BEST SCIENCE

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FOR THE MOST NEGLECTED

GHIT PDP Webinar
Byron Arana
DNDi Geneva, Switzerland
Head of the Cutaneous
Leishmaniasis Clinical Program

20 October 2021

www.dndi.org

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Leishmaniasis: 98 countries,
1 billion people at risk•

Leishmaniasis is a complex vector-borne disease withdifferent clinical manifestations:••Primary targets for the programme: VL and CL.
Secondary targets: PKDL, HIV-VL, complicated CL.

•Linked to environmental changes such as deforestation,building of dams, irrigation schemes and urbanization*.

•Affects some of the poorest people on earth*.

•Prone to outbreaks, mainly related to displacement ofvulnerable population due to conflict.

•700,000 to 1.4 million new cases occur annually*; 14,454
deaths associated with leishmaniasis

50,000 – 90,000
estimated VL
cases/year worldwide,
half of them are children

Endemicity of Cutaneous Leishmaniasis* WHO, 2020www.dndi.org

Cutaneous Leishmaniasis• Endemic in 88 countries• 0.7 to 1.2 million new CL cases annually worldwide.
• Every 30 seconds there is a new case of CL• Eastern Mediterranean region contribute to ~60% of global CLburden••••3>12 species and dozens of proven vectors and reservoirs
No vaccine
No chemoprophylaxis
Limited number of drugs with variable efficacy

Diseases Severity

No TxLocal topical

Systemic oral

Small lesion, L.
major or L.
mexicana

IL antimonials
Liquid Nitrogen
Thermotherapy

Miltefosine

Syst. Parenteral
MA / SSG
Pentamidine
Amphotericin B

Combinations
TT + MF
SbV + Allopurinol
SSG + Pentoxifylline

Variable efficacy, high rate of AEs, lengthily schemes, low compliance

Topical & oral drug, safe, effective against all forms of CL, at a low-cost and be adapted for use in rural areas

4CL Scarring, stigma and mental health problem

DNDi Cutaneous leishmaniasis strategy

5To achieve short, safe, non-invasive, efficacious, affordable, and field-friendly
treatments for CL or at least for lesions caused by L. tropica and L. braziliensis.

Complicated Forms(LR, DCL, PKDL, nonresponders)

Immunemodulator
CpG D35
1-4 lesions, ≤ 4 cm

Multiple or large lesions,or lesions in face

Combination
TT + MIL

Oral NCEs
0690, 6148, etcTopicals

www.dndi.org

6CpG ODN D35
v Patent owned by the US government and licensed to DNDi.
D. Verthelyi, D. Klinman and K. Ishii are named as inventors
on the patent covering D35 filed on April 1999.

Mode of Actionv CpG D35 is a Class A (also know as class D) synthetic
oligonucleotide, TLR9 agonist, designed to activate theinnate immune system and enhance the effector
mechanism to control Leishmania infection.
v It has been tested in a monkey CL model (with L. major andL. amazonensis) with encouraging results (reduction ofpathogenicity, enhanced healing - even without anantiparasitic drug)v Preclinical and CMC studies have been completed by DNDiwith the support from GHIT and in collaboration withGeneDesign and Tokyo University
v First in human study (SAD in HV) is being conducted in UK
and MAD in CL patients will start in mid 2022
v CpG D35 is planned to be administered for CL treatment incombination with an oral antiparasitic drug.
www.dndi.org

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CpG D35: A long Journey
2028
2025-2027
2023-2025

2016-20172014 -2015
1999ODNs andtheir use toinduce
immuneresponse,
Patented byUSG

DNDi
Selection &Pre-clinicalnomination

Preclinicalefficacy
Characterization /Immunostimulatory
effect of D35
Effect of D35 + SbV
in healthy andLeishmania infectedmonkeys

2017-2020
PreclinicalDevelopment

Demonstrate
the suitabilityof CpG D35 forprogression toFIH.

2020-2023
Early clinicaldevelopment

SAD / MAD
studies
API formulation
optimization

Phase II clinicalstudy

Registration

Phase III
clinical study

Effectiveness
Preliminary
efficacy
assessment
Safety in CL
patients

Is it better
than what’s
alreadyavailable?

www.dndi.org

8CpG D35: A global collaboration of drug development expertisewww.dndi.org

9CpG D35 in the time of COVID-19
COVID-19 has impacted in different ways the development of the project• The lockdown and stay-at-home orders by the end of 2020 and beginning of 2021 caused a drop in thenumber of study participants, forcing the CROs to postpone the initiation of new studies.
• Many CROs were fully involved in conducting large studies on COVID-19 vaccines and not accepting newprojects.
• Because the effects of CpG D35 in the immune system, an exclusion period of one month before and afterreceiving a COVID-19 vaccine has been imposed for all participants.
• The fear that CpG D35 interact with the host immune system is making potential participants being morehesitant to participate in a FIH study of an injectable product.

www.dndi.org

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Lessons learned• GHIT funds has created an especial environment with Japanese pharmaceutical companies and internationalorganizations fostering global partnership committed to patients’ needs, creating medicines and vaccines
against diseases for which there is a lack of R&D funding.
• Japanese pharma companies, research organizations and universities bring unique resources and capabilities
including alternative drug discovery approaches, chemical classes not found abundantly in other libraries,
technologies, insights and experiences gained through the whole process of product development.
• Oligonucleotides are not simple small molecules, so both the discovery and manufacturing require work withexperts at the forefront of oligonucleotide. Having the opportunity to work with one of the creators of CpG
D35 and with a pharma company with the expertise on GMP manufacturing oligos is exceptional and prizedexperience.
• Working in international environment always brings some challenges, often related to communication andculture, time zones differences and others but the politeness, diplomacy and Japan’s gastronomy compensatesin abundance any of the challenges.

www.dndi.org

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Thank You
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