Introduction and Background of the Project

Introduction

Malaria continues to inflict a devastating burden on low-income countries, and development of effective new liver-stage prophylactic agents is a priority for the antimalarial field. Antisense oligonucleotides (ASOs) are well-matched to this unmet need, offering the possibility of long-duration activity and benefiting from effective delivery to hepatocytes using well-established conjugation technology. Furthermore, ASOs are a platform technology that enable highly selective targeting of essential Plasmodium genes, with the potential to access previously undruggable targets and accelerate development of additional drugs following initial validation. Eisai has developed proprietary nucleic acid technologies that enhance these advantageous properties.

Project objective

This project will undertake a rigorous investigation as a novel antimalarial strategy, with the goal of demonstrating in vivo proof-of-concept for ASOs as long-acting malaria prophylactic.

Project design

Well-validated malaria target genes will be examined for tractability, and ASOs against the selected target will be optimized using high-throughput cell culture assays at UCSD and Eisai’s nucleic acid technologies. High-potency optimized ASOs will be tested in a causal prophylaxis animal model to assess in vivo efficacy.

How can your partnership (project) address global health challenges?

Despite significant advances, malaria continues to inflict a devastating public health burden on low-income countries, claiming over 400,000 lives and infecting 228 million people in 2018. The development of new prophylactic agents is a priority for antimalarial development, for protection of low-income migrants and travelers, non-immune populations in the event of outbreaks or epidemics, and – notably – to replace successful seasonal malarial chemoprevention programs with a more easily delivered prophylaxis program. In each case, long action is highly desirable to reduce dosing frequency; delivery is a large fraction of the cost of deployment, and to mitigate difficulties in ensuring multiple doses are taken to achieve continued protection. Injectable drugs that can achieve long duration, including antibodies, have therefore been the subject of increased interest, and MMV has recently set out a working target product profile for injectable prophylactics with minimum and ideal dosing criteria of monthly and 3-monthly, respectively (Macintyre et al. 2018).

ASOs are well-matched to this unmet need, but have not been thoroughly-explored as antimalarials. ASOs can exert activity in target tissues over extended periods, and clinical data support monthly dosing (Crooke et al. 2019). A well-established hepatocyte delivery technology, GalNAc conjugation, can be leveraged to effectively target ASOs against liver schizonts. Importantly, by acting at the mRNA level ASOs provide opportunities to access previously undruggable target genes, offering the potential to expand the repertoire of malaria drug targets. Extensive nucleotide divergence with the human genome also means essential Plasmodium genes can be targeted with high selectivity. As a platform technology whose toxicity and pharmacokinetic profiles are primarily driven by chemistry rather than sequence, a validated approach can enable accelerated development against additional targets. Furthermore, ASOs have excellent bioavailability following subcutaneous administration – a route consistent with the injectable TPP – and lyophilization formulation avoids the necessity for cold supply chain.

What sort of innovation are you bringing in your project?

This project sets out a robust investigation of ASOs as an innovative antimalarial strategy with the potential to deliver a safe, long-acting prophylactic. The validation of this platform would add a new modality with transformative potential to the antimalarial arsenal. A not insignificant additional benefit would be the provision of a new tool for validation of malaria drug targets. The collaborative project team brings together cutting-edge target biology and screening capabilities with advanced nucleic acid technologies and pharmaceutical development expertise.

Role and Responsibility of Each Partner

At UCSD, Prof. Winzeler’s laboratory will identify gene targets for evaluation, and has established high-throughput liver-stage and blood-stage cell culture assays that will be employed for ASO profiling. In addition, the Winzeler lab will be responsible for conducting animal efficacy studies.

Eisai will be responsible for design and optimization of ASOs, and contribute its proprietary nucleic acid technologies to these efforts. In addition, Eisai will be responsible for PK studies of ASO candidates.

Both teams will collaboratively contribute to development strategy, experimental design and data analysis based on their experience in development of novel antimalarials.

Others (including references if necessary)

Crooke S.T., et al. (2019). Nucleic Acid Ther. 29,16–32.

Macintyre F. et al. (2018) Malar J. 17, 402.