Introduction and Background of the Project

Introduction

Dengue fever is a mosquito-borne viral infection found in tropical and subtropical regions around the world. There are 4 distinct, but related, serotypes of dengue virus (DENV) that cause dengue fever. The viral infection leads to symptoms that can include high fever, severe headache, joint, muscle and bone pain and skin rash. Mild bleeding is often observed because DENV inhibits the blood clotting function. In severe cases, plasma leaks out from blood vessels and the fluid loss can be fatal. A recent study estimates that approximately 390 million people are infected, and 500,000 people with severe dengue require hospitalization each year. A specific treatment for dengue has not been established yet.

Project objective

This Project aims to develop a safe and highly effective anti-DENV antibody that neutralizes all 4 serotypes for treatment of dengue fever without a risk of antibody-dependent enhancement (ADE), which is assumed to be related to severe disease during secondary DENV infection.

Project design

In partnership with the GHIT Fund, Chugai and SIgN are working on preclinical development of the novel anti-DENV antibody. The objectives of the continuing project are shown below.

1)        Manufacturing of drug substance and drug product under GMP conditions for the First-in-Human (FIH) clinical trial (Phase I)

2)        Completion of preclinical studies (e.g. GLP-toxicology studies) enabling the Investigational New Drug (IND) application for testing in human

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

Symptomatic patients with dengue fever are often forced to be absent from work for 1 to 2 weeks due to high fever, severe pain and exhaustion. If children are infected, their parents will also be absent from work for 1 to 2 weeks. During DENV peak season or in outbreak situation, number of ambulatory patients as well as hospitalized patients can increase rapidly, straining existing resources of medical institutions. The annual economic burden, including medical expenses for dengue disease and the cost of economic loss, is estimated to be $ 8.9 billion globally. The economic loss related to dengue diseases is substantial. Reducing the duration of the illness, preventing the progression to severe dengue and shortening the hospitalization period will have a big economic impact.

The novel anti-DENV antibody is expected to accelerate recuperation from dengue fever and shorten hospitalization period. It could also be used as a unique prophylactic treatment with fast-acting and long half-life due to the antibody-specific properties. Unlike a vaccine, the novel anti-DENV antibody can provide a rapid preventive effect which is independent from individual immune competence. An anti-DENV antibody is expected to provide a new treatment option to minimize disease and economic burden in endemic countries globally.

What sort of innovation are you bringing in your project?

To prevent dengue fever, several vaccines against DENV are being developed and evaluated currently. However, there are some limitations and restrictions in vaccination and an effective virus-targeting drug is required immediately. Importantly, the antibody drug will be used together with vaccines in a complementary manner. The novel anti-DENV antibody will be effective for dengue patients who haven’t received a dengue vaccine or for whom prior vaccination was ineffective.

Role and Responsibility of Each Partner

Chugai has various advanced antibody technologies and years of experience in developing antibody drugs from preclinical to clinical stages. Chugai will be responsible for project management, manufacturing of drug substance and drug product, nonclinical toxicology and pharmacokinetic studies, clinical study, regulatory science, and communication with the health authorities in this Project.

SIgN has extensive expertise in DENV biology and is part of the dengue research network in Singapore, one of the epidemic areas of dengue fever. SIgN will be responsible for conducting and reporting the nonclinical pharmacology studies, including the in vitro and in vivo anti-viral studies.

Others (including references if necessary)

Xu M. et al. A potent neutralizing antibody with therapeutic potential against all four serotypes of dengue virus. npj Vaccines 2, 2 (2017).