Wilson disease (WD) was always fatal until  Dr. John Walshe, an English physician, discovered penicillamine in 1956.  While WD was no longer a death sentence, with time, complications with the drug started to appear.

“We had run into trouble with penicillamine and I wanted an alternative treatment,” Dr. Walshe explained to me in 2018, when I traveled to Cambridge, England to meet him. “One morning I ran into a biochemist, Dr. Hal Dixon, and I explained my problem to him and he pulled off the shelf triethylene tetramine and said ‘it should be non-toxic, known to bind to copper, try it.’ And that’s how we got trientine. It was Hal Dixon’s idea, and my work proving that it worked, and it was safe.”

News that trientine worked as a backup to penicillamine made its way to the United States, and after studies of the drug were done here, the FDA approved it for WD.  It went on the market as Syprine in 1985 for patients who couldn’t tolerate the side effects of penicillamine, or who weren’t helped by it.

However, there’s a downside to trientine that can make it burdensome for patients to use:  The drug must be refrigerated, or it loses its potency over time and is less or no longer effective.

No refrigeration needed

It all started with a group of French scientists who came across a hospital in Paris, France where trientine was being compounded by its pharmacy for use in WD.  What made the formulation notable, was that it was stable at room temperature.  So, no need for refrigeration.

To understand why, involves a lesson in chemistry.

“Trientine is a petroleum based product.  It’s very volatile and an unstable molecule,” explained Dr. Omar Kamlin, senior medical advisor at Orphalan.  There are four reactive amino groups on trientine, and to stabilize it enough to work as a medicine, drug companies chlorinate two of the four amino groups. Chemically, this product is called trientine hydrochloride. “Our compound is different because we have further stabilized the molecule by having a hydrochloride molecule atom occupy all four amino groups.”  Although trientine is derived from petroleum, it ends up with a chemical structure similar to natural compounds in our bodies called polyamines.

The chemical name for the new formulation is trientine tetrahydrochoride (TETA 4HCI).

Scientists at Orphalan then converted their new formulation of trientine from a powder-filled capsule to a tablet that’s stored individually in blister packs, so they remain stable, and therefore potent, at room temperature for up to three years.  It will be marketed as Cuvrior in the United States.

“It’s a nice convenience factor for sure!” said Dr. Michael Schilsky who directs the WD Center of Excellence at Yale University.  “It takes the worry out of the product being left out of the refrigerator and is more portable for travel.”

There’s more to trientine’s makeover:

“We’ve enhanced the medication by making it smaller and it has a coated film so it’s more palatable,” said Dr. Kamlin, “and we scored the tablet so you can split it, and theoretically give the physician and patient more options for precise dosing.”

Making medications easy for patients to take is essential. The need is even greater for those who must take multiple doses, every day, for life.  Up to half of all patients on daily medications are non-compliant at some point in their lives.

“You want to avoid missing doses because we know that at least one-third of WD patients who are non-adherent end up either with a significant irreversible neurologic dysfunction that doesn’t resolve, or long-term liver damage, even necessitating a liver transplant,” said Dr. Michael Heifets, Orphalan’s head of medical affairs in the US.

Some WD patients may recall the launch of another brand of trientine, called Clovique made by Kadmon Pharmaceuticals, that was stored in special packaging, and claimed to not need refrigeration. It remained stable at room temperature for a while, but was ultimately pulled from the market.  A generic trientine, made by Dr. Reddy’s, claims it can be kept at controlled room temperature for up to two years.  However, it has no special packaging, and the chemical formulation is the same as Syprine and all other generic forms of trientine on the market.

A head-to-head comparison of penicillamine and trientine

Ever since Dr. Walshe proved that trientine was a suitable backup to penicillamine, doctors have followed that advice.  So, penicillamine has been considered the go-to option for Wilson disease.  One reason, is that until now, there have not been any studies comparing the two drugs head-to-head, that would change that perception.

Orphalan launched the CHELATE trial to compare Cuvrior with penicillamine in WD patients who were in the maintenance phase of their disease.  The findings were published in the leading research journal, Lancet Gastroenterology Hepatology, in 2022.

“We wanted to prove that Cuvrior was similarly effective to the standard of care, which was penicillamine,” said Dr. Kamlin.

There were 53 adults with Wilson disease patients in the study from Europe, Brazil and the US.  All were stable, and had been on penicillamine for at least a year at the start of the study.  Half the patients were then switched to Cuvrior, while the other half remained on penicillamine.  After a year, the two groups were compared, and all the patients remained stable.

“For maintenance therapy, both are now considered equivalent,” said Dr. Schilsky.  Yale University was the CHELATE trial site in the US.

Before approving Cuvrior for patients to use, the FDA also wanted evidence that there wasn’t any neurological worsening in the WD patients who were switched to Cuvrior.

“The literature shows that patients starting new treatment might suffer from a change in their neurological symptoms.  We found overall across the group, no change.  That was reassuring,” said Dr. Kamlin.  “We also did tests of cognition, and saw their mental state was also stable throughout.”

How to get Cuvrior

Since 2018, trientine tetrahydrochoride (TETA 4HCI) has been on the market as Cuprior in Europe, where more than 1,000 WD patients are now using it.  Approvals followed in Saudi Arabia, and in some Latin American countries and they’re ongoing in China.

The FDA approved Cuvrior for the treatment of adults with WD in May 2022, and it came on the market in the US in April 2023.

The question for patients: Will my insurance cover it, and what will be the cost?

“Our philosophy is to have the best product available to patients, while minimizing the hurdles they have to go through to get it,” said Dr. Kamlin.

Orphalan is offering various services to support patients and physicians in navigating insurance coverage.  Cuvrior is available through the specialty pharmacy, PantherRx*, which offers reimbursement support, access to copay assistance and free drug programs for patients who qualify.

Still, despite the increasing number of treatment options available for people living with WD, the challenge remains to identify them early, before devastating neurological dysfunction, psychiatric illness or liver damage set in.  When doctors look for it, diagnose it, and treat it, people with Wilson disease can live a healthy, normal life.

*For more information see https://www.cuvrior.com/