Introduction and Background of the Project

Introduction

Filarial diseases are a debilitating group of diseases caused by parasitic worms transmitted by the bite of blood-feeding insects. People are infected with river blindness (also known as onchocerciasis) by repeated exposure to blackflies that breed in fast-flowing rivers. The flies transmit worms that can cause severe itching and disfiguring skin lesions, and repeated infection can lead to blindness.

Onchocerciasis is a major cause of blindness in many African countries, the disease is also prevalent in Latin America. The Global Burden of Disease Study estimated in 2017 that there were 20.9 million prevalent O. volvulus infections worldwide: 14.6 million of the infected people had skin disease and 1.15 million had vision loss. Onchocerciasis represents a major public health problem in affected countries with up to 1.34 million disability-adjusted life years (DALYs) lost in 2017. This high number is driven by disease-induced disability and overall loss of economic productivity. Given the strong associations between helminthic infections and mental, physical and economic human development it is essential to consider disease elimination.

Current control strategies are based on preventive chemotherapy programs administered to the population at risk as a whole via mass drug administration (MDA) of ivermectin. While successful in reducing the prevalence of the disease, these programmes need to be repeated for 10-12 years because the drug only kills juvenile worms – not the adult worms, which can live for more than ten years in the human body.

Project objective

The objective of this project is to develop a safe, efficacious, affordable, and field-adapted macrofilaricidal or long-term sterilizing drug for onchocerciasis.

Within the timeframe of this project, DNDi and its partners aim to complete the preclinical development of the molecule DNDI-6166 and make it ready to enter Phase I studies in healthy human volunteers.

Project design

The main objective for this project will be to assemble a data package around DNDI-6166 to support the initiation of first in human (FIH) studies. To reach this objective we propose to conduct four different work packages.

Work package 1, Chemistry, Manufacturing and Controls (CMC): to develop a suitable active pharmaceutical ingredient (API) manufacturing process for scale-up synthesis, to develop and manufacture an enabling FIH formulation.

Work package 2, preclinical safety: to establish the safety profile of DNDI-6166 through regulatory Good Laboratory Practice (GLP) studies.

Work package 3, mechanism of action (MoA): elucidation of the MoA of DNDI-6166.

Work package 4, to refine the safety margin, to refine the human efficacious dose, and to establish the pharmacokinetic/pharmacodynamic (PK/PD) relationship.

How can your partnership (project) address global health challenges?

MDA programmes are being in place for over twenty years but in many countries’ disease endemicity is not under control as a public health problem, let alone being eliminated. There remains an urgent need for a macrofilaricide, targeting the adult stage of Onchocerca volvulus for use in individual case management. Also, MDA will reach a tipping point when test and treat approaches are more cost effective to reach disease elimination. Furthermore, the COVID-19 pandemic had an important impact on treatment coverage which decreased significantly.

In 2020, the World Health Organization (WHO) renewed specific targets for control, elimination, and eradication (https://www.who.int/neglected_diseases/WHONTD-roadmap-2030/en/), including the need for a macrofilaricide for onchocerciasis.  The WHO road map for neglected tropical diseases 2021–2030 calls for the development of a macrofilaricide to accelerate interruption of transmission and an integrated approach to the management of skin NTDs to reduce morbidity, disability, and the psychosocial impacts of debilitating skin NTDs.

The drug research and development pipeline for onchocerciasis needs to be strengthened, of note filarial diseases are among the most neglected, lagging even behind other neglected tropical diseases. This is a very preoccupying situation given the shortcomings of the few available treatments.

Given the rate of attrition in drug discovery and development, it is important to strengthen the pipeline by introducing additional new chemical entities with novel mechanisms of action into the drug development pathway. Additional, more effective, safe and affordable drugs are urgently required to reduce the burden of onchocersiasis and increase the human development index (HDI) in endemic nations.

Research and development activities to develop next generation treatments are indispensable to reach the target set in the WHO road map.

What sort of innovation are you bringing in your project?

New macrofilaricidal drugs will help accelerating elimination of the disease and improve individual patient treatment options. A new treatment such as DNDI-6166, depending on its clinical efficacy, is expected to bring significant benefits to the patients and the community at large with a direct impact on the quality of life and the health of individuals, reducing morbidity and DALYs.

Specifically, DNDI-6166 treatment in onchocerciasis patients will prevent the development of microfilariae -induced dermatitis and vision loss. Furthermore, the predicted lack of efficacy against microfilariae will prevent specific induced adverse events in onchocerciasis and loiasis patients. Indeed, such adverse events are currently observed following administration of ivermectin or diethylcarbamazine (DEC). DNDI-6166 is expected to eliminate the adult filariae and therefore prevent the transmission of onchocerciasis, mansonellosis and loiasis. Treatment of individuals will also shorten and facilitate the elimination program for onchocerciasis.

Because of its specific macrofilaricidal activity, DNDI-6166 could be administrated to patients in loiasis co-endemic areas. Also, it may have an impact on non-communicable diseases onchocerciasis-associated epilepsy and nodding syndrome. The etiology of both diseases is not well understood, but it coincides with the occurrence of onchocerciasis, thus successful treatment and elimination of onchocerciasis may also prevent these life-threatening diseases.

We strongly believe that DNDI-6166 with its broad-spectrum anthelmintic activity will bring the population in need a significant step forward in reducing mortality and morbidity, poverty and hunger and eliminating helminthic infections.

Role and Responsibility of Each Partner

The overall project management will be led by DNDi. 

BoZo Research -ITR will be responsible to conduct preclinical studies (pharmacology studies, general toxicity studies, toxicokinetic and nonclinical pharmacokinetic studies, reproduction toxicity studies, and genotoxicity studies). 

DNDi will conduct procurement to select a Contract manufacturing organisation to develop a suitable chemical process for scale-up synthesis, to develop a formulation for Phase I, and to produce a clinical lot under Good Manufacturing Practice (GMP). 

The Mahidol Oxford Tropical Medicine Research Unit will be responsible to establish the PK/PD relationship using preclinical pharmacology data, to refine the predicted human efficacious dosing regimen, and to establish the pharmacokinetic driver responsible for toxicological effects in animals. 

The UKB University of Bonn will study the mechanism of action and focus on the specific biochemical interaction through which the drug substance produces its pharmacological effect against the parasite. 

Others (including references if necessary)

Caption

“Mama Cecile” in front of her house in Babagulu. Her full name is Cecile Olonga and she was at the Salambongo village health clinic to see doctors who came to her village to screen for river blindness. She arrived to the health clinic accompanied by a neighbor wearing a donated T-shirt that said “Live Fast.” She is blind from river blindness. Mama Cecile is 67 years old and lives alone – her husband is dead. She lives in a small community walking distance away from the health clinic in Salambongo and lives next to her daughters, who help with her care. “One day I went to tend to the fields,” she says. “I was walking behind one of my children and then I started to see poorly – I almost fell into a hole.” One of her children died soon after but afterwards she started to see poorly. Cecile said her child was killed by sorcery. Her legs started to swell and her vision got fuzzier and fuzzier. This was in 2016 – her child died in 2015. I thought it was God doing this to me,” she says, tearing up. There were tons of blackflies in her fields “You couldn’t go out with short sleeves.” She only remembers taking ivermectin one time, in 2003. She remembers having serious side effects [according to health workers back then MDA of ivermectin was 6mg, now it is 3mg a dose] “I didn’t want to take it afterwards,” she says. Mama Celie’s son-in-law and daughter help her a lot. “I am completely dependent,” she says. Even though this care is a huge burden, her children do not want to take ivecmetin. “I’m not interested,” says the son-in-law.

Diseases: Filarial Disease
Region: Africa
Region - African countries Democratic Republic of the Congo (DRC)
Copyright: Ley Uwera-DNDi

Final Report

1. Project objective

The primary objective of the project is to evaluate an amorphous solid dispersion (ASD) formulation of DNDI-6166 through non-GLP exploratory toxicology studies in the rat and the dog. The focus is on refining the therapeutic window for DNDI-6166 in these animal models. The outcomes of these studies will inform and guide the continuation of preclinical development for DNDI-6166, with a specific emphasis on the ASD formulation. This approach aims to establish a more precise understanding of the compound's safety profile and therapeutic range, providing essential insights for subsequent pivotal studies.

2. Project design

Dose Range finding (DRF) in the dog: the study design involved the dosing of 2 dogs per group (one male and one female) at 7, 25, and 75 mg/kg/day for 7 consecutive days.
For rats, 6 animals per group (three males and three females) were administered doses of 7, 25, and 50 mg/kg/day for 14 consecutive days.
Both arms of the study incorporated toxicokinetic assessments and comprehensive pathology examinations to evaluate the compound's pharmacokinetic profile and potential impact on various organs and tissues.

3. Results, lessons learned

We have successfully developed an amorphous solid dispersion of DNDI-6166 and conducted a comprehensive characterization of its physical and chemical properties. Subsequently, we have conducted pharmacokinetics studies in both dogs and rats before initiation of dose range finding studies in these species.

In the dog study, clinical signs such as slight salivation and vomitus were observed in both sexes. Platelet count changes occurred in females and males, with cell infiltration in adipose tissue at 75 mg/kg/day, deemed non-adverse. The No Observed Adverse Effect Level (NOAEL) was established at 75 mg/kg/day, with corresponding mean AUC0-24h and Cmax values of 221,000 [h·ng/ml] and 25,300 [ng/ml] for males and 204,000 [h·ng/ml] and 23,100 [ng/ml] for females.

In the rat study, mortality was observed in the high dose group and dosing was discontinued. At the mid dose, mild and no adverse effects were observed on bone marrow, thymus, spleen, kidneys, liver, and adrenal gland. Based on infiltration of mononuclear cells in the adipose tissues, the NOAEL was determined to be 25 mg/kg/day in males and 7 mg/kg/day in females. Corresponding to AUC0-24h and Cmax values of 104,000 [h·ng/ml] and 14,000 [ng/ml] in males and 65,200 [h·ng/ml] and 10,400 [ng/ml] in females.

The ASD formulation exhibited an expected improvement in the therapeutic index (TI) in both species, with TI values of 19.0 in dogs and 4.0 in rats based on in vitro activity against O. volvulus.