Why Pediatric Rare Medicine is Like Timeshare Sales

It is well-recognized that our commercial drug development process, a process that has led to so many nearly miraculous advancements, serves people with rare diseases poorly. Kate Edwards’ experiences are ones that I could not have guessed were possible. 

Adam Cifu

Sensible Medicine readers appreciate a well-designed clinical trial. Clinical trials, however, aren’t helping everyone. 

Imagine that you are working for an agriculture company. Your job is to tend to a genetically modified plant. There are six other people who also tend to this super important plant. You are told to never touch it because it causes a terrible rash.

One day you accidentally touch it. The skin on your face feels like it is on fire and your hands swell. Your skin is turning a worrisome orange. Your supervisor says, “Look, the plant has some similarities to poison ivy. When we tested a treatment for this rash in mice, a specific prescription strength poison ivy cream cleared it right up. Go to the company doctor and get a tube. This cream has always worked in the past.”

You go to the Doctor, and she agrees that there are strong indicators that you should try this cream and that BAD things might happen if you don’t. But this cream is not FDA approved for “freaky plant rash“, it is only approved for poison ivy. 

Imagine how you respond to these suggestions from the doctor.

1. “This is off-label use. We should start clinical trials. Please raise $400,000 so that we can first give this cream to forty healthy adults to see if they die. Then you will need to keep raising money so that we can do three phases of clinical trials. Safety is of utmost importance!” 

2. “Of course, we should try this right away. However, this is off label use. Do you have $100,000? That would allow us to do a real “n of 1” clinical trial. It requires a lot of paperwork.”

3. “This is off-label use and “freaky plant rash” represents a new type of disorder. We are going to need to wait until we have six other examples before we can begin clinical trials. Can you start an advocacy group and raise funds for us in the meantime?” 

Your hair is starting to fall out. 

From a patient’s point of view, at this precise moment, what is the value of those clinical trials to you? Do the doctor’s questions feel like extortion? 

Your tooth might be loose. Your eye is swollen shut. 

My child has a single knockout of a protein gene (LRRC4). There are maybe three known cases in North America, probably seven globally. My kid has severe intellectual disability, epilepsy, autism, etc. It’s a whole damn thing but the details aren’t important. By 2050 there may be two more people with germline mutations. The gene/protein are well studied due to their relationship with cancer (caused by environmental mutations). 

Our doctor appointments always pivot into what we refer to as the “timeshare sales pitch.” By this I mean, the strong urging from our doctors that we will agree to raise money to study the repurposing of available drugs for my child's condition. Here is a sample of what I have heard: 

• “You don’t want to raise research funds? Don’t you love your child?” 

• “Don’t you want to put d-cycloserine through all three FDA clinical trials? This was never done as the drug was approved in 1954. How do you know if the drug is safe?” 

• “You can’t expect any doctor to take you seriously if you don’t start fundraising.” 

• "You should fundraise to increase awareness.” 

• “Fundraising and advocacy are important.” 

• “There is only one other case of this in the literature. Find four other families, so that we have a total of six. Then we can study you as a cohort.” 

• “I have been working with a family for ten years on re-using an FDA approved drug for their disease. We are still conducting clinical trials and research.” 

• “Think about what is best for the hospital.” 

To some extent I understand the reasoning here for “research". Deciding when to repurpose a drug for off-label use for ultra rare diseases is complicated, even before you consider side effects. 

But is it right (or ethical, or efficient) to ask a family to raise hundreds of thousands, if not millions of dollars, to fund research into the off-label use of drugs like d-cycloserine, metformin, or lithium? These drugs have been around since 1954, 1922 and 1870, respectively. All have been used off label for epilepsy (and other conditions). All are safe. 

Doctors are encouraged to fundraise and conduct research, so I am not completely offended by the timeshare sales pitch. I am offended that doctors are trying to get me to fund their research on old, well-studied drugs that sort of work. It is like someone trying to sell you a timeshare for an ancient, rundown resort in a not very nice town.

I want to buy a timeshare at a fancy resort. I want pools, waterslides, lazy rivers, and real marble in the bathrooms.  I cannot overstate my excitement for the several gene therapies that have already been created for my specific gene: Adeno-Associated Virus (AAV-LRRC4), AAV9-LRRC4, germline derived monoclonal antibodies (LRRC4 antibody mab) and perhaps an upcoming fourth treatment of the protein itself injected into the brain (for glioblastoma)... But these are not FDA approved treatments and the logistics are horrible and spectacular. I hope by 2026, the gene therapy market will be more mature.  We want a resort that runs with military precision, especially the plumbing.      

In 2024, I'd prefer a second tier resort. Maybe one with a bowling alley? This might be a GLP-1 RA. These have actions on the pathways affected by our mutation. Liraglutide or tirzepatide are strong contenders. 

If I was a doctor at a pediatric research hospital, I would focus on transformational drugs. GLP-1 drugs present a unique opportunity.  They may have fewer side effects than epilepsy drugs. There are over ten years of data on long term use in patients with diabetes and these drugs represent a truly novel drug class that is already FDA approved. Establishing GLP-1 drugs as a bridge treatment to gene therapies for pediatric rare disease, as GLP-1 drugs may be a bridge treatment to gene therapy for some types of diabetes, would be transformational.  

There is real evidence supporting the promise of these drugs:  

Liraglutide in mice with Dravet syndrome = positive result.

Liraglutide in large diverse patient populations = positive results.

Liraglutide in patients with diverse neurological disorders = positive results.

Adults with epilepsy on Liraglutide (and other GLP-1 RAs) report significant improvements.

“N of 1” trials for a GLP-1 drug merits discussion. 

“N of 1” trials for drugs discovered before I was born do not. 

Think about the plant scenario. For a one in a billion genetic mutant, how much re$earch should be required to try low dose metformin? Epilepsy drugs have safety issues and severe side effects. The economic analysis tends to argue against conducting clinical trials where the patient population is effectively non-existent. Remember this is not an “only seven people with a mutation on position 437 of BRCA2 and both my sisters died from breast cancer” situation; this is “we know of only seven people with pathogenic mutations ANYWHERE on this gene.” 

It was thrilling when my non-verbal child, after a week on D-cycloserine, screamed at my husband “I am not a baby.” 

It shocked his teacher when he wrote his name in magnet letters after a week of taking lithium. 

He can hear better after six months on metformin. 

Lithium is the clear winner of these three; no formal clinical trial predicted that result. Even small improvements in very disabled children improve the quality of their lives and their families’ lives. 

I want to be part of the solution. I cannot see the next move.

Kate Edwards is a mother and a wife.

Photo Credit: Louis Reed