R&D Portfolio Update March 2018: DNDi Leishmaniasis programme

 

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DNDi aims to deliver:

  • An oral, safe, effective, low-cost and short-course treatment for visceral leishmaniasis (VL).

  • A new treatment for post-kala-azar dermal leishmaniasis (PKDL) that is shorter and better tolerated than current options.

  • A new treatment regimen for patients co-infected with HIV and VL.

  • A safe, effective, and shorter-course treatment for cutaneous leishmaniasis (CL).

 

DNDi’s current leishmaniasis portfolio includes:

VL patient under treatment in Sadar Hospital Chapra

Research

Research

Seven projects in the research phase:

  • Leish hit-to-lead: The process of hit-to-lead optimization is ongoing with multiple series from several pharmaceutical companies and with hits from libraries purchased from commercial vendors and screened by DNDi. If promising activity can be demonstrated in pre-clinical models of leishmaniasis, the series will be advanced into full lead optimization.
  • Booster hit-to-lead: Two new companies joined the booster in 2017 with Merck KGaA becoming the sixth consortium partner and AbbVie the seventh, with an eighth under negotiation to join. To date, 32 iterations of the booster have been launched around 16 distinct seed compounds. Ten hit series have been identified, four of which will enter into proof-of-concept in vivo efficacy studies by Q1 2018.  
  • Daiichi-Sankyo leishmaniasis hit-to-lead (new project in 2017): The objective of this 18-month hit-to-lead collaboration project, which is supported by GHIT and was initiated in April 2017, is to identify at least one – possibly two – progressable lead series meeting DNDi lead stage criteria for visceral leishmaniasis and/or Chagas disease. Three T. cruzi active series (series 1-3) were identified from a high throughput screening of 40,000 members of the Daiichi Sankyo Pharma Space Library. Current medicinal chemistry efforts of this hit-to-lead collaboration focus on one series (series 1) that was confirmed as the most promising chemotype in terms of activity and selectivity profile. To date, over 100 analogs to series 1 have been synthetized and tested for T. cruzi activity at Institut Pasteur Korea, leading to the identification of four preferred molecules nominated to proceed with pharmacokinetics studies. A parallel screening of a representative compound set of the still unscreened part of the Daiichi Sankyo Pharma Space Library has enabled us to identify T. cruzi active chemotypes, of which two have been prioritized for resynthesis and follow-up activity.
  • DNDI-5421 & DNDI-5610 oxaborole: These two compounds from the oxaborole class serve as back-ups to DNDI-6148. Their further development is currently on hold and will only recommence should problems be encountered with the pre-clinical development of DNDI-6148.
  • Aminopyrazoles: Four back-up compounds to DNDI-5561, which was nominated as a pre-clinical candidate from the aminopyrazoles series (VL series 12), are well advanced and offer similar profiles to DNDI-5561. Additional studies, including preliminary toxicology assessment, are being planned to further understand the safety profiles of these compounds and identify the best back-up to DNDI-5561.
  • CGH VL series 1: DNDi’s collaboration with Celgene Global Health continues to explore the potential of this series to deliver a pre-clinical candidate.
  • Leish L205 series (new project in 2017):  Following proof-of-principle with 205 series for VL, compounds of this series showed 100% parasite load reduction in liver and spleen in a VL murine model. Further characterization of this series is ongoing.

 

Translation

Translation

Five 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 and possibly CL. The preclinical toxicology studies package was completed in 2017. The decision was made to progress to Phase I single ascending dose in healthy volunteers in parallel with additional toxicological investigations. Satisfactory outcome of these two studies will trigger initiation of the multiple ascending dose part of Phase I.  
  • DNDI-0690 nitroimidazole: DNDI-0690, a nitroimidazole for the treatment of VL and possibly CL, was selected for pre-clinical development in September 2015. A full preclinical toxicology and safety studies package was completed in 2017. The decision to progress to Phase I Single Ascending Dose in healthy volunteers was agreed in January 2018.
  • DNDI-5561 (new project in 2017): DNDI-5561 is the front-running second-generation aminopyrazole. Following positive results of efficacy and safety studies, DNDI-5561 was selected as pre-clinical candidate.
  • 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. 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.  
  • New cutaneous leishmaniasis (CL) combination therapies: Recruitment of patients continued in Peru with the inclusion of 41 patients, and started in Colombia with the inclusion of 21 patients (out of 130 patients in total). An interim analysis is planned in early 2018 once 65 patients have completed the day 90 follow-up visit.

 

DevelopmentDevelopment

Four projects in the clinical development phase:

 

  • New treatments for HIV/VL: Main efficacy results were presented to the Ethiopian authorities and WHO in Addis Ababa, Ethiopia, in June and December 2017, to promote the implementation of the combination of AmBisome® and miltefosine as first line treatment for HIV/VL co-infected patients, using the strategy of one or two treatment cycles. A scientific paper should be published in 2018 and open the discussions with other stakeholders to support new recommendation for HIV/VL co-infection.

    In India, DNDi is technical partner with the Rajendra Memorial Research Institute (RMRI) in a study sponsored by MSF and launched in Bihar in 2017.  This Phase III study will test Ambisome monotherapy and Ambisome in combination with miltefosine in 150 patients. 113 patients have been included so far. This will then feed into the national road map of kala azar elimination from India.

  • New treatments for PKDL: Recruitment started with 6 patients enrolled in clinical sites in India (RMRI in Patna and KAMRC in Muzzafarpur) for the Phase II study to test both AmBisome® monotherapy and a combination of AmBisome® and miltefosine, while the clinical site in Bangladesh received final approvals and is preparing for initiation. The clinical site in Sudan (Dooka) for the Phase II study to test both AmBisome® in combination with miltefosine, and paromomycin in combination with miltefosine is in preparation for the initiation visit. The PKDL infectivity study in Bangladesh completed the recruitment of 65 patients. In Sudan, the preparation of the insectarium for the same study continues.
  • Miltefosine/paromomycin combo for Africa: Clinical sites for the Phase III study to compare two combination regimens of miltefosine and paromomycin with the current standard VL treatment, sodium stibogluconate, and paromomycin, in both paediatric and adult patients started with the recruitment of the first patient in Sudan (Dooka) in January 2018. Clinical sites in Kenya (Kacheliba) and Ethiopia (Gondar) are about to be initiated, followed by other sites in Uganda and Kenya.

 

Implementation

Implementation and Access
 
 
 
  • SSG&PM Africa: KalaCORE, the UK Aid-funded partnership, which includes DNDi, to support the control and elimination of visceral leishmaniasis in six countries (India, Nepal, Bangladesh, Ethiopia, Sudan and South Sudan), continued to support the implementation of SSG&PM in East Africa. Access has been considerably improved by strengthening the national control programmes of Ethiopia, South Sudan, and Sudan, and regular supply and distribution of diagnostics and medicines.    
  • New VL treatments Asia: Following a 2016 pilot study in Bihar, India on three regimens (including new combination therapies (single dose AmBisome® (SDA), a combination of miltefosine and paromomycin, and a combination of AmBisome® and miltefosine) whose results contributed to a change in the national treatment guidelines in India, a follow-up protocol was developed for a cohort observational study to estimate the incidence of post-kala-azar dermal leishmaniasis (PKDL) during or more than 24 months post-treatment in VL patients treated with any of the three regimens. Enrolment started in June 2016, and by the end of 2017, recruitment was completed with 1622 participants assessed (representing 92% of the VL patients treated in the India implementation study). Preliminary results show that PKDL was observed in 3.6% of patients at least 24 months after treatment of VL. Further analysis is ongoing.  

 

 

Photo credit: Kishore Pandit-DNDi