SEARCHING FOR SUPERBUG'S KRYPTONITE
By Nuala Moran
LONDON Amongst all the talk, the reports and the policy initiatives, there is a palpable sense that Europe is starting to make some headway in the practicalities of dealing with the threat of antimicrobial resistance (AMR).
A prime example is the EU-wide ban on using antibiotics in livestock except in the case of infection.
There also is progress in encouraging and accelerating the discovery and development of new antimicrobials. At the EU's prompting, AMR research now features in member states' individual action plans, R&D programs have been established at a pan-European level, and both the EMA and national regulators have been looking into how to speed up approvals.
In R&D, the most prominent single program in Europe and one of the largest in the world is New Drugs for Bad Bugs (ND4BB), which started in May 2012 as part of the Innovative Medicines Initiative.
Europe's pharmaceutical companies threw their weight behind the European Commission's plan to revive research in the field, including putting some of their own products into ND4BB.
Apart from sharing failures so that others do not waste time on fruitless research ND4BB is sponsoring biomarker research and the development of rapid diagnostics to enable fast recruitment of likely responders in clinical studies and to support the development of narrow-spectrum antibiotics.
It also is promoting the formation of clinical trials consortia, which are conducting pan-European studies in multidrug-resistant infections.
At a more basic level, another strand of research is focusing on developing the ability to rationally design compounds that can penetrate the cell walls of gram-negative bacteria.
ND4BB was not Europe's first investment in that field. In the seven years before the IMI program launched in 2012, the EU had awarded €600 million (US$681 million) for research in AMR.
However, that research effort was fragmented, and despite ND4BB's attempts at coordination, Pierre Meulien, executive director of IMI, said he thinks that remains an issue. "AMR is not a money-only problem," Meulien told the Oxford Drug Discovery conference at Oxford University earlier this month.
IMI is investing €600 million in the current AMR program, but Meulien is concerned that its research "is not particularly connected with what is happening around the world. The question is, are we using the existing pool of money efficiently?" he said.
Meulien said it is critical for all those involved in the AMR research to work together in the most efficient way possible. To help with that, IMI is redesigning its website to include a page where people can contribute ideas.
One sign that pieces of the jigsaw being advanced by ND4BB are falling into place came in September 2015, when the U.S. Biomedical Advanced Research and Development Authority (BARDA) signed a deal with Astrazeneca plc to co-develop a portfolio of antibiotic drugs over the next five years, picking up a program that has been partially funded through the EU program.
In the cost-sharing arrangement, BARDA initially will provide $50 million and could provide up to a total of $170 million for development of additional products.
The first product in the portfolio combines two antibiotics, aztreonam and avibactam, known together as ATM-AVI. The combination is being developed to treat gram-negative infections. ND4BB is supporting the phase IIa study of ATM-AVI in Europe, and under the BARDA agreement, IMI will be involved in funding additional studies needed up to approval.
Pooling national R&D funding
As part of its antimicrobial action plan, the EU has encouraged member states to pool national research funding, backing the formation of the Joint Programming Initiative on Antimicrobial Resistance, which was launched in 2014.
The intention is to coordinate research between countries and allow researchers funded from national grants to collaborate across borders. The initiative has 19 member countries working to a strategic research agenda encompassing six topics.
To date, it is clear joint programming is scratching the surface in terms of harmonizing research and aligning national AMR research with the six priorities set down at a European level, according to a survey of publicly funded R&D in the 19 member countries published in The Lancet Infectious Diseases in April.
That identified AMR resistance research projects with a total public investment of €1.3 billion (including the Innovative Medicines Initiative). Of that, €646.6 million or 49.5 percent, was invested at the national level, the rest at an EU level.
When projects were classified under the joint programming initiative's six priority topics, it was shown to be unevenly spread: 763 of 1,208 projects funded nationally were in drug discovery and development, 185 in infectious disease transmission, 131 in diagnostics, 53 in interventions, with only 39 in surveillance and 37 in environmental aspects.
The study clearly highlights the gap between the research needed to reduce resistance and what is actually being funded, said Mats Ulfendahl, chair of the joint programming initiative. "As well as increased funding, we need to tackle this growing concern together, by strengthening national and international collaborations, co-ordinating research activities and combining resources," he said.
The European Commission has encouraged the EMA to play its part, by looking to see if it could iron out regulatory barriers. The agency acknowledged that "clinical trials for antibacterials treating multidrug-resistant infections are scientifically demanding and burdensome" when it updated its guidance to companies in 2012.
Amongst moves to reduce the burden, the EMA said that if pharmacokinetic and pharmacodynamic analyses are convincing, "it may be possible to completely omit clinical dose-finding studies."
In addition, a single pivotal study may be acceptable to support an approval, adult efficacy data in some indications can be extrapolated to children, and the minimum number of patients that must be enrolled in trials treating certain multidrug-resistant pathogens will be judged on a case-by-case basis.
Changes in the EMA's approach to regulation were cited as an influence in Roche Holding AG's decision in November 2013 to license Polyphor Ltd.'s antibiotic program, POL7080, in a deal worth potentially $510 million.
The EMA also has taken steps to promote development of alternative products, for example opening the way for the approval of bacteriophages as approved medicinal products in June 2015.
Much remains to be done, as was highlighted last month in the publication of one of the most comprehensive investigations of the problem, the UK Review of AMR. One major conclusion of the review is that a supranational entity is required to set the global priorities on tackling the threat.
EU policy in AMR may have been a long time in the formulation and only now is picking up pace in the implementation, but it is starting to demonstrate the value of such concerted international action.
Published June 24, 2016