When drug development and the immune system collide we get CAR-T, checkpoint inhibitors, oncolytic vaccines, monoclonal antibodies and more.
These fields have produced many therapies and garnered a lot of media attention in recent years. But they all focus on the adaptive immune system, which is just one-half of the equation.
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Humans also have an innate immune system that, among other things, activates antibodies and tags dubious cells for destruction. It does this through a biological cascade known as the complement system.
After a slow start, the race is on to successfully drug different stages and pathways within the complement system. And there’s a pretty big carrot incentivizing the next generation of companies.
One drug, Soliris (eculizumab), is approved to treat two rare blood disorders that arise from a dysfunctional complement cascade; atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH).
Developed and commercialized by Alexion Pharmaceuticals, Soliris gained infamy as the most expensive drug in the world, with a list price of $440,000 per year.
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It has been a revelation for patients with the rare diseases it treats. But there is plenty of room for improvement and, of course, a lower price tag.
Akari Therapeutics is chasing the same market with its lead candidate Coversin. The drug is derived from a protein produced by ticks, which allows the parasite to peacefully feed on mammals without eliciting an immune response. Coversin targets the same complement component as Soliris, C5. By doing so, it inhibits the release of C5a and the formation of C5b, otherwise known as the membrane attack complex (MAC).
Side effects are minimal, said Akari CEO Gur Roshwalb in a phone interview, because earlier steps in the cascade (C1-C3) can still function. Of note, the drug is designed to be taken once daily as a self-injected therapy, potentially liberating customers from the weekly grind of outpatient infusions required by Soliris (which, incidentally, further adds to the total price of the drug). A second C5 inhibitor in the pipeline is designed to be taken orally.
Akari expects to move into Phase 3 trials of Coversin in aHUS and PNH in 2017.
In South San Francisco, True North is starting higher up in the cascade. The drug targets C1s, but it selectively blocks just one of three downstream pathways in the complement cascade. The classical pathway is interrupted, while the alternative and lectin pathways remain intact, True North CEO Nancy Stagliano explained in a phone interview.
“We’ve really paved the way for the proof of principle that drugging the classical pathway selectively has clinical benefit,” she said. “And this is just the beginning, with something like cold agglutinin disease, because there are a number of diseases that involve a dysregulation of the classical pathway.”
In cold agglutinin disease (CAD), patients have autoantibodies against an antigen on red blood cells. When the circulating antibodies detect these antigens, they bind the red blood cells and form an immune complex. That typically triggers the classical pathway, which recruits macrophages and other inflammatory cells.
True North’s lead candidate, TNT009 puts the breaks on that cascade, Stagliano said. At the moment the science is directing the program towards orphan diseases, but systemic lupus erythematosus and rheumatoid arthritis are also linked to the classical complement pathway, making them a possible future target.
“Now there are selective inhibitors available, we can begin asking those questions,” she said.
The company has raised $142 million in four financing rounds to further its C1s program. Like Soliris, TNT009 is delivered intravenously every 1-2 weeks.
In parallel, New Haven, Connecticut-based Achillion Pharmaceuticals is developing therapeutics that target the alternative pathway. The company has homed in on a protein called factor D, which plays a critical role in the activation of the cascade. It’s also druggable with small molecules that can be taken once or twice daily as an oral pill.
Achillion entered the clinic earlier this year, pitching ACH-4471 as the first factor D inhibitor to demonstrate complement alternative pathway inhibition. Along with blood disorders, Achillion is also targeting chronic hepatitis C (HCV). That program is in Phase 2 trials, as part of a collaboration with Janssen Pharmaceuticals.
All told there’s a lot of activity, which should deliver data and clinical results throughout 2017. Beyond the orphan disease indications, there is hope for patients with some common autoimmune diseases. If not a cure, targeting the innate system might produce a different, complementary approach.
Photo: Joshua Blake, Getty Images
