CpG-D35 (DNDI-2319)

The multiple ascending dose study was stopped due to futility after the enrolment of six participants. Four participants received CpG-D35; two received miltefosine. All adverse events reported were mild or moderate and did not require the interruption of treatment. Recruitment difficulties were related to the need for hospitalization and particularly narrow inclusion and exclusion criteria. Ongoing efforts aim to simplify the study protocol and procedures and expand the pool of potential participants.

The Phase I multiple ascending dose study protocol was approved by the Colombian regulatory authorities in June 2023, allowing for the importation of study drugs and organization of the study site initiation visit, which was held in July 2023. The screening of potential participants started in September. Although 42 potential participants were pre-screened by the end of December, the number of subjects meeting enrolment criteria was below expectations. An amendment to the study protocol that aims to expedite enrolment and complete the study by the end of 2024 is under development.

The results of the single ascending dose study conducted in 2021 were analyzed and supported continuation to a multiple ascending dose study to take place in the second quarter of 2023 in Medellin, Colombia. The study design, protocol, and other key documents were developed, internally approved, and submitted to the local ethics committee in late 2022 for review and approval. The study testing the efficacy of CpG-D35 (DNDi-2319) for the treatment of uncomplicated cutaneous leishmaniasis lesions is expected to begin in the second quarter of 2023.

Following the completion of the pre-clinical toxicology studies in 2020, the CpG-D35 clinical trial progressed to first-in-human clinical trials in 2021. As chemistry, manufacturing, and control activities continued as planned, a single ascending dose study in healthy volunteers was initiated and completed in the UK. Overall, CpG-D35 was found to be well tolerated and safe, and none of the criteria for stopping dose escalation were met. Based on these results, plans are underway to progress to a multiple ascending dose study in patients with cutaneous leishmaniasis.

Pre-clinical toxicology studies were completed in late 2020 and demonstrated the suitability of CpG-D35 to progress to first-in-human clinical trials. Clinical and pharmaceutical development will continue with support from Japan’s Global Health Innovative Technology Fund (GHIT Fund), with planned initiation of a single ascending dose study in healthy volunteers in the UK by mid-2021.

Pre-clinical toxicology studies were initiated in 2019 and should be completed by mid-2020. Pending positive results, DNDi hopes to initiate a first-in-human Phase I study by late 2020.

A pre-clinical package enabling a first-in-human study (Phase I) will be performed in 2019. A meeting with the UK Medicines and Healthcare Products Regulatory Agency is planned for 2019 to discuss the pre-clinical development plan and clinical package.

Final results of the preclinical in vivo efficacy study showed an improved outcome for CpG-D35, either alone or in combination with pentavalent antimony (glucantime). These results supported the completion of the pre-clinical package and initiation of the preparation of clinical supplies for a Phase I study.

Two studies, one in vitro and one in vivo, were initiated in 2016. The in vivo study aims to demonstrate if CpG-D35 – whether alone or in combination with antimonials chemotherapy – will lead to improved leishmania infection outcomes, compared with antimonials alone. Results are expected by mid-2017. The in vitro study aims to assess the stimulatory capability of CpG-D35 in both peripheral blood mononuclear cells and whole blood samples from patients with both cutaneous leishmaniasis, due to different leishmania species, and PKDL patients and to determine which host genes are modulated in these two conditions. Results are expected by the end of 2017.

IND-enabling pre-clinical safety prerequisites and service providers for entry into Phase I proof-of-concept clinical trials were identified.