Jaci Hermstad's story is compelling. The bright-eyed 25-year-old from Iowa who loves horseback riding has, since February, had her world rocked by a rare genetic form of amyotrophic lateral sclerosis (ALS).
She has survived longer than her identical twin sister, Alex, who developed her first ALS symptoms at age 11 and died in 2011 when she was 17.
Her helped broker Jaci's entrance into an "n-of-1" trial of an antisense oligonucleotide targeted at the gene mutation responsible for her ALS. Her experience prompted friends and family and those on her social media networks to raise hundreds of thousands of dollars for her treatment. The " and aired her story. She caught the attention of her congressional representatives who nudged the FDA to approve her experimental treatment, which went beyond recent "right-to-try" laws since it hadn't been tested in humans.
Jaci's story is the latest example of patients pursuing custom-designed antisense oligonucleotide (ASO) therapies. These compounds lend themselves to personalization, as their chemistry is well understood and their production is relatively simple. As patients become increasingly savvy about raising money and awareness, researchers and regulators expect increased demand for personalized treatments with these compounds.
There are at least five n-of-1 trials with ASOs. Jaci's is one. Others include Mila Makovec, who has Batten disease; an unnamed young girl with ataxia-telangiectasia (A-T); and two others who prefer not to go public at all. Experts say it's highly likely more are in the works.
"[ASOs] are relatively easy to synthesize, and the chemistries have been worked out for a couple of instances in FDA-approved drugs, so these are the [compounds] people will reach for first in these n-of-1 studies," Jaci's doctor, Neil Shneider, MD, PhD, of Columbia University, told 番茄社区.
The trend raises scores of questions: Are regulators prepared to handle a potential influx of requests? What about patients who don't have the resources to make the connections and raise the money needed to obtain such treatments, which run into six or even seven figures for each patient?
The big question, of course, is whether the treatments will even work. But for some, this type of personalized medicine offers a hope that far outweighs any potential risks.
"Hearing there was this new personalized drug that could bring hope, we felt reborn and like we were getting a second chance," Jaci's mom, Lori Hermstad, told 番茄社区. "To hear there was hope with ALS we literally felt alive again. We believed in it and we haven't looked back."
Five Trials, More To Come
Antisense oligonucleotides bind to messenger RNA in order to alter protein expression, so it's a way to target some genetic defects without full-on gene therapy. While there are other ways to target RNA -- including small interfering RNAs like patisiran (Onpattro) in hereditary transthyretin amyloidosis (hATTR) -- ASOs have come to the forefront as 40 years of discovery has led to recent approvals of therapeutics including eteplirsen (Exondys 51), nusinersen (Spinraza), and inotersen (Tegsedi).
ASOs have had a few stumbles along the way, notably two that were pulled from the market due to lagging sales. These were mipomersen (Kynamro), which was approved in 2013 to treat homozygous familial hypercholesterolemia, and fomivirsen (Vitravene), approved in the late 1990s for CMV retinitis.
Now the technology looks to be hitting its stride, with products in development for Huntington's disease, ALS, and rare diseases including Angelman syndrome.
Since ASO chemistry is well characterized, these compounds can be developed to target specific mutations in individual patients. That's not to say it's an easy process; but it is possible, with the right resources, experts said.
ASO specialist Ionis Pharmaceuticals -- which developed nusinersen, inotersen, and a third agent (volanesorsen) approved in Europe -- has been involved in many of the cases. Timothy Yu, MD, PhD, of Boston Children's Hospital, pioneered the first n-of-1 trial with an ASO and has become the go-to expert on how to make them happen.
Yu's first trial was with 3-year-old Mila Makovec, and was . Mila's parents raised $3 million to build an ASO customized to treat her Batten disease. They extensively researched her condition, and Mila's mother posted a plea on Facebook for an expert to do a more thorough assessment of genetic contributors to her daughter's disease, which eventually led them to Yu.
Jaci Hermstad's family raised several hundred thousand dollars both and through community events. Her ASO wasn't tailor-made, as Ionis had been investigating a compound to target her type of ALS, but she was the first and so far the only human to receive it. Shneider, her doctor, knew about the compound and had recommended it.
A 2-year-old girl with ataxia-telangiectasia (A-T) is , which will also be overseen by Yu. A philanthropy called the -- run by Brad Margus, a biotech entrepreneur whose two sons have the condition -- is footing the girl's bill.
番茄社区 learned of two other n-of-1 trials that are in various stages but haven't dosed a patient yet. The parties involved did not want to publicize their cases.
One thing is consistent across these cases: sleuthing and fundraising by driven parents who connect with the right specialists.
How It's Done
Shneider and Margus offered insights into the processes behind their n-of-1 trials.
Shneider met Jaci when she enrolled in his , a longitudinal study that offers genetic testing and counseling to ALS patients, in October 2018 when her disease hadn't yet manifest.
When she developed symptoms this past February, Shneider knew Ionis had been working on an ASO that targeted Jaci's mutation -- -- and thought it might be worth a try.
The agent had not yet reached even phase I clinical testing, so Shneider knew getting the drug to Jaci would be a heavy lift. The federal "right-to-try" law enacted last year requires that any compound being tried must have completed a phase I trial to prove safety in humans.
He worked with his own institutional review board (IRB) at Columbia, and started on an expanded access IND to submit to the FDA.
He had help from Yu, who had pioneered the process with Mila's treatment.
"We modeled our effort very much on his -- how one writes an expanded access IND application, the kinds of data FDA would want from us," Shneider said. "He was a very helpful guide."
Ionis provided a large amount of in vitro and animal data for the IND, which was extremely valuable given the short timeline spurred by Jaci's rapidly progressing disease, Shneider said.
But the FDA wanted additional toxicology studies, adding time and money -- both of which were running short.
Jaci's mom Lori, who'd been doing community fundraisers as well as a campaign, kicked her public relations machine into gear.
Soon, Jaci's story was being told in Washington by the family's congressman, Rep. Steve King (R-Iowa), who in an attempt to strong-arm FDA into moving her n-of-1 ahead.
National media also came calling and Jaci appeared on network TV morning shows.
Before long, the FDA had greenlighted the trial. Shneider recruited a contract research organization (CRO) to manufacture the drug and do toxicology work in mice and rats; luckily, expensive primate studies weren't required.
Jaci started her treatment at Columbia in June, and received her fourth and final infusion of the drug in July. Shortly thereafter, she returned home to Iowa.
Asked to estimate the total cost, Shneider put it at "hundreds of thousands of dollars."
From the Ground Up
For the 2-year-old A-T patient, Margus and his team developed an ASO candidate from scratch.
Since A-T is so rare, no company was working on an ASO to treat it. Mutations in the ATM gene are the underlying cause, but the particular mutations can differ from patient to patient in this autosomal recessive disorder -- all of which points to a customized therapy as the solution.
Children with A-T develop ataxia that begins in early childhood, and most are wheelchair-bound by adolescence.
Margus's background as a biotech entrepreneur and as a parent of two boys with A-T provided him a solid understanding of both the science and the drug development process. After consulting with specialists, he hired a CRO that developed cell lines using the girl's stem cells, differentiating them into neurons to test about 20 different ASO molecules to see which worked best, Margus said.
They settled on one candidate that showed the greatest protein expression.
"We have an ASO molecule that makes that little girl's cells look normal, at least in a lab dish," Margus said. The next step is to deliver the drug intrathecally and hope it gets to the cerebellum, the part of the brain most affected by A-T.
Yu's lab is involved in the project, Margus said, and Ionis was "willing to give us advice on whether our ASO would reach the cerebellum, based on data they had from their [spinal muscular atrophy] trials."
Funding for the upcoming n-of-1 trial is coming through his philanthropy, the A-T Children's Project.
Their goal is to dose the little girl by September.
What It Takes
While ASO technology is amenable to personalized therapeutics, it's an option only for families who can raise hundreds of thousands of dollars.
Steve Joffe, MD, MPH, chief of medical ethics at the University of Pennsylvania Perelman School of Medicine, said there's no "realistic alternative" to funding these efforts, since they're more an "attempt to do something highly novel and unproven in hopes of benefiting an individual patient."
"We all have a moral right to medical care that has been proven effective, and so there is a collective responsibility to pay for that care," Joffe said. "But we don't have a right to collective payment for unproven treatments, which means that we don't have a right to have someone else pay for n-of-1 trials."
The hope, Margus said, is that "by doing many of these, we're going to get faster and cheaper so ultimately you can make a personalized drug for each kid who has a different mutation, and you won't have all the expense of development."
He expects that as more ASO therapies are approved, "manufacturing capacity will increase and competition, as well as economies of scale, will drive costs down."
It's not clear exactly how large the market would be for individual ASO therapies. Margus says there are more than 10,000 human disorders caused by mutations in single genes, which together affect about 1% of the population, or 3.3 million people in the U.S.
Some already have treatments, and some may not be severe enough to merit an ASO-based therapy. Margus said experts estimate that individualized ASOs could be developed for perhaps 15% of the population with single-gene mutations -- still a market of hundreds of thousands of people, he noted.
Toxicology testing usually carries the heftiest price tag, as the know-how and the animals -- especially primates -- do not come cheap, specialists agreed.
"It requires a lot of expertise, and not a lot of CROs are able to do this, so the companies that are able to can charge significant fees," Shneider said.
Costs could be trimmed, for instance, if regulators became comfortable with relying on data from other ASOs, that while not exact copies, are similar in structure, Margus said.
How best to handle n-of-1 ASO trial requests has been a "work in progress," FDA spokesperson Charlie Kohler told 番茄社区.
"We are seeing more of these requests, and so are thinking about broader policies that can assure that we are consistent in how we approach the individual requests," Kohler said.
He said individual trial circumstances "often vary quite a bit" and that FDA looks carefully at each request to understand the disease, including how fatal and progressive it is, as well as the known risks and benefits of the drug.
Desperate families are less concerned with risk than regulators, even when clinicians like Shneider emphasize the uncertainties and make no promises of success.
Jaci's mom Lori said her daughter is "trying to hang in there."
"She keeps grounded in her faith and has hope, but she doesn't have a lot of room to go backwards," Lori said.
Shneider said that "if in the end we're not successful -- of course I hope that we are -- her parents will be able to say that they did everything that was reasonable for her, and even some things that were beyond reason."
"I'll walk away with the sense that we offered her a lot of hope," he said, "and maybe for just a few short weeks, she and her family lived with a sense of hope ... that came from at least trying to do something to change the course of this disease."