Trikafta: The life-changing wonder drug that costs $250,000 a year

There are before and after worlds in Professor Hiran Selvadurai’s respiratory ward.

The ‘before’ would be a dozen or so children lying in beds with severe pulmonary exacerbations, coughing up bacteria-ridden mucus, almost drowning in their own sputum.

Some would become hypoxic and need the oxygen masks to prevent brain injury. And all of them would need a long line of intravenous antibiotics, along with a regime of brutal physiotherapy and a carefully controlled diet.

In the words of Professor Selvadurai, the head of the respiratory department at the Children’s Hospital at Westmead in Sydney, their lives were being broken by cystic fibrosis.

“When you walked into the room and told families that their child has CF, you were looking at their faces and you knew you were shattering their dreams and aspirations.

“You were talking to them with a sledgehammer and you would see their hearts break.”

But there is also the ‘after’.

And this is where those beds are rarely occupied by these children — less than 10 admissions a year — and the reason for the ‘after’ is a medical wonder but also the vast quantities of money to pay for it.

Back in March 2021, the PBAC went through the cost-benefit number crunching and — after twice deferring the decision — eventually concluded that the combination CFTR modulator therapy agent Trikafta (elexacaftor/tezacaftor/ivacaftor) should be listed on the PBS.

Initially recommended for 12-year-olds and older in April 2022, the taxpayer cost was some $475 million to treat an estimated 1900 patients. This wasn’t a lifetime cost but the annual cost — $250,000 per patient per year.

The recommendation, given its budgetary impact, had to go before national cabinet but it was signed off.

As a result of the listing — which was last year expanded to include children aged 6-12 years — 148 of the 210 patients attending Professor Selvadurai’s clinic are on Trikafta.

He says the changes have astonished him.

“With many of these kids, when the exacerbations came they had to spend the next two weeks in hospital with an IV drip.

“It was exceptionally emotionally draining, but Trikafta has been an enormous game changer.”

But there has been a fierce debate around the world about the costs, amid accusations that the US company responsible for bringing it to market, Vertex Pharmaceuticals, is exploiting its discovery.

In October last year, the UK health economists, consultants, GPs and pharmacologists who make up the National Institute for Health and Care Excellence (NICE) were doing their own cost-benefit sums.

And they didn’t work out in the same way.

A final decision has yet to be made — but the committee’s draft recommendation was that Trikafta wasn’t worth the money.

As with any taxpayer subsidy decision, the price at which drug companies offer to sell their products varies with the buyer and the specific cash figure is usually commercial in confidence.

But according to NICE, what the NHS was being asked to pay was “substantially above” (AUS)$59,000 for each quality adjusted life year (QALY) generated by the treatment, where each year is equivalent one perfect year of health.

As a rough guide, the Australian Federal Government would be very reluctant to pay above this figure for health interventions either – although there is no official threshold for PBS listing.

The NICE conclusion was that Trikafta was a waste of precious health resources.

Parents of children with the disease described the conclusion as “unthinkable”.

As here, at the sight of young suffering the British media usually takes aim at the spectre of cold bureaucratic hearts.

One exception was The Guardian.

“Parents have been on a rollercoaster ride in the last few years,” it wrote in an editori a l.

“They have been taken to the giddy heights of hope by the invention of drugs that for the first time work on the underlying causes of the illness where previous treatment just alleviated symptoms.

“And they have been plunged to the depths when those new drugs have been denied them because of their cost.”

But it added: “It would be easy to paint NICE as the villain of the piece. But it is doing the job it was set up to do. There is a good reason why it can’t green light [Trikafta]. The price is astronomical.

“If the NHS chose to pay the price for these drugs, and had no extra cash, what would it have to cut? How many hip replacements? How much cancer care?”

Vertex has reported more than $31 billion in sales since it was first approved by the US Food and Drug Administration in 2019.

It has always defended itself saying that novel drug development is not a cheap, risk-free business when outcomes are not guaranteed. There are many promised drugs now in a pharma graveyard.

Vertex told the BBC last year: “The price of our medicines reflects their clinical value and benefits to patients, caregivers and healthcare systems.”

It told AusDoc this week: “The protection that patents provide enables us to continue to invest in our extensive research and development program into CF…we invest more than 70% of our operating expenses into research and development, which is far higher than the industry average.”

But what is the wonder of this drug? How does it work?

It starts with the cystic fibrosis transmembrane regulator (CFTR) protein, one of a group of proteins that function as cellular transmembrane channels.

One of its roles is the regulation of the movement of salt and water across cells.

In cystic fibrosis, however, mutations of the CFTR gene mean this protein doesn’t work effectively.

Scientists have now identified 2000 mutations, but the most common is known as delta F508.

Professor Selvadurai says Trikafta functions as a modulator and is one of a class of drugs engineered to fix a number of problems resulting from some of these mutations.

For example, one problem could be insufficient protein getting to the surface of the cell, or the protein getting to the surface but the channel not working effectively or consistently — known as “gating mutations”.

The first-generation CFTR modulators successfully addressed the gating mutations, but Trikafta managed to address the specific deficiencies caused by delta F508 — where the problem lies with misfolding of the protein, preventing it from reaching the cell surface.

“What these new generations do is to facilitate the proper folding of the protein to get it up to the surface,” Professor Selvadurai explains.

“There was a drug called Symdeko [tezacaftor/ivacaftor] which was approved about seven years ago now, and more recently what has really set the world alight is Trikafta.”

He adds: “Trikafta has in effect got three different types of CFTR modulators, which encompass two of the previous modulators, as well as another modulator.”

Increased longevity?

Cystic fibrosis remains relatively rare — about one in 2500 babies are born with the condition.

Although the name ‘cystic fibrosis’ wasn’t coined until the 1930s where it was used to capture the association of exocrine pancreatic insufficiency and chronic lung disease, references to the doomed fate of young babies who tasted salty when kissed — a physical hallmark of the disease — go as far back as the Middle Ages.

As the European medieval folklore goes: “Woe to the child who tastes salty from a kiss on the brow, for he is cursed and soon will die.”

Even in the 1930s, when scientists were getting a better idea of what was happening, life expectancy was barely more than five years.

It has risen dramatically since then — partly because of antibiotic treatment, airway clearance techniques, and the process of increasing enzyme doses to allow for a high-fat diet.

The average lifespan for a person with cystic fibrosis now stands at around 47 years.

But that median age doesn’t include the impact of the CFTR modulators, says Professor Selvadurai.

“That is the reason why we are very excited about what it implies for the long-term future.

“Historically, when I was training as a fellow, the prognosis of children with cystic fibrosis was around 30 years … and now there are some good modelling studies that show children born now who access CFTR modulators will lead a normal lifespan.”

He points to one study — carried out by Vertex and the department of respiratory medicine at Glasgow Royal Infirmary in Scotland — that estimated the survival and lifetime clinical benefits of Trikafta versus other CFTR modulator combinations.

It found that young people aged 12-17 years who were treated with the drug could on average live to an age of 82.5.

Professor Selvadurai stresses this transformation carries complexities.

“I tell you some of our teenagers can be a little mischievous with all their other therapies…

“I find their adherence with the modulators is generally outstanding — they’re not dropping Trikafta, because they’ve figured out they will pay for it.

“But they’ve figured out they can drop various other stuff, including physiotherapy — God help us.”

But clinicians have also needed to adapt how they manage children because they are preparing them for a full, not a partial, life.

“Previously we would encourage a high-fat diet and high nutrition, for example, because the more the better — and now we’re looking at the quality of nutrition that we’re giving them.

“We know there is a risk of cardiovascular disease, because they are going to be living to 70 or 80, and we don’t want to be giving them that.”

Access for all?

There is still a battle for the children who can’t access the therapy.

For some it simply won’t work on genetic grounds.

As made clear above, Trikafta only works for those with the most common delta F508 mutation.

This means 18 of Professor Selvadurai’s patients don’t benefit.

For the others, age is the barrier. Trikafta is currently only available in Australia for children older than six years.

The TGA has recently approved the use of the drug for children aged 2-5 years — and this month it’s back on the PBAC meeting agenda for whether taxpayers should fund it.

There are 313 children with cystic fibrosis in this age group, according to the Australian Cystic Fibrosis Data Registry, and Professor Selvadurai says 90% would be eligible for Trikafta.

But a PBS listing could still take around six months.

“The difficulty is what kind of outcome can you measure in the 2-5 age group, which is robust and objective, to convince the powers that be to prescribe it,” says Professor Selvadurai.

“We can’t reliably measure lung function in that age group … We are pretty much stuck with nutrition and sweat tests.”

Professor Selvadurai explains that, clinically, children of this age are often healthy — they haven’t been hit by the “vagaries of CF yet, but there is a need to future-proof against inflammation that could lead to poorer longer-term outcomes”.

“Given the opportunity, we would like to get in there earlier so that we prevent inflammation, which we presume will reduce the chances of developing long-term scarring of their lungs.”

He also believes that to take the pathway of NICE and recommend against the drugs would be short-sighted.

“You are risking not only individuals and their lifespan, quality of life, but also from an NHS point of view … it will end up costing them much more.

“Various modelling has shown it will end up costing more … in terms of service delivery, access to medical, allied health, nursing care.

“There’s a lot of data to support that — as ridiculously expensive as it seems to us — this is actually cost-effective.”

He adds that Trikafta is a treatment that respiratory physicians have dreamt of “for years and years and years”.

“It is amazing to have this tangible access to something that is tangibly better for the children, to give them hope. This drug is giving them back their childhood, their future.

“It is enormously rewarding. It’s the highlight of my career so far.”