Effective, affordable antimicrobial drugs are desperately needed around the world, and last November, a clinical trial offered a glimmer of hope, when an oral antibiotic, called zoliflodacin, was shown to be effective against the bacterium that causes gonorrhoea.
Because it is the first of a new class of antibiotics, the drug also offers hope of stopping the spread of “super gonorrhoea”, which is resistant to most standard treatments.
That month brought good news on another front, too, reports Nature. An international research team reported that a new antifungal drug, fosravuconazole, was safe and effective at treating a devastating disease called fungal mycetoma, which scars and damages the skin and can lead to amputation if left untreated.
Antifungal drugs are difficult to develop and are scarce. The only existing mycetoma treatment requires taking expensive pills for a long time: two pills per dose, twice daily, for several months.
The new drug requires only two pills once weekly, which could reduce stress and expense for tens of thousands of people in South Asia and sub-Saharan Africa.
What is especially notable about the success of these two drugs, however, is that they followed a new path to get this far. Both trials were conducted by non-profit organisations founded specifically to bring new drugs to the market: zoliflodacin by the Global Antibiotic Research and Development Partnership (GARDP) based in Geneva, Switzerland, and fosravuconazole, by the Drugs for Neglected Diseases Initiative (DNDi), also in Geneva.
These organisations hope to fill a big gap in the development and testing of medicines at a time when most legacy pharmaceutical firms have withdrawn from antimicrobial drug discovery, and many of the small biotechnology companies that picked up the torch have gone bankrupt.
These two latest achievements suggest non-profits could help to solve the problem of drug access, while fending off the rise of drug-resistant microbes contributing to almost 5m deaths annually.
Pass-along value
Both drugs followed a complicated path to the market. They were originally developed by conventional pharmaceutical companies: fosravuconazole by Eisai in Tokyo, and zoliflodacin by Entasis Therapeutics in Massachusetts, now part of Innoviva in California.
Under the agreements these companies have with the NPOs, the original firms retain some rights to the drugs, either for manufacturing and distribution, or for sales in high-income countries. But the goal has been to get both to low-income countries at affordable prices.
For the antifungal, fosravuconazole, that is already happening. On the basis of the trial results reported last year, Sudan’s Ministry of Health has allowed people to receive the drug while the country’s National Medicines and Poisons Board evaluates its registration.
The trial, which recruited 104 people in Sudan between 2017 and 2020, compared treatment using fosravuconazole over 12 months with the standard of care, a drug called itraconazole.
The trial found no statistically significant clinical difference – meaning treatment for mycetoma could be made in a less expensive, less complex way.
Eisai first developed ravuconazole, the predecessor to fosravuconazole, as part of a search for treatments for skin infections. But in 2003, a Venezuelan research project found the drug was effective in mice against Chagas disease, a parasitic infection affecting several million people in Latin America.
The study caught the attention of the DNDi, which was searching for treatments to address the neglected disease at the time.
Eisai and the DNDi jointly launched a phase two trial in Bolivia to explore the drug’s efficacy against Chagas disease. Although it was unsuccessful, an unrelated research project at the Mycetoma Research Centre at Sudan’s University of Khartoum found ravuconazole was effective against fungal mycetoma.
This offered the compound a second chance at approval, and validated a strategy that the DNDi has pursued since 2003, when the organisation was founded by members of Médecins Sans Frontières (Doctors Without Borders): breathing life into drugs that have been abandoned or underused.
“We call it repurposing: taking a drug that was developed for one indication, that was left on the shelf for whatever reason, that we then repurpose for another indication,” says Rachel Cohen, the DNDi’s senior adviser for global policy advocacy and access. (The organisation has since developed its own drug discovery programme, but it does not operate laboratories or manufacturing facilities.)
The development of zoliflodacin was bumpier; its route to market encapsulates the decline of antibiotics research. The compound was first identified at Pharmacia, in Michigan, which was acquired by Pfizer in 2003. When Pfizer exited antibiotics research in 2011, zoliflodacin went to AstraZeneca, in Cambridge, UK. Then, when AstraZeneca began to withdraw from antibiotic research, the drug ended up at the newly founded Entasis in 2015.
Then the US National Institute of Allergy and Infectious Diseases funded a clinical phase 2 trial, testing the safety and efficacy of zoliflodacin in 179 people. Entasis also managed to acquire an agreement from the US Food and Drug Administration (FDA) that will earn it regulatory approval once the company has completed one successful phase 3 trial.
During this time, the incidence of gonorrhoea was rising worldwide; in the US, it increased by two-thirds between 2013 and 2017.
And the bacterium was steadily gaining resistance to the several families of antibiotics used to cure it, turning what had been an easily handled infection into an almost untreatable menace.
“DNDi is set up to focus on neglected diseases, and we were set up to address antimicrobial resistance,” says microbiologist Laura Piddock, the GARDP’s scientific director. In 2019, the GARDP became an independent organisation with a focus on specific bacterial infections in low-income nations that lack full access to new drugs.
Around the same time, Entasis decided to focus its limited funding on a different drug from its AstraZeneca programme, a new combination antibiotic aimed at drug-resistant pneumonia.
Innoviva licensed zoliflodacin to the GARDP, nd agreed to collaborate with the NPO on the phase 3 trial – which expanded to 16 sites in five countries – and the subsequent FDA registration.
Push and pull
As large pharmaceutical companies continue to withdraw from the antibiotics business, drug developers have been trying to stimulate public conversation about creating better incentives for small biotechnology firms.
There are two basic strategies: push and pull. Push incentives support research by getting new compounds through trials and up to the point of approval; pull incentives take over afterwards, supporting companies so they can survive until their earnings start flowing.
Push incentives have had some success. The best example is the non-profit organisation CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator), at Boston University, which has committed US$452m to early-stage research, contributed by governments and big philanthropic organisations.
Pull incentives, however, have faced political headwinds. Although many options have been debated, only one has launched: a subscription-style arrangement whereby drug companies receive grants that constitute advance down payments on future sales.
The idea is that by removing the incentive for a company to sell a new drug aggressively, and thereby reducing the use of the drug, it will delay the inevitable arrival of resistance to it.
Only one entity has committed to that subscription programme so far: the UK government. In 2022, the UK National Institute for Health and Care Excellence (NICE) decreed that the National Health Service (NHS) could justify paying £10m per year to two companies for future purchases of two drugs to be used against severely drug-resistant, hospital-acquired infections.
In mid-2023, the NHS endorsed the concept and announced plans to expand it, potentially raising the payments to £20m. By contrast, in the US, a piece of legislation – the PASTEUR Act – which would create a similar programme, has not made it through Congress despite repeated tries.
But, by funding the registration and launch of drugs in countries that cannot afford to pay commercial prices for them, both the DNDi and the GARDP are effectively providing pull incentives – something these organisations can afford to do because, as non-profits with external funders, they don’t need to earn the level of income a company would require.
That means they are providing a model not only for how much-needed drugs can be rescued in the development process, but also for how companies can be supported when their compounds are released on to the market.
Specialists who have been watching this field for a while say it’s important not to forget the part that pharmaceutical companies have played in developing fosravuconazole and zoliflodacin, which both emerged from conventional discovery programmes.
Nature article – Can non-profits beat antibiotic resistance and soaring drug costs? (Open access)
See more from MedicalBrief archives:
First new gonorrhoea drug in 40 years offers promise
South Africa in phase three trial to combat global gonorrhoea threat
GARDP: SA site activation in global phase 3 study of Zoliflodacin as gonorrhoea treatment
Declining susceptibility to azithromycin found in German gonorrhoea samples