1. health and fitness
2. disease

The Antibacterials Market Outlook
to 2016
Competitive landscape, pipeline analysis, and growth opportunities
Reference Code: BI00042-010
Publication Date: May 2011
1
About the author
Business Insights has a team of in-house pharmaceutical and regulatory analysts drawn from consulting,
R&D and competitive intelligence life sciences backgrounds. Our analysts specialize in providing detailed
insight into the future of therapeutic drug markets and emerging pharmaceutical markets and have extensive
analytical, forecasting and research experience in the pharmaceutical, biotech and outsourcing sectors. Our
team maintains regular contact with industry executives to track market developments and base their market
models on a wide range of proprietary drug sales, pipeline and epidemiological databases to provide up to
date, accurate strategic insight on the future of the pharmaceutical market.
Disclaimer
Copyright © 2011 Business Insights Ltd
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2
Table of Contents
About the author
2
Disclaimer
2
Executive summary
10
Disease overview and epidemiology
10
Global market analysis
10
Pipeline analysis
11
Competitive landscape
12
Chapter 1 Disease overview and epidemiology
13
Summary
13
Introduction
14
Bacterial infections
14
Respiratory tract infections
14
Urinary tract infections
15
Skin and skin structure infections
15
Gynecological infections
17
Diagnosis, treatment and management
17
Respiratory tract infections
17
Urinary tract infections
18
Skin and skin structure infections
18
Gynecological infections
19
Epidemiology of bacterial infections
19
Respiratory tract infections
19
Urinary tract infections
21
Skin and skin structure infections
22
Gynecological infections
23
Forecast epidemiology
23
3
Respiratory tract infections
23
Urinary tract infections
26
Skin and skin structure infections
27
Gynecological infections
28
Chapter 2 Global market analysis
29
Summary
29
Introduction
30
Market dynamics
30
Market analysis by drug class
31
Leading brands dynamics
34
Levaquin (levofloxacin) – Johnson & Johnson
34
Zyvox (linezolid) – Pfizer
35
Avelox (moxifloxacin) – Bayer
36
Augmentin (amoxicillin + clavulanic acid) – GSK
36
Tazocin (piperacillin + tazobactam) – Pfizer
37
Cravit (levofloxacin) – Daiichi Sankyo
38
Merrem (meropenem) – AstraZeneca
38
Cubicin (daptomycin) – Cubist
38
Primaxin (imipenem + cilastatin) – Merck & Co.
39
Zithromax (azithromycin) – Pfizer
39
Resistors of the antibacterial market
41
Growing antibacterial resistance
41
Roadblocks to attractive antibacterial market
42
Shrinking antibacterial pipeline
43
Challenging regulatory requirements
43
Drivers of the antibacterial market
45
Product lifecycle management through expanding indications and formulations
45
Combination products
46
Product development partnerships
46
Product differentiation through technological innovations
47
Monoclonal antibodies (mAbs) to combat bacterial infections
47
Global antibacterial market sales forecast
48
4
Chapter 3 Pipeline analysis
49
Summary
49
Introduction
50
Antibacterial pipeline
50
Key events in antibacterial R&D
51
Optimer to exploit Cubist’s competitive advantage to market Dificid in the US
51
Cubist settles patent infringement litigation with Teva over Cubicin
52
Merck & Co. intends to strengthen antibacterial research through BioRelix
52
GSK exercises its option with Anacor to commercialize GSK2251052
52
Zeftera withdrawn following concerns raised by the FDA and the EMA
53
Durata Therapeutics initiates Phase III trials for dalbavancin
53
Leading drugs in development
54
Profiles of key pipeline products
55
Teflaro (ceftaroline fosamil) – Forest Laboratories/Takeda/AstraZeneca
55
Dificid (fidaxomicin) – Optimer Pharmaceuticals/Astellas/Cubist
56
PTK-0786 (omadacycline) - Paratek Pharmaceuticals/Novartis
57
RX-3341 (delafloxacin) – Rib-X Pharmaceuticals
59
TR-701 (torezolid phosphate) – Trius Therapeutics/Dong-A Pharmaceutical
60
RX-1741 (Radezolid) – Rib-X Pharmaceuticals
62
ACHN-490 – Isis Pharmaceuticals/Achaogen
63
CXA-201 (CXA-101/tazobactam) – Cubist Pharmaceuticals
64
Pipeline forecast to 2016
65
Chapter 4 Competitive landscape
67
Summary
67
Introduction
68
GlaxoSmithKline
68
Overview
68
Financial performance
68
5
Marketed product portfolio
69
Augmentin (amoxicillin + clavulanate)
69
Zinnat (cefuroxime)
70
Altabax (retapamulin ointment)
71
Research and development
71
Strategic and growth analysis
72
Drivers
72
Resistors
73
Pfizer
73
Overview
73
Financial performance
74
Marketed product portfolio
74
Zyvox (linezolid)
74
Tazocin/Zosyn (piperacillin + tazobactam)
75
Zithromax/Zmax (azithromycin)
76
Tygacil (tigecycline)
76
Research & development
77
Strategic and growth analysis
77
Drivers
77
Resistors
78
Johnson & Johnson
78
Overview
78
Financial performance
79
Marketed product portfolio
79
Levaquin (levofloxacin)
79
Doribax (doripenem)
80
Research & development
80
Strategic and growth analysis
81
Drivers
81
Resistors
81
Merck & Co.
82
6
Overview
82
Financial performance
82
Marketed product portfolio
82
Primaxin (imipenem + cilastatin)
83
Invanz (ertapenem)
83
Avelox (moxifloxacin)
84
Research & development
84
Strategic and growth analysis
85
Drivers
85
Resistors
86
Novartis
86
Overview
86
Financial performance
86
Marketed product portfolio
86
Tobi (tobramycin)
87
Research & development
87
Strategic and growth analysis
88
Drivers
88
Resistors
89
Appendix
90
Scope
90
Market size methodology
90
Epidemiology
91
Market forecast
91
Abbreviations
91
7
Table of figures
Figure 1:
Antibacterial market resistors
41
Figure 2:
Drivers of the antibacterial market
45
Figure 3:
The global antibacterials’ pipeline by stage of development, 2011
51
Figure 4:
Selected late-stage and recently launched antibacterials
54
8
Table of tables
Table 1:
Incidence of community acquired pneumonia infections in the 7MM, 2010
19
Table 2:
Incidence of upper respiratory tract infections caused by streptococcus infection in the 7MM,
2010
20
Table 3:
Incidence of community acquired urinary tract infections in the 7MM, 2010
21
Table 4:
Incidence of bacterial skin and skin structure infections in the 7MM, 2010
22
Table 5:
Prevalence of bacterial vaginosis infections in the 7MM, 2010
23
Table 6:
Forecast epidemiology of community acquired pneumonia infections in 7MM, 2010–16 24
Table 7:
Forecast epidemiology of upper RTIs caused by streptococcus infection in 7MM, 2010–1625
Table 8:
Forecast epidemiology of urinary tract infections in 7MM, 2010–2016
26
Table 9:
Forecast epidemiology of skin and skin structure infections in the 7MM, 2010–2016
27
Table 10:
Forecast epidemiology of bacterial vaginosis in the 7MM, 2010–16
28
Table 11:
Leading antibacterial drug classes with their mechanism of action
32
Table 12:
Leading brands in the global antibacterial market ($m), 2010
34
Table 13:
Leading antibacterial brands sale forecast ($m), 2010–16
48
Table 14:
An overview of Teflaro
55
Table 15:
An overview of Dificid
57
Table 16:
An overview of PTK-0786
58
Table 17:
An overview of RX-3341
59
Table 18:
An overview of TR-701
61
Table 19:
An overview of RX-1741
62
Table 20:
An overview of ACHN-490
64
Table 21:
An overview of CXA-201
65
Table 22:
Sales forecast for leading drugs in development ($m), 2010–16
66
Table 23:
GSK's leading antibacterial products ($m), 2010
69
Table 24:
GSK’s antibacterial R&D pipeline, February 2011
72
Table 25:
Pfizer's leading antibacterial products ($m), 2010
74
Table 26:
J&J's leading antibacterial products ($m), 2010
79
Table 27:
Merck & Co.'s leading antibacterial products ($m), 2010
83
Table 28:
Merck & Co.’s antibacterial R&D pipeline, February 2011
85
Table 29:
Novartis’ antibacterial R&D pipeline
87
9
Executive summary
Disease overview and epidemiology

Bacterial infections are extremely common, with an estimated incidence of 236m or an incidence rate
of 31% in the seven major markets (7MM) in 2010 (for the three most common sites of bacterial
infection respiratory, urinary tract and skin).

Upper respiratory tract infections affecting an estimated 116m in the 7MM, in 2010, but are associated
with low mortality in comparison with lower respiratory tract infections.

Urinary tract infections are common, with an estimated incidence of 73m, translating to an incidence
rate of 9.6% in 2010 in the 7MM. Urinary tract infections typically affect post-pubescent females and the
elderly.

In 2010, skin infections, with an incidence rate of 4.4%, resulted in 34m affected individuals in the
7MM. Although such infections are largely superficial, they can cause complications if left untreated.

The prevalence of bacterial vaginosis in the 7MM was 70m, a rate of 9.4% in 2010.
Global market analysis

The global antibacterial market reached $43.9bn in 2010 showing a Y-o-Y decline of 2.0%. The decline
was primarily due to the sales erosion of leading brands due to generic competition and lack of new
product launches over the last few years.

Of the competing drug classes in this market, cephalosporins occupied the leading position with over
25% share in the global antibacterials market followed by penicillins and fluoroquinolones. However, all
these drug classes declined in sales in 2010.

The concern regarding tendon ruptures and other tendon damage following fluoroquinolones therapy,
particularly in older patients, has been one of the strongest reasons for the sales erosion of this class.
10

In 2010, Johnson & Johson’s Levaquin was the largest brand with a share of 3.1% in the global
antibacterial market followed by Pfizer’s Zyvox (2.7%) and Merck & Co.’s Avelox (2.2%).

Bacterial resistance is negatively impacting efficacy for a significant number of marketed drugs, leaving
huge unmet need and opportunities for innovators.

Despite the market attractiveness, the cost and complexities coupled with regulatory uncertainties and
challenges have shifted the investment focus of pharmaceutical manufacturers from antibacterial to
treatments for chronic conditions.

Expanding product indications as a means of lifecycle management is one of the growing trends in the
global antibacterial market.
Pipeline analysis

As commercial opportunity in antibacterials has become progressively more limited due to heightened
competition, increasing genericization and comparatively short treatment regimens, the area is
attracting reduced R&D funding from big pharma companies.

Small pharmaceutical and biotech companies are performing much of the discovery and early
development of antibacterials. Typically these are then out-licensed to big pharma companies for
further development and commercialization.

Community acquired pneumonia (CAP) and hospital acquired pneumonia (HAP) infections are
attracting research interest. Additionally, the majority of companies developing new antibiotics are
targeting cell wall synthesis inhibitors, DNA topoisomerase II inhibitors, ribosomal inhibitors and
methionine tRNA ligase inhibitors.

Quinolones continue to lead the antibacterial pipeline due to their broad spectrum of activity followed by
the glycopeptides which demonstrate efficacy against MRSA and VRE strains.

Of over 199 antibacterial compounds in development, only 28% are in the late stage pipeline (preregistration and Phase III).
11

Regulatory uncertainty in antibacterials is inhibiting investment in pipeline products.
Competitive landscape

GSK’s antibacterial franchise recorded sales of $2.2bn (£1.4bn) in 2010 (a Y-o-Y decline of 4.4%),
accounting for 6.0% to the company’s revenues in 2010.

GSK is adopting a competitive pricing strategy to drive growth in emerging markets. With the reduction
in Zinnat prices by 22% in first quarter of 2010, GSK has reportedly doubled sales volume of in East
Africa.

Zyvox was Pfizer’s leading antibacterial product with 2010 sales of $1.2bn followed by Tazocin
($952m) and Zithromax/Zmax ($415m).

Aiming to reduce costs, Pfizer plans to shift its antibacterial research from US to China.

Of Merck & Co.’s antibacterial products, Avelox and Invanz will to continue to grow strongly patent
expiries in 2013 and 2015 respectively. Primaxin will continue to decline in sales.

Due to the high number of blockbuster off-patent compounds, Novartis is expected to continue
pursuing an aggressive generics development strategy for its antibacterial franchise.

Due to the anticipated sales erosion of Levaquin (levofloxacin), after its patent expiry in June 2011,
Johnson & Johnson shifted its focus on developing US market with Doribax by expanding the drugs
indication to nosocomial infections.
12
Chapter 1 Disease overview and epidemiology
Summary

Bacterial infections are extremely common, with an estimated incidence of 236m or an incidence rate
of 31% in the seven major markets (7MM) in 2010 (for the three most common sites of bacterial
infection respiratory, urinary tract and skin).

Upper respiratory tract infections affecting an estimated 116m in the 7MM, in 2010, but are associated
with low mortality in comparison with lower respiratory tract infections.

Urinary tract infections are common, with an estimated incidence of 73m, translating to an incidence
rate of 9.6% in 2010 in the 7MM. Urinary tract infections typically affect post-pubescent females and the
elderly.

In 2010, skin infections, with an incidence rate of 4.4%, resulted in 34m affected individuals in the
7MM. Although such infections are largely superficial, they can cause complications if left untreated.

The prevalence of bacterial vaginosis in the 7MM was 70m, a rate of 9.4% in 2010.
13
Introduction
This chapter provides a background to the antibacterial therapeutic area in terms of the major indications, an
overview of each of the indications, and their diagnosis, management and treatment, and forecast
epidemiology to 2016. The major bacterial infections covered in this report include respiratory infections
(RIs), urinary tract infections (UTIs), skin and skin structure infections (SSSIs) and gynecological infections
(GIs).
Bacterial infections
Bacterial infections affect tissues and organs throughout the human body. The most common sites of
infection are those that are exposed directly to bacteria, such as the lungs, skin, and urinary tract. The
epidemiologies of these infections are analyzed in this section. Outside of these common sites of infection,
CNS infections, intra-abdominal infections, cardiac and bone infections also occur, but collectively, these
affect only a relatively small number of patients each year, typically those patients which have had invasive
surgery or have contracted the disease in the hospital setting.
Respiratory tract infections
Respiratory tract infections can occur in the lower or upper respiratory tract. Lower respiratory tract infections
comprise infections located below the vocal cords. The most common sites of infection are the bronchi and
the lobes of the lungs. Viruses are the most common pathogens causing infections in the lungs. Notable
bacterial infections include pneumonia, caused by Streptococcus pneumoniae and tuberculosis (TB), caused
by Mycobacterium tuberculosis both of which are associated with high rates of mortality.
Bacterial lower respiratory tract infections are common, particularly in children, the elderly and
immunocompromised patients. In developed pharmaceutical markets, pneumonia is more common than TB,
with substantial differences in species occurring in community acquired pneumonia (CAP) and nosocomial
infections. The majority of upper respiratory tract infections (URIs) are caused by viruses. Common sites of
bacterial infection include the pharynx (colonized by Streptococcus sp.), the middle ear, and the sinuses
(with S. pneumoniae).
14
Urinary tract infections
The urinary tract is a common site for bacterial infections, particularly in patients that are using a catheter,
women, those who are sexually active, diabetics, the elderly, and patients with a malformed urinary tract.
Most commonly urinary tract infections (UTIs) are caused by Escherichia coli and to a lesser extent
Staphylococcus sp., but may be caused by sexually transmitted organisms such as Chlamydia and
Mycoplasma sp. The symptoms of a UTI can include a higher frequency of urination, urges to urinate,
burning sensations while passing urine, urinary incontinence, foul smelling urine and the presence of blood in
the urine. UTIs pften reoccur, but are typically confined to the bladder and urethra. However, infection may
spread to the kidneys, requiring hospitalization, and potentially posing greater risks for the spread of
infection.
Skin and skin structure infections
Skin and skin structure infections (SSSIs) are caused by many species of bacteria, and can occur
spontaneously, or in a wound, ulcer or burn. The most common uncomplicated SSSIs present limited
problems for diagnosis and treatment, but following a lack of treatment, bacteria may enter underlying
tissues, circulatory or lymphatic systems, causing complicated infections such as bacteremia, which are
associated with high rates of mortality. Bacterial infections are associated with a variety of symptoms and
treatment outcomes, which vary according to the bacterial species and the area of the body which is
infected. Some of the most common forms and symptoms of bacterial infections of the skin are:
Cellulitis and erysipelas
Cellulitis is one of the most common forms of bacterial infection, and is usually caused by Streptococci
bacteria, however other species of bacteria have also been associated with the condition. Cellulitis typically
occurs within an open wound or a subcutaneous abscess. Infections are relatively common in patients with
animal bites and may also result from exposure to contaminated standing water for example in a jacuzzi or
spa. Cellulitis typically occurs in the lower extremities, and is associated with increased redness, changes in
the textural nature of the skin, irritation, and inflammation. Occasionally, cellulites can lead to the formation of
erysipelas, inflamed raised lesions of the skin, which can indicate infection of the lymphatic system.
15
Folliculitis
Folliculitis, the infection of hair follicles by Staphylococcus aureus and P. aeuroginosa, is associated with
mild swelling and inflammation of the hair follicle, often resulting in the development of a pustule. A common
cause of infection is via use of a contaminated jacuzzi or spa. The condition is seldom complicated and
resolves quickly.
Impetigo and ecthyma
Impetigo is a skin infection caused by Streptococci or Staphylococci colonizing broken skin, typically
following injury. Risk factors are humid and warm climates and poor hygiene. Impetigo typically appears as a
cluster of vesicles that may rupture and secrete fluid produced by bacterial metabolism, which in turn
commonly forms a crust. Ecthyma is a form of impetigo which is characterized by ulceration.
Abcesses
Cutaneous abcesses are typically caused by bacteria that naturally occur on the surface of the skin such as
S aureus and result in a localized build-up of pus in the infected area, accompanied by pain and
inflammation. Cutaneous abcesses are common in the perineal area, and infections typically feature
organisms that are found in the feces of the patient. Subcutaneous abcesses represent serious infections
that can cause tissues necrosis. Such infections typically occur in the perineal area and the extremities of the
body. Subcutaneous abcesses are often caused by the migration of bacteria from a prior cutaneous
infection, with symptoms resembling that associated with cellulitis. If left untreated, the infection can lead to
gangrene and bacteremia.
Carbuncles and furuncles
Furuncles appear as raised boil-like lesions that may contain pus and necrotizing tissue. They are typically
caused by infection with staphylococcus bacteria. Carbuncles are clusters of connected furuncles caused by
subcutaneous infection. Both carbuncles and furuncles typically appear on the neck, face, buttocks or
breasts. Risk factors are poor hygiene, humidity, diabetes, immunocompromization, and some forms of acne.
Lymphadenitis and lymphangitis
16
Lymphadenitis, the infection of lymph nodes by bacteria, typically streptococci, commonly occurs as a
secondary infection associated with disease such as tuberculosis, cytomegalovirus infection, herpes
infection, syphilis and mononucleosis amongst other diseases. Lymphadenitis can be caused by fungal or
viral infection, although bacterial infections are common causes. Lymphangitis, the infection of peripheral
lymphatic channels, has a similar etiology to lymphadenitis, with a primary infection being the most common
cause. If left untreated, prognosis can be poor, with a likelihood of bacteremia, and leukocytosis.
Gynecological infections
Bacterial vaginosis
Bacterial vaginosis (BV) is the most common cause of vaginal infection and is often referred to as vaginal
bacteriosis. BV is a polymicrobial syndrome associated with a change in the vaginal flora, resulting in a loss
of normally present lactobacilli and the appearance of increased numbers of other bacteria such as
Prevotella, Mobiluncus, Gardnerella vaginalis and Mycolasma hominis. However, the exact cause for this
change remains unknown. Although BV is frequently associated with sexually transmitted infections, such as
Chlamydia trachomatis and Neustria gonorrhea, it also occurs in sexually abstinent women.
Diagnosis, treatment and management
Respiratory tract infections
Diagnosis of lower respiratory tract infections is achieved by means of a sputum sample or swab and
corresponding culture. Diagnosis can be rapid and is an aid in the selection of antibiotic therapy. X-ray and
other imaging techniques can be useful tools to provide assessment of the extent of the infection. The
treatment of lower respiratory tract infections is linked to the species of bacteria which is identified by culture,
although broad spectrum antibiotics, taking into account patient’s allergies and history of treatment are
typically prescribed. For upper respiratory tract infections, an estimated 95-98% of infections are caused by
viruses rather than bacteria. In cases of pharyngitis, a bacterial culture may be taken in order to determine
the pathogen causing the infection, and antibiotic treatment chosen accordingly. The most common antibiotic
therapies that are prescribed for the treatment of all respiratory tract infections are penicillins,
fluoroquinolones and macrolides.
17
Urinary tract infections
Urinary tract infections are typically diagnosed through interview and examination of the presenting patient. A
urine sample may be taken, analysis of which may provide identification of the bacterial species responsible
for the infection. Recurrent infections, or any infections in men, may require pyelography or ultrasonography
in order to determine whether any abnormalities or lesions exist, which may be provoking an infection. In
men, examination of the prostate may be necessary in order to assess whether this organ is promoting
infection, particularly in older men. Treatment of urinary tract infections varies according to the bacterial
species that has been identified. Fluoroquinolones and penicillin products are the most popular treatments,
although cephalosporins may play an important part in treatment, particularly in hospital settings.
Skin and skin structure infections
Diagnosis may be undertaken by visual examination, but in rare bacteria species, a bacterial culture coupled
with examination of patient history, including potential for exposure and travel may provide insight into the
primary organism responsible for the infection. Treatment is with topical antibiotics if possible, although oral
antibiotic therapy is typically recommended in moderate to severe infection, particularly those that are
associated with a higher risk of spread or invasion into neighboring tissues. Imaging techniques may be
employed to gauge the extent of the bacterial infection, and assess risk, thus further informing treatment
choice. For complicated skin and skin structure infections treatment, with clindamycin, erythromycin, and
doxycycline are the usual first-line treatments. Fluoroquinolones and cephalosporins are usual second-line
treatment of these conditions. The key unmet need in SSSIs is that the present therapies are not very
effective against the resistant strains of bacteria particularly methicillin-resistant Staphylococcus aureus
(MRSA). However, there are multiple drugs under developments to target resistant organisms.
18
Gynecological infections
The presence of bacterial vaginosis (BV) is suspected when a grayish white discharge covers the wall of
vagina which has a pH of ≥4.5, generally ≥5.5. In BV, amines are produced in large amounts, leading to the
fishy odor of the secretions. If the pH of the secretions is raised (either by semen in vivo or by potassium
hydroxide in the laboratory), this odor is accentuated. This is referred to as a positive Whiff Test.
Vaginosis is usually treated with the antibiotic metronidazole that can be administered either orally or in a gel
form. If the vaginosis occurs simultaneously with Candida, patients are typically treated with antifungals such
as butoconazole, clotrimazole, and miconazole which are administered directly into the vagina in the form of
suppositories, tablets, creams or ointments.
Epidemiology of bacterial infections
Respiratory tract infections
Penumonia is the most common lower respiratory tract infection. Table summarizes the estimated incidence
of this indication in the seven major markets (7MM).
Table :
Incidence of community acquired pneumonia infections in the 7MM,
2010
Country
Incidence (000s)
Incidence (%)
Share (%)
587
0.94
8.1
1,027
1.24
14.1
Italy
555
0.94
7.6
Spain
393
0.88
5.4
UK
474
0.77
6.5
Total 5EU
3,044
0.98
41.8
US
3,401
1.1
46.7
839
0.66
11.5
7,284
0.97
100.0
France
Germany
Japan
Total 7MM
Source: CDC, WHO
BUSINESS INSIGHTS
19
There is limited comparable data across bacterial species causing respiratory tract infections, although data
points to wide variations across countries, even in Western Europe. Higher risk populations include the
elderly, children, immunocompromised, and individuals in the institutional setting.
An estimated 95–100% of the population acquire at least one upper respiratory tract infection each year,
although the vast majority of these infections are viral. The estimated incidence of upper respiratory bacterial
infections, using the most common pathogen, Streptococcus, is summarized in the table below.
Table :
Incidence of upper respiratory tract infections caused by streptococcus
infection in the 7MM, 2010
Country
Incidence (000s)
Incidence (%)
Share (%)
9,743
15.6
8.4
12,425
15
10.7
Italy
8,733
14.8
7.6
Spain
6,658
14.9
5.8
UK
9,551
15.5
8.3
Total 5EU
47,210
15.2
40.8
US
49,466
16
42.8
Japan
18,949
14.9
16.4
115,625
15.6
100.0
France
Germany
Total 7MM
Source: CDC, WHO
BUSINESS INSIGHTS
Due to a lack of comprehensive studies, and the low rates of reporting, diagnosis and treatment of
pharyngitis, it is difficult to estimate the incidence of the disease. Therefore, estimates are based on US
studies, adjusted for demographics in order to reflect the increased incidence of pharyngitis among children.
Age and annual climatic conditions represent the most significant risk factors for an increased annual
incidence of pharyngitis, of which only a small proportion (approximately 15–20%), are caused by
streptococcus species.
20
Urinary tract infections
Estimates of the incidence of UTIs across the seven major markets are summarized in the table below.
Table :
Incidence of community acquired urinary tract infections in the 7MM,
2010
Country
Incidence (000s)
Incidence (%)
Share (%)
6,995
11.2
10.0
10,106
12.2
14.4
Italy
6,903
11.7
9.8
Spain
5,317
11.9
7.6
UK
6,840
11.1
9.7
Total 5EU
36,029
11.6
51.3
US
22,569
7.3
32.1
Japan
11,700
9.2
16.7
Total 7MM
70,212
9.4
100.0
France
Germany
Source: CDC, WHO
BUSINESS INSIGHTS
The incidence of UTIs is similar among the seven major markets, although due to a greater incidence of the
condition in the elderly, institutionalized, patients using a catheter, and women, incidence rates vary from
country to country. In community acquired UTIs, age and gender are the most important determinants of
incidence, which favors countries with the highest percentage of elderly people, such as Germany, Spain
and Italy.
21
Skin and skin structure infections
Estimates of the incidence of skin and skin structure infections across the seven major markets are
summarized in the table below.
Table :
Incidence of bacterial skin and skin structure infections in the 7MM,
2010
Country
Incidence (000s)
Incidence (%)
Share (%)
France
2,623
4.2
8.4
Germany
3,479
4.2
11.1
Italy
2,478
4.2
7.9
Spain
1,877
4.2
6.0
UK
2,588
4.2
8.2
Total 5EU
13,045
4.2
41.6
US
12,985
4.2
41.4
Japan
5,341
4.2
17.0
Total
31,371
4.2
100.0
Source: CDC, WHO
BUSINESS INSIGHTS
There is limited epidemiological data available on skin and skin structure infections due to the wide range of
conditions, and difficulties in detection and surveillance. Rarer and more serious conditions such as
necrotizing infections are more likely to be tracked. Skin and skin structure infections are believed to be more
common in children, the elderly and institutionalized patients, particularly those with limited levels of mobility,
although there are no studies available to assess the incidence of the sub-indications within this category by
country and demography.
22
Gynecological infections
Estimates of the prevalence of bacterial vaginosis across the seven major markets are summarized in the
table below.
Table :
Prevalence of bacterial vaginosis infections in the 7MM, 2010
Country
Prevalence (000s)
Prevalence (%)
Share (%)
France
4,996
8
7.1
Germany
6,627
8
9.4
Italy
4,071
6.9
5.8
Spain
3,128
7
4.5
UK
5,546
9
7.9
Total 5EU
24,847
8
35.4
US
43,592
14.1
62.1
7,631
6
10.9
70,212
9.4
100.0
Japan
Total 7MM
Source: Business Insights, CDC, WHO, various other sources
BUSINESS INSIGHTS
Forecast epidemiology
This section provides forecasts on the incidence of the four major bacterial infections analyzed in this report.
Respiratory tract infections
Table summarizes the forecast incidence of Community acquired pneumonia (CAP) over the period 2010–
2016. In the absence of any major factors exerting an influence on the prevalence of upper and lower
respiratory tract infections, incidence of the infection remains in line with demographic changes. As a result
the US, Germany and Japan, with the largest population are forecast to have the highest incidence.
The US, Japan and Germany are forecast to feature the largest patient populations for upper RTIs over the
forecast period, with the highest incidence rates forecast to continue to be in the US, France and the UK.
Table summarizes the forecast incidence of upper RTIs to 2016.
23
Table :
Forecast epidemiology of community acquired pneumonia infections in
7MM, 2010–16
Country
2010
2011
2012
2013
2014
2015
2016
Incidence (000s)
587
590
599
602
604
607
609
Incidence (%)
0.94
0.94
0.95
0.95
0.95
0.95
0.95
1,027
1,027
1,036
1,036
1,036
1,044
1,044
1.24
1.24
1.25
1.25
1.25
1.26
1.26
Incidence (000s)
555
555
561
562
562
562
562
Incidence (%)
0.94
0.94
0.95
0.95
0.95
0.95
0.95
Incidence (000s)
393
395
400
401
402
408
409
Incidence (%)
0.88
0.88
0.89
0.89
0.89
0.9
0.9
Incidence (000s)
474
477
485
487
489
498
500
Incidence (%)
0.77
0.77
0.78
0.78
0.78
0.79
0.79
3,044
3,052
3,090
3,097
3,104
3,142
3,148
0.98
0.98
0.99
0.99
0.99
1
1
3,401
3,430
3,491
3,521
3,551
3,613
3,643
1.10
1.10
1.11
1.11
1.11
1.12
1.12
Incidence (000s)
839
838
848
846
843
853
850
Incidence (%)
0.66
0.66
0.67
0.67
0.67
0.68
0.68
7,245
7,276
7,382
7,412
7,441
7,546
7,574
0.97
0.97
0.98
0.98
0.98
0.99
0.99
France
Germany
Incidence (000s)
Incidence (%)
Italy
Spain
UK
5EU
Incidence (000s)
Incidence (%)
US
Incidence (000s)
Incidence (%)
Japan
Total 7MM
Incidence (000s)
Incidence (%)
Source: Business Insights
BUSINESS INSIGHTS
24
Table :
Forecast epidemiology of upper RTIs caused by streptococcus infection in
7MM, 2010–16
Country
2010
2011
2012
2013
2014
2015
2016
9,743
9,789
9,897
9,941
9,984
10,090
10,131
15.6
15.6
15.7
15.7
15.7
15.8
15.8
12,425
12,428
12,513
12,514
12,513
12,594
12,591
15
15
15.1
15.1
15.1
15.2
15.2
8,733
8,741
8,806
8,810
8,812
8,871
8,870
14.8
14.8
14.9
14.9
14.9
15
15
6,658
6,680
6,746
6,765
6,782
6,842
6,854
14.9
14.9
15
15
15
15.1
15.1
9,551
9,593
9,698
9,742
9,786
9,894
9,939
15.5
15.5
15.6
15.6
15.6
15.7
15.7
47,210
47,331
47,758
47,869
47,972
48,384
48,476
15.2
15.2
15.3
15.3
15.3
15.4
15.4
49,466
49,892
50,636
51,069
51,503
52,260
52,697
16
16
16.1
16.1
16.1
16.2
16.2
18,949
18,910
18,991
18,938
18,879
18,940
18,869
14.9
14.9
15
15
15
15.1
15.1
116,521
117,020
118,262
118,742
119,210
120,428
120,875
15.6
15.6
15.7
15.7
15.7
15.8
15.8
France
Incidence (000s)
Incidence (%)
Germany
Incidence (000s)
Incidence (%)
Italy
Incidence (000s)
Incidence (%)
Spain
Incidence (000s)
Incidence (%)
UK
Incidence (000s)
Incidence (%)
5EU
Incidence (000s)
Incidence (%)
US
Incidence (000s)
Incidence (%)
Japan
Incidence (000s)
Incidence (%)
Total 7MM
Incidence (000s)
Incidence (%)
Source: Business Insights
BUSINESS INSIGHTS
25
Urinary tract infections
Table :
Forecast epidemiology of urinary tract infections in 7MM, 2010–2016
Country
2010
2011
2012
2013
2014
2015
2016
6,995
7,028
7,123
7,155
7,186
7,280
7,310
11.2
11.2
11.3
11.3
11.3
11.4
11.4
10,106
10,108
10,192
10,193
10,193
10,274
10,272
12.2
12.2
12.3
12.3
12.3
12.4
12.4
6,903
6,910
6,974
6,977
6,979
7,038
7,037
11.7
11.7
11.8
11.8
11.8
11.9
11.9
5,317
5,335
5,397
5,412
5,425
5,482
5,492
11.9
11.9
12
12
12
12.1
12.1
6,840
6,870
6,963
6,994
7,026
7,121
7,153
11.1
11.1
11.2
11.2
11.2
11.3
11.3
36,091
36,183
36,584
36,668
36,747
37,073
37,144
11.6
11.6
11.7
11.7
11.7
11.8
11.8
22,569
22,763
23,274
23,473
23,672
24,194
24,397
7.3
7.3
7.4
7.4
7.4
7.5
7.5
11,700
11,676
11,774
11,742
11,705
11,790
11,746
9.2
9.2
9.3
9.3
9.3
9.4
9.4
70,212
70,512
71,560
71,850
72,134
73,172
73,443
9.4
9.4
9.5
9.5
9.5
9.6
9.6
France
Incidence (000s)
Incidence (%)
Germany
Incidence (000s)
Incidence (%)
Italy
Incidence (000s)
Incidence (%)
Spain
Incidence (000s)
Incidence (%)
UK
Incidence (000s)
Incidence (%)
5EU
Incidence (000s)
Incidence (%)
US
Incidence (000s)
Incidence (%)
Japan
Incidence (000s)
Incidence (%)
Total
Incidence (000s)
Incidence (%)
Source: Business Insights
BUSINESS INSIGHTS
26
Skin and skin structure infections
Table summarizes the forecast incidence of skin and skin structure infections over the period to 2016.
Table :
Forecast epidemiology of skin and skin structure infections in the 7MM, 2010–
2016
Country
2010
2011
2012
2013
2014
2015
2016
2,623
2,635
2,711
2,723
2,734
2,810
2,821
4.2
4.2
4.3
4.3
4.3
4.4
4.4
3,479
3,480
3,563
3,563
3,563
3,646
3,645
4.2
4.2
4.3
4.3
4.3
4.4
4.4
2,478
2,481
2,541
2,543
2,543
2,602
2,602
4.2
4.2
4.3
4.3
4.3
4.4
4.4
1,877
1,883
1,934
1,939
1,944
1,994
1,997
4.2
4.2
4.3
4.3
4.3
4.4
4.4
2,588
2,599
2,673
2,685
2,697
2,773
2,785
4.2
4.2
4.3
4.3
4.3
4.4
4.4
13,045
13,078
13,422
13,453
13,482
13,824
13,850
4.2
4.2
4.3
4.3
4.3
4.4
4.4
12,985
13,097
13,524
13,640
13,755
14,194
14,313
4.2
4.2
4.3
4.3
4.3
4.4
4.4
5,341
5,330
5,444
5,429
5,412
5,519
5,498
4.2
4.2
4.3
4.3
4.3
4.4
4.4
31,371
31,505
32,390
32,522
32,650
33,537
33,661
4.2
4.2
4.3
4.3
4.3
4.4
4.4
France
Incidence (000s)
Incidence (%)
Germany
Incidence (000s)
Incidence (%)
Italy
Incidence (000s)
Incidence (%)
Spain
Incidence (000s)
Incidence (%)
UK
Incidence (000s)
Incidence (%)
5EU
Incidence (000s)
Incidence (%)
US
Incidence (000s)
Incidence (%)
Japan
Incidence (000s)
Incidence (%)
Total
Incidence (000s)
Incidence (%)
Source: Business Insights
BUSINESS INSIGHTS
27
Gynecological infections
Table 10 summarizes the forecast prevalence of bacterial vaginosis to 2016.
Table :
Forecast epidemiology of bacterial vaginosis in the 7MM, 2010–16
Country
2010
2011
2012
2013
2014
2015
2016
4,996
5,020
5,106
5,129
5,151
5,237
5,258
8
8
8.1
8.1
8.1
8.2
8.2
6,627
6,628
6,712
6,713
6,712
6,794
6,793
8
8
8.1
8.1
8.1
8.2
8.2
4,071
4,075
4,137
4,139
4,140
4,199
4,198
6.9
6.9
7
7
7
7.1
7.1
3,128
3,138
3,193
3,202
3,210
3,262
3,268
7
7
7.1
7.1
7.1
7.2
7.2
5,546
5,570
5,657
5,683
5,709
5,797
5,824
9
9
9.1
9.1
9.1
9.2
9.2
24,847
24,911
25,284
25,342
25,397
25,763
25,812
8.0
8.0
8.1
8.1
8.1
8.2
8.2
43,592
43,968
44,660
45,042
45,425
46,131
46,516
14.1
14.1
14.2
14.2
14.2
14.3
14.3
7,631
7,615
7,723
7,701
7,678
7,777
7,748
6
6
6.1
6.1
6.1
6.2
6.2
70,212
70,512
71,560
71,850
72,134
73,172
73,443
9.4
9.4
9.5
9.5
9.5
9.6
9.6
France
Prevalence (000s)
Prevalence (%)
Germany
Prevalence (000s)
Prevalence (%)
Italy
Prevalence (000s)
Prevalence (%)
Spain
Prevalence (000s)
Prevalence (%)
UK
Prevalence (000s)
Prevalence (%)
5EU
Prevalence (000s)
Prevalence (%)
US
Prevalence (000s)
Prevalence (%)
Japan
Prevalence (000s)
Prevalence (%)
Total
Prevalence (000s)
Prevalence (%)
Source: Business Insights
BUSINESS INSIGHTS
28
Chapter 2 Global market analysis
Summary

The global antibacterial market reached $43.9bn in 2010 showing a Y-o-Y decline of 2.0%. The decline
was primarily due to the sales erosion of leading brands due to generic competition and lack of new
product launches over the last few years.

Of the competing drug classes in this market, cephalosporins occupied the leading position with over
25% share in the global antibacterials market followed by penicillins and fluoroquinolones. However, all
these drug classes declined in sales in 2010.

The concern regarding tendon ruptures and other tendon damage following fluoroquinolones therapy,
particularly in older patients, has been one of the strongest reasons for the sales erosion of this class.

In 2010, Johnson & Johson’s Levaquin was the largest brand with a share of 3.1% in the global
antibacterial market followed by Pfizer’s Zyvox (2.7%) and Merck & Co.’s Avelox (2.2%).

Bacterial resistance is negatively impacting efficacy for a significant number of marketed drugs, leaving
huge unmet need and opportunities for innovators.

Despite the market attractiveness, the cost and complexities coupled with regulatory uncertainties and
challenges have shifted the investment focus of pharmaceutical manufacturers from antibacterial to
treatments for chronic conditions.

Expanding product indications as a means of lifecycle management is one of the growing trends in the
global antibacterial market.
29
Introduction
This chapter gives an overview of the global antibacterials market, with competitive analysis of the leading
antibacterials brands, and drug classes. Key brands are profiled. The chapter also highlights the challenges
and drivers of the antibacterial market.
Market dynamics
The global antibacterial market reached $43.9bn, showing a Y-o-Y decline of 2.0% in 2010. The decline was
primarily due to infiltration of generics which led to sales erosion of a number of leading brands, including
Pfizer’s Tazocin and Johnson & Johnson’s (J&J) Levaquin, and lack of new product launches over the last
few years. The bacterial infections market can be broadly categorized into community acquired and hospital
acquired bacterial infections. Although, the prevalence of community acquired bacterial infections is also on
a rise, hospital acquired bacterial infections are growing at a higher rate due to increased incidence of
resistant bacteria in hospital settings. The community market is highly dominated by the generic brands while
the sale of branded antibacterial products is primarily driven by the hospital sector.
Nosocomial (hospital acquired) infections is the most attractive segment in the antibacterial space with
growing antibiotic resistance and significantly higher mortality and morbidity rate. Due to the nature of
bacterial infections, mutations rapidly lead to the development of drug resistance over the course of
treatment particularly in hospital settings. Methicillin-resistant Staphylococcus aureus (MRSA), vancomycinresistant enterococci (VRE), Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter species
represent the most important drug resistant pathogens that have been the focus of antibacterial R&D activity
in recent years. However, this may lead to an over-crowded market with similar products fighting for their
share of the market. Thus, the uptake and commercial success of the drug will be highly dependent on the
market entry strategy of the company. First mover advantage will be a major factor for success. It will be
challenging to to differentiate late-entering drugs and gain market share. Despite this, the nosocomial drug
market is expected to dominate the antibacterial market in the near term.
30
Cephalosporins formed the largest drug class in 2010, with over 25% share in the global antibacterial
market, followed by broad-spectrum penicillins (20%) and fluoroquinolones (15%) in 2010. However, all the
major drug classes including cephalosporins, penicillins and fluoroquinolones witnessed declining sales in
2010. GSK, Pfizer, Johnson & Johnson (J&J) and Merck & Co. were the leading players in the global
antibacterial market in 2010. Tazocin, Levaquin, Augmentin, Zyvox, and Avelox were the key brands
accounting for 12.4% of the total antibacterial market in 2010.
Market analysis by drug class
The major drug classes in the antibacterial therapeutic category include:

cephalosporins

penicillins

fluoroquinolones

macrolides

carbapenems.
31
Table :
Leading antibacterial drug classes with their mechanism of action
Drug class
Mechanism of action
Drugs
Brands
Cephalosporins
Cell wall synthesis
inhibitors
ceftobiprole,
ceftaroline
cephalexim, cefixime
Rocephin, Fortum,
Suprax, Flomox,
Zinnat, Keflex
Penicillins
Cell wall synthesis
inhibitors
piperacilin,
flucloxacillin
Augmentin, Zosyn,
Amoxil, Tazocin,
Floxapen
Fluoroquinolones
Nucleic acid synthesis
inhibitors
gatifloxacin,
moxifloxacin,
levofloxacin
Avelox, Levaquin,
Tavanic, Cravit,
Ciproxin
Macrolides
Protein synthesis
inhibitors
clarithromycin,
telithromycin,
azithromycin
Zithromax, Klacid,
Clarith, Azithromycin,
Dalacin, Ketek
Carbapenems
Cell wall synthesis
inhibitors
meropenem,
imipenem
Merrem, Primaxin
Source: Business Insights
BUSINESS INSIGHTS
Cephalosporins
Cephalosporins are part of the beta-lactams group and work by interfering with the synthesis of the bacterial
cell wall. Some may be given orally but most are given by injection. They are typically the second choice
antibiotic, their main uses being in pneumonia, septicemia, meningitis, sinusitis, and UTIs. Unwanted side
effects are similar to those seen with the penicillins, such as stomach upset, nausea, vomiting, and diarrhea.
However, all these side effects are mild in nature and subside with time. Despite their second-line usage,
cephalosporins have a broader spectrum of activity and are more potent than penicillins. In 2010,
cephalosporins were the leading drug class with over 25% sales share of the global antibacterials market.
Penicillins
Penicillin was the first modern antibiotic from the beta-lactam group and acts by interfering with the synthesis
of bacterial cell walls. Despite the age of the class, penicillins remain the most widely used antibiotics, owing
to their broad activity base and good safety profile. They remain the drugs of choice for many clinical uses,
32
including bacterial meningitis, skin infections, pharyngitis, middle ear infections, bronchitis, gonorrhea, and
syphilis, among other infections. They can be taken orally, although different products are absorbed to
different degrees and thus, in some cases, injection may be more efficacious. They are well tolerated and
toxic side effects are rare, although allergic reactions such as rashes and fever occur in about 10% of
patients. In 2010, penicillins accounted for around 20% of the total antibacterial sales.
Fluoroquinolones
Fluoroquinolones work by inhibiting a bacterial enzyme called DNA gyrase, which prevents bacterial DNA
from coiling, so preventing replication. Fluoroquinolones are broad spectrum antibiotics but are particularly
effective against many gram-negative bacteria, including many organisms that are resistant to penicillin.
Taken orally or by injection, their main uses are in UTIs. Fluoroquinolones have seen sales erosion due to a
decline in the sales of oral fluoroquinolones and a rise in resistant strains of bacteria.
Macrolides
Macrolides interfere with bacterial protein synthesis by attaching to bacterial ribosomes (the cellular
constituents that read RNA as a template for protein synthesis). Their spectrum of activity is similar to that of
penicillins (although they are mainly effective against gram-positive bacteria) and they have proven useful
alternatives in penicillin-sensitive patients. They are typically administered orally, with the main side-effects
being gastrointestinal disturbances.
Carbapenems
Carbapenems, a beta-lactam antibiotic, was developed from thienamycin, a naturally-derived product of
Streptomyces cattleya. Carbapenems have been highly effective against multiple bacterial infections
including Escherichia coli, however, the recent discovery of drug resistance to carbapenem antibiotics is
raising a global concern. Most of the nosocomial strains of Acinetobacter are antibiotic-resistant which is a
notable challenge.
33
Leading brands dynamics
The key 10 brands in the global antibacterials market generated sales of $8.7bn accounting for 19.9% of the
market in 2010. J&J’s Levaquin was the largest brand with a share of 3.1% in the global antibacterial market
followed by Pfizer’s Zyvox (2.7% ) and Merck & Co.’s Avelox (2.2%).
Table :
Leading brands in the global antibacterial market ($m), 2010
Brands
Generic
name
Sales 2010
($m)
Sales growth
2010 (%)
Market share
2010 (%)
CAGR
2006–10 (%)
Levaquin
levofloxacin
1,357
-12.5
3.1
-3.0
Zyvox
linezolid
1,176
3.1
2.7
10.7
Avelox
moxifloxacin
984
-1.0
2.2
3.5
Augmentin
amoxicillin +
clavulanic
acid
966
-6.3
2.2
2.3
Tazocin
piperacillin +
tazobactam
952
94.9*
2.2
-0.5
Cravit
levofloxacin
820
-17.5
1.9
-8.8
Merrem
meropenem
817
-6.3
1.9
7.8
Cubicin
daptomycin
625
16.2
1.4
33.8
Primaxin
imipenem +
cilastatin
610
-11.5
1.4
-3.5
Zithromax
azithromycin
415
-3.5
0.9
-10.2
8,721
-0.1
19.9
1.1
Others
35,156
-2.5
80.1
4.3
Total
43,877
-2.0
100.0
3.7
Key brands
total
Note: *2009 sales included only six months sales from Wyeth and 2 months sales through Pfizer.
Source: company reports, PharmaVitae
BUSINESS INSIGHTS
Levaquin (levofloxacin) – Johnson & Johnson
Levaquin is a broad-spectrum fluoroquinolone drug with activity against wide range of gram-positive and
gram negative pathogens including S. aureus (not MRSA), Streptococcus pneumoniae (including multiple
drug-resistant), Streptococcus pyogenes, E. coli, Haemophilus influenzae, Chlamydia pneumoniae,
Legionella pneumophila, Proteus mirabilis, and Mycoplasma pneumoniae. The drug inhibits the activity of
34
DNA gyrase, a type II topoisomerase, and topoisomerase IV, which are necessary for bacterial cell wall
synthesis. The drug was initially developed by Daiichi Sankyo and commercialized under the brand name
Cravit in Japan in 1993. Later, in 1997, it was launched in the US under the brand name Levaquin through a
licensing agreement with J&J; in 1998 the brand was introduced in Europe as Tavanic.
Levaquin has been approved for multiple expanded indications since its launch, for instance in 2007,
Levaquin was approved for the treatment of complicated UTIs (cUTIs) and acute polynephritis; in 2005 the
FDA approved Levaquin for five-day course for the treatment of acute bacterial sinusitis. The product is
available as an oral solution, tablet, and as an intravenous formulation. Levaquin is covered by a
composition-of-matter patent through December 20, 2010 held by Daiichi Sankyo, which includes a threeyear Hatch-Waxman extension; this same patent also covers the method of manufacture and its use as an
anti-microbial. The FDA granted an additional six months of pediatric exclusivity to Levaquin in 2008 which
has extended Levaquin’s patent exclusivity to June 2011 instead of December 2010.
In 2010, sales of Levaquin declined to $1.4bn, a contraction of 12.5% on 2009. The entire fluoroquinolones
category saw falling sales in 2010, primarily due to the litigations on fluoroquinolones about causing tendon
ruptures and other tendon damage particularly in older patients. Levaquin is expected to face further sales
erosion after its patent expiry in June 2011.
Zyvox (linezolid) – Pfizer
Zyvox is an oxazolidinone antibiotic indicated for treatment of resistant gram-positive infections, which
account for over 50% of critical bacterial infections. Zyvox, a bacteriostatic, acts by binding on the ribosomal
50S subunit, thus inhibiting protein synthesis. Zyvox was first launched in the US in 2000, and was
subsequently launched in other major markets including Japan, France, Germany, Italy, Spain, and the UK in
2001. Zyvox was approved for MRSA in Japan in 2007.
Zyvox is one of six drugs approved for MRSA infections, including vancomycin, Cubicin, Tygacil, Vibativ and
recently launched Teflaro. Zyvox biggest advantage over competitor products is its 100% oral bioavailability
and rapid absorption with no cross-resistance with other antibiotics. This oral/intravenous switching enables
physicians to initiate intravenous therapy in the hospital and smoothly transition patients to the oral
35
formulation for out-patient usage, which results in early discharge of patients from hospital, thus saving
additional costs associated with extended hospital stays. Moreover, Cubicin’s ineffectiveness in community
and hospital acquired pneumonias and increasing resistance to vancomycin in this indication is expected to
further strengthen Zyvox’s position in the market. Zyvox was one of the leading brands in the global
antibacterial market in 2010 with sales of $1.2bn and Y-o-Y growth of 3.1%.
Avelox (moxifloxacin) – Bayer
Avelox, a fourth-generation fluoroquinolone with a broad spectrum of activity against gram-positive and
gram-negative bacteria, was launched in 1999 in the US and Europe. Bayer markets Avelox in the 7MM
except the US while Merck & Co. markets the brand in the US. Avelox can be taken once-daily, for five days
for the treatment of acute exacerbation of chronic bronchitis, as opposed to seven-day therapy with BMS’
Tequin (gatifloxacin). Avelox is also indicated for skin and skin structure infections (SSSIs) and can be
administered orally and intravenously. The drug inhibits the activity of deoxyribonucleic acid (DNA) gyrase
and topoisomerase IV enzymes which are required for the replication of bacterial DNA.
The brand had been growing through expanded indications, for instance, in June 2005, Avelox was granted
an additional indication for the treatment of SSSIs. In November 2005, the drug was approved for treatment
of intra-abdominal infections, further increasing the addressable market opportunity. Avelox had worldwide
sales of $984m in 2010, a Y-o-Y sales decline of 1.0%. Avelox sales are expected to decline significantly in
the near term primarily due to uptake of generics, particularly after the patent expiry of Levaquin in 2011, in
addition to growing safety and resistance concerns surrounding the use of fluoroquinolone drugs due to
associated risk of fulminant hepatitis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN).
Augmentin (amoxicillin + clavulanic acid) – GSK
GSK's Augmentin is an antibacterial drug launched in 1984 in the US. It is a penicillin antibiotic indicated for
the treatment of pneumonia, bronchitis, sinusitis and urinary tract, ear, and skin infections. Amoxicillin is a
semi-synthetic antibiotic that provides bactericidal activity against a wide range of gram-positive and gramnegative bacteria. However, amoxicillin is also prone to degradation by beta-lactamases and thus it is not
36
active against organisms that produce these enzymes. Clavulanic acid, on the other hand, is a beta-lactam
that is structurally similar to penicillins and has the ability to make beta-lactamase enzymes inactive.
Clavulanic acid is particularly effective against plasmid-mediated beta-lactamases, a clinically important
class that is commonly associated with transferred drug resistance. The combination of clavulanic acid and
amoxicillin in Augmentin prevents the degradation of amoxicillin by the beta-lactamase, effectively extending
its spectrum to cover even bacteria that are generally resistant to amoxicillin. Augmentin is suitable for adults
pediatric patients over 40kgs.
Augmentin sales declined by 6.3% to $966m in the year to 2010. Augmentin generated $450m sales from
emerging countries in 2010, while the sales from the US were $17m and $371m from Europe. GSK has sold
its penicillin manufacturing facility and the US marketing rights of Augmentin to Dr Reddy’s, a generic drug
company based in India. GSK will continue to market Augmentin in rest of the geographies except the US.
Augmentin’s broad coverage of pathogens, oral availability, and relatively lower price than competitors is
driving the growth in emerging markets including BRIC.
Tazocin (piperacillin + tazobactam) – Pfizer
Tazocin is an intravenous antibiotic combination product consisting of piperacillin (semi-synthetic penicillin)
and tazobactam (beta lactamase inhibitor). Tazocin is indicated for the treatment of patients with moderate to
severe infections caused by piperacillin resistant, piperacillin/tazobactam-susceptible strains. Tazocin
administration is limited to hospital settings as it is only available in an injectable formulation. The drug was
developed by Taiho Pharmaceutical in Japan and was in-licensed to Pfizer (then Wyeth) for marketing in the
US (Zosyn) and Europe (Tazocin). Tazocin was commercialized in 1994 in Europe. In 2001, Taiho entered
into an agreement with Taisho Pharmaceutical to market the drug in Japan.
The brand sales were eroded due to generic competition after its patent expiry in 2008. Although, Tazocin is
is meeting generic competition, due to formulation differences, marketed generics should not be
administered with aminoglycosides for example, according to a safety update by the MHRA. This
complication combined with Tazocin’s strong brand in the global antibacterial market will help to protect sales
from generic erosion. In 2010, Tazocin generated sales of $952m.
37
Cravit (levofloxacin) – Daiichi Sankyo
Cravit is a broad-spectrum fluoroquinolone drug with activity against a wide range of gram-positive and
gram-negative bacteria. Cravit is indicated for the treatment of bacterial conjunctivitis, sinusitis, chronic
bronchitis, community acquired pneumonia (CAP), pneumonia caused by penicillin-resistant strains of
Streptococcus pneumoniae, SSSI, cUTI and acute pyelonephritis. The brand was launched by Daiichi
Sankyo in Japan in 1993 and since than the brand has been granted approvals for treating 43 indications
and 32 species of bacteria, due to its superior efficacy and safety profile. While the brand was initially
approved for oral administration in 100mg dosage, in July 2009, Cravit was approved as a once-daily
administration in 500mg for antibacterial treatment. In January 2011, a new intravenous formulation of Cravit
was approved in Japan.
Daiichi Sankyo is struggling to sustain the market share of Cravit through expanded therapeutic indications.
With an aim to penetrate in the ASEAN (Association of Southeast Asian Nations) region, Daiichi Sankyo,
granted the marketing rights for Cravit to Ranbaxy in March 2011,. Kyowa Hakko Bio was marketing Cravit in
these regions prior to transferring the marketing rights to Ranbaxy. Cravit recorded sales of $820m in 2010,
exhibiting 17.5% decline in the sales over previous year.
Merrem (meropenem) – AstraZeneca
Merrem is a broad spectrum, beta lactamase resistant carbapenem drug developed by Dainippon Sumitomo,
and licensed to AstraZeneca. The drug acts by inhibits bacterial cell synthesis. Merrem is indicated for
treatment of multiple infections including lower RTIs, UTIs, gynecological infections, bacterial meningitis ,
septicemia, and complicated/uncomplicated skin and skin structure infections caused by a range of grampositive, gram-negative and anaerobic bacteria. In 2010, Merrim captured 1.9% of the antibacterials market
by generating sales of $817m, a Y-o-Y decline of 6.3%.
Cubicin (daptomycin) – Cubist
Cubicin was approved in September 2003 for the treatment of complicated SSSIs caused by gram-positive
microorganisms including both susceptible and resistant strains of S. aureus (MSSA and MRSA). Cubicin
38
was the first of the cyclic lipopeptides drugs, which work by binding bacterial cell membranes and causing
depolarization of membrane potential. As a result, protein, DNA, and RNA synthesis is inhibited thus leading
to cell death. In May 2006, the FDA approved an expanded label for Cubicin for the treatment of S. aureus
bloodstream infections (bacteremia), including right-sided infective endocarditis caused by MRSA and
MSSA. In January 2006, Cubicin received approval from the EMEA for the treatment of cSSSIs where the
presence of gram-positive bacteria is confirmed or suspected. Prior to approval, Cubist entered a licensing
agreement with Chiron for the development and commercialization of Cubicin in the UK. Chiron subsequently
launched the product in the UK and the Netherlands in March 2006 and in Germany in April 2006.
In December 2006, Cubist licensed development and commercialization rights of Cubicin to AstraZeneca in
China and Merck & Co. in Japan. Cubicin will benefit from patent protection in the US through 2019.
Although, the launch of new treatment options against MRSA will compete with Cubicin, the brand is well
placed to sustain sales until its patent expiry. In August 2010, the FDA revealed the association of
intravenous Cubicin with eosinophilic pneumonia and suggested Cubist to include the information in the
"Warnings and Precautions" and "Adverse Reactions, Post-marketing Experience" sections of the drug label.
In 2010, sales of Cubicin grew by 16.2% on the previous year, reaching $625m.
Primaxin (imipenem + cilastatin) – Merck & Co.
Primaxin is a potent broad spectrum antibacterial agent for intravenous administration and is indicated for the
treatment lower respiratory tract infections, UTIs, intra-abdominal infections (IAIs), gynecological infections,
bacterial septicemia, bone and joint infections, SSSIs, endocarditis, and polymicrobic infections. Having been
approved in 1985 in the US, the wide-spectrum of antimicrobial activity of has been the key to the Primaxin’s
success. The brand sales were growing until 2009 due to absence of generic competition, however, post
patent protection sales are eroding radically. Showing a Y-o-Y decline of 11.5%, Primaxin garnered sales of
$610m in 2010.
Zithromax (azithromycin) – Pfizer
Zithromax indicated for the treatment of CAP, was originally developed by Pliva. In 1986, Pfizer aquired
exclusive marketing rights for Zithromax in Western Europe and the US. Zithromax was commercialized in
39
1992 in the US and the product’s commercial success had been driven by its broad efficacy, compliance
advantages, favorable side-effect profile and a range of formulations that cater to a vast spectrum of the
patient population.
The blockbuster status of the Zithromax franchise faltered after the patent expiry across all the major
markets, having first lost patent protection in the US in November 2005, followed by Japan and the majority
of markets in the EU in 2006. In an attempt to extend the lifecycle of Zithromax and to counter the loss in
sales due to generic attrition, Pfizer launched Zmax, a one-dose-only azithromycin treatment for mild-tomoderate acute bacterial sinusitis (ABS) and CAP in adults, which was granted approval in the US and EU in
June and September 2005, respectively. Despite the transfer of a large proportion of its sales force and
marketing expenditure from Zithromax, Zmax has not sold well. Entry of generic azithromycin has also
hampered the market penetration of Zmax. High costs coupled with concerns over adverse events such as
gastrointestinal complications with once-daily dosing regimen has impacted the brand.
Another strategy employed by Pfizer to maintain a share of the azithromycin market was the launch of its
own generic azithromycin through its subsidiary, Greenstone. In November 2005, the FDA approved a
generic version of azithromycin. While Pfizer’s generic azithromycin may enable the company to retain a
comparatively minor share of the macrolide market, sales of the class as a whole are likely to contract due to
increasing resistance. In 2010 Zithromax/Zmax generated sales of $415m, a Y-o-Y decline of 3.5%.
40
Resistors of the antibacterial market
The antibacterial market has a high level of unmet need. Despite this, most pharmaceutical companies are
shifting focus to other therapeutic areas, primarily due to high R&D costs and declining R&D productivity in
addition to the uncertainties in the regulatory regime. In response, the FDA and other regulatory bodies are
planning to provide incentives for companies investing in antibacterial research.
Figure illustrates resistors of the antibacterial market.
Figure :
Antibacterial market resistors
Uncertain regulatory
environment
Empty pipeline
Declining R&D
productivity
Antibacterial market
resistors
Antibiotic resistance
Rising R&D costs
Source: Business Insights
BUSINESS INSIGHTS
Growing antibacterial resistance
The development of antibiotic resistance is a rising global concern in the antibacterial space. Although It
creates a opportunities for the drug industry, as new anti-infectives are constantly needed to target resistant
organisms, it is very challenging for the companies to discover novel products and new classes of antibiotics
for both hospital and community acquired bacterial infections. A major opportunity in antibacterial drug
41
development is in treatment of nosocomial (hospital acquired) infections which are becoming more resistant
and are associated with significant mortality and morbidity. Due to the nature of bacterial infections,
mutations often rapidly lead to the development of drug resistance bacteria over the course of treatment.
Resistance also comes from poor patient compliance and ill-advised use of antibiotics particularly in hospital
settings. The three classes of antibiotic-resistant pathogens that are emerging as a major threat globally are:

methicillin-resistant Staphylococcus aureus (MRSA)

multidrug-resistant (MDR) and pan-drug-resistant (PDR) gram-negative bacteria

MDR and extensively-drug-resistant (XDR) strains of Mycobacterium tuberculosis (MDR-TB and XDRTB).
Although, gram-negative bacteria are less prevalent than MRSA, they cause infections that are difficult to
treat. Although, the strains of Mycobacterium tuberculosis are a growing concern in many emerging counties,
the US and other developed countries is also has reported cases of multi drug-resistant tuberculosis (MDRTB) and extensively drug-resistant tuberculosis (XDR-TB). The treatment for these infections lasts for around
two years and often causes multiple side-effects. Many national health authorities have launched initiatives
to in response to this threat. In April 2011, the Chinese government announced its plans of strict regulation
on antibacterial drugs whilst holding hospital authorities to account for any improper use of antibacterial
drugs.
Roadblocks to attractive antibacterial market
Although antibacterials are a potentially attractive market with significant unmet needs, many pharmaceutical
manufacturers are restricting themselves from developing antibacterial drugs due to low return of investment
as compared with other therapeutic categories. Continuously evolving resistant pathogens not only present a
development challenge, they also shorten the lifecycle of any approved product. The cost and complexities
involved in antibacterial drug development have shifted the investment focus of big pharma companies from
antibacterial to long-term treatment of chronic conditions and vaccines. Moreover, there are many
uncertainties and challenges associated with designing the clinical trials for antibacterial drugs. Guidance
issued by CDER in November 2010 suggested that trial sponsors re-evaluate ongoing and completed non42
inferiority (NI) trials to ensure that there is adequate scientific basis for the effect size of the active control
and the NI margin. This presents a further barrier to approval. This will also be applicable for the clinical trials
which have been reviewed. In the backdrop of failure of large investments to discover novel antibacterial
drugs most of the pharmaceutical companies have exited from antibacterial research, despite a growing
clinical need.
Shrinking antibacterial pipeline
The antibacterial pipeline is relatively empty with few products in late stages clinical development. In the last
three decades only two new classes of antibiotics, oxazolidinones and cyclic lipopeptides, have been
introduced. Small biotech and pharmaceutical companies have started to focus on the antibacterial research
to fill the void, however the majority of the developmental programs have been out-licensed to multinational
companies due to limited financial capabilities of small companies to conduct late-stage clinical trials.
Antibacterials present extra challenges for clinical trials, demanding more complex designs, which reduces
the attractiveness of the area. As discussed in the following section, high regulatory barriers are also
inhibiting the antibacterial pipeline.
Challenging regulatory requirements
The clinical development of an antibacterial drug differs from other therapeutic categories with respect to the
trial design, analysis, and interpretation. There are significant challenges in designing informative, ethical,
and scientifically appropriate clinical trials for antibacterial drugs. For the development of an antibacterial
drug the sponsor has to conduct non-inferiority trials in comparison with a currently registered antibacterial
drugs.
Prior to 2001, a delta value of 15% was used to determine non-inferiority, which means that a new drug
could be up to 15% lower in efficacy than the reference drug and still be within the lower limit of the 95%
confidence interval of the reference products efficacy, and so be deemed non-inferior. Later in 2001, the FDA
recommended use of a delta value of 10%. For many trials this necessitated a doubling of the sample size.
However, the challenge with 10% delta was that by the time clinical trial ended, the comparator would have
changed and the study results will become irrelevant. Following this announcement, most of the companies
43
put their clinical trials on hold which led to the FDA choosing the delta value on a case to case basis. Still the
challenge with conducting non-inferiority trials is defining a margin of inferiority to assess the performance of
the new molecule. In the absence of clinical data of earlier approved drugs, it becomes even more difficult.
Another challenge with conducting clinical trials is enrolling patients, for instance, the requirement of enrolling
patients with serious acute bacterial infection is very challenging as the patient may not be willing to wait for
treatment to be enrolled in the clinical trials and if the patient is treated with antibiotics before enrollment, it
will be difficult to assess the efficacy of the drug being developed. However, to address these challenges, the
FDA has recently published regulatory draft guidelines for multiple indications including community acquired
bacterial pneumonia, use of non-inferiority trials to support antibacterial approval, hospital acquired bacterial
released pneumonia and ventilator associated bacterial pneumonia, and acute bacterial skin and skin
structure infections to clarify the regulatory expectations for antibacterial clinical trials.
44
Drivers of the antibacterial market
The following figure depicts the major drivers of the antibacterial market
Figure :
Drivers of the antibacterial market
Product lifecycle
management through
expanding indications
and formulations
Monoclonal
antibodies (mAbs)
to combat bacterial
infections
Combination
products
Antibacterial market
drivers
Product
differentiation
through
technological
innovations
Product development
partnerships
Source: Business Insights
BUSINESS INSIGHTS
Product lifecycle management through expanding indications and formulations
As the antibacterial market is getting highly competitive, companies are leaving no stone unturned to
maximize the profits from the existing drugs. More often, companies are expanding the indications of the
drug, or issuing their drugs with a new administration route. In antibacterials, oral to intravenous switching is
one of key factors defining the success of the drug. This is primarily because the oral/intravenous switching
enables physicians to initiate intravenous therapy in the hospital and smoothly transition them to the oral
formulation for out-patient usage, which results in early discharge of patients from hospital, thus saving
additional costs associated with extended hospital stays. Physicians also prefer antibiotics which are
available in both the forms as they will not have to change the prescription when the patients are discharged
from hospital. For example, Daiichi Sankyo announced launch of Cravit intravenous injection in Japan, in
45
January 2011. The oral form of Cravit has been marketed in Japan since 1993 and both oral and intravenous
forms were being marketed in other markets including Singapore.
Combination products
Most of the pharmaceutical manufacturers are developing combination products in an aim to broaden activity
spectrum in addition to combating the growing bacterial resistance. Forest Laboratories is developing CAZ104 a combination of ceftaroline and NXL-104, which is presently undergoing Phase II clinical trials for the
treatment of cIAI and cUTI. CAZ-104 has a broad spectrum of activity and is claimed to be effective against
resistant gram-negative infections, including resistant pseudomonas infections. Forest has acquired the US
and Canadian developmental rights to CAZ-104 from Novexel. Cubist is developing CXA-201, a combination
of CXA-101 and tazobactam, as the first-line intravenous therapy for the treatment of multiple serious
nosocomial gram-negative bacterial infections. CXA-201 is presently undergoing Phase II clinical trials. CXA101 is currently being studied in Phase II trials for the treatment of cUTI, while tazobactam is a betalactamase inhibitor.
Product development partnerships
Declining R&D productivity and rising costs are exerting pressure on the pharmaceutical manufacturers to
enter into collaborative partnership with small biotech and research companies. These small companies
usually have strong R&D capabilities but do not have sufficient capital for conducting multicentre late stage
clinical trials. Most of these small companies out-license the product after taking it through the early clinical
development phase. These agreements usually include one-time payment for obtaining the rights in addition
to the milestone payments on completing designated developmental phase and royalties on sales. For
instance, GSK entered into research collaboration agreement with Anacor Pharmaceuticals for the discovery,
development and commercialization of antibacterial and anti-viral drugs in October 2007. While both GSK
and Anacor were responsible for the development of molecules, GSK had an exclusive option to license
each compound from preclinical to further development and commercialization of the drug. In July 2010,
GSK announced its plan to exercise its option to exclusively develop and commercialize GSK2251052
46
(AN3365), a systemic antibiotic with novel mechanism of action with the potential to be the first new class
antibacterial for the treatment of complicated UTIs.
Product differentiation through technological innovations
In the crowded market of antibacterials, manufacturers have to continuously innovate to differentiate their
products from competitors. The innovations could be in the form of a novel mechanism of action, new drug
class or technological innovations. In October 2010, Merck & Co. entered into a research collaboration with
BioRelix to strengthen its antibacterial research capabilities. The collaboration will enable Merck & Co. to
leverage Riboswitch technology, an innovative drug discovery technology, to identify molecules with activity
against multiple bacterial targets. One possible avenue of innovation in the field is the use of nanotechnology
for the treatment of the resistant pathogens such as MRSA. The Institute of Bioengineering and
Nanotechnology and IBM are evaluating the possibility of using nanotechnology for treating bacterial
infections. According to the researchers, the new antimicrobial agents will target the infected area for
systemic delivery of the drug.
Monoclonal antibodies (mAbs) to combat bacterial infections
Growing antibiotic resistance and generic competition has led pharmaceutical manufactures to investigate
biologics as a development area for antibacterials. There are a significant number of monoclonal antibodies
being developed for the treatment of bacterial infections, however the majority of them are still at early stage
of development. Although, researches have been going on from a long time to evaluate the potential of
antibodies for bacterial infections, there are currently no FDA approved antibacterial monoclonal antibody
products.
The present pipeline for monoclonal antibody includes products target to target P. aeruginosa and
Clostridium difficile. Merck’s Phase II compound MK3415A, being developed as an intravenous formulation
for the treatment of C. difficile associated diarrhea, is a combination of MDX1388 and MDX066, two novel
fully human monoclonal antibodies of C. difficile Toxin A and Toxin B respectively. Merck is also evaluating
Staphylococcus aureus antibodies, which is presently in pre-clinical stage of development. Crucell is
evaluating antibacterial antibodies for the treatment and prevention of hospital-acquired bacterial infections
47
using MAbstract technology, which is presently in pre-clinical development. It is believed that mAbs will
command a premium price, thus limiting its administration to cases where present treatment is unavailable or
against resistant pathogens.
Global antibacterial market sales forecast
The global antibacterial market is expected to continue witnessing declining sales in the 7MM, however the
antibacterial market is expected to exhibited modest growth in the emerging markets particularly BRIC
countries. The key brands in the market will continue to face generic competition which will lead to further
sales erosion during the forecast period. The global antibacterial market is expected to witness influx of new
drugs during 2014–2015.
Table :
Leading antibacterial brands sale forecast ($m), 2010–16
Brands
Sales
2010
($m)
Sales
2011
($m)
Sales
2012
($m)
Sales
2013
($m)
Sales
2014
($m)
Sales
2015
($m)
Sales
2016
($m)
CAGR
2005-09
(%)
Levaquin
1,357
347
34
35
34
32
31
-46.8
Zyvox
1,176
1,231
1,255
1,273
1,277
912
614
-10.3
Avelox
984
1,578
1,290
1,309
1,311
944
644
-6.8
Augmentin
966
972
978
982
986
989
991
0.4
Tazocin
952
506
396
325
263
204
178
-24.4
Cravit
820
621
561
506
423
343
268
-17.0
Merrem
817
733
741
749
757
766
773
-0.9
Cubicin
625
716
800
879
947
986
1,010
8.3
Primaxin
610
563
573
571
564
557
544
-1.9
Zithromax
415
397
382
370
359
350
342
-3.2
Others
35,156
36,653
37,748
38,208
38,739
40,033
41,180
2.7
Total
43,877
44,316
44,759
45,207
45,659
46,115
46,576
1.0
Source: PharmaVitae, Business Insights
BUSINESS INSIGHTS
48
Chapter 3 Pipeline analysis
Summary

As commercial opportunity in antibacterials has become progressively more limited due to heightened
competition, increasing genericization and comparatively short treatment regimens, the area is
attracting reduced R&D funding from big pharma companies.

Small pharmaceutical and biotech companies are performing much of the discovery and early
development of antibacterials. Typically these are then out-licensed to big pharma companies for
further development and commercialization.

Community acquired pneumonia (CAP) and hospital acquired pneumonia (HAP) infections are
attracting research interest. Additionally, the majority of companies developing new antibiotics are
targeting cell wall synthesis inhibitors, DNA topoisomerase II inhibitors, ribosomal inhibitors and
methionine tRNA ligase inhibitors.

Quinolones continue to lead the antibacterial pipeline due to their broad spectrum of activity followed by
the glycopeptides which demonstrate efficacy against MRSA and VRE strains.

Of over 199 antibacterial compounds in development, only 28% are in the late stage pipeline (preregistration and Phase III).

Regulatory uncertainty in antibacterials is inhibiting investment in pipeline products.
49
Introduction
This chapter covers key late-stage pipeline drugs, providing analysis of completed and ongoing clinical trials,
with forecast sales through 2016. The chapter also includes key R&D events in the antibacterial market and
profiles of key late-stage/recently launched drugs. The antibacterial market is presently witnessing the
development of drugs targeting hospital and community acquired bacterial infections to address the unmet
need for treating resistant organisms including MRSA and gram-negative infections.
Antibacterial pipeline
Figure
illustrates the global antibacterials pipeline by stage of development. The global antibacterials
pipeline represents a key opportunity for pharmaceutical companies, with over 199 compounds believed to
be in development. However, only 28% of the total drugs being developed forms a part of the late stage
pipeline (Pre-registration and Phase III). The development of innovative drugs is restricted due to the
increased genericization in the industry and strict regulatory guidelines, which drives pharmaceutical
manufacturers to focus on easy to develop and cost effective drugs. In the extreme examples, the patent
protected drugs are even launched only a year earlier or in the year of patent expiry, which results in a major
revenue loss to the company developing the drug as its reduces the exclusivity period of the drug.
50
The global antibacterials’ pipeline by stage of development, 2011
Figure :
Number of pipeline compounds
100
91
90
80
70
60
50
37
40
25
30
27
20
11
8
10
0
Preclinical
Phase I
Phase II
Phase III
Pending
approval
Approved
Phase of development
Note: Includes extended indications trials.
Source: MedTRACK
BUSINESS INSIGHTS
Key events in antibacterial R&D
Optimer to exploit Cubist’s competitive advantage to market Dificid in the US
In April 2011, Optimer announced an exclusive two-year co-promotion deal with Cubist to market Dificid
(fidaxomicin) in the US. Dificid, a macrocyclic antibiotic indicated for the treatment of C. difficile infection,is
currently being reviewed for approval by the FDA. Optimer will be responsible for obtaining FDA approval,
manufacturing, and distribution in the US, while Cubist will deploying its sales force medical affairs team to
market the drug in the US.
Under the terms of the agreement, Cubist will receive quarterly service fees of $3.8m for two years following
the commercialization of Dificid in the US, in addition to $5m in the first year and $12.5m in the second year
subject to achieving mutually agreed annual sales targets. Although, Optimer plans to build its own sales
force of around 100 sales representatives to target 1,100 hospitals, the collaboration is expected to
51
significantly expand the market reach of Dificid by providing access to over 2,000 hospitals accounting for
over 90% of hospital C. difficile cases.
Cubist settles patent infringement litigation with Teva over Cubicin
In April 2011, Cubist announced the settlement of patent infringement litigation of Cubicin with Teva. Under
the settlement Teva will be able to sell a generic version of Cubicin by 2017 (2018, if Cubist obtains a sixmonth extension under pediatric exclusivity rules). However, if any other generics firm enters the market
earlier than Teva will be allowed to enter at that time. Cubicin, generated total sales of over $625m in 2010,
over 90%of which were in the US. The brand is expected to achieve sales of over $1bn before its patent
expiry.
In Q1 2009, Teva submitted an ANDA to the FDA for seeking approval to market a generic version of
Cubicin. Cubist reacted by filing a patent infringement suit against Teva for US Patent 6,468,967 and
6,852,689 expiring in September 2019 and RE39,071 expiring in June 2016. However, to avoid the risk of
losing the court battle, Cubist entered into an agreement with Teva providing rights to market the generic
version after patent expiry of Cubicin.
Merck & Co. intends to strengthen antibacterial research through BioRelix
In October 2010, Merck & Co. entered into a collaboration with BioRelix to strengthen its antibacterial
research capabilities. The collaboration will allow Merck & Co. to leverage Riboswitch, an innovative drug
discovery technology, to identify molecules with activity against multiple bacterial targets. While both the
companies will be responsible for conducting preclinical studies, Merck will undertake the clinical evaluation
of the molecules for further development. Under the terms of the agreement, BioRelix will receive an upfront
fee and research funding in addition to receiving milestone payments and royalties on any approved
products.
GSK exercises its option with Anacor to commercialize GSK2251052
In July 2010, GSK announced its plan to exercise the option to exclusively develop and commercialize
GSK2251052 (AN3365). GSK2251052 is a systemic antibiotic with novel mechanism of action with the
52
potential to be the first new class antibacterial for the treatment of complicated UTIs, complicated intraabdominal infections, HAP and VAP. In early stage studies, GSK2251052 showed robust activity against
multi-resistant gram-negative bacteria without showing any cross resistance to existing antibiotics. Anacor
received an option exercise fee of $15m in addition to receiving developmental and commercialization
milestone payments apart from royalties on product sales.
GSK had entered into research collaboration agreement with Anacor Pharmaceuticals for the discovery,
development and commercialization of antibacterial and anti-viral drugs in October 2007. The agreement
allowed GSK to utilize Anacor's proprietary boron-based chemistry for use against selected targets. While
both GSK and Anacor were responsible for the development of molecules, GSK had an exclusive option to
license each compound from preclinical to further development and commercialization of the drug.
Contingent on achieving certain milestones, Anacor is eligible to receive development and milestone
payments up to $84m in addition to commercial milestones.
Zeftera withdrawn following concerns raised by the FDA and the EMA
The sale of Zeftera (ceftobiprole), a broad-spectrum antibiotic for the treatment of cSSSIs is being
discontinued in Canada following the rejection of the drug by the FDA and the EMA. In 2008 the drug was
positively evaluatied by the FDA, however, the regulator later released its negative opinion about Zeftera in
2009 stating its concern over the conduct of the clinical studies. It is believed that the clinical trials were not
GCP compliant, which raised concerns over the overall results of the trials. The drug was initially developed
by Basilea Pharmaceuticals and licensed to J&J in 2005. However, following the Zeftera’s non-approval, J&J
terminated the agreement with Basilea. While the FDA has indicated that Basilea will have to conduct two
Phase III trials prior to re-filling the drug for approval, the EMA has not disclosed the requirement of obtaining
the marketing authorization. It is expected that it will take more than three years for Zeftera to be available in
major markets.
Durata Therapeutics initiates Phase III trials for dalbavancin
In April, 2011, Durata Therapeutics attained the global rights for the development and commercialization of
its lead candidate dalbavancin, an intravenous lipoglycopeptide indicated for the treatment of acute bacterial
53
SSSIs. In December 2009, Durata acquired the rights to develop and commercialize dalbavancin in almost
all geographies including North America and the European Union from Pfizer, except Japan, which was
acquired from RaQualia in December 2010. In April 2011 Durata initiated a randomized, double-blind, Phase
III trial to compare the efficacy and safety of dalbavancin with vancomycin under a Special Protocol
Assessment (SPA) in agreement with the FDA,. The SPA demonstrates the FDA’s approval of the trial
design.
Leading drugs in development
The following section analyzes the performance and potential of recently approved and most promising latestage drugs in development for the treatment of various antibacterial infections. The following figure
illustrates the key drugs in late-stage development and recently approved status in the antibacterial market.
Figure :
Selected late-stage and recently launched antibacterials
Teflaro
Dificid
omadacycline
delafloxacin
TR-701
Radezolid
ACHN-490
CXA-201
Phase II
Phase III
Source: Business Insights
Approved/ filed
BUSINESS INSIGHTS
54
Profiles of key pipeline products
Teflaro (ceftaroline fosamil) – Forest Laboratories/Takeda/AstraZeneca
Overview
Teflaro is a fifth-generation cephalosporin which was approved by the FDA for the treatment of communityacquired bacterial pneumonia (CABP), and acute bacterial skin and skin structure infections in October 2010.
Teflaro is N-phosphono prodrug of ceftaroline, a derivative of a fourth-generation cephalosporin. Forest
Laboratories markets the product as Teflaro in the US. In August 2009, Forest Laboratories entered into a
definitive agreement with AstraZeneca to co-develop and commercialize ceftaroline in all markets excluding
the US, Canada and Japan. The drug is expected to dominate the broad-spectrum market due to its
favorable safety and efficacy profile as demonstrated in clinical trials.
Table :
An overview of Teflaro
Brand name
Teflaro
Generic name
ceftaroline fosamil
Company
Forest Laboratories/Takeda/AstraZeneca
Indication
Community-acquired bacterial pneumonia and acute bacterial skin and
skin structure
Mechanism of action
Bacterial cell wall synthesis inhibitor
Status
Approved in the US, pre-registration in EU, Phase III in Japan
Source: Business Insights
BUSINESS INSIGHTS
Clinical
Teflaro has been evaluated in a number of trials: two Phase III clinical trials, FOCUS I and II for CABP, and
two Phase III clinical trials for cSSSI, CANVAS I and II. Teflaro was found to be well-tolerated in all the
clinical trials. Diarrhea, nausea, and rash were the common adverse reactions that occurred in >2% of
patients, administered with Teflaro.
FOCUS I and II studies evaluated Teflaro for the treatment of moderate to severe CABP. The clinical trials
assessed the efficacy, safety, and tolerability of a five to seven day treatment regimen of Teflaro 600mg
55
administered twice daily, in 1,241 patients. While, FOCUS I clinical results demonstrated a clinical cure rate
of 86.6% in Teflaro treated group versus 77.7% for ceftriaxone, FOCUS II studies demonstrated a cure rate
of 82.1% for the Teflaro treated group versus 77.2% for ceftriaxone treated patients in the clinically evaluable
population. Teflaro demonstrated a cure rate of 85.5% in patients infected with Streptococcus pneumoniae,
as compared with 68.6% in ceftriaxone treated patients. However, the company has not disclosed the cure
rates in MRSA patients.
The CANVAS I and II studies evaluated Teflaro in 1,396 adult patients for the treatment of complicated skin
infections caused by gram-positive and gram-negative bacteria. Teflaro demonstrated a clinical cure rate of
91.6% as compared with 92.7% in the vancomycin/aztreonam group. Teflaro achieved a favorable tolerability
profile with relatively low discontinuation rate of 3.0% as compared with 4.8% for the vancomycin treated
patients.
Dificid (fidaxomicin) – Optimer Pharmaceuticals/Astellas/Cubist
Overview
Dificid is a narrow-spectrum macrocyclic antibiotic for the treatment of Clostridium difficile infection (CDI) and
prevention of recurrences while used for treating initial stage of C. difficile infection. The infection is a
common cause of hospital-acquired diarrhea. Optimer Pharmaceuticals submitted the marketing
authorization application to the EMA in July 2010, and filed NDA for Dificid in November 2010. The FDA has
granted six-month priority review to Dificid, and assigned a Prescription Drug User Fee Act (PDUFA) goal
date of May 30, 2011 for the review.
Dificid acts by inhibiting RNA polymerase activity, a bacterial enzyme, which results in the death of C.
difficile. In February 2011, Optimer Pharmaceuticals collaborated with Astellas to develop and commercialize
Dificid in Europe and few Middle East, Africa and the CIS countries. Under the terms of the agreement
Optimer received an upfront payment of €50m ($69.2m) and additional cash payments of €115m after
regulatory and commercial milestones. Moreover, the company will also be entitled to receive royalties on
sales of Dificid. In April 2011, Optimer Pharmaceuticals announced an exclusive two-year agreement with
Cubist to co-market Dificid in the US.
56
Optimer Pharmaceuticals has received a favorable response by the Anti-Infective Drugs Advisory Committee
(AIDAC) for Dificid and the drug is expected to be approved by in 2011. Optimer Pharmaceuticals is also
developing an oral formulation for pediatric C. difficile infection treatment and treatment of patients in
intensive care units and elderly patients.
Table :
An overview of Dificid
Brand name
Dificid
Generic name
Fidaxomicin
Company
Optimer Pharmaceuticals/Astellas/Cubist
Indication
Clostridium difficile infection
Mechanism of action
Bacterial protein synthesis inhibitor, RNA polymerase inhibitor
Status
Pre-registration in EU
Source: Business Insights
BUSINESS INSIGHTS
Clinical
Optimer Pharmaceuticals conducted two multicenter, randomized, double-blind Phase III trials for Dificid.
These studies evaluated a primary endpoint of clinical cure and a secondary endpoint of C. difficile
recurrence up to four weeks post therapy. In both the trials, Dificid achieved the primary endpoint of clinical
cure and demonstrated a lower recurrence rate and higher global cure rate as compared with Vancocin.
Collectively both the studies enrolled 1,165 patients with the diarrhea associated with the infection. While,
Dificid achieved a cure rate of 91.9% vs. 90.2% for Vancocin, recurrence rates were 13.0% for Dificid and
24.6% for Vancocin, and the global cure rates .were 78.6% for Dificid and 66.4% for Vancocin. Additional
data from the second Phase III trial demonstrated significant reduction in recurrence rates and higher global
cure rates as compared with Vancocin in both the hyper-virulent BI/NAP1/027 and the non-BI strain
subgroups. Adverse events reported were similar for both the drugs.
PTK-0786 (omadacycline) - Paratek Pharmaceuticals/Novartis
Overview
57
Paratek Pharmaceuticals is developing Omadacycline, a broad-spectrum antibiotic, as a tablet and
intravenous infusion under a licensing agreement with Novartis. Omadacycline, currently in Phase III, is
being evaluated for the treatment of bacterial infections including cSSSIs, moderate-to-severe CAP, MRSA,
multidrug-resistant
Streptococcus
pneumoniae
(MDRSP)
and
vancomycin-resistant
enterococci.
Omadacycline acts by inhibiting bacterial protein synthesis and efflux mediated tetracycline resistance. In
August 2009, Paratek Pharmaceuticals entered into a collaborative agreement with Novartis to co-develop
and market omadacycline worldwide. Under the terms of the agreement, Paratek will be entitled to receive
milestone payments and royalties in addition to the upfront payment.
Table :
An overview of PTK-0786
Generic name
omadacycline
Company
Paratek Pharmaceuticals/Novartis
Indication
cSSSIs, CABP, MRSA, MDRSP
Mechanism of action
Bacterial protein synthesis inhibitor
Status
Phase III
Source: Business Insights
BUSINESS INSIGHTS
Clinical
Paratek Pharmaceuticals is conducting a randomized, evaluator-blinded, Phase III clinical trial for
omadacycline to compare the safety and efficacy of omadacycline with linezolid for the treatment of adult
patients with cSSSIs. In Phase II trials, omadacycline safety and efficacy was studied against Zyvox in
patients suffering from cSSSIs. The Phase II study was a multi-center, randomized, investigator-blinded,
comparative clinical trial and enrolled 234 patients with cSSSI requiring initial intravenous (IV) therapy.
Patients were randomized to receive up to 14 days treatment of either omadacycline 100mg once-daily IV
with 200mg once-daily oral step-down or Zyvox 600mg twice-daily IV with 600mg twice-daily oral step-down.
Omadacycline achieved the primary safety and tolerability endpoint, and reported no distinct incidence or
adverse events with none of the patients discontinuing the treatment with omadacycline. The clinical cure
58
rate of omadacycline treated patients was higher at 98.0% as compared with a clinical cure rate of 93.2% for
Zyvox in the clinically evaluable population.
RX-3341 (delafloxacin) – Rib-X Pharmaceuticals
Overview
Delafloxacin is being developed by Rib-X Pharmaceuticals under the licensing agreement with Wakunaga
Pharma, for the treatment of cSSSIs. It is a next generation fluoroquinolone and acts by inhibiting the
bacterial DNA gyrase. Delafloxacin is presently undergoing Phase III clinical trials, following positive results
from its Phase II trials, in which it demonstrated a significantly higher activity against gram-positive
organisms, including quinolone-resistant strains and MRSA. The company claims that delafloxacin is 16
times more effective than levofloxacin, ciprofloxacin, gatifloxacin and moxifloxacin against ciprofloxacin
resistant MRSA. Rib-X Pharmaceuticals is developing both oral and intravenous formulations of this
compound.
Table :
An overview of RX-3341
Generic name
Delafloxacin
Company
Rib-X Pharmaceuticals
Indication
Complicated skin and skin-structure infections
Mechanism of action
Bacterial nucleic acid synthesis inhibitor; DNA gyrase inhibitor
Status
Phase III
Source: Business Insights
BUSINESS INSIGHTS
Clinical
Delafloxacin has been examined in 12 Phase I and three Phase II clinical trials that enrolled 1,300 patients
collectively. In both the clinical phases delafloxacin is found to be efficacious and safe. While delafloxacin
intravenous formulation demonstrated superior efficacy in Phase II clinical trial for cSSSI as compared with
tigecycline, its oral formulation showed no evidence of phototoxicity or QTc prolongation in Phase I studies
and demonstrated superior efficacy in both Phase II clinical trials for CAP and bronchitis as compared with
levofloxicin. In the Phase II trials delafloxacin achieved a clinical cure rate of 92.5% to 97.2% vs. 91.2% for
59
Tygacil treated patients in the clinically evaluable population. Delafloxacin was found to be safe and well
tolerated with lower rates of adverse events. In September 2010, while presenting at the 50th Interscience
Conference on Antimicrobial Agents and Chemotherapy, Rib-X Pharmaceuticals announced that among
multiple studies presented at the conference, delafloxacin demonstrated higher potency at the site of
infection as compared with other leading approved drugs including the most difficult to treat fluoroquinolone
resistant gram-positive and resistant gram-negative bacteria.
TR-701 (torezolid phosphate) – Trius Therapeutics/Dong-A Pharmaceutical
Overview
Torezolid phosphate, a second generation oxazolidinone is being developed for acute bacterial skin and skin
structure infections (ABSSSI), in both intravenous and oral formulations. Torezolid phosphate is chemically
different from first generation oxazolidinones reportedly having higher efficacy and a broader spectrum of
activity against serious gram-positive infections, including MRSA. Presently, linezolid is only marketed first
generation oxazolidinone for serious gram-positive infections. The clinical studies suggests that torezolid
phosphate will present strong competition to linezolid, due to its higher efficacy, convenient dosing, shorter
duration of therapy, lower frequency of resistance, activity against linezolid-resistant bacterial strains and
fewer drug interactions. Trius has plans to develop torezolid phosphate for treatment of multiple indications,
including ABSSSI, CABP, HAP, ventilator acquired pneumonia (VAP) and bacteremia. Trius is also
conducting non-inferiority clinical trials in its Phase III studies in compliance with the new protocols outlined
in the FDA draft guidelines for ABSSSI. While, Dong-A Pharmaceutical is developing the drug in Korea, Trius
has the worldwide developmental and commercialization rights to torezolid phosphate.
60
Table :
An overview of TR-701
Generic name
torezolid phosphate
Company
Trius Therapeutics/Dong-A Pharmaceutical
Indication
Acute bacterial skin and skin structure infections
Mechanism of action
Bacterial cell wall synthesis inhibitor
Status
Phase III
Source: Business Insights
BUSINESS INSIGHTS
Clinical
Trius is currently conducting Phase III clinical trials for the treatment of cSSSI infections, following the
favorable results from Phase II trials completed in June 2009. In August 2010, Trius initiated its Phase III
study for torezolid phosphate to evaluate the safety and efficacy of 200mg oral dose once daily for six days
of treatment as compared with oral 600mg Zyvox twice daily for 10 days for the treatment of ABSSSI, a new
classification for cSSSI. Trius is also conducting a special populations study and a study to assess the PK,
safety, and tolerability of TR-701 FA and its active metabolite in adolescents. The primary endpoint measure
was the cessation of spread of skin lesions and absence of fever in 48 to 72 hours. The aim of the trial was
also to evaluate non-inferiority in six day oral torezolid phosphate treatment as compared with that oral 10
day linezolid treatment at 48 to 72 hours. Trius plans to develop the intravenous formulation of torezolid in
ABSSSI, and oral and intravenous formulations for the treatment of CABP, HAP, VAP, bacteremia, and
osteomyelitis.
The Phase II clinical study enrolled 180 patients and evaluated the safety, tolerance, and efficacy of 200mg,
300mg, and 400mg doses of torezolid phosphate once-daily for five to seven days of treatment. Torezolid
phosphate achieved clinical cure rates of 98% for the 200mg dose, 94% for the 300mg dose, and 94% for
the 400mg dose, in the clinically evaluable population. The drug achieved clinical cure rates of 100% when
treated with 200mg dose, 93% with 300mg dose, and 95% with 400mg dose. All the dosage of torezolid
61
phosphate were found to be well tolerated, however some adverse events such as nausea, diarrhea,
vomiting, and headache were also reported.
RX-1741 (Radezolid) – Rib-X Pharmaceuticals
Overview
Radezolid, a novel oxazolidinone antibiotic, is being developed by Rib-X Pharmaceuticals for the treatment
of CAP and uncomplicated skin and skin-structure infections (uSSSI). The drug which is being developed in
both oral and intravenous formulation has a broad spectrum of coverage with increased activity against
gram-positive organisms as compared with other oxazolidinones. Radezolid uses Rib-X’s proprietary
antibiotic discovery process with an aim to achieve broader bacterial spectrum and increased activity against
gram-positive bacteria. Presently, Zyvox (linezolid) is the only marketed oxazolidinone worldwide. Radezolid
is expected to present strong competition to Zyvox, as it has demonstrated a superior microbiological activity
than linezolid against gram-positive bacteria, including potent activity against linezolid resistant bacteria in
the clinical trials.
Table :
An overview of RX-1741
Brand name
Radezolid
Generic name
Radezolid
Company
Rib-X Pharmaceuticals
Indication
Community-acquired pneumonia and uncomplicated skin and skinstructure infections
Mechanism of action
Bacterial cell wall synthesis inhibitor
Status
Phase II
Source: Business Insights
BUSINESS INSIGHTS
Clinical
Radezolid, which is being developed in both oral and intravenous formulations, has completed two Phase II
clinical trials for the treatment of CAP and uSSSI. In the Phase II multicenter randomized double-blind clinical
trial, radezolid was studied to evaluate the safety and efficacy for the treatment of mild to moderate CAP.
The study which enrolled 160 patients, administered three different oral doses of the drug: 300 mg once
62
daily, 450 mg once daily and 450 mg twice daily for seven to 10 days. Radezolid achieved comparable
efficacy across all three doses, with clinical cure rates of 78% to 92% in the clinically evaluable population
and superior activity against multiple CAP bacteria.
In October 2008, Rib-X Pharmaceuticals announced the results from a Phase II clinical trial of radezolid for
the treatment of uSSSI at the 48th ICAAC Infectious Diseases Society of America (IDSA) annual meeting.
The multicenter, randomized, open label, comparative study which enrolled 150 patients evaluated the safety
and efficacy of radezolid in comparison with linezolid for the treatment uSSSI. The open label trial met both
its primary and secondary endpoints. In the poster presentation the company reported the clinical cure rates
of radezolid as 97.4% at a dosage of 450 mg once daily; 94.4% at a dosage 450 mg twice daily; and 97.4%
for patients treated at a dosage of 600 mg twice daily in the clinically evaluable population.
ACHN-490 – Isis Pharmaceuticals/Achaogen
Overview
ACHN-490, a broad spectrum second-generation aminoglycoside, is being developed for the treatment of
multi-drug resistant gram-negative bacterial infections. ACHN-490 acts by inhibiting bacterial protein
synthesis and uses aminoglycoside technology licensed from Isis Pharmaceuticals. In clinical trials, ACHN490 demonstrated broad-spectrum activity against multi-drug resistant gram-negative bacteria, including E.
coli and MRSA.
In January 2006, Isis Pharmaceuticals entered into an agreement with Achaogen to develop and
commercialize ACHN-490 worldwide. Under the terms of the agreement, Isis Pharmaceuticals received an
upfront payment of $1.5m of Achaogen stock, and a milestone payment of $1m in 2009, of which $0.5m in
cash and $0.5m in Achaogen securities. In addition, Isis Pharmaceuticals will receive total milestone
payments of $33.5m following the completion of key clinical, regulatory and sales milestones. The company
will also receive royalties on sales of drug following its approval.
63
Table :
An overview of ACHN-490
Brand name
-
Generic name
-
Company
Isis Pharmaceuticals/Achaogen
Indication
Methicillin-resistant Staphylococcus aureus
Mechanism of action
Bacterial cell wall synthesis inhibitor
Status
Phase II
Source: Business Insights
BUSINESS INSIGHTS
Clinical
In September 2009, Achaogen completed a Phase I study on ACHN-490 and initiated Phase II study in
August 2010. ACHN-490 demonstrated broad spectrum activity against multi-drug resistant gram-negative
bacteria in the in-vitro and in-vivo studies. An international double-blind randomized comparator-controlled
Phase II study is being conducted to evaluate ACHN-490 for the treatment of complicated urinary tract
infections (cUTI). The study, which was initiated in March 2010, aims to enroll 225 patients. The primary
endpoint will be to evaluate the microbiological eradication in modified intent to treat population and
microbiologically evaluable population, while the secondary endpoint will be to assess the clinical cure rate in
cUTI.. Patients will be administered intravenous ACHN-490 at two different doses and compared with
patients receiving a standard approved intravenous treatment for cUTI/acute pyelonephritis (AP). Patients
with a clinical diagnosis of cUTI/AP will be randomly assigned to any one of three treatment regimens. The
study is expected to be completed by November 2011.
CXA-201 (CXA-101/tazobactam) – Cubist Pharmaceuticals
Overview
CXA-201, a combination of CXA-101 and tazobactam, is being developed as a first-line intravenous therapy
for the treatment of certain serious gram-negative bacterial infections prevalent in hospitals, including multidrug resistant (MDR) Pseudomonas aeruginosa. The company believes that the broad spectrum and activity
64
against resistant P. aeruginosa strains will differentiate CXA-201 from currently marketed drugs and compete
heavily with Zosyn.
CXA-201 was added to Cubist pipeline following the acquisition of Calixa Therapeutics in December 2009.
The acquisition gave Cubist the rights to develop and commercialize Calixa’s lead compound, CXA-201, and
other products including CXA-101 (under license from Astellas Pharma) worldwide except select Asia-Pacific
and Middle East countries.
Table : An overview of CXA-201
Brand name
-
Generic name
-
Company
Cubist Pharmaceuticals
Indication
Complicated urinary tract infections, complicated intra-abdominal
infection, nosocomial pneumonia
Mechanism of action
Bacterial cell wall synthesis inhibitor
Status
Phase II
Source: Business Insights
BUSINESS INSIGHTS
Clinical
Cubist is presently conducting Phase II clinical trials of CXA-201 for the treatment of cUTIs and complicated
intra-abdominal Infections (cIAI), and Phase I clinical trials for nosocomial pneumonia (NP). The regulatory
uncertainty on clinical trials requirements for nosocomial pneumonia indication has pushed it behind the cUTI
and cIAI indications. In June 2010, Cubist initiated a multicenter double-blind randomized Phase II study
enrolling 120 patients, to compare the safety and efficacy of intravenous CXA-201 with an active comparator
in patients with cIAI. Cubist aims to file a New Drug Application for CXA-201 by mid 2013.
Pipeline forecast to 2016
Apart from three compounds, most of the pipeline compounds are expected to be launched after 2013.
Business Insights analysis indicates that ceftaroline fosamil and CXA-201 will take a lead over other pipeline
65
drugs by 2016, as these drugs have potential to satisfy key unmet need and have shown higher efficacy
against resistant bacteria.
Table :
Sales forecast for leading drugs in development ($m), 2010–16
Compounds
Generic
Sales
2011
($m)
Sales
2012
($m)
Sales
2013
($m)
Sales
2014
($m)
Sales
2015
($m)
Sales
2016
($m)
Teflaro
ceftaroline fosamil
50
120
200
260
325
426
Dificid
fidaxomicin
–
25
80
95
125
160
PTK-0786
omadacycline
–
20
90
150
180
200
RX-3341
delafloxacin
–
–
–
–
70
100
TR-701
torezolid phosphate
–
–
–
75
125
111
CXA-201
CXA-101/tazobactam
–
–
–
45
135
253
Source: Business Insights
BUSINESS INSIGHTS
66
Chapter 4 Competitive landscape
Summary

GSK’s antibacterial franchise recorded sales of $2.2bn (£1.4bn) in 2010 (a Y-o-Y decline of 4.4%),
accounting for 6.0% to the company’s revenues in 2010.

GSK is adopting a competitive pricing strategy to drive growth in emerging markets. With the reduction
in Zinnat prices by 22% in first quarter of 2010, GSK has reportedly doubled sales volume of in East
Africa.

Zyvox was Pfizer’s leading antibacterial product with 2010 sales of $1.2bn followed by Tazocin
($952m) and Zithromax/Zmax ($415m).

Aiming to reduce costs, Pfizer plans to shift its antibacterial research from US to China.

Of Merck & Co.’s antibacterial products, Avelox and Invanz will to continue to grow strongly patent
expiries in 2013 and 2015 respectively. Primaxin will continue to decline in sales.

Due to the high number of blockbuster off-patent compounds, Novartis is expected to continue
pursuing an aggressive generics development strategy for its antibacterial franchise.

Due to the anticipated sales erosion of Levaquin (levofloxacin), after its patent expiry in June 2011,
Johnson & Johnson shifted its focus on developing US market with Doribax by expanding the drugs
indication to nosocomial infections.
67
Introduction
This chapter focuses on the performance of the five leading players in the global antibacterials market in
2010. It also provides a detailed description of each company's financial performance, key marketed
products, R&D focus and strategic growth analysis.
GlaxoSmithKline
Overview
GSK is a research-based pharmaceutical company, engaged in the manufacture and marketing of
prescription drugs and vaccines. Its prescription drugs range across various therapeutic categories including
anti-infectives, dermatology, women’s health, diabetes, cardiovascular disease, central nervous system
conditions, and respiratory diseases. The company was incorporated in 1999 and is headquartered at
London. GSK is present in over 100 countries through its subsidiaries and most of its research activities are
conducted from its facilities in the UK, US, Belgium and China.
In 2010, GSK was the one of the leading companies in the global antibacterial market with 2010 sales of
$2.2bn (£1.4bn). GSK’s antibacterial portfolio showed a Y-o-Y decline of 4.2% in 2010. The decline was
primary due to decline in sales of Augmentin, GSK’s flagship antibacterial brand, which accounted for 44.8%
of the total antibacterial sales of GSK in 2010. Augmentin was heavily impacted by the generic competition
and garnered sales of $966m (£625m) at a Y-o-Y decline of 6.3% in 2010.
Financial performance
In 2010, GSK achieved total sales of $36.2bn (£23.4bn), a Y-o-Y decline of 1.3%. This decline can be
attributed to revenue lost to generic competition. In 2010, GSK’s antibacterial franchise recorded sales of
$2.2bn (£1.4bn), a Y-o-Y decline of 4.4%. The therapeutic area accounted for 6.0% to the total company’s
revenues. GSK’s antibacterial business is heavily dependent on the emerging markets, from where it
generated 43.6% of its sales in 2010. Europe with 2010 sales of $829m (£536m) and a contribution of 38.4%
remained the other important region for the company. GSK’s antibacterial portfolio demonstrated a decline in
68
sales in all the regions, primarily due to lack of patented products and intensified generic competition.
However, the decline was significantly higher in the US as compared with Europe and emerging markets.
Augmentin, the key product in GSK’s antibacterial portfolio, accounted for 44.8% of the total antibacterial
sales with revenues of $966m (£625m) in 2010. Although, Augmentin also demonstrated a decline in sales in
all the regions in 2010, its relatively lower cost than other branded peers, and strong physician brand
awareness was instrumental in making it one of the leading antibacterial products particularly in emerging
countries.
Marketed product portfolio
GSK’s marketed product portfolio is extensive and features a range of products, the majority of which are
positioned for continued sales growth. GSK's portfolio in the global antibacterial market is led by Augmentin,
a broad-spectrum penicillin antibiotic, however the brand demonstrated a negative Y-o-Y growth of 6.3% in
2010. Other key antibacterial products in the GSK portfolio include Zinnat, Altabax, Fortum and Amoxil.
Table :
GSK's leading antibacterial products ($m), 2010
Product
Generic
Sales
2010
Sales growth
2010 (%)
CAGR
2006–10 (%)
Augmentin
amoxicillin + clavulanate
966
-6.3
2.3
Zinnat
aefuroxime
202
-4.3
-5.4
Fortum
aeftazidime
147
-13.7
-13.6
Amoxil
amoxicillin
124
-0.6
-0.7
Altabax
retapamulin ointment
24
20.3
–
Source: Company reports, PharmaVitae
BUSINESS INSIGHTS
Augmentin (amoxicillin + clavulanate)
GSK's Augmentin is an antibacterial drug launched in 1984 in the US. It is a penicillin antibiotic indicated for
the treatment of pneumonia, bronchitis, sinusitis and urinary tract, ear, and skin infections. Amoxicillin is a
semi-synthetic antibiotic that provides bactericidal activity against a wide range of gram-positive and gramnegative bacteria. The combination of clavulanate and amoxicillin in Augmentin prevents the degradation of
69
amoxicillin by beta-lactamase, effectively extending its spectrum to cover even bacteria that are generally
resistant to amoxicillin. Although, Augmentin can be consumed at any time, absorption of clavulanate
potassium is relatively higher when taken along with food than the fasted state. Augmentin is suitable for
adults as well as pediatric patients over 40kg in weight.
Augmentin recorded sales of $966m (£625m) globally. Most of these sales came from emerging markets
($450m), and Europe ($371m). 2010 US sales were $17m. The brand has been thriving in the emerging
markets owing to its strong brand name and competitive pricing. In first quarter of 2010, GSK reduced the
prices of its antibacterial products particularly Augmentin by around 50% in the emerging countries including
Brazil, China, India, Indonesia and Thailand, which increased sales volumes in these geographies.
Zinnat (cefuroxime)
Zinnat is an oral pro-drug of cefuroxime, a second generation cephalosporin antibiotic. It is a broad spectrum
antibiotic with activity against a range of gram-positive and gram-negative bacteria and acts by inhibiting the
synthesis of the bacterial cell wall. Zinnat is indicated for the treatment of a wide range of respiratory
infections including tonsillopharyngitis, sinusitis, otitis media, and pneumonia in addition to uncomplicated
UTIs, complicated UTIs, SSTIs, acute uncomplicated gonorrhoea and Lyme disease. It is suitable for adult
and patients and pediatric older than three months. Zinnat is found to be resistant to numerous betalactamases produced by bacteria which cause penicillin resistance. The main markets for Zinnat are China,
Turkey, Spain, Poland, Greece, Germany, Romania, Vietnam, Philippines, UAE and Saudi Arabia.
Zinnat’s principal competitors are second-generation cephalosporins such as BMS’ Cefzil. The majority of
these are generic, causing Zinnat to be sold in a price-sensitive market. Zinnat, on account of its
intramuscular formulation also competes with Roche’s Rocephin, which is viewed to be the gold standard
Injectable cephalosporin treatment against which Zinnat suffers from an inferior dosing schedule.
Opportunities for Zinnat remain limited owing to widespread generic competition and new generation
cephalosporins. However, GSK is adopting a competitive pricing strategy to drive the growth of Zinnat in
least developed countries. For instance in East Africa GSK reduced the prices of Zinnat by 22% in the first
70
quarter of 2010 to drive sales growth and the price reduction is believed to have doubled sales volumes of
Zinnat in East Africa.
Altabax (retapamulin ointment)
Altabax, a pleuromutilin antibacterial, is indicated for the treatment of impetigo caused by Staphylococcus
aureus or Streptococcus pyogenes and is suitable for use in patients aged nine months or older. Altabex was
approved in 2007 in the US and Europe and is marketed as Altargo in Europe. Altabex, is a new class of
antibiotic that acts by inhibiting bacterial protein synthesis by binding to the 50S subunit of the bacterial
ribosome thus making it inactive. Altabax has shortened the therapy duration and frequency of application in
and is required to be used twice daily for a five-day period while other prescription topical antibacterials are
used three times daily for up to 12 days. Moreover, it does not show any cross-resistance to other
established classes of antibacterials.
Although, Altabax demonstrated a strong uptake in the first year of launch achieving sales of $17m (£11m), it
faced intense competition in the topical antibiotic market against multiple generic competitors, including
generic mupirocin and fusidic acid. In April 2010, GSK received a warning for Altabax for its misleading
promotional literature which indicated a broader indication, in addition to superiority claims and minimized
important risk information.
Research and development
GSK’s research activities are carried out of its centers located in the UK, US, Belgium and China. The
company has 13,000 employees in R&D, of whom 85% work in pharmaceutical R&D. In 2010, GSK invested
15.7% of the net revenues to R&D activities. Although the company has a robust pipeline with over 30 late
stage compounds, most of its pipeline antibacterial products are in early stage of clinical investigations.
Table details GSK’s antibacterial R&D pipeline.
71
Table :
GSK’s antibacterial R&D pipeline, February 2011
Compound
Mechanism of action
Phase
GSK1322322
Polypeptide deformylase inhibitor
II
GSK2251052
Leucyl t-RNA synthetase inhibitor (oral & iv)
I
Source: Company reports
BUSINESS INSIGHTS
GSK1322322, currently in Phase II, is a novel class antibacterial compound which is being developed in oral
formulation for the treatment of bacterial skin and skin structure infections. It acts by inhibiting bacterial
peptide deformylase (PDF) function. In January 2011, GSK completed a randomized double-blind
multicenter Phase IIa to assess safety, tolerability and efficacy of GSK1322322 vs linezolid for the treatment
of acute bacterial skin and skin structure infections.
GSK is developing GSK2251052 under license from Anacor Pharmaceuticals. GSK2251052 is a novel
boron-based, small-molecule candidate that targets the bacterial enzyme leucyl tRNA synthetase. The
compound is being developed for the treatment of cUTI, complicated intra-abdominal infections, HAP and
ventilator associated pneumonia (VAP). In pre-clinical studies GSK2251052 demonstrated robust activity
against multi-resistant broad range of gram-negative bacteria, including E. coli, Klebsiella pneumoniae,
Citrobacter spp, Serratia marcescens, Proteus vulgaris, Providentia spp, Pseudomonas aeruginosa and
Enterobacter spp. Moreover, it did not show any cross resistance to existing classes of antibiotics.
Strategic and growth analysis
Drivers
GSK2251052 described above could provide a large boost for the company, given that it would represent the
first in a new class of antibacterial drugs
72
GSK’s sale of penicillin manufacturing site in Bristol and divestiture of Augmentin and Amoxil in the US to Dr
Reddy’s would enable GSK to divert its resources and efforts on growing these brands in emerging
geographies. While, Augmentin saw sales erosion in the US after its patent expiry, the product’s sales are
growing in Europe and emerging countries. The company is expected to drive sales in the emerging markets
through aggressive pricing.
Resistors
Generic competition to major antibacterial brands remained the key impediment to growth of the company’s
antibacterial portfolio as a whole, with generic versions of Augmentin, a major blockbuster product exerting a
drag on continued growth. Scrutiny of Altabax for misleading promotional literature described above may be
detrimental in the growth of the brand which is already facing intense generic competition. A further resistor
is that company does not have any late stage compounds in its antibacterial pipeline.
Pfizer
Overview
Pfizer, a global biopharmaceutical company, is engaged in the discovery, development, manufacture and
marketing of prescription medicines, vaccines, nutritional and consumer health products for humans and
animals. The company primarily has two operating business segments including Biopharmaceutical and
Diversified. The Biopharmaceutical segment includes five customer-focused units including, primary care,
specialty care, oncology, established products, and emerging markets. The Diversified segment includes
animal health, consumer healthcare, nutrition and capsugel. Following the acquisition of Wyeth in October
2009, the specialty care customer-focused unit expanded to include vaccines. Pfizer is realigning its
business operations to better identify and address local market dynamics and customer needs.
In 2010, Pfizer generated sales of $67.8bn, including revenue generated through products formerly
belonging to Wyeth. Cardiovascular and metabolic diseases products were the highest contributor to Pfizer’s
total revenues in 2010. Following the acquisition of Wyeth in 2009, the company changed its business unit
structure and antibacterials became a part of the Biopharmaceutical segment.
73
Financial performance
In 2010, the biopharmaceutical segment generated sales of $58.5bn, 28.8% growth over 2008, while the
overall revenues were $67.8bn. This also includes the revenues generated from Wyeth’s operations. Pfizer’s
four key antibacterial products collectively generated sales of $2.9bn in 2010. Zyvox was the leading
antibacterial product with 2010 sales of $1.2bn followed by Tazocin and Zithromax/Zmax which generated
sales of $952m and $415m respectively in 2010.
Marketed product portfolio
Pfizer’s marketed antibacterial product portfolio is overwhelmingly built on the successful antibacterial brands
from Wyeth’s portfolio. Pfizer’s antibacterial franchise was heavily dependent on Zithromax, however after its
patent expiry the brand sales showed significant decline due to generic competition. To compensate the loss
Pfizer also released a generic version of azithromycin across several markets and launched Zmax, a onedose-only azithromycin treatment for mild-to-moderate acute bacterial sinusitis (ABS) and CAP in adults.
Table :
Pfizer's leading antibacterial products ($m), 2010
Product
Generic
Sales 2010
Sales growth
2010 (%)
CAGR
2006–10 (%)
Zyvox
linezolid
1,176
3.1
10.7
Tazocin*
piperacillin +
tazobactam
952
417.4
-0.5
Zithromax/Zmax
azithromycin
415
-3.5
-10.2
Tygacil*
tigecycline
152
232.7
–
Note: *Wyeth products, only Pfizer 2009 sales included.
Source: Company reports, PharmaVitae
BUSINESS INSIGHTS
Zyvox (linezolid)
Pfizer’s Zyvox (linezolid) was initially approved in the US in April 2000 for the treatment of cSSSIs and
nosocomial pneumonia, including those caused by MRSA. Zyvox inhibits protein synthesis through binding to
the ribosomal 50S subunit. In December 2002, Zyvox was approved for use in paediatric patients and
subsequently received approval for diabetic foot infections in July 2003. Marketed in Japan since 2001 for
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the treatment of infections associated Vancomycin Resistant Enterococcus (VRE), Zyvox received approval
for an additional indication in April 2006 for the treatment of infections associated with MRSA. This labelling
extension is expected to further contribute to the strong sales growth of Zyvox across the major
pharmaceutical markets.
Zyvox is available in interchangeable intravenous and oral formulations and currently the only drug available
in both forms for MRSA. The oral formulation of the drug has 100% bioavailability bringing an advantage
over other drugs which are only available in an intravenous formulation. Physicians also prefer Zyvox over
other available drugs as its availability in both oral and intravenous formulation provides a smooth transition
from intravenous administration in hospitals to oral for out-patient usage. In 2010, Zyvox registered sales of
$1.2bn, an increase of 3.1% over previous year, primarily due to growth in emerging markets and Europe.
However, the sales in the US were negatively impacted by stagnant market growth and intense generic
competition.
Tazocin/Zosyn (piperacillin + tazobactam)
Tazocin is an intravenous antibiotic combination product consisting of piperacillin (semi synthetic penicillin)
and tazobactam (beta-lactamase inhibitor). Tazocin is indicated for the treatment of patients with moderate to
severe infections caused by piperacillin resistant, piperacillin/tazobactam-susceptible strains of indicated
organisms. Tazocin administration is limited to hospital settings as it is only available in an injectable
formulation. At the time of its launch, Tazocin was administered as a six times daily intravenous infusion for
the treatment of hospital acquired pneumonia. In 2003, the FDA approved a new dosage regime for Tazocin
which involved a four times daily requirement for the intravenous infusion. This reduction of two doses
resulted in lowering of costs for hospitals in addition to an increase in convenience and comfort for patients.
Fluroquinolones such as moxifloxacin which have demonstrated equivalent efficacy in the treatment of
complicated intra abdominal infections (cIAI) with lower dosing regimens, multiple dosing remains one of the
major disadvantages for Tazocin. Moreover, the brand sales have been eroded due to intensified generic
competition since patent expiry in 2008. Although, Tazocin is expected to encounter generic competition, it
will continue to be a strong brands in the global antibacterial market, primarily due to limited compatibilities of
75
the generics with other drugs in comparison with Tazocin and strong brand recognition. In 2010, the brand
recorded sales of $952m.
Zithromax/Zmax (azithromycin)
Zithromax is indicated for the treatment of CAP and the product’s success can be attributed to its broad
spectrum, compliance advantages, favorable side-effect profile and a range of formulations that cater to a
vast range of the patient population. However, Zithromax sales started to decline after its expiry across all
the major markets in 2005 and 2006. With an aim to extend the lifecycle of Zithromax and counter the loss in
sales due to generic competition, Pfizer launched Zmax, a one-dose-only azithromycin treatment for mild-tomoderate acute bacterial sinusitis (ABS) and CAP in adults, which was granted approval in the US and EU in
June and September 2005, respectively. Despite this, Zmax could achieve limited market penetration due to
the availability of cheaper generic versions of azithromycin.
Pfizer launched its own generic azithromycin through its subsidiary, Greenstone. While Pfizer’s generic
azithromycin enabled the company to retain a comparatively minor share of the macrolide market, the
macrolide class as a whole has been declining due to increased resistance. Zithromax/Zmax generated
sales of $415m, a Y-o-Y decline of 3.5% in 2010. The brand still accounted for 3.5% of the total antibacterial
market in 2010.
Tygacil (tigecycline)
Tygacil, a former Wyeth product, was the first market entrant in a new class of antibiotics, the glycylcyclines,
and received FDA approval in May 2005 in the US and in May 2006 in the Europe. It was initially approved
as a single-agent, intravenous therapy for the treatment of cIAI and cSSSI but was granted approval for
treatment of CABP in adults in March 2009. While Tygacil as a glycylcycline, a new class of tetracyclines, the
drug is a semi-synthetic derivative of minocycline and has demonstrated potent activity against tetracyclineresistant gram-positive and gram-negative pathogens. Due to its unique structure, which enables it to bind
30S ribosomal unit and inhibit protein translation, Tygacil is unaffected by ribosomal alteration and efflux, the
two major mechanisms of tetracycline resistance. As such Tygacil has a broader spectrum of activity than
traditional tetracyclines.
76
However, concerns have ben raised over the increased mortality risk as compared with other drugs which
are being used to treat various serious complications. In September 2010, Pfizer updated the warnings and
precautions and adverse reactions sections of the label following the FDA warning pertaining to the
increased risk of mortality associated with Tygacil. This was later acknowledged by the EU's CHMP and
suggested that the product should be administered only for the treatment of cIAI and cSSSI, and used when
other antibiotics are unsuitable, while closely monitoring patients for the development of superinfections,
specifically pneumonia. In 2010, the product generated sales of $324m, however, the unfavorable safety
profile is expected to negatively impact product sales in the near term.
Research & development
In 2010, Pfizer’s R&D spending was $9.4bn, an increase of 20% over 2009. By the end of 2010 the company
had 24 compounds in Phase III. Apart from developing new products, Pfizer’s research activities are also
focused on improving the effectiveness of the existing products and discovering expanded indications.
Pfizer’s late-stage antibacterial pipeline includes two products: Tygacil which is in Phase II trials for bacterial
pneumonia and moxidectin which is in a Phase III trial for onchocerciasis. The company is planning to shift
its antibacterial research team from the US to China, primarily to reduce costs. Pfizer intends to improve its
margins through reduced labor and infrastructure costs in China.
Strategic and growth analysis
Drivers
Zyvox is the one among the six MRSA drugs to be approved for the treatment for severe bacterial infections.
An additional advantage is its availability in both oral and intravenous formulation for the treatment of
community acquired and hospital acquired pneumonias. The acquisition of Wyeth has also strengthened
Pfizer position in the antibacterial market, with the addition of Tazocin and Tygacil in the antibacterial
portfolio.
Pfizer intends to penetrate in the antibacterial market through expanding indications of its existing products
and through the introduction of new formulations. In November 2010, Pfizer introduced PrZmax SR in
77
Canada, a new antibiotic formulation with once-daily treatment regimen for acute bacterial sinusitis, acute
bacterial exacerbations of chronic bronchitis and mild CAP.
Resistors
Zithromax sales are rapidly declining following the launch of generics in the market. Pfizer’s Zithromax brand
franchise including Zmax recorded a negative CAGR of 10.2% during between 2006 and 2016. Zyvox has
however been at the centre of safety concerns, which showed that Pfizer’s product was associated with an
increasing level of mortality over a range of comparator treatments. Given that Zyvox is being positioned for
an indication with severe unmet need that of bloodstream infections, in which mortality is already high, the
negative findings may be detrimental for Zyvox brand equity.
Pfizer has lost developmental rights of dalbavancin, a novel lipoglycopeptide with activity against grampositive bacteria, to Durata Therapeutics. Durata has initiated the Phase III clinical trials for the drug. Pfizer’s
weak antibacterial pipeline coupled with the loss of dalbavancin is expected to inhibit the growth of Pfizer’s
antibacterial portfolio in the long-run.
Johnson & Johnson
Overview
Johnson & Johnson (J&J), incorporated in New Jersey in 1887, is involved in the research and development,
manufacturing and sale of healthcare related products. It operates through three business segments, namely
consumer, pharmaceutical, and medical devices and diagnostics. The consumer segment primarily includes
baby care, oral care, skin care, wound care and women's healthcare, as well as nutritional and OTC
pharmaceutical products. The pharmaceutical segment comprises products ranging across multiple
therapeutic categories including anti-infectives, antipsychotics, contraceptives, cardiovascular products, and
anti-virals. The pharmaceutical products are distributed directly to retailers, wholesalers and health care
professionals for prescription use. The Medical devices and diagnostics segment includes products which
are primarily used by physicians, nurses, therapists, hospitals, diagnostic laboratories and clinics. With over
250 operating companies, J&J is present in almost all the countries across the globe.
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Financial performance
In 2010, J&J reported total sales of $61.6bn, a decline of 1.3% on 2009. This decline can be attributed to the
sales lost due to OTC product recalls and prevailing generic competition in the pharmaceuticals segment.
The antibacterial franchise showed declining sales due to the sales erosion of J&J’s flagship product
Levaquin, which witnessed a sharp decline of 12.4% in 2010. The decline is primarily due to higher
penetration of generics in the US market as compared with other developed regions. Levaquin sales are
concentrated in the US market, which accounted for over 95% of sales in 2010.
Marketed product portfolio
J&J’s antibacterial franchise is relatively mature with few products retaining patent exclusivity. Revenue
generation of J&J’s antibacterial franchise hinges heavily upon the performance of Levaquin (levofloxacin).
J&J’s doripenem, originally developed by Japanese drug major Shionogi pharmaceuticals, was approved by
the FDA under the brand name Doribax for the treatment of complicated urinary tract and intra-abdominal
infections in October 2007 and has demonstrated a rapid uptake from the first year of its launch.
Table :
J&J's leading antibacterial products ($m), 2010
Product
Generic
Sales
2010
Sales growth
2010 (%)
CAGR
2006–10 (%)
Levaquin
levofloxacin
1,357
-12.5
-3.0
Doribax
doripenem
215
147.3
–
Source: Company reports, PharmaVitae
BUSINESS INSIGHTS
Levaquin (levofloxacin)
Levaquin is the flagship antibacterial brand of J&J and contributed around 2% to the total sales of the
company in 2010. The brand sales were driven by several differentiated indications, particularly multi-drug
resistant strains of CAP, acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis,
nosocomial pneumonia, complicated skin infections, pyelonephritis and prostatitis. The product which is
available as an oral solution, tablet, and intravenous formulation is covered by a composition-of-matter
79
patent through December 20, 2010 held by Daiichi Sankyo, which includes a three-year Hatch-Waxman
extension; the same patent also covers the method of manufacture and its use as an anti-microbial.
However, a pediatric extension granted by the FDA in 2008 has extended the patent exclusivity until June
2011. Levaquin had worldwide sales of $1.4bn in 2010, of which US accounted for over 95% with 2010 sales
of $1.3bn. In 2010, Levaquin sales showed a Y-o-Y decline of 12.4% primarily due to the decline in the
overall antibacterial market and intensified generic competition. Levaquin is expected to suffer from
substantial sales erosion after its patent expiry in June 2011.
Doribax (doripenem)
Doribax, a carbapenem antibiotic, was approved by the FDA for the treatment of complicated urinary tract
and intra-abdominal infections in October, 2007. The drug was first approved in Japan in September, 2005
and launched in a nebulized (inhaled) version in June, 2006. Ortho-McNeil markets Doribax in the US
through its institutional franchise. Doribax inhibits the synthesis of bacterial cell membrane through
inactivating multiple essential penicillin-binding proteins (PBPs). Doribax has been granted approval for the
treatment of nosocomial pneumonia (NP), including ventilator-associated pneumonia (VAP), however, in the
US, the FDA has requested additional information prior to approving Doribax for these additional indications.
Doribax exhibited greater in vitro activity against Pseudomonas aeruginosa isolates and is active against
MRSA with a broader spectrum of activity than the currently marketed carbapenems.
In February 2010, J&J announced that Doribax was recommended for the treatment of certain high-risk
cIAIs, in the January 2010 edition of Clinical Infectious Diseases, an important guidelines publication. The
updated recommendations are expected to help physicians to treat patients with life-threatening bacterial
infections. Witnessing a strong growth of around 150%, the drug garnered sales of $215m in 2010. Doribax
is expected to exhibit strong sales until 2012, and the brand will witness sales erosion thereafter due to its
patent expiry in mid July/September 2012.
Research & development
J&J invested around $7bn in research and development activities in 2010. In emerging markets, J&J’s
research strategy is focused on developing the drugs based on the requirements of the domestic market.
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Although J&J is highly active in research for the treatment of infectious diseases, presently its pipeline is
dominated by antivirals. The company is presently developing Doribax for the treatment of nosocomial
pneumonia in the US. While it was approved for the treatment of nosocomial pneumonia in the Europe in
2008, the FDA requested J&J to conduct additional clinical trials to gain approval in the US.
Doribax conducted two multicenter, open-label, randomized, active-controlled Phase III trials to assess the
efficacy of the drug against nosocomial pneumonia. The FDA Advisory Committee found 500mg dosage of
Doribax at one-hour and four-hour infusion regimens safe and effective for the treatment of nosocomial
pneumonia and VAP. However, the committee suggested that Doribax did not demonstrate sufficient noninferiority margin for nosocomial pneumonia and requested additional studies to gain approval. Doribax has
demonstrated a strong sales uptake in the first year of its launch. Approved for nosocomial pneumonia would
provide strong sales boost.
Strategic and growth analysis
Drivers
Current growth in J&J’s antibacterial franchise is driven by the performance of the Levaquin (levofloxacin),
which continues to maintain patent exclusivity until June 2011. The performance of this franchise is expected
to be boosted by Doribax, its latest new antibacterial product. The company is presently developing Doribax
for the treatment of nosocomial pneumonia in the US, which would be strong driver for the company..
Resistors
J&J’s current growth driver, Levaquin, is expected to lose patent exclusivity in June 2011. The brand is
expected to witness a sharp decline in sales due to potential at-risk launch by generic drug manufacturers.
J&J was developing ceftobiprole, a novel cephalosporin antibiotic for the treatment of cSSTIs, with activity
against MRSA and pathogens resistant to vancomycin, under licensing agreement with Basilea. However,
after the rejection of ceftobiprole by the FDA, J&J returned the global developmental rights to Basilea. It was
a major setback for J&J’s weak antibacterial pipeline.
J&J has shifted its focus from antibacterial to anti-viral research. Under the licensing agreement with Furiex
Pharmaceuticals, J&J had an option to regain rights to JNJ-Q2, an investigational broad-spectrum
81
fluoroquinolone
antibiotic,
however
the
company
granted
the
developmental
rights
to
Furiex
Pharmaceuticals. It has been reported that antibacterial are a low R&D priority for J&J..
Merck & Co.
Overview
Merck & Co. is one of the leading pharmaceutical companies worldwide, with a diverse product offering
across a broad range of therapeutic areas, a strong pipeline and extensive global reach. In 2009, Merck and
Schering-Plough merged. The company has only one reportable segment: Pharmaceuticals which includes
human health pharmaceutical and vaccine products. Merck & Co. has a worldwide presence and markets its
products either directly or through joint ventures.
Merck & Co. has a strong infectious diseases product portfolio, however it is dominated by anti-viral drugs.
The key antibacterial products in its marketed portfolio are Primaxin, Avelox and Invanz. The sales of
Primaxin have been declining sharply since its patent expiry and approval of multiple generics. Avelox is a
broad-spectrum fluoroquinolone antibiotic and demonstrated a strong growth in 2010. Merck & Co. markets
Avelox only in the US.
Invanz is a broad-spectrum carbapenem antibiotic and its unique antimicrobial
spectrum makes it more suitable for community-acquired infections and outpatient intravenous therapy.
Financial performance
Merck’s total 2010 sales were $46.0bn and the three key antibacterial brands accounted for 4.3% of the
company’s total revenues with 2010 sales of around $1.2bn. Primaxin was the leading product in Merck’s
antibacterial product portfolio with 2010 sales of $610m followed by Invanz and Avelox with sales of $362m
and $316m in 2010. Among the key antibacterial brands, Primaxin was the only drug to witness an 11.5%
decline in sales in 2010, as both Avelox and Invanz are patent protected and expected to show strong sales
growth until the patent expiries in 2013 and 2015 respectively.
Marketed product portfolio
The key marketed products in Merck & Co.’s portfolio are listed below.
82
Table :
Merck & Co.'s leading antibacterial products ($m), 2010
Product
Generic
Sales
2010
Sales growth
2010 (%)
CAGR
2006–10 (%)
Primaxin
imipenem +
cilastatin
610
-11.5
-3.5
Invanz
ertapenem
362
23.5
27.0
Avelox
moxifloxacin
316
378.8
–
Source: Company reports, PharmaVitae
BUSINESS INSIGHTS
Primaxin (imipenem + cilastatin)
Primaxin, a broad-spectrum beta-lactam antibiotic, is indicated for the treatment of serious lower RTIs, UTIs,
intra-abdominal infections, gynecologic infections, and SSTIs caused by a range of gram-positive and gramnegative bacteria. The drug is a combination of imipenem and the dehydropeptidase inhibitor, cilastatin in a
50:50 ratio. Primaxin can either be administered intravenously or intramuscularly, and has a twice-daily
dosing regimen. While, imipenem targets penicillin-binding proteins, inhibiting the synthesis in bacterial cellwall, Cilastatin acts by inhibiting dehydropeptidase-I, the renal enzyme that metabolizes and inactivates
imipenem, thus improving urinary recovery of imipenem. Primaxin has been losing sales to Merrem due to a
more limited range of indications than Merrem. While Primaxin is believed to be more efficacious for treating
gram-positive bacteria, Merrem is considered to be highly efficacious against gram-negative bacteria. The
growing incidence of gram-negative infections, is working in favor of Merrem over Primaxin. Moreover, the
brand has also lost patent exclusivity in all geographies. Primaxin is expected to witness further sales
erosion in the near term. In 2010, the brand recorded sales of $610m, a decline of 11.5% over 2009.
Invanz (ertapenem)
Invanz is a broad-spectrum, parenteral carbapenem antibiotic with activity against cephalosporin-resistant
bacteria and anaerobes. Invanz was approved by the FDA in November 2001 and is administered once
daily. Carbapenems have traditionally been reserved for second-line treatment of nosocomial infections
especially extended-spectrum betalactamase (ESBL) producing Klebsiella species which are resistant to
83
beta-lactam anti-infectives including cephalosporins. However, Invanz is being used as a first-line agent.
Invanz is indicated for the treatment of intra-abdominal infections, cSSSIs, complicated UTIs, acute pelvic
infections and diabetic foot infections. The bactericidal activity is demonstrated by targeting PCBs thus
inhibiting the bacterial cell-wall synthesis. Invanz recorded sales of $362m in 2010 and is expected to see
strong growth until the loss of exclusivity in 2016.
Avelox (moxifloxacin)
Bayer/Schering-Plough’s Avelox is indicated for skin and skin structure infections. Avelox carries more
strongly worded warnings against heart rhythm disturbances than do its competitors in this class, however
Avelox is not associated with phototoxicity. Loss of market share to ciprofloxacin generics has been less in
the US than in other markets, given that Cipro is used mainly for urinary tract infections and Avelox for
respiratory tract infections. In June 2005, Avelox was granted an additional indication for the treatment of
skin and skin structure infections, which increased the market opportunity for Avelox. The brand recorded
sales of $316m in 2010 and is expected to achieve peak sales in 2013, thereafter the sales will decline due
to patent expiry in Q1 2014.
Research & development
In 2010, Merck & Co.’s R&D spending was $8.1bn, which accounted for 18.2% of the total revenues
recorded by the company. Merck’s R&D activities are focused on multiple therapeutic categories including
infectious disease, oncology, cardiovascular disease, diabetes and obesity, respiratory disease, immunology,
and dermatology, neurosciences, ophthalmology, women's health and endocrine. The company presently
has only two antibacterial compounds in development. In infectious diseases the company’s research is
focused on anti-virals and vaccines.
84
Table :
Merck & Co.’s antibacterial R&D pipeline, February 2011
Compound
Mechanism of action
Phase
MK 3009 (daptomycin)
Bacterial cell membrane
permeability inducer
Filed in Japan
MK3415A
Clostridium difficile toxin
binder
II
Source: Company reports
BUSINESS INSIGHTS
MK 3009 (daptomycin) is a novel lipopeptide indicated for the treatment of cSSSIs caused by gram-positive
bacteria including MRSA. The drug is approved and being marketed in all major markets including the US
and Europe, however the drug is presently filed for approval in Japan. In 2007, Merck & Co. and Cubist
entered into a licensing agreement for the development and commercialization of daptomycin in Japan.
Banyu, Merck's wholly owned local subsidiary is developing MK 3009. The drug is expected to exhibit the
same strong sales growth as it has seen in the other markets.
Merck is also developing MK3415A, a combination of MDX1388 and MDX066 (or CDA-1 and CDB-1) for the
treatment of C. difficile associated diarrhea. MDX1388 and MDX066 are two novel fully human monoclonal
antibodies of C. difficile Toxin A and Toxin B respectively. MK3415A is being developed as an intravenous
injectable formulation and is presently undergoing Phase II clinical trials.
Strategic and growth analysis
Drivers
Avelox and Invanz are the major drivers of Merck & Co.’s antibacterial franchise The brands are patent
protected until 2013 and 2015 respectively and are expected to exhibit strong growth in the coming years.
Additionally, as mentioned above, if the company can secure approval for daptomycin in Japan the drug is
likely to drive uptake and growth Furthermore, Merck is developing MK 3415A, a combination of monoclonal
85
antibiodies, which is expected to expand its prescription base, as no monoclonal antibodies have been
approved for antibacterial infections so far.
Resistors
Merck & Co.’s antibacterial brand Primaxin has been losing sales to Merrem due to its limited range of
indications than Merrem. The growing incidence of gram-negative infections, is working in favor of Merrem
than Primaxin as Primaxin is believed to be more effective against gram-positive infections. Moreover, the
brand has been negatively impacted by generics following its patent expiry in 2009.
Novartis
Overview
Novartis is engaged in research, development and manufacturing of healthcare products including branded
and generic pharmaceuticals, vaccines and non-prescription consumer healthcare products. It operates
through four divisions: Pharmaceuticals, Vaccines and Diagnostics, Sandoz (generics) and Consumer
healthcare. Novartis operates in approximately 140 countries and is headquartered at Basel, Switzerland. In
2010, Novartis garnered total sales of $50.6bn, an increase of 14% over 2009. The pharmaceutical division
was the largest division, contributing 60% of revenues in 2010.
Financial performance
Novartis recorded total revenues of $50.6bn, witnessing a Y-o-Y increase of 14% in 2010. Revenues derived
from Novartis’ marketed antibacterial product portfolio are heavily weighted towards generic antibacterials.
The expanded indication approval of Cubicin for the treatment of both methicillin-sensitive and resistant
Staphylococcus aureus (MSSA and MRSA) bloodstream infections (bacteraemia) and heart infections have
added to the company’s growth.
Marketed product portfolio
Novartis markets a range of generic antibacterial, including branded and generic versions of Augmentin
(amoxicillin clavulanate) as well as amoxicillin, ampicillin, cefazolin and penicillin. Novartis, which also
markets Cubicin in the Europe, gained the rights through acquisition of the Chiron Corporation.
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Tobi (tobramycin)
Tobi (tobramycin) is an aminoglycoside which has been available for intravenous administration since 1975.
Originally developed by PathoGenesis, Chiron acquired Tobi through acquisition in August 2000. Tobi has
been approved as an inhaled antibiotic for the treatment of cystic fibrosis (CF) and is indicated to treat P.
aeruginose infections, a common cause of lung infections in CF patients. Tobi continues to be the gold
standard inhaled antibiotic therapy among the CF patient population, registering sales of $279m in 2010.
Coupled with the product’s established clinical profile, Tobi also maintains a competitive advantage due to
the drug’s inhalation route of administration, which targets drug delivery to the site of infection in the lung.
Tobi is currently used in combination with the Pari LC Plus reusable nebulizer and a DeVilbiss Pulmo-Aide
air compressor, which deliver high concentrations to the site of infection while minimizing systemic toxicities.
Whilst highly efficacious, the costs associated with this delivery system are high when compared with
competing products such as Genentech's Pulmozyme (dornase alfa).
Research & development
Innovations are the core of Novartis’ R&D activities and its pharmaceutical R&D pipeline has 143 projects in
clinical development. In 2010, Novartis invested 16% of its total net sales in R&D. However, Novartis’
antibacterial pipeline is relatively weak with two key antibacterial compounds in clinical development, PTK
0796 and Tobi-TIP.
Table :
Novartis’ antibacterial R&D pipeline
Compound
Mechanism of action
Phase
PTK 0796
Bacterial Protein Synthesis Inhibitor
III
Tobi-TIP
Clostridium difficile toxin binder
Pending approval in Europe and
Phase III in other geographies
Source: Company reports
BUSINESS INSIGHTS
PTK 0796 (omadacycline), a broad-spectrum antibiotic, is being developed as tablet and intravenous infusion
under a licensing agreement with Paratek. Omadacycline, currently in Phase III, is being studied for the
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treatment of bacterial infections including complicated skin and skin structure infections, moderate-to-severe
community acquired bacterial pneumonia, MRSA, multidrug-resistant Streptococcus pneumoniae (MDRSP)
and vancomycin-resistant enterococci. Omadacycline is expected to be studied for other potential indications
including CABP.
Novartis is extending its Tobi franchise with the developmental drug Tobi-TIP, a powder formulation of
tobramycin that is inhaled directly into the lungs using a T-326 inhaler. Tobi-TIP uses Nektar's Advanced
Pulmonary Delivery technology for the treatment of Pseudomonas aeruginosa infections in cystic fibrosis
patients associated lung infections. In September 2009, the drug was approved in the EU, and is expected to
be filed in 2011 in the US.
Strategic and growth analysis
Drivers
Novartis’ has signed an exclusive worldwide collaborative licensing agreement with Paratek, for the
development, manufacture and commercialization for its lead broad-spectrum antibiotic, PTK 0796. It is the
only once-daily, oral and intravenous MRSA active compound in clinical development. Tobi’s extended
franchise, Tobi-TIP is also expected to expand the market for Novartis as it is administered through a
handheld device which offers convenience. Cubicin is also expected to drive growth of Novartis antibacterial
portfolio due to superior efficacy and patent protection through 2019.
Novartis markets a range of key antibacterial products including branded and generic versions of Augmentin
(amoxicillin clavulanate) as well amoxicillin, and penicillin. Although the majority of these products are
expected to grow, however, the profit margins are very low and the sales are difficult to sustain due to
intense competition. Due to the high number of blockbuster off-patent compounds, Novartis is expected to
continue pursuing an aggressive generics development strategy in its antibacterial franchise.
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Resistors
Although Novartis has taken steps to further develop and reinvigorate its small antibacterials portfolio,
dependence on in-licensing and acquisitions may inhibit growth. The company is plowing its efforts into
research in vaccines rather than antibacterials.
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Appendix
Scope
The Antibacterial Market Outlook to 2016 provides comprehensive coverage of the global antibacterial
market, incorporating disease overview and detailed epidemiological analyses of the major indications. This
report makes a comprehensive assessment of the marketed product portfolios, R&D pipelines, sales
forecast, and the competitive landscape for the major players. Further, this report highlights the key market
challenges and drivers, and R&D events, with a thorough analysis of the competitive dynamics of leading
brands to enable you to identify growth brands, key drug classes and leading players through to 2016.
Key diseases covered in this report

bacterial infections

respiratory tract infections

urinary tract infections

skin and skin structure infections

gynecological infections
Market size methodology
The leading products and companies in the global antibacterial market were identified using companyreported sales sourced from PharmaVitae and company annual reports. Where applicable, reference was
also made to multiple secondary resources, in-house databases, scientific journals, and analyst reports to
derive additional insights into currently marketed drugs.
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Epidemiology
The epidemiology of relevant indications is derived from the cohort studies. The epidemiology forecast is
extrapolated based on the cohort studies and forecast population changes sourced from the US Census
Bureau. The forecast does not take into account any genetic, cultural, environmental, social, or racial
changes to population demographics that could have an impact on disease epidemiology in the various
markets.
Market forecast
To forecast future market sizes, regression analysis was used to establish a forward-looking baseline trend.
This baseline was then adjusted to take into account future events that are not reflected by the historical
trend. Examples of these events include:

The launch of new products, with peak sales forecasts based on expected patient numbers and
expected price.

Patent expirations, generic competition, any ongoing patent litigation, or restricted label warnings (black
box warnings).

Product extensions based on superior administration/dosage profiles, expanded indications, or postmarketing studies.

For biologics, the likely entry of biosimilars/follow-on biologics in the developed (mostly the US and EU)
and developing countries, and the competitive dynamics that these may introduce post-approval.

Special consideration is also given to the impact of first-in-class, novel drugs that result in a paradigm
shift in the treatment algorithm in therapy areas and diseases with significant unmet medical need.
Abbreviations
7MM:
Seven major markets
ABS:
Acute bacterial sinusitis
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ABS:
Acute bacterial sinusitis
ABSSSI:
Acute bacterial skin and skin structure infections
AIDAC:
Anti-infective drugs advisory committee
AP:
Acute pyelonephritis
BV:
Bacterial vaginosis
CABP:
Community-acquired bacterial pneumonia
CAP:
Community acquired pneumonia
CE:
Clinically evaluable
CF
Cystic fibrosis
cIAI:
Complicated intra-abdominal infections
cUTIs:
Complicated urinary tract infections
GIs:
Gynecological infections
IAIs:
Intra-abdominal infections
ICAAC:
Interscience conference on antimicrobial agents and chemotherapy
LRTIs:
Lower respiratory tract infections
MDR:
Multidrug-resistant
MDRSP:
Multidrug-resistant streptococcus pneumoniae
MRSA:
Methicillin-resistant staphylococcus aureus
MSSA
Methicillin-sensitive staphylococcus aureus
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NP:
Nosocomial pneumonia
PBPs:
Penicillin-binding proteins
PDF:
Peptide deformylase
PDR:
Pan-drug-resistant
PDUFA:
Prescription Drug User Fee Act
QD:
Once daily
RI:
Respiratory infections
ROI:
Return on investment
SSSIs:
Skin and skin structure infections
TB:
Tuberculosis
UTIs:
Urinary tract infections
VAP:
Ventilator acquired pneumonia
VAP
Ventilator-associated pneumonia
VRE:
Vancomycin-resistant enterococci
VRE:
Vancomycin resistant enterococcus
XDR:
Extensively-drug-resistant
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