The U.S. Food and Drug Administration (FDA) has a specific classification for what is known as a “rare pediatric disease.” Every condition that meets that designation is, by definition, horrible. These are the diseases that most families are blissfully unaware of, while for others the names of these diseases—Severe Combined Immunodeficiency Disease, CANDLE Syndrome, Pompe Disease—become a dark drumbeat that sounds behind each moment of their lives.
For every parent who has sat up nursing a child fighting through a bout of colic, or who has fretted over each stage of their child’s progress along those markers of crawling, standing, walking, and talking, it is all too easy to imagine that moment when ordinary concern becomes a conviction that something isn’t right. The fear and anguish that lies behind that moment isn’t just a waking nightmare—it can become an infinite pool of grief.
Now imagine that this darkness is abated with the promise of a treatment, one that genuinely seems to help and sustain your child. Imagine being handed hope. Then imagine it taken away.
This is the story of a terrible disease, a hopeful treatment, hundreds of ill children, and a drug that could be readily available … but isn’t. It’s not a story with a happy ending, because there is no ending. It’s a story still teetering on a knife edge between joy and disaster. Where it goes now requires several things to go right—and the clock is ticking.
MOMMY AND ME
When Sara McGlocklin took her daughter Marian to a “Mommy and Me” class, one of the first activities was to have the moms lie flat on their backs and hold their babies up, like a room full of tiny superheroes. All around her, the 6-month-olds seemed to love that moment. They raised their heads in wonder, arched their backs, threw out their chubby arms, and gurgled happily. But Marian only languished limply in Sara’s hands, her head and arms dangling, a puppet with her strings cut.
It was one in a series of moments that had Sara and her husband Paul rushing to their family pediatrician in concern. Marian was their second child, and they had expected to sail through this repeat visit to parenthood without all the jitters and missteps that come with a firstborn child. Instead, Marian worried them constantly. She was born small—just over five pounds—and while she grew, she didn’t ever seem to be growing fast enough. She remained tiny, always in the lowest percentiles of the standard charts. Her accomplishments also came behind schedule, never quite hitting the marks that parenting books—and their experience with their older daughter—suggested.
But Marian’s pediatrician cautioned them not to be too concerned. Children grow at their own pace, and exactly when they check off those anxiety-relieving moments says little about who they will be later in life. Which is absolutely true. Walking at 10 months doesn’t foretell a future Usain Bolt, babbling through an early vocabulary doesn’t guarantee a budding Dickinson, and missing one of those early benchmarks isn’t like failing to file your taxes on time—kids can catch up later.
Only it wasn’t just one benchmark. And Marian wasn’t catching up.
Niemann-Pick type C (NPC) is incredibly rare. In the United States, it affects only around 43 children each year, and only a few hundred cases have been diagnosed. It’s a genetic disorder, one that involves a gene known as NPC1. This gene is so rare that there is no readily available test to see if parents are carrying it. It’s also recessive, so even if both parents happen to have this exceedingly rare gene, the odds are only one in four that any child will develop the disorder.
The damaged gene is responsible for the coding of a particular protein. Without it, children can’t properly metabolize certain fats and cholesterol. Over time these substances pile up within the lysosomes inside the child’s cells. They damage the liver. The spleen. The lungs. They especially damage the brain and central nervous system.
Children can have symptoms of the disease at birth, or these symptoms can develop later. In general, the later the symptoms appear, the milder the form of the disease. Sometimes the onset of first symptoms doesn’t appear for years. In some cases, symptoms may not appear until the patient is an adult.
When those symptoms do appear, they can include seizures, poor muscle coordination, and difficulty in breathing or swallowing. Historically the disease was also called “down gaze palsy,” because many of those affected have difficulty controlling the vertical movement of their eyes. But the real impact of NPC might be seen in another name sometimes given to this disease: “Childhood Alzheimer’s.”
NPC offers all the devastation, all the crushing loss, and the same inevitable end as regular Alzheimer’s. Except it happens to children.
SEARCHING FOR AN ANSWER
The McGlocklin’s family pediatrician retired when Marian was 9 months old. The new doctor was still encouraging, but no longer quite so reassuring as before. Marian was smiling and happy, but she wasn’t even trying to stand. Sara still had to prop pillows around her daughter because Marian couldn’t sit up for longer than a minute.
The new pediatrician insisted they should keep “an aggressive eye” on Marian’s progress. Marian was diagnosed with “hypotonia”—poor muscle tone—which didn’t sound that bad. The pediatrician ordered tests for an enzyme related to muscular disorders, none of which was exactly great.
In the meantime, Sara began taking Marian to a physical therapist even though insurance wouldn’t cover the visits, hoping that with the right exercises Marian’s legs and arms would grow stronger.
As they worked with the therapist, Sara also began Marian’s visits with the first in a series of specialists. They ordered up a whole series of exams and lab work. Some of the results were unusual. Not in a way that indicated the kind of muscular disorders or neuromuscular conditions they had suspected, but … unusual. Still, Marian seemed to be making progress with the help of the physical therapy. After just over a month, she was much better at being able to get herself into a sitting position and stay there. But the doctors seemed less impressed with this change than Sara and Paul. Now they worried that Marian might have a genetic muscle issue called congenital myopathy. More tests: It wasn’t congenital myopathy.
Just before Marian's first birthday, her parents took her to see a neurologist at Children's Hospital Los Angeles (CHLA). The CHLA neurologist ordered up a series of MRIs and ultrasounds to look at everything from Marian’s brain to the shapes of the bones in her legs. Getting all those images would take months, but in the meantime, both the neurologist and the pediatrician noticed something else: Marian’s liver and spleen were enlarged.
“… and then she sat at her kitchen table and cried.”
For the first time, Sara heard the term “lysosomal storage disorder.” And then she did what everyone does when confronted with a medical term they don’t understand: She went to Google. From the internet, Sara learned that there are dozens of types of lysosomal storage disorders. They are all rare. Most of them—in fact, 95% of them—have no treatment. Sara read the results of her search, and then she sat at her kitchen table and cried.
Tests continued. There was blood work in October. A genetic screening in November. The MRI of Marian’s brain finally took place just two days before Christmas. Through it all, Marian had been doing so well with her physical therapy. She was making progress. She was bright, and more active than ever, and so very much there.
On New Year’s Eve, more blood was drawn for “whole exome testing.” This was a kind of DNA sequencing that might catch issues that the standard tests had missed. It was this test that finally produced results two months later, at the end of February.
Marian was 18 months old, and she had NPC. By then Sara and Paul knew well enough what that meant. NPC was not just fatal; it was fatal in childhood. Even though they had braced themselves against such news, it seemed as if the world froze as soon as the words were spoken.
Then, just 10 days later, their world turned over. Again.
A SOURCE OF HOPE
Since NPC involves metabolizing cholesterol, it’s not surprising that the earliest treatments involved attempts to reduce cholesterol in the diet and to treat children with cholesterol-lowering drugs. This helped a little with the levels of cholesterol accumulating in organs like the liver and spleen. It didn’t help to protect the brain. It didn’t stop children from losing their abilities, or slow their dying. Something else had to be found.
Cyclodextrin is not a cure for NPC. In fact, cyclodextrin wasn’t even supposed to be a treatment.
In 2004, a study by the University of California suggested that a neurosteroid might be helpful in NPC treatment, and a test seemed to prove this to be the case. In fact, the treatment seemed spectacularly successful in animals … until it was discovered that it wasn’t. Because the drug was being delivered in a mixture of cyclodextrin. And when the animals were given cyclodextrin without the steroid, the helpful effect was still there.
Cyclodextrins are a family of complex sugars known as oligosaccharides, and they’re often used as a delivery agent for other drugs. Their discovery as a possible treatment for NPC wasn’t quite an accidental discovery since realizing what was going on took some quick thinking and careful analysis of unexpected data, but it was close.
In those animal tests, cyclodextrin—specifically a version known as hydroxypropyl-beta-cyclodextrin—seemed to be very effective in extending life and function. The results were so good that the National Institutes of Health (NIH) rushed into further study. As might be expected, many of the families of children who were afflicted with NPC followed these trials closely. What they saw was that cats with the equivalent of the NPC1 gene who were untreated followed a rapid disease course in which they lost control over their bodies, suffered difficulty in eating and breathing, and eventually died. Cats treated with cyclodextrin were still up, walking around … being cats.
When the first information was made public, the positive results from animal tests were so compelling that a small number of families fought for and received permission to begin treating their children with cyclodextrin right away, even before a phase 1 human trial had begun. This was unusual, but because cyclodextrins were already used to deliver other drugs, there was a general feeling that their safety was well understood. Add to that how NPC is invariably degenerative and fatal, and compassionate use of cyclodextrin for treating NPC began in 2009.
On March 10, 2017, Sara, Paul, and Marian went to the Mayo Clinic to meet with Dr. Marc Patterson. It was an appointment they had made two weeks before Marian’s final diagnosis with NPC, and to some extent the visit seemed hopeless. They didn’t expect much more than confirmation of a dire future for their child.
After conducting an examination and looking over the results of the genetic testing, Patterson agreed with the diagnosis: Marian did have NPC. But he disagreed with the inevitability of the outcome.
It was at that meeting that the McGlocklin family learned about testing that was then underway using cyclodextrin to treat NPC. Based on not just the animal data but on personal stories from families whose children had been receiving treatment for a nearly a decade, Patterson was able to offer what had seemed impossible up until that moment: hope.
However, that hope came with a lot of preconditions. One was that the drug, by then known as VTS-270, was still in early testing. So even with several families vouching for the treatment, there was no guarantee that it had any real benefit. But the even bigger issue was that even though there was a trial underway, Marian could not get into it. With a disease as rare as NPC, the FDA often allows the phase 2 and phase 3 trials to be rolled together. That was the case with NPC. Since the trial was underway, there would be no more enrollments.
If Marian was going to get her chance at VTS-270, a number of things would need to happen. First, her parents would have to apply to get her the drug through compassionate use. Then they would have to find a doctor and a facility that were willing to administer the drug every two weeks even though there was no FDA approval. And, because this was completely experimental, they would have to find a way to pay for something that was well outside most medical insurance coverage.
Clinging to their newfound hope, Sara and Paul left the clinic and considered their options. Then, sitting in their hotel room, they took what may be the most defining step of the American healthcare system: They opened a GoFundMe page.
A ‘BREAKTHROUGH DRUG’
The goal of the trials that started in 2006 was not to find a cure for NPC, but to find a way to stabilize children against the neurological damage that the disease causes over a period of years. A collaboration among multiple institutes within the NIH, that original path toward finding a treatment began with the “Natural History Study — NPC,” which was not so much a trial in the sense that term is used in association with drugs and vaccines, but an effort to find the markers that could be used to identify and determine the progress of the disease.
At the time, diagnosing NPC was very difficult. The average time between symptoms and diagnoses was four to five years, meaning that those who expressed symptoms as infants were largely not being diagnosed at all. Because they were dying before diagnosis.
To address this, NIH collected accounts of symptoms, diagnoses, and outcomes and examined measures such as speech, balance, and fine motor skills. It also included a measure that speaks to the level of loss being suffered by those in the study: the ability to swallow. The most important factor about the Natural History Study was that it collected data over periods of five to 10 years. That was necessary to evaluate the course of the disease because patients who are diagnosed later also progress more slowly. Their symptoms don’t often change in a measurable way over the course of weeks, or months, or even a year.
This information not only provided a background for searching out symptoms and biochemical markers that could be used to track NPC’s progress, it also showed that one drug already being used in treatment did have a positive effect, especially on that measure of swallowing ability.
Miglustat, a drug developed to treat another genetic disorder known as Gaucher's disease, had a demonstrated a positive effect for those NPC patients who took it. This study, along with anecdotal evidence, helped miglustat become the standard of care for children with NPC in several countries. However, because the drug can also cause serious side effects including tremor and potential neuropathy, not every child can stay on the drug. And miglustat’s effects are definitely limited. It’s a treatment, but it’s not a great treatment.
On the basis of those good animal results for cyclodextrin, by 2013 institutes within the NIH translated this into a phase 1/2 human trial to test safety and determine something like an effective dosage. In 2015, small pharmaceutical firm Vtesse—the result of a Pfizer-funded incubator designed to create companies to deal with rare diseases—was formed as part of a Cooperative Research and Development Agreement with the NIH for the specific purpose of taking the treatment to a phase 2b/3 trial. They gave hydroxypropyl-beta-cyclodextrin the somewhat more manageable label of VTS-270. With families eager to participate, a ready supply of drugs on hand, and the backing of federal agencies, everything seemed to be firing on all cylinders. But right from the beginning, there were issues.
NPC can manifest at any point from birth to adulthood. Its severity can vary. Because the disease involves a basic metabolic function that affects almost every organ in the body, it generates a wide variety of symptoms. And by the time the phase 1/2 trial began, several patients were already taking miglustat, so it was difficult to separate the effects of that drug from any benefits of VTS-270.
Still, the results of the phase 1/2 trial had been so good that the FDA awarded the potential treatment. VTS-270 was named as a “breakthrough drug.”
Dr. Elizabeth Berry-Kravis practices at the pediatric specialty unit of Rush University Medical Center in Chicago. Her practice touches on a number of rare diseases, so when she was asked about administering VTS-270 to one family during the phase 1/2 trial, she readily agreed. Considering that she had adequate staff and was already running trials on other rare diseases, Berry-Kravis felt assisting the NPC community was something that she should do.
Except it wasn’t VTS-270—not yet. The hydroxypropyl-beta-cyclodextrin for those first patients was provided by Johnson & Johnson, which manufactured the drug as an excipient, a substance that is used to dissolve other drugs. Johnson & Johnson offered cyclodextrin as an excipient at a very low cost, and even made it available to competitors for use in delivering their own drugs. It was an unusual situation for the manufacturer to find itself offering up this component for treatment of a rare disease, but Johnson & Johnson appeared supportive of the use early on, as well as of the community of NPC patients and their families. The company also provided the drug that was used in the phase 1 trial.
“… some parents from as far away as Russia were more than willing to make regular flights to Chicago if it meant having some hope for their children.”
To find an adequate collection of patients, that phase 2b/3 trial took place at locations around the world. After all, even if the trial had enrolled every NPC patient in America (and there were reasons why that was not possible), it would still be only a small clinical trial. To reach even the measure of an “intermediate” trial meant going global, and at each of those locations some patients were coming in who for some reason did not meet the criteria of the trial—too young, too old, too ill. So the compassionate use program was also taking in patients from across the globe. Berry-Kravis soon found that some parents from as far away as Russia were more than willing to make regular flights to Chicago if it meant having some hope for their children.
Even though many of Berry-Kravis’ patients were not part of the trial, she still collected all the information possible from her patients. She also worked with other doctors who were conducting compassionate use programs, coordinating their methodology and keeping everything as consistent as possible. With a disease this rare, every patient counts when it comes to learning how to provide effective treatment. The formal trial and the compassionate use program continued side by side, both contributing to the knowledge about the disease and the treatment.
When it came to patient follow-up, Berry-Kravis was able to go beyond the sparse information being collected at some trial locations, including gathering information that would be valuable in looking at patient outcomes over a longer period. With a trial that was taking place with multiple teams in multiple countries, the data on patients was sometimes restricted to what little information could be collected during a treatment visit. Berry-Kravis spoke to her families more regularly, following up on how the children were doing and collecting an extended set of measurements.
What those measures showed was evident early on: Cyclodextrin is not a cure for NPC. The dramatic differences seen in the animal studies were not a measure of improvement. Instead, they were an example of the drug’s ability—in animal models, at least—to slow the progress of the disease. Patients who had already lost significant abilities to damage from NPC were not going to get those abilities back.
What the drug offered was a holding action—a firewall—against further damage and all-too-rapid death. If a real cure for NPC was coming, that solution probably laid with directly addressing the NPC1 gene. But any such treatment was still years in the future.
In the meantime, all Berry-Kravis could do was try to hold the line.
NPC patients do not get better in the sense that the damage done by the disease is repaired through treatment with cyclodextrin. But, oddly enough, that doesn’t mean that a patient can’t demonstrate major improvements.
The younger a patient shows symptoms, the more likely those symptoms can get worse rapidly, robbing the child of movement, mental functions, and a future. Conversely, the sooner a patient is able to begin treatment, the more likely it is that an effective treatment can prevent further degradation. Because the youngest patients are still growing, still learning, still picking up basic skills, arresting the progress of NPC as soon as possible means providing the best possible chance that the children will make progress, rather than the disease.
In those first hours after the NPC diagnosis, Sara Googled her way along the internet, learning everything she could about the disease and the possible treatment described by Patterson. Thanks to social media, she quickly made contact with other parents whose children had been diagnosed with NPC. Within a day, Sara was on the phone with some of these families and experiencing a huge sense of relief and comfort from the stories they shared—particularly families who were part of Dr. Elizabeth Berry-Kravis’ extended compassionate use program.
The McGlocklins headed for Chicago.
The date of Marian’s diagnosis, Feb. 28, also happens to be World Rare Disease Day. On April 17, 2017, Marian received her first treatment. For months, the McGlocklin family made the pilgrimage from Los Angeles to Chicago every two weeks.
And on each one of those visits, Marian got an intrathecal injection—that is, cyclodextrin was injected directly into her spinal fluid.
Oligosaccharides like cyclodextrin are large molecules. That doesn’t prevent these molecules from passing around the body quite freely. However, there is one boundary these molecules have a very difficult time crossing: the blood-brain barrier.
That barrier is a protective system of cells that surrounds the brain and the rest of the central nervous system. While most cells in the body are directly in touch with the blood that moves through the circulatory system, the neurons of the brain and spinal cord are instead bathed in cerebrospinal fluid. The blood-brain barrier stands as a guardian over this connection, allowing only certain molecules to pass in and out.
Ingesting cyclodextrins (which is certainly something that people do, as various cyclodextrins are widely available in nutritional supplements) results in the complex sugar being broken down in the digestive system. Injected cyclodextrins also have a difficult time when it comes to getting the substance where it’s needed in the brain.
That’s not to say that this method hasn’t been tried. A small pharmaceutical company now known as Cyclo Therapeutics is involved in a trial on NPC that uses cyclodextrin delivered by IV. Because NPC affects organs outside the central nervous system, these IV treatments hold value in treating the liver, spleen, and other organs affected by the liposome storage issues of NPC. By using relatively large quantities of cyclodextrin in this way, Cyclo Therapeutics also reports being able to get some amount of their version of cyclodextrin—given the label Trappsol Cyclo—across the blood-brain barrier.
However, the NIH and most researchers involved in the study of using this class of drugs to treat NPC believe that the most effective treatment requires getting the cyclodextrin directly into the cerebrospinal fluid. In the earliest days of the NIH trials, that was done using an intracerebroventricular injection—essentially a shot to the brain. However, complications related to using a port for delivering cyclodextrin to the brain ventricles led to changing over to intrathecal injections in short order.
No one exactly likes the idea of giving spinal injections to toddlers. However, it has the advantage of not just being effective in delivering the drug to the brain, but also being quite fast. Patients getting the intrathecal injections are in and out of the office in a short period—which can be extremely helpful for families who are flying from overseas and hoping to turn around and head back. Because the IV injection involves a much higher quantity of drug in hopes of thwarting the blood-brain barrier, administration of these treatments can take several hours. That’s not just frustrating to families eager to get back home, but extremely difficult to explain to an unhappy 2-year-old attached to an IV for most of a day.
A CHANGE IN OWNERSHIP
By the time Marian arrived in Chicago for her first visit with Berry-Kravis, Vtesse had taken over the production of the relabeled VTS-270 and had already begun a phase 2b/3 clinical trial. Recruiting for that trial began in 2015, but it took until near the end of 2016 before patients were getting their first doses of the drug as part of this trial.
Even if Marian had begun her treatment in time for the trial, she wasn’t eligible. The biggest reason was that she was simply too young.
In putting together the protocols for the phase 2b/3 trial, Vtesse used many of the boundaries that the NIH had helped to define for the original phase 1 trial. One of those was a lower limit of 4 years of age for patients being admitted to the trial. The total age range of patients enrolled was eventually quite high—some were just under 20 years old when the trial began. That 4-year-old minimum was a wall that didn’t move, which was a principle reason why Marian became part of Berry-Kravis’ compassionate use program, and not a part of the trial itself.
By the start of Vtesse’s trial, both the FDA and the European Medicines Agency had granted Orphan Drug status to VTS-270. The FDA had also lauded the treatment with that rare “breakthrough” designation. Vtesse, a small firm with a dedication to this single drug, seemed to be 100% behind the trial, was extremely supportive of the families, and had been more or less created by an NIH program to take over this treatment. But at the beginning of April 2017—the same month that Marian began treatment—Vtesse was purchased by Sucampo Pharmaceuticals for $200 million in cash and shares.
”All of this left the families of NPC patients confused and worried.”
Sucampo’s announced intention was that they made the purchase specifically to obtain VTS-270 and to take over the ongoing trial. However, there was a suspicion from the beginning that the actual motivation was more in VTS-270 as a financial investment rather than a treatment. For months, as Marian continued her treatment in the extended compassionate use program, the phase 2b/3 trial also continued to enroll and treat patients. But without the Vtesse team at the helm, momentum seemed to be slipping.
Then, just eight months after they had purchased Vtesse, Sucampo turned its investment into a very nice profit by selling out to Mallinckrodt Pharmaceuticals, an Ireland-based company, in December 2017 for $1.2 billion. All of this left the families of NPC patients confused and worried. Still, Mallinckrodt was a relative giant compared to either Vtesse or Sucampo. With revenues close to $200 billion a year and ownership of some very widely used pharmaceuticals, Mallinckrodt seemed much better suited to push VTS-270 across the finish line and move from trial to treatment.
In fact, that’s exactly what Mallinckrodt executives said they intended to do when they took over management of both drug production and the trial at the start of 2018. With the trial continuing, the compassionate use program still taking on new patients, and an industry giant taking over the manufacture of the drug, there were plenty of reasons for optimism.
And a couple of really big reasons for concern.
When Marian began treatment at Berry-Kravis’ office, she was 19 months old, but still not walking. The physical therapy had helped to strengthen her muscles and she was still very much present and still apparently happy, but her physical progress had slowed down even more than before. After lingering at around the 3-5% point on the standard pediatric progress charts, Marian was threatening to fall off those charts completely.
Though Marian wasn’t displaying the worst symptoms of NPC, the disease was clearly wearing on her more than before. She had stopped gaining weight. Her day was down to a handful of waking hours between bouts of fitful sleep. Traveling back and forth to Chicago, she seemed on the brink of slipping away—and Sara and Paul were caught on the edge between hope and terror, concerned that Marian’s tiny body was beginning to shut down. Even the small advances she had been making had hit a plateau.
Ten weeks after starting treatment, Marian took her first steps. Her legs were still weak. She still had to be supported. But her level of activity, of movement, and desire to be up and around was growing. So was Marian.
By then Marian had received five treatments from Berry-Kravis and her family was working with doctors at CHLA to eliminate the 4,000-mile round trip they were taking twice a month. Soon after those first steps, the hospital in Los Angeles approved providing cyclodextrin as a remote site of Berry-Kravis’ compassionate use program.
Compared to the utter despair the family had felt on the day of Marian’s diagnosis, everything seemed transformed in just a few weeks. The treatment appeared to be working, Marian was finally making some of those long-promised advances, and life was returning to something that seemed more like normal. Or at least, as normal as it could be under the shadow of such an awful disease.
But as Sara and dozens of other parents traded stories of personal advances and the relief they felt at seeing their children emerge from NPC’s shadow, the trial—now under the control of Mallinckrodt—was continuing.
And every moment of hope was heading for a crash.
End of Part I. This article will conclude tomorrow in Part II (click here to read it).
ADDITIONAL READING AND VIEWING
Webinar from Dr. Denny Porter and Dr. Elizabeth Berry-Kravis
Hope for Marian
Brave Like Emma
Part II of this story