Maddie Niles, 17, has a rare, metabolic disorder that is not known to have a name or cause. She also did not know what treatment she would receive for the majority of her life. When she was in the second grade, Maddie Niles was dependent on a wheel chair and a central tube that provided her with fluids and nutrients.
A suitcase was always packed for her hospitalizations, which were inevitable. When it was possible, she attended school with a nurse or service dog.
A merry-go round of medical specialists was unable to find the cause of an array of confusing symptoms, including gastrointestinal bleeding, fatigue, low oxygen, and auditory processing disorder.
Maddie Niles’ mother, Cheryl Niles, says: “We just compiled this list of strange things.” “I have always referred to her life as medical whack-a mole. Niles says that every time she thought her life was settled, another problem would arise. She lives in Woodbridge with her family.
Cheryl Niles says, “We knew she was going to be gone as soon as Maddie reached her teenage years.”
Maddie’s family and she stumbled across something 2 years ago almost by accident. It would change their life forever.
Maddie’s doctor switched her medication routinely for a recurrent symptom, kidney stones. Maddie began to feel better within a few weeks of taking the medication. She felt more energetic and was able to concentrate for longer periods.
Her doctors noticed. Maddie’s symptoms continued to improve over the next year. She no longer needed an oxygen tank at night and, after nine years of being wheelchair-dependent, she was able to walk on her own.
The doctors at Children’s National Hospital, Washington DC’s rare disease center — which is one of the most prestigious in the world — are surprised. The doctors had seen no indication that the drug could help with anything but Maddie’s renal stones.
Was it a fluke of luck? Perhaps.
Maddie’s story raises another important question: How many treatments that are effective and affordable for those with rare diseases already exist in the local pharmacy, despite the time-consuming and expensive race to find new treatments?
A rare disease in the United States is a condition that affects less than 200,000 individuals. With around 10,000 rare diseases this number can quickly add up. About 30 million Americans have a rare illness. This is about 1/10 of the population — roughly the same as those with diabetes or depression.
These numbers could be very low. According to Marshall L. Summar MD, Director of the Rare Disease Institute Laboratory, Children’s National Hospital, Washington DC, scientists are discovering 10 to 12 genetic diseases each week.
Summar’s lab develops devices and treatments to treat patients with genetic or biochemical diseases.
He says, “We are witnessing the emergence a whole new field of medical science that has its very own rules.”
There is no cure or treatment for many of these diseases, and there are not enough diagnoses to help patients.
It is not profitable for pharmaceutical companies to create drugs for small populations. Jansen’s Disease (Jansen’s Metaphyseal Chondrodysplasia) is one of the rarest diseases. It affects less than 100 people.
Although government incentives (see the Orphan Drug Act) have been helpful, basic logistics can make it difficult to develop drugs for populations that are small and scattered around the globe. Even if research and development is successful, it could take 10 to 15 year and cost up to $1 billion.
Rare diseases can be fatal for many people.
How to Use What You Have
David Fajgenbaum MD, assistant professor of medicine, University of Pennsylvania believes that there is a simpler answer.
Fajgenbaum, a third-year student of medicine in 2010, was diagnosed with a rare disease called idiopathic multcentric Castleman Disease. This condition causes a cell overgrowth within multiple lymph nodes that can lead to organ failure or life-threatening infection. Life expectancy: Around 1 year.
Since the 1950s, doctors have been aware of the disease. No cure was known. Fajgenbaum says he spent three years in hospital, where he nearly died five times. He was saying goodbye to his loved ones when a priest gave him the last rites.
Fajgenbaum, along with a small group of researchers, continued to analyze his blood in order to find clues as to existing drugs that could help. After a few dead ends, the researchers decided to test a cheap kidney transplant drug, sirolimus, that had been around for 25 years and appeared to target some of the same pathways.
The drug also had a profound impact on Maddie. Fajgenbaum is in almost perfect health since then, which was about nine years ago. The drug has also saved the lives other people with the same disease.
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After finding sirolimus, Fajgenbaum made a disappointing discovery. “I found out that it didn’t work for Castleman. It only benefits some of us.”
He continued to work on repurposing medications with a team of researchers at the University of Pennsylvania where he now directs the Center for Cytokine Storm Treatment & Laboratory. He says that the team continued to research 9 additional treatments for Castleman disease in the years following. Fajgenbaum reports that four of these treatments have been used off-label and one is slated to undergo a clinical study at CSTL.
The team also helped to repurpose treatment for other illnesses including Angiosarcoma, a rare, but particularly deadly form of cancer, and COVID-19. They used drugs that were already available.
Fajgenbaum says he still knew that it was a mere drop in the sea. There are thousands upon thousands of rare diseases that have few or no treatments.
Fajgenbaum, a longtime friend, Grant Mitchell, MD and a team of experts from the University of North Carolina, among others, joined forces in September 2022 to use machine learning to sort through the vast amount of medical research and find drugs that treat rare diseases. Every Cure is the name of their organization.
Through a recent partnership with Penn State University Every Cure has used its powerful software in order to find connections between 3,000 FDA approved drugs and 12,000 different diseases. The 36,000,000 scores were ranked. Fajgenbaum said that the top hits looked very promising and his team was going through them in order to identify promising areas for further research.
Why hasn’t it been done already? Fajgenbaum explains that the problem is that there is no financial incentive to find a new way to use them.
This is the ultimate dream use case where one drug can treat multiple conditions. “
— Christine Colvis, PhD
The drug companies are more profitable on newer drugs than older ones that do not have a patent protection or exclusivity right. Fajgenbaum says that drug companies might also be hesitant to conduct further clinical research, as it could reveal previously unknown side effects. Drug companies do not spend time researching the current medication, but rather move on to new products.
Beyond Rare Disease
Sirolimus, the drug that saved Fajgenbaum’s life, is FDA-approved only for “off label” use. Clinical phase II trials are currently underway. The sirolimus treatment will be approved for the 4thrare diseases if the trial is successful, according to Christine Colvis PhD, Director of the Office of Drug Development Partnership Programs, at the National Center for Advancing Translational Sciences, in Bethesda.
Colvis says that this is a “dream-use case” where one drug could be used to treat multiple conditions. Colvis says that the number of rare diseases make it impossible to find a treatment for just one disease, even by repurposing. We would therefore like to determine if there are any instances where a single drug could treat multiple diseases.
How many existing drugs have a similar wide range of uses? Colvis and her NCATS team want to know the same thing as Fajgenbaum did at Every Cure. Colvis and her team are building a tool, the Biomedical data Translator, which, like Every Cure aims to make connections between vast amounts of information with the hope of finding viable treatment.
Colvis warns that the computerized system can only point out what couldwork. It won’t be capable of predicting all potential dangers. Further research will be crucial in this area. She still sees tremendous promise.
She says, “It will turn on more light bulbs for the researchers.”
Joni Rutter PhD, NCATS director, said that research like this could benefit people with rare diseases and more.
Scientists are dividing more common conditions, such as breast cancer, into subtypes that have smaller populations. She says that the same rules for diagnosing and treating rare diseases are increasingly applicable to more common illnesses.
Rutter says that the more rare diseases we understand, the better we will be able understand the nuances of common diseases. This can help us develop better therapeutics to treat these common diseases.
A New Beginning
Maddie Niles can’t reclaim the years that her illness has stolen from her. She says that there are times you can be sad about what you’ve lost, but you must move forward. If you don’t, you won’t have a real life.
Maddie Niles is getting ready to dance. A bandage covering a fluid port on her chest is visible.
Maddie appears to be doing exactly that. The suitcase, which was once ready to go for hospital visits, is now unpacked, and stored in a wardrobe, despite the fact that she’s still on an extensive medication regimen that includes weekly intravenous fluids. She attends high school full time with honors courses and weekly dance and voice lessons. She hopes to pursue a career in Broadway and plans to study music theater at college.
Two years ago, she needed an oxygen tank and a wheelchair to make it through the day.
The Niles family thanks God for this. They never imagined that it would turn out this way.
“We were always hopeful that we would find a solution. Cheryl Niles says, “We really believed we were waiting for that major, significant breakthrough of something nobody had seen or known.” She says they never thought the answer was a generic, simple drug (potassium citrate) which had been readily available for years.
Niles remains wary of simple answers. “What worked for Maddie doesn’t mean that it will work for everyone. It’s the missing piece of her puzzle. I’ve witnessed the desperation of families dealing with rare diseases. I’ve seen families with rare diseases make the mistake of trying to treat themselves, causing severe setbacks.
You have to believe that your doctor is doing all they can to make sure you are well. Waiting for science to catch-up is painful.
Fajgenbaum asks, could it be that the answer to reducing the wait time is right there in front of us? He and his team are trying to find the answer.
The Financial Cost of Rare Disease
By Deborah Gastfreund Schuss
Years ago, the Niles family home was punctuated with the alarming sounds of various medical devices alerting Maddie’s parents that they needed to be attended to. The days were often devoted to a variety of appointments with a wide range of specialists. The car rides to and back from the hospital involved reviewing schoolwork.
“It was a very mobile school,” says Maddie Niles’ mother Cheryl Niles. Maddie was homeschooled for three years by Cheryl Niles when it was deemed too dangerous for her to go to school.
Annie Kennedy, policy director at the EveryLife Foundation for Rare Diseases, says that insurance does not cover the majority of the costs of hiring domestic help for such tasks, so the parents are left to do the majority of the work.
(L to R): Cheryl Niles, Maddie Niles, Lindsey Niles (Maddie’s sister), Sean Niles (Maddie’s dad).
Cheryl Niles was a computer engineer before Maddie was born and expected to return to her job. Over time, however, it became apparent that Maddie’s medical needs, which included hospitalizations and appointments, would make that impossible.
The Nileses were hit hard financially, as are many other families who have a rare disease. According to a report published by the Lewin Group & the EveryLife Foundation last year, the average loss of income for families with children with rare diseases was $34,000.
According to the study, the economic impact of an estimated 15,5 million Americans living with rare diseases was close to a trillion dollars by 2019.
Kennedy claims that it has a “devastating impact” on both the rare disease community and the society as a whole.
This is higher than heart disease or some cancers. It’s even higher than the Alzheimer’s disease, says Joni Rutter PhD, Director of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health. This is a serious problem.
The Niles’ decision to stay in Washington, DC after Sean Niles retired from the U.S. Navy to ensure Maddie’s continued care added to their financial burden.
It was only the beginning. Insurance companies cut coverage when the Nileses could not find enough nurses to cover the required hours to maintain Maddie’s complex medicine program during Maddie’s school day. Cheryl Niles, who had performed these duties at home for several weeks before, filled in this role.
She says, “She’d qualify for a specific number of hours but there were not enough nurses qualified to fill it. So we would use less, and they’d say, “Oh, you don’t obviously need it so we’re going to reduce your authorization.” We would then go in circles.
Insurance refused to pay for Maddie’s essential hearing aids because she was not “profoundly deaf.” They also didn’t cover the hundreds of dollars per month that Maddie needed for her essential medications because they were “over-the counter.”
In addition, the study found that families with children with rare diseases had an average of $32,000 higher medical costs than a similar family without a rare disease. There were also about $12,000 in additional non-medical costs, such as dental surgery, alternative therapies, experimental treatment, and over-the counter medications.
These are average figures. The costs may be higher in some cases depending on the disease, its medical needs and insurance rules in your state.
The Cost of a Diagnosis
Maddie Niles was diagnosed 7 years ago. This is not uncommon. According to the EveryLife Foundation, it takes on average 6.3 years for a diagnosis of a rare condition. This can increase the financial strain.
Insurance can be difficult, especially prior to diagnosis. Around 80% of rare disorders have a genetic component. When insurance does not cover genetic testing, families who cannot afford it are left in the dark. A powerful diagnostic tool is wasted.
Insurance companies pay or refuse to cover medical expenses based on the ICD code (International Classification of Diseases), assigned by the provider of health care. No diagnosis, however, means no ICD codes. This leaves patients virtually invisible to the healthcare system. Providers assign codes based on the “best match.” Most rare diseases do not have ICD codes, even if they are and have adiagnosis.
So begins a never-ending back and forth between insurance providers, medical providers, and patient families.
Families also travel at their own expense to find an expert who can diagnose the condition of their loved ones. This incurs costs such as missed work, airline tickets, hotel rooms and more. This can continue even after diagnosis. According to a study conducted by the National Organization for Rare Disorders (NORD) in 2019, nearly 40% of families with rare diseases traveled more than 60 kilometres to visit their healthcare providers.
COVID brought some relief, as the states relaxed their restrictions on telehealth. Families with rare diseases, particularly those living in remote locations, could see specialists via videoconference for a time. Children’s National’s Rare Disease Institute, for instance, saw an increase of 24% in patients outside Washington between 2020 and 2022. As the pandemic recedes, states are reintroducing these restrictions. This forces families to travel and incur more expenses.