A new drug, created to treat just one patient, has resulted in a controversy in the arena of personalised medicine by raising regulatory and ethical questions, according to a report in October 2019.
The drug, which has been described in The New England Journal of Medicine, is said to be the first ‘custom’ treatment for a genetic disease that is fatal. The disease, a rapidly progressing neurological disorder, has been given the name ‘milasen’, after the only patient who will ever take it, Mila Makovec. Milasen is believed to be the first drug developed for a single patient (CAR-T cancer therapies, while individualised, are not drugs).
The symptoms in Mila, 8, started at age 3. Within a few years, she had gone from an agile, talkative child to one who was blind and unable to stand or hold up her head. She needed a feeding tube and experienced up to 30 seizures a day, each lasting one or two minutes.
It came to her mother’s attention in December 2016 that Mila had Batten’s disease. But the girl’s case was puzzling, as Batten’s disease is recessive — a patient must inherit two mutated versions of a gene, MFSD8, to develop the disease, but in Mila’s case, she had just one mutated gene and the other copy seemed normal. The normal one should have been sufficient to prevent Batten’s disease.
In March 2017, Timothy Yu and his colleagues at Boston Children’s Hospital discovered that the problem with the intact gene lay in an extraneous bit of DNA that had scrambled the manufacturing of an important protein. So, they thought of a custom piece of RNA to block the effects of the extraneous DNA. Developing such a drug is expensive, but Mila’s Miracle Foundation was set up and it began appealing for donations on GoFundMe. It raised as much as $3 million for a variety of research efforts.
Yu’s team oversaw development of the drug, tested it in rodents, and consulted with the Food and Drug Administration. In January 2018, the agency granted permission to give the drug to Mila. She got her first dose on January 31, 2018.
The drug was delivered through a spinal tap, so it could reach her brain. Within a month, Mila was having fewer seizures, and they were not lasting as long.
With continued treatments, the number of seizures diminished so much that the girl has between none and six a day, and they last less than a minute. Mila rarely needs the feeding tube now, and is able once again to eat pureed foods. She cannot stand unassisted, but when she is held upright, her neck and back are straight, no longer slumped. However, now she has lost the last few words of her vocabulary that she knew and has stopped responding to things that made her smile or laugh before the drug therapy began. She also remains severely disabled. So it is not clear how the new drug has really helped.
Problems with Custom Drugs
The controversy relates to specifically the new drug milasen and custom drugs in general.
Milasen will not cure Mila, everybody knew that. Mila was 7 when she got her first dose. So why throw millions, apart from the labour and hours of research undertaken, into a drug that cannot even give a hope for lasting cure to one patient, leave alone being capable of curing a general disease that affects many? And the argument that it could be given to another child at an initial stage, has no weight, as this ‘custom drug’, as its name suggests, was tailor-made for one individual only, Mila, and cannot be used for others whose conditions would differ.
There are over 7,000 rare diseases, and over 90 per cent have no FDA-approved treatment in USA. Tens of thousands of patients could be in Mila’s situation in the United States alone. But there are not enough researchers to make custom drugs for all who might want them.
Cost of custom drugs is so high that neither the federal government nor drug companies nor insurers want to venture into producing them. And families cannot afford it. So custom drugs would be an option only for the very wealthy, those with the skills to raise large sums of money, or those who gain the support of foundations.
The idea of custom drugs also leads the FDA into uncharted territory. Some critical questions are, what type of evidence is needed before exposing a human to a new drug? Even in rapidly progressing, fatal illnesses, precipitating severe complications or death is not acceptable, so what is the minimum assurance of safety that is needed? As a custom drug cannot be tested on anybody before administering it to the intended patient, it’s efficacy cannot be evaluated beforehand; so its use on the patient himself would be an experiment that may be successful or not. It may rise in other complications, as in the case of Mila. How can the regulators weigh the urgency of the patient’s situation and the number of patients who could ultimately be treated?
Now there are requests for other custom drugs. Brad Margus, founder of the A-T Children’s Project, is calling for a custom drug for A-T, or ataxia telangiectasia, an extremely rare genetic disorder that causes a variety of symptoms, including problems in moving, a weakened immune system and slowed mental development. Margus’s two sons have A-T. He said that his foundation would pay for the work, although the drug he is calling for would be suitable for only one child—a 2-year-old who has the disease.