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Collaboratives, Companies Mobilize to Build Momentum for 'N-of-1' ASO Therapies

Double-stranded DNA with mutation in a gene, conceptual illustration

NEW YORK – A neurologist at Boston Children's Hospital in 2018 created what was widely reported as the first medicine developed for a single patient: a 7-year-old girl, Mila, who suffered from a fatal neurological condition. But it will be years before that therapeutic approach becomes accessible for many other rare genetic diseases.

The personalized medication, named milasen after the young patient, was created and administered just one year after Mila was diagnosed with Batten disease, a congenital condition in which patients progressively lose neurological function and experience frequent seizures. Scientists led by Timothy Yu, the neurologist who treated Mila, used antisense oligonucleotides (ASOs) to target Mila's specific genetic mutation.

Mila's story, which reached the international news circuit after investigators published a report of the drug development and treatment process in the New England Journal of Medicine, put a spotlight on ASOs as a potentially scalable approach to treat various rare genetic diseases. Since then, a spate of consortiums, nonprofits, and research efforts have cropped up to build on this momentum and attempt to create paths forward for getting treatments from the lab to the clinic. These efforts, though, face regulatory, ethical, funding, and other barriers.

More than a dozen ASO therapies have been approved by the US Food and Drug Administration for multiple diseases since the first therapy, Ionis Pharmaceuticals' Vitravene (fomivirsen), was greenlighted by the regulator as a treatment for cytomegalovirus retinitis in 1998 — though none for indications as rare as Mila's N-of-1 mutation. Most recently, the FDA granted accelerated approval to Biogen's Qalsody (tofersen) as a treatment for a genetic form of amyotrophic lateral sclerosis (ALS), which is estimated to affect about 3,000 patients globally.

But Yu and colleagues at his lab at Boston Children's designed milasen to target the specific mutation that Mila harbored in one copy of the MFSD8 gene that caused her form of Batten disease. As an ASO therapy, milasen comprised short strands of modified DNA designed to target messenger RNA of a defective gene — in this case, MFSD8 — and correct the abnormality.

While milasen improved Mila's quality of life by suppressing her seizures, the disease had already progressed to an advance stage by the time it was administered, and Mila died from Batten disease at the age of 10 years old in 2021. Still, Mila's mother Julia Vitarello, who continues to advocate for improvements to rare disease treatment, said her story has represented hope for the field.

"Even though it wasn't the time for my daughter, it showed what was possible," Vitarello said. "We have the technology to find the underlying genetic cause — in her case, it was a single mutation — and we also have the technology to design the medicine to target that underlying genetic cause."

Vitarello and Yu went on to cofound the N=1 Collaborative as an international hub to improve upon personalized medicine and make such individualized treatments more accessible, starting with ASOs, though they hope its framework can extend to other precision medicine approaches like gene editing and RNA therapeutics. The collaborative works closely with the Oligonucleotide Therapeutics Society's Rare Disease Task Force, of which Yu is also a founding member, to organize workshops and other efforts.

As early as 2018, when Yu and Vitarello first began speaking publicly about milasen, they knew they would have to educate the field and the public about ASOs — to share not only their potential but also their limitations.

"We were already getting the sense that there would be a lot of people who would want to know how this approach could work," said Yu, who is also an associate professor of pediatrics at Harvard Medical School. "We felt a lot of pressure to manage expectations and to explain to folks that it is really still a brand-new area."

'The rules of engagement remain to be defined'

As hundreds of requests were piling up from a range of stakeholders, from scientists to patient families, Vitarello and Yu realized they needed a central hub to release information and share lessons from trials of these types of N-of-1 therapies, as well as help to define the avenues to get these treatments to patients in need.

"As the reaction to the original milasen paper evolved and grew in the years since we published that, we were just getting so many requests from academics, from clinicians, from scientists, from pharma, and from families," Yu said. "We just felt that we needed a place to host these conversations, so we could try to get information out in a more efficient way."

There's still much to learn. Last year at the American Neurological Association's annual meeting, Yu reported that two patients developed hydrocephalus after receiving an ASO drug for a rare form of epilepsy caused by a mutation in the KCNT1 gene, one of whom died, and investigators continue to study the risk of other drugs resulting in similar adverse events. The field is also still grappling with figuring out which patients are best suited for this type of splice-switching ASO therapy, though earlier this year Yu and colleagues proposed a framework for prospectively identifying such patients in Nature.

One of the N=1 Collaborative's goals is to launch a database through which researchers at academic organizations and biopharmaceutical companies can share data on therapeutic development, clinical outcomes, and safety for these medications, in an effort to identify trends that can inform other studies. Data from Mila's trial will be included, for example, Vitarello said.

"Let's learn from Mila," she said. "Let's learn from every kid after that, so we get better at it, and it becomes safer, and faster, and better."

In addition to KCNT1 epilepsy, Yu and colleagues have also launched ASO research efforts in ataxia telangiectasia. While both of these conditions are being developed for a very small handful of patients, they aren't a true N-of-1 approach, as seen with Mila.

Gaining permission from regulators to administer a drug, an already arduous process for drugmakers in more established areas, presents a challenge for these medicines treating ultra-rare conditions. "I think all parties recognize that the rules for engagement for these 'individualized trials' really … remain to be defined," Yu said.

The gold standard to prove safety and efficacy for most drugs is a randomized controlled trial with a placebo control. But that's not possible for truly individualized trials. Mila, for example, was the only known patient with her specific mutation — so there was no way to run a controlled trial, and there wasn't yet a standard on what to do instead, Yu said.

Yu ultimately was able to submit an investigational new drug (IND) application proposing to use Mila as her own control, tracking outcomes like seizure frequency, brain volume, and neurologic assessments. That process to establish the study was a collaboration with the FDA across a series of meetings that took place before administering the ASO therapy to Mila.

In an editorial accompanying the original paper on milasen in the New England Journal of Medicine, two leaders from the FDA's Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research raised questions about what evidence should be expected before exposing humans, even those with fatal illnesses, to new drugs.

"What is the minimum assurance of safety that is needed? How persuasive should the mechanistic or functional data be?" the FDA's Janet Woodcock and Peter Marks wrote. "How should the urgency of the patient’s situation or the number of people who could ultimately be treated affect the decision-making process?"

The FDA has since come out with a draft guidance for how to file INDs for ASO therapies designed to treat life-threatening conditions for extremely rare disease populations, typically just one or two patients. While Yu said the guidance, released in December 2021, is light on specifics, he stressed that it's a positive step forward. The document outlines clinical considerations like confirming the role of the genetic variant targeted and assessing clinical and safety outcomes.

In a separate draft guidance, released in April 2021, the FDA described preclinical information the agency recommends to support INDs, such as safety testing in animal studies.

While guidance for INDs is helpful, additional information is still needed for how to, someday, have these treatments approved outside of a research setting, Yu said.

"At risk of getting ahead of ourselves — because we still need to do scientific work to show that this process works — I think everyone is looking forward to a time when we can more concretely say how a series of these INDs will lead to substantial evidence of benefit, such as is necessary for the FDA to give formal approval to something," he said.

But to move outside of the research setting, this ASO approach will likely need attention from biopharma, in addition to academic institutions.

Drugmakers can be hesitant to invest the millions of dollars needed into R&D for treatments for rare diseases, which can only be marketed to a small population and for which there are few efficiencies of scale.

N-of-1 therapies would "turn the current drug development system on its head," Vitarello said, adding that they would require a rethinking of therapeutic development, clinical trials, and drug administration.

In addition to the N=1 Collaborative, Vitarello is also the founder of Mila's Miracle Foundation, a research funding organization that provided most of the funding for the development and testing of milasen, and cofounder of EveryONE Medicines, a newer company working to develop a sustainable business model for individualized medicines.

"How do you create a viable business model around a future of thousands, tens of thousands, millions of drugs, each for one or a few people," she asked. "If we have the technology, and we have the dying and sick children, but we don't have access — how do we create a system that allows for access?"

A nonprofit model for 'nano-rare' diseases

These investigational treatments, which can cost upwards of $1 million to develop and study, are part of experimental research, and as such, aren't going to be reimbursed by insurance. 

The N-Lorem Foundation, founded in 2020, is homed in on that challenge in particular, as a nonprofit funded by philanthropy that aims to create ASO therapies that it can provide to patients for free. The organization develops treatments for so-called "nano-rare diseases," which it defines as those affecting fewer than 30 people worldwide, and those caused by a single gene mutation.

N-Lorem was founded by Stanley Crooke, former CEO of Ionis, with initial funding from Ionis and Biogen. The foundation now counts more than two dozen organizations as sponsors, including genomic sequencing companies and biotechnology companies that provide donations and in-kind contributions to support manufacturing and testing.

The philanthropy model has been a good fit for the organization's rare disease work, said Joe Gleeson, chief medical officer at N-Lorem and director of neuroscience research at Rady Children's Institute for Genomic Medicine. "Nobody would ever make money on these drugs that are for a single patient," he said. However, to be sustainable, he added that the foundation is also starting to look into grant funding and other partnerships, so it's not reliant on donations alone.

Gleeson initially connected with N-Lorem through his role as a pediatric neurologist when he nominated one of his patients to receive a personalized ASO therapy through the foundation.

Physicians and patient families nominate patients to N-Lorem for potential treatment. For those who are eligible, N-Lorem designs and manufactures the drug, which is then presented to the FDA for permission to do a first-in-human trial of the experimental treatment. N-Lorem continues to follow patients for at least a year to track their outcomes.

N-Lorem has submitted 10 INDs and, so far, seven patients have been administered personalized ASO therapies, with dosing for the rest expected to be completed by year-end, Gleeson said. The company's first dosed patient was an 8-year-old girl named Susannah, who had a specific mutation in the KIF1A gene that leads to a progressive neurological disorder.

It typically takes about 18 to 24 months from the point a patient is nominated until the drug is ready to be administered, and costs roughly $1 million to develop each drug, according to Gleeson.

Beyond animal models

Since patients receiving personalized ASO therapies are likely the first in-human test for their particular drug, preclinical testing is essential, and researchers are working to find other ways to test drugs that might supplement or even take the place of animal studies.

Scott Younger, director of disease gene engineering at Children's Mercy Kansas City's genomic medicine center, is hoping that his research on organoids — miniaturized versions of organs generated from patient stem cells that mimic those organs' functions — can support testing personalized therapies. His lab at Children's Mercy, founded in 2019, researches rare genetic variants and their impact on disease, which can inform treatment approaches.

One of the lab's projects involves creating brain organoids to test possible ASO therapies for rare seizure disorders. The organoids are generated from induced pluripotent stem cell lines, derived from peripheral blood mononuclear cells that are collected from blood draws that patients submit when enrolling in the pediatric hospital system's Genomic Answers for Kids program, which sequences genomes of children with rare genetic conditions.

As part of this research, which is preclinical, Younger's team is designing ASO leads based on variants identified through genomic testing as likely to be causing the condition — with each ASO personalized to the particular variants in a patient's genome. From there, researchers in the lab will test the personalized therapeutics using the brain organoids.

One day, that could mean researchers are able to test the effect of a personalized drug on a patient's own cells, rather than on only animal models. But there are still a multitude of payment, regulatory, and ethical questions. While Mila's seizure disorder was fatal, not all are — so determining when it's appropriate to give a child an experimental treatment carries a different set of considerations.

"How do you go from a laboratory into a patient?" Younger said. "We're definitely moving there, but it's not going to be an overnight task."