photo of Maggie NilesMaddie Niles

Rare Disease: Could Existing Drugs Turn the Tide?

Maddie Niles stumbled on an existing drug that changed her life forever. How many other rare disease treatments are sitting unused on the shelf at the local pharmacy?

By Paul Frysh and Deborah Gastfreund Schuss
May 18, 2023

Seventeen-year-old Maddie Niles has a rare metabolic disease with no name, no known cause, and — at least for most of her life — no clear treatment plan. By the time she was in second grade, she was dependent on a wheelchair and a central line that fed her fluids and nutrients.

For most of her childhood, a packed suitcase stood permanently at the ready for the inevitable and recurring hospitalizations. She attended school — when that was even possible — with a private nurse attendant or a service dog.

Endless testing by a merry-go-round of medical specialists could not get to the bottom of a perplexing array of symptoms: Gastrointestinal bleeding, choking, fatigue, low oxygen levels, and an auditory processing disorder, among other things.

"We were just compiling this list of weird things," says Maddie's mother, Cheryl Niles. "I always described her life as 'medical whack-a-mole.' Every time we thought we had something settled, something else would pop up," says Niles, who lives with her family in Woodbridge, VA.

Rare Diseases by the Numbers

As Maddie entered her teenage years, says Cheryl Niles, "We knew we were losing her." 

Then, 2 years ago, almost by chance, Maddie and her family stumbled upon something that would change their lives forever.

One of Maddie's doctors did a routine switch of medicines for a recurring symptom: kidney stones. Within a week or two of starting that medication, Maddie started to feel better than she had in a while. She had more energy and could concentrate for longer periods of time.

Her doctors took notice. Over the next year, with changes in dosing, Maddie's symptoms improved even more dramatically: She ate what she wanted, no longer required an oxygen tank during the day, and — after 9 years of wheelchair dependence — walked on her own.

Doctors at the Rare Disease Institute at Children's National Hospital in Washington, DC — one of the preeminent rare disease centers in the world — were surprised. They'd seen no sign that the drug would help with anything other than Maddie's kidney stones.

Was it just a lucky fluke? Perhaps. 

But Maddie's story also raises an important issue: In the expensive and time-consuming race for new treatments for people with rare diseases, how many viable treatments are already sitting on the shelf at the local pharmacy?

'Rare' Disease?

In the U.S., a rare disease is one that affects fewer than 200,000 people. But with around 10,000 rare diseases, that number adds up quickly. There are about 30 million people in the U.S. living with a rare disease. That's about 1 in 10 people — about the same number that have diabetes or depression.

And those numbers may be low. Scientists are identifying about 10 to 12 new genetic diseases per week, says Marshall L. Summar, MD, director of the Rare Disease Institute Laboratory at Children's National Hospital in Washington, DC.

Rare Disease in Children

"Imagine a field of medicine where, every Friday, you've got 10 new diseases to learn about," says Summar, whose lab works on devices and treatments for patients with genetic and biochemical diseases. 

"We're really witnessing the emergence of a new field of medicine that has its own unique rules," he says. 

Many of these diseases have no cure and treatment, and for many patients, there is not even a full diagnosis.

Most rare diseases lack treatments partly because it is often unprofitable for pharma companies to develop drugs for small populations. Some very rare diseases, such as Jansen's disease (Jansen's metaphyseal chondrodysplasia), may affect less than a hundred people.

The Orphan Drug Act

Government incentives have helped (see The Orphan Drug Act above), but basic logistics make it hard to develop drugs for a population that may be very small and spread all around the world. Even if you can get traction in research and development, the wait can be 10 to 15 years — and it can cost $1 billion or more.

Many people with rare diseases won't make it that long.

Using What We Have

David Fajgenbaum, MD, an assistant professor of medicine at the University of Pennsylvania, believes there's an easier answer.

Fajgenbaum was a third-year medical student in 2010 when doctors diagnosed him with a rare condition called idiopathic multicentric Castleman disease, which causes cell overgrowth in multiple lymph nodes and often leads to life-threatening infections or organ failure. Life expectancy: About 1 year.

Doctors had known about the disease since the 1950s. There was no known cure. Over the next 3 years, Fajgenbaum spent months in the hospital where he almost died five times, he says. At one point, he bade farewell to loved ones, and a priest came in to give him last rites.

All the while, Fajgenbaum and a small team of researchers continued to examine his own blood to search for clues about existing drugs that might help. They found an overactive pathway in his immune system and, after a couple of dead ends, they decided to test an inexpensive 25-year-old kidney transplant drug called sirolimus that appeared to work on some of the same pathways.

As with Maddie, the drug had a profound effect. Since then — about 9 years ago — Fajgenbaum has been in near perfect health and the drug has saved the lives of others with the disease.

David Fajgenbaum, center, confers with colleagues at Every Cure.

David Fajgenbaum, center, confers with Every Cure cofounder Tracey Sikora, left, and CEO Grant Mitchell, MD.

After finding sirolimus, Fajgenbaum made a disappointing discovery. "I learned it doesn't help all Castleman patients. It only helps some of us."

So he continued to work with a team at the University of Pennsylvania, where he is now the director of the Center for Cytokine Storm Treatment & Laboratory (CSTL), to repurpose medications. The team advanced research on 9 more treatments for different forms of Castleman disease over the following years, he says. Four of these treatments are now often used off-label, and one of them is slated for a clinical trial at CSTL, Fajgenbaum says.

The team has also helped repurpose treatments for a number of other illnesses, including angiosarcoma (a rare and particularly virulent form of cancer), and COVID-19, among others. In every case, they used medications already on the market. 

Still, says Fajgenbaum, he knew it was just a drop in the ocean. There are thousands of rare diseases with few or no viable treatments.

That's why, in September 2022, Fajgenbaum joined forces with longtime friend and fellow doctor Grant Mitchell, MD, and a group of experts at the University of North Carolina and beyond to leverage the power of machine learning to sift through the ocean of existing medical research to connect rare diseases to existing drugs. Their organization is called Every Cure.

Recently, through a partnership with Penn State University, Every Cure used its powerful software to look for connections between each of 3,000 FDA-approved drugs and approximately 12,000 diseases. The result was 36,000,000 ranked scores. The top hits look very promising, Fajgenbaum says, and the team is going through them to identify promising opportunities for further study.

Why isn't this already being done? "The problem is there's zero financial incentive for anyone to figure out a new use for them," Fajgenbaum says. 

"This is like the dream-use case, where you have one drug that actually could treat many different conditions."

— Christine Colvis, PhD

One reason is that drug companies make far more money on new drugs compared to older drugs no longer protected by a patent or exclusivity rights. In addition, drug companies may be wary of further clinical research because it can occasionally expose previously unknown side effects, says Fajgenbaum. So, instead of researching current medications, drug companies move on to the next big thing.

Beyond Rare Disease

Though already prescribed "off label" for certain forms of Castleman disease, sirolimus (the drug that saved Fajgenbaum) is not yet FDA-approved for this use. (Clinical phase II trials are underway.) If successful, it will make the fourth rare disease approved for treatment with sirolimus, says Christine Colvis, PhD, director of the Office of Drug Development Partnership Programs at the National Center for Advancing Translational Sciences (NCATS), in Bethesda, MD.

"This is like the dream-use case, where you have one drug that actually could treat many different conditions," says Colvis. "The number of rare diseases makes it ridiculous to think about finding treatments for one disease at a time, even through repurposing, so we would like to figure out any time there may be many diseases that could be treated with just one drug."

How many other existing drugs could have similarly broad uses? Like Fajgenbaum at Every Cure, Colvis and her team at NCATS want to find out. Her team is building a tool called the Biomedical Data Translator, that, like Every Cure, aims to forge connections among vast pieces of information in the hope of finding viable treatments.

Colvis cautions the computerized system will only be able to point to what might work. And it won't be able to predict all the potential dangers. That's where further research is key. Still, she sees incredible promise.

"It's gonna turn on a lot more light bulbs for researchers," she says.

Research like this could have benefits well beyond just those with rare disease, says Joni Rutter, PhD, the director of NCATS.

Scientists are breaking down more common conditions like breast cancer into subtypes with much smaller populations. Increasingly, the rules of rare disease diagnosis and treatment apply to common diseases as well, she says.

"So the more we can understand about rare diseases, the more we might be able to understand those nuances in common diseases and then help understand how we can deliver better therapeutics for those common diseases as well," Rutter says.

A New Beginning

Maddie Niles cannot recapture the years her illness stole from her. "There are times when you just have to be sad for what you lost, but then you have to move on, because if you don't move on, you're not allowing yourself to have a life," she says. 

photo of Maggie Niles

Maddie Niles prepares to dance. A bandage on her chest covers a port for fluids.

And Maddie seems to be doing just that. Today, though still on a complex medication program that includes weekly IV fluids, the suitcase that once stood at the ready for hospital visits is unpacked and stowed in a closet. She is enrolled in high school full-time with an honors course load and takes weekly voice and dance lessons. She plans to study musical theater in college and dreams of an eventual Broadway career. 

None of this was even conceivable just 2 years ago, when she required an oxygen tank and wheelchair to get through the day. 

And for that, the Niles family is grateful. But they never thought it would happen this way.

"We always were hopeful we were gonna find an answer. But we really thought we were waiting on that major, major breakthrough of something that nobody had ever seen or known," says Cheryl Niles. They never suspected the answer would be a simple, inexpensive, generic drug (potassium citrate) that had been available all along, she says.

Still, Niles is wary of easy answers. "What worked for Maddie isn't a 'wonder drug' that will fix everyone. It's a missing piece in her puzzle. I've seen the desperation in families with rare disease. I've seen people make the poor choice to just try treatments themselves — sometimes causing serious setbacks."

"You have to trust that your doctor wants you to be well, too, and that they are doing everything that they can. Then wait for science to catch up — which is agonizing."

Could it be, asks Fajgenbaum, that one of the best ways to shorten that wait is staring us right in the face? That's just what he and his team at Every Cure aim to find out.

The 'Crushing' Financial Cost of Rare Disease

By Deborah Gastfreund Schuss

For years, nights in the Niles home were punctuated by the piercing sounds of alarms alerting Maddie's parents to a variety of medical devices that needed attention. Days often were devoted to appointments spanning a dizzying array of specialists. Car rides to and from the hospital were spent reviewing schoolwork.

"It was very much a mobile school," says Maddie's mother, Cheryl Niles, 47, who had to homeschool Maddie for 3 years when it was considered too risky for her to attend school.

Hiring domestic help for these kinds of tasks is mostly not covered by insurance, leaving the bulk of this essential work to the parents, says Annie Kennedy, policy chief at the EveryLife Foundation for Rare Diseases.

Maddie Niles' family

(L to R): Cheryl Niles, Maddie Niles, Lindsey Niles (Maddie's sister), Sean Niles (Maddie's dad).

Before Maddie's birth, Cheryl Niles had worked as a computer engineer and was expecting to return to work. But over time, it became clear that juggling Maddie's multiple medical needs, including appointments, hospitalizations, and homeschooling, made that impossible. 

It was a significant financial hit for the Nileses — as it is for many other families with rare disease. Average loss of income in families with a child with a rare disease was around $34,000 in 2019, according to a study published last year by the Lewin Group and the EveryLife Foundation. 

The study found that the total economic impact for an estimated 15.5 million people in the U.S. living with a rare disease was nearly a trillion dollars in 2019.

It is a "crushing impact" on the rare-disease community and society at large, Kennedy says.

"That's higher than heart disease, it's higher than some cancers, it's higher than Alzheimer's disease," says Joni Rutter, PhD, director of the National Center for Advancing Translational Sciences, or NCATS, at the National Institutes of Health. "So this is a problem."

Adding to the financial strain — "a double whammy," Cheryl Niles says — was their decision to remain in the high-cost Washington, DC, area after her husband Sean's retirement from the U.S. Navy, to avoid disruption of Maddie's care.

And it was just the beginning. When the Nileses couldn't find enough qualified nurses to cover all the hours needed to keep up Maddie's complex medication program during her school day, the insurance company responded by cutting coverage. For several weeks, Cheryl Niles filled that role with her know-how from performing those duties at home. 

"She would qualify for a certain number of hours, but there weren't enough qualified nurses to fill it, so we would use less and then they would say, 'Oh, you obviously don't need it, so we're reducing your authorization,'" she says. "So we would go around those kinds of circles."

Other expenses not covered by insurance included $90,000 to make their home accessible for Maddie, $7,000 for essential hearing equipment that insurance refused to cover because Maddie was "not profoundly deaf," and hundreds of dollars a month for essential medications that insurance won't cover because they're "over-the-counter." 

The study also found that families with a child with rare disease had on average around $32,000 more in medical care costs than a family without rare disease. And there was about $12,000 more in nonmedical costs and health care costs not covered by insurance such as alternative therapies, experimental treatments, dental surgeries, and over-the-counter medications.

And these are average numbers. In certain cases, the costs can be much higher, depending on the rare disease and its unique medical needs, and the rules for insurance coverage in your state.

The Price of a Diagnosis

It took doctors 7 years to come up with a diagnosis for Maddie Niles. That's not unusual. It takes an average of 6.3 years and 17 providers to diagnose a rare disease, according to the EveryLife Foundation. That can compound the economic strain.

Insurance can be tricky, especially before diagnosis. For example, around 80% of rare diseases have a genetic component. If, as sometimes happens, insurance doesn't cover genetic testing, patient families that can't afford the testing sit in limbo while a powerful diagnostic tool remains unused.

Insurance companies usually pay — or refuse to pay — medical expenses according to the ICD (International Classification of Diseases) code assigned by the health care provider. But no diagnosis means no ICD code, leaving those patients essentially invisible in the health care system as their providers assign codes according to the "best available match." (Even with a diagnosis, most rare diseases don't have an ICD code.)

And so begins an endless back-and-forth between patient families, insurance providers, and medical providers. 

In addition, families often travel widely at their own expense in search of that one expert who could possibly diagnose their loved one's condition — incurring costs for missed work, plane tickets, hotel rooms, and more. This often continues even after diagnosis. Nearly 40% of rare disease families traveled more than 60 miles to see their health care providers, according to a 2019 study by the National Organization for Rare Disorders, or NORD. 

There was some relief during COVID, as states reduced restrictions on telehealth. Rare disease families, especially those in remote areas, were for a while able to see specialists on video conference. The Rare Disease Institute at Children's National, for example, saw a 24% increase in patients from outside the Washington area between 2020 and 2022. Unfortunately, as the pandemic fades, many states are reinstating these restrictions, forcing these families to get back on the road and incur far more expense. 

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