Researchers at KU Leuven Rega Institute and Center for Drug Design and Discovery (CD3), Leuven, Belgium, have identified a new target for treating dengue in collaboration with Jannsen Pharmaceutica, NV. As reported in Nature, the antiviral compound showed strong activity in mice for prophylaxis against dengue and for treatment of the infection.
Dengue is a viral infection acquired through the bite of an Aedes mosquito. It’s endemic in many tropical and subtropical areas globally, particularly in Asia and Latin America. About four billion people are at risk for infection; about 400 million become infected, 100 million become ill, and 40,000 die. There is no specific therapy. People can receive only supportive care.
Co–lead investigator Johan Neyts, PhD, professor of virology, Rega Institute, told Medscape Medical News that it took many years of research, funded by the Wellcome Trust, to find this new molecule. The unique inhibitor, JNJ-A07, prevents two proteins (NS3 and NS4B) from interacting, thereby blocking replication of the virus. Neyts described this as identifying “one of the Achilles heels of your opponent that you…can basically exploit for drug development.”
Neyts stressed that it took months to select for resistance mutations in the lab and that the mutant virus “cannot replicate anywhere in mosquitoes.” Because of this, he said, “the likelihood that it will happen in patients is almost nonexistent.”
After the test tube phase, the researchers proceeded to test the drug in a mouse model. They found that the compound was very effective both prophylactically and as treatment after inrfection. The drug is more efficacious given earlier in the course of infection.
Eng Eong Ooi, MD, PhD, professor of microbiology and immunology, National University of Singapore, told Medscape, “I think this is the first time that there is a compound that works in nanomolar range…. So, in terms of in vitro potency, it’s the best compound…in clinical trials.”
Ooi praised the researchers for exploring “how late dosing can be before they start to see no difference compared to placebo…. For this compound, they’ve pushed the boundary before they got to the clinics.” Findings were so promising that “the conclusion has to be that we take this forward into a clinical trial.”
Ooi did express concern that resistance could emerge with prolonged use. He concluded, “If we want to go down the path of therapeutics, we probably have to start thinking of multiple drugs so as to avoid resistance.”
Alan Rothman, MD, professor of cell and molecular biology at the University of Rhode Island, Kingston, Rhode Island, told Medscape that he views this as a good “technological advance, identifying a new way to inhibit viral replication” and that a “new target is always exciting.”
Rothman said that only “5% to 8% of people in an endemic area might get an infection in a given year.” Only about a quarter of those have symptoms — many don’t know they’re infected. Of those who do get sick, about a quarter become really ill. Most patients delay treatment and “will probably be like the day 6 treatment mice. The impact at day 6 was quite modest.” So, in endemic areas, there is “not likely to have uptake” of this compound for treatment. As prophylaxis for “people who are traveling…it will have to be incredibly safe.”
Ooi added, “Prophylaxis would be a very good way of using this [drug], provided the safety profile is maintained over long-term use.”
Duane Gubler, ScD, chair, Global Dengue and Aedes-Transmitted Diseases Consortium, told Medscape, “My only criticism is their use of the terms ‘viremia’ and ‘viral load.’ The quantitative PCR [polymerase chain reaction] method they used to measure these values does not measure infective virus, only RNA levels. And we know that RNA levels do not necessarily correlate with infectious virus levels, ie, viremia or viral load.”
Both Neyts and Ooi stressed the need for better rapid diagnostics for dengue. Neither felt those would be difficult to develop, but Neyts said that there has been no incentive to do so because no antivirals are available.
Ooi and Rothman were excited by the finding of a new mechanism of action and target for drug treatment. However, their enthusiasm was tempered by the knowledge that most drugs in development fail in clinical trials in people, either because of lack of efficacy or because of safety concerns that emerge.
Gubler concluded, “This is a potentially exciting discovery since we have not been successful in identifying compounds with effective anti-dengue activity. Of definite importance, however, is the discovery that blocking the interaction between NS3 and NS4B is a new mechanism of antiviral action. If this compound succeeds in clinical trials, it would be the first treatment for dengue.”
Neyts is the inventor on the patents on the anti-dengue activity of this compound; these have been licensed to J&J, which is further developing the drug. Ooi and Rothman report no relevant financial relationships.
Nature. Published online October 6, 2021. Abstract
Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.