Moving closer to the patient
Thoughts on the journey from bench to bedside for patients at risk of C. difficile infection
By Jake Siegel and Brian Finrow
Today we announced several milestones in the clinical development of LMN-201, Lumen’s orally delivered biologic cocktail to prevent C. difficile infection (CDI). The big headline: the FDA has greenlit Phase 2 studies of LMN-201. Soon we will start enrolling hundreds of newly diagnosed CDI patients across multiple sites in the U.S. (Physicians interested in participating should contact Lumen’s clinical operations team at firstname.lastname@example.org.)
It’s an exciting moment for our company, and an exciting opportunity to help patients suffering from CDI. Nearly half a million people are diagnosed with the disease each year in the U.S. alone. A distressingly high number of these patients live with the specter of recurrence, and they have very few options to prevent the disease’s return. The experience can be horrific: a shocking 7% of CDI patients died within 12 weeks of diagnosis in one particularly well-done study. Worryingly, there are signs that antibiotic resistant strains of C. difficile are spreading in the U.S., compounding the risks to us all.
It’s expensive, too: one leading study estimates that it drains $8 billion out of the U.S. hospital system each year. The problem is even bigger overseas.
Throwing the kitchen sink at it
Given all that, it’s not surprising that an awful lot of resources have been directed at CDI. CDI patients who develop colitis suffer from severe diarrhea, abdominal pain, fever, and malaise.
A major paradox of treating CDI is the use of antibiotics, which often trigger the disease by damaging the patient’s microbiome. It’s a paradoxical situation: the thing used to cure CDI (antibiotics) also happens to be the thing that causes CDI. (Antibiotics!)
Yet the oldest idea for grappling with this paradox has been to attempt to create new antibiotics that are “narrow spectrum” — meaning that they wipe out less of the patient’s healthy microbiome. This is not easy. Novel antibiotics are extraordinarily difficult to develop to begin with, even harder if narrow-spectrum activity is required. To cite just two recent examples: a Phase 3 trial for ridinilazole failed in December; and tucked away in a recent fecal microbiota transplant (FMT) paper was a curious report that fidaxomicin — a narrow-spectrum antibiotic increasingly prescribed for CDI in the U.S. — actually suffered a higher CDI recurrence rate than the old standby, vancomycin. CDI vaccines have been attempted too, but all have failed to date.
More recently some unconventional things have been tried. One creative approach takes stool from a healthy donor and transplants it into the GI tract of those at risk — in effect giving our healthy commensal bacteria a head start in the re-colonization race against C. difficile. Aside from the natural patient acceptance considerations with stool transplant via “crapsule”, clinical results have been mixed and some fatalities have occurred due to the accidental transfer of pathogenic bacteria in the donor stool. Above all, persistent concerns remain about the scalability and cost effectiveness of this approach, which in most cases requires enema administration or bowel prep and necessarily incorporates a human donor into the supply chain. Some are now approaching FDA review, though, so hopefully FMT will add options for these patients.
As of today, though, the only non-antibiotic product to reach the market is a bezlotoxumab, an IV-infused monoclonal antibody drug. It’s a good product, for those with access, cutting CDI recurrence rates by up to a third. But further progress is still possible: this product is unaffordable to many (especially outside the U.S.), has a safety warning on the label, and is administered only by I.V. infusion, which is a well-known barrier to adoption. But it certainly works and saves lives, and we’re doubly grateful to Merck for developing it because it has served as an inspiration and jumping-off point for our development of LMN-201.
What’s different; what’s new?
Just like bezlotoxumab, LMN-201 is also designed to neutralize the main toxin that causes the symptoms of disease: a multi-domain exotoxin called TcdB. But things get more interesting from there. To begin with, rather than just a single monoclonal therapeutic protein, Lumen’s product contains four of them in two distinct classes. Both are lab-made versions of molecules that nature has been refining for millions of years to do exactly what we’re using them for here. The first class is comprised of three antibody-like proteins that bind and neutralize TcdB, the main cause of diarrhea and other severe symptoms of CDI. The second class contains just one monoclonal protein: an enzyme called an endolysin that destroys the cell wall of the C. difficile bacterium itself without upsetting the patient’s healthy GI microbiome. It is derived from a molecular “battering ram” deployed by bacteria-invading viruses to punch holes in the cell walls of their bacterial hosts.
These four monoclonal proteins are expressed and delivered within whole spirulina biomass, a type of blue-green algae widely consumed as a food and nutritional supplement (our platform paper published in Nature Biotechnology a few weeks ago explains why a nontraditional biomanufacturing host is necessary). The drug material comes in a tidy capsule, easy to take and easy to ship. This means that LMN-201 — like all Lumen products — should benefit from some big advantages: (1) 100% oral delivery (no needles or enemas), (2) shelf stability for easy distribution and storage (see our recent paper on this), (3) superior safety (low risk of systemic exposure; no risk of inadvertent pathogen transfer from stool donors), and (4) lower cost of production. Most importantly, in the upcoming trial we hope to improve on previous records for CDI recurrence prevention.
An ounce of prevention…
Prevention, of course, trumps treatment every time; it is far better to stop illness before it starts. It is far better for the healthcare system, too — ICU time is extraordinarily expensive. Both facts are particularly true with CDI, an insidious disease that can keep returning like something from a horror film. Severe disease is responsible for approximately 20,000 deaths annually, just in the U.S. These non-fiscal costs are inherently harder to estimate, but probably amount to $25-$30 billion a year altogether on reasonable assumptions about quality-adjusted life years. (While the Phase 2 trial’s primary endpoint focuses on prevention of recurrence, secondary endpoints will explore whether LMN-201 offers additional benefits during the treatment phase — hopefully accelerating recovery and/or improving the symptoms.) As a bonus, LMN-201 should be fully compatible — perhaps even synergistic according to preclinical data — with all currently available therapies, including antibiotics and FMT. This means even more options for physicians and their patients, particularly those at the very highest risk.
This is where all the threads come together: the platform, the product, and the market. We have noticed that in addition to being best for patients, prevention markets are also appealing commercial opportunities. The best-selling drug class in the world, statins, are for prevention — in that case preventing heart attacks and strokes. So far, though, biologic drugs haven’t featured prominently in the prevention world. With traditional technologies they’re simply too costly to make, and too cumbersome to distribute and administer. LMN-201’s unique attributes — especially its expected distributability, safety, and cost profile — are a step in the right direction for realizing their full potential for preventive use. It gives us a real shot at wiping C. difficile off the map not just in the U.S., but globally.
Looking forward to the finish line
We’ve written before about the pre-clinical science behind the LMN-201 cocktail and our spirulina-based platform more broadly. We are extremely proud of that work. Today, we our one step closer at translating years of scientific research into a product for CDI patients, who desperately need relief.
Yet delivering breakthroughs from the lab to real patients in the clinic — the “bench to bedside” journey — is one of the toughest challenges in science. It so perilous a trip that it has been dubbed the valley of death. We know it’s just Day One of our journey, as our friends down the road at Amazon famously put it. But we are excited that LMN-201 — the product of so many long hours in the lab, so many hard-won insights — will now have its opportunity to help these patients suffering from this awful disease. If it works, it sets the stage for significantly impacting the lives of hundreds of thousands of CDI patients.
Plenty of hard work remains. But we are thrilled to take these early steps on a path toward delivering novel treatments to patients around the world.
We’ll see you down the road.
Jake Siegel is a science writer at Lumen Bioscience; Brian Finrow is Lumen’s cofounder and CEO.