Sepsis: The Hydra Within Us
As Wallstreet Funding for Sepsis Research has Evaporated US Government Funding Picks Up the Slack
As punishment for the murder of his wife and children during a bout of temporary insanity, Hercules was to perform twelve death-defying impossible feats at the behest of Apollo’s oracle. The second feat was to kill the dreaded nine-headed monster called the Lernaean Hydra. The difficulty with this task was that one of the heads was immortal and hence indestructible. The hydra could generate a new head immediately after one was severed all while spewing forth poisonous venom and vapors from the other eight.
The story though mythical is strangely analogous to the Herculean effort that will be required to defeat sepsis — the multi-headed hydra within us. While most people have heard of sepsis and may know someone who has been afflicted, few can define its genesis no less its symptoms.
In the past, even pathologists looking at post-mortem tissue damage could not understand why a sepsis patient had died. They could see that the specific organ was damaged, but they could not explain how it got that way. It wasn’t until they employed more powerful microscopes capable of seeing the endothelial lining of affected organs that they could understand the effects of sepsis.
Loosely defined, sepsis is caused by bacteria entering the bloodstream causing a powerful systemic, out-of-control inflammatory response that triggers deadly biological IEDs even after the body has successfully eliminated the offending organism. As the destruction spirals out of control, more toxins enter the bloodstream through the progression of injured organ systems until the body loses the battle and the patient descends into shock and ultimately succumbs. This can happen with astounding rapidity — often before the condition is positively identified.
An Enormous Opportunity Attracted No Dearth of Investment Capital
In earlier days of biotechnology, capital flowed into stories driven by new discoveries like monoclonal antibodies that could be used to attack foreign toxins. Centocor bet the ranch on Centoxin which was intended to treat gram-negative sepsis. They expected the market opportunity to be in excess of $1 billion per year. In the 1990’s this was considered an enormous potential market.
The development and commercialization effort was funded with hundreds of millions of dollars raised in public offerings. In anticipation of Centoxin’s ultimate success the company built out a massive sales force and manufacturing capacity. Surprisingly for the company and its investors, the FDA did not approve Centoxin because the clinical trial data revealed that people taking the drug had a higher chance of dying than the placebo group. This disappointment rocked the stock and brought the company to the brink of bankruptcy as investors suffered spectacular losses.
If this were the only sepsis related disaster, the funding environment for the indication might have not been so bad. However, this was only the beginning of an extended series of monumental failures.
Ely Lilly developed Xigris which was approved for treating severe sepsis in 2001. The actual drug was activated protein C which worked as an anti-coagulant. The side effect profile was risky as the drug could cause significant bleeding and doctors were reticent to prescribe a drug that could cause a patient to bleed-out. It was eventually pulled from the market after additional trials showed that there was a higher mortality risk in the treatment arm than the placebo arm.
According to a report published in 1999 in Infectious Disease Clinics of North America,
“Over 13,000 patients have been enrolled in at least 23 multicenter, double-blind, placebo-controlled, clinical trials in an attempt to develop new treatments for septic shock. Unfortunately, the results have been generally disappointing and interspersed with some spectacular failures and unexpected toxicities.”*
*Infectious Disease Clinics of North America
Volume 13, Issue 2, 1 June 1999, Pages 285–297
Sepsis: The Problem as it Exists Today
From a clinical perspective, septic patients are not much better off today than they were decades ago. The incidence is also growing as “baby-boomers” contribute to the aging of the population. It is likely that sepsis will continue to proliferate as pneumonia is the most common infection to precede the condition:
- More than 1.7 million people in the U.S develop sepsis¹
- Nearly 270,000 adult Americans die as a result of sepsis¹
- More than $62 billion is spent on sepsis healthcare costs²
²Buchman TG, Simpson SQ, Sciarretta KL, et al: Sepsis Among Medicare
Beneficiaries: 3. The Methods, Models, and Forecasts of Sepsis, 2012–2018. Crit Care Med 2020; 48:302–318
Inadequacy of Current Day Treatments
There hasn’t been anything new in the medical armamentarium to treat sepsis since the advent of antibiotics and these agents are losing their effectiveness due to antimicrobial resistance. As a last resort, steroids and anti-interleukin 6 receptor antagonists are administered but the data on these has been mixed and inconclusive. That leaves supportive care which includes giving fluids, managing secretions, and intubation to ameliorate ARDS (Acute Respiratory Distress Syndrome).
Failure After Failure: Why Sepsis is Difficult to Treat
Sepsis has continued to elude treatment because much like the 9-headed Hydra, there is an enormous amount of redundancy within an out-of-control inflammatory response. Blocking one component would be like cutting off only one of hydra’s heads. Also, the condition can emerge unpredictably and magnify so quickly that by the time it is identified, patients are likely to have already suffered significant damage in a cascade of afflicted organ systems. Even if a prescribed antibiotic were to be successful against the specific offending bacteria, the immune system gets so amped-up that the response itself becomes the instrument of destruction and death.
Another difficulty complicating the treatment of sepsis is that due to the common side-effects, patients are required to manifest the condition before being administered what is considered a risky treatment. Unfortunately, once the sepsis train has left the station it becomes progressively more difficult to reverse the course of the condition.
Wallstreet Investment Evaporates in the Face of Multiple Failures
As one might expect, the funding environment for sepsis has been reduced to a trickle with very few companies bold enough to embark upon such a dangerous road strewn with the remains of previously failed ventures. If a startup company were to approach a sophisticated venture capital firm today with a sepsis business plan, it would quickly end up in the circular file — perhaps, after first being torn to shreds.
Government Attempts to Fill the Void: Division of Research, Innovation & Ventures (DRIVe)
Recently, the Biomedical Advanced Research Development Authority (BARDA) initiated a Division of Research, Innovation & Ventures (DRIVe) with a mission to accelerate the development of new approaches to take-on or prevent the biggest health threats facing the country. DRIVe pushes innovation boundaries to tackle these health security challenges while seeking new ideas and new approaches
As part of this initiative the Solving Sepsis program aims to reduce the incidence, morbidity, mortality, and cost of sepsis by investing in key strategic areas. A graphic representation of their approach identifies the key points of intervention in the progression of sepsis where they believe there are potential drug candidates:
The Search for a Cure
While there has been a progression of drugs that have been tried and failed, it is vital to continue to search for a successful treatment even as the number of potential candidates has dwindled. Perhaps the answer already lies in the body itself. Modulating the body’s own inflammatory response can be a safer approach with the ability to intervene earlier — before a positive diagnosis.
If one were to make a wish-list of properties you would want for a drug to treat sepsis, it would look like this:
- Safe (no harmful side-effects to preclude early treatment)
- Anti-microbial and pathogen agnostic (to help the body fight infection even if the specific microbial threat is not identified)
- Anti-Inflammatory (to prevent the spread of over-exuberant inflammation)
- Works with antibiotics that have become ineffective (despite anti-microbial resistance)
This list of daunting — even seemingly contradictory properties has lead researchers at BARDA’s DRIVe program to BioAegis Therapeutics which is commercializing gelsolin, a naturally occurring human protein that has exhibited precisely the properties that one would want in a sepsis drug.
Developed by millions of years of evolution, only Mother Nature could have designed a molecule with such a diverse set of functionalities.
Gelsolin, an Immune Modulator
Gelsolin is a highly abundant protein in the blood of healthy individuals. And it meets all the aspirational goals for an ideal sepsis therapy:
- Safe: Gelsolin is naturally occurring and has been demonstrated to be safe even when patients have received massive doses resulting in higher-than-normal levels.
- Anti-microbial and pathogen agnostic: Gelsolin has been shown to boost the immune response to bacteria by empowering white blood cells to have greater uptake and killing of pathogens.
- Anti-Inflammatory: Gelsolin binds to inflammatory mediators (components of inflammation) and naturally works to keep inflammation local to the area of injury
- Works with antibiotics that have become ineffective: In animal models of infection Gelsolin treatment has demonstrated a synergistic effect to improve the killing of pathogens, even those that are 100% resistant to antibiotics.
In patients, gelsolin is rapidly depleted in response to injury or infection and patients with the lowest blood levels experience the most severe outcomes in diseases including sepsis, pneumonia, trauma, burns and other inflammatory conditions. Gelsolin supplementation holds the promise that there will finally be a safe treatment to reduce the devastating toll that sepsis inflicts on the world each year.
Ultimately, Hercules defeated Hydra with the help of his nephew Iolaus who was able to cauterize the fresh wound from the severed head before a new one could grow. Gelsolin treatment could be the help that the body needs to defeat sepsis by being able to respond simultaneously to the many sources of harm. We may finally be able to defeat the hydra within us.