EnLAmB - Enabling global access to affordable generic liposomal amphotericin B injectable formulations via advanced manufacturing technology

Over 1 billion people are currently affected by Neglected Tropical Diseases (NTDs), resulting in half a million deaths and up to 57 million disability-adjusted life years lost annually. Within the NTD population, many deaths are also attributed to HIV-associated fungal infections, such as cryptococcal meningitis (CM), talaromycosis, and histoplasmosis. Recently, the burden of fungal infections was further deepened by COVID-associated pulmonary aspergillosis and mucormycosis. Liposomal amphotericin B (L-AmB)/AmBisome® has been the treatment of choice for these opportunistic fungal infections, offering superior safety and efficacy for immunocompromised patients. However, since the approval of L-AmB in 1997, the availability and affordability of this essential medicine remain a major challenge in low/middle-income countries (LIMCs). Only 22 of the 116 epidemic countries have L-AmB registered and available, representing an underserved population of over 2.8 billion. Access to the L-AmB in these countries has heavily relied on the donations made by the only manufacturer of AmBisome®, and private treatment can cost as high as £50,000 per patient. The lack of access to L-AmB at affordable prices is a public health crisis and represents a significant challenge to global health equity.

Given the difficulties and high costs of new drug development and the current commercial and public health deficiencies in this field, it is more realistic and impactful to resolve the L-AmB global supply issues through the cheaper and scalable generic medicine approach. However, the current method for generic L-AmB manufacturing is costly and unscalable. We have developed a simple, cost-effective, scalable manufacturing technology for directly producing L-AmB. Our approach aims to transform the traditional 5-step complex process into a single-step continuous process, significantly reducing costs and increasing production efficiency. We plan to further develop this technology for generic L-AmB bioequivalence study in humans.

Since the 1950s, amphotericin B has been the medicine of choice for invasive fungal diseases (IFD) and is listed on the WHO Essential Medicine List. To improve the drug's efficacy and reduce its toxicity, LAmB has been developed, binding and disrupting the fungal cell walls with enhanced fungicidal activity. Nanomedicine L-AmB has a prolonged circulating half-life and enhanced localised delivery at the sites of infection in the brain, lungs, and liver, leading to its success in the treatment of HIV-associated fungal infections and visceral leishmaniasis. However, limited by its production capacity, this essential medicine has a significant global supply shortage and disproportionate high prices, particularly in low/middle-income countries. Moreover, the development of complex generic medicine has been very challenging. Several generic versions of L-AmBs have previously been approved outside the US, but many have subsequently been withdrawn due to safety concerns. The difficulty for LAmB is also accentuated by the costs associated with large-scale manufacturing and low-profit margins, making it challenging to produce a generic product at affordable prices. To resolve the fundamental issues related to supply and demand challenges for affordable L-AmB in lower/middle-income countries, we have developed an alternative method that produces generic L-AmB with higher throughput and lower manufacturing costs. In this project, we are proposing to bridge the in-vivo efficacy gaps of the in-house LAmB and deliver the product profiles required for the next phase of human bioequivalence studies. Ultimately, we want to improve the accessibility, affordability, and sustainability of L-AmB through our new approach, helping to bring health equity to patients across the globe.