DNDi’s current leishmaniasis portfolio includes:

Research

Four projects in the research phase:

• Leish H2L: This project continues to evaluate hits identified from high-throughput screens and to begin the process of optimizing these new chemical series. If promising activity can be demonstrated in in vivo models of leishmaniasis, the series will be advanced into full lead optimization. This process of ‘hit-to-lead’ optimization is ongoing with multiple series from several pharmaceutical companies.

• DNDI-5421 & DNDI-5610 oxaboroles: These two compounds from the oxaborole class serve as back-ups to DNDI-6148. Their further development is currently put on hold and will only recommence should problems be encountered with the pre-clinical development of DNDI-6148.

• Aminopyrazoles: The aminopyrazole class of compounds has shown promising early profiles for the treatment of both visceral and cutaneous leishmaniasis. Profiling of current and new leads in a panel of drug-sensitive and drug-resistant strains of leishmania, exploration of the in vivo dose response, rat pharmacokinetics, and initial in vitro safety assays are all underway. The ongoing lead optimization programme aims to select an optimized lead.

• CGH VL series 1: US pharmaceutical company Celgene has been optimizing a series of quinazolines/pyridopyrimidines for VL in collaboration with the London School of Hygiene and Tropical Medicine and Advinus. An in vivo proof-of-concept has been achieved for this series. An intensive lead optimization programme is ongoing with Celgene to identify an optimized lead.

Translation

Four projects in the translation phase:

 DNDI-6148 oxaborole: In January 2016, DNDI-6148, from the oxaborole class, was nominated as a pre-clinical candidate for the treatment of VL. Pharmaceutical development activities (drug substance and drug product development and manufacture) have now been initiated, and the toxicity/safety pre-IND package was launched starting with dose range finding studies, along with refinement of ADME (absorption, distribution, metabolism and elimination), efficacy and safety profile to ensure a smooth transition from the pre-clinical phase to Phase I clinical phase, which should happen over the course of 2017.

• DNDI-0690 nitroimidazole: DNDI-0690, a nitroimidazole for the treatment of VL and possibly CL, was selected for pre-clinical development in September 2015. In 2016, DNDi activities focused on pharmaceutical development activities (drug substance and drug product development and manufacture), launching of toxicity/safety pre-IND package with dose range finding studies, as well as refinement of ADME, efficacy and safety profile to ensure a smooth transition from the pre-clinical phase to Phase I clinical phase, which should happen over the course of 2017.

• CpG-D35 for CL: This project aims to produce an immunomodulator to stimulate the innate immune system to fight the parasitic infection, as an adjunct to drug therapy. 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 bothperipheral blood mononuclear cells and whole blood samples from patients with both CL, 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.

• New CL combination therapies: When administrated alone, the safety and efficacy profiles of current CL treatments (antimonials, miltefosine, and thermotherapy) are well established. Using a combination of therapeutic approaches may improve efficacy rates, reduce treatment duration, and improve the rate of adverse events. A combination of one single application of thermotherapy at 50°C for 30 seconds with a three-week course of oral miltefosine will be tested in order to gain information about safety and efficacy. At the end of 2016, official approvals were obtained, a site initiation visit conducted and the first patients were enrolled in Peru, while final approvals are expected by early 2017 for a second site in Colombia.

Two projects in early clinical phases were interrupted in 2016:

• Fexinidazole/miltefosine combination: Before proceeding to a proof-of-concept study in patients, a drug-drug interaction study was to be conducted in up to 60 healthy volunteers to assess the combination’s pharmacokinetics, tolerability and safety. While ethical approval was granted, French regulatory authorities stated that there was not sufficient information available to completely rule out the fertility risk related to miltefosine exposure to justify a study in healthy volunteers. Considering the excellent activity of the new oral chemical entities currently in pre-clinical development for VL, the development of fexinidazole/miltefosine combination was therefore stopped.

• Anfoleish for CL: The rationale for the development of a topical formulation of amphotericin B was to provide a treatment to be applied locally at the CL lesion, showing high anti-parasitic effect, but without the systemic toxicity associated with amphotericin B. A Phase Ib/II open-label, randomized, non-comparative, two-arm exploratory study was conducted in Colombia. Initially planned to include only patients with CL caused by braziliensis, recruitment was widened to include people with CL caused by L. panamensis. Enrolment of all 80 patients was completed in November 2015. Study results did not support the continuation of the clinical development of Anfoleish in its current formulation. Alternatives options are currently under consideration.

Development

Four projects in the clinical development phase:

• New treatments for HIV/VL: In 2014, a Phase III study testing both AmBisome® monotherapy (at a higher dose than current practice) and a combination of AmBisome® and miltefosine was initiated at two sites in Ethiopia for the treatment of HIV/VL co-infection. After 132 patients had been enrolled, recruitment was interrupted at the time of the second interim analysis, as efficacy at the end of treatment was lower than expected. Patients who had not achieved cure at the end of treatment were given a second cycle of the same treatment. With the extended treatment duration, results achieved with the combination treatment were found to be very promising, with the majority of patients achieving VL cure. These results were based on a limited number of patients; a new HIV/VL study is therefore under consideration to confirm the results.
• New treatments for PKDL: A Phase II study testing both AmBisome® monotherapy and a combination of AmBisome® and miltefosine is underway in India and Bangladesh to assess the safety and efficacy for patients with post-kala-azar dermal leishmaniasis (PKDL). A separate Phase II study to assess the safety and efficacy of both AmBisome® in combination with miltefosine, and paromomycin in combination with miltefosine, is planned in Sudan. Site visits have been undertaken at all participating sites in the three countries, and protocols and study documents are under finalization for submission to ethical and regulatory review. In addition, two PKDL infectivity studies are under preparation in Bangladesh and Sudan. Their objective is to establish the infectivity of PKDL patients to sandflies, to determine if PKDL patients maintain inter-epidemic transmission of VL. If this is confirmed, early treatment of PKDL patients would be critical elements of any VL public health and elimination strategy.

• Miltefosine/paromomycin combo for Africa: A Phase III clinical trial will be conducted in East Africa to compare the efficacy and safety of two combination regimens of miltefosine and paromomycin with the current standard VL treatment sodium stibogluconate (SSG)-paromomycin, in both paediatric and adult patients. Sites will be located in Kenya, Sudan, Uganda and Ethiopia. If the combination is proven safe and efficacious, current treatment would no longer rely on SSG, an injectable drug, which would be replaced with miltefosine, an oral drug. A safer, more field-adapted, patient-friendly treatment would particularly benefit children, who represent a high proportion of the population at risk in East Africa. The trial protocol is under finalization and will be submitted to ethics committees and regulatory authorities in early 2017.

• New VL treatments in Latin America: In 2011, a Phase IV study sponsored by the Brazilian Ministry of Health was initiated at five sites in Brazil to evaluate the efficacy and safety of Amphotericin B deoxycholate, AmBisome® and a combination of AmBisome® and Glucantime®, in comparison to Glucantime®, the existing first-line treatment of VL. 378 patients were recruited. Brazil’s national guidelines for VL were revised in 2013 based on the interim safety data from the trial. While Glucantime® remains the first-line treatment, AmBisome® replaced Amphotericin B deoxycholate as a second-line treatment. The final results of this trial were presented to the Ministry of Health, and are expected to guide further policy change in Brazil.

Implementation and Access