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A serious consequence of the Covid-19 infection is severe pneumonia, which can lead to acute respiratory distress syndrome (ARDS) and the subsequent need for respiratory treatment. Earlier this week, SynAct Pharma announced that it intends to position its clinical anti-inflammatory drug candidate AP1189 as an adjunctive therapy in hospitalised patients with Covid-19 infection in order to prevent ARDS. BioStock contacted the company’s CEO Jeppe Øvlesen for a comment.

At the moment, significant research efforts are being made around the world to develop a vaccine against Covid-19 (Coronavirus disease 2019), the disease caused by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) virus. However, it is not the virus per se that kills, but rather the systemic harmful effects on the body’s organs caused by the virus. One of the most serious effects of Covid-19 is severe pneumonia, which in turn can lead to acute respiratory distress syndrome (ARDS). The condition often requires respiratory therapy and is the most common cause of death in the ongoing virus outbreak.

ARDS requires anti-inflammatory actions

In addition to the fact that patients with ARDS often require respiratory assistance with a respirator, which provides extra oxygen to the lungs so that the carbon dioxide can exit the body, the disease is also associated with a high risk of developing systemic inflammation distress syndrome (SIDS). This is in turn associated with a high mortality caused by an overactivated immune system (a so-called cytokine storm).

One way of inhibiting inflammation in the lungs is through anti-inflammatory treatment. However, this is a complicated clinical consideration as this treatment can weaken the immune system, which in turn can make it harder for the patient to survive the disease.

This is where Danish biotech SynAct Pharma has identified a potential expanded positioning of its drug candidate AP1189 – the company’s leading candidate and a First-in-Class “biased” melanocortin receptor agonist targeted at active inflammatory and autoimmune diseases. The first-in-class designation refers to a drug that uses a new and unique mechanism-of-action to treat a medical condition.

The research platform builds on an endogenous hormone

SynAct Pharma’s research and patents are based on the endogenous hormone melanocortin. The hormone is typically activated in inflammatory conditions and contributes anti-inflammatory effects that are crucial for the healing process and for recovering normal tissue function. More specifically, melanocortin activates specific receptors on the cell surface of a type of white blood cell, thereby initiating processes for slowing inflammation and stimulating tissue-healing.

The immune defences remain intact

SynActs Pharma’s goal is to become a leading player in resolution therapy against inflammatory and autoimmune diseases. The treatment concept is based on strengthening the immune system’s healing mechanisms by activating the body’s own immune cells. This is different from biological and immunosuppressive drugs that instead act by inhibiting the immune system.

Thus, SynAct Pharma’s treatment concept does not involve the same risk of causing negative immunological side effects associated with current therapies. It also means that the patient’s immune system retains the ability to protect against infectious diseases and the development of cancer among other indications.

Intended treatment for Covid-19

March 31, it was announced that SynAct Pharma intends to expand the indication for its candidate AP1189 and study whether it can have a therapeutic effect in the treatment of Covid-19 patients. The company hypothesises that a therapeutic effect could be achieved by diminishing the inflammatory response of these patients without leading to immunosuppression and a worsening inflammatory status, whilst, at the same time, ensuring adequate respiratory function.

Great market outlook also outside COVID-19

Although Covid-19 has created a new indication space for AP1189, it should not be forgotten that ARDS poses a major challenge to healthcare, beyond the ongoing pandemic.

Mechanical ventilation is still the main therapeutic intervention in ARDS and is, in fact, the only approach that has been shown to reduce the inflammatory response and mortality. For at least 25 years, no major advances have been achieved in this field, thus the mortality rate remains high: 27 percent, 32 percent, and 45 percent for mild, moderate, and severe disease, respectively.

Estimates of the incidence of ARDS in the United States, for example, range from 64.2 to 78.9 cases/100,000 persons. 25 percent of ARDS cases are initially classified as mild and 75 percent as moderate or severe. However, a third of the mild cases go on to progress to moderate or severe disease.

So, in spite of the fact that our understanding of the causes and pathophysiology of ARDS has increased, the epidemiology of the disease contains large knowledge gaps, mortality remains unacceptably high, and new innovative treatments are sorely needed.

The global ARDS market was valued at MUSD 583.8 in 2018 and is expected to reach MUSD 934.8 by the year 2026. Thus, AP1189 has a very exciting market space to exploit, even if the potential COVID-19 market is not taken into account and given the under-treated patient group and the lack of active substances on the market.

Financing clinical studies

The press release of March 31 stated that SynAct Pharma estimates that the cost of a clinical trial with AP1189 on Covid-19 patients will not exceed 15-20 million SEK.

The company expects that today’s cash and an expected 32.8 million SEK from the redemption of subscription rights T0 2 July 2020 will fund the company through to important milestones in other projects. This includes covering the costs for the phase II study with AP1189 in rheumatoid arthritis as well as all the costs until the company reaches Proof-of-Concept with AP1189 in Nephrotic Syndrome.

The CEO comments

BioStock contacted SynAct Pharma’s CEO Jeppe Øvlesen to get a comment about the expanding indication of AP1189.

Jeppe Øvlesen, CEO SynAct Pharma

Jeppe Øvlesen, earlier this week SynAct decided to investigate the potential for the development of AP1189 as additional therapy in hospitalised patients with COVID-19 infection. At what stage of the disease do you think the substance can be of most use to the patient?

– The compound should be given to patients with signs of reduced oxygenation. Either from admission to test whether the compound could protect against the need for non-invasive as well as invasive ventilator treatment. Alternatively, it could be used in patients in need of non-invasive ventilator treatment, i.e. CPAP, to test whether the treatment could avoid or reduce the need for invasive ventilator treatment. This is what we currently discuss with the clinicians.

Currently the primary indications for AP1189 are active RA and Nephrotic Syndrome, but you also believe that your candidate could be of clinical use in Covid-19 patients. How so?

– Because severe Covid-19 infection in many perspectives has similarities with active autoimmune disease as RA and also to some degree NS. The key problem in the RA patients we currently include in our clinical phase II study is overactivation of the immune system in the joints. The joints are swollen, tender and painful because of active uncontrolled inflammation. Likewise, in severe Covid-19 infection the inflammatory response in the lungs is out of control. So, the purpose of our treatment would, just as in RA, be to get the inflammation balanced so that inflammatory system still can fight the virus infection, without all the devastating effects associated with an overactivation.

Can you tell us more about the candidate’s dual mechanisms-of-action?

When we describe that compound as having a dual mechanism of action it refers to the compound’s ability to

  1. Reduce, but not block, proinflammatory pathways like the activation of neutrophils and release of pro-inflammatory cytokines like IL-1β, IL-6 and TNF-α.
  2. To stimulate resolution of inflammation, i.e. boost endogenous pathways that is aimed to clear up inflammations and thereby avoid avid inflammation and subsidiary development into chronic inflammation. A key pathway is to induce the macrophages’ ability to clear neutrophils, a mechanism called efferocytosis.

 How soon will you be able to begin studies in Covid-19 and what regulatory processes do you need to go through before this is possible?

– The first thing would be to setup collaborations with the right clinical sites, then make the right study design. Many sites have initiated or are about to initiate studies on already approved compounds like Chloroquine, IL-6 blockers, immunoglobulins and JAK inhibitors, and we have to have his in mind when we come with a new treatment approach currently in Phase II development. However, we firmly believe that we have something to offer.

– Next would then be to file for the clinical trial application and in parallel secure all the logistics and secure finances to run the study. This is not trivial, but pending financing and authority approval, we would be able to have the compound in patients in less than three months.

AP1189 leads to faster healing of the infection. Can you explain how this process works and why this is of specific interest in the treatment of ARDS in Covid-19?

– Because the AP1189 compound would be able to balance the immune response by combining the inhibition of some unwanted pathways and the stimulation of other beneficial pathways, together with what we call induced resolution. And from what we know about Covid-19 infections, that combination is exactly what is needed to avoid the development of the devastating symptoms that too often kill the patients.

»With our drug candidate AP1189, we have good reasons to believe it could make a difference for these patients. Furthermore, we know that it is safe and have the drug available so that we will be able to start a study very soon« — Jeppe Øvlesen, CEO SynAct Pharma

The decision to expand the indication of AP1189 is based on the fact that IL-6-inhibitors have been reported as potential treatment alternatives to reduce ARDS in patients with serious Covid-19-inflammation. What AP1189-related data do you have that support the assumption that the candidate has potential to also be effective against Covid-19?

– We have data in animal models associated with development of Systemic Inflammatory Distress Syndrome, where the compound inhibits the proinflammatory pathways including secretion of IL-6 and, in parallel, stimulates resolution, not least by stimulating the macrophages’ ability to clear the inflammation.

There is consensus in the research community that we will see new viruses in the future, possibly mutated versions of SARS-CoV-2. Do you see more potential uses for AP1189 in addition to those currently included in your pipeline?

– From the mode of action of the compound it would be likely to conclude that it would work in other infections associated with overactivation of the immune system. Every winter many patients suffer from complications related to the influenza virus infection, and many of these cases are fatal. Consequently, it would be logic to consider to test the AP1189 compound in patients infected with other virus other than SARS-CoV-2, including mutated versions of this virus.

You have stated that the financing of the potential clinical activities will be carried out separately, and thus will not affect SynAct’s ongoing activities within the company’s existing projects. Can you develop this reasoning, and tell us what is needed in order to be able to start a study in Covid-19 patients?

– With the present coronavirus pandemic, there is obviously a lot of attention from governments, hospitals and various funds to find solutions that can avoid or help the many affected patients. With our drug candidate AP1189, we have good reasons to believe it could make a difference for these patients. Furthermore, we know that it is safe and have the drug available so that we will be able to start a study very soon.

Your business strategy is to conduct phase II clinical studies and then sign commercial agreements with one or more major pharmaceutical companies. What is the general interest in your research platform like among these companies?

– In our interactions with pharmaceutical companies we have been met with great interest in our resolution therapy approach, i.e., the fact that our melanocortin-based drug candidate is able to create a balanced immune response through the combination of inhibition of some unwanted pathways and the stimulation of other beneficial pathways. Furthermore, we will soon have a pipeline with three clinical trials in some very interesting indications (RA, NS and Covid-19) with substantial medical needs for new and better solutions.

Finally, which milestones can we look forward to from Synact Pharma during the next 12 -18 months?

– If everything develops in accordance to our plans we will reach proof-of-concepts from phase II studies in RA, NS and Covid-19.

The content of BioStock’s news and analyses is independent but the work of BioStock is to a certain degree financed by life science companies. The above article concerns a company from which BioStock has received financing.

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