rom my days in medical school, I vaguely remember learning about lysosomal storage disorders. They occupied at most part of a lecture or two in my second-year pathophysiology course. I memorized a few details about these rare diseases in preparation for my board exam, and then never gave them another thought. These diseases were treated by pediatric specialists and wouldn’t be part of my life as a cardiologist.
That changed a few weeks ago when my 28-month-old daughter, Radha, was diagnosed with a lysosomal storage disorder. Now I know far more about these diseases than I did in medical school. I’ve also learned a frustrating fact that no medical school teaches its students: While the FDA has a compassionate use program to allow people access to experimental drugs, it can’t compel a company to provide those drugs. The newly signed “right-to-try” law doesn’t either.
Radha’s birth went perfectly. She was a healthy baby and met all of her developmental milestones — until it came to walking. My wife, Sonal, a pediatric gastroenterologist, recognized this and we had Radha evaluated by several specialists. None thought anything was physically wrong and indicated that she would learn to walk with the help of some physical therapy sessions.
They initially helped. Then Radha’s progress slowed. Just after her second birthday, additional testing, including an MRI of her brain and spine followed by a genetic analysis, revealed that our daughter had metachromatic leukodystrophy.
This lysosomal storage disorder is an autosomal recessive genetic disease that interferes with the body’s production of a single enzyme, arylsulfatase A. Not enough arylsulfatase A causes a buildup of fats called sulfatides inside cells. In cells that make myelin, the substance that insulates and protects nerves, an abundance of sulfatides destroys tissue throughout the brain, spinal cord, and other parts of the nervous system.
Children with the most severe form of metachromatic leukodystrophy develop symptoms like trouble walking or poor muscle tone before the age of 30 months. Once symptoms appear, the prognosis is grim. Radha’s health will decline rapidly over the next three to six months. She will soon lose her ability to move, speak, see, and eat, and will be prone to seizures. The disease will then plateau for several years, leaving her in a vegetative state and unable to communicate. Our only hope is that she’ll always understand us when we tell her we love her, but we may never know. Most children with metachromatic leukodystrophy don’t survive beyond their 8th birthday.
Because we live in an era of rapid genomic innovation, gene-editing technologies such as CRISPR, proteomics, and rational drug design, I assumed that a disease caused by a single-enzyme deficiency was treatable. In my search for ways to help my daughter, I came across enzyme replacement therapies being developed for a number of conditions, including metachromatic leukodystrophy.
Shire Pharmaceuticals has developed a therapy for the disease and has even found a way to deliver it across the blood-brain barrier, which is no mean feat. The company has even completed a multicenter Phase 1/2 trial of the drug, called SHP-611 (also known as HGT-1110) in Europe, with what appear to be promising results. There was enough of a signal of therapeutic benefit from this trial to move forward with another one, though it appears to be several months to a year away.
Children with metachromatic leukodystrophy who were involved in the original trial have access to the drug as part of an extension of the trial. Radha developed the disease too late to take part in the first trial, and too soon to join the second one (if and when it happens).
Even so, that discovery gave me hope. It meant that Radha should qualify for what the Food and Drug Administration calls its expanded access program, also known as compassionate use. It governs the use of an investigational medicine that has not been approved by the FDA outside of a clinical trial.
Here’s how it is supposed to work. A physician caring for a patient with a terminal illness who has exhausted all other treatment options and isn’t eligible for a clinical trial appeals to the pharmaceutical company to provide an investigational drug that has undergone at least a Phase 1 trial, which studies the safety of a drug. If the pharmaceutical company agrees, the treating physician applies to the FDA for approval for expanded access to the investigational drug.
Thanks to policy changes at the FDA, it has become easier than ever for physicians seek access to investigational drugs. The application form has been significantly simplified and now only one member of a facility’s institutional review board needs to sign off on the petition. The FDA approves more than 95 percent such requests, and does so swiftly, usually in a matter of a few days.
Radha’s physicians followed Shire’s protocol for applying for compassionate use exactly as directed on the company’s website. Within a day or two, their request was denied, without any legitimate medical reason given.
With my daughter’s life on the line, I shamelessly used every contact and connection I have to reach someone at Shire to ask about compassionate use of SHP-611. When that effort yielded no responses, I called and emailed the current and former FDA commissioners, the head of the pharmaceutical trade association, PhRMA, the former CMO of a major pharmaceutical company, and even the dean of the medical school I attended. Most were cordial, even supportive.
Sonal and I even started a Change.org petition to help us nudge Shire to give Radha and her doctors compassionate access to SHP-611.
All of our efforts to get answers from Shire have been repeatedly rebuffed with vague, unsatisfying responses, leaving me to wonder why the company is denying my daughter’s only hope. In fact, Shire has refused to correspond with me directly, and has instructed me to direct questions to it via my daughter’s treating physicians.
Large pharmaceutical companies are notoriously risk averse when it comes to expanding access to medications that are still in the testing phase. Many refuse to grant access to investigational drugs outside of clinical trials, and efforts to lobby them to release the medication as part of compassionate use are often rebuffed.
One fear they have is that an adverse event, like an injury or death — even if it is not directly due to the medication — will derail a company’s ability to push a drug forward for FDA approval, something they argue would ultimately undermine efforts to develop drugs that can help other families.
In response to this fear, FDA Commissioner Scott Gottlieb unveiled an updated policy on reporting adverse events that occur during compassionate use. It now requires reporting “only if there is evidence to suggest a causal relationship between the drug and the adverse event.”
Pharmaceutical companies also worry that if an experimental medication is given to one patient through compassionate use, it must be given to all patients who request it. In the case of rare diseases like metachromatic leukodystrophy — in the U.S., only about 60 children develop the late infantile form of the disease each year — this could mean that a company would have trouble enrolling enough patients when it eventually opens a clinical trial.
That’s a valid concern when access to the therapy is not time-sensitive. But in disorders such as the late infantile form of metachromatic leukodystrophy, the disease progresses so fast and irreversibly that patients who are denied access to the medication today will soon be so debilitated that they would not derive any benefit from it if and when it became available via a clinical trial, and so would not be able to enroll in the trial anyway.
The push for a federal right-to-try process culminated this week with President Trump signing a new law in a ceremony surrounded by patients with life-threatening illnesses and their families. In theory, this law will let patients and physicians bypass the FDA and go directly to pharmaceutical companies for access to investigational therapies that have undergone early testing. But it doesn’t require pharmaceutical companies to accede to these requests.
This new law requires drug companies to report clinical outcomes and adverse events, though it reduces their implications by stating that the FDA should not use this information to delay or adversely affect the approval of investigational drugs. As a physician, I believe that removing federal safeguards for experimental drugs is dangerous, and I believe that adverse events should be reported to the FDA as a way to prevent them from happening to other patients. As a parent desperate to help his daughter in any way I can, though, I hope this bill will allay Shire’s fears and encourage it to give SHP-611 to Radha.
I have never been one to malign pharmaceutical companies because I believe they are our best source of new and improved treatments. Yet Radha’s situation has made me cynical of a system in which pharmaceutical companies cater to investors and the physicians who prescribe their products rather than to the consumers of their therapies. I wish I could say that Shire is an outlier, but a quick internet search shows many similar situations where other pharmaceutical companies have denied compassionate use requests for what amount to business decisions.
Shire’s therapy represents the only reasonable hope for Radha and our family. If the company continues to refuse access to SHP-611 outside of a clinical trial, then why not open a new one? Its previous trial ended 15 months ago and yet there is still no sign of the follow-up trial that Shire claims it is working hard to start as soon as possible.
Much of what we do in medicine is based on analyses of benefits and risks. Shire has produced a drug that in early testing demonstrated safety with enough benefit to push forward follow-up trials. In Radha’s case, the potential benefits of SHP-611 clearly outweigh the risks, but only if we get the drug to her soon, before her condition deteriorates further.
Compassionate use and right-to-try are billed as ways to give hope to patients who have exhausted all other options. From Radha’s perspective, they are nothing more than a cruel joke, dangling a potential lifesaving therapy just out of her reach.
Vibhav Rangarajan, M.D., is a fellow in advanced cardiovascular imaging at Northwestern University’s Feinberg School of Medicine.