Treatment of a teenager with an ultra-rare condition is a medical milestone

Mila Makovec was ten in 2021 when she died from an ultra-rare neurodegenerative disorder. But, though it had not saved her, she was nevertheless in the history books as the first to receive a drug designed for a single patient. And her story did not end there. After her death her mother, Julia Vitarello, set out to change how drugs are made, so that others with obscure genetic faults could have bespoke treatments more quickly and easily.

Ultra-rare disorders are those affecting fewer than one person in 50,000. Sometimes, they are unique. And unique problems need unique solutions. To that end, Ms Vitarello had, when her daughter was diagnosed, launched Mila’s Miracle Foundation with the goal of finding her a treatment and paying for it. In collaboration with doctors at Boston Children’s Hospital, it did so in the form of a molecule called an antisense oligonucleotide (ASO).

After Mila’s death Ms Vitarello pushed regulators—first in America and then, with more success, in Britain—to think how developing individualised drugs for ultra-rare conditions might be simplified and accelerated. She also started a biotech company, EveryONE Medicines, in Boston, to try to work out how to do this at scale.

January 13th marked a turning point in her quest. After a change in the British rules, which her lobbying helped bring about, a girl known as patient A, who has an ultra-rare condition called Niemann-Pick disease type C (NPC), was treated at Great Ormond Street Hospital (GOSH), in London, with an ASO devised by EveryONE Medicines. And this time, rather than being a one-off, it is part of a trial intended to make such treatments routine.

The rule change was made by Britain’s Medicines and Healthcare products Regulatory Agency (MHRA). This regulator has agreed that patient A and nine other children with similarly threatening neurodegenerative conditions can be treated with custom drugs under a new “master protocol” that is intended to standardise trials for the treatment of groups of genetic conditions within a single framework. It thus tests a way of making drugs rather than assessing a single medicine. Lawrence Tallon, the MHRA’s head, said it was the “start of what is a very, very exciting future for the treatment of genetic diseases”.

NPC is caused by a mutation in a gene encoding a protein responsible for clearing brain cells of surplus fats and other chemicals. The build-up of these substances kills those cells and the brain atrophies. As a consequence, patient A has epilepsy, suffers sudden losses of muscle tone, and has cognitive, memory and learning difficulties. Without treatment, her condition will worsen and will probably kill her.

ASOs work by ambushing RNA messenger molecules that carry genetic instructions from a cell’s nucleus to its protein factories, and then either neutralising or altering them. The drug that patient A received at the hands of Paul Gissen, a paediatrician at GOSH, is called avasen and was made by EveryONE Medicines. In her case it binds to the RNA messenger in a way that masks the error, allowing the cell’s protein-making machinery to create healthy proteins. That means production of normal proteins should have started within hours of the infusion—although it will take much longer to see whether this helps, because a backlog of toxic fats will need to be cleared out first.

The MHRA’s protocol covers data collection, safety assessments and how a drug’s movement through the body is measured. It sets out which conditions can be treated—they have to be fatal or life-threatening neurodegenerative disorders. And it specifies a particular type of ASO, the length and chemical composition of which are well understood, as a “platform” molecule, which needs only tiny changes to customise it to a particular illness.

The goal of the trial, says the MHRA, is to show that, with such a standard set of procedures, it can grant a “process approval” for making these ASOs. The challenge regulators faced was that one-off drugs intended for individual patients cannot be run through conventional randomised controlled trials. Process-based approval, which requires close analysis of patients before and after treatment, is riskier. But, since the outcome without treatment is death, that risk seems worth taking. If it works, it will be a medical milestone. Not only will it make easier the use of ASOs to treat rare and fatal neurological disorders; it will also open the door for process approvals of other styles of drugmaking, and for other groups of patients.

One reason Ms Vitarello found more enthusiasm for this approach in Britain than in America was because Genomics England, a government-owned provider of genetic-sequencing data, was diagnosing a lot of children with rare genetic disorders who were in need of treatment. The question was how to provide it. In 2023, therefore, the MHRA, Genomics England and Mila’s Miracle Foundation teamed up with a group of experts at Oxford University to create an organisation called the Rare Therapies Launch Pad to work out how to regulate custom drugs. In November America’s Food and Drug Administration said it was developing a similar “plausible mechanism” pathway.

To help others, the British protocol requires that data collected be shared. This should assist firms wanting to build businesses around the idea. In Europe, meanwhile, an academic group called 1 Mutation 1 Medicine is trying to advance ASO-based treatments. And Ms Vitarello, who agreed on January 5th to become EveryONE Medicines’ boss, with a view to working out how these treatments will be paid for in the long run, has had from interested scientists and parents around the world.

Customised treatment could also offer a new tool for public health. Though the conditions it is aimed at are individually rare, collectively they add up to a significant burden. If tweakable platforms meant they could be treated routinely, it would become worthwhile to screen the genomes of newborns, so that conditions could be nipped in the bud. That would allow affected children to swap short and horrible lives for something closer to normality.

Process approval should also speed and cheapen development of custom drugs. At present, developing an individualised ASO takes two to three years and costs $2m-3m. Ms Vitarello says process approval could bring the cost below $1m and the time below nine months. That would be far less than the cost per treatment for most of the one-off gene therapies currently on the market, although ASOs do need to be given over a lifetime, rather than as a single dose.

Bundling groups of ultra-rare genetic diseases together into treatable packages might also make them attractive to drugmakers, which currently focus on more common genetic conditions, like sickle-cell disease and spinal-muscular atrophy. And process approval will allow firms that use other ways of interfering with RNA messengers, and also firms that edit DNA directly, to consider treating ultra-rare disorders. One such, Aurora Therapeutics, was launched on January 9th by Jennifer Doudna, a Nobel-prizewinning pioneer of gene-editing. For the first ten patients in Britain, however, ASOs are not just another option but their only hope of survival—and, with that, a chance to thrive. ■