The following is a guest article by Dr. Zach Landman, Co-Founder of Moonshots for Unicorns.
As a physician who trained at UCSF, Harvard, and Stanford, I assumed that when my youngest daughter, Lucy – at 10-months old – was diagnosed with an ultra-rare genetic disorder of glycosylation called PGAP3, the answers would reside within a hospital or academic laboratory.
Unfortunately, my pediatrician wife and I were told that our smiling, seemingly healthy babbling 10-month-old baby would likely never walk normally, never talk, and was likely to develop severe and refractory seizures at some point in her childhood. And as we sat there, shell-shocked like any other parents would be, we were told there were no treatments or cures, or even any research into them at any academic institution in the world. As is true for many patients with rare disorders and their families, we were told there was nothing to be done but wait and hope for the best.
However, we refused to let that be Lucy’s story, or that of Ella or Matthew, or the many hundreds of thousands of other children with potentially curable ultra-rare genetic disorders. We soon learned that the science exists today to effectively treat and potentially “cure” (if done early enough in childhood) the vast majority of these disorders. Gene therapy, antisense oligonucleotide (ASO), and now even CRISPR based therapies are being used today, but the process to get them into patients with rare disorders is slow, costly, and disjointed.
After Lucy’s diagnosis, we explored how quickly we could get these potential curatives treatments into Lucy before the more severe symptoms began to develop. Unfortunately, we learned there were significant barriers to getting these therapies into patients on a timeline that is meaningful to them (and us).
First, by their very nature, rare disorders are rare, and patients are spread out across the globe making studying and following patients over time expensive and challenging. This prerequisite to any FDA drug approval, termed a natural history study, does exactly what it sounds like – it studies what happens to patients over time without treatment. It establishes the baseline from which to judge any potential therapeutics.
Historically, these natural history studies would be individually and quixotically sponsored and recruited at tertiary academic medical centers, following a researcher’s particular interests. Today, however, biotechnology companies like Invitae are meeting the patient at the time of genetic diagnosis (with their permission) and enrolling them in real-world natural history data collection. Patients don’t need to travel across the country or world to enroll; a parent or caregiver can submit the necessary data securely and electronically wherever they reside. Already, this real-world, distributed time of diagnosis approach, has been used to cut down more than four years of estimated drug development timeline in the instance of PRAX-222, a new therapy for SCN2A, a rare genetic disorder of pediatric epilepsy.
Second, the FDA was designed to serve as a safety check for the masses to help ensure safe and effective medical treatments. The long and expensive process of submitting a new drug to the FDA is intentionally so, and it works well to ensure the highest standards of safety for medicines use to treat common conditions such as high blood pressures or diabetes for millions of Americans. However, for patients suffering from ultra-rare disorders, it suffocates innovation.
The costs and current timeline to develop a novel therapeutic will never be covered by individual market sizes in the dozens or hundreds of patients, such as is with PGAP3 and many other ultra-rare disorders. AAV9 gene therapy, for instance, was shown to be safe and nearly curative for spinal muscular atrophy (SMA-1) in a hallmark clinical trial more than five years ago and the same vector and promoter has been repeatedly used by many research teams. However, each new AAV9 gene therapy is treated by the FDA as a completely novel technology, requiring the most basic of safety and efficacy testing. This process can take years and is often estimated to cost upward of $3 million to $7 million per disorder. That is not scalable or sustainable, and it stifles private innovation. One highly promising technology has seen countless ventures fail over the past 24 months due to the regulatory burden alone.
Fortunately, the current Biden administration has begun to place a priority on ensuring broader access to genomic testing and therapeutics by assigning a work stream specifically to “developing policy solutions to advance development for ultra-rare and n of 1 conditions.” Currently, however, these barriers remain, meaning most therapies are never made or the immense costs are swallowed by an extremely motivated family (such as ours); oftentimes, a resulting non-profit may fund the development of these life-altering genetic therapies.
Until a more effective framework for ultra-rare novel drug development exists, patients with rare genetic disorders (and usually their families and advocates) can use the tenants of distributed biotechnology to find an effective treatment at a cost which is within reach of many families. Currently, there are more than 20,000 FDA-approved prescription medicines available in the United States. As we saw with COVID, when treatments were needed more rapidly than the typical drug development timeline could offer, we identified existing medicines that could be repurposed (such as remdesevir and dexamethasone, among many others.) This same process is now being done at the individual and family basis through a distributed biotech model.
Perlara, a San Francisco based, biotechnology company doesn’t have a physical office. The team of scientists pool resources from multiple families to rent pop-up lab space to develop yeast and animal “avatars,” which are used to screen thousands of existing medicines to see which have a positive effect on the specific genetic defect. Already, this process has been used to identify epalrestat, a Japanese nerve pain medication, which was initially tested on yeast and worms designed to resemble the effects of PMM2, a similar rare disorder of glycosylation. After it showed remarkable efficacy on the patient’s own cells in the lab, it was given to the child and, over the coming months, a young girl who could not previously walk or utter words was taking unassisted steps, speaking dozens of words, and riding a tricyle. Her father recalls it being the first time he felt like he got to meet his daughter. It is now in a fast track phase III clinical trial at Mayo Clinic. As a physician, non-profit founder, and most importantly as a father, I hope that I can say the same thing about Lucy, and the many others we hope to help through our non-profit public charity, Moonshots for Unicorns.
Editor’s Note: You can support Lucy’s GoFundme.
About Zachary Landman, MD MPH
Zachary Landman MD MPH is an interventional pain management physician in the Bay Area. Dr. Landman and his wife Geri Landman MD MPH, a pediatrician, are parents to the ultra-rare disease PGAP3 unicorn, Lucy, and co-founders of the non-profit, Moonshots for Unicorns, whose mission is to streamline the development of cures for rare genetic disorders.
