Individualised Genetic Therapies Test Regulation, Payment and HTA

Individualised genetic therapies are designed for one patient or a small handful of patients, and they can change outcomes where no other treatment exists. The science is working. The harder problem is the system around it: regulators, payers and health technology assessment (HTA) bodies were built for drugs that reach thousands of people. OHE’s podcast A Dose of Economics (series two) explored that gap with two guests: Julia Vitarello, founder of Mila’s Miracle Foundation, and Amanda Cole, director at OHE, who leads its economics of innovation research theme.

Why individualised genetic therapies break the usual model

Cole said around 80% of rare diseases are genetic in origin. Genetic medicines range from antisense oligonucleotides (ASOs), short synthetic strands that correct how an RNA message is read or stop a faulty message from being used, to gene therapies that add a working copy of a gene, and gene editing that changes the DNA itself. Diagnosis is often slow. Symptoms are complex, and the conditions are so rare that clinicians may not know what to look for. Cole put the number of rare diseases at around 7,000, with about 5% having an approved treatment.

The drug business model depends on recovering large upfront investment during a period of market exclusivity. Population size matters enormously here. A rare disease is defined as one affecting fewer than one in 2,000 people, and Cole said 85% of rare conditions affect fewer than one in a million. When the patient pool is that small, the model stops working.

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Existing incentives have worked for the more common rare diseases. The US Orphan Drug Act gives seven years of market exclusivity plus tax credits. The EU orphan regulation gives ten years. NICE runs a separate reimbursement pathway for highly specialised technologies, with a higher cost-effectiveness threshold than standard. Cole said these levers have produced successes, including some gene therapies, but the population still has to be large enough to make the product commercially viable.

One patient, one year: Mila’s story

Vitarello described her daughter Mila as a healthy, active child who was hiking, skiing and rock climbing at two or three years old. Between the ages of four and six, a string of symptoms began. Over two years, Vitarello took Mila to about a hundred appointments with doctors and therapists in the US and Canada, and she said most of them dismissed her as a crazy mom. Eventually she took Mila to an emergency room in Colorado. Genetic testing found a rare form of an already rare condition, Batten disease. Vitarello was told her daughter would lose all her abilities except hearing and would die within a few years.

Only one of the two mutations needed for the disease was found at first. Vitarello had her son tested as well, to confirm they were chasing the right disease. Dr Timothy Yu and his team at Boston Children’s Hospital found the second mutation after a few months. That confirmed Mila’s diagnosis, and it also showed her mutation could be targeted with an ASO. The catch was that no one else in the world was known to have the same genetic change. At the time, the disease had about 25 known patients worldwide. Vitarello said some people asked how anyone could make a medicine for one child. Yu’s team answered that an ASO looked promising in the lab and in independent labs, and that there was no reason to stop.

The result was a year of work that moved Mila and her family from Colorado to Boston, where she received an ASO named after her. Vitarello said Mila was the first person in the world to receive a medicine made for one person.

Vitarello said the treatment made a visible difference. Before it began, Mila had up to 30 seizures a day. Afterwards, they had almost disappeared. Mila had a feeding tube and was getting most of her food through it, but she went back to drinking from a straw and eating by mouth, though her food was still pureed. She sat up straight, lifted her feet higher and was more aware and alert. She had already lost her sight. About three years into treatment, Vitarello said, too many genetic changes had already taken place and it was clear they were too late. Mila died at the age of 10.

Vitarello said Mila’s story showed what might be possible: find the root cause, then design a precise treatment for it. About 100 other patients have since received individualised ASOs over the past eight and a half years. “We’ve seen that it’s possible,” Vitarello said. “We’ve seen it’s repeatable, but what we haven’t seen is that it’s scalable.”

Regulation is the first barrier

Vitarello said the most important barrier is regulatory. Each medicine currently needs its own authorisation for one disease at a time. “It’s just a math game,” she said, adding that at that pace it would take around 3,000 years to treat the conditions involved. Her argument is that medicines must be grouped together, in hundreds rather than handfuls or dozens, and that there are different ways to do this.

Vitarello moved to the UK three or four years ago because the UK seemed well placed to tackle the problem. The regulator had begun talking about proportionate regulation, and Genomics England’s whole genome sequencing for newborns was a draw. Her goal was to show the change in a pilot. The Rare Therapies Launchpad is now moving to LifeArc, which she hopes will bring stakeholders together.

Cole said the MHRA’s draft rare disease framework responds to the same problem. Conventional trials assume large numbers of patients, which ultra-rare conditions cannot provide. The draft proposes a more flexible, risk-proportionate and iterative approach, with earlier and more frequent dialogue with developers and greater use of real-world evidence and natural history data. One element is an investigational marketing authorisation, which could let a therapy be used while evidence continues to be generated. Cole said this matters most for individualised therapies, because evidence for a single patient cannot be generated in the conventional way.

Paying for a process, not a molecule

Cole said reimbursement is the next barrier, and the right payment model depends on the challenge it addresses. Budget impact can be handled with instalments, which helped with a gene therapy, or with subscription arrangements, sometimes called the Netflix model, where a fixed payment covers an uncertain number of patients. That approach has been used for direct-acting antivirals. Uncertainty about value can be handled with coverage with evidence development, as used in the Cancer Drugs Fund and the Innovative Medicines Fund, or with outcome-based payments that depend on how well a treatment works for the individual patient.

Cole said individualised therapies combine very high value, probably high cost, extreme uncertainty and high stakes. For a treatment that serves one person, she said, the honest answer is that the arrangements are not fully solved at scale. The most useful reframing she has come across is that the product is the process of developing and delivering a treatment, not the molecule. That changes the pricing question. It becomes less about what one molecule is worth and more about what it is worth to have the capability to produce a treatment when someone needs it. Cole said it might be billed like a procedure rather than a drug, perhaps with a tariff per category set at average cost plus a margin. A heart transplant is one example she said could offer lessons.

Cole said health systems show genuine appetite for this flexibility, but the arrangements are administratively difficult and depend on real-world data from medical records, registries and studies of how a disease develops over time. Without knowing the natural history of a disease, she said, you cannot measure how well a treatment works. Foundations are investing in patient registries to build that baseline.

HTA may need to assess the process

Cole said HTA is the step the discussion has not yet reached. Agencies may need to assess the process or capability behind a therapy rather than the specific molecule. She said the field knows how to put monetary values on improved lives and lives saved, and how to set parameters around health system costs. Doing that up front for individualised therapies will be very hard. She suggested a more practical role: value assessment could help set entry criteria for pilots, based on the size of the unmet need and the opportunity to benefit. Those conversations, she said, are not well advanced yet.

Cole listed four priorities. The first is better recognition and faster diagnosis, because early treatment depends on catching conditions early. The second is reimbursement: getting payers to commit to funding a process before they know which patient, mutation or disease it will serve. The third is data on disease progression and on outcomes that matter to patients and families, since data is what makes every payment model work. The fourth is political will to try something that does not fit the existing framework.

Vitarello’s vision is for children like Mila to be found at birth, with genomics and NHS England playing a role, and for a rapid process to deliver a precise treatment early enough that families never live with the disease. “I think today we actually have the technology and science to be able to do that,” she said. Whether the regulatory, payment and HTA systems can follow is the question that national rare disease policy will have to answer.

Source: OHE, “Individualised genetic therapies: A medicine for one”, A Dose of Economics, series two. Quotes and figures are taken from the episode transcript.