Editor’s note: This is Part II of a two-part story. You can read Part I, which was originally published on April 14, by clicking here.
A rare childhood disorder, Niemann-Pick Disease type C (NPC), affects just a few dozen children in the United States each year. One of a number of lysosomal storage disorders, the disease affects the ability to metabolize cholesterol, and results in widespread damage over time. Symptoms from this very rare, recessive genetic disorder can occur at any time, but for those who show symptoms as infants, the disease is often fatal in childhood. In fact, the disease is uniformly fatal. It affects a number of organs, including the liver and the lungs, but it particularly impacts the brain and central nervous system. Children with NPC may seem to progress normally for some time, then gradually lose their ability to walk, crawl, speak, or even swallow. This horrible sequence has earned NPC the nickname of “childhood Alzheimer’s.”
Part I of this story examined how for over a decade there was a suggestion of hope for NPC patients in the form of a treatment known first as 2-hydroxypropyl-ß-cyclodextrin (HPBCD), then as VTS-270, and finally as adrabetadex. That drug was examined in animal trials by the National Institutes of Health (NIH), then taken into human trials first by the NIH and later by a start-up pharmaceutical company called Vtesse. In 2019, this treatment continued into a phase 2b/3 trial under its new owner, Mallinckrodt Pharmaceuticals.
But while most of America was fretting under the weight of the COVID-19 pandemic, for families of children with NPC the past year brought a decision that could bring an end to a decade that engendered hope. Whether that decision was sound science that represents the proper and ethical action going forward or whether it was the calculated act of a for-profit business that chose its bottom line over hundreds of young lives remains horribly unclear.
By 2018, Mallinckrodt had given VTS-270 the name adrabetadex. That may seem like a step backward when it comes to pronouncing the drug’s name, but it actually represents progress—it’s a name meant to meet the FDA’s criteria for an approved pharmaceutical.
But if the name was making progress, it was just about the only thing advancing. In November 2018, less than a year after announcing its buyout of Sucampo, Mallinckrodt announced that there was an issue with the trial of its newly acquired drug. The good news was that patients in the phase 2b/3 trial who were receiving treatment were not getting worse. The bad news—or at least, the puzzling news—was that the placebo group was also not showing disease progression.
On the one hand, a group of 36 children suffering from NPC who were not getting worse represents a victory. On the other, the failure of the children in the placebo group to get worse meant that Mallinckrodt could, in a phrase that would soon become repeated all too often, “not demonstrate any positive benefit” for those children receiving adrabetadex.
If the news was upsetting to Mallinckrodt’s investors, it was greeted with a jolt of fear and disbelief from families of NPC patients. It also generated concern from researchers over the future of adrabetadex and other potential drugs for NPC. A treatment that had seemed very promising, and which had been administered to patients for years, was suddenly imperiled by factors that seemed to have been built into the design of the study.
From the very beginning, there had been a real debate about whether it was advisable to even have a placebo group. After all, this is a disease that is both invariably fatal and irreversible. When testing any treatment that has shown to be effective in both laboratory testing and animal models, is it really ethical to deny that treatment to one-third of the children in a trial? That concern was increased by the simple fact that the drug in question is an excipient. Its use as a carrier for other drugs meant that the FDA already had a great deal of safety information.
There was another issue with the trial. By specifically excluding children under 4 years old, the trial shut out those being diagnosed as infants, who are specifically the patients in whom the disease progresses most rapidly. There were reasons for doing this—having infants in a drug trial is never without a host of both practical difficulties and ethical dilemmas—but selecting older patients, including those up to 20, created an obvious problem. That problem was: A year was simply not long enough.
In patients diagnosed with NPC later in life, the disease progresses more slowly. With the older patients who were included in the trial, it was unlikely that either group—those receiving treatment or those in the placebo group—would see much progress of the disease in the space of a single year. In fact, going into the trial, Dr. Elizabeth Berry-Kravis as well as others had predicted that a year would not be long enough to determine whether adrabetadex was demonstrating any protective effect on the rate of change in the disease.
In fact, there were at least three children in the placebo group who did begin to show disease progression over the course of the year. In each case, the researchers involved did the right thing: They began giving these children the actual treatment. It’s unclear if this small number was factored into the results, or whether it would have made a difference.
Marian McGlocklin being treated at CHLA in 2020.
Another good reason for not having a placebo group was simply the size of the trial. Because of the rarity of the disease, the enrollment for the trial was fewer than 60 patients. At that size, random chance alone could obscure any potential results. All of this was made worse because the trial was being conducted by different teams in different locations around the world, some of whom had much more restricted access to their patients. These teams were attempting to measure the progress of the disease against standards that were all too often vague and arbitrary.
In light of the inherent problems with having a placebo group in such a small trial involving a rare and fatal disease, researchers had proposed that Mallinckrodt employ a larger database of possible outcomes: the results of the Niemann-Pick type C Natural Trial that had been carried out back in 2006. In addition, by 2018 there was another potential source of data in the form of the records that were being kept by Berry-Kravis and others involved in the extended compassionate use program.
However, attempts to employ these data sets didn’t seem to get past the watchdogs at the FDA. Repeated attempts to propose a different approach to analyzing the trial data met with resistance from the agency.
Though the whole saga of the treatment had started within the NIH and the government had played a key role in both moving adrabetadex forward and seeing it gain corporate support, at this critical moment it seemed that the FDA was playing hardball with Mallinckrodt.
But there may have been reasons that had little to do with either adrabetadex or the trial results.
Mallinckrodt’s acquisition of Sucampo at the beginning of 2018 was nothing special for that company. Mallinckrodt bought out Ocera a year earlier. And Stratatech a year before that. And Therakos a year before that. In fact, Mallinckrodt acquired at least one other pharmaceutical firm every single year since 2011—and often more than one. The $1.2 billion price paid for Sucampo was typical.
In many of these acquisitions, what Mallinckrodt was hunting appeared to be drugs that were—like VTS-270—well along in their trials. Orphan drugs to treat rare childhood diseases were also no stranger to Mallinckrodt.
In 2015, Mallinckrodt snapped up Questcor Pharmaceuticals for the hefty price of $5.6 billion. In doing so, they obtained both the natural and synthetic forms of a corticosteroid that was used in treating a form of epileptic seizures in infants. In the space of a a dozen years, the cost of that drug, called Acthar gel, had already increased over 50,000%. Mallinckrodt then proceeded to nearly double the price again. The result was that a drug that had been in use since 1952 with a synthesis that was supposed to make it cheap and readily available was instead selling for $34,000 a vial in 2018. Its price is now over $40,000 for a single vial. Families with children suffering from the treated disorder can expect to run through several such vials in a year.
The price gouging was so extreme that Martin Shkreli—yes, the infamous “Pharma Bro” Shkreli—acted as a whistleblower in the case. Mallinckrodt ended up having to leave the lobbying group PhRMA just ahead of new rules that would have resulted in the company being thrown out. Mallinckrodt then paid a $100 million fine for maintaining an illegal monopoly and agreed to license Acthar to other manufacturers. It was a sizable fine, but investors saw it as a hand-slap considering the size of the deals—and profits—involved.
All of this happened around the same time that Marian McGlocklin was getting her first treatment of VTS-270. It was less than a year before Mallinckrodt would buy out Sucampo and take over the NPC phase 2b/3 trial. With that in the background, it’s not hard to see why the FDA might have been skeptical in looking at Mallinckrodt. Why would the company pay $1.2 billion for a drug that treated only a few hundred people? The easy assumption is that the company intended to charge highly for it—very, very highly.
In a meeting for investors in 2018, Mallinckrodt executives titled a presentation, “Acthar Modernization Strategy defines the Future of the Brand as either a Growth Asset or Cash Cow.” It’s not difficult to suspect that the company might have had similar goals for VTS-270.
This is a company that even by the standards of the pharmaceutical marketing group was engaged in overcharging for its drugs. Regulators complained that Mallinckrodt devoted very little of its budget to research and development, and instead focused on gambling on buying out companies with drugs that were just months away from going to market, then schemed to generate maximum profit from these purchases. The result was something that was more corporate raider than pharmaceutical company. And that might very well have had some effect on what was happening with the adrabetadex trial.
While the NIH might have been eager to work with a rare-drug incubator like Vtesse, it doesn’t seem all that strange that the FDA might have been less than thrilled when a company with Mallinckrodt’s track record asked for leeway for the next drug they were attempting to bring to market.
The best that Mallinckrodt appeared capable of managing was an extension of the trial in an effort to find some evidence of positive benefit they could take back to the FDA. With that extension, Mallinckrodt carried on the trial with a targeted end date of November 2021.
But before it could get there, the company would end up filing for Chapter 11 bankruptcy.
Emma was very small at birth and seemed to have trouble gaining weight. Though her parents, Sara and Mitch Peterka, were worried about her, the pediatrician diagnosed a cow’s milk allergy and hoped that a change in formula would do the trick. It did seem to help, and Emma hit many of the early milestones—like rolling over and sitting up—on schedule. But when it came time to get crawling, Emma couldn’t quite get the hang of things, though she could wiggle around, and came up with a unique pivot-scoot combo that would eventually get her across the room.
It was at that point, about eight months in, where the developmental delays started to pile up. Emma was also diagnosed with low muscle tone, and it was clear that every motion simply took a greater effort than it should have. Still, by the time Emma hit her first birthday, she was wiggle-scoot-pivoting around the room, giggling at her family, and seemed right on the verge of getting engaged with talking. Her signing skills ran ahead of her verbalizing, and she learned to make signs for different things she wanted, including a toy octopus and stuffed pig. If she wasn’t hitting every mark, she didn’t seem to be that far behind. She wasn’t walking or even standing, but the pediatrician advised patience. Which, really, is good advice almost all the time.
Emma started physical therapy shortly after that first birthday. Only the therapy didn’t seem to be helping. Emma’s progress plateaued midway through her first year. At 18 months Emma was really no further along than she had been on her birthday. She was still happy, still giggly and social, but by then Sara and Mitch were worried enough that they asked their pediatrician for referrals so that Emma could be tested.
Emma Peterka.
Only just as those arrangements were being made in the first months of 2020, another medical emergency happened that had nothing to do with Emma, but everything to do with delaying her diagnosis: the COVID-19 pandemic. With medical offices shutting down and hours reduced, getting the tests they needed for Emma became an increasing challenge, especially when those tests sometimes meant travel at a point where restrictions—and reactions—were changing rapidly.
But if the pandemic was a disaster for most of the world and a roadblock to getting the tests that were necessary to determine what was behind Emma’s slow progress, the Peterka family also saw those months as something of a blessing. Because of COVID-19, Sara and Mitch were at home with their first and only child every day. They spent long hours together, soaking in her presence, even as they worried about what came next.
It wasn’t until May 2020 that Emma started getting the panels of genetic testing needed to identify what was by then both a mystery and a reason for serious concern. Soon after that, things began to change—and not in a good way.
Emma had never really stood, but in early summer she stopped trying. She stopped using her unique crawl to get around the room. As the weather warmed, the Peterkas’ animated and bubbly daughter was becoming more motionless. Worse, the light of recognition and presence began to fade from her eyes. She stopped pointing at things she wanted. She stopped asking to play with her toy octopus. She stopped playing.
A dark tide was dragging Emma back and down, and diagnosing the cause was becoming a matter of frantic urgency.
There are some communities that everyone wants to join—like the kids at the cool table or some eclectic group of artists united in a recognition of mutual brilliance. There are other communities that, even when they’re populated by the most wonderful and warm people, everyone would very much like to skip.
The community of NPC parents is like that. They’re a fabulous group, offering a lot of mutual support and fierce energy for the kids afflicted by the disease. But everyone—everyone—would rather be on the outside looking in.
The Peterka family wasn’t given that option. When the first round of genetic tests failed to produce a diagnosis for Emma, it was actually a good old-fashioned observation that put them on the right path. A hematologist noted that Emma had an enlarged spleen. That, along with her symptoms, raised the idea of lysosomal storage disorders. Soon after that came the lysosomal test panel and exome sequencing.
Screen capture from a Firefly NPC Moms’ chat.
On Sept. 21, 2020, Emma Peterka was diagnosed with Niemann-Pick type C. And, as it was for every other parent in the NPC community, that news was absolutely crushing. Until that moment, it was possible for all of them to believe that their children might have something serious, but also something that was temporary. Something that could be remedied by invoking the right name and applying the right drug.
But with the diagnosis of NPC comes a certainty that leaves very little chance of ever sitting in the front row at a wedding, or watching a graduation cap tossed in the air, or even smiling in the audience for a grade school dance recital. For Emma’s family, the diagnosis of NPC wound back the clock to those spring months when Emma was doing well and the whole family was together under the shadow of the pandemic. It very suddenly seemed that those few good months might be the only ones they would ever get.
Like every single person confronted with such a terrifying moment in this modern world, Sara and Mitch began to Google NPC. And just like other families in the same position, nothing they learned was good. For a week, the Peterkas huddled together, unsure where to go next. However, one thing they learned from their research was that one of the world’s experts on NPC was just a short drive away at the Mayo Clinic in Rochester, Minnesota.
It was only October but by then, Emma’s decline was so steep that they worried and wondered if their little girl would still be with them for Christmas. Still, they got in the car and went to visit Dr. Marc Patterson. As awful as the diagnosis of NPC was (and is), Patterson gave the family reassurance that the advances in treatment offered hope. There wasn’t a cure for the disease, but with the treatments available, there was a much better chance—not just of keeping Emma with them longer, but keeping her present, active, and ready to meet that cure when it finally arrives.
In addition to getting Emma started on miglustat, Patterson promised to see if he could get Emma into any experimental trials. The next day, he sent the family a note telling them that Berry-Kravis would love to have Emma join her still-expanding compassionate use program for adrabetadex. At 9:30 that same night, Berry-Kravis called them. The next week, Emma began treatment.
At that first treatment, Berry-Kravis put the Peterka family in touch with the McGlocklin family and with others in the NPC community. The parents welcomed them in, knowing exactly the pain and confusion they were experiencing. They assured Sara and Mitch that there was hope for Emma—hope for all the children. And they were especially happy for Emma because she got her diagnosis so soon and started treatment immediately. As frustrating as the process had seemed, it really had worked much faster for Emma than it does for most children.
“This medicine works,” Marian’s mom assured Emma’s mom. “And you’re going to see a difference.” That same message came from other families involved in the compassionate use program. In the face of this optimism, Mitch and Sara felt buoyed up by hope for the first time since getting Emma’s diagnosis.
That first treatment was on Oct. 25, 2020. As with other patients, there was no immediate result, but after a few visits Emma’s decline seemed to stabilize. After five treatments, it seemed that she was starting to come back to them; that inner spark was reigniting. They knew that the treatment was not a cure, but they also felt it was helping Emma to fight back.
Then, in January, hope took a big boot to the face.
For those parents who felt their children were being helped by adrabetadex, doom came with the opening of an envelope. On Jan. 21, 2021, Mallinckrodt sent a letter to families enrolled in the trial.
If the announcement from Mallinckrodt seemed bad on the surface, the truth was worse. Not only was Mallinckrodt ending the trial 10 months early, and not only did the company have no plans for future trials involving adrabetadex—there was a bigger axe still to fall.
After October, there would be no more trial, no more involvement by the company, and no source of drug for the 60 children around the world who were part of the trial, or for the 50 in Berry-Kravis’ compassionate use program, or for the dozens of others who, like Marian, were getting the drug at a nearby hospital.
All of these children—from those who had been on the drug for 10 years since the start of the NIH trials, to Marian who had just turned 5 following three years of treatment, to Emma who was just starting to return from the depths of her abrupt decline—now faced a deadline. And for some of them, that word could be literal.
For some of those children taking adrabetadex, the offer to continue making the drug available until October didn’t matter. Hospitals that had been willing to provide compassionate use for a drug under active investigation were much less willing to continue treatment with an experimental drug no longer part of an FDA trial. That was compounded by the way in which Mallinckrodt ended the trial. There are few things more certain to make a hospital’s attorney blanch than informing them that patients are getting a drug after the manufacturer has declared that “the risks associated with the treatment, outweigh the potential benefit.”
However, the actual findings were a lot less clear. Mallinckrodt had not identified any new issues with adrabetadex. The only real side effect of any consequence was the possibility of partial hearing loss, a factor that had been understood from the beginning and that could be mediated by dosage adjustment.
In a later video presentation to patients and their families, the company made its statement even more definitive: Company leaders were not acknowledging any positive benefit at all for adrabetadex. So any negative effect, even one that was relatively minor and already known, put the study in the red. Mallinckrodt was putting on the brakes even though essentially no more data had been collected other than what was available at the time they extended the trial.
In both the letter and the presentation, the company’s position remained clear: Mallinckrodt was done. The drug company had zero intentions of conducting another trial, or of applying to the FDA for some other means of making the drug available. In the company leaders’ view, the net-negative results meant that they were washing their hands of adrabetadex. Immediately.
For the parents of the children undergoing treatment, Mallinckrodt’s reluctance to push ahead might have been more understandable had the company still been getting pressure from the FDA to demonstrate clear evidence of adrabetadex’s benefits. However, according to Berry-Kravis, that hadn’t been the case for some months. No matter what doubts the FDA might have had about Mallinckrodt, in the intervening months before the summer of 2020, the agency had come back to the company and invited it to go ahead with a New Drug Application. And where previously the agency had indicated it was concerned by Mallinckrodt’s efforts to use data from outside the trial, by 2020, the FDA was encouraging Mallinckrodt to do exactly that.
The company was invited to bring in data from the original Natural History Study. And, as referenced in Mallinckrodt’s presentation to the parents, its scientists were told they could use anecdotal evidence from the compassionate use program. To all appearances, the FDA was telling Mallinckrodt that the government agency would look at anything the drug company wanted to submit. The government was also acknowledging the difficulty of maintaining a placebo group, the concerns with the varying ages and conditions of the patients in the trial, and the difficultly of making out a signal among all the noise, including the use of miglustat by some patients in both the trial and placebo groups.
Even so, Mallinckrodt continued to state that they didn’t feel they were able to develop information that would have been sufficient to convince the FDA. In a presentation to the Ara Parseghian Research Medical Foundation, Mallinckrodt’s chief scientific officer, Dr. Steven Romano, stated that the officials at the FDA had been very challenging at the start of 2020, and that the company had to argue simply to continue the trial as long as they did. “We had concerns come up from multiple regulators around whether or not we should continue to expose patients to this drug,” said Romano. This issue came not just from regulators in the U.S., but also from agencies in Germany, France, and the U.K., according to Romano. “Now we come back, six months or a year later, and we have different information. Bottom line, we understand the tragedy of an individual case where benefit might be perceived. Unfortunately, those individual cases they simply don’t make it to the level of evidence required for the agency to review this, and that is painful.”
Berry-Kravis and others stood ready to help. And everyone, even the researchers on Mallinckrodt’s team, was willing to acknowledge that the trial had been poorly designed to test whether or not there was actual benefit. To get real evidence of adrabetadex’s efficacy, they needed to go back to square one with a trial that included younger patients, extended over a longer period, and used standard, easily measured physical capabilities. But Mallinckrodt stated that they didn’t feel such a trial was practical, or that there was any way for them to carry on with the existing trial.
Romano insisted to the The Wall Street Journal: “There were no business considerations here. This would have been a real win for us to progress a program for such a rare and serious disease.” However, in the same discussion, Romano admitted that to actually prove the effectiveness of adrabetadex, a three- to five-year study might be required. “It is not a practical trial to conduct,” said Romano. Still, when Cyclo Therapeutics set up its study, they expressly made it longer than a single year to avoid the problem of the disease's progression not necessarily being evident within that time span. If Mallinckrodt needed a longer trial, company executives could have arranged a longer trial.
Adrabetadex may or may not be a failed drug. When the Peterka family made a follow-up visit to Patterson in early March 2021, he expressed the belief that Emma was seeing significant benefit from adrabetadex. Similar opinions were voiced by several doctors and by dozens of families who believe it provides real help to their children, including many who believe those children would not be alive without this treatment.
The doctors who have had long association with cyclodextrin under all its different names could be wrong. The parents could be wrong. Hope, after all, is a powerful emotion in many ways. But there’s really nothing in the trial data that suggests they are wrong.
The only thing that’s certain is that the adrabetadex trial was a failed trial. It collapsed under the weight of a poor design that made it impossible to determine the value of the treatment.
Even so, the FDA was ready to keep going. The doctors in the compassionate care program were ready to keep going. The families were ready to keep going. It was only Mallinckrodt that was determined to stop, and no one is quite sure why. Maybe it has to do with the ongoing reorganization of the company under Chapter 11. Maybe it has to do with a recent ruling on Acthar that suggests that, in the future, charging exorbitant prices for this kind of drug will no longer be tolerated. Maybe some accountants simply went over the books and decided that further research on this drug was a loser. Or maybe, just as they have said, Mallinckrodt simply could not see a way forward with the trial.
Whatever the reason, the trial is over and the source of adrabetadex is drying up all too soon.
Dr. Jonathan Kimmelman is the director of Biomedical Ethics at McGill University in Montreal. A PhD in molecular biophysics and biochemistry, he's an expert in the issues surrounding taking basic research out of the lab and bringing it to patients in the form of new treatments. At the end of a long day in March, Kimmelman agreed to discuss the adrabetadex trial.
When it comes to the issue of whether any company is obligated to continue providing a treatment after a trial has ended, the answer isn't as comfortable as many might wish. "Parents may think that their child is benefiting from receiving a drug, but the reason we do clinical trials is that we know that when we eliminate various sources of bias, those benefits may turn out not to be real." As Kimmelman pointed out, only a small fraction of drugs that enter into human trials go on to become effective, available treatments. That includes many drugs that appear to have a powerful benefit in animal trials.
The perception that a drug has benefits outside of a trial may be due to placebo effects, or patients might be confused by the variations in the natural course of the disease. There are any number of reasons why people might appear to benefit that have little to do with the actual pharmaceutical effects of the drug. "That's why we do randomized controlled trials," said Kimmelman. "It's pretty much the best way, if not the only way, to isolate the relationship between a disease and a drug."
In the purest sense, if Mallinckrodt ended the trial because adrabetadex turned out to have no net benefit, the anecdotal evidence from patients outside that trial doesn't really matter. There's no clear obligation for the company to continue providing the product if the product has not proven effective.
However, if that sounds like a definitive statement that the end of Mallinckrodt's phase 2b/3 trial is the appropriate end for this story, it's not.
"There is a standard between what might be the right time to pull the plug on a drug trial,” said Kimmelman. “However, there's a difference between what society may choose, and what a company may choose." The average person, even one with no personal stake in the outcome, might feel that it's perfectly appropriate to continue testing and to make the drug available for a longer period, especially if that drug represents the only real hope for a community. But a drug company is fundamentally a company. It is there not to make a drug: It’s there to make a profit.
"That’s the tension that is embedded within drug development," said Kimmelman. "A tension that I think patients don't really adequately understand." Patients enroll in trials, or enroll their children in trials, for two reasons. The first is in hope of getting direct benefit from the treatment being tested. The second is to advance medical knowledge about the disease being treated. On the other side of the aisle, researchers at the drug company are also interested in advancing knowledge. However, they’re limited by a greater concern. Their primary goal is to bring a profitable product to market. The result is a clash between the altruistic goals of patients and the commercial goals of companies.
"One thing that patients might not appreciate is that there are times when companies make decisions during clinical trials that are not in the best interests of the patient population," said Kimmelman.
That's because when a patient enters a drug trial, under the system as it exists today, they've entered into what is fundamentally a commercial activity. Companies may make decisions based on the bottom line that differ from those of an enlightened outsider unburdened by concerns about profits and shareholders.
Anyone facing a disease that lacks effective treatment is already facing enormous stress. Entering into a trial, even a failed trial, can at least leave a patient (or their family) with the knowledge that they've helped move the ball forward, and advanced insights that may help the next person in their unenviable position. But when there’s concern that a trial ended due to commercial rather than medical reasons, even that last crumb of positive feeling can be jerked away.
It's impossible to say that Mallinckrodt ended the adrabetadex trial inappropriately because it's not possible to know to what extent potential profit was factored into continuing the trial. However, it's certain that potential profit was a factor. Because it always is.
When it comes to keeping the drug available for patients, the answer may also seem to be rather bleak. According to Kimmelman it may not be compassionate, in any sense, to subject parents and children to both the false hope and financial burden of continuing a treatment that's ineffective. Even keeping adrabetadex out there as an option may be unethical, especially if that prevents patients from getting other care. On the other hand, considering the state in which the trial ended, and the evidence—backed up by the doctors administering the drug—that there is benefit for individual patients, that hard line grows softer.
"That's a complex equation,” said Kimmelman. “If the drug has really just started working, and someone is benefiting, and you withdraw it—that's horrible."
Having just witnessed the successful development of vaccines against COVID-19, society may be primed to believe that every disease, even one that's brand new to science, can be swiftly overcome. However, Kimmelman pointed out the examples of ALS and Huntington's disease, both of which have inevitable dire outcomes and both of which have been diligently researched for decades without finding effective treatment. Sometimes the strongest desire, the most deeply felt concern, and the concentrated attention of the best researchers around the world is simply not enough to generate results in a time that seems either reasonable or just.
It should be up to regulators, in the FDA and elsewhere, to be sure that patients are aware of their role in a trial conducted by a commercial company, and to find some balance between the financial goals of the company and the broader goals of society. In the case of a drug like adrabetadex, that balance needs to consider the direct role that the NIH played in the early development and phase 1 testing, and the government’s role in helping Vtesse to bring the drug to trial.
Mallinckrodt did not invent adrabetadex. They bought it, and then they halted further research. Both of those were unmistakably commercial decisions. When the chief science officer of the company states that a three- to four-year trial is impractical, that's not because such a trial is outside of scientific reason. That’s a financial limitation. All of which suggests that there need to be better mechanisms, especially in situations where the cost of conducting a trial may exceed what might be expected to be earned if drugs are made available at a reasonable price.
"At the end of the day," said Kimmelman, "drug development is based on the idea that, because of the free market, we'll get the best results. But there are any number of dramas that play out showing just how much that market can be in conflict with the needs of the patient. In the end, it's up to society to decide which set of standards they want to dominate."
This is a complicated story. It involves a drug that has been under development for 15 years. That drug has passed through the hands of four pharmaceutical firms and been distributed under three different names. It has been the subject of multiple studies, both in animals and in humans. Add in an assortment of federal agencies, a smattering of doctors in a program outside the trials, and a lot of struggling families, and it’s not hard to get lost in the details.
Most of the studies on this drug—from the first animal trials right up through the phase 1/2 testing—seemed extremely hopeful. But the phase 2b/3 trial appears to have ended with what wasn’t so much a negative result as a collapse of the trial itself. That collapse has spelled disaster for everyone involved.
Most of all, this is a story about children. It’s not just Marian’s story and Emma’s story: It’s the story of the hundreds who have already been diagnosed. Those families are facing a clock that is ticking fast toward the day when the treatment they’ve been using to push back the darkness will no longer be available.
This is also the story of the 43 families whose children will receive this diagnosis in the next year. Unless something changes, what those families will learn is that their child has an invariably fatal disease. And that there is no hope.
To stop the clock from running down on existing families, and to throw a lifeline to those families getting diagnosed today, several things have to happen.
The first thing: Someone has to manufacture this drug and agree to provide it to patients who want to continue the treatment. As it happens, Johnson & Johnson still makes the drug available to a small number of patients who have been with them from the beginning. It’s unlikely that Johnson & Johnson will take over as the drug’s new manufacturer for every child who needs it. However, they might act as a bridge that could extend availability until a new manufacturer comes on board.
This is not an expensive or difficult-to-manufacture drug and is, after all, something that Johnson & Johnson was already producing before the first animal trials began. However, Mallinckrodt currently owns the use of this drug in treating NPC, and that company needs to surrender this right to make it possible for someone else to provide adrabetadex to the whole NPC community.
Next, someone needs to pick up the study of adrabetadex. It’s clear that no matter how many parents with stories of positive results step forward, and no matter how many well-intentioned physicians are willing to participate, no drug can stay in this holding pattern forever. To move forward, the situation with adrabetadex must change.
That doesn’t necessarily mean a new phase 3 trial in the traditional sense. The same problems that caused the collapse of the Mallinckrodt trial, from the small pool of patients to the basic immorality of creating a placebo group by denying children possible life-saving treatment, are still there. But the FDA has made exceptions in the past for just such situations. It is possible for someone to pick up this banner and carry it to a solution where parents have the option of employing this drug and hospitals feel protected enough to administer it. But that can’t happen without someone—specifically, a pharmaceutical manufacturer—who will stand behind the drug to make it available.
As Sara McGlocklin explained, a group of moms whose children all have the infantile version of NPC had hoped to take their case to the FDA. However, “You can’t go to the FDA without the drug manufacturer being part of the meeting.” Without a manufacturer, there is no path forward.
It would be nice, at the end of this long article, if “the ask” was as simple as a request to “call your congressman” or “give $5 now.” Though, honestly, both of those things would help. Congress needs to pressure the administration to provide more support to children affected by rare diseases, and should ask the FDA to seek creative ways to encourage manufacturers to get involved. And the families of children with NPC could definitely use that funding considering that they’re not just facing the exorbitant costs of dealing with a rare disease, but fighting to mount a campaign of public awareness.
Emma Peterka
Letter from Mallinckrodt to phase 3 trial families
Mallinckrodt presentation to NPC families
Webinar from Dr. Denny Porter and Dr. Elizabeth Berry-Kravis
Don’t Give Up on NPC
Firefly Fund: NPC moms react to adrabetadex news
Hope for Marian
Brave Like Emma
Part I of this story
Thursday, Apr 15, 2021 · 3:14:17 PM +00:00 · Mark Sumner
On April 15, Sara McGlocklin wrote to provide an update on how the parents seeking to continue this treatment for their children are organizing, fundraising, and advocating at Don’t Give Up On NPC. The group has already passed its initial fundraising goal and is continuing to add families and advocates. Their aim is find a fast solution that brings government and industry together to maintain access to adrabetadex treatment. They are currently reaching out to Sen. Dianne Feinstein, Sen. Alex Padilla, and Rep. Grace Napolitano in hopes of finding the help they need.
A rare childhood disorder, Niemann-Pick Disease type C (NPC), affects just a few dozen children in the United States each year. One of a number of lysosomal storage disorders, the disease affects the ability to metabolize cholesterol, and results in widespread damage over time. Symptoms from this very rare, recessive genetic disorder can occur at any time, but for those who show symptoms as infants, the disease is often fatal in childhood. In fact, the disease is uniformly fatal. It affects a number of organs, including the liver and the lungs, but it particularly impacts the brain and central nervous system. Children with NPC may seem to progress normally for some time, then gradually lose their ability to walk, crawl, speak, or even swallow. This horrible sequence has earned NPC the nickname of “childhood Alzheimer’s.”
Part I of this story examined how for over a decade there was a suggestion of hope for NPC patients in the form of a treatment known first as 2-hydroxypropyl-ß-cyclodextrin (HPBCD), then as VTS-270, and finally as adrabetadex. That drug was examined in animal trials by the National Institutes of Health (NIH), then taken into human trials first by the NIH and later by a start-up pharmaceutical company called Vtesse. In 2019, this treatment continued into a phase 2b/3 trial under its new owner, Mallinckrodt Pharmaceuticals.
But while most of America was fretting under the weight of the COVID-19 pandemic, for families of children with NPC the past year brought a decision that could bring an end to a decade that engendered hope. Whether that decision was sound science that represents the proper and ethical action going forward or whether it was the calculated act of a for-profit business that chose its bottom line over hundreds of young lives remains horribly unclear.
THE PLACEBO EFFECT
By 2018, Mallinckrodt had given VTS-270 the name adrabetadex. That may seem like a step backward when it comes to pronouncing the drug’s name, but it actually represents progress—it’s a name meant to meet the FDA’s criteria for an approved pharmaceutical.
But if the name was making progress, it was just about the only thing advancing. In November 2018, less than a year after announcing its buyout of Sucampo, Mallinckrodt announced that there was an issue with the trial of its newly acquired drug. The good news was that patients in the phase 2b/3 trial who were receiving treatment were not getting worse. The bad news—or at least, the puzzling news—was that the placebo group was also not showing disease progression.
On the one hand, a group of 36 children suffering from NPC who were not getting worse represents a victory. On the other, the failure of the children in the placebo group to get worse meant that Mallinckrodt could, in a phrase that would soon become repeated all too often, “not demonstrate any positive benefit” for those children receiving adrabetadex.
If the news was upsetting to Mallinckrodt’s investors, it was greeted with a jolt of fear and disbelief from families of NPC patients. It also generated concern from researchers over the future of adrabetadex and other potential drugs for NPC. A treatment that had seemed very promising, and which had been administered to patients for years, was suddenly imperiled by factors that seemed to have been built into the design of the study.
From the very beginning, there had been a real debate about whether it was advisable to even have a placebo group. After all, this is a disease that is both invariably fatal and irreversible. When testing any treatment that has shown to be effective in both laboratory testing and animal models, is it really ethical to deny that treatment to one-third of the children in a trial? That concern was increased by the simple fact that the drug in question is an excipient. Its use as a carrier for other drugs meant that the FDA already had a great deal of safety information.
There was another issue with the trial. By specifically excluding children under 4 years old, the trial shut out those being diagnosed as infants, who are specifically the patients in whom the disease progresses most rapidly. There were reasons for doing this—having infants in a drug trial is never without a host of both practical difficulties and ethical dilemmas—but selecting older patients, including those up to 20, created an obvious problem. That problem was: A year was simply not long enough.
In patients diagnosed with NPC later in life, the disease progresses more slowly. With the older patients who were included in the trial, it was unlikely that either group—those receiving treatment or those in the placebo group—would see much progress of the disease in the space of a single year. In fact, going into the trial, Dr. Elizabeth Berry-Kravis as well as others had predicted that a year would not be long enough to determine whether adrabetadex was demonstrating any protective effect on the rate of change in the disease.
In fact, there were at least three children in the placebo group who did begin to show disease progression over the course of the year. In each case, the researchers involved did the right thing: They began giving these children the actual treatment. It’s unclear if this small number was factored into the results, or whether it would have made a difference.
Marian McGlocklin being treated at CHLA in 2020.
Another good reason for not having a placebo group was simply the size of the trial. Because of the rarity of the disease, the enrollment for the trial was fewer than 60 patients. At that size, random chance alone could obscure any potential results. All of this was made worse because the trial was being conducted by different teams in different locations around the world, some of whom had much more restricted access to their patients. These teams were attempting to measure the progress of the disease against standards that were all too often vague and arbitrary.
In light of the inherent problems with having a placebo group in such a small trial involving a rare and fatal disease, researchers had proposed that Mallinckrodt employ a larger database of possible outcomes: the results of the Niemann-Pick type C Natural Trial that had been carried out back in 2006. In addition, by 2018 there was another potential source of data in the form of the records that were being kept by Berry-Kravis and others involved in the extended compassionate use program.
However, attempts to employ these data sets didn’t seem to get past the watchdogs at the FDA. Repeated attempts to propose a different approach to analyzing the trial data met with resistance from the agency.
Though the whole saga of the treatment had started within the NIH and the government had played a key role in both moving adrabetadex forward and seeing it gain corporate support, at this critical moment it seemed that the FDA was playing hardball with Mallinckrodt.
But there may have been reasons that had little to do with either adrabetadex or the trial results.
A MONOPOLY—AND A HAND-SLAP
Mallinckrodt’s acquisition of Sucampo at the beginning of 2018 was nothing special for that company. Mallinckrodt bought out Ocera a year earlier. And Stratatech a year before that. And Therakos a year before that. In fact, Mallinckrodt acquired at least one other pharmaceutical firm every single year since 2011—and often more than one. The $1.2 billion price paid for Sucampo was typical.
In many of these acquisitions, what Mallinckrodt was hunting appeared to be drugs that were—like VTS-270—well along in their trials. Orphan drugs to treat rare childhood diseases were also no stranger to Mallinckrodt.
In 2015, Mallinckrodt snapped up Questcor Pharmaceuticals for the hefty price of $5.6 billion. In doing so, they obtained both the natural and synthetic forms of a corticosteroid that was used in treating a form of epileptic seizures in infants. In the space of a a dozen years, the cost of that drug, called Acthar gel, had already increased over 50,000%. Mallinckrodt then proceeded to nearly double the price again. The result was that a drug that had been in use since 1952 with a synthesis that was supposed to make it cheap and readily available was instead selling for $34,000 a vial in 2018. Its price is now over $40,000 for a single vial. Families with children suffering from the treated disorder can expect to run through several such vials in a year.
”Why would the company pay $1.2 billion for a drug that treated only a few hundred people?”
The price gouging was so extreme that Martin Shkreli—yes, the infamous “Pharma Bro” Shkreli—acted as a whistleblower in the case. Mallinckrodt ended up having to leave the lobbying group PhRMA just ahead of new rules that would have resulted in the company being thrown out. Mallinckrodt then paid a $100 million fine for maintaining an illegal monopoly and agreed to license Acthar to other manufacturers. It was a sizable fine, but investors saw it as a hand-slap considering the size of the deals—and profits—involved.
All of this happened around the same time that Marian McGlocklin was getting her first treatment of VTS-270. It was less than a year before Mallinckrodt would buy out Sucampo and take over the NPC phase 2b/3 trial. With that in the background, it’s not hard to see why the FDA might have been skeptical in looking at Mallinckrodt. Why would the company pay $1.2 billion for a drug that treated only a few hundred people? The easy assumption is that the company intended to charge highly for it—very, very highly.
In a meeting for investors in 2018, Mallinckrodt executives titled a presentation, “Acthar Modernization Strategy defines the Future of the Brand as either a Growth Asset or Cash Cow.” It’s not difficult to suspect that the company might have had similar goals for VTS-270.
This is a company that even by the standards of the pharmaceutical marketing group was engaged in overcharging for its drugs. Regulators complained that Mallinckrodt devoted very little of its budget to research and development, and instead focused on gambling on buying out companies with drugs that were just months away from going to market, then schemed to generate maximum profit from these purchases. The result was something that was more corporate raider than pharmaceutical company. And that might very well have had some effect on what was happening with the adrabetadex trial.
While the NIH might have been eager to work with a rare-drug incubator like Vtesse, it doesn’t seem all that strange that the FDA might have been less than thrilled when a company with Mallinckrodt’s track record asked for leeway for the next drug they were attempting to bring to market.
The best that Mallinckrodt appeared capable of managing was an extension of the trial in an effort to find some evidence of positive benefit they could take back to the FDA. With that extension, Mallinckrodt carried on the trial with a targeted end date of November 2021.
But before it could get there, the company would end up filing for Chapter 11 bankruptcy.
EMMA
Emma was very small at birth and seemed to have trouble gaining weight. Though her parents, Sara and Mitch Peterka, were worried about her, the pediatrician diagnosed a cow’s milk allergy and hoped that a change in formula would do the trick. It did seem to help, and Emma hit many of the early milestones—like rolling over and sitting up—on schedule. But when it came time to get crawling, Emma couldn’t quite get the hang of things, though she could wiggle around, and came up with a unique pivot-scoot combo that would eventually get her across the room.
It was at that point, about eight months in, where the developmental delays started to pile up. Emma was also diagnosed with low muscle tone, and it was clear that every motion simply took a greater effort than it should have. Still, by the time Emma hit her first birthday, she was wiggle-scoot-pivoting around the room, giggling at her family, and seemed right on the verge of getting engaged with talking. Her signing skills ran ahead of her verbalizing, and she learned to make signs for different things she wanted, including a toy octopus and stuffed pig. If she wasn’t hitting every mark, she didn’t seem to be that far behind. She wasn’t walking or even standing, but the pediatrician advised patience. Which, really, is good advice almost all the time.
Emma started physical therapy shortly after that first birthday. Only the therapy didn’t seem to be helping. Emma’s progress plateaued midway through her first year. At 18 months Emma was really no further along than she had been on her birthday. She was still happy, still giggly and social, but by then Sara and Mitch were worried enough that they asked their pediatrician for referrals so that Emma could be tested.
Emma Peterka.
Only just as those arrangements were being made in the first months of 2020, another medical emergency happened that had nothing to do with Emma, but everything to do with delaying her diagnosis: the COVID-19 pandemic. With medical offices shutting down and hours reduced, getting the tests they needed for Emma became an increasing challenge, especially when those tests sometimes meant travel at a point where restrictions—and reactions—were changing rapidly.
But if the pandemic was a disaster for most of the world and a roadblock to getting the tests that were necessary to determine what was behind Emma’s slow progress, the Peterka family also saw those months as something of a blessing. Because of COVID-19, Sara and Mitch were at home with their first and only child every day. They spent long hours together, soaking in her presence, even as they worried about what came next.
It wasn’t until May 2020 that Emma started getting the panels of genetic testing needed to identify what was by then both a mystery and a reason for serious concern. Soon after that, things began to change—and not in a good way.
”As the weather warmed, the Peterkas’ animated and bubbly daughter was becoming more motionless.”
Emma had never really stood, but in early summer she stopped trying. She stopped using her unique crawl to get around the room. As the weather warmed, the Peterkas’ animated and bubbly daughter was becoming more motionless. Worse, the light of recognition and presence began to fade from her eyes. She stopped pointing at things she wanted. She stopped asking to play with her toy octopus. She stopped playing.
A dark tide was dragging Emma back and down, and diagnosing the cause was becoming a matter of frantic urgency.
THE BEST, WORST COMMUNITY
There are some communities that everyone wants to join—like the kids at the cool table or some eclectic group of artists united in a recognition of mutual brilliance. There are other communities that, even when they’re populated by the most wonderful and warm people, everyone would very much like to skip.
The community of NPC parents is like that. They’re a fabulous group, offering a lot of mutual support and fierce energy for the kids afflicted by the disease. But everyone—everyone—would rather be on the outside looking in.
The Peterka family wasn’t given that option. When the first round of genetic tests failed to produce a diagnosis for Emma, it was actually a good old-fashioned observation that put them on the right path. A hematologist noted that Emma had an enlarged spleen. That, along with her symptoms, raised the idea of lysosomal storage disorders. Soon after that came the lysosomal test panel and exome sequencing.
Screen capture from a Firefly NPC Moms’ chat.
On Sept. 21, 2020, Emma Peterka was diagnosed with Niemann-Pick type C. And, as it was for every other parent in the NPC community, that news was absolutely crushing. Until that moment, it was possible for all of them to believe that their children might have something serious, but also something that was temporary. Something that could be remedied by invoking the right name and applying the right drug.
But with the diagnosis of NPC comes a certainty that leaves very little chance of ever sitting in the front row at a wedding, or watching a graduation cap tossed in the air, or even smiling in the audience for a grade school dance recital. For Emma’s family, the diagnosis of NPC wound back the clock to those spring months when Emma was doing well and the whole family was together under the shadow of the pandemic. It very suddenly seemed that those few good months might be the only ones they would ever get.
Like every single person confronted with such a terrifying moment in this modern world, Sara and Mitch began to Google NPC. And just like other families in the same position, nothing they learned was good. For a week, the Peterkas huddled together, unsure where to go next. However, one thing they learned from their research was that one of the world’s experts on NPC was just a short drive away at the Mayo Clinic in Rochester, Minnesota.
It was only October but by then, Emma’s decline was so steep that they worried and wondered if their little girl would still be with them for Christmas. Still, they got in the car and went to visit Dr. Marc Patterson. As awful as the diagnosis of NPC was (and is), Patterson gave the family reassurance that the advances in treatment offered hope. There wasn’t a cure for the disease, but with the treatments available, there was a much better chance—not just of keeping Emma with them longer, but keeping her present, active, and ready to meet that cure when it finally arrives.
In addition to getting Emma started on miglustat, Patterson promised to see if he could get Emma into any experimental trials. The next day, he sent the family a note telling them that Berry-Kravis would love to have Emma join her still-expanding compassionate use program for adrabetadex. At 9:30 that same night, Berry-Kravis called them. The next week, Emma began treatment.
“’This medicine works,’ Marian’s mom assured Emma’s mom. ‘And you’re going to see a difference.’”
At that first treatment, Berry-Kravis put the Peterka family in touch with the McGlocklin family and with others in the NPC community. The parents welcomed them in, knowing exactly the pain and confusion they were experiencing. They assured Sara and Mitch that there was hope for Emma—hope for all the children. And they were especially happy for Emma because she got her diagnosis so soon and started treatment immediately. As frustrating as the process had seemed, it really had worked much faster for Emma than it does for most children.
“This medicine works,” Marian’s mom assured Emma’s mom. “And you’re going to see a difference.” That same message came from other families involved in the compassionate use program. In the face of this optimism, Mitch and Sara felt buoyed up by hope for the first time since getting Emma’s diagnosis.
That first treatment was on Oct. 25, 2020. As with other patients, there was no immediate result, but after a few visits Emma’s decline seemed to stabilize. After five treatments, it seemed that she was starting to come back to them; that inner spark was reigniting. They knew that the treatment was not a cure, but they also felt it was helping Emma to fight back.
Then, in January, hope took a big boot to the face.
THE LETTER
For those parents who felt their children were being helped by adrabetadex, doom came with the opening of an envelope. On Jan. 21, 2021, Mallinckrodt sent a letter to families enrolled in the trial.
If the announcement from Mallinckrodt seemed bad on the surface, the truth was worse. Not only was Mallinckrodt ending the trial 10 months early, and not only did the company have no plans for future trials involving adrabetadex—there was a bigger axe still to fall.
After October, there would be no more trial, no more involvement by the company, and no source of drug for the 60 children around the world who were part of the trial, or for the 50 in Berry-Kravis’ compassionate use program, or for the dozens of others who, like Marian, were getting the drug at a nearby hospital.
All of these children—from those who had been on the drug for 10 years since the start of the NIH trials, to Marian who had just turned 5 following three years of treatment, to Emma who was just starting to return from the depths of her abrupt decline—now faced a deadline. And for some of them, that word could be literal.
WHEN RISKS ‘OUTWEIGH THE POTENTIAL BENEFIT’
For some of those children taking adrabetadex, the offer to continue making the drug available until October didn’t matter. Hospitals that had been willing to provide compassionate use for a drug under active investigation were much less willing to continue treatment with an experimental drug no longer part of an FDA trial. That was compounded by the way in which Mallinckrodt ended the trial. There are few things more certain to make a hospital’s attorney blanch than informing them that patients are getting a drug after the manufacturer has declared that “the risks associated with the treatment, outweigh the potential benefit.”
However, the actual findings were a lot less clear. Mallinckrodt had not identified any new issues with adrabetadex. The only real side effect of any consequence was the possibility of partial hearing loss, a factor that had been understood from the beginning and that could be mediated by dosage adjustment.
In a later video presentation to patients and their families, the company made its statement even more definitive: Company leaders were not acknowledging any positive benefit at all for adrabetadex. So any negative effect, even one that was relatively minor and already known, put the study in the red. Mallinckrodt was putting on the brakes even though essentially no more data had been collected other than what was available at the time they extended the trial.
In both the letter and the presentation, the company’s position remained clear: Mallinckrodt was done. The drug company had zero intentions of conducting another trial, or of applying to the FDA for some other means of making the drug available. In the company leaders’ view, the net-negative results meant that they were washing their hands of adrabetadex. Immediately.
For the parents of the children undergoing treatment, Mallinckrodt’s reluctance to push ahead might have been more understandable had the company still been getting pressure from the FDA to demonstrate clear evidence of adrabetadex’s benefits. However, according to Berry-Kravis, that hadn’t been the case for some months. No matter what doubts the FDA might have had about Mallinckrodt, in the intervening months before the summer of 2020, the agency had come back to the company and invited it to go ahead with a New Drug Application. And where previously the agency had indicated it was concerned by Mallinckrodt’s efforts to use data from outside the trial, by 2020, the FDA was encouraging Mallinckrodt to do exactly that.
The company was invited to bring in data from the original Natural History Study. And, as referenced in Mallinckrodt’s presentation to the parents, its scientists were told they could use anecdotal evidence from the compassionate use program. To all appearances, the FDA was telling Mallinckrodt that the government agency would look at anything the drug company wanted to submit. The government was also acknowledging the difficulty of maintaining a placebo group, the concerns with the varying ages and conditions of the patients in the trial, and the difficultly of making out a signal among all the noise, including the use of miglustat by some patients in both the trial and placebo groups.
Even so, Mallinckrodt continued to state that they didn’t feel they were able to develop information that would have been sufficient to convince the FDA. In a presentation to the Ara Parseghian Research Medical Foundation, Mallinckrodt’s chief scientific officer, Dr. Steven Romano, stated that the officials at the FDA had been very challenging at the start of 2020, and that the company had to argue simply to continue the trial as long as they did. “We had concerns come up from multiple regulators around whether or not we should continue to expose patients to this drug,” said Romano. This issue came not just from regulators in the U.S., but also from agencies in Germany, France, and the U.K., according to Romano. “Now we come back, six months or a year later, and we have different information. Bottom line, we understand the tragedy of an individual case where benefit might be perceived. Unfortunately, those individual cases they simply don’t make it to the level of evidence required for the agency to review this, and that is painful.”
”Adrabetadex may or may not be a failed drug.”
Berry-Kravis and others stood ready to help. And everyone, even the researchers on Mallinckrodt’s team, was willing to acknowledge that the trial had been poorly designed to test whether or not there was actual benefit. To get real evidence of adrabetadex’s efficacy, they needed to go back to square one with a trial that included younger patients, extended over a longer period, and used standard, easily measured physical capabilities. But Mallinckrodt stated that they didn’t feel such a trial was practical, or that there was any way for them to carry on with the existing trial.
Romano insisted to the The Wall Street Journal: “There were no business considerations here. This would have been a real win for us to progress a program for such a rare and serious disease.” However, in the same discussion, Romano admitted that to actually prove the effectiveness of adrabetadex, a three- to five-year study might be required. “It is not a practical trial to conduct,” said Romano. Still, when Cyclo Therapeutics set up its study, they expressly made it longer than a single year to avoid the problem of the disease's progression not necessarily being evident within that time span. If Mallinckrodt needed a longer trial, company executives could have arranged a longer trial.
Adrabetadex may or may not be a failed drug. When the Peterka family made a follow-up visit to Patterson in early March 2021, he expressed the belief that Emma was seeing significant benefit from adrabetadex. Similar opinions were voiced by several doctors and by dozens of families who believe it provides real help to their children, including many who believe those children would not be alive without this treatment.
The doctors who have had long association with cyclodextrin under all its different names could be wrong. The parents could be wrong. Hope, after all, is a powerful emotion in many ways. But there’s really nothing in the trial data that suggests they are wrong.
The only thing that’s certain is that the adrabetadex trial was a failed trial. It collapsed under the weight of a poor design that made it impossible to determine the value of the treatment.
Even so, the FDA was ready to keep going. The doctors in the compassionate care program were ready to keep going. The families were ready to keep going. It was only Mallinckrodt that was determined to stop, and no one is quite sure why. Maybe it has to do with the ongoing reorganization of the company under Chapter 11. Maybe it has to do with a recent ruling on Acthar that suggests that, in the future, charging exorbitant prices for this kind of drug will no longer be tolerated. Maybe some accountants simply went over the books and decided that further research on this drug was a loser. Or maybe, just as they have said, Mallinckrodt simply could not see a way forward with the trial.
Whatever the reason, the trial is over and the source of adrabetadex is drying up all too soon.
A TENSION THAT PATIENTS DON’T ADEQUATELY UNDERSTAND
Dr. Jonathan Kimmelman is the director of Biomedical Ethics at McGill University in Montreal. A PhD in molecular biophysics and biochemistry, he's an expert in the issues surrounding taking basic research out of the lab and bringing it to patients in the form of new treatments. At the end of a long day in March, Kimmelman agreed to discuss the adrabetadex trial.
When it comes to the issue of whether any company is obligated to continue providing a treatment after a trial has ended, the answer isn't as comfortable as many might wish. "Parents may think that their child is benefiting from receiving a drug, but the reason we do clinical trials is that we know that when we eliminate various sources of bias, those benefits may turn out not to be real." As Kimmelman pointed out, only a small fraction of drugs that enter into human trials go on to become effective, available treatments. That includes many drugs that appear to have a powerful benefit in animal trials.
The perception that a drug has benefits outside of a trial may be due to placebo effects, or patients might be confused by the variations in the natural course of the disease. There are any number of reasons why people might appear to benefit that have little to do with the actual pharmaceutical effects of the drug. "That's why we do randomized controlled trials," said Kimmelman. "It's pretty much the best way, if not the only way, to isolate the relationship between a disease and a drug."
In the purest sense, if Mallinckrodt ended the trial because adrabetadex turned out to have no net benefit, the anecdotal evidence from patients outside that trial doesn't really matter. There's no clear obligation for the company to continue providing the product if the product has not proven effective.
However, if that sounds like a definitive statement that the end of Mallinckrodt's phase 2b/3 trial is the appropriate end for this story, it's not.
"There is a standard between what might be the right time to pull the plug on a drug trial,” said Kimmelman. “However, there's a difference between what society may choose, and what a company may choose." The average person, even one with no personal stake in the outcome, might feel that it's perfectly appropriate to continue testing and to make the drug available for a longer period, especially if that drug represents the only real hope for a community. But a drug company is fundamentally a company. It is there not to make a drug: It’s there to make a profit.
"That’s the tension that is embedded within drug development," said Kimmelman. "A tension that I think patients don't really adequately understand." Patients enroll in trials, or enroll their children in trials, for two reasons. The first is in hope of getting direct benefit from the treatment being tested. The second is to advance medical knowledge about the disease being treated. On the other side of the aisle, researchers at the drug company are also interested in advancing knowledge. However, they’re limited by a greater concern. Their primary goal is to bring a profitable product to market. The result is a clash between the altruistic goals of patients and the commercial goals of companies.
"One thing that patients might not appreciate is that there are times when companies make decisions during clinical trials that are not in the best interests of the patient population," said Kimmelman.
That's because when a patient enters a drug trial, under the system as it exists today, they've entered into what is fundamentally a commercial activity. Companies may make decisions based on the bottom line that differ from those of an enlightened outsider unburdened by concerns about profits and shareholders.
Anyone facing a disease that lacks effective treatment is already facing enormous stress. Entering into a trial, even a failed trial, can at least leave a patient (or their family) with the knowledge that they've helped move the ball forward, and advanced insights that may help the next person in their unenviable position. But when there’s concern that a trial ended due to commercial rather than medical reasons, even that last crumb of positive feeling can be jerked away.
It's impossible to say that Mallinckrodt ended the adrabetadex trial inappropriately because it's not possible to know to what extent potential profit was factored into continuing the trial. However, it's certain that potential profit was a factor. Because it always is.
When it comes to keeping the drug available for patients, the answer may also seem to be rather bleak. According to Kimmelman it may not be compassionate, in any sense, to subject parents and children to both the false hope and financial burden of continuing a treatment that's ineffective. Even keeping adrabetadex out there as an option may be unethical, especially if that prevents patients from getting other care. On the other hand, considering the state in which the trial ended, and the evidence—backed up by the doctors administering the drug—that there is benefit for individual patients, that hard line grows softer.
"That's a complex equation,” said Kimmelman. “If the drug has really just started working, and someone is benefiting, and you withdraw it—that's horrible."
Having just witnessed the successful development of vaccines against COVID-19, society may be primed to believe that every disease, even one that's brand new to science, can be swiftly overcome. However, Kimmelman pointed out the examples of ALS and Huntington's disease, both of which have inevitable dire outcomes and both of which have been diligently researched for decades without finding effective treatment. Sometimes the strongest desire, the most deeply felt concern, and the concentrated attention of the best researchers around the world is simply not enough to generate results in a time that seems either reasonable or just.
It should be up to regulators, in the FDA and elsewhere, to be sure that patients are aware of their role in a trial conducted by a commercial company, and to find some balance between the financial goals of the company and the broader goals of society. In the case of a drug like adrabetadex, that balance needs to consider the direct role that the NIH played in the early development and phase 1 testing, and the government’s role in helping Vtesse to bring the drug to trial.
Mallinckrodt did not invent adrabetadex. They bought it, and then they halted further research. Both of those were unmistakably commercial decisions. When the chief science officer of the company states that a three- to four-year trial is impractical, that's not because such a trial is outside of scientific reason. That’s a financial limitation. All of which suggests that there need to be better mechanisms, especially in situations where the cost of conducting a trial may exceed what might be expected to be earned if drugs are made available at a reasonable price.
"At the end of the day," said Kimmelman, "drug development is based on the idea that, because of the free market, we'll get the best results. But there are any number of dramas that play out showing just how much that market can be in conflict with the needs of the patient. In the end, it's up to society to decide which set of standards they want to dominate."
THE ASK
This is a complicated story. It involves a drug that has been under development for 15 years. That drug has passed through the hands of four pharmaceutical firms and been distributed under three different names. It has been the subject of multiple studies, both in animals and in humans. Add in an assortment of federal agencies, a smattering of doctors in a program outside the trials, and a lot of struggling families, and it’s not hard to get lost in the details.
Most of the studies on this drug—from the first animal trials right up through the phase 1/2 testing—seemed extremely hopeful. But the phase 2b/3 trial appears to have ended with what wasn’t so much a negative result as a collapse of the trial itself. That collapse has spelled disaster for everyone involved.
Most of all, this is a story about children. It’s not just Marian’s story and Emma’s story: It’s the story of the hundreds who have already been diagnosed. Those families are facing a clock that is ticking fast toward the day when the treatment they’ve been using to push back the darkness will no longer be available.
This is also the story of the 43 families whose children will receive this diagnosis in the next year. Unless something changes, what those families will learn is that their child has an invariably fatal disease. And that there is no hope.
To stop the clock from running down on existing families, and to throw a lifeline to those families getting diagnosed today, several things have to happen.
The first thing: Someone has to manufacture this drug and agree to provide it to patients who want to continue the treatment. As it happens, Johnson & Johnson still makes the drug available to a small number of patients who have been with them from the beginning. It’s unlikely that Johnson & Johnson will take over as the drug’s new manufacturer for every child who needs it. However, they might act as a bridge that could extend availability until a new manufacturer comes on board.
This is not an expensive or difficult-to-manufacture drug and is, after all, something that Johnson & Johnson was already producing before the first animal trials began. However, Mallinckrodt currently owns the use of this drug in treating NPC, and that company needs to surrender this right to make it possible for someone else to provide adrabetadex to the whole NPC community.
Next, someone needs to pick up the study of adrabetadex. It’s clear that no matter how many parents with stories of positive results step forward, and no matter how many well-intentioned physicians are willing to participate, no drug can stay in this holding pattern forever. To move forward, the situation with adrabetadex must change.
That doesn’t necessarily mean a new phase 3 trial in the traditional sense. The same problems that caused the collapse of the Mallinckrodt trial, from the small pool of patients to the basic immorality of creating a placebo group by denying children possible life-saving treatment, are still there. But the FDA has made exceptions in the past for just such situations. It is possible for someone to pick up this banner and carry it to a solution where parents have the option of employing this drug and hospitals feel protected enough to administer it. But that can’t happen without someone—specifically, a pharmaceutical manufacturer—who will stand behind the drug to make it available.
As Sara McGlocklin explained, a group of moms whose children all have the infantile version of NPC had hoped to take their case to the FDA. However, “You can’t go to the FDA without the drug manufacturer being part of the meeting.” Without a manufacturer, there is no path forward.
It would be nice, at the end of this long article, if “the ask” was as simple as a request to “call your congressman” or “give $5 now.” Though, honestly, both of those things would help. Congress needs to pressure the administration to provide more support to children affected by rare diseases, and should ask the FDA to seek creative ways to encourage manufacturers to get involved. And the families of children with NPC could definitely use that funding considering that they’re not just facing the exorbitant costs of dealing with a rare disease, but fighting to mount a campaign of public awareness.
Emma Peterka
ADDITIONAL READING AND VIEWING
Letter from Mallinckrodt to phase 3 trial families
Mallinckrodt presentation to NPC families
Webinar from Dr. Denny Porter and Dr. Elizabeth Berry-Kravis
Don’t Give Up on NPC
Firefly Fund: NPC moms react to adrabetadex news
Hope for Marian
Brave Like Emma
Part I of this story
Thursday, Apr 15, 2021 · 3:14:17 PM +00:00 · Mark Sumner
On April 15, Sara McGlocklin wrote to provide an update on how the parents seeking to continue this treatment for their children are organizing, fundraising, and advocating at Don’t Give Up On NPC. The group has already passed its initial fundraising goal and is continuing to add families and advocates. Their aim is find a fast solution that brings government and industry together to maintain access to adrabetadex treatment. They are currently reaching out to Sen. Dianne Feinstein, Sen. Alex Padilla, and Rep. Grace Napolitano in hopes of finding the help they need.