CO-ADD's Dr Karl Hansford has just returned from Boston for the 2017 ASM/ESCMID conference. Read his latest blog post below summarising all the conference activities.
By Dr Karl Hansford, CO-ADD Medicinal Chemist: Hit Confirmation & Validation
I have just returned from the 2017 ASM/ESCMID conference on Drug Development to Meet the Challenge of Antimicrobial Resistance, which was held in Boston. Prior to the main meeting, which ran for three days, a pre-conference antibiotic development bootcamp was offered to all participants. The workshop was sponsored by the two non-profit R&D initiatives CARB-XED (Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator) and GARDP (Global Antibiotic Research and Development Partnership), in conjunction with ASM and ESCMID. John Rex, Chief Strategy Officer for Carb-X, opened the session to a full house. The bootcamp discussed aspects related to the discovery phase, analysing what makes a good hit and a good lead, with detailed discussion of the associated pitfalls encountered during lead optimisation and ultimately pre-clinical development. The importance of writing a Target Product Profile (TPP) was also discussed, as was aspects of CMC (Chemistry, Manufacturing and Controls) during the drug development phase.
At the end of the day, it became very clear that the discovery phase is fraught with many hidden dangers, failure is all too common, and that one should not neglect the importance of CMC.
We got to hear about the accelerated development of three relatively new Gram-negative treatments on day one of the conference: a third generation cephalosporin ceftazidime, used in combination with the beta-lactamase inhibitor avibactam (caz-avi, Allergan), the new aminoglycoside plazomicin (Achaogen) and meropenem-vaborbactam (Vabormere, Rempex), the latter a novel cyclic boronic acid broad spectrum beta-lactamase inhibitor. Interestingly, recent clinical studies for caz-avi and plazomicin highlight their superiority over colistin, relegating this dirty cousin to the clinical backbench. In the afternoon during the session “challenges with clinical trial design and funding issues”, we heard about pathogen specfic agents: Glenn Dale (Head of Early Development, Antimicrobials) from Polyphor spoke about murepavadin, which targets XDR Pseudomonas aeruginosa infections, and Robin Isaacs (Chief Medical Officer) from Entasis Therapeutics presented data on the combination therapy sulbactam-ETX2514 which is effective against MDR A. baumannii infections. Both talks highlighted the unique challenges of clinical trial design for pathogen specific agents, and the importance of a robust PK/PD package to support intended use.
In the evening, Giovanni Salerno and Jean-Pierre Paccaud from GARDP hosted a cozy gathering to introduce their Antimicrobial Memory Recovery Programme, 1 of 4 focus areas for GARDP (EUR 56 million was recently raised to support their research programmes!). It is an initiative aimed at recovering the knowledge, data and know-how of forgotten or abandoned antibiotics by building a global panel of antibiotic experts from academia and industry who will collectively identify drug opportunities from a pool of forgotten or abandoned molecules. Their goal is to advance 1-2 new chemical entities into pre-clinical or clinical development by 2023. The audience contained a mix of researchers from both academia and industry, including veterans such as Lynn Silver (ex Merck) and Barry Eisenstein (Carb-X), as well as our very own Matt Cooper. It made for a great forum with much thoughtful discussion and at times heated debate! A great end to the evening!
Day two started with a keynote talk by Nicola Magrini from the WHO. He discussed the global priority list of AMR and the 2017 essential medicine list. Pathogens considered critical priorities were: A. baumannii, P. aeruginosa, and carbapenem-resistant, ESBL-producing Enterobacteriaceae. We also heard from John Rex (Carb-X) and Tim Jinks, Head of Drug-Resistant Infections (Wellcome Trust) on their strategic action plans to tackle AMR. The 2016-2017 highlights for Carb-X were revealed: $95 million of funding to support 18 projects (8 new classes of antibiotics) from 368 applications! Despite their projected investment of $455 million over five years, John highlighted that much more is needed to implement the long term recommendations of the DRIVE-AB global workplan – somewhere in the vicinity of USD $1b annually from 2020!
To put this into perspective, he concluded by pointing out that the Internation Space Station cost USD $150b, and that CERN’s annual operating budget is USD $1.2b. Based on this, it is clearly entirely possible to commit the necessary funds to tackle global AMR!
On the last day, we got to hear some great talks on strategies to understand and overcome the barriers of Gram-negative entry. Lynn Silver gave an insightful talk on the challenges of drug penetration, and put forward the stern belief that combination therapies will be critical to overcoming rapid resistance development. Next up Ruben Tommasi (Entasis) gave a fascinating talk on strategies to improve outer membrane permeability of compounds using a cell-based porin overexpression assay to guide SAR. Lastly, Aileen Rubio, Head of Biology (Spero Therapeutics) described their outer membrane permeabiliser compound SPR741, which garnered a lot of interest from the audience and shows great promise as an antibiotic potentiator.
I will also mention that I took advantage of being located on the East coast, which enabled me to meet face-to-face with our CO-ADD collaborator Prof. William Scott from Indiana University Purdue University Indianapolis. Bill is part of the Distributed Drug Discovery (D3) program, which harnesses the collective power of groups of undergraduate chemistry students to synthesise molecules toward lead discovery for neglected diseases. CO-ADD has screened compounds from the D3 program. It was the perfect opportunity to meet up in Cambridge, where we took a stroll through the Harvard University campus before sitting down to lunch in a quaint pub to discuss ways to continue our fruitful collaboration.
Karl presented his poster: “Octapeptins – a New Hope in The Treatment of Multi-Drug Resistant Gram-Negative Infections?” – Synthesis and activity analysis of novel octapeptin and polymyxin analogues shown to be active against polymyxin resistant gram negative pathogens