We are still in the middle of the COVID-19 crisis, but another potentially larger crisis is ahead that threatens our global healthcare system; the anti-microbial resistance (AMR) crisis. Whilst we weren’t ready for COVID-19, it emerged as much of a surprise, this latter point cannot be said of antibiotic-resistant pathogens which we still remain woefully unprepared for.
Globally, an estimated 700,000 people die from drug-resistant infectious diseases per year.
Further compounding the detrimental state of affairs is the economic and innovation-inhibiting challenges faced by researchers and companies attempting to introduce novel antibiotic compounds, which receive a dearth of attention. In this series of blogs, we illuminate the mechanisms driving the collapse of the antibiotics industry, discuss a case study, and propose ways to bring stakeholders together to come to a solution. At ttopstart, we believe such healthcare challenges can be evaded by creative strategic thinking and pragmatism.
Drug-resistant diseases will have a serious impact on society
Globally, an estimated 700,000 people die from drug-resistant infectious diseases per year. In several EU member states, 25% of clinical isolates of pathogenic Gram-positive and Gram-negative bacteria are showing resistance to one or more antibiotics. Experts at the UN and WHO estimate that this number will increase to 10 million annual deaths by 2050 if infection rates remain as they are and new intervention strategies remain absent. Moreover, AMR is estimated to force up to 24 million people into extreme poverty by 2030. The AMR crisis will be significantly more destructive than the current COVID-19 pandemic, both with regards to number of casualties as well as economic damage, and antibiotic use. For context, at the at the time of writing there are 667 000 deaths from COVID-19 and the end economic impact is estimated to be around $8.8 trillion (keeping in mind that once a vaccine is in place future mortality will be largely ablated), whilst up to 444 million deaths and $124.5 trillion in economic damage is estimated to be the end result by 2050 if there is the same levels of obfuscation around tackling AMR.
We urgently need new antibiotics
Clearly, action is required against AMR, however, whilst evidence-based prescribing practices and the smart use of current antibiotics (stewardship) can significantly slow down the AMR crisis, they cannot prevent it. Further, global antibiotic stewardship efforts have contributed significantly to the collapse of the industry for nascent antibiotics. This is due to the focus on what is effectively rationing the drugs rather than the production of new antibiotics. Today, the introduction of novel antibiotics stays dramatically behind. Shockingly, the introduction of the newest class of broad-spectrum antibiotic, quinolones, dates from 1962. Resistance against most drugs in this class has evolved rapidly and experts today recommend their usage to be limited to last-resort cases. Since then, only two non-broad-spectrum classes of clinically relevant antibiotics have reached the market (i.e. oxazolidines and lipopeptides, and to note, they are only effective against Gram-positive bacteria). Hence, the urgency for novel antibiotic compounds is clear.
Economic challenges outpace the need for novel compounds
High development costs and the lack of fair return on investment for antibiotics are the main reasons why innovation in antibiotics is staying behind. Antibiotics have a short prescription period and their tendency to lose usefulness due to resistance building in bacterial strains; these facts further compound the financial problem at hand. And as mentioned previously, the antibiotic stewardship strategy further exacerbates these innate challenges, with the end result being that many antibiotics being shelved: the better the drug, the less likely it is to be used in practice.
Many small to medium-size biopharma companies are going bankrupt (three major US-based ones in the last 18 months) and the large pharmaceutical players are abandoning the antibiotics market one by one. Of the 25 large pharmaceutical companies with active antibiotic discovery programmes in 1980, only three remain today with very small pipelines each: Pfizer, MSD, and GSK. This amount is expected to decrease even further soon with GSK trying to sell of their entire antibiotics development arm.
Case: a novel high-potential glycopeptide antibiotic
What is particularly shocking is that these economic challenges even hamper opportunities for state of the art antibiotics with vast improvements over the most modern currently used antimicrobial derivatives. Normally, vis-à-vis pharmaceuticals, those which are newer and scientifically better are seen as highly financially attractive. One may think that this is prima facie the case for antimicrobials, but unfortunately that is not so. This is supported by our recent market study on a scientifically robust and novel vancomycin-derivative glycopeptide antibiotic. Together with Professor Nathaniel Martin from Leiden University, we investigated whether there is a viable business case for his contemporary antibiotic compound. To note, glycopeptides are among the most important classes of antibiotics, as they are traditionally considered the last line of defence against the ghastly hospital bacteria, MRSA (methicillin-resistant Staphylococcus aureus).
Our investigations quickly identified a number of failures associated with the current primary clinical standard glycopeptides, vancomycin and teicoplanin, with regards to safety and efficacy (kidney toxicity and skin rash, and drug-related fever, respectively). While the more recently approved glycopeptide antibiotics oritaviancin and dalbavacin address some of these issues, they also have extremely long residence times (in vivo half lives of ca. 300 hours). The novel glycopeptide compound discovered by the Leiden University researchers perfectly addresses these problems. Additionally, it has a dramatically higher activity, lower toxicity risks, favourable pharmacokinetics, lower potential for resistance development, and a more straightforward preparation procedure.
Unfortunately, our study of the glycopeptide market revealed that sales numbers for the newest therapeutics in this space (oritavcin and dalbavacin) are very poor. In fact, the producer of oritavancin (Melinta Therapeutics) even filed for bankruptcy recently. The reason for these low sales numbers is twofold. First, the attractive pricing of alternative generics offset interest in a nascent ‘best-in-class’ drug. Second, clinicians tend to choose the older ‘standard’ antibiotics over these novel compounds to limit resistance development for these newer compounds, regardless of their serious side effects. Based on these findings, we concluded that in the current climate a viable business case would be very challenging for a novel ‘best-in-class’ glycopeptide antibiotic. We therefore advised the client to hold off market entry until the economic circumstances are more favourable.
Professor Martin: “While there are abundant scientific opportunities to pursue in finding new and improved antibiotics, the current market for these drugs presents a serious roadblock. The market insights provided by ttopstart indicate that at this time the prudent course of action is to continue development of our new glycopeptides in the academic setting with support of public funding via research grants.. Ultimately, in order for these new antibiotics to reach patients private partners will be needed. I am hopeful that new incentives will be introduced to the market to provide such partnership opportunities. In this regard I look forward to working with ttopstart in the future to jointly develop a solution for this urgent AMR crisis we are facing.”
At ttopstart, we have an integral interest in removing the roadblocks holding back the introduction of novel antibiotic compounds. We are of the opinion that public awareness on the matter is the first hurdle to take. As such, we will share the visions of key opinion leaders in the field and investigate alternative business models.
Jelle Eikelhof, MSc & Christopher Haggarty-Weir, MRSB, MRSC, PhD, MBA