The neurological drug NNZ-2566 or Trofinetide - now marketed as Daybue - was discovered by a team of scientists at the University of Auckland team more than 20 years ago. Photo / Supplied Photo / Supplied
The neurological drug NNZ-2566 or Trofinetide - now marketed as Daybue - was discovered by a team of scientists at the University of Auckland team more than 20 years ago. Photo / Supplied Photo / Supplied
Kiwi scientists may be about to make New Zealand history, with a breakthrough treatment on the cusp of becoming the first drug of its kind to make it to market.
Within days, researchers expect to hear whether a drug that came out of New Zealand is granted final marketing approval by the US Food and Drug Administration (FDA).
If so, trofinetide will prove the first Kiwi-discovered neurological drug to be cleared by the major regulator – and offer a long-awaited therapy for a rare and severe neurological disorder affecting hundreds of thousands of girls and women worldwide.
Distinguished Professor Dame Margaret Brimble, director of Medicinal Chemistry at the University of Auckland, described Rett Syndrome as a “debilitating disease” and one still without an approved treatment.
It almost exclusively affects females – including one in 10,000 girls born in the US alone and some 350,000 worldwide – stalling or regressing their motor control and communication skills at ages six to 18 months.
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 has shown exciting promise at treating Rett symptoms, potentially improving the quality of life for the girls and their families.
By next week, the companies aiming to bring it to market expect to hear the FDA’s decision.
For Brimble herself, approval would mark the ultimate fulfilment of a life-long dream to help other women through drug discovery.
“I can now go to my grave knowing that I have used my science to try to help others.”
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 pharmacologist 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.
Dr Jian Guan. Photo / Supplied
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, NeuronZ, to see if that knowledge could be commercialised.
Dr Robin Congreve, at that time the chair of the School of Medicine Foundation, became an investor in and director of, NeuronZ.
The company, arguably the first spin-out 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.
Nueronz, 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.
In children with the condition, mutations within MECP2 inhibit the formation of a molecule essential to cognitive and motor function.
The approval of Trofinetide for treating this disease will be the culmination of years of work by Neuren scientists and clinicians.
Professor Sir Peter Gluckman. Photo / Supplied
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, Neuren 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.
*This story has been edited to reflect the contributions of others in Trofinetide’s discovery and development.
