Aqualung Takes Genomic Approach to COVID-19’s Killer Lung Inflammation
04.17.2020
Targets Protein Linked To Acute Respiratory Distress Syndrome
Andrew McConaghieandrew.mcconaghie@informa.com
Executive Summary
Acute respiratory distress syndrome is one of the prime causes behind the mounting global death toll of COVID-19, but there are currently no FDA-approved treatments. Armed with biomarker and genotyping assays, Aqualung hopes to speed its antibody candidate into development by next year.
In the battle against COVID-19, one of the most urgent medical puzzles is how to prevent and treat acute respiratory distress syndrome (ARDS), which is among the main causes of death in patients hospitalized with the virus.
Lots of potential drug therapies are being fast tracked by academic and biopharma companies to improve ARDS treatment, including Roche’s repurposing of its IL-6 targeting drug Actemra (tocilizumab), which has now entered Phase III trials.
However, one US biotech start up, Aqualung Therapeutics, has isolated a protein which it says plays an even more crucial, upstream role in ARDS inflammation, and is developing an antibody therapy to block it.
The protein in question is extracellular nicotinamide phosphoribosyltransferase (eNAMPT) and its receptor, Toll-like receptor 4 (TLR4) which are important in regulating the upstream inflammatory cascade that contributes to ARDS morbidity and mortality.
The Tucson, AZ-based company is developing a novel monoclonal antibody, ALT-100, as a treatment to reduce mortality caused by ARDS as well as ventilator-induced lung injury (VILI).
What is more, the company is also developing a eNAMPT biomarker and a NAMPT genotype assay: these promise to identify level of the protein in the blood, as well as those patients with a raised genetic risk of ARDS, thereby flagging which patients are most likely to respond to the antibody therapy.
Aqualung Therapeutics was founded by Joe ‘Skip’ Garcia, a renowned physician-scientist in pulmonary medicine, who had been pursuing a therapy for ARDS long before the novel coronavirus first emerged in January 2020.
ARDS already causes 500,000 deaths per year in the US, and around 2 million globally, with sepsis, trauma and a myriad of diverse stimuli the causes. But COVID-19 is now taking a deadly toll across the world, with more than 136,000 deaths recorded, many of these beginning with virus-induced pneumonia.
As this progresses, air sacs in the lungs become filled with fluid leaking from capillaries. Eventually, shortness of breath sets in, and can lead to acute respiratory distress syndrome (ARDS), a form of lung failure.
This can in turn lead to low levels of oxygen in the blood (hypoxemia), which can then trigger multi-organ failure, which is the ultimate cause of death in many of these patients.
Intensive care units are using ventilators to keep these patients alive and give their lungs time to recover – however it has become clear that mechanical ventilation can cause VILI. This is what makes acute COVID-19 treatment so risky, with ARDS patients having a very high 30-40% mortality rate.
“Patients today that are dying of COVID-19 infection are dying because they develop ARDS and the inflammatory injury associated with the ARDS,” said Garcia. “So we’ve worked a lot on this gene [NAMPT] and protein [eNAMPT] and we’ve found out how the protein works to produce inflammation.”
ALT-100 has shown encouraging activity in animal studies, and the company is now finalizing the antibody candidate for manufacturing and working towards an IND filing with the US FDA.
The company is now actively engaged with US government agencies such as the National Institutes of Health (NIH) and the Department of Defense for additional funding opportunities.
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As eNAMPT interacts with TLR4 receptor upstream of IL-6, Garcia believes it will offer a superior anti-inflammatory effect to drugs such as Actemra.
“Targeting IL-6 I think is a good strategy. But I think a better strategy would be targeting an upstream major regulator of that inflammatory pathway, and that’s our premise here.”
The company believe that the use of the antibody in tandem with its assays could transform treatment. The biomarker assay measure the protein in the blood, and the genotyping assay to identify individuals with the genetic variants which produce a higher risk of developing ARDS, and also identify patients most likely to respond to ALT-100, which means treatment would see their risk of death dramatically reduced.
“It’s really a precision medicine type platform, which we’re very excited about,” he adds.
The company anticipates having its antibody ready for a Phase Ia/Ib study within 12 months. Garcia says it is keen to talk to the FDA about a fast track for the drug candidate, but says it will still need rigorous safety data.
The potential for its use in a COVID-19 setting is clear, and Garcia says he would give it to any patient admitted to an emergency room who has evidence of a severe pneumonia or increasing respiratory distress prior to intubation.
Even if patients are not caught this early, the antibody therapy could still help fight inflammation and reduce the time a ventilator is needed.
“It’s all about regulating the inflammation,” he adds. “That gives them time to resolve and absorb the fluid that has leaked into their lungs and then that gets them off a ventilator sooner. Every day on the ventilator is increasing their mortality.”
Raising Funds
Garcia founded Aqualung in 2016, basing the company around the identification of eNAMPT and the potential of antibody therapies to target it.
The company has progressed to this stage on seed funding so far, but now Garcia is looking to finance a series A funding round to help move into clinical studies.
He says investors had been “scared away” by that lead indication of ARDS, viewing it as a rare complication in a relatively small number of patients – even though the actual number of cases even before COVID-19 was 500,000 per year in the US, and around 2 million globally because of those non-coronavirus causes such as sepsis and trauma.
Having established eNAMPT as a protein which plays a central to innate immunity, Aqualung sees the potential for targeting it in a number of other conditions, including radiation induced lung injury, trauma induced lung injury, we’ve shown this and pulmonary hypertension and, and prostate cancer.
“This has been a vexing challenge for physicians like myself, because there are no FDA-approved drugs for ARDS, none. Talk about a serious unmet need, nothing could highlight that more than the COVID-19 pandemic.
“Of course, now that’s all changed [because of COVID-19]. And so we’re thinking we should be able to obtain the series A funding that we need in order to move forward, for all the right altruistic reasons. We think we have a drug that has very high potential of impacting the challenging outcomes in patients with ARDS.”