How Atypical Hemolytic Uremic Syndrome Research Has Improved Treatment

Why is it important to keep iterating on existing treatments for a rare disease and exploring new avenues for deeper understanding?

Bradley Dixon, MD, thinks of the body’s powerful complement system as a Ferrari. For most people, the Ferrari is a well-oiled, impressive machine. But if you take something that powerful out for a drive with faulty brakes, someone’s getting hurt. That’s exactly what happens in patients with an ultrarare genetic disease called atypical hemolytic uremic syndrome, or aHUS. Kids diagnosed with this condition are literally one in a million. They’re also the reason Dr. Dixon, a nephrologist at Children’s Hospital Colorado, gets up every morning and continues his endless search for better and better treatments.

The complement system is made up of a series of proteins that evaluate danger signals on cell surfaces, such as specific patterns of sugar molecules, to identify and target infectious organisms. An essential part of the human immune system, the complement system is something we are born with, and it’s always working in the background. But it’s not a perfect system, and sometimes it can’t easily recognize our own cells from invaders. In a healthy individual, built-in brakes pull the system back before it can run wild. In aHUS, these regulating factors don’t function as they should.

When triggered by something as simple as a cold, the unregulated complement system is a wildfire, causing unmitigated damage across the body. Most concerningly, this process damages the endothelial cells lining blood vessels, signaling platelets to create clots, and causes red blood cells to breakdown. Together, these reactions choke critical organs, limiting oxygen supply and ultimately reducing function.

For decades, the condition was a death sentence with unreliable treatment options. Even if patients were able to replace a failing organ with a transplant, aHUS would continue to wreak havoc. But in 2009, the U.S. Food and Drug Administration (FDA) approved a new drug, eculizumab, that completely rewrote the story.

“That was a life changer,” Dr. Dixon says. “Patients could come off dialysis. It could suppress the disease from coming back in a transplant. This completely revolutionized the way these patients experience life.”

The drug, given by intravenous (IV) infusion every two weeks, was able to stop this runaway train in its tracks. But the inconvenience of lifelong, twice-monthly infusions, plus the challenges of such frequent and painful IVs, necessitated more work and more discovery.

A step forward with ravulizumab

In 2017, at just 3 years old, Juliette Picard came down with a case of strep. The common childhood illness, routinely treated with antibiotics, kept getting worse. When her pediatricians noticed concerning trends in Picard’s bloodwork, they immediately referred the family to Children’s Colorado and Dr. Dixon. Within one visit, Picard was diagnosed with aHUS. At the time, Dr. Dixon was beginning a clinical trial for a new drug to treat the condition, and Picard was almost immediately enrolled. Ravulizumab was designed as a variation of eculizumab, but instead of every two weeks, patients could go four to eight weeks between infusions, depending on their weight. Today, that drug is FDA approved. And since beginning treatment, Picard has been symptom-free.

Improving treatment for aHUS

With a cure in hand and lives saved, Dr. Dixon could have stopped pursuing new treatments for the pediatric population. But he knew that as patients like Picard continued to age, they’d still be held back by aHUS.

“We’ve had a great drug for this disorder for many, many years now. But it’s all about the patient experience,” he says. “It means being able to take vacations, not having school disrupted by having to go to an infusion center, not having to travel great distances if you’re in a geographically dispersed region like we are here. Even just the pain and suffering of an infusion itself. I think that’s why these continual improvements are needed.”

That’s what pushed both Dr. Dixon and the Picard family to explore a second clinical trial together. The new drug, crovalimab, can be given via a quick injection under the skin rather than an IV infusion, meaning that instead of spending hours at the hospital, Picard can be in and out in a matter of minutes, and her mother, Erica, recently learned to give the injections at home, eliminating the need for frequent hospital visits almost entirely.

“I’m not really concerned about the disease anymore. I’m more concerned about making sure Juliette can manage this moving forward because at some point, we’re not going to be here to take her to the hospital,” Erica says. “How do we make sure moving forward, she has the best quality of life and can do all the things?”

Starting in 2025, Dr. Dixon will begin testing yet another improvement to aHUS — this time in adult patients. Instead of injections or IVs, this new option only requires patients to take two pills each day.

“To go from no therapy to one therapy that’s good but inconvenient, to lots of options and even something that you can control with oral medication is just, in my mind, a fantastic journey for a rare disease like this,” Dr. Dixon says.

The importance of nomenclature 

Though treatments for aHUS exist, it’s not always easy for the right patients to get the right treatment due to confusing nuances in the disorder’s naming conventions. This stems from early understandings of how the disease functioned.

There are two primary ways to categorize hemolytic uremic syndromes: atypical HUS and “typical” HUS (now known as Shiga toxin-associated HUS). The “typical” version is often caused by a bout of food poisoning and usually resolves on its own without long-term medical intervention. Providers have historically distinguished between them based on whether or not the patient has diarrhea, but this symptom can occur in both versions of the condition, creating a significant barrier to accurate diagnosis.

That means that not everyone who needs the drugs Dr. Dixon has carefully worked to test and understand receives them. He’s part of a team working to change that.

“About 30% to 40% of patients with atypical HUS have diarrhea. So, 30% to 40% of these patients could be classified incorrectly and may be excluded from receiving these targeted treatments,” he explains. “I have had the privilege to be a part of a group of experts to come up with a better name for this so that people aren’t inadvertently being denied or being left out of important treatment advances.”

Of course, it’s not as simple as changing a word, because for decades, those words have held a weighty meaning for patients, families and communities. Chronic conditions like these can become a part of someone’s identity and a way to connect with others who share similar experiences. Removing the words that people have organized their lives around can have a powerful impact.

“It can change patients’ ability to find each other and be empowered by each other,” Dr. Dixon adds. “We have to be very thoughtful about a nomenclature change, not just on the scientific side, but also to make sure patients aren’t disadvantaged in any way.”

Integrated testing for aHUS

Dr. Dixon’s work to continuously improve treatments will soon get a boost from colleagues in Children’s Colorado’s newly minted Precision Medicine Institute. Because aHUS is a genetic condition, understanding the specific mutations at play and how they differ from patient to patient is essential.

For example, researchers and providers already understand that some people require lifelong treatment, while others might have differing genetic factors that allow them to discontinue treatment and remain safe from relapse. By identifying these genetic differences, Dr. Dixon and his colleagues can more precisely target treatments and choose between the growing list of options.

That’s where the new institute comes into play.

“There are only a few labs in the U.S. that really have results you can put your money behind,” Dr. Dixon says. “Eventually we will have one of those labs because Dr. Alisa Gaskell is just a superb scientist, and she’s invested in our program to do this kind of testing.”

That genetic testing will live side by side with functional testing, thanks to Dr. Dixon’s partnership with other complement scientists on the University of Colorado Anschutz Medical Campus. These partners will be able to run extensive tests related to the complement system itself, so that when genetic testing identifies a mutation, doctors can understand what exactly that mutation alters.

“This is a great campus for studying these disorders because we have lots of people with different experience and different scientific expertise. So, we’re poised to be one of the leaders in testing in this field,” Dr. Dixon says.

For families like the Picards, whose lives are literally in the hands of providers like Dr. Dixon, this unending commitment to improved treatments, better diagnosis and a more accurate understanding of aHUS is tough to capture in words.

“The team there — I have had the best people,” Erica says of the providers who helped her daughter Juliette. “I am always going back to how thankful I am for Dr. Dixon and our research team.”