Delivery of new drugs for visceral leishmaniasis

There are estimated to be 600 million people at risk of visceral leishmaniasis (VL) across the globe with 50,000 to 90,000 new cases every year, mainly among the poorest of the poor. The disease is caused by Leishmania parasites and is spread through the bite of infected sandflies. Limited therapeutic options make the treatment of this neglected disease very challenging. Each drug currently in use has serious drawbacks, such as difficulty in administration, length of treatment, toxicity, cost, and emerging drug resistance.

The DDU in 2011 initiated a major research programme to uncover new drugs for this disease, including developing novel assay platforms to revolutionise leishmaniasis drug discovery [1, 2]. A ‘Mode of Action’ research team was also established to discover the molecular targets of drug candidates that were at an advanced stage of development [3-5]. The DDU and GlaxoSmithKline currently have a research team of >40 scientists working on this Wellcome-funded programme of translational research for VL. Success of the programme is evidenced by the discovery and development of two clinical drug candidates for VL, each with different mechanisms of action. The first candidate arose from a compound series previously discovered in the DDU that inhibited growth of the related Trypanosoma brucei. Through clever iterative changes to the chemical core scaffold, we were able to produce a compound active against the Leishmania parasite. The work, published in 2018, also identified the target of the compound as cyclin-dependent related kinase 12 (CRK12), providing a completely novel validated drug target for Leishmania [3]. Discovery of the second clinical drug candidate also began with compounds discovered in Dundee to be active against a different related parasite, Trypanosoma cruzi, which causes Chagas disease. Repurposing and optimisation [4, 5] produced a compound with potent activity against Leishmania that was shown to act through inhibition of the proteasome [5].

There is an urgent need for new oral treatments for VL that work through novel modes of action. This enables combination therapies that will improve efficacy and reduce the risk of resistance. In April 2017, DNDi and GlaxoSmithKline, in collaboration with the DDU, entered into a formal agreement for the preclinical development of the two drug candidates discovered in Dundee. The most advanced compound was declared as a preclinical candidate by GlaxoSmithKline in July 2018 [6] and human Phase 1 clinical trials began in May 2019 [7]. The second compound was approved for Phase 1 clinical trials in June 2020 [8] and the first subjects were dosed in October that year.

These clinical candidates represent step-changes in the development of treatments for VL since both are orally bioavailable in humans. Globally, only three other oral VL candidates are currently being clinically assessed [9]. Dundee has therefore contributed 40% of the global new compounds in the pipeline for combination clinical testing. Addressing the impact of these new drug treatments, the Discovery Director at DNDi said:

References

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2. Nühs, A, De Rycker, M, Manthri, S, Comer, E, Scherer, CA, Schreiber, SL, Ioset, J-R & Gray, DW 2015, 'Development and validation of a novel Leishmania donovani screening cascade for high-throughput screening using a novel axenic assay with high predictivity of Leishmanicidal intracellular activity', PLoS Neglected Tropical Diseases, vol. 9, no. 9, e0004094. https://doi.org/10.1371/journa...;
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4. Thomas, MG, De Rycker, M, Ajakane, M, Albrecht, S, Álvarez-Pedraglio, AI, Boesche, M, Brand, S, Campbell, L, Cantizani-Perez, J, Cleghorn, LAT, Copley, RCB, Crouch, SD, Daugan, A, Drewes, G, Ferrer, S, Ghidelli-Disse, S, Gonzalez, S, Gresham, SL, Hill, AP, Hindley, SJ, Lowe, RM, MacKenzie, CJ, MacLean, L, Manthri, S, Martin, F, Miguel-Siles, J, Nguyen, VL, Norval, S, Osuna-Cabello, M, Woodland, A, Patterson, S, Pena, I, Quesada-Campos, MT, Reid, IH, Revill, C, Riley, J, Ruiz-Gomez, JR, Shishikura, Y, Simeons, FRC, Smith, A, Smith, VC, Spinks, D, Stojanovski, L, Thomas, J, Thompson, S, Underwood, T, Gray, DW, Fiandor, JM, Gilbert, IH, Wyatt, PG, Read, KD & Miles, TJ 2019, 'Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis', Journal of Medicinal Chemistry, vol. 62, no. 3, pp. 1180-1202. https://doi.org/10.1021/acs.jm...
5. Wyllie, S, Brand, S, Thomas, M, De Rycker, M, Chung, C-W, Peña, I, Bingham, R, Bueren-Calabuig, J, Cantizani, J, Cebrian, D, Craggs, PD, Ferguson, L, Goswami, P, Hobrath, J, Howe, J, Jeacock, L, Ko, EJ, Korczynska, J, MacLean, L, Manthri, S, Santos Martinez, M, Mata-Cantero, L, Moniz, S, Nuhs, A, Osuna-Cabello, M, Pinto, E, Riley, J, Robinson, S, Rowland, P, Simeons, F, Shishikura, Y, Spinks, D, Stojanovski, L, Thomas, J, Thompson, S, Viayna Gaza, E, Wall, R, Zuccotto, F, Horn, D, Ferguson, M, Fairlamb, A, Fiandor, JM, Martín, J, Gray, D, Miles, TJ, Gilbert, I, Read, K, Marco, M & Wyatt, PG 2019, 'Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition', Proceedings of the National Academy of Sciences, vol. 116, no. 19, 201820175, pp. 9318-9323. https://doi.org/10.1073/pnas.1...
6. Press release citing R1 on declaration of preclinical drug candidate to treat VL, GSK3186899/DDD853651. University of Dundee 2018, ‘Discovery of a new potential treatment for visceral leishmaniasis’ ScienceDaily. 26^th July 2018. Available at http://bit.ly/38a4Api
7. Phase I Clinical Trial. Sponsor: GlaxoSmithKline 2019, ‘Safety, Tolerability and Pharmacokinetics (PKs) investigation of GSK3186899 in Health Subjects’ ClinicalTrials.gov (NCT03874234). 14^th March 2019. Available at https://bit.ly/3rpe9Zg
8. Phase I Clinical Trial. Sponsor: GlaxoSmithKline 2020, ‘Safety, Tolerability and Pharmacokinetics (PK) Investigation of GSK3494245 in Healthy Participants’ 7th August 2020 ClinicalTrials.gov (NCT04504435). Available at http://bit.ly/3rmWgKi
9. DNDi 2020 portfolio update validating that Dundee’s GSK3186899/DDD853651 & GSK3494245/DDD1305143 are two of only five candidate drugs in Phase 1 for treatment of VL (CpG-D35 is for CL, not VL): ‘R&D Portfolio December 2020’ DNDi https://bit.ly/3sVbkQ2