Virus Induced Respiratory Insufficiency

Virus Induced Respiratory Insufficiency

Disease Background: Virus infected patients can develop a variety of symptoms, but lung involvement is very common – and in some viral diseases like COVID-19 it is the main cause of death. Patients can develop respiratory insufficiency where they are unable to provide enough oxygen to the body and these patients often require oxygen supplementation in order to maintain adequate levels. As respiratory insufficiency continues it can cause severe pneumonia and can also develop into acute respiratory distress syndrome (ARDS), a very serious condition where patients often require mechanical ventilation to breathe adequately.

Viral or secondary bacterial infections can also cause the immune system to be highly overly active and produce excessive quantities of pro-inflammatory molecules (a ‘cytokine storm’, also known as Systemic Inflammatory Distress Syndrome or SIDS) which can cause damage to key organ systems like the lungs, kidneys and heart.

COVID-19 virus infections can cause significant respiratory issues.  In order to prevent the inflammation-associated damage that COVID infection can cause, it is important to resolve the excessive inflammation without suppressing the immune system’s ability to fight the viral infection.  The goal of therapy would be to arrest the excessive inflammation and prevent severe disease which can quickly consume available hospital resources.

COVID-19 Respiratory Distress Development:  AP1189 has been tested in animal models with SIDS and shown to selectively reduce inflammation and stimulate macrophages to clean-up the inflamed tissue.  In order to effectively investigate the potential for AP1189 to help COVID-infected patients, we formed the RESOVIR (Resolution Therapy for Viral Inflammation Research) collaboration.  RESOVIR is a scientific and clinical collaboration between Professor Mauro Teixeira, MD, PhD, Universidade Federal de Minas, Belo Horizonte, Brazil, Professor Mauro Perretti, PhD William Heavy Research Institute, Barts and the London School of Medicine, Queen Mary University, London, UK, and SynAct Pharma AB. The aim of the RESOVIR collaboration is to investigate the utility of resolution therapy to resolve the cytokine storm inflammation associated with significant viral infections.

Clinical development of AP1189 in COVID-19-induced respiratory insufficiency

Working in the RESOVIR collaboration, we designed and executed a 60 patient Phase 2a clinical trial in Brazil.  Patients were enrolled in the study who required supplemental oxygen (experiencing respiratory insufficiency).  These patients were hospitalized, and all received steroids (dexamethasone) at an average dose of 6mg/day.  After an initial open-label safety run-in of 6 patients, the blinded placebo-controlled portion of the trial dosed an additional 36 patients with 100mg of AP1189 and 18 patients with placebo, each given orally once-daily for 2 weeks.

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Results

The trial concluded in June of 2021 and topline data has been released.  Patients treated with 100mg AP1189 orally once-daily for 2-weeks achieved respiratory recovery (no longer requiring oxygen therapy) on average 3.5 days (35%) quicker than placebo treated patients (6.4 days and 9.9 days on average respectively).  All AP1189 treated patients (including the first 6 open-label safety patients) recovered respiratory recovery on average 4.0 days (40%) quicker than placebo treated patients (5.9 days and 9.9 days on average respectively).

Randomized AP1189 treated patients were on average discharged from the hospital 2.8 days earlier than placebo treated patients.  When the 6 open-label patients are added to this assessment the average hospital discharge time was 3.3 days quicker for AP1189 patients.

By day 4, 50% of all AP1189 treated patients had achieved respiratory recovery (Vs 34% for placebo) and 41% had been discharged from the hospital (Vs 0% for placebo).

AP1189 treated patients were also less likely to require mechanical ventilation and to develop acute kidney injury (AKI).

Importantly AP1189 was well tolerated and safe with treatment limiting AEs, no discontinuations and no serious adverse events in the AP1189 group.   Reported adverse events were numerically higher in the AP1189 group and most were mild and self-limiting and believed to be tied to the current oral suspension dosing which can cause nausea and GI discomfort.  Data from this exploratory pilot clinical trial supports that AP1189 may help COVID-19 infected patients recover impaired lung function, be discharged from the hospital quicker and prevent bad outcomes like the need for mechanical ventilation or the development of AKI.

Next Steps for AP1189 in COVID-19-induced respiratory insufficiency

We are exploring a potential path to emergency use authorization (EUA) with ANVISA, the Brazilian health authority. We believe that this would require an additional confirmatory trial. In parallel, SynAct is also accelerating development of its oral tablet form of AP1189 to be able to use the tablet form in the confirmatory trial. If we can align on a path to EUA in Brazil, design a feasible confirmatory study and the tablet formulation is ready, we anticipate being able to initiate the new trial the first half of 2022.

Given that the excessive inflammation seen with COVID-19 infections is a common outcome of serious viral and bacterial infections, SynAct will also investigate other infection settings characterized by respiratory insufficiency like influenza or RSV where AP1189 may have utility.