• lloydczaplewski

Discovering, developing and commercialising novel antibacterials is hard. The science is tough, finding funding is challenging and if successful, the commercial rewards are insignificant. We have seen companies that should have been rewarded for delivering new treatments collapse.

Some of our best scientific and medical communicators have been effective, convincing Governments that antibacterial R&D is special and needs extra-ordinary levels of support. We have seen remarkable amounts of early stage R&D “push” funding to aid attractive projects and we are starting to see novel approaches to reward product developers that reach the market with subscription models.

But we should not be surprised that the consistent message that the antibacterial market is broken should eventually put off investors and lead to low valuations for companies in the space.

Looking at the likely life cycle for an antibacterial R&D project – it starts in academia or biotech, where grant funding and or investors supported by non-dilutive grants can get the project to early clinical trials. To complete the clinical development and to get to market with global distribution the project probably has to transition into a larger organisation. The valuation of an antibiotic asset is currently so low that the early-stage investors are unlikely to see a return at this stage. They must wait for milestones and royalties. The larger company, if successful, may get a market entry reward, but once they take out their costs, how much will be shared with the early investors? How long will the angel and series A-D investors have to wait for their reward?

Furthermore, we have increased project risk, not reduced it. One of the major advantages of antibacterial R&D is the predictive animal models which means that projects can be derisked early, by Phase II you have a good idea of whether the antibiotic works. Now nobody knows how market-entry rewards will work or what projects will be rewarded. We have added a layer of uncertainty and time onto an already unattractive investment.

Unless each stakeholder can make an adequate return on investment in a reasonable time frame I don’t see how we are fixing the model. It feels like we are delaying the fix because it is hard.

To build a sustainable antibacterial R&D environment for the long-term, 30-, 100- and 300-years, we need to reassess antibacterial pricing and encourage a commercial model that rewards risk and investment. The alternative is that tax-payers will have to fund antibacterial R&D forever, and that feels fragile and unsustainable. But it may be the only option for the short term.

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The recent publication of the output from the Global Research on AntiMicrobial resistance (GRAM) project in the Lancet provides the most comprehensive estimate of the AMR burden to date.

The headline message is that they found that there were 1.2m deaths attributable to bacterial AMR and nearly 5m deaths associated with bacteria AMR in 2019.

Lower respiratory infections were the most common disease associated with AMR.

The six most problematic pathogens – in order- were E. coli, S. aureus, K. pneumoniae, S. pneumoniae, A. baumannii and P. aeruginosa.

Access to better treatment and/or prevention options for the Gram-positives, S. aureus and S. pneumoniae, particularly in north Africa and the Middle East, are urgently required.

It takes decades for academic research to mature into translational projects and ultimately new therapies. Almost all current antibacterial R&D is focused on Gram-negatives. We can’t afford to ignore Gram-positive antibacterial R&D because in 10-30 years we will need new therapies – we must do it all – consistently.

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  • lloydczaplewski

Imitation of beta-lactam binding enables broad-spectrum metallo-beta-lactamase inhibitors by Brem et al., (2022)

This international collaboration led to the identification of indole-2-carboxylates as a novel metallo-beta-lactamase inhibitor warhead that mimics the enzyme-substrate complex.

InC58

I’m fortunate to have reviewed many hit-, lead-, candidate- and clinical phase projects in the antibiotic space, mostly from pharma and biotech for funders, and this outstanding paper is exceptional in its breadth, quality and potential impact.

The paper demonstrates what can be achieved through largely academic collaboration and appropriate funding – an example of the future for antibiotic discovery given the state of the industry.

It describes the output of a combination of activities by the European Lead Factory, the European Gram-negative Antibacterial Engine (ENABLE) (http://nd4bb-enable.eu/) and the University of Oxford which led to the identification of the novel warhead.

The programme covered biochemistry, chemistry, structural biology (over 50 structures were obtained), ADME and optimisation to reduce liabilities such as protein binding and metabolic stability and to improve potency against target MBLs.

Compound InC58 was identified which potentiated carbapenem activity against an impressive range of otherwise carbapenem-resistant clinically relevant strains. Looks like it may have useful activity against Enterobacterales but maybe not against P. aeruginosa and A. baumannii.

They used high hurdle animal models including neutropenic thigh models, allowed infection to develop for 1 hour prior to therapy and only administered a single dose of s.c meropenem with i.v. InC58 and assessed efficacy 3 hours later. This is an atypical short design of in vivo study. Others may have used multiple doses of meropenem, to mimic human pharmacokinetics, over a longer period e.g. 9 hours, to maximise effect. We need to wait and see what additional PK/PD studies show, but it looks very encouraging. With optimal dosing even greater efficacy may be anticipated, especially against K. pneumoniae.

I did not notice combinations of InC58 with serine lactamase inhibitors which may help coverage and I wonder how InC58 potentiates other lactam antibiotic activity e.g. temocillin against ESBL clinical isolates with a high prevalence of MBLs.

It will be interesting to see how the collaboration have managed the project intellectual property.

The project is advancing towards clinical trials and with the Ineos Oxford Institute’s funding and expertise they have every chance of success!

Building virtual pharma within and across academic organisations will be essential to create the critical mass of skills, expertise and experience needed to nurture antibiotic R&D post-industry collapse.

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