Calibr is a nonprofit drug discovery institution founded in 2012 with expertise in high-throughput screening and medicinal chemistry. The organisation also has well-established partnerships with companies like Pfizer, BMS, and AbbVie. Anil Gupta, Associate Director, Calibr at Scripps Research, presented his work on developing a long-acting injectable, Atovaquone prodrugs for Malaria Chemoprophylaxis.
Over the last six years, Gupta and his team have been building their long-acting injectable platform. The main objective of this platform is to reduce the frequency of dosing and reliance on expensive polymers and improve patient compliance. Often, patients do not take their medication, perhaps due to side effects or simply forgetting, which can result in relapse or disease progression.
He explored how different formulations of the prodrugs compared in terms of stability and injectability. The three prodrugs developed were DHA ester, heptanoic acid ester, and a methyl ester. When the pro-drugs were formulated in aqueous suspension and oil solutions, they showed promising results in terms of maintaining high concentrations and stability under various conditions.
Malaria is a prominent infectious disease in Sub-Saharan Africa. Gupta developed multiple prodrugs of Atovaquone to flatten the PK curve and achieve sustained drug release without using enhanced formulation to save cost. In rodent studies, the pro-drugs showed flattened PK curves with reduced Cmax and extended duration up to 11 weeks. In cyno studies, T max was delayed to day 16, which lowered the Cmax and sustained drug levels for up to 15 weeks. This far surpassed the 20-day duration of native atovaquone.
With injectables for malaria and other infectious diseases, Gupta explained that it is ideal to deliver just a small amount of the compound (approximately 1 -2 mL), which means the compound has to be potent. The team managed to achieve formulations that were stable under tropical conditions, injectable with small-gauge needles, and maintained high drug concentrations to minimise injection volume. A long half-life is another vital feature for adequate safety profiles.
This work represents an important step towards malaria prevention. Gupta is aiming to progress to first-in-human trials. He wrapped up his talk by emphasising the broader potential of this platform for other diseases like HIV, highlighting the importance of modifying active pharmaceutical ingredients to achieve desirable release profiles.
