Antibiotic Resistance and Prices: How Non-Profits Fight Back

Non-profit efforts in drug development

In November of last year, a glimmer of hope emerged in the battle against antimicrobial resistance with the announcement of a breakthrough clinical trial. The trial showcased the effectiveness of zoliflodacin, an oral antibiotic, against the bacterium responsible for gonorrhoea. Notably, zoliflodacin belongs to a novel class of antibiotics, raising prospects of combatting the spread of drug-resistant strains of gonorrhoea, often dubbed ‘super gonorrhoea’.

Simultaneously, another positive development surfaced on the medical horizon. An international team of researchers disclosed the promising results of a new antifungal medication, fosravuconazole, in treating fungal mycetoma. This debilitating disease inflicts skin damage and scarring, with severe cases potentially leading to amputation if left untreated. The scarcity and difficulty in developing antifungal drugs exacerbate the challenge. Presently, the existing treatment regimen demands expensive pills taken over several months, twice daily. In contrast, fosravuconazole only requires a weekly dose of two pills, presenting a potential relief for tens of thousands affected in South Asia and sub-Saharan Africa, both in terms of stress and financial burden.

What distinguishes the success of these two drugs is the unconventional path they took to reach this milestone. Both clinical trials were orchestrated by non-profit organizations explicitly established to usher new drugs into the market. Zoliflodacin was shepherded by the Global Antibiotic Research and Development Partnership (GARDP) headquartered in Geneva, Switzerland, while fosravuconazole’s development was spearheaded by the Drugs for Neglected Diseases Initiative (DNDi), also based in Geneva.

These organizations aim to bridge a significant void in drug development and testing, especially at a time when major pharmaceutical companies have largely retreated from antimicrobial research, and many smaller biotechnology firms that assumed the mantle have succumbed to bankruptcy. The recent achievements of these non-profits signify a potential solution to the challenge of drug accessibility while countering the surge of drug-resistant pathogens, which claim nearly five million lives annually.

Helen Boucher, an infectious-diseases physician and dean of the Tufts University School of Medicine in Boston, Massachusetts, lauds these developments as a boon for frontline clinicians. She emphasizes the pressing need for more antibiotics and the imperative to explore diverse avenues for their development.

Fosravuconazole and zoliflodacin’s journey to accessibility

The journey of both drugs to the market was intricate and multifaceted. Initially developed by conventional pharmaceutical companies, fosravuconazole originated from Eisai in Tokyo, while zoliflodacin stemmed from Entasis Therapeutics in Waltham, Massachusetts, now part of Innoviva in Burlingame, California. Under agreements with non-profit organizations, these original firms retained certain rights to the drugs, whether for manufacturing, distribution, or sales in select high-income countries. However, the primary objective has been to make both drugs accessible and affordable in low-income countries.

In the case of fosravuconazole, progress towards this goal is underway. Building on the trial results reported last year, Sudan’s Ministry of Health has authorized the distribution of the drug while the country’s National Medicines and Poisons Board evaluates its registration. The trial, conducted between 2017 and 2020, enlisted 104 participants in Sudan and compared fosravuconazole treatment over 12 months with the standard of care, itraconazole. The findings revealed no statistically significant clinical disparities, suggesting a more cost-effective and streamlined approach to mycetoma treatment.

Borna Nyaoke-Anoke, a Nairobi-based physician and head of DNDi’s mycetoma disease program, who oversaw the trial, highlights the financial burden faced by patients in African endemic regions, where itraconazole can exceed $2,000 per year. Addressing a neglected tropical disease affecting the most marginalized and impoverished individuals, the need for accessible treatments is paramount, particularly for those struggling to earn even $1 a day.

The journey of fosravuconazole traces back to Eisai’s development of ravuconazole, initially explored for treating skin infections. However, a pivotal 2003 Venezuelan research project discovered its effectiveness against Chagas disease in mice, an infection afflicting millions in Latin America. This finding captured the attention of DNDi, prompting a collaborative phase II trial in Bolivia to assess its efficacy against Chagas disease. Though unsuccessful, a separate initiative at the Mycetoma Research Center at the University of Khartoum in Sudan unveiled ravuconazole’s effectiveness against fungal mycetoma, paving the way for its repurposing and eventual success in combating this neglected disease.

The revival of ravuconazole marked a second chance for approval, affirming the strategy pursued by Drugs for Neglected Diseases Initiative (DNDi) since its inception in 2003. Founded by Médecins Sans Frontières (MSF or Doctors Without Borders) members, DNDi specializes in breathing new life into abandoned or underused drugs through a process termed “repurposing.” Rachel Cohen, the DNDi’s senior adviser for global policy advocacy and access, explains this approach of repurposing involves taking drugs originally developed for one purpose but left dormant for various reasons and repurposing them for another indication. Despite having established its own drug discovery program, DNDi does not directly operate laboratories or manufacturing facilities.

The trajectory of zoliflodacin’s development reflects the challenges within the field of antibiotics research and the drug’s tumultuous journey to market. Initially identified at Pharmacia in Kalamazoo, Michigan, zoliflodacin passed through the hands of Pfizer, AstraZeneca, and eventually Entasis, illustrating the decline in antibiotic research by major pharmaceutical companies. The US National Institute of Allergy and Infectious Diseases supported a clinical phase II trial for zoliflodacin, assessing its safety and efficacy in 179 individuals. Entasis secured an agreement with the US Food and Drug Administration (FDA), allowing regulatory approval pending successful completion of one phase III trial, contrary to the usual requirement of two such trials.

During this period, global gonorrhoea rates surged, with a 66% increase in the United States from 2013 to 2017. Simultaneously, the bacterium responsible for gonorrhoea developed resistance to multiple antibiotic families, transforming a once easily treatable infection into a formidable challenge. The World Health Organization (WHO) responded to the growing threat of antibiotic resistance by proposing a global action plan in 2015. In 2016, the WHO played a role in establishing the Global Antibiotic Research and Development Partnership (GARDP), backed by €2 million from various governments and MSF. GARDP, with administrative support from DNDi, adopted a similar model to identify cost-effective opportunities for developing useful drugs.

Laura Piddock, microbiologist and GARDP’s scientific director, emphasizes the distinction between DNDi’s focus on neglected diseases and GARDP’s mission to address antimicrobial resistance. GARDP evolved into an independent organization in 2019, concentrating on specific bacterial infections prevalent in low-income nations lacking access to new drugs. Concurrently, Entasis, facing budget constraints, redirected its efforts towards a different drug from its AstraZeneca program— a combination antibiotic for drug-resistant pneumonia. The collaboration between Innoviva (which acquired Entasis in 2022) and GARDP materialized, with Innoviva licensing zoliflodacin to GARDP. Together, they embarked on a phase III trial across 16 sites in 5 countries and subsequent FDA registration.

Push vs. pull incentives in the antibiotic market

As major pharmaceutical companies continue to withdraw from the antibiotics sector, efforts to stimulate discourse on creating better incentives for small biotechnology firms have intensified. These efforts primarily focus on two strategies: push and pull incentives. Push incentives aim to support research by facilitating the progress of new compounds through trials and towards approval. Notably, the non-profit organization CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator), based at Boston University, stands out as a prominent example. CARB-X has allocated a substantial sum of US$452 million, sourced from governments and major philanthropic entities, towards early-stage research initiatives.

In contrast, pull incentives, which sustain companies post-approval until they begin to generate revenue, have encountered political obstacles. While various options have been deliberated, only one model has been actualized: a subscription-style arrangement where drug companies receive grants serving as advance down payments on future sales. The UK government has spearheaded this initiative, with the National Institute for Health and Care Excellence (NICE) sanctioning annual payments of £10 million (US$12.6 million) to two companies for future purchases of drugs combating severely drug-resistant, hospital-acquired infections. Despite attempts, similar legislation in the United States, such as the PASTEUR Act, has yet to pass through Congress.

Nevertheless, the Drugs for Neglected Diseases Initiative (DNDi) and the Global Antibiotic Research and Development Partnership (GARDP) play a pivotal role in funding drug registration and launch in countries unable to afford commercial prices. Acting as non-profits with external funders, they provide pull incentives, a model financially unattainable for profit-oriented companies. This approach not only rescues much-needed drugs during development but also supports companies upon their market release.

Experts emphasize the crucial contribution of pharmaceutical companies to the development of drugs like fosravuconazole and zoliflodacin, both originating from conventional discovery programs. Drug discovery entails exorbitant costs, with estimates suggesting expenses of up to $1.4 billion from compound identification to FDA approval. While DNDi and GARDP have garnered significant funding, they have not faced such formidable financial burdens. Kevin Outterson, executive director of CARB-X, underscores the indispensable nature of DNDi and GARDP’s contributions, characterizing them as unique and vital. Nevertheless, he emphasizes that these non-profits cannot replace the role of pharmaceutical companies in drug development.

Resources

1. ^JOURNAL McKenna, M. (2024). Can non-profits beat antibiotic resistance and soaring drug costs? Nature, 626, 942–944. [Nature]
2. ^JOURNAL Urbina, J. A., Payares, G., Sanoja, C., Lira, R., & Romanha, Á. J. (2003). In vitro and in vivo activities of ravuconazole on Trypanosoma cruzi, the causative agent of Chagas disease. International Journal of Antimicrobial Agents, 21(1), 27–38. [International Journal of Antimicrobial Agents]
3. ^JOURNAL Ahmed, S., Kloezen, W., Duncanson, F. P., Zijlstra, E., De Hoog, G. S., Fahal, A. H., & Van De Sande, W. W. J. (2014). Madurella mycetomatis Is Highly Susceptible to Ravuconazole. PLOS Neglected Tropical Diseases, 8(6), e2942. [PLOS Neglected Tropical Diseases]
4. ^JOURNAL Taylor, S. N., Marrazzo, J., Batteiger, B. E., Hook, E. W., Seña, A. C., Long, J., Wierzbicki, M. R., Kwak, H., Johnson, S. M., Lawrence, K., & Mueller, J. P. (2018). Single-Dose zoliflodacin (ETX0914) for treatment of urogenital gonorrhea. The New England Journal of Medicine, 379(19), 1835–1845. [The New England Journal of Medicine]

Cite this page: