Tuesday, October 15, 2019

The first drug developed for just one person

Eight-year-old Mila Makovec was diagnosed with a rare, usually fatal neurological disorder in 2016, but now—thanks to a "custom" drug that researchers developed specifically for her—many of Mila's symptoms have been halted or reversed, according to a report published Wednesday in the New England Journal of Medicine.

Mila's condition

Mila's symptoms began when she was three years old. Previously a healthy young girl, she began to suffer from frequent seizures—as many as 30 per day, lasting up to a few minutes each. As the disease progressed, she lost her eyesight, became unable to stand on her own, and ultimately needed a feeding tube.

In December 2016, Mila was diagnosed with Batten's disease, a rapidly progressing neurological disorder. However, Mila's case was unusual, according to doctors. Batten's disease is recessive, which means it occurs when a patient inherits two mutated versions of the MFSD8 gene—but Mila has only one mutated gene. The other was apparently normal, which should have left her unaffected.

Timothy Yu and colleagues at Boston Children's Hospital examined Mila's intact MFSD8 gene, and in March 2017, they found it contained a DNA error that interfered with the production of a key protein.

The good news was that Yu thought he could make a custom piece of RNA to fix the problem. But such a step would be extraordinarily expensive. To support the necessary research, Mila's mother established Mila's Miracle Foundation, and she managed to raise $3 million.

Yu's team was able to develop a new drug, which they called "milasen," after Mila. They tested it in rodents and consulted FDA, which in January 2018 permitted doctors to give the drug to Mila.

Doctors administered the drug via spinal tap so it could go directly into Mila's brain. Within a month, Mila started improving, according to her mother, Julia Vitarello. Mila started having fewer and shorter seizures and now rarely needs her feeding tube. Instead, she's able to eat pureed foods. Mila still can't stand by herself, but when she's held, her neck and back stay straight.

According to the New York Times, Mila remains very disabled, and she has lost the last few words of her vocabulary. Vitarello acknowledged that milasen won't cure Mila, but added that Mila was seven when she received her fist dose. "What if the next Mila is treated when she is four or five?" Vitarello asked, adding that milasen's development "is opening up an entirely new treatment path."

Experts express concern over personalized medicine

Milasen is believed to be the first drug developed for just one person, but Yu and colleagues acknowledged that they're unsure what may come next.

According to Rachel Sher, VP of regulatory and government affairs at the National Organization for Rare Disorders, there are more than 7,000 rare diseases, more than 90% of which have no treatment approved by FDA. That means there may be thousands of patients in a similar situation as Mila, and there aren't enough researchers to design customize drugs for all of them, the Times reports.

And even if there were enough researchers, cost would be a concern, Steven Joffe, professor of medical ethics and health policy at the University of Pennsylvania, said. The government wouldn't pay for the drugs, nor would drug companies or insurers, Joffe said. "Unfortunately, that leaves it to families. It feels awfully uncomfortable, but that is the reality."

Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, expressed concern about how a custom drug's efficacy might be evaluated. As for cost, Woodcock said, "We have to figure it out, collectively, because these people are suffering—many of them children. If we have the scientific ability to develop treatments for these rare diseases, we should find a way to make the financial side of this work" .

Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J, Larson A, Pendergast MK, Goldkind SF, Lee EA, Kuniholm A, Soucy A, Vaze J, Belur NR, Fredriksen K, Stojkovska I, Tsytsykova A, Armant M, DiDonato RL, Choi J, Cornelissen L, Pereira LM, Augustine EF, Genetti CA, Dies K, Barton B, Williams L, Goodlett BD, Riley BL, Pasternak A, Berry ER, Pflock KA, Chu S, Reed C, Tyndall K, Agrawal PB, Beggs AH, Grant PE, Urion DK, Snyder RO, Waisbren SE, Poduri A, Park PJ, Patterson A, Biffi A, Mazzulli JR, Bodamer O, Berde CB, Yu TW. Patient-Customized
Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019 Oct 9.
doi: 10.1056/NEJMoa1813279. [Epub ahead of print]

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).

Courtesy of a colleague

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