Despite the urgent danger of antibiotic resistance, investments into European biotech antibiotic players have remained flat. However, growing regulatory and societal awareness could spell fresh investments in the coming years.
Over the last decade, pressure has been mounting on healthcare systems as infectious microbes become harder and harder to fight with antibiotics. Some strains of bacteria, including Clostridium difficile, are seen as urgent threats that need a better range of antibiotic treatments.
There are 43 antibiotics in development globally, according to a report from the World Health Organization in April this year surveying antibacterial treatments in the pipeline. However, most of these are derivatives of existing drug classes. This makes it more likely that drug-resistant microbes will develop resistance against the new antibiotics.
“The scientific and medical communities have been very worried and asking for funds for more than two decades,” said Juanjo Infante, CEO of the Spanish vaccine developer VaxDyn. “The problem is serious.”
In the last couple of years, the Covid-19 pandemic has had a positive impact on investments into strategies against viral infections, including vaccines and diagnostics. However, this is of limited help for companies developing other anti-infectives such as antibiotics and antifungals.
“While massive amounts of money have been invested in antiviral vaccines and therapeutics, the funding environment for antibiotics and antifungals has remained relatively flat with a few noticeable exceptions,” said Aleks Engel, Partner of Novo Seeds, the startup-focused arm of the Danish investor Novo Holdings.
One of the biggest exceptions to this trend was the establishment of the €870M ($1B) AMR Action Fund last year, with the aim of marketing two to four new antibiotics by 2030. The fund’s first investments are expected to be announced by the end of the year.
Much of the biotech industry is experiencing an investment boom but the same isn’t the case for European and Israeli biotechs working on treatments for bacterial infections. These players bagged around €380M in 2018, and this hasn’t been matched in subsequent years. This year seems set to continue the trend.
In this year alone, hot research areas like oncology have generated huge private funding rounds, such as Apollo Therapeutics’ €117M ($145M) investment in June. Meanwhile, the biggest fundraisings for European companies developing antibacterial approaches have barely topped €20M. The most recent entry was a €17.7M Series A round from the Scottish firm Enterobiotix, which is developing a microbiome treatment for a range of conditions including infectious diseases.
Some of the top fundraisers in the European antibiotic resistance space have also faced stormy seas.
One example is Polyphor, which slammed the brakes on two phase III trials of its antibiotic murepavadin in 2019 due to safety fears. After the failure of its cancer treatment in phase III trials this year, the hard-pressed Polyphor began preparations to merge with the US firm Enbiotix this month.
Meanwhile, Iterum Therapeutics hit a bump in July this year as the FDA snubbed its antibiotic treatment for urinary tract infections, requesting more clinical evidence for its efficacy. The company’s share price tanked by more than 60% after the news broke and hasn’t recovered since.
One of the central reasons for the lackluster investment situation in antibiotics is that it is seen as a broken market. Medical professionals typically use antibiotics only sparingly to prevent exposing microbes to them and developing antibiotic resistance. This in turn harms the producer’s bottom line.
“Since the [generic drugs] are very cheap, they will first use them and only then use the others,” said Moshik Cohen-Kutner, CEO of the Israeli biotech Omnix Medical. “And since it is very expensive to develop a new drug, why should they invest in this kind of area when they can gain much more money from cancer or autoimmune diseases?”
Without a financial incentive to develop these drugs, big pharma companies have progressively abandoned antibiotics. This has a knock-on effect on small companies that aim to address the crisis, because investors see few ways to get a return on their investment.
“You need to have some signs of efficacy in humans before [pharma companies] start to look at you,” said Cohen-Kutner. “It’s very hard to bridge this gap because this is a gap of $20M or $30M. Many companies do not survive this gap. They just can’t raise money.”
The recent AMR Action Fund is one of a group of funding organizations attempting to de-risk antibiotic research, including CARB-X, the NIH, and Novo Seeds’ Repair Impact Fund.
“There is definitely more focus on the issue of antibiotic resistance now than there was five years ago when we started our development,” said Annette Säfholm, CEO of Gedea Biotech, a Swedish firm treating bacterial vaginosis.
“In general though, given the magnitude and importance of this question, the current initiatives and funding alternatives are not in any way sufficient.”
To fix the broken market, there are movements to reform how we pay for antibiotics. One common suggestion is the so-called Netflix model, where an antibiotic developer is paid independently of how much drug is used. The UK is leading the charge in this direction, closely followed by Sweden. The EU is considering such an option, while the US is debating this legislation in the form of the Pasteur Act.
“It is important to note that this is not a giveaway to big pharmaceutical companies because 95% of antimicrobials are developed by small companies,” wrote Stephen Quake, Professor of Bioengineering at Stanford University, and Sevahn Vorperian, a graduate student in his lab, for STAT in June this year.
There is also growing interest in next-generation technologies that could circumvent antibiotic resistance in invading bacteria. The World Health Organization’s recent antibacterial treatments report for the first time gave comprehensive coverage to antibiotic alternatives such as bacteria-hunting viruses, antibody drugs, and immunotherapies.
Omnix Medical gained an NIH grant last month to bankroll the development of antimicrobial peptide drugs against multi-drug resistant Acinetobacter baumannii. Unlike current antibiotics, the peptide drugs are designed to rip apart the protective membrane of bacteria.
“It’s the difference between a physical mechanism of action and a biochemical one, where we inhibit some kind of process within the bacteria that causes it to die,” said Omnix Medical’s CSO, Niv Bachnoff. “This is something that bacteria can overcome really easily. But when you just punch holes in them, it’s this physical damage that they cannot overcome.”
In its quest to treat bacterial vaginosis, Gedea Biotech uses a tablet to restore the acidity of the vagina to a healthy state and encourage the growth of beneficial bacteria. This way, antibiotics — the typical treatment for the condition — could be spared for emergency uses.
“So far, we see many initiatives from national and international policymakers to reduce the use of antibiotics or to develop new ones,” said Säfholm. “There is not much focus on alternative treatments that actually treat infections without antibiotics.”
While viral vaccines and treatments have been in the spotlight during the Covid-19 pandemic, an indirect consequence of the coronavirus pandemic is that hospitals have become increasingly crowded, and more patients are at risk of catching antibiotic-resistant superbugs. This accelerates the need for new options against them.
Additionally, the stunning changes in fortune for the biggest vaccine makers have boosted morale in other areas of infectious disease research.
“Right before the Covid-19 pandemic, we were in a very bad situation. We said, ‘this is not going to work with antibiotics; it is becoming very, very hard to raise money,’” said Cohen-Kutner. “The pandemic changed this because companies like BioNTech and Moderna gained billions in their valuations.”
If a glorious return in antibiotic investments does happen, it’s likely years away. The market remains broken, and much hinges on whether it can be repaired via drug pricing reforms and the adoption of new technology.
“We kind of solved the anti-infective problem for about 40 years, which was like the golden age,” said Bachnoff. “But ever since then, it’s been downhill.”
“We have to stop this decline, because otherwise we’re going to end up back in the pre-antibiotic era, and it’s going to be messy.”
This article was updated on 23 September 2021 to clarify a quote from Aleks Engel. Cover image from Elena Resko