- Email: [email protected]
Antibiotic development pipeline slows to a trickle
Newsdesk
Antibiotic development pipeline slows to a trickle New antibiotics are needed as part of the global effort to tackle antimicrobial resistance, but WHO warns that few are in development. Talha Burki reports. For WHO’s report on the antibiotic pipeline see http://www.who.int/medicines/ areas/rational_use/antibacterial_ agents_clinical_development/en/ For more on WHO’s priority pathogen list see http://www. who.int/medicines/publications/ global-priority-list-antibioticresistant-bacteria/en/
1128
A new report by WHO has laid bare the scarcity of the antibacterial drug pipeline. The report focused on the 12 families of antibioticresistant bacteria on WHO’s global priority pathogen list as well as tuberculosis. It noted that there are only 33 new antibiotics currently in clinical development that target these infections. The situation for Gram-negative bacteria is particularly dire. 12 agents in the current pipeline show activity against the carbapenem-resistant pathogens Acinetobacter baumannii, Pseudomonas aeruginosa, and the Enterobacteriaceae family. These three pathogens have been identified as crucial priorities by WHO, and the five antibiotics targeting them in phase 3 trials are all modifications of existing classes. Excluding bedaquiline and delamanid, which have already obtained conditional market approval, the pipeline for tuberculosis is made up of a mere seven new antibiotics, only one of which is in phase 3 trials. Nine antibiotics in the pipeline satisfy one of the following conditions: absence of crossresistance to existing antibiotics, new chemical class, new target, or new mechanism of action. Only two of these antibiotics show activity against Gram-negative bacteria. The authors of the WHO report estimate that about ten new antibiotics are likely to enter the market over the next 5 years, a woefully inadequate number given the need. 86% of phase 1 compounds are not developed further, so of the ten agents targeting Gram-negative bacteria at this stage, no more than one or two are likely to gain market authorisation. “It is a crisis, and this report really shows how the innovation model is broken”, said Otto Cars (Uppsala University, Uppsala, Sweden).
When WHO first released its list of priority pathogens in February 2017, the omission of tuberculosis proved to be controversial. The new report firmly establishes tuberculosis within the drug-resistance agenda, but considers it separately from the infections on the priority pathogen list.
“...of the ten agents targeting Gram-negative bacteria...no more than one or two are likely to gain market authorisation.” Peter Beyer (WHO, Geneva, Switzerland) notes that the tuberculosis community has built up enormous experience in addressing drug-resistance, and their response can help guide efforts for the other priority pathogens. “We have had the opportunity to think hard about some of the problems that are now being talked about with antimicrobial resistance”, agrees Grania Brigden (The International Union Against Tuberculosis and Lung Disease, Geneva, Switzerland). “Tuberculosis programmes have been working on building surveillance systems in an effort to try to get data on the epidemic and the state of resistance, and ensuring the availability of antibiotics at the lowest levels of health care”. The 2011–2015 Global Plan to Stop TB envisaged an expenditure of US$3·7 billion on drug discovery and development over the 5-year period. In the event, less than a third of this sum was delivered. “The situation for tuberculosis research and development is really symptomatic of antimicrobial resistance and infective research and development more generally”, said Brigden. Last year, WHO and the Drugs for Neglected Diseases initiative launched
the Global Antibiotic Research and Development Partnership (GARDP), a product development partnership analogous to the TB Alliance. GARDP intends to secure €270 million to fund its activities until 2023. Several European nations, led by Germany, along with South Africa and the Wellcome Trust have already pledged over €56 million. “We hope this will create a momentum for other countries to support our work in the future”, said Jean-Pierre Paccaud (GARDP, Geneva, Switzerland). The immediate priorities will be to deliver new therapies for neonatal sepsis and gonorrhoea. In July 2017, GARDP entered a partnership with biotechnology company Entasis Therapeutics to bring zoliflodacin, a drug from an entirely new class of antibiotics, into a phase 3 trial for treatment of gonorrhoea. “Say it costs around $30–50 million to put such a drug through phase 3 trials—if the trial is successful then for not very much money, at least in terms of drug development, you can help a new, innovative antibiotic go from phase 2 to marketing approval”, notes Beyer. The CARB-X project is backed by seven partners in the USA and UK. It was set up in 2016 and has secured about half a billion dollars to advance the preclinical antibiotic pipeline. “They are investing in companies worldwide who have innovative approaches in the preclinical phase, with aim of pushing products into phase 1”, explained Beyer. “It is a very important initiative, because often these smaller companies do not have the money to get to the next stage”. Nonetheless, although funding has historically proved to be a major obstacle, the scientific barriers are formidable. In the 1960s and 1970s, the pharmaceutical industry spent
www.thelancet.com/infection Vol 17 November 2017
billions of dollars searching for promising lead compounds with scant success. “Finding antibiotics with new mechanisms of action, that overcome all the resistance mechanisms that bacteria across various species have developed over millions of years, is an astonishing scientific challenge”, concedes Paccaud. GARDP ’s Antimicrobial Memory Recovery Programme will revisit failed and discontinued research, both to avoid duplication and to pick up any promising leads that may have been deprioritised for, for example, strategic reasons. “The real bottleneck is the early stages”, said Cars. “We need to do far more to solve the scientific challenges by creating new incentives and open collaborative partnerships to get new molecules.” Cars believes this will be best achieved by a greater emphasis on push mechanisms. He cites the example of the ENABLE project, run by the Innovative Medicines Initiative,
and focused on Gram-negative bacteria. It is a consortium of partners in academia and industry dotted across Europe, who share the costs of preclinical development. “In principal this system could be looked upon as a model for tackling these difficult bottlenecks”, said Cars. 2018 should see the launch of the Life Prize (formerly the 3P Project), an attempt to kickstart the development of new antibiotics and treatment combinations for tuberculosis using a coordinated system of research grants, prizes, and pooled intellectual property. Plans to establish the Global Antimicrobial Resistance Collaboration Hub were announced at the July 2017 meeting of the G20 countries. The aim is to “work with existing groups to promote collaboration, sharing of information, and a means to invest funding more efficiently”. Since 2009, when Sweden hosted an international conference to draw attention to the
Doncaster and Bassetlaw Hospitals/Science Photo Library
Newsdesk
issue of antimicrobial resistance, there has been a steady build-up of momentum. The WHO report gained a great deal of international attention, as did last year’s O’Neill report. “But things are still not moving fast enough”, stressed Cars. “The state of the pipeline is scary; we have to take action immediately.”
Talha Burki
Infectious disease surveillance update Cholera in Yemen
As of Oct 7, the number of people who have died in the cholera epidemic that started in April 2017, in Yemen, has risen to 2151. A total of 800 626 cases have been reported across 22 of the 23 provinces in Yemen. Most of the reported deaths have been from the northern province of Hajjah.
Plague in Madagascar
Since Aug 2017, 231 cases (suspected, probable, or confirmed) of plague have been reported in Madagascar, and 33 patients died from their illness. Most of the cases have been pneumonic plague: plague is endemic to parts of Madagascar and cases of bubonic plague are reported every year. This is the first outbreak in which pneumonic plague has been reported in a nonendemic area and in densely populated areas. As of Oct 6, pneumonic plague has been reported in ten cities, with Antananarivo, the capital, being the
most affected, followed by Toamasina and Faratshio. The outbreak was detected in Sept 11, following the death of a 31-year-old man from the plague-endemic district of Ankazobe. Both pneumonic and bubonic plague can be cured with antibiotics if detected early and WHO has delivered 1·2 million doses of antibiotics and released emergency funds to fight the outbreak.
been identified in Bayelsa state in southern Nigeria. The first patient was notified to authorities on Sept 22, an 11-year-old boy who presented with symptoms at the Niger Delta University Teaching Hospital, in Yenagoa. 32 close contacts of the patients have also been identified and are being monitored.
Hepatitis A virus in Brazil
Chikungunya virus in Italy
Between Jan 1, and Sept 16, 2017, São Paulo recorded 517 cases of hepatitis A virus infection, compared with 64 cases recorded in the whole of 2016. The cases have been predominantly men who have sex with men; 87% of the patients are male and aged between 18 and 39 years.
Monkeypox virus infection in Nigeria
As of Oct 1, 12 patients with monkeypox virus infection have
www.thelancet.com/infection Vol 17 November 2017
183 locally acquired cases (confirmed and suspected) of chikungunya virus infection have been reported in the Lazio region of Italy as of Sept 26. 109 cases have been confirmed and 74 additional cases are being investigated. All cases have an epidemiological link to the Lazio region, where cases have been reported in the coastal areas of Anzio and Latina, as well as in Rome.
For more on cholera in Yemen see http://www.promedmail. org/post/5367259 For more on plague in Madagascar see http://www. who.int/csr/don/02-october2017-plague-madagascar/en/ For more on hepatitis A virus in Brazil see http:// outbreaknewstoday.com/brazilhepatitis-cases-700-percentsao-paulo-35732/ For more on monkeypox virus in Nigeria see http://ncdc.gov. ng/news/104/press-release%3Asuspected-monkeypoxoutbreak-in-bayelsa-state For more on chikungunya in Italy see http:// outbreaknewstoday.com/italychikungunya-outbreak-promptscdc-travel-notice-32299/
Ruth Zwizwai 1129
Antibiotic development pipeline slows to a trickle New antibiotics are needed as part of the global effort to tackle antimicrobial resistance, but WHO warns that few are in development. Talha Burki reports. For WHO’s report on the antibiotic pipeline see http://www.who.int/medicines/ areas/rational_use/antibacterial_ agents_clinical_development/en/ For more on WHO’s priority pathogen list see http://www. who.int/medicines/publications/ global-priority-list-antibioticresistant-bacteria/en/
1128
A new report by WHO has laid bare the scarcity of the antibacterial drug pipeline. The report focused on the 12 families of antibioticresistant bacteria on WHO’s global priority pathogen list as well as tuberculosis. It noted that there are only 33 new antibiotics currently in clinical development that target these infections. The situation for Gram-negative bacteria is particularly dire. 12 agents in the current pipeline show activity against the carbapenem-resistant pathogens Acinetobacter baumannii, Pseudomonas aeruginosa, and the Enterobacteriaceae family. These three pathogens have been identified as crucial priorities by WHO, and the five antibiotics targeting them in phase 3 trials are all modifications of existing classes. Excluding bedaquiline and delamanid, which have already obtained conditional market approval, the pipeline for tuberculosis is made up of a mere seven new antibiotics, only one of which is in phase 3 trials. Nine antibiotics in the pipeline satisfy one of the following conditions: absence of crossresistance to existing antibiotics, new chemical class, new target, or new mechanism of action. Only two of these antibiotics show activity against Gram-negative bacteria. The authors of the WHO report estimate that about ten new antibiotics are likely to enter the market over the next 5 years, a woefully inadequate number given the need. 86% of phase 1 compounds are not developed further, so of the ten agents targeting Gram-negative bacteria at this stage, no more than one or two are likely to gain market authorisation. “It is a crisis, and this report really shows how the innovation model is broken”, said Otto Cars (Uppsala University, Uppsala, Sweden).
When WHO first released its list of priority pathogens in February 2017, the omission of tuberculosis proved to be controversial. The new report firmly establishes tuberculosis within the drug-resistance agenda, but considers it separately from the infections on the priority pathogen list.
“...of the ten agents targeting Gram-negative bacteria...no more than one or two are likely to gain market authorisation.” Peter Beyer (WHO, Geneva, Switzerland) notes that the tuberculosis community has built up enormous experience in addressing drug-resistance, and their response can help guide efforts for the other priority pathogens. “We have had the opportunity to think hard about some of the problems that are now being talked about with antimicrobial resistance”, agrees Grania Brigden (The International Union Against Tuberculosis and Lung Disease, Geneva, Switzerland). “Tuberculosis programmes have been working on building surveillance systems in an effort to try to get data on the epidemic and the state of resistance, and ensuring the availability of antibiotics at the lowest levels of health care”. The 2011–2015 Global Plan to Stop TB envisaged an expenditure of US$3·7 billion on drug discovery and development over the 5-year period. In the event, less than a third of this sum was delivered. “The situation for tuberculosis research and development is really symptomatic of antimicrobial resistance and infective research and development more generally”, said Brigden. Last year, WHO and the Drugs for Neglected Diseases initiative launched
the Global Antibiotic Research and Development Partnership (GARDP), a product development partnership analogous to the TB Alliance. GARDP intends to secure €270 million to fund its activities until 2023. Several European nations, led by Germany, along with South Africa and the Wellcome Trust have already pledged over €56 million. “We hope this will create a momentum for other countries to support our work in the future”, said Jean-Pierre Paccaud (GARDP, Geneva, Switzerland). The immediate priorities will be to deliver new therapies for neonatal sepsis and gonorrhoea. In July 2017, GARDP entered a partnership with biotechnology company Entasis Therapeutics to bring zoliflodacin, a drug from an entirely new class of antibiotics, into a phase 3 trial for treatment of gonorrhoea. “Say it costs around $30–50 million to put such a drug through phase 3 trials—if the trial is successful then for not very much money, at least in terms of drug development, you can help a new, innovative antibiotic go from phase 2 to marketing approval”, notes Beyer. The CARB-X project is backed by seven partners in the USA and UK. It was set up in 2016 and has secured about half a billion dollars to advance the preclinical antibiotic pipeline. “They are investing in companies worldwide who have innovative approaches in the preclinical phase, with aim of pushing products into phase 1”, explained Beyer. “It is a very important initiative, because often these smaller companies do not have the money to get to the next stage”. Nonetheless, although funding has historically proved to be a major obstacle, the scientific barriers are formidable. In the 1960s and 1970s, the pharmaceutical industry spent
www.thelancet.com/infection Vol 17 November 2017
billions of dollars searching for promising lead compounds with scant success. “Finding antibiotics with new mechanisms of action, that overcome all the resistance mechanisms that bacteria across various species have developed over millions of years, is an astonishing scientific challenge”, concedes Paccaud. GARDP ’s Antimicrobial Memory Recovery Programme will revisit failed and discontinued research, both to avoid duplication and to pick up any promising leads that may have been deprioritised for, for example, strategic reasons. “The real bottleneck is the early stages”, said Cars. “We need to do far more to solve the scientific challenges by creating new incentives and open collaborative partnerships to get new molecules.” Cars believes this will be best achieved by a greater emphasis on push mechanisms. He cites the example of the ENABLE project, run by the Innovative Medicines Initiative,
and focused on Gram-negative bacteria. It is a consortium of partners in academia and industry dotted across Europe, who share the costs of preclinical development. “In principal this system could be looked upon as a model for tackling these difficult bottlenecks”, said Cars. 2018 should see the launch of the Life Prize (formerly the 3P Project), an attempt to kickstart the development of new antibiotics and treatment combinations for tuberculosis using a coordinated system of research grants, prizes, and pooled intellectual property. Plans to establish the Global Antimicrobial Resistance Collaboration Hub were announced at the July 2017 meeting of the G20 countries. The aim is to “work with existing groups to promote collaboration, sharing of information, and a means to invest funding more efficiently”. Since 2009, when Sweden hosted an international conference to draw attention to the
Doncaster and Bassetlaw Hospitals/Science Photo Library
Newsdesk
issue of antimicrobial resistance, there has been a steady build-up of momentum. The WHO report gained a great deal of international attention, as did last year’s O’Neill report. “But things are still not moving fast enough”, stressed Cars. “The state of the pipeline is scary; we have to take action immediately.”
Talha Burki
Infectious disease surveillance update Cholera in Yemen
As of Oct 7, the number of people who have died in the cholera epidemic that started in April 2017, in Yemen, has risen to 2151. A total of 800 626 cases have been reported across 22 of the 23 provinces in Yemen. Most of the reported deaths have been from the northern province of Hajjah.
Plague in Madagascar
Since Aug 2017, 231 cases (suspected, probable, or confirmed) of plague have been reported in Madagascar, and 33 patients died from their illness. Most of the cases have been pneumonic plague: plague is endemic to parts of Madagascar and cases of bubonic plague are reported every year. This is the first outbreak in which pneumonic plague has been reported in a nonendemic area and in densely populated areas. As of Oct 6, pneumonic plague has been reported in ten cities, with Antananarivo, the capital, being the
most affected, followed by Toamasina and Faratshio. The outbreak was detected in Sept 11, following the death of a 31-year-old man from the plague-endemic district of Ankazobe. Both pneumonic and bubonic plague can be cured with antibiotics if detected early and WHO has delivered 1·2 million doses of antibiotics and released emergency funds to fight the outbreak.
been identified in Bayelsa state in southern Nigeria. The first patient was notified to authorities on Sept 22, an 11-year-old boy who presented with symptoms at the Niger Delta University Teaching Hospital, in Yenagoa. 32 close contacts of the patients have also been identified and are being monitored.
Hepatitis A virus in Brazil
Chikungunya virus in Italy
Between Jan 1, and Sept 16, 2017, São Paulo recorded 517 cases of hepatitis A virus infection, compared with 64 cases recorded in the whole of 2016. The cases have been predominantly men who have sex with men; 87% of the patients are male and aged between 18 and 39 years.
Monkeypox virus infection in Nigeria
As of Oct 1, 12 patients with monkeypox virus infection have
www.thelancet.com/infection Vol 17 November 2017
183 locally acquired cases (confirmed and suspected) of chikungunya virus infection have been reported in the Lazio region of Italy as of Sept 26. 109 cases have been confirmed and 74 additional cases are being investigated. All cases have an epidemiological link to the Lazio region, where cases have been reported in the coastal areas of Anzio and Latina, as well as in Rome.
For more on cholera in Yemen see http://www.promedmail. org/post/5367259 For more on plague in Madagascar see http://www. who.int/csr/don/02-october2017-plague-madagascar/en/ For more on hepatitis A virus in Brazil see http:// outbreaknewstoday.com/brazilhepatitis-cases-700-percentsao-paulo-35732/ For more on monkeypox virus in Nigeria see http://ncdc.gov. ng/news/104/press-release%3Asuspected-monkeypoxoutbreak-in-bayelsa-state For more on chikungunya in Italy see http:// outbreaknewstoday.com/italychikungunya-outbreak-promptscdc-travel-notice-32299/
Ruth Zwizwai 1129