An investigator-initiated phase II study has been launched with SynAct Pharma’s lead candidate, resomelagon, in patients with dengue in Brazil. This trial runs in parallel with the ongoing study in rheumatoid arthritis. BioStock spoke with the company’s CSO, Thomas Jonassen, who sees strong potential for resomelagon in both RA and dengue, as well as other indications:
– We work behind the scenes to expand our pipeline and look forward to presenting the next program(s) once we are ready, says Jonassen.

These efforts reflect SynAct Pharma’s broader mission to develop therapies that restore immune balance and resolve inflammation by activating the melanocortin system. Unlike traditional treatments, resomelagon is designed to provide both anti-inflammatory and pro-resolving effects without suppressing the immune system.

This approach is relevant in several diseases and conditions connected to excessive inflammation, for example viral-induced hyperinflammation. Several viral infections, including dengue, can trigger a cytokine storm – an excessive and dysregulated immune response that can lead to severe complications.

Growing dengue threat highlights unmet medical need

Dengue is a mosquito-borne viral illness that primarily affects people in tropical and subtropical regions. In recent years, however, the virus has spread into temperate areas, including parts of Europe and the US – a shift likely driven by climate change.

Symptoms typically include high fever, severe headaches, muscle and joint pain, nausea, and skin rashes. In some cases, dengue can progress into a severe and potentially life-threatening form, marked by internal bleeding, organ damage, and circulatory shock. Despite its growing global spread and severity, no targeted pharmacological treatments are currently available once symptoms develop – a gap SynAct Pharma aims to address.

By targeting immune resolution, resomelagon presents a novel therapeutic strategy to address this critical unmet medical need. According to SynAct Pharma’s CSO, Thomas Jonassen, preclinical studies have shown promising results:

– Resomelagon has shown to reduce severity of Dengue in experimental animal models and to reduce the proinflammatory activity of human white cells challenged with Dengue Virus, says Jonassen.

Dengue study underway in Brazil as part of RESOVIR collaboration

To explore the potential of resomelagon as an add-on therapy for severe viral infections, SynAct Pharma has established the RESOVIR collaboration (Resolution Therapy for Viral Inflammation Research) in partnership with the Universidade Federal de Minas Gerais (UFMG) in Brazil and Queen Mary University of London.

As part of this initiative, a phase II clinical study in dengue patients has been launched, led by Professor Mauro Teixeira at UFMG, with clinical sites spread across Brazil. SynAct Pharma notes that patient recruitment and study progression will depend on the severity of this year’s dengue outbreak in these regions.

The study will assess the efficacy of once-daily oral resomelagon compared to placebo in 120 patients with symptomatic dengue. The primary endpoint is time to disease resolution, while secondary endpoints include reducing early warning signs and preventing progression to severe dengue.

Previously, under the same collaboration, resomelagon has demonstrated positive clinical outcomes as an add-on therapy in a phase II study involving hospitalised COVID-19 patients – further supporting its potential to address inflammation in severe viral infections.

Q&A with CSO

BioStock spoke with SynAct Pharma’s CSO, Thomas Jonassen, to gain deeper insight into the potential of resomelagon as a novel treatment for virus-induced inflammation.

What motivated SynAct to expand its pipeline to dengue?

– During the pandemic we set up the RESOVIR collaboration aimed to investigate the potential of our resomelagon compound and other compounds that induce inflammatory resolution. The first study we conducted was in COVID-19 patients where we showed that resomelagon significantly reduced time clinical resolution of severe respiratory insufficiency with the result that the patients were faster discharged from hospital. For us, it is very clear that the potential of the compound was not restricted to Covid-19 virus, but had the potential as being a new treatment approach to reduce severity of viral infections, a so-called host-directed therapy to remodulate the overactivity in the immune system induced by a given virus.

– We therefore continue the work in the RESOVIR collaboration to further substantiate the clinical potential of the compound and among the diseases of interest is Dengue.

– Dengue is an arboviral infection, i.e. a viral infection transmitted from the bite of infected mosquitos. The incidence of the disease is increasing and the mosquitos that transmit the disease are spreading outside the tropical and subtropical part of the world, most likely due to climate changes. As a result, mosquito is now established in Europe and US with increased reports of local infections.

– When epidemics are present, one example is Brazil last year, several thousand new cases can develop every day with many severe cases needing hospitalization. It is estimated that more than 100 million people around the world get infected with the virus every year.

– As Dengue can develop into severe disease and no specific treatment is available, we found it logical to evaluate the compounds potential in Dengue and found very promising data in disease models including human white cells infected with the virus. The next step was therefore to continue with the RESOVIR-2 study.

Can you tell us a bit more about what resomelagon could mean for those suffering from dengue fever?

– Dengue is associated with fever and other signs of infections not so different from what we know for influenza and in most cases the disease will be self-limiting with days, but some patients develop severe symptoms with hemoconcentration and increased risk of bleeding that further can develop with shock symptoms, internal bleeding, organ failure and death. These severe symptoms are associated with what is called a hyperinflammatory response, i.e. that the virus infection induces an inappropriate response in the immune system. In principle, through mechanisms, comparable from what was seen in severe COVID-19 infections. In other words, the virus induces the disease, but the overactivity in the immune system induced by the virus induces life-threatening symptoms.

– Consequently, if you had a treatment option to rebalance the immune system, not just suppress it, it could protect the development of severe Dengue and or reduce the severity of the symptoms in established severe Dengue. Resomelagon is one such treatment option as it has the potential to be introduced in established disease with the potential to reduce symptoms and reduce the likelihood of developing severe Dengue.

The first patient has now been dosed with resomelagon in the RESOVIR-2 study in Brazil. What can we expect?

– We had set the study up with the potential to recruit at several sites in Brazil with the aim to focus our activities where the disease is present. Last year it would have been very easy to recruit as most metropolitan areas experienced large epidemic. In fact, even Buenos Aires in Argentina had, for the first time ever, a large out brake. This is not the case this year where no real epidemic has been present in big metropolitan areas including Belo Horizonte, the hometown of the principal investigator, Professor Mauro Teixeira. Further, we are already in the late season for the mosquito and thereby Dengue in Brazil, meaning that the recruitment rate will be slower than what would be possible during an epidemic. Or phrased differently, we are not able to give more information about timing at this time point. However, we know that the mosquitos will come back and then we will be ready.

How is the RESOVIR-2 dengue study financed?

– The study is as the previous clinical study in the RESOVIR collaboration set up as an investigator-driven study. It means that the investigator and not the company is the one who gets the approvals and runs the study. This is a much more cost-effective approach than a sponsor (company) initiated study, and can, in the right format, as we have through the RESOVIR collaboration, be a very attractive way of running the study. From a financial perspective, it means that we can run it within our current budget.

Will SynAct consider other indications beyond rheumatoid arthritis and dengue?

– Absolutely. We see two very attractive parallel development paths for resomelagon.

– The first is a novel treatment option in inflammatory and autoimmune diseases, where the compound though its mode of action could be a game changer with regard to early and patient-friendly intervention. Here is our current rheumatoid arthritis program the front runner project, but we do not see the potential restricted to RA. We are looking into other indication where we from a setup as the one applied to the RESOVIR-2 study, will have the possibility to run smaller proof of concept studies, without breaking the bank, in collaboration with key opinion leaders to support the potential of the compound.

– The second path for the potential of the compound is host-directed treatment in viral infections. Here the RESOVIR-2 study is the next step, but definitively not the only opportunity.  Not only COVID-19 virus induces severe viral infection with development acute respiratory insufficiency. Infuenza virus and RS virus do the same and we have seen and will see significant manifestations of these virus infections where resomelagon potentially could reduce the severity of the disease.

– In other words, even though we are not ready to commit to development in additional diseases, we work behind the scenes to expand our pipeline and look forward to presenting the next program(s) once we are ready.

Any implication on your business development strategy?

– We continue to see a strong interest for partnerships and an additional indication adds value to the total deal potential for us. So yes, further discussions are in progress and now more indications to discuss.

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