Susannah Rosen, 8, spent most of her childhood in New York City hospitals when doctors noted that she gradually lost the ability to stand, walk and see.
But on a visit this October, her parents thought for the first time that she might be better off leaving the hospital than before. That’s when surgeons infused a drug into her spine to correct an extremely rare genetic problem that has plagued her nervous system since childhood.
Susannah’s father, Luke Rosen, said: ‘Every time we go to the hospital it’s because something terrible has happened. “This time, there is hope for something that will heal her.”
Susannah was the first to receive a drug designed to treat the neurological disorder KIF1A, or KAND, a progressive disease caused by a genetic mutation that affects only 400 people worldwide. In doing so, the young girl and her parents found themselves on the edge of personalized medicine.
Since technology for such separate genetic drugs debuted in 2018, about two dozen patients have received infusions — up to $2 million per patient — to treat a wide range of syndromes. neurological disease. But hundreds of millions more, mostly children, live with rare genetic diseases and have no treatment options.
Susannah’s drug, nearly two years in the making, is paid for by a nonprofit, n-Lorem, which aims to do the same for at least 1,000 patients over the next decade. The founder of n-Lorem believes that by raising funds and negotiating discounts and in-kind donations from biotech companies for drug manufacturing, the organization can fulfill its mission of “no children who are left behind”.
But other rare disease experts doubt that the donation-based funding model will be large or sustainable enough to help millions of patients. They are looking for other ways to accelerate the development of technology, including seeking help from for-profit businesses.
Teams developing treatments for these diseases also struggle with how to share precious — and rare — data. N-Lorem has been criticized for failing to commit to sharing information about its patients and methods quickly and transparently, an issue that became more pressing after a girl who died last year from complications in another investigator’s clinical trial.
“These are really complex questions that the field has opened up,” said Issi Rozen, a venture partner at GV, formerly known as Google Ventures, a firm that has invested in the sector. “The worst thing I can imagine is that there exist technologies that can treat children, but there is no framework to do that.”
cut down the costs
Susannah’s parents first noticed something was wrong with their daughter when she was young and couldn’t kick her feet in the bathtub. As a toddler, she used a leg brace to stand and walk and suddenly fell. When Susannah was 2 years old, doctors discovered she had seizures while sleeping.
In 2016, her parents learned that she carried a glitch in the gene, called KIF1A, that causes KAND. The incurable disease causes growth retardation, vision loss, seizures and physical disabilities that worsen over time, her doctor said.
“What can we do to fix that?” Mr. Rosen recalled asking Wendy Chung, Susannah’s physician and a pediatrician and geneticist at Columbia University.
Dr. Chung advised them to find other patients. Mr Rosen and his wife, Sally Jackson, founded the fund in 2017, found about 400 other patients, raised $2 million for research and began lobbying scientists to develop treatments. .
One of the companies Mr. Rosen calls Ionis Pharmaceuticals, is based in Carlsbad, Calif. Ionis has used fragments of genetic material — known as antisense technology — to produce drugs to treat rare diseases that affect tens of thousands of people in the United States, but are far more common than KAND.
The following year, Dr. Timothy Yu, a neurologist and geneticist at Boston Children’s Hospital, announced that in just 10 months he had developed a custom anti-sensory drug for a person. . 8-year-old girl named Mila Makovec. The drug, named milasen after its patient, treated Mila’s rare neurological condition, Batten disease.
Ionis founder Dr. Stanley Crooke also wants to treat extremely rare diseases, but he believes companies cannot profit from drugs used by fewer than 30 people. So, in 2020, he and his wife, Rosanne Crooke, founded the n-Lorem fund with two founding partners, Ionis and Biogen, a biotech company in Cambridge, Mass. Since then, n-Lorem has raised $40 million to produce such drugs.
Ionis and other companies have agreed to provide free or discounted equipment and services, including drug manufacturing and safety testing. In return, n-Lorem will provide free patient infusions indefinitely.
Dr Crooke said: “Developing, producing and then giving away for free for life is a great concept, for the most desperate, underserved group of patients we know.
To date, N-Lorem has enrolled more than 80 patients, including Susannah, to this lifelong treatment plan, and its leaders hope to treat many more in the coming years. Dr. Crooke says that the reduction in drug prices and efficiency cuts the cost of implementing each personalized therapy by up to 40%. For example, Dr. Yu at Boston Children’s Hospital needed $2 million to produce the drug for Mila. But n-Lorem has cut that cost down to an average of $800,000 per patient, Dr. Crooke said.
It took scientists at n-Lorem 17 months to create a drug that blocks Susannah’s specific malfunction in the KIF1A gene, which is not shared by any other patients in the country.
In the meantime, Susannah grew sicker and sicker. She has broken many bones from a fall and is confined to a wheelchair most of the time. Her vision gradually blurred. Whenever Mr. Rosen travels, he worries that his daughter won’t be able to see his face when he gets home.
Her parents know that the new drug won’t cure Susannah, but they hope it will ease her seizures and difficulty controlling her movements. They thought maybe by Christmas she would be able to walk up to her brother and give him a hug.
On October 10, Dr. Jennifer Bain, a pediatric neurologist at NewYork-Presbyterian Morgan Stanley Children’s Hospital in Manhattan, injected the drug into Susannah’s spine.
The next morning, Susannah woke up with a bright smile. Her parents wondered if the medication had worked, even though they knew it was unlikely.
Mr. Rosen and Mrs. Jackson record daily seizures and falls. The neuroscientists planned to test Susannah’s mental abilities, brain activity and motor skills every few weeks.
Susannah was the first patient to receive the drug n-Lorem, followed by two adult patients in October and November.
Pain is increasing
Some rare disease experts doubt that a nonprofit will be able to serve every patient in need.
Instead, some are looking for a viable business model that could bring in millions or billions of dollars in investor funding. This money is needed to accelerate the competition needed to reduce costs, prove drugs work, and convince insurance companies to pay for them.
In 2021, Julia Vitarello, mother of Mila, co-founds EveryONE Medicines, a for-profit company in Boston that is exploring how to create custom genetic drugs in a sustainable way.
And Jeff Milton, a former Ionis scientist, hopes to develop rare disease drugs that target biological systems that are also affected in more common diseases. That could convince investors to invest in his startup La Jolla Labs, he said, to develop drugs that could treat both rare and common diseases.
Both also focus on how different outfits can share data.
Ms. Vitarello also founded a non-profit organization with Dr. Yu, called the N=1 Collaboration, which aims to make personalized medicines more accessible. Its 311 members, including parents, patients, investors and scientists from academia, companies and other institutions, have committed to sharing information with each other.
“We are talking about dying children,” Ms. Vitarello said. Mila died at age 10, three years after receiving the first dose of the drug she customized. “Companies, academic institutions and institutions all have a duty to share data so we can find out what works, because not doing so is unethical.”
These stresses have increased since the recent death of a child who was injected with a custom anti-sensitiser.
On October 23, Dr. Yu reported at a scientific meeting that two of his patients develop a buildup of fluid in the brain, called hydrocephalus, after receiving a drug for severe epilepsy, and one person died. He and other scientists are studying whether other anti-sense drugs might cause the same problem.
Dr Yu published the results before publishing them in a peer-reviewed journal article, he said, in part to emphasize the importance of sharing data across channels like N=1 Collaboration. .
Dr. Crooke said that n-Lorem will not contribute its data to the N=1 Collaboration database. He said the organization has presented data at scientific conferences and will publish data on its patients in peer-reviewed journals. It will also alert the Food and Drug Administration if death or serious side effects occur.
He said he doesn’t think it’s a good idea to compare n-Lorem’s data with others’ data because the n-Lorem team has more expertise in making anti-sensory drugs, also known as ASOs. “We will not mix data from our optimized ASOs with data from non-optimized ASOs,” said Dr.
But Dr Yu says Dr Crooke’s claim that n-Lorem’s drug is superior is “unwarranted and easily refuted”. For example, a clinical trial using a licensed antisense drug from Ionis induced hydrocephalus in patients with Huntington’s disease receiving the highest dose.
About two dozen patients have received customized anti-sensation medication since Dr. Yu informed Mila in 2018. His team has treated four other patients, including two children with hydrocephalus. Water.
N-Lorem is racing to produce the drug for the patients it has registered. The organization hopes to add 100 to 150 patients to its list each year, reaching about 1,000 patients within a decade.
Dr. Yu and others say that if they can prove that the drug saves lives, investors can get in.
“Lastly, before this approach exploded to treat dozens of families each year,” said David Corey, a biochemist at the University of Texas Southwestern Medical Center in Dallas who was not involved in the study. , they will have to prove that it works. antisense field.
On November 9, Susannah returned to the hospital for a second dose of the drug. After the procedure, she cuddled her doll in bed and chatted with her parents, occasionally making eye contact with them. This is unusual; Her vision problems often force her to use her peripheral vision.
Susannah opened the lid of the doll’s pink plastic drinking cup and held it out to Mr. Rosen.
“Daddy, can you fill this with water?” she asked.
Mr. Rosen obligated. He thinks her voice has improved recently and is impressed with her ability to focus her gaze more clearly.
Less than a month later, Susannah surprised her parents when she was able to stand on her own for the first time in two years. After getting up from the rug in the living room, Susannah, flushed with exertion, straightened and high-fived Miss Jackson.
Susannah received her third dose of the drug on December 7. With four months to go before the trial, Mr. Rosen and Mrs. Jackson felt cautiously optimistic.
“It’s not easy to be Susannah because there’s no roadmap,” Mr. Rosen said. “She’s making it.”
