Therapeutic focus - Anti-infectives market shrinking as new superbug fears emerge

Stories of superbugs rampaging unchecked are normally guaranteed a fair amount of attention in the mainstream press; a report in The Lancettoday highlighting growing concern about a strain of particularly nasty bacteria proved no exception. These baddies have a specific gene, called NDM-1, which confers resistance to most antibiotics, even some of the toughest, carbapenems, which are mainly reserved as treatments of last resort.

Given the seemingly growing prevalence of bacteria carrying this gene and lack of new agents in the pipeline able to mount a fight, the paper's authors believe they represent a major global health problem. Anti-infectives have certainly been largely neglected for many years and although some companies are now paying more attention to the field, such as GlaxoSmithKline and AstraZeneca, many scientists remain concerned about the implications of a lack of research. It is undeniable that the value of the market has been in gradual decline since 2003, with few significant products in the late stage pipeline (see tables below). As such real breakthroughs in the fight against these new superbugs could well be on the distant horizon.

Market decline

According to EvaluatePharmadata, the market for systemic anti-infectives peaked in value in 2003, recording sales of almost $20bn. Last year the market was worth $16bn, a figure that will shrink to $12bn by 2016, the table below shows.

Biggest anti-infectives in 2016 WW Sales ($m)
Rank Product Generic Name Pharma class Company Patent Expiry 2009 2016
1 Augmentin IR amoxicillin & clavulanate potassium  Penicillin & beta-lactamase inhibitor GlaxoSmithKline Jul 2002 1,044 950
2 Cubicin daptomycin Lipopeptide Cubist Pharmaceuticals Jun 2016 524 837
3 Doribax doripenem Carbapenem Johnson & Johnson Jun 2015 167 634
4 PPI-0903 ceftaroline fosamil Cephalosporin Forest Laboratories/AstraZeneca Dec 2018 - 615
5 Tygacil tigecycline Glycylcycline Pfizer Apr 2016 61 580
6 Merrem meropenem Carbapenem AstraZeneca Jun 2010 872 509
7 Zyvox linezolid Oxazolidinone Pfizer May 2015 1,141 501
8 Zithromax azithromycin Macrolide Pfizer Nov 2005 430 359
9 Tazocin/Zosyn piperacillin sodium & tazobactam sodium Penicillin & beta-lactamase inhibitor Pfizer Feb 2007 184 354
10 Invanz ertapenem sodium Carbapenem Merck & Co May 2016 293 316
Total market 15,693 12,187

Several former blockbusters such as Cipro and Zithromax losing patent protection and the absence of big brand replacements can be blamed for the erosion of market value. The table shows where analysts see the top end of the market in 2016, it is interesting to see that none are forecast to be blockbusters.

What will remain big sellers, financial analysts believe, are the carbapenems Doribax and Merrem. Professor Tim Walsh of Cardiff University, the main author of the report published today, raised concerns in several press interviews about the medical community's chances in fighting infections should resistance to this class emerge more widely.

Professor Walsh also claims there are no antibiotics in the pipeline with activity against NDM-1 bacteria, a worrying situation if this resistance strain spreads as quickly as he predicts.

The Lancet report mentions that only two drugs, colistin and Pfizer's Tygacil (tigecycline), have shown efficacy against NDM-1 producing bacteria. Tygacil is forecast as the fifth biggest anti-infective in 2016, with $580m in projected sales.

A review of pipeline data from EvaluatePharma indeed confirms no pipeline anti-bacterial agent has yet been disclosed as targeting NDM-1 bacteria. Although the pipeline overall appears relatively well stocked, with 97 candidates in clinical stage development and 290 in active development in total, the lack of research into agents that target NBM-1 needs to be addressed.

Count of anti-bacterial pipeline products
Status Count
Filed 6
Phase III 19
Phase II 37
Phase I 41
Pre-clinical 106
Research project 81
Total 290

Gram negative threat

It certainly seems that new approaches are going to be required to overcome mounting bacterial resistance. The bacteria found so far to be carrying the NDM-1 gene are gram-negative, and these in particular Professor Walsh believes could pose the major threat in the future, in contrast to gram positive bacteria such as MRSA that have been the focus of much of the recent research into anti-infectives. The added obstacle in treating gram-negative bacterial infections is due to the presence of an outer membrane around the bacterial cell wall that a drug must permeate.

Glaxo, which has historically had a big presence in this field with Augmentin, is certainly making some significant and seemingly well-timed moves in this regard.

Last week, the company and research partner the Wellcome Trust demonstrated a novel genomic approach to developing antibacterial agents. The two parties reported that they had elucidated the x-ray crystal structure image of a novel topoisomerase IIa inhibitor, GSK 299423, bound to topoisomerase, an enzyme that processes bacterial DNA involved in replication. The compound binds to a different, but adjacent, domain to quinolones, a large class of antibiotic against which drug resistance has developed. The images not only support its potential for broad-spectrum efficacy, but also against antibiotic-resistant targets, the companies believe.

Glaxo and Wellcome showed their compound to be potently active against resistant Gram-positive bacteria, such as MRSA, and resistant Gram-negative bacteria such as E. coli, Pseudomonas, and Klebsiella, some of which have been found to express the NDM-1 gene.

In a separate move in this area last week, Glaxo exercised an option to license GSK2251052 (GSK’052; AN3365), a first-in-class systemic antibiotic against multidrug-resistant gram-negative bacteria, from Anacor Pharmaceuticals. The companies began collaborating in late 2007 to discover novel antibacterial and antiviral compounds using Anacor’s proprietary boron chemistry-based technology.

Modest interest

Yet Glaxo's recent moves and AstraZeneca's deals with Forest Laboratories and Novexel last year for ceftaroline, currently one of the most promising anti-bacterial pipeline candidates, masks an underlying theme of declining interest in the field, if the numbers of product deals in the last ten years can be used as a yardstick (Astra steps back on M&A path with Novexel deal, December 24, 2009).

According to EvaluatePharma, the numbers of deals for pipeline stage assets peaked at the same time as the overall market value, with 29 product deals in 2003, yet just eight deals were struck last year. It seems it may take further high profile and headline-grabbing reports on the depth and breadth of the bacterial resistance problem for interest and significant investment to return.

Product deals for pipeline stage anti-bacterial agents
Year Product Count
2010 (YTD)  5
2009  8
2008  15
2007  13
2006  13
2005  14
2004  26
2003  29
2002  15
2001  13
2000  14
Total 165

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