The Antibacterials Market Outlook to Competitive landscape, pipeline analysis, and growth opportunities

Transcription

1 The Antibacterials Market Outlook to 2016 Competitive landscape, pipeline analysis, and growth opportunities Reference Code: BI Publication Date: May

2 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 This report is published by Business Insights (the Publisher). This report contains information from reputable sources and although reasonable efforts have been made to publish accurate information, you assume sole responsibility for the selection, suitability and use of this report and acknowledge that the Publisher makes no warranties (either express or implied) as to, nor accepts liability for, the accuracy or fitness for a particular purpose of the information or advice contained herein. The Publisher wishes to make it clear that any views or opinions expressed in this report by individual authors or contributors are their personal views and opinions and do not necessarily reflect the views/opinions of the Publisher. 2

3 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

4 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

5 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 GSK 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 Chapter 4 Competitive landscape 67 Summary 67 Introduction 68 GlaxoSmithKline 68 Overview 68 Financial performance 68 5

6 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

7 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

8 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, Figure 4: Selected late-stage and recently launched antibacterials 54 8

9 Table of tables Table 1: Incidence of community acquired pneumonia infections in the 7MM, Table 2: Incidence of upper respiratory tract infections caused by streptococcus infection in the 7MM, Table 3: Incidence of community acquired urinary tract infections in the 7MM, Table 4: Incidence of bacterial skin and skin structure infections in the 7MM, Table 5: Prevalence of bacterial vaginosis infections in the 7MM, Table 6: Forecast epidemiology of community acquired pneumonia infections in 7MM, Table 7: Forecast epidemiology of upper RTIs caused by streptococcus infection in 7MM, Table 8: Forecast epidemiology of urinary tract infections in 7MM, Table 9: Forecast epidemiology of skin and skin structure infections in the 7MM, Table 10: Forecast epidemiology of bacterial vaginosis in the 7MM, Table 11: Leading antibacterial drug classes with their mechanism of action 32 Table 12: Leading brands in the global antibacterial market ($m), Table 13: Leading antibacterial brands sale forecast ($m), Table 14: An overview of Teflaro 55 Table 15: An overview of Dificid 57 Table 16: An overview of PTK Table 17: An overview of RX Table 18: An overview of TR Table 19: An overview of RX Table 20: An overview of ACHN Table 21: An overview of CXA Table 22: Sales forecast for leading drugs in development ($m), Table 23: GSK's leading antibacterial products ($m), Table 24: GSK s antibacterial R&D pipeline, February Table 25: Pfizer's leading antibacterial products ($m), Table 26: J&J's leading antibacterial products ($m), Table 27: Merck & Co.'s leading antibacterial products ($m), Table 28: Merck & Co. s antibacterial R&D pipeline, February Table 29: Novartis antibacterial R&D pipeline 87 9

10 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 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 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

11 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

12 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 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

13 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

14 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 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

15 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

16 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

17 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

18 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

19 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 : 2010 Incidence of community acquired pneumonia infections in the 7MM, Country Incidence (000s) Incidence (%) Share (%) France Germany 1, Italy Spain UK Total 5EU 3, US 3, Japan Total 7MM 7, Source: CDC, WHO BUSINESS INSIGHTS 19

20 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 % 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 (%) France 9, Germany 12, Italy 8, Spain 6, UK 9, Total 5EU 47, US 49, Japan 18, Total 7MM 115, 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

21 Urinary tract infections Estimates of the incidence of UTIs across the seven major markets are summarized in the table below. Table : 2010 Incidence of community acquired urinary tract infections in the 7MM, Country Incidence (000s) Incidence (%) Share (%) France 6, Germany 10, Italy 6, Spain 5, UK 6, Total 5EU 36, US 22, Japan 11, Total 7MM 70, 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

22 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 : 2010 Incidence of bacterial skin and skin structure infections in the 7MM, Country Incidence (000s) Incidence (%) Share (%) France 2, Germany 3, Italy 2, Spain 1, UK 2, Total 5EU 13, US 12, Japan 5, Total 31, 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

23 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, Germany 6, Italy 4, Spain 3, UK 5, Total 5EU 24, US 43, Japan 7, Total 7MM 70, 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 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

24 Table : 7MM, Forecast epidemiology of community acquired pneumonia infections in Country France Incidence (000s) Incidence (%) Germany Incidence (000s) 1,027 1,027 1,036 1,036 1,036 1,044 1,044 Incidence (%) Italy Incidence (000s) Incidence (%) Spain Incidence (000s) Incidence (%) UK Incidence (000s) Incidence (%) EU Incidence (000s) 3,044 3,052 3,090 3,097 3,104 3,142 3,148 Incidence (%) US Incidence (000s) 3,401 3,430 3,491 3,521 3,551 3,613 3,643 Incidence (%) Japan Incidence (000s) Incidence (%) Total 7MM Incidence (000s) 7,245 7,276 7,382 7,412 7,441 7,546 7,574 Incidence (%) Source: Business Insights BUSINESS INSIGHTS 24

25 Table : 7MM, Forecast epidemiology of upper RTIs caused by streptococcus infection in Country France Incidence (000s) 9,743 9,789 9,897 9,941 9,984 10,090 10,131 Incidence (%) Germany Incidence (000s) 12,425 12,428 12,513 12,514 12,513 12,594 12,591 Incidence (%) Italy Incidence (000s) 8,733 8,741 8,806 8,810 8,812 8,871 8,870 Incidence (%) Spain Incidence (000s) 6,658 6,680 6,746 6,765 6,782 6,842 6,854 Incidence (%) UK Incidence (000s) 9,551 9,593 9,698 9,742 9,786 9,894 9,939 Incidence (%) EU Incidence (000s) 47,210 47,331 47,758 47,869 47,972 48,384 48,476 Incidence (%) US Incidence (000s) 49,466 49,892 50,636 51,069 51,503 52,260 52,697 Incidence (%) Japan Incidence (000s) 18,949 18,910 18,991 18,938 18,879 18,940 18,869 Incidence (%) Total 7MM Incidence (000s) 116, , , , , , ,875 Incidence (%) Source: Business Insights BUSINESS INSIGHTS 25

26 Urinary tract infections Table : Forecast epidemiology of urinary tract infections in 7MM, Country France Incidence (000s) 6,995 7,028 7,123 7,155 7,186 7,280 7,310 Incidence (%) Germany Incidence (000s) 10,106 10,108 10,192 10,193 10,193 10,274 10,272 Incidence (%) Italy Incidence (000s) 6,903 6,910 6,974 6,977 6,979 7,038 7,037 Incidence (%) Spain Incidence (000s) 5,317 5,335 5,397 5,412 5,425 5,482 5,492 Incidence (%) UK Incidence (000s) 6,840 6,870 6,963 6,994 7,026 7,121 7,153 Incidence (%) EU Incidence (000s) 36,091 36,183 36,584 36,668 36,747 37,073 37,144 Incidence (%) US Incidence (000s) 22,569 22,763 23,274 23,473 23,672 24,194 24,397 Incidence (%) Japan Incidence (000s) 11,700 11,676 11,774 11,742 11,705 11,790 11,746 Incidence (%) Total Incidence (000s) 70,212 70,512 71,560 71,850 72,134 73,172 73,443 Incidence (%) Source: Business Insights BUSINESS INSIGHTS 26

27 Skin and skin structure infections Table summarizes the forecast incidence of skin and skin structure infections over the period to Table : Forecast epidemiology of skin and skin structure infections in the 7MM, Country France Incidence (000s) 2,623 2,635 2,711 2,723 2,734 2,810 2,821 Incidence (%) Germany Incidence (000s) 3,479 3,480 3,563 3,563 3,563 3,646 3,645 Incidence (%) Italy Incidence (000s) 2,478 2,481 2,541 2,543 2,543 2,602 2,602 Incidence (%) Spain Incidence (000s) 1,877 1,883 1,934 1,939 1,944 1,994 1,997 Incidence (%) UK Incidence (000s) 2,588 2,599 2,673 2,685 2,697 2,773 2,785 Incidence (%) EU Incidence (000s) 13,045 13,078 13,422 13,453 13,482 13,824 13,850 Incidence (%) US Incidence (000s) 12,985 13,097 13,524 13,640 13,755 14,194 14,313 Incidence (%) Japan Incidence (000s) 5,341 5,330 5,444 5,429 5,412 5,519 5,498 Incidence (%) Total Incidence (000s) 31,371 31,505 32,390 32,522 32,650 33,537 33,661 Incidence (%) Source: Business Insights BUSINESS INSIGHTS 27

28 Gynecological infections Table 10 summarizes the forecast prevalence of bacterial vaginosis to Table : Forecast epidemiology of bacterial vaginosis in the 7MM, Country France Prevalence (000s) 4,996 5,020 5,106 5,129 5,151 5,237 5,258 Prevalence (%) Germany Prevalence (000s) 6,627 6,628 6,712 6,713 6,712 6,794 6,793 Prevalence (%) Italy Prevalence (000s) 4,071 4,075 4,137 4,139 4,140 4,199 4,198 Prevalence (%) Spain Prevalence (000s) 3,128 3,138 3,193 3,202 3,210 3,262 3,268 Prevalence (%) UK Prevalence (000s) 5,546 5,570 5,657 5,683 5,709 5,797 5,824 Prevalence (%) EU Prevalence (000s) 24,847 24,911 25,284 25,342 25,397 25,763 25,812 Prevalence (%) US Prevalence (000s) 43,592 43,968 44,660 45,042 45,425 46,131 46,516 Prevalence (%) Japan Prevalence (000s) 7,631 7,615 7,723 7,701 7,678 7,777 7,748 Prevalence (%) Total Prevalence (000s) 70,212 70,512 71,560 71,850 72,134 73,172 73,443 Prevalence (%) Source: Business Insights BUSINESS INSIGHTS 28

29 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 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

30 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 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

31 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 However, all the major drug classes including cephalosporins, penicillins and fluoroquinolones witnessed declining sales in GSK, Pfizer, Johnson & Johnson (J&J) and Merck & Co. were the leading players in the global antibacterial market in Tazocin, Levaquin, Augmentin, Zyvox, and Avelox were the key brands accounting for 12.4% of the total antibacterial market in Market analysis by drug class The major drug classes in the antibacterial therapeutic category include: cephalosporins penicillins fluoroquinolones macrolides carbapenems. 31

32 Table : Leading antibacterial drug classes with their mechanism of action Drug class Mechanism of action Drugs Brands Cephalosporins Penicillins Fluoroquinolones Macrolides Carbapenems Cell wall synthesis inhibitors Cell wall synthesis inhibitors Nucleic acid synthesis inhibitors Protein synthesis inhibitors Cell wall synthesis inhibitors ceftobiprole, ceftaroline cephalexim, cefixime piperacilin, flucloxacillin gatifloxacin, moxifloxacin, levofloxacin clarithromycin, telithromycin, azithromycin meropenem, imipenem Rocephin, Fortum, Suprax, Flomox, Zinnat, Keflex Augmentin, Zosyn, Amoxil, Tazocin, Floxapen Avelox, Levaquin, Tavanic, Cravit, Ciproxin Zithromax, Klacid, Clarith, Azithromycin, Dalacin, Ketek 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

33 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

34 Leading brands dynamics The key 10 brands in the global antibacterials market generated sales of $8.7bn accounting for 19.9% of the market in J&J s Levaquin was the largest brand with a share of 3.1% in the global antibacterial market followed by Pfizer s Zyvox (2.7% ) and Merck & Co. s Avelox (2.2%). Table : Leading brands in the global antibacterial market ($m), 2010 Brands Generic name Sales 2010 ($m) Sales growth 2010 (%) Market share 2010 (%) CAGR (%) Levaquin levofloxacin 1, Zyvox linezolid 1, Avelox moxifloxacin Augmentin amoxicillin + clavulanic acid Tazocin piperacillin + tazobactam * Cravit levofloxacin Merrem meropenem Cubicin daptomycin Primaxin imipenem + cilastatin Zithromax azithromycin Key brands total 8, Others 35, Total 43, 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

35 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 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 In 2010, sales of Levaquin declined to $1.4bn, a contraction of 12.5% on 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 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 Zyvox was approved for MRSA in Japan in 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