A drug designed by New Zealand scientists to combat a rare neurological disorder is one trial away from being the first locally-developed drug to be approved by the FDA in the US.

Trofinetide, developed by a team of medicinal chemists led by Auckland University distinguished professor Margaret Brimble, has been approved for a phase three clinical trial for Rett syndrome patients in the US, with the hope of getting the drug into hospitals for use. 

If it passes the trial for use for Rett Syndrome, it will be the first drug made by a New Zealander to be approved by the US Food and Drug Administration (FDA).

Rett syndrome, which causes problems with brain function and has symptoms similar cerebral palsy and autism, affects one in about 10,000 women worldwide. It is caused by a gene mutation that inhibits the natural formation of a molecule essential to cognitive and motor function. Brimble, who is chair of organic chemistry and director of medicinal chemistry at Auckland University, developed a synthetic version of this molecule with her research team about 12 years ago. At the time, it was referred to as NNZ2566, and originally intended for the treatment of traumatic brain injury.

Since then, it has been developed commercially – through Auckland University spin-out company Neuren Pharmaceuticals (now based in Melbourne) – and tested in two clinical trials for Rett syndrome sufferers in the US. Both Rett syndrome sufferers and those who have brain injuries fail to naturally produce enough of the peptide molecule which has been synthesised in trofinetide. In March, Neuren announced the success of its second trofinetide clinical trial, which involved girls with Rett syndrome aged 5 to 15, at 12 hospitals. A third clinical trial, set down for next year, is expected to fine-tune the dosage of the drug.

“They found that it was really well tolerated and safe, so now they know they can do an even higher dose in the brain injury patients,” Brimble said of the second trial.

“It turns out that people who suffer from brain injuries, because their brain is compromised, they’re not absorbing as much of the drug as a normal person, and they didn’t take account of that for the trial. It’s very clear that they have to do a brain injury trial at a much higher dose.”

In the most recent trial, which was a double-blind, randomised, placebo-controlled study that tested three doses of trofinetide, all participants slurped backed strawberry milkshakes. Girls who were in the group of participants that received the drug had it mixed in with their milkshakes.

“One of the reasons why they do so many clinical trials is to look at the dose, the dosing regime, the dosing schedule, how much you give to the patient and when you give it to the patient,” Brimble said.

Trial results showed the drug not only worked for addressing Rett syndrome symptoms, but also in reversing the disease.

“If you’re a mother with a little child that can’t walk or talk and has no cognitive function, and then you see them progressing and the symptoms reversing – it must be amazing,” she said.

Following the third clinical trial, trofinetide would need to be registered and approved by the FDA to be made available for all Rett syndrome sufferers. And while its path from the NNZ2566 molecule had taken more than a decade, its development had actually been fast-tracked because of its status as an “orphan drug”. In the US, drugs developed for rare diseases like Rett syndrome can be assigned this status – which results in faster FDA approval – to encourage research into treatments for rare diseases. Once the drug is approved by the FDA, countries that want to purchase it for use locally will be able to do so.

Meanwhile, Neuren had already started looking for manufacturers for trofinetide, Brimble said. The drug would be approved for treatment for Rett syndrome first. It could also be approved for the Fragile X neurological disorder, which affected mainly boys. While Rett syndrome did occur in males, it was rare. Further studies and trials would determine whether and how the drug could be used to treat brain injuries, Brimble noted.

“It’s just fantastic to see that a molecule born here went that far,” she said.

“So many molecules fail – a lot don’t even get to clinical trial, and if they get to clinical trial, they fall over, especially in the [field of] neurodegenerative diseases and neuro-development disorders.”

Trofinetide’s success had been particularly special for Brimble because of how the drug was discovered.

“It was a New Zealand company and they did it all locally. And it’s a drug for females from a female lab which is very rare,” she said.

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