IL-23R being the unique subunit of the receptor for IL-23. It has been hypothesized that the autoimmune actions of IL-12 are attributable to IL-23. Studies have shown that while knockout of IL-23p19 (only IL-23 absent) and IL-12p40 (both IL-12 and IL-23 absent) results in protection from autoimmune encephalomyelitis and collagen-induced arthritis, knockout of IL-12p35 (only IL-12 absent) confers more severe disease. Overexpression of IL-23 and/or IL-12 or a defect in their receptors may be involved in autoimmune conditions such as psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Crohn’s disease and ankylosing spondylitis. Monoclonal antibodies directed against both IL-12 and IL-23 may be effective treatment options for these diseases (7, 9-11). Canakinumab is an mAb specific for human IL-1β. It was launched last year for the treatment of CAPS in adults and children 4 years of age and older, including FACS and MWS. IL-1β is a soluble protein cytokine (17 kD, 269 amino acids) that is a member of the IL-1 superfamily, which also includes IL-1β and the IL-1 receptor antagonist (IL-1ra). IL-1α and IL-1β are proinflammatory cytokines that are involved in inflammatory and A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

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Figure 2. Mechanism of action of ustekinumab. Ustekinumab (Stelara®) is a fully human monoclonal antibody and immunosuppressant that selectively targets the p40 subunit of interleukin-12 (IL-12) and interleukin-23 (IL-23), two cytokines that are implicated in the onset and development of inflammatory and immune responses.

immune responses, while IL-1ra competes for receptor binding with these two isotypes, thus blocking inflammatory and/or immune activation. Both isotypes are secreted by monocytes, macrophages and/or accessory cells early during an immune response and they activate T and B cells, stimulate T-cell proliferation and enhance T- and B-cell responses to antigens. Overproduction of IL-1 has been implicated in several diseases, including CAPS, COPD, rheumatoid arthritis, type 2 diabetes, Alzheimer’s disease and IBD, and inhibitors of this cytokine may be effective treatment options for these disorders (12-14) (Fig. 3). Catumaxomab is a trifunctional bispecific antibody against human Ep-CAM and human CD3 (anti-Ep-CAM x anti-CD3) which was approved last year for the treatment of malignant ascites. Catumaxomab recognizes CD3+ T cells and Ep-CAM+ tumor cells, and binds with its Fc fragment to antigen-presenting cells. The formation of this tri-cell complex enables the immune cells to be introduced directly to the tumor cells, where they can then be activated. The CD3 antigen is a protein complex composed of four distinct chains: CD3γ chain, CD3δ chain and two CD3ε chains. These chains are highly homologous cell-surface A.I. Graul et al. pp.

Figure 3. Mechanism of action of canakinumab. Canakinumab (Ilaris®) is a recombinant human monoclonal antibody that specifically targets the proinflammatory cytokine interleukin-1β (IL-1β). Canakinumab prevents IL-1β from binding to its receptor, thereby suppressing the autoinflammatory response associated with familial cold autoinflammatory syndrome (FCAS) and other disorders.

proteins that are members of the immunoglobulin superfamily and contain a single extracellular immunoglobulin domain. The transmembrane region of these CD3 chains is negatively charged, allowing them to associate with the positively charged T-cell antigen receptor (TCR) chains (TCRα and TCRβ). The intracellular tails of the CD3 chains contain a single conserved motif known as an immunoreceptor tyrosine-based activation motif (ITAM), which is essential for the signaling capacity of the TCR. Association of the CD3 chains with TCR and the ζ-chain (accessory molecules of TCR) generates an activation signal in T lymphocytes. Thus, the TCR complex is composed of the TCR, ζ-chain and CD3 molecules. Numerous studies suggest that T cells are able to control tumor growth and survival. Antibodies that are bispecific for a surface target antigen on cancer cells and for CD3 on T cells could link a particular type of cytotoxic T cell to a cancer cell. This would be independent of TCR specificity, costimulation or peptide antigen presentation. Thus, targeting CD3 represents a therapeutic option for the treatment of various cancers (15-16). Ep-CAM is a glycoprotein of about 40 kD that is involved in cell adhesion, as well as cell signaling, migration, proliferation and

differentiation. It is highly expressed in tumors of epithelial origin, including carcinomas of the colon, rectum, ovary, stomach, esophagus, lung, pancreas, breast and head and neck. It is therefore considered a marker for carcinoma (17-18) (Fig. 4). Plerixafor hydrochloride is a chemokine CXCR4 receptor antagonist launched in 2009 for the treatment of lymphoma, NHL and MM. By blocking CXCR4, plerixafor triggers the rapid movement of stem cells out of the bone marrow and into circulating blood. Once in the circulating blood, the stem cells can be collected for use in stem cell transplant. CXCR4 (also known as fusin), is an α-chemokine, 7-transmembrane G protein-coupled receptor that specifically binds stromal cell-secreted CXCL12 (also called stromal cell-derived factor 1, SDF-1) and transduces a signal by increasing intracellular calcium ion levels. CXCR4 displays potent lymphocytic chemotactic activity and plays a role in hematopoiesis, neuronal and cardiovascular development, the spread and progression of tumors, and organization of the immune system. CXCR4 is found on the surface of both hematopoietic and nonhematopoietic tumor cells. Interaction between this receptor and its ligand CXCL12 regulates hematopoietic stem cell quiescence and 23

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Drug News Perspect 23(1), January/February 2010

Figure 4. Mechanism of action of catumaxomab. Catumaxomab (Removab®) is a trifunctional antibody that simultaneously activates T cells and accessory immune cells to target and destroy cancerous tumor cells. This mutual stimulation via co-receptor molecules and cytokines results in T-cell-mediated lysis and ADCC/phagocytosis of the tumor cell via Fcγ receptor activation. Tumor cell necrosis is thus induced not only by targeted antitumor cytotoxicity, but also by the simultaneous induction of innate, humoral and cell-mediated immune responses.

Figure 5. Mechanism of action of plerixafor hydrochloride. Plerixafor (Mozobil™) is a macrocyclic chemokine CXCR4 (SDF-1 receptor) antagonist. It prevents the binding of CXCL12 (also known as stromal cell-derived factor, SDF-1) to the cellular receptor CXCR4, thereby facilitating the mobilization of hematopoietic stem cells (HSCs) from bone marrow to the peripheral bloodstream. Such cells, subsequently referred to as peripheral blood progenitor cells (PBPCs), are then collected and used for autologous transplantation in patients with lymphoma and multiple myeloma.

Figure 6. Mechanism of action of ulipristal acetate. Ulipristal acetate (ellaOne®) is a selective progesterone receptor modulator (SPRM) that possesses tissueselective agonist, antagonist or mixed agonist/antagonist properties. For instance, it can competitively inhibit the binding of the hormone progesterone to its receptor or, conversely, activate the receptor, depending on tissue type. In the case of receptor antagonism, ulipristal prevents thickening of the endometrial wall, and hence, implantation of the egg.

homing. Antagonism of CXCR4 releases and mobilizes hematopoietic stem cells into the bloodstream, which is a crucial step in stem cell transplantation. CXCR4 is also implicated in cancer cell migration and metastasis, 24

since it promotes tumor spread to organs where CXCL12 is expressed (e.g., bone marrow). CXCL12 itself can stimulate survival and growth of neoplastic cells in a paracrine fashion and can promote tumor angiogene-

sis by attracting endothelial cells to the tumor microenvironment. CXCR4 has been demonstrated to be involved in several diseases, including cancer cell metastasis and leukemia cell progression (19-21) (Fig. 5). A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

The synthetic steroid ulipristal acetate is an SPRM that was launched last year as a newgeneration emergency contraceptive. SPRMs possess mixed agonist–antagonist properties and have a wide range of potential therapeutic applications in female healthcare. It has been shown to have direct antiproliferative effects, with no evidence of being associated with hypoestrogenism or bone loss. The progesterone receptor (PR) is a nuclear receptor of the NR3 class that exists as a dimer coupled with chaperone molecules (e.g., HSP90, HSP70). The chap-

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erone molecules are shed subsequent to ligand binding. PR binds the naturally occurring antiestrogenic steroid progesterone (4-pregnene-3,20-dione) produced by the corpus luteum and placenta. Activation prepares the uterus for implantation and growth of fertilized ovum, and thereafter maintains pregnancy by inhibiting uterine contractions during gestation. Thus, PR modulators, particularly SPRMs which have significantly reduced adverse effects and/or an increased safety margin, may be effective in the treatment of ovarian and breast can-

cers, osteoporosis, endometriosis and postmenopausal syndrome, and for use as contraceptives (22-24) (Fig. 6). THE LIFE SPANS OF DRUGS & BIOLOGICS New or unconventional information may help to provide a more accurate picture of the discovery and development of new drugs and biological therapeutics. For this reason, a new section has been added in recent years to our annual review, providing

1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 2019 2021 2023 2025 2027

Besifloxacin hydrochloride

12

(BesivanceTM; Bausch & Lomb)

Bimatoprost

6

TM (Latisse ; Allergan)

Bupropion hydrobromide

19

TM

(Aplenzin ; Biovail/sanofi-aventis)

Degarelix acetate

10

(Firmagon®; Ferring)

Dexamethasone intravitreal implant

6

TM

(Ozurdex ; Allergan)

Dronedarone hydrochloride

12

(Multaq®; sanofi-aventis)

Febuxostat

51

(Uloric®; Takeda Pharmaceuticals North America)

Fospropofol disodium

15

TM

(Lusedra ; Eisai)

Guanfacine hydrochloride

7

TM

(Intuniv ; Shire)

Pazopanib hydrochloride

10

TM

(Votrient ; GlaxoSmithKline)

Saxagliptin

13

TM

(Onglyza ; Bristol-Myers Squibb/AstraZeneca)

Tapentadol hydrochloride

10

TM

(Nucynta ; Ortho-McNeil-Janssen)

Telavancin hydrochloride

34

TM

(Vibativ ; Astellas Pharma/Theravance)

Tolvaptan

19

TM

(Samsca ; Otsuka)

Development times

Approval times in months

Patent protection after marketing

Figure 7. Estimated life spans of selected drugs and biologics introduced in 2009, from patent priority to patent expiration (Source: Prous Science Integrity®, the U.S. FDA’s Orange Book and Thomson Pharma®). Data presented in this figure (current as of December 31, 2009) are susceptible to change. A.I. Graul et al. pp.

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Drug News Perspect 23(1), January/February 2010

Table III. Patent life span information for selected products launched in 2009* Product name and company

Patent number and applicant

Priority date***

Expiration date***

Besifloxacin hydrochloride (BesivanceTM; Bausch & Lomb)

US 5447926; WO 1992001676 (SSP Co., Ltd.)

19910717

20120905

Bimatoprost (LatisseTM; Allergan)

US 7351404; WO 2003066008 (Allergan, Inc.)

20020204***

20240525

Bupropion hydrobromide (AplenzinTM; Bioavail/sanofi-aventis)

US 7241805; WO 2007002597 (Biovail Laboratories International SRL)

20050627***

20260627

Degarelix acetate (Firmagon®; Ferring)

US 5925730; WO 1998046634 (Ferring BV)

19970411

20170411

Dexamethasone intravitreal implant (OzurdexTM; Allergan)

US 6726918; WO 2002002076 (Oculex Pharmaceuticals, Inc.)

20000705***

20201020

Dronedarone hydrochloride (Multaq®; sanofi-aventis)

US 5223510; EP 0471609 (sanofi-aventis)

19900806

20110726

Febuxostat (Uloric®; Takeda Pharmaceuticals North America)

US 5614520; WO 1992009279 (Teijin Ltd.)

19901130

20140325

Fospropofol disodium (LusedraTM; Eisai)

US 6204257; WO 2000008033 (University of Kansas)

19980807

20180607

Guanfacine hydrochloride (IntunivTM; Shire)

US 5854290

19950921***

20150921

Pazopanib hydrochloride (Votrient ; GlaxoSmithKline)

US 7105530; WO 2002059110 (GlaxoSmithKline plc)

20001221

20211219

Repaglinide/metformin hydrochloride (PrandiMetTM; Sciele)

US 6677358; WO 1998056378 (Novo Nordisk A/S)

19970613***

20180612

Saxagliptin (OnglyzaTM; Bristol-Myers Squibb/AstraZeneca)

US 6395767; WO 2001068603 (Bristol-Myers Squibb Co.)

20000310

20210216

US RE 39593 (US 6248737); EP 0693475 (Gruenenthal GmbH)

19940723

20180618

Telavancin hydrochloride (VibativTM; Astellas Pharma/Theravance)

US 6635618; WO 2001098328 (Theravance, Inc.)

20000622

20210922

Tolvaptan (SamscaTM; Otsuka)

US 5258510; US 5985869 (Otsuka Pharmaceutical Co., Ltd.)

19910419

20101102

TM

Tapentadol hydrochloride (NucyntaTM; Ortho-McNeil-Janssen)

*Data provided are based on patent information from Prous Science Integrity®, the U.S. FDA’s Orange Book and Thomson Pharma®, where more information can be found. **Priority and expiration dates correspond to U.S. patent. All dates are in YYYYMMDD format. ***First patent claiming the new use or new formulation marketed in 2009.

an analysis of the discovery and development periods for selected new medicines, from patent application to drug approval to patent expiration and subsequent generic status. This information provides a framework to visually understand the relationship between the many processes that occur during the life of a drug or biologic. After the discovery period (coinciding approximately with the priority date of patents), an IND plan is established and filed, and clinical studies are initiated. Phase I clinical trials focus on safety and last about 1 year. Phase II focuses on effectiveness in the expected indication(s) and lasts any26

where from 2 to 5 years. Phase III confirms the results of earlier studies in a large patient population and requires between 2 and 4 years. Life spans for selected new drugs and biologics introduced in 2009 are depicted in Figure 7. Additional information on patent life spans is presented in Table III. Another significant factor influencing the life span of a new drug is the length of time elapsed between regulatory filing and approval. As can be seen in Table IV, approval times are typically shorter and a greater number of new medicines are

approved by U.S. regulators as compared to those in the European Union, Japan and other countries. However, last year FDA approval times ranged from 1,521 days in the case of febuxostat (Uloric®) to just 120 days for armodafinil (Nuvigil™), showing that generalizations cannot be made. DRUG REPURPOSING IN 2009 In contrast to traditional drug discovery, which typically involves the development of a new bioactive compound in an oral formulation for a therapeutic indication that is frequently identified at the beginning of the A.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

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Table IV. Regulatory approval times for selected products launched in 2009 Product name and company

Filing date*

Approval date*

Time elapsed (days)

Aliskirin fumarate/valsartan (Valturna®; Novartis)

20081126

20090916

294

Amlodipine/valsartan/hydrochlorothiazide (Exforge HCT®; Novartis)

20080630

20090430

304

Aripiprazole (Abilify®; Bristol-Myers Squibb/Otsuka)

20090121

20091119

302

Armodafinil (Nuvigil™; Cephalon)

20081126

20090326

120

Asenapine maleate (Saphris®; Schering-Plough)

20090212

20090813

182

Bepotastine besilate (Bepreve™; ISTA)

20081112

20090908

300

Besifloxacin hydrochloride (Besivance™; Bausch & Lomb/Pfizer)

20080530

20090528

363

Bimatoprost (Latisse™; Allergan)

20080626

20081224

181

Bupropion hydrobromide (Aplenzin™; Biovail/sanofi-aventis)

20060927

20080423

574

Canakinumab (Ilaris®; Novartis)

20081215

20090617

184

Colchicine USP (Colcrys™; URL Pharma)

20081125

20090730

247

Dapoxetine hydrochloride (Priligy™; Janssen-Cilag)

20071207

20090210

431

Degarelix acetate (Firmagon®; Ferring)

20080214

20081224

314

Dexamethasone intravitreal implant (Ozurdex™; Allergan)

20081223

20090617

176

Dexlansoprazole (Kapidex™; Takeda)

20071228

20090130

399

Dronedarone hydrochloride (Multaq®; sanofi-aventis)

20080627

20090701

369

Febuxostat (Uloric®; Takeda)

20041215

20090213

1521

Ferumoxytol (Feraheme™; AMAG)

20071218

20090630

560

Fospropofol disodium (Lusedra™; Eisai)

20070926

20081212

443

Golimumab (Simponi™; Centocor Ortho Biotech/Schering-Plough)

20080624

20090424

304

Guanfacine hydrochloride (Intuniv™; Shire)

20090129

20090902

216

Liraglutide (Victoza®; Novo Nordisk)

20080523

20090630

403

Milnacipran hydrochloride (Savella™; Forest/Cypress Bioscience)

20071218

20090114

393

Minodronic acid (Recalbon®; Ono/Bonoteo®; Astellas)

20060707

20090121

929

Morphine sulfate/naltrexone hydrochloride (Embeda™; King)

20080630

20090813

409

Nalfurafine hydrochloride (Remitch®; Toray)

20061128

20090121

785

Nicotinic acid/laropiprant (Tredaptive™; Merck & Co.)

20070625

20080703

374

Ofatumumab (Arzerra™; GlaxoSmithKline)

20090130

20091026

269

Olanzapine pamoate (Zypadhera™; Lilly)

20070627

20081119

511

Oxybutynin chloride (Gelnique™; Watson)

20080326

20090127

307

Paliperidone palmitate (Invega® Sustenna™; Johnson & Johnson)

20071025

20090731

645

Pazopanib hydrochloride (Votrient™; GlaxoSmithKline)

20081218

20091019

305

Phentolamine mesilate (OraVerse™; Novalar)

20070409

20080509

396

Plerixafor (Mozobil™; Genzyme)

20080616

20081215

182

Pneumococcal conjugate vaccine (Synflorix™; GlaxoSmithKline)

20071230

20090331

457

Pralatrexate (Folotyn™; Allos Therapeutics)

20090323

20090924

185

Prasugrel (Efient®; Lilly)

20080206

20090225

385

Rotigotine (Neupro®; UCB)

20071205

20080829

268 Continued

A.I. Graul et al. pp.

27

DRUGLINE

Drug News Perspect 23(1), January/February 2010

Table IV. Cont. Regulatory approval times for selected products launched in 2009 Product name and company

Filing date*

Approval date*

Time elapsed (days)

Saxagliptin (Onglyza™; Bristol-Myers Squibb/AstraZeneca)

20080701

20090731

395

Tadalafil (Adcirca™; United Therapeutics)

20080723

20090522

303

Tapentadol hydrochloride (Nucynta™; Ortho-McNeil-Janssen)

20080123

20081120

302

Telavancin hydrochloride (Vibativ™; Theravance/Astellas)

20061206

20090911

1010

Telmisartan/amlodipine besylate (Twynsta®; Boehringer Ingelheim)

20081218

20091016

302

Tolvaptan (Samsca™; Otsuka)

20071023

20090519

574

Treprostinil (Tyvaso™; United Therapeutics)

20080627

20090730

398

Ulipristal acetate (ellaOne®; HRA Pharma)

20080530

20090515

350

Source: Prous Science Integrity®. *Dates are in YYYYMMDD format. In cases of line extensions, dates refer to filing and approval of the new formulation, new combination or new indication discussed in the article.

developmental process, drug repurposing is an altogether different process. In the case of developing new formulations, development centers on alternative dosing forms with improved safety, convenience or efficacy, with the added advantage (to the developer) of extended patent protection. In other cases, new therapeutic uses (“therapeutic switching”) may be identified for existing drugs, often on the basis of information that did not even exist at the time the molecule was originally discovered and developed. Sometimes the new presentation is developed specifically for the new indication. As a commercial strategy, drug repurposing generally entails a lower risk for the developer, but also is less likely to reap major therapeutic advances for patients (25). An analysis of the pharmaceutical pipeline in the context of the products considered in this article, based on information from Prous Science Integrity®, confirms the importance of repurposing and repositioning, both in present and future terms. The present: Drug repositioning, reprofiling and repurposing is a phenomenon with a significant impact on market introductions. Line extensions (new formulations, new indications and/or new combinations of previously marketed products) accounted for more than 30% of the new launches discussed in this article. The future: More than 50 new indications are reported to be under clinical evaluation for 15 of the new drugs and biologics that were 28

launched for the first time in 2009 (see Table V). WHAT’S NEXT? – OUTLOOK FOR 2010 AND BEYOND Which drugs will be next to market? Which therapeutic groups could incorporate the greatest number of new members in 20102011? In the changing and increasingly complex world of drug development, no one can answer these and related questions with complete certainty. At present, more than 100 new drugs and biologics await approval by regulatory authorities worldwide. Some of these new medicines will be approved and/or introduced in the next 2 years. Based on a careful analysis of company communications, clinical studies and other parameters, we can predict with some confidence which new medicines could be expected to be included in future editions of this annual article. Of course, some of these drugs may not achieve regulatory approval, while others that we have not highlighted here will nonetheless be approved. In any case, several promising new products deserve mention. In December 2009, the CHMP recommended marketing authorization for Amgen’s denosumab (Prolia™) for the treatment of osteoporosis in postmenopausal women at increased risk of fractures, and for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. The drug is also

under regulatory review in the U.S., Switzerland, Australia and Canada for the treatment and prevention of postmenopausal osteoporosis and for the treatment of bone loss in patients undergoing hormone ablation therapy for breast or prostate cancer. Velaglucerase alfa, a gene-activated enzyme replacement therapy developed by Shire for the treatment of type 1 Gaucher’s disease, has been filed for marketing approval in the European Union. The CHMP has accepted the company’s request for an accelerated assessment of the approval application, based on a global supply shortage of the currently approved and marketed treatment for Gaucher’s disease patients and on positive results from all three phase III trials of the compound. Review of the Marketing Authorisation Application (MAA) was expected to begin in December. Under the accelerated assessment, its timeline is shortened from 210 to 150 days. In the area of oncology, Roche’s trastuzumab-MCC-DM1 could reach its first markets in the next year or two. The product, a tumor-activated prodrug immunoconjugate comprising the humanized anti-HER2 antibody Herceptin® (trastuzumab) and the antimitotic maytansinoid DM1 (mertansine), is being developed for the treatment of HER2-positive metastatic breast cancer. The calcineurin inhibitor voclosporin is being developed by Lux Biosciences for the treatment of uveitis. The company is predicting a 2010 launch for the product in the treatA.I. Graul et al. pp.

Drug News Perspect 23(1), January/February 2010

DRUGLINE

Table V. Drugs and biologics repurposing: selected new indications in active development for products launched in 2009 Drugs and biologics

Sponsor

Indication

Armodafinil

Cephalon Cephalon

Excessive sleepiness associated with jet lag disorder Major depression associated with bipolar disorder (adjunctive therapy) Cancer-related fatigue Cognitive deficits in schizophrenia Improving neurocognitive functioning and reducing cognitive fatigue in multiple sclerosis

NDA filed Phase II

Phase III Phase III Phase II/III Phase II/III Phase II

Cephalon Cephalon University of Missouri-Kansas City

Status

Phase II Phase II Phase II

Canakinumab

Novartis Novartis Novartis Novartis Novartis

Juvenile idiopathic arthritis Gout Rheumatoid arthritis Type 2 diabetes Chronic obstructive pulmonary disease

Catumaxomab

TRION Pharma/Fresenius TRION Pharma/Fresenius

Gastrointestinal cancer Ovarian cancer

Phase II Phase II

Degarelix acetate

Ferring

Female infertility

Phase II

Dexamethasone cipecilate

Nippon Shinyaku

Bronchial asthma

Phase II

Ferumoxytol

AMAG Pharmaceuticals

Magnetic resonance imaging agent

Phase II

Golimumab

Centocor Ortho Biotech/Merck & Co. Centocor Ortho Biotech/Merck & Co.

Ulcerative colitis Sarcoidosis

Phase III Phase II

Liraglutide

Novo Nordisk

Obesity in nondiabetic patients

Phase III

Ofatumumab

GlaxoSmithKline/Genmab GlaxoSmithKline/Genmab GlaxoSmithKline/Genmab GlaxoSmithKline/Genmab GlaxoSmithKline/Genmab

Diffuse large B-cell lymphoma Follicular lymphoma Rheumatoid arthritis Multiple sclerosis Waldenstrom’s macroglobulinemia

Phase III Phase III Phase III Phase II Phase II

Pazopanib hydrochloride

GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline Mayo Clinic Mayo Clinic Mayo Clinic National Cancer Institute (US) National Cancer Institute (US) National Cancer Institute (US) National Cancer Institute (US) Indiana University GlaxoSmithKline

Breast cancer Ovarian cancer Soft tissue sarcoma Non-small cell lung cancer Metastatic breast cancer Multiple myeloma Cervical cancer Macular degeneration Bladder cancer Metastatic melanoma Thyroid cancer Nasopharyngeal cancer Prostate cancer Glioblastoma multiforme Pleural mesothelioma Lymphedema Colorectal cancer

Phase III Phase III Phase III Phase II/III Phase II Phase II Phase II Phase II Phase II Phase II Phase II Phase II Phase II Phase II Phase II Phase II Phase I

Plerixafor hydrochloride

Genzyme Washington University Cincinnati Children’s Hospital Medical Center

Chronic lymphocytic leukemia Acute myeloid leukemia Fanconi’s anemia

Phase I/II Phase I/II Phase I/II

Pralatrexate

Allos Therapeutics Allos Therapeutics Allos Therapeutics Allos Therapeutics Allos Therapeutics Allos Therapeutics

Bladder cancer Non-small cell lung cancer Lymphoma Non-Hodgkin’s lymphoma Hodgkin’s lymphoma Cutaneous T-cell lymphoma

Phase II Phase II Phase II Phase II Phase I/II Phase I

Telavancin hydrochloride

Theravance/Astellas

Community-acquired pneumonia

NDA filed Continued

A.I. Graul et al. pp.

29

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Drug News Perspect 23(1), January/February 2010

Table V. Cont. Drugs and biologics repurposing: selected new indications in active development for products launched in 2009 Drugs and biologics

Sponsor

Indication

Status

Tolvaptan

Otsuka Otsuka Otsuka

Congestive heart failure Autosomal-dominant polycystic kidney disease Hepatic edema

NDA filed Phase III Phase II

Ulipristal acetate

PregLem National Institute of Mental Health

Uterine fibroids (myoma) Premenstrual syndrome

Phase III Phase II

Source: Prous Science Integrity®, consulted December 29, 2009.

ment of noninfectious intermediate, anterior and intermediate, posterior or pan-uveitis. The FDA has granted fast-track designation to the compound for this indication.

2. Prous Science Integrity® Disease Briefing: Hepatitis B. 3. Prous Science Integrity® Disease Briefing: Influenza.

15. Sebastian, M., Kuemmel, A., Schmidt, M., Schmittel, A. Catumaxomab: A bispecific trifunctional antibody. Drugs Today (Barc) 2009, 45(8): 589-97.

Novavax’s 2009 H1N1 virus-like particle pandemic influenza vaccine is expected to reach the market in Mexico during 2010. The vaccine is currently being evaluated in a large (1,000-patient) phase III study in Mexico in collaboration with development partner Avimex.

4. Graul, A.I., Revel, L., Barrionuevo, M. et al. The year’s new drugs and biologics, 2008. Drug News Perspect 2009, 22(1): 7-29.

16. Baeuerle, P.A., Reinhardt, C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res 2009, 69(12): 4941-4.

5. Prous Science Integrity® Disease Briefing: Cutaneous T-cell lymphoma.

17. Munz, M., Baeuerle, P.A., Gires, O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res 2009, 69(14): 5627-9.

Other new products that could see approval and/or launch in the near future include: omacetaxine mepesuccinate, developed by ChemGenex for the treatment of chronic myeloid leukemia; pixantrone maleate (Cell Therapeutics), a topoisomerase II inhibitor for the treatment of NHL; BioMarin’s amifampridine phosphate for the treatment of Lambert-Eaton myasthenic syndrome; vinflunine, a vinca alkaloid developed by Pierre Fabre for the treatment of metastatic bladder cancer; Xiaflex™ (collagenase clostridium histolyticum; BioSpecifics Technologies), a novel, first-in-class, orphan-designated biologic for the treatment of Dupuytren’s disease; and the meningococcal conjugate vaccine Menveo®, from Novartis. ACKNOWLEDGMENTS Thanks to Devakumar Sundaravinayagam, Shakthi Suranya, Sridharan Rajendran and Janaka Aravamudan for their assistance in developing Figures 2-6. REFERENCES 1. Prevalence of autism spectrum disorders — Autism and Developmental Disabilities Monitoring Network, United States, 2006. Morbidity and Mortality Weekly Report 2009, December 18. Available at http://www.cdc. gov/mmwr/preview/mmwrhtml/ss5810a1. htm (accessed December 21, 2009).

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18. Carpenter, G., Red Brewer, M. EpCAM: Another surface-to-nucleus missile. Cancer Cell 2009, 15(3): 165-6. 19. Ooi, L.L., Dunstan C.R. CXCL12/CXCR4 axis in tissue targeting and bone destruction in cancer and multiple myeloma. J Bone Miner Res 2009, 24(7): 1147-9. 20. Wu, X., Lee, V.C., Chevalier, E., Hwang, S.T. Chemokine receptors as targets for cancer therapy. Curr Pharm Des 2009, 15(7): 742-57. 21. Wagstaff, A.J. Plerixafor: In patients with nonHodgkin’s lymphoma or multiple myeloma. Drugs 2009, 69(3): 319-26. 22. Pintiaux, A., Chabbert-Buffet, N., Foidart, J.M. Gynaecological uses of a new class of steroids: The selective progesterone receptor modulators. Gynecol Endocrinol 2009, 25(2): 67-73. 23. Zhi, L. Discovery of structurally diverse nonsteroidal SPRMs based on a screening hit, 1,2dihydro-2,2,4-trimethyl-6-phenylquinolinone. Curr Top Med Chem 2008, 8(9): 766-80. 24. Benagiano, G., Bastianelli, C., Farris, M. Hormonal contraception: State of the art and future perspectives. Minerva Gynecol 2007, 59(3): 241-70. 25. Cavalla, D. APT drug R&D: The right active ingredient in the right presentation for the right therapeutic use. Nat Rev Drug Disc 2009 8(11): 849.

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