Pharma Playbook: Xigris

The Eli Lilly med displaced a cheap and effective alternative for decades before ultimately being revealed to do more harm than good - and they knew the whole time.

Per the CDC:

Sepsis is the body’s extreme response to an infection. It is a life-threatening medical emergency. Sepsis happens when an infection you already have triggers a chain reaction throughout your body. Most cases of sepsis start before a patient goes to the hospital. Infections that lead to sepsis most often start in the lung, urinary tract, skin, or gastrointestinal tract. Without timely treatment, sepsis can rapidly lead to tissue damage, organ failure, and death.

In a typical year:

• At least 1.7 million adults in America develop sepsis.

• At least 350,000 adults who develop sepsis die during their hospitalization or are discharged to hospice.

• 1 in 3 people who dies in a hospital had sepsis during that hospitalization

Acute respiratory distress syndrome (ARDS) is an often fatal complication of sepsis.

In 2002, a new sepsis drug, Xigris, passed FDA approval with some controversy; ten of twenty panelists voted the drug down because of underwhelming clinical trial data, and their skepticism was shared by doctors who were less than enthusiastic to use Xigris once it was on the market.

Was their skepticism justified? After a decade, Xigris was “voluntarily withdrawn” on October 25, 2011. Lilly said they were “surprised” Xigris wasn’t more effective and pointed at “improvements in the care of septic patients” as an explanation for why Xigris underperformed.

Superficially, this looks like the system working as intended: a product entered the market, its safety and efficacy were closely watched, and when it didn’t perform well, it was withdrawn. Follow the science, right?

Wrong.

The story of Xigris is one of fraud, lies, and unnecessary death. It shares ethical ground with Vioxx, Oxycontin, and Zantac: all drugs where their profitability was prioritized above their safety, and many thousands died as a result. Instead of an outrage, it is a sad, repetitive cliché. Where there should be outcries from medical professionals, there is silence. Where there should be headlines, there is propaganda.

Let’s take a closer look, starting back a couple of decades.

In 2001, two articles related to the treatment of sepsis were submitted to the New England Journal of Medicine at the same time: Xigris was the focus of Lilly’s study, and corticosteroids were the focus of a study out of France.

Corticosteroids had already been around for half a century; as such, doctors were familiar and comfortable with their risks and benefits. Being off patent, they cost pennies. Comparatively, Xigris cost around seven thousand dollars for a round of treatment, and there was immediate concern about side effects (clotting issues in particular).

In the studies submitted to NEJM, only one ever saw the light of day: the study on Xigris. It was published and robustly promoted as the new standard of care. The study from France? It spent nearly a year in journal limbo before ultimately being rejected on shallow reasoning. Eventually, the French study was published elsewhere; though corticosteroids were safer, more effective, and cheaper than Xigris, they lacked the marketing and lobbying necessary to be widely adopted.

Around that same time, G. Umberto Meduri, tenured Professor in the Department of Medicine at the University of Tennessee Health Science Center in Memphis and director of the Memphis Lung Research Program, had been researching corticosteroid use for ARDS for years. Like his French colleagues, Dr. Meduri became an outspoken proponent of corticosteroid use in ARDS. He knew the treatment could save lives, and he had the receipts: he was involved in a multitude of research projects that formed a strong foundation of evidence for treating ARDS effectively.

Dr. Meduri stood in the way of Lilly’s profits, and he paid.

A very abbreviated summary of what Dr. Meduri endured: Lilly tenaciously tried to end his career. To do so, they needed to slander him and bury the science showing that cheap drugs worked far better than Xigris. They leveraged their powers over the institutions of medical research, higher education, clinical journals, and weaponized the legal system to guard their profits at the expense of hundreds of thousands of lives. They fought him at work, they fought him in court, they fought him on campus, and the fought him at the patient bedside - publicly and viciously.

Sound like hyperbole? It’s happened before; Merck did the same with Vioxx, creating a list of MDs to “discredit, neutralize, or destroy” - for physicians that Merck knew were right in recognizing that their ten-billion dollar product was a killer. Just two examples:

When Dr. Joan-Ramon Laporte of the Catalan Institute of Pharmacology in Spain edited a publication that included safety concerns about Vioxx, Merck officials sent him a "rectification" for publication. After he refused, Merck filed a lawsuit against him and the institute.

Eric Topol, prominent cardiologist at the Cleveland Clinic, was publicly raising concerns about the cardiac safety of Vioxx in 2004. Two days after the Merck CEO contacted the head of the Cleveland Clinic medical board, Topol was removed from his position as chief academic officer at the Cleveland Clinic and as provost of the Cleveland Clinic Lerner College of Medicine, which he had founded.

After years of fighting to defend his medical license, his reputation, and his job, Dr. Meduri was vindicated: his research was robustly validated to the point that corticosteroid use became a standard of care in ARDS. Lilly’s claims of academic fraud against him were disproven. He retained his medical license. By that point, Xigris was already off the market; Lilly was fighting him on principle. They had their profits, and harassing a doctor who stood in their was a fulfilling way to spend some small fraction.

That Dr. Meduri ultimately prevailed was a shallow victory. Nobody at Lilly suffered any consequences for their actions. With no hyperbole, it can be stated that Lilly lied in order to profiteer off the deaths of hundreds of thousands of people (mothers, fathers, sons, daughters, and spouses that might have been saved had only the treatment been profitable). There are no class action lawsuits. No prison time. Not even a fine. At least with Vioxx, Merck was eventually fined for half their profits (an amazingly low bar after at least tens of thousands of preventable deaths). The financial toll is in the billions; it’s a sad state of affairs when billions of dollars are a miniscule loss in comparison to the human toll of a lie.

What helpful medical research is lost to Pharma’s black void because doctors like G. Umberto Meduri are forced to spend decades of their careers defending their research, position, license, and reputation from the “neutralize, discredit, or destroy” campaigns of Pharma?

It is impossible to overstate the amount of influence Pharma has over medical journals, medical education, health policy, politicians, and the media. The strategies and money spent to assert such control is beyond the scope of this Substack, so I will summarize with one quote:

It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of the New England Journal of Medicine.

-Marcia Angell MD

If ever a quote was a prescient understatement, it’s this. Marcia left her post as editor of the NEJM in 2000, before the Vioxx, Oxycontin, SSRI, Zantac, etc. scandals - before the NEJM promoted Xigris instead of corticosteroids.

Cue the Billy Mays infomercial voice: but wait, there’s more!

The amount of time Xigris spent on the market - ten years - is neither arbitrary nor coincidental. Ten years is the amount of time Pharma is able to hold patents on new therapeutics - it’s the lifespan of profitability. Lilly, the FDA, and doctors all recognized that the approval of Xigris was based off tenuous evidence at best. Given the widespread prevalence of ARDS, having an easily-studied endpoint (death), and high stakes involved (hundreds of thousands of lives per year), there was no valid reason a follow-up study couldn’t have been expedited. Xigris was allowed its full market lifespan and was only withdrawn when it was about to face the profit-sinking availability of a generic. In Pharma, profits are always prioritized over patient outcomes.

But wait, there’s more!

Remember how doctors were underwhelmed by the data supporting Xigris, and uptake was slow? When a product’s profitability is hampered by its efficacy, Pharma has developed many workarounds; one is via CMS “add-on” payments. Here’s how it works: the Centers for Medicare & Medicaid Services create guidelines by which hospitals are paid extra to use certain therapeutics. This program is marketed as a “win-win” for hospitals and patients. It is not; it is only a win for Pharma. Think of it this way: your taxes are used to bribe hospitals to use underwhelming treatments after CMS is lobbied by Pharma.

Know what other, more recent treatment had CMS “add-on” payments attached? Remdesivir, the Gilead moneypit developed for Ebola that was so toxic, a person is better off with just Ebola.

Remdesivir was so bad, even the WHO (poster child for being captured by industry) wouldn’t recommend it for Covid - that only happened in the US.

Speaking of the WHO, here’s a phrase to have loaded in your Pharma bullshit detector: “We don’t recommend the use of [insert cheap generic drug here] outside of clinical trials.” As Dr. Angell hinted two decades ago, clinical trials are structured marketing campaigns aimed at profits and not at truth.

In healthcare, Truth died years ago, in a hospital bed, with an IV in its arm; CMS paid the hospital extra.

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Watch / Read More

The Destruction of the Memphis Lung Research Program and the Global Human and Economic Repercussions

Dr. Meduri on the Darkhorse podcast: