A just-announced decision by US regulators has made New Zealand science history, with the Food and Drug Administration (FDA) approving this country’s first locally-discovered neurological treatment. Photo / AP
A just-announced decision by United States regulators has made New Zealand science history, with the Food and Drug Administration (FDA) approving this country’s first locally-discovered neurological treatment to make it to market.
Today’s final marketing approval for Trofinetide – marketed as Daybue – also marks the first-ever FDA-approved drug for Rett syndrome, a severe neurological disorder, estimated to affect 350,000 girls and women worldwide.
Symptoms range from loss of speech, mobility and muscle tone to seizures, breathing problems and slowed growth, with near-constant hand movement a common hallmark.
But Trofinetide - a product of University of Auckland spin-out company Neuren Pharmaceuticals and US company Acadia Pharmaceuticals - has shown exciting promise at treating Rett symptoms, potentially improving the quality of life for the girls and their families.
One of the researchers involved in the founding chemistry work, University of Auckland chemist Distinguished Professor Dame Margaret Brimble, was celebrating the announcement.
“I am shaking with excitement but filled with emotion for all the Rett families,” she told the Herald on Sunday.
Daybue - just one of a handful of NZ-discovered drugs to gain FDA approval - is expected to be available in the US as early as next month.
At this point it’s not clear when it will be accessible to Kiwi patients.
Rett NZ national co-ordinator Lady Gillian Deane understood the drug would also need to go through European approval, but said Kiwi families were eagerly awaiting it.
“They can’t believe it,” she said of their reaction to today’s news.
“This is terribly exciting for us – but also for NZ scientists – that we have this wonderful drug.”
Acadia chief executive Steve Davis said the announcement marked an “important milestone” for the Rett community.
“As the first FDA-approved drug for the treatment of Rett syndrome, Daybue now offers the potential to make meaningful differences in the lives of patients and their families who have lacked options to treat the diverse and debilitating array of symptoms caused by Rett syndrome,” Davis said.
International Rett Syndrome Foundation chief executive Melissa Kennedy said the decision made for a historic day.
“Rett syndrome is a complicated, devastating disease that affects not only the individual patient, but whole families,” Kennedy said.
Rett syndrome is caused by errors in a particular gene, MECP2, which is found throughout the human body but has especially important properties for the brain.
In children with the condition, mutations within MECP2 inhibit the formation of a molecule essential to cognitive and motor function.
The story of Trofinetide began back in the 1990s, when Professor Sir Peter Gluckman and colleagues in the university’s Department of Pediatrics started exploring a hypothesis that the brain made “growth factors” after it was injured, in an attempt to reduce effects of injury.
This work, which involved Dr Jian Guan, then a PhD student, and brain phamacologist Professor Mike Dragunow, was carried out using a combination of animal models and molecular biology.
The first findings involved a growth factor called TGFb, and then the human insulin-like growth factor 1 (IGF-1), a naturally-occurring protein that Gluckman happened to be a global expert in.
When Guan investigated whether injections of IGF into the brain could be neuroprotective, rat studies indicated they indeed were.
The university’s commercial arm, Uniservices, then formed a company, NuerenZ, to see if that knowledge could be exploited, with Dr Robin Congreve signing on as an initial investor.
The company, arguably the first spin-out company with private investment from the university, was housed alongside the Liggins Institute that Gluckman helped establish.
At the same time, Gluckman was elected as a Fellow of the Royal Society of New Zealand in recognition of his work on brain repair, and the role of growth factors.
Moving further, Gluckman and Guan set out to investigate whether a small tripeptide derived from IGF-1, and called glycine-proline-glutamate (GPE), itself had neuroprotective properties.
Again, rat studies suggested it did – and so Neuronz and Liggins shifted their focus to GPE, as a simpler model to work with.
While Guan was able to show GPE’s protective benefits in many animal studies, she and colleagues also found it to be inherently unstable – meaning it would need to be either directly injected into the brain or given by continuous infusion.
At that point, Gluckman approached Brimble to make a stable form of GPE which wouldn’t require direct injection – which her team was able to do, with a peptide “mimic” designated NNZ-2566.
That synthesised molecule, ultimately the basis of Trofinetide, was also found by Guan to be neuroprotective in animals.
NuerenZ, meanwhile, was renamed Neuren because of a merger with another small Liggins spinout, while Guan and Gluckman left their roles with the company around 2007.
That early work led to a series of studies including safety studies in humans in New Zealand and later, a variety of clinical studies.
Although the molecule was originally designed to be an intravenous treatment for traumatic brain injury (TBI), Neuren scientists – led by then director of research Dr Mike Bickerdike – discovered in 2009 that the compound might be surprisingly effective in autism-spectrum disorders, such as Rett Syndrome.
The company subsequently abandoned the development of the drug as a TBI treatment in favour of redirecting efforts toward treating Rett Syndrome.
The approval of trofinetide for treating this disease will be the culmination of years of work by Neuren scientists and clinicians.
Neuren partnered with US company Acadia Pharmaceuticals to carry out the expensive phase-3 trials, with Acadia paying US$10m (NZ$16m) for the drug’s exclusive rights in North America as well as royalties on any sales, plus up to US$455m (NZ$741m) in milestone payments.
Another potential target for Trofinetide is Fragile X syndrome: the most commonly inherited cause of intellectual disability, as well as the most common known cause of autism.
As with Rett, there are currently no medicines approved for its treatment.
Meanwhile, Nueren continued to develop a second related compound NZ2591 - also discovered by Guan and Gluckman – with potential use for other serious neurological conditions that emerge in early childhood.
It has already gained FDA approval to enter phase 2 clinical trials for the treatment of PhelanMcDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome and Prader-Willi syndrome.
While working as an academic at Liggins, Guan – now based in the private sector - has since been able to reveal much about the mode of action of this family of peptides.
What’s it like to live with Rett syndrome? Auckland mum Kimberley Sullivan shares this story about her five-year-old daughter Macy Hoyes.
“The happiest baby in the world!”
People would stop me in the mall to comment as I pushed around this perfect cherub-looking angel in the buggy. She smiled at strangers, was happy in anyone’s arms, made all the right noises.
She sat and she crawled, at 17 months she got up and walked and never looked back. Where was the red flag? Should we have known then?
On New Year’s Eve 2018 she spoke her first words: “Pooh Bear.” I couldn’t believe my ears – but she was nearly 19 months old by now and it was starting to play on my mind.
From here on she steadily gained expressive and receptive language, she developed a love for monkeys and could spot a monkey a mile away; a toy in a shop window, a tiny picture on the corner of a page in a book.
Her baby brother was born the day after she turned two, she learned his name and used it and “baby” interchangeably.
But soon we noticed she didn’t care about monkeys any more. She didn’t want to sit and read a book.
She didn’t follow simple instructions any more and she didn’t use the dozen or more words she knew.
She cried a lot, she didn’t seek out the company of others, she didn’t notice other children in the room.
What was happening to our happy girl?
Doctors told us it was autism; “sometimes this happens with autism,” they said about the sudden loss of skills.
We had an MRI and EEG to rule out anything like a tumour or growth in her brain.
“Her brain function is completely normal,” the neurologist told me after the MRI. I thought this was a strange choice of words, because anyone who knew Macy could see that she was not the same child she was six months previously, her brain function quite clearly was not normal.
Her finger clicking was becoming more and more like a tic than a stim – she couldn’t stop herself from doing it and she didn’t seem to enjoy it or find any comfort from doing it.
She could no longer eat with any sort of utensil; her right hand was rendered useless by now, taken over with clicking and mouthing only.
Her left hand would accept food, but toys held no purpose and books wouldn’t hold her interest.
By age 3.5 we were offered further investigation in the way of genetic testing. I had found Rett syndrome online and was fully convinced this was what we were dealing with.
Two geneticists told me that it couldn’t be Rett syndrome – girls with Rett syndrome aren’t as mobile as Macy and they wring or clasp their hands together.
Macy’s hands are never together and one also still works, to a certain extent.
Almost a year later we had an appointment confirming what I had thought the whole time.
“Do you feel vindicated?” the paediatrician asked me.
Yes, I do, but it’s not exactly the result we would ever ask for.
It’s 2023 and our girl is now 5.5 years old. She is very talkative, with various and constant consonant sounds and babble, not amounting to words although on some occasions you would swear she was saying “mama mama” or “no no no” in the right context.
She is still completely mobile, she can climb stairs independently when she wants to.
She has come through her very long, very late and tough regression stage and has been calm and delightful (for the most part) since she turned five.
She looks us in the eyes and gives kisses constantly and we treasure this.
We could consider ourselves lucky; we got several months of meaningful chatter from our girl. I have many videos of her using the words we now yearn for.
I know many Rett families don’t get this. Many don’t ever get to see their girls walk.
But what if her hands worked for something other than constantly clicking fingers and hitting herself in the mouth? What if she could find interest in anything else other than the one TV show she has watched constantly for the last 3 years?
What if she could tell us what she wanted or how she was feeling?
A small improvement in just one of those areas would change Macy’s life.
Here in New Zealand, there is a lot of uncertainty for our small community of Rett families, around when, how and if we will be able to access Trofinetide.
An opportunity to improve our girls’ lives in any way is something we are all desperate for as soon as possible.
They allege the Crown ignored Treaty obligations by not engaging with them.