Despite the exorbitant costs, the most expensive medication in the world will not necessarily result in a cure for a rare disease, as some desperate parents are finding out.
Baby Ben Kutschke was diagnosed at three months with spinal muscular atrophy (SMA), a rare inherited disorder and the leading genetic cause of death in infancy globally. It leaves children too weak to walk, talk, swallow or even breathe.
So when in 2021 his parents heard about Zolgensma – a one-time therapy costing millions of dollars that promises to replace genes needed for the body to control muscles – they had high hopes.
They were disappointed.
After the $2.25m therapy treatment at almost eight-months-old, Ben was able to hold his head up for a few seconds, a significant milestone, his mother Elizabeth Kutschke told Reuters. But he did not advance to rolling over or sitting up, and after a few weeks, doctors recommended the family add another drug to help him.
Ben is one of a growing number of patients with SMA whose doctors are turning to additional drugs on top of the gene therapy, top US neurologists said.
Their experience raises broader questions around other high-cost gene therapies coming to market, sometimes after accelerated regulatory approvals, drug pricing experts said.
Zolgensma, launched in 2019 by Swiss healthcare group Novartis as a “potential cure” for SMA, was the most expensive drug in the world at the time.
Gene therapies work by replacing genes – the body’s blueprint for its development. The gene Zolgensma delivers instructs the body to make a protein vital for muscle control.
Other SMA therapies need to be taken continuously, but Zolgensma’s price was justified by hopes this revolutionary approach could beat the condition permanently.
Zolgensma has been given to more than 3 000 children globally, with 2022 sales of $1.4bn representing 91% of gene therapy sales worldwide, according to the IQVIA Institute for Human Data Science.
In the US, where costs are borne by government health programmes well as private insurance, IQVIA estimated Zolgensma sales totalled $434m last year.
It has worked well for many. March data from Novartis show that depending on the timing of treatment, most patients have gone on to swallow, breathe, or even walk independently, said Sitra Tauscher-Wisniewski, vice-president at Novartis Gene Therapies. Some can now run and climb.
Three of six families interviewed by Reuters whose children received Zolgensma said they were progressing as well as hoped; Ben’s was the only one to turn to another treatment.
But the company’s data also show almost one-third of children in an ongoing study went on to be given other drugs.
If gene therapies fall short, it becomes harder to justify prices researchers argue are already poor value.
“The perception that Zolgensma is going to be a complete cure … is not coming to fruition from data we have seen over four years,” said Dr Roger Hajjar, director of the Mass General Brigham Gene & Cell Therapy Institute.
Novartis has, notably, dropped the term “potentially curative” – common in its analyst calls in 2018 and 2019 – from descriptions of Zolgensma, instead calling it a “one-time treatment”.
“People still have misconceptions about Zolgensma,” Kutschke said. “It is a treatment, not a cure.”
In the pipeline
In 1918, Novartis CEO Vasant Narasimhan spelled out the pricing argument: “Payers appreciate that when you deliver a potentially curative therapy that takes cost out of their healthcare system and enables people to live, hopefully, a more normal life, they are willing to pay and they see the value.”
Drugmakers say the long-term benefits are worth it. CSL said it is confident its treatment can generate cost savings and has offered partial refunds if patients need to resume injections of blood-clotting proteins in the first four years after the therapy.
Novartis offers payment by instalments – although it said no one in the US has taken them. It also has plans linking payment to how well a patient responds, but said refunds under them have been rare.
The economics of treating the relatively small number of patients make a high price tag imperative for manufacturers.
“One of the arguments is you’re saving all of these millions of dollars down the line,” said Stacie Dusetzina, professor of health policy at Vanderbilt University School of Medicine.
“But if you found out later on that actually you have to get most of those other treatments, I think the question is, ‘was that price really a fair price to begin with?’”
The Institute for Clinical and Economic Review (ICER), a drug pricing research group, has said Zolgensma’s maximum price should be $900 000, less than half its current cost.
The two other available SMA treatments are also not cheap.
Biogen’s Spinraza, injected into the spine, has a US price of $800 000 in the first year, followed by maintenance doses at $400 000 a year. Roche’s Evrysdi, an oral solution, costs $100 000 to $340 000 annually, depending on the patient’s weight.
Both Biogen and Roche said studies of their drugs as treatments for patients who do not respond sufficiently to Zolgensma have been encouraging. Biogen’s Chief Medical Officer Maha Radhakrishnan said a second drug could still add value, given the high cost of caring for severely disabled patients.
However, the fact that some children need treatment with other expensive drugs after Zolgensma shows the gene therapy represents “poor value”, said Steven Pearson, ICER president.
Amazing progress
Many parents of children with SMA say Zolgensma is worth it. Amanda Cook of Virginia already knew when she gave birth to her son Weston in 2021 that he was diagnosed with SMA. It had led to the death of his older brother, Jackson, at seven months.
Weston had a flaw in the gene that produces a protein critical to the function of cells that move muscles. The lack of that protein, known as SMN (survival motor neuron), results in SMA, affecting fewer than 300 babies a year in the US.
But he had Zolgensma at 11-days-old and “is ahead of everything”, Cook said.
All therapies have been stopped and he is “doing amazingly”.
The treatment works best when infused as soon as possible after birth (some patients can begin suffering from degeneration before birth) and Ben Kutschke was a relative latecomer.
His parents detected his problems when he was about a month old. Formula spilled from the corners of his mouth. He couldn’t hold a dummy; his doctor suggested they try different sizes but it became clear his condition was serious when Elizabeth heard liquid slipping down his windpipe.
Ben was found, like about 60% of cases, to have the most severe form of SMA, often leading to paralysis and death before two.
“The earlier and better preserved the nerves are, the better chance of success,” said Dr Jerry Mendell, director of the gene therapy centre at Nationwide Children’s Hospital, Ohio, and principal investigator in the Zolgensma trials.
Zolgensma is becoming available to younger babies across the US: most states screen newborns for it, and health insurers typically cover Zolgensma for children with the most severe form.
Antibodies
But even after diagnosis, not all children are immediate candidates.
Zolgensma delivers the gene through a modified virus. Ben had already been exposed to the virus in nature and had developed antibodies, which would neutralise the replacement genes in his body.
Dr Russell Butterfield, paediatric neurologist, University of Utah Health and Intermountain Primary Children’s Hospital, said it’s “not all that rare” for babies to have antibodies to the vector. He put the incidence at 15% to 20%.
Babies can also be ineligible due to issues such as liver problems: Zolgensma’s label warns it can cause these. Last year, two children in Russia and Kazakhstan died of acute liver failure several weeks after receiving it.
Ben was originally treated with Evrysdi, which aims to boost SMN levels directly. It took months for his antibody levels to fall to the point he could start Zolgensma.
When he finally received Zolgensma, his hand movements became smoother and he was able to lift his head, “but then after that big rocket forward, it seemed to just stall”, his mother said.
The body develops antibodies to the virus used, so each therapy using it can only be administered once. Doctors recommended a third treatment, Biogen’s Spinraza.
‘Real life’
The most recent Novartis data, in March, shows this was not unusual. Its study found 24 of 81 children given Zolgensma by May 2022 had been subsequently treated with other SMA drugs.
“There are a whole lot of things that happen in real life circumstances to affect treatment with Zolgensma,” Mendell said. For less responsive patients, “it is reasonable to use other treatments”.
But it can be difficult to get insurance coverage after Zolgensma. Some health plans exclude add-on therapies.
Kutschke said her insurance company balked at reimbursing another drug.
Kutschke said the fund reasoned that Ben “should be fine” after getting Zolgensma. “Which is heartbreaking because we thought he would be too.”
It took nearly six months of paperwork and appeals, supported by Ben’s medical team, before Spinraza payment was approved.
Since then Ben, now two, and who has to use a wheelchair, has begun talking more. He was also suddenly able to move his lower body, his mother said.
Reuters article – Insight: What happens when a $2 million gene therapy is not enough (Open access)
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