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Frontier Pharma: Antibiotics - Identifying and Commercializing First-in-Class Innovation

Published: Dec-2014 | Format: PDF | GBI Research | Number of pages: 91 | Code: MRS - 6659

An Extensive Developmental Pipeline, but Limited First in Class Innovation

The antibiotics pipeline is very active, with 741 products in development. Of these, the majority (85%) are at the Discovery or Preclinical stages and have not yet entered human trials. Such a high proportion of drugs at the earliest stages of development would, in other indications, provide hope of a steady stream of drugs due to advance through the stages of development and be approved within the next decade. However, the development of antibiotics, particularly the progression of drug candidates from Discovery to human trials, is notoriously difficult, with only 12 new antibiotics approved since 2000. Of these pipeline drugs, the distribution of molecular targets is very limited, with the majority having targets observed among marketed products.

Reflecting this trend is the fact that despite the large pipeline, first-in-class drug development is minimal, with only 10% of pipeline drugs acting on a first-in-class target. This distribution reflects the pipeline, in which 85% is at either Discovery or Preclinical. Three first-in-class drugs are at Phase I, eight are at Phase II, but none are at Phase III. These 75 drugs act on 38 first-in-class targets.

Diversity is low among these 38 targets, of which 21, acted upon by 39 products, have mechanisms of action that can be classified under the broad modes of action common to established classes of antibiotics. One of the most common is protein synthesis inhibitors, under which eight first-in-class targets can be grouped. Other categories include RNA and DNA synthesis inhibitors, as well as bacterial cell wall and membrane disruptors. Of the drugs targeting first-in-targets, clinical trial data regarding their safety and efficacy are limited, with the majority of drugs being at either the Discovery or Preclinical stages of development. As such, firm conclusions can only be drawn on a select number of targets. Those with the most promising results include inhibitors of UDP2 epimerase, Methionine tRNA synthase, the FtsZ proteins, and NDM-1 beta lactamase.

Many of the targets under these categories were highlighted by research into conserved genomes of bacteria, driven by a desire to generate antibiotics with as broad a spectrum of use as possible. These studies have uncovered a plethora of targets that act upon mechanisms not yet utilized in the treatment of bacterial infection. It was hoped that high-throughput screens against these targets would lead to the development of novel classes of antibiotics; however, since the 1990s, only four new classes of antibiotics have been approved. With the failure of the genomic approach and the fact that the natural sources of many bacteria are thought to be exhausted, many companies have left the field altogether. However, incentives to draw pharma back to the field, and methods of improving success with compound searches, as outlined in this report, provide hope for the future.

A Moderate Number of Deals and Strategic Consolidations, but Little Interest in First-in-Class Products

Deals involving antibiotics are common, with 266 conducted from 2006–2014. Of these, the majority were licensing deals (64%), with 46% conducted once the product was marketed. This reflects the fact that drug development in antibiotics is relatively simple and has easy-to-assess endpoints, reducing the requirement of co-development deals to develop an antibiotic successfully once a strong lead candidate has been identified.

Deal values varied widely from $4.3m to $480m, but most were below $100m. Only 19% of deals were completed before the drug entered human trials, again supporting the theory that drug development in antibiotics does not require significant investment.

Reflective of the lack of first-in-class targets in the developmental pipeline, only six deals involve drugs against first-in-class targets. Two deals were conducted at Phase I, two at Phase II and one at an undisclosed Phase. No robust trends can be drawn from such limited data. However, with all disclosed deals conducted after the drug has entered human trials, it can be speculated that the historic trend in the failure of identified chemicals to translate into lead compounds strongly deters potential investors from investing in first-in-class compounds. With few first-in-class compounds in the current developmental pipeline, 80% of which are at Discovery or Preclinical, few deals involving first-in-class drugs are expected to be announced within the next few years.


  • The report covers and provides - 
  • A brief introduction to antibiotics, including profiles of clinically relevant infectious strains, bacteria virulence, and an overview of pharmacotherapy
  • Highlights of the changing molecular target landscape between market and pipeline, focusing on points of innovation
  • An overview of how innovation products are contributing to the pipeline and market for antibiotics
  • A comprehensive review of the pipeline for first-in-class therapies, analyzed on the basis of Phase distribution, molecule type, molecular target, and route of administration
  • Identification and assessment of first-in-class molecular targets with a particular focus on early-stage programs of which clinical utility has yet to be evaluated, as well as literature reviews of novel molecular targets
  • Assessment of the licensing and co-development deals for antibiotic therapies

Reasons to buy

  • The report provides the following - 
  • Understanding of the overall focal shifts in the molecular targets in the antibiotics pipeline
  • Understand of the distribution of pipeline programs by Phase of development, molecule type and molecular target
  • Scientific and clinical analysis of first-in-class developmental programs
  • Assessment of the valuations of licensed and co-developed antibiotic treatments
  • A list of first-in-class therapies potentially open to deal-making opportunities
  • Analysis of financial valuations on licensed or co-developed first-in-class therapies and generics

1 Table of Contents 2

1.1 List of Tables 3
1.2 List of Figures 3

2 Executive Summary 4

2.1 A Low Degree of First-in-Class Innovation in a Very Active Pipeline 4
2.2 A low Diversity in the Mechanisms of Action of First-in Class Targets 4
2.3 A High Number of Deals Involving Antibiotics, but Few involving First-in-Class Targets 5

3 The Case for Innovation in Antibiotic Development 6

3.1 Diversification of Molecular Targets 6
3.2 Growing Opportunities for Biological Products 6
3.3 Innovative First-in-Class Product Developments Remain Attractive 7
3.4 Regulatory and Reimbursement Policy Shifts Favor First-in-Class Product Innovation 7
3.5 Financial Incentives 8
3.6 Report Guidance 8

4 Clinical and Commercial Landscape 9

4.1 Etiology 9
4.1.1 Adherence to Host Cells and Biofilm Formation 9
4.1.2 Toxins and Toxin Secretion Systems 11
4.1.3 Ability to Evade the Host Immune System 12
4.2 Pathophysiology 12
4.3 Traditional Antibiotic Development and Associated Mechanisms of Action 13
4.3.1 Overview 13
4.3.2 DNA Synthesis and Transcription Machinery 15
4.3.3 RNA Synthesis Arrest 15
4.3.4 Disruption of Cell Wall Stability of Formation 16
4.3.5 Disruption of Cell Membrane Formation and Stability 17
4.3.6 Disruption of Cell Metabolism 17
4.3.7 Inhibition of Protein Synthesis 17
4.4 Mechanisms of Antibiotic Resistance 19
4.4.1 Target Modification 19
4.4.2 Efflux Pumps 19
4.4.3 Enzymatic Inactivation of Antibiotics 20
4.4.4 Changes to Outer Membrane Permeability 20
4.5 Treatment Algorithm 21
4.6 The Future of Antibiotic Development 22

5 Assessment of Pipeline Product Innovation 26

5.1 Antibiotic Pipeline by Phase, Molecule Type and Molecular Target 26
5.2 Antibiotic Pipeline by Mechanism of Action 27
5.3 First-in-Class Pipeline Programs Targeting Novel Molecular Targets 31

6 First-in-Class Target Evaluation 35

6.1 Pipeline Programs which Target Lipoteichoic Acid or Lipoteichoic Acid Synthase 35
6.2 Pipeline Programs which Target Pseudomonas Aeruginosa Lectins LecA and LecB 37
6.3 Pipeline Programs which Target Sortase A 38
6.4 Pipeline Programs which Target Pyruvate Kinase 41
6.5 Pipeline Programs which Target UDP-N-acetylglucosamine 2-epimerase 43
6.6 Pipeline Programs which Target Peptide Deformylase 44
6.7 Pipeline Programs which Target LpxC enzyme 46
6.8 Pipeline Programs which Target Sialic Acid Transporter TRAP 48
6.9 Pipeline Programs which Target Methionine tRNA Ligase 49
6.10 Pipeline Programs which Target FtsZ Protein 51
6.11 Pipeline Programs which Target Clostridium Difficile Toxins A and B 53
6.12 Pipeline Programs which Target Staphylococcus Enterotoxins A and B 55
6.13 Pipeline Programs which Target NDM-1 Beta Lactamase 56
6.14 Pipeline Programs which Target DegS Serine Endoprotease 57
6.15 Pipeline Programs which Target A Disintegrin and Metalloproteinase 10 59
6.16 Pipeline Programs which Target Translocase-1 60

7 Patent Filings 63

8 Deals and Strategic Consolidations 65

8.1 Industry Wide First-in Class Deals 65
8.2 Antibiotics Deals Landscape 66
8.3 Licensing Deals 67
8.3.1 Molecule Type and Mechanism of Action 69
8.4 Co-Development Deals 72
8.4.1 Molecule Type and Mechanism of Action 73
8.5 First-in-Class Programs Not Involved in Licensing or Co-Development Deals 77

9 Appendix 79

9.1 Abbreviations 79
9.2 References 79
9.3 Contact Us 91
9.4 Disclaimer 91

Table 1: Market for Antibiotics, Global, Bacterial Species Specifically Mentioned in Chemical Entity Patent Families, (2003–2012) 63
Table 2: Organizations Frequently Applying for Antibiotic Chemical Entity Patent Families, 2003–2012 64
Table 3: Abbreviations 79
Figure 1: Colorectal Cancer Therapeutics, Global, European Society for Medical Oncology Treatment Guidelines (Colorectal Cancer at Stage I to III) 18
Figure 2: Colorectal Cancer Therapeutics, Global, European Society for Medical Oncology Treatment Guidelines (Colorectal Cancer at Stage IV) 19
Figure 3: Colorectal Cancer Therapeutics, Global, Heat Map (Marketed Products) 32
Figure 4: Colorectal Cancer Therapeutics, Global, Pipeline by Stage of Development and Program Type, 2014 33
Figure 5: Colorectal Cancer Therapeutics, Global, Pipeline by Molecule Type and Stage of Development, 2014 34
Figure 6: Colorectal Cancer Therapeutics, Global, Pipeline by Mechanism of Action and Stage of Development, 2014 36
Figure 7: Colorectal Cancer Therapeutics, Global, Clinical Trial Failure Rate (%), 2014 38
Figure 8: Colorectal Cancer Therapeutics, Global, Clinical Trial Size, 2014 40
Figure 9: Colorectal Cancer Therapeutics, Global, Clinical Trial Duration (months), 2014 42
Figure 10: Colorectal Cancer Therapeutics, Global, Treatment Use Patterns (‘000) and Market Size ($bn), 2013–2020 50
Figure 11: Colorectal Cancer Therapeutics, US and Canada, Treatment Use Patterns (‘000), 2013–2020 51
Figure 12: Colorectal Cancer Therapeutics, US and Canada, Annual Cost of Therapy ($), 2013–2020 52
Figure 13: Colorectal Cancer Therapeutics, US and Canada, Market Size ($m), 2013–2020 53
Figure 14: Colorectal Cancer Therapeutics, Top Five European Markets, Treatment Use Patterns (‘000), 2013–2020 54
Figure 15: Colorectal Cancer Therapeutics, Top Five European Markets, Annual Cost of Therapy ($), 2013–2020 55
Figure 16: Colorectal Cancer Therapeutics, Top Five European Markets, Market Size ($m), 2013–2020 57
Figure 17: Colorectal Cancer Therapeutics, Japan, Treatment Use Pattern, 2013–2020 58
Figure 18: Colorectal Cancer Therapeutics, Japan, Annual Cost of Therapy, 2013–2020 59
Figure 19: Colorectal Cancer Therapeutics, Japan, Market Size ($m), 2013–2020 60
Figure 20: Colorectal Cancer Therapeutics, Global, Licensing Deals by Geography, 2006–2014 63
Figure 21: Colorectal Cancer Therapeutics, Global, Licensing Deals by Phase, Value, Mechanism of Action, 2006–2014 64
Figure 22: Colorectal Cancer Market, Global, Co-development Deals by Geography and by Value, 2006–2014 66
Figure 23: GBI Research Market Forecasting Model 103

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