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When Amber Freed heard in 2020 that a drug might help save her young child from a rare, progressive form of epilepsy, she was ecstatic. The news came just in time. Many children with the genetic mutation that causes her son’s illness begin experiencing debilitating seizures as 4-year-olds. Maxwell was 3.

Even better, the drug, Ravicti, was already approved by the Food and Drug Administration, so a doctor might be able to prescribe it right away. But there was a catch: At around $740,000 per year, Ravicti is one of the most expensive drugs in the world.

It’s a common story for rare disease drugs, even older “repurposed” ones like Ravicti that aren’t gene therapies or other complex technologies. But what Freed and other parents did next is less common: They are funding a clinical trial to investigate whether Ravicti can help their children, hoping to generate enough data to convince insurers that they should pay for the treatment. One patient has already completed the trial, which aims to enroll 19 more children with rare diseases caused by mutations in two genes, STXBP1 and SLC6A1.

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The trial both highlights the increasingly popular strategy of repurposing existing drugs for rare diseases, and exposes growing tensions over the prices for these treatments.

“This is a safe, known drug,” said Freed, who hopes her son will soon enroll in the trial. “A small molecule should not be this hard to get.”

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There are as many as 7,000 rare diseases, each found in fewer than 200,000 U.S. patients, but altogether seen in as many as 25-30 million Americans. Many of these diseases are too rare to interest drug companies. So Freed and a growing number of other parents are raising money for clinical trials — as much as $4 million to $7 million for research on cures, such as gene therapies.

They’re also funding drug repurposing studies, which aim to find existing drugs to stabilize their children during the long hunt for cures. These trials are usually much cheaper and faster than developing new drugs. Parent foundations are paying $320,000 for the Ravicti trial, which has been in the making for three years. In contrast, developing a new drug can cost billions of dollars over a decade or more. Freed calls the trial — for which the drug’s maker is providing Ravicti for free — a “steal of a deal.”

But a trial might not even be necessary if Ravicti — which was approved in 2013 to treat rare urea cycle disorders that disrupt the body’s waste removal system — were less costly. The trial is just the first of many steps needed to ensure that patients can access the drug. Even if the drug appears to help some patients, for instance, insurers might not pay for it based on the results of a small trial. Further studies may be needed, and the company that sells Ravicti might need to agree to apply for FDA approval for STXBP1 and SLC6A1 patients.

“The problem with these rare disease drugs is that the prices that are being asked by the drug manufacturers are not based on any reality at all,” said Stacie Dusetzina, associate professor of health policy at Vanderbilt University.

“It’s basically pricing as high as the market will bear, and in the rare disease context, that number is very rapidly growing,” Dusetzina said.

The motivation for the trial came from a mother named Charlene Son Rigby. In 2016, Son Rigby learned that her daughter, Juno, carried a mutation in the STXBP1 gene. Little was known about the incurable condition, which affects at least 1,000 people worldwide and causes epilepsy, autism, and intellectual and physical disabilities.

Juno, now 7, has global developmental delay. She didn’t walk until she was almost 5, and speaks just a few words, including “balloon” and “ball.”

In 2017, Son Rigby formed the STXBP1 Foundation to spur research into potential gene therapies and other treatments. She soon got promising news. Scientists led by Jacqueline Burré at Weill Cornell Medicine in New York had tested a molecule called 4-phenylbutyrate in brain cells and in C. elegans worms with STXBP1 mutations. The molecule improved some of the damage caused by the genetic mutations, Burré’s team reported in 2018.

Weill Cornell pediatric neurologist Zach Grinspan was eager to try the molecule in his patients. It’s sold in two forms, sodium phenylbutyrate and glycerol phenylbutyrate, or Ravicti.

Grinspan wanted to use the better-tasting Ravicti in his patients. Since it is already approved, Grinspan could have written his patients an “off-label” prescription for Ravicti, allowing them to try it even though it wasn’t approved to treat their disease.

But he realized that insurers would likely balk at the drug’s price. So he began organizing a clinical trial of Ravicti in patients with STXBP1 disorders.

At the same time, Freed was learning that her son, Maxwell, also had a rare, incurable childhood epilepsy. Maxwell’s disease results from errors in the gene SLC6A1. When Maxwell received his diagnosis, Freed quit her job as an equity analyst and formed a foundation, SLC6A1 Connect. The foundation funded research on a gene therapy, which may enter clinical trials as soon as this year.

In 2020, a researcher funded by SLC6A1 Connect brought hopeful news. Jing-Qiong (Katty) Kang, a Vanderbilt University neurologist, found that Ravicti could help correct some of the defects seen in cells and mice carrying Maxwell’s specific mutation.

Freed connected with Son Rigby, and the two decided to collaborate. Grinspan and Scott Demarest of Children’s Hospital Colorado will test whether Ravicti is safe and well-tolerated in 10 children with STXBP1 mutations and 10 with SLC6A1 mutations. They will also look for improvements in symptoms such as seizures, brain activity, movement disorders, sleep, and quality of life to help inform future studies. The trial is expected to report results in the fall of 2022.

The drug seems to work similarly in both Juno’s and Maxwell’s diseases. In both, genetic mutations cause proteins to form incorrectly. This prevents neurons from communicating with each other.

In the lab tests, Ravicti seems to fix these defects by acting as a “molecular chaperone,” a type of molecule that stabilizes healthy proteins.

“This could be a home run,” Freed said.

Maxwell 01
Maxwell Freed plays at home, while his mom reads to his twin sister, Riley. Kim Leeson for STAT

The lab data have already convinced some patients to try the drug related to Ravicti, sodium phenylbutyrate, sold as Buphenyl in the United States.

In Belgium, for instance, Leyla Vardar’s son, who carries an SLC6A1 mutation, began taking sodium phenylbutyrate this year. At first, he experienced severe headaches and other side effects, so his doctor reduced his dose. Now, after three months on the drug, Vardar said she has seen “amazing” physical and intellectual improvements in her son, Axel — though one child’s experience isn’t hard evidence that the drug works.

Axel’s teachers say he is more engaged in school, his reading has improved, and he interacts more with his parents and the world around him. He’s having fewer physical symptoms, such as seizures and vomiting, and he can jump higher in his soccer games, Vardar said.

Axel feels better about himself, and her family is more stable, Vardar said: “This is the first time that we see him building and not losing what he’s doing.”

Vardar’s family is paying the full cost of the drug, about 795 Euros a month, or roughly $12,000 per year. But that’s not possible in the United States, where one company sells both Ravicti and Buphenyl.

Horizon Therapeutics bought both drugs from another company in 2015. Horizon then tripled Ravicti’s price, and has raised Buphenyl’s price from $40,000-$130,000 per year to $243,000.

Asked about the price increases, the company told STAT, “Horizon evaluates price adjustments based on several factors including the costs to invest in research to improve our current therapies and develop new rare disease medicines.” The company added in a statement that it has expanded the ages of patients approved to receive Ravicti, provides free genetic testing to patients with urea cycle disorders, and provides financial assistance for patients who need it.

It’s not the first time that Horizon has raised a drug’s price by a large margin. In 2013, for instance, it bought the rights to sell the pain drug Vimovo, then increased the drug’s price by 597% in 2014.

Indeed, some economists question whether patients’ families should have to pay for the Ravicti trial in STXBP1 and SLC6A1 patients.

Ravicti has already generated $1.15 billion in sales for Horizon. At this rate, it could well earn the company enough money to develop its next new drug, said William Padula, a health economist at the University of Southern California.

“Expecting the public at this point to help fund their R&D for them, independent of the money they’re making in revenue off of Ravicti, doesn’t seem fair, given the price,” he said.

Horizon emphasized in a statement that the current trial “is designed to assess tolerability, safety and pharmacokinetics (the absorption, distribution, metabolism, and excretion) of glycerol phenylbutyrate [Ravicti] for those with STXBP1 or SLC6A1, not efficacy.”

What happens next, the company says, depends on the results of the trial.

“In terms of access to our medicine, at this point there are no efficacy or safety data for glycerol phenylbutyrate for people living with SLC6A1 or STXBP1. That is the purpose of research such as the [investigator-initiated trial], to begin the process of determining if potential efficacy outweighs potential risk in this unique patient population,” the company said.

Even if Ravicti works in Maxwell, Freed is worried that it will be difficult to convince her insurance company to pay for it.

“It’s more expensive than a gene therapy, because you seriously could be on this drug for the rest of your life,” she said.

Son Rigby appreciates that Horizon is collaborating with the clinical trial and is staying positive, though she lives with a difficult reality: In 2019, she found out that Juno would not qualify for the trial because she doesn’t have seizures.

Investigators have decided that all trial participants must be experiencing active seizures, because decreasing seizures is one of the clearest signals they might detect to prove that the drug is working.

Son Rigby supports the decision, which will improve the chances that the trial succeeds. To her, it just means that she must do all she can to move the trial full speed ahead, to find out if the drug works, and if so, to convince both Horizon and their insurers that Juno and other children should receive Ravicti.

“This is the first thing we’ve been able to get out of the gate,” Son Rigby said. “So let’s push it as hard as we can.”

  • It borders on criminal activity for a company to buy up patented drugs then increase the price multi-fold, as in doing the life-saving drugs are rendered out of reach for far too many patients. Horizon Therapeutics has 11 drugs in the US and 3 in Canada (google). For some there are less costly replacements / alternatives. Also – these trials are really cheap for the company, and the patients involved in these trials ought to get life-time huge price reductions. Just hope that this company changes its rather unscrupulous disposition.

  • We really need laws in the US to prevent a company from buying a patent on a drug and then increasing the price to multi-millionaire billionaire income levels.

    And the drug is usually super expensive at middle class income level already.

    This needs to stop and it will take price gouging laws to do it.

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