The following feature story was written by an experienced biotechnology market commentator in the US, following an interview with Implicit Bioscience CEO, Garry Redlich.
Implicit Bioscience Ltd was founded in 2004 with an unusual business plan. Instead of spinning out discoveries from a university lab, like many biotech companies do, it aimed to ferret out promising drugs that had already passed important milestones, but which were sitting neglected on a dusty shelf.
Spotting possible blockbusters that others had missed is a daunting task—harder than finding needles in haystacks. But even though Implicit is a tiny Australian company, it has a powerful team with the experience, knowledge and connections to pull it off. The founders included Professor Ian Frazer, inventor of the human papillomavirus vaccine, Gardasil, which has brought dramatic declines in cervical cancer, and Garry Redlich, a co-founder and former CEO of Australian biotech company Peplin, which successfully developed a drug against skin cancer.
And in 2009, the team found its elusive, potentially groundbreaking drug. Known as IC14, it is an antibody that acts on a master switch in the immune system. It offers the promise of dialing down immune system overreactions that cause serious illness and death in many types of acute injuries and neurodegenerative diseases. The drug has already shown tantalising preliminary results in small trials for acute lung injury and amyotrophic lateral sclerosis (ALS), and may finally bring hope for tackling the scourges like Alzheimer’s and Parkinson’s diseases.
But in the meantime, IC14 is coming to the forefront during the COVID-19 pandemic as a potential method of rescuing the sickest patients from the immune system overreactions that threaten their lives. Two trials at major medical centres, one led by the U.S. National Institutes of Health and the other by Quantum Leap Healthcare, are now underway to test whether IC14 can save these patients.
“Our small biotech company can make a major contribution to what we think is the most urgent need in this and future pandemics, which is to stop people dying when they reached the point where their immune systems have taken over,” says Redlich.
The story of IC14 and Implicit Bioscience begins back in the early 1980s in the lab of immunologist Richard Ulevitch at the Scripps Research Institute. Searching for biological targets that controlled the immune system, he found a receptor that acted as a switch for the entire system. It was boringly labeled as “Cluster of Differentiation 14” (CD14). The Ulevitch lab was focused on how CD14 helped control the immune response to pathogens, like bacteria and viruses, but later researchers have shown it also responds to stress signals from other cells, helping to explain how the immune system kicks in after trauma or injury, such as a car crash.
Ulevitch got financial support from Johnson & Johnson and The Rockefeller University to make an antibody that blocks CD14. Seeing its potential, the Seattle-based biotech company ICOS Corporation acquired the antibody from Scripps. ICOS further refined it and began testing it against a deadly condition called sepsis, which occurs when the immune system attacks the body after an infection.
But then, the drug, named IC14, began to fall through the cracks, for reasons unrelated to its own potential. Another sepsis drug ICOS was developing failed in clinical trials, and the company decided to get out of sepsis entirely. Then pharmaceutical giant Eli Lilly swooped in to acquire ICOS in 2007. Lilly was mainly interested in another drug, Cialis for erectile dysfunction, which had already reached blockbuster status with $1 billion in sales worldwide in 2005. Other ICOS programs were shut down.
IC14 could have been forgotten then. But Dr. Thomas Martin, a leading pulmonary and critical care professor at the University of Washington, was fascinated by its potential. He had heard of it in the Ulevitch lab while working during a sabbatical. Martin was able to get a supply of the drug from ICOS. He started testing it in patients on ventilators with acute lung injury. Those patients suffer when substances called cytokines produced by the immune system flood into the lungs after the injury and worsen the outcome. “He found that, remarkably, the drug caused all the bad things, like cytokines and suffocating fluids, to go down in these patients,” says Redlich.
That’s when Implicit caught wind of the drug, thanks to its founders’ connections. The company is headquartered in Brisbane, Australia, and also has an office in Seattle. In 2009, Redlich came to Seattle to hire for another project. One of the applicants was a former scientist at ICOS. “He told us we needed to come talk to Tom Martin,” Redlich says.
They did—and Martin showed them his results. “We looked at his data and we thought this is too good to be true,” Redlich recalls. Implicit quickly acquired the drug from Lilly and spent a couple of million dollars making larger amounts. The company worked with Martin to help design future clinical trials.
Since then, Implicit has begun to test IC14 in patients with ALS. So far, the ALS studies show that the drug is safe, even when given for more than a year, and that “there are very encouraging trends in slowing progression,” says Redlich.
Perhaps most exciting, however, is that the drug doesn’t switch off the immune system entirely; rather it seems to stop only the part that’s gone haywire while restoring normal functioning. In chronic neurodegenerative diseases like ALS, Alzheimer’s and Parkinson’s, “the handbrakes of the immune system come off,” Redlich explains. “With IC14 in our ALS patients, we are seeing those handbrakes go back on. We think IC14 has the potential to be the first drug that can do this.”
More evidence comes from experiments in mice that have been genetically engineered to lack CD14, the cellular receptor that IC14 blocks. “These CD14 knockout mice live long healthy lives,” says Redlich. Even mouse strains that normally get forms of Alzheimer’s or diabetes are protected from these diseases when they lack CD14.
So when the COVID-19 pandemic swept around the world in early 2020, Implict’s drug was a logical choice for trying to prevent the deaths of patients with the most severe disease. Under attack by the novel coronavirus, patients’ immune systems respond not just by making antibodies against the invader, but also by producing 20 to 30 types of cytokines as part of an immune reaction run amok. Those substances then wreak havoc in the lungs and other organs in a so-called cytokine storm.
Medical teams around the world thus figured that blocking the immune system overreaction could be an effective strategy. They raced to test a slew of already available drugs that target individual cytokines, such as the rheumatoid arthritis drug tocilizumab, which blocks a cytokine called interleukin-6. “There has been a lot of desperate throwing of very specific approaches up against the wall to see what will stick,” says Redlich.
None of these targeted drugs has shown much of a benefit. The problem, Redlich explains, is that each one stops only part of the immune system response, not the entire dangerous cascade.
“When patients are very sick, the only thing you can do that will work is to turn down the master switch on the immune system,” says Redlich. “We think IC14 may do that.”
One drug has reduced mortality by nearly 30%—an inexpensive steroid called dexamethasone that does suppress the immune response in general and which has been hailed as an important advance in treatment. Redlich, however, is convinced that IC14 can do much better. In fact, Quantum Leap Healthcare’s trial, called I-SPY, sets a minimum criteria of success as a 40% reduction in deaths, which Redlich hopes IC14 will meet. “But this will be a tough hurdle for IC14 to jump, since all patients in the I-SPY study are also now getting dexamethasone,” he said.
In addition, the evidence so far suggests that IC14 avoids one of the pitfalls of some current drugs that suppress the immune system or that block individual immune system components. By weakening the immune response, they open the door to infections from potentially deadly viruses, bacteria, or fungi. Indeed, some drugs for autoimmune diseases like multiple sclerosis or Crohn’s disease come with prominent “black box” warnings about the risk of serious opportunistic infections.
In contrast, what makes IC14 unique and promising is its apparent ability to dial down dangerous immune system overreactions while maintaining normal functions. So far, more than 200 people have been treated with IC14 for sepsis, acute lung injury, ALS, or pneumonia, Redlich says. “There has not been a single reported case of an opportunistic infection attributable to dosing with IC14.”
The timing thus presents a unique opportunity for investors willing to take risks—if they move quickly. Invest before the I-SPY results are known, and there could be enormous gains if the news is good. And given that IC14 has two shots on goal with COVID-19, that risk is mitigated by the much bigger NIAID study which will report results towards the end of the year. Given that IC14 appears to be a platform drug, as well as a promising product on its own, there also is plenty of longer-term potential for the drug in critical care and neurodegenerative diseases.
“After a decade of flying under the radar, IC14 is now out in prime time, giving hope in some of the toughest disease challenges facing medicine,” says Redlich. “Apart from this and future pandemics, we’re confident that IC14 will have a very important place in the immunotherapy toolbox as we get back to addressing the key diseases of ageing and lifestyle.”
