Rett Syndrome – Mother of Trofinetide

Posted: January 22, 2023  |  Categories: Uncategorized

Rett Syndrome is a genetic brain disorder. I don’t normally talk about personal stuff on my blog but this is so important that I want to write about.

This story is about my wife, Dame Margaret Brimble’s life work. She is the Mother of Trofinetide because her laboratory made this new drug called Trofinetide that treats this brain disorder. On 11/3/2023 this drug was approved for treatment of Rett Syndrome. Trofinetide is the first approved treatment for this neurogenetic disorder. Moreover, it is the first FDA approval of be commercialized by a NZ company, Neuren Pharmaceutical. They are registered in NZ and listed on the ASX. I don’t know if any other female academic like my wife have produced a new drug. The rest of this blog tries to record the journey that led to its discovery from my perspective.

2019 Investiture Ceremony Government House

Dark days – The beginning

Returning to NZ in 1999 Margaret and I found the country had changed a lot since we left. Taking up the role of Chair and Professor of Organic Chemistry at The University of Auckland, Margaret arrived to find all her resources swallowed up by budget and staff cuts. She delayed her starting date due to the birth of our daughter, Rebecca. She lost her secretary and her set up grant. Coming from The University of Sydney where her research group was well funded and large, this was devastating. Now she had nothing. I could not find a job for six months because NZ was in the depth of a recession.

Nevertheless, we both made the best of it. Margaret devoting her efforts to creating the first course in medicinal chemistry at Auckland and applying for NZ government research grants. The course in medicinal chemistry was a huge success drawing large enrolments. After some success with grants Margaret was still unhappy because she could not fund her the science. Thus, she engaged in contract research through Uniservices so that she could use this money to fund her basic research. This is where her involvement with Manuka honey and rat poison started but I digress. I went back to university for six months before finally obtaining a job in information technology.

Notwithstanding this, things took a turn for the worse, Auckland University imposing user charges for NMR spectroscopy. An organic chemist uses this as tool to do their research. The cost to fund this was unsustainable, and Margaret began searching for opportunities in Australia.

A new dawn – Neuronz ( later Neuren)

Late one night, in 2001, Professor Peter Gluckman(now sir) rang Margaret and said, “I hear you are very good at making compounds, would you like to join a team working on traumatic brain injury”. That was the beginning of Margaret’s involvement which would eventually lead to the discovery of Trofinetide. A group at the University of Auckland’s Medical school knew that glycyl-L-prolyl-L-glutamic acid (GPE) had neuroprotective properties. Unfortunately, it had a very short half live in the brain and was not suitable for clinical use. Thus, the idea was to make a series of compounds that might have better a better half live, requiring a synthetic organic chemist like Margaret.

glycyl-L-prolyl-L-glutamic acid

Funding of a medicinal chemistry programme came then from the New Zealand Seed Fund.

Early Sucess

With this funding in hand, Margaret with other members of the team wrote a list of compounds to synthesize. Subsequent testing of the compounds for neuroprotective properties would select one compound for a clinical trial.

Making and testing many compounds, for example Synthesis and neuroprotective activity of analogues of glycyl-L-prolyl-L-glutamic acid (GPE) modified at the alpha-carboxylic acid – PubMed (, identifying one NNZ-2566. This was its laboratory number. This was later trademarked as Trofinetide. Surprisingly this compound might never have been made if it were not for the tenacity of the chemists. It is quite difficult to make because of the chiral centres that it contains. They continued when others wanted them to move on to make other compounds and they were eventually successful after several months trying to make NNZ2586.

Trofinetide NNZ-2566

Spies and Clinical Trials

With a viable drug candidate in hand, clinical trials to prove the efficacy of NNZ2566 could start. Securing funding from the U.S.A. Army & by floating a company called Neuren Pharmeuticals Ltd on the ASX enabling this. The first phase 1 trial of NNZ2566 was on healthy males to showing that there were no side effects on healthy patients. Here is a picture of one of these trials.

Phase 1 Clinical Trial

Commercial realities now became the main concern of the team. Planning of Clinical trials for TBI and regulatory approval, manufacture of Trofinetide and a patent position where some of the concerns.

Firstly, manufacturing of Trofinetide under Good Manufacturing Practices (GMP), in sufficient quantity for the clinical trials was not possible in Margaret’s academic laboratory. A search for a company to carry out the large-scale synthesis began. Margaret recommending a US company. In the end Neuren choose a manufacturer in India based on a much cheaper price. This was a costly mistake and after two years that company could not supply Trofinetide in sufficient quantity. Thus, a new contract with Albany Molecular secured material for the clinical trials.

Secondly, an expert began preparing the final patent applications. The expert left Neuren abruptly filing the patents under his own name. After a costly battle to reclaim the patents through the courts, Neuren was ultimately successful. It was rumored that the expert was planted by a rival to spy on Neuren.

Thirdly with the patent and drug supply secure a clinical trial for TBI could begin. The trial finished in April 2016. Unfortunately, the trial did not demonstrate a difference between drug and placebo. The safety results, which was the primary endpoint of the trial, identified no treatment- related or dose-dependent trends in adverse events or laboratory results. Thus 5 years had elapsed since the work began without proving efficacy.

Rett Syndrome clinical trials

Nevertheless, after this setback Neuren began clinical trials for Rett syndrome. With Neuren, moving to Melbourne, focusing on progressing clinical trials, Margaret’s association with this work diminished. Margaret summarized her research succinctly at NZ biannual Retts Syndrome conference in 2014(Margaret Brimble on Vimeo). At this conference Margaret made friends with Lady Gillian Deane, whose husband Sir Roderick Deane was the chair of the NZ Seed fund that started all of this. Lady Gillian subsequently funds some of Margaret’s other research work.

Promising results were obtained in a Phase 2 trial in March 2017 and Neuren now had a promising drug to develop further. The FDA has granted Orphan Drug designation to Neuren’s drug trofinetide for treatment of Rett syndrome. Orphan Drug designation is a special status that the FDA may grant to a drug intended to treat a rare disease or condition. The designation qualifies the sponsor of the drug for 7 years of marketing exclusivity following marketing authorization. summarizes the historical clinical trials here.

Other Clinical Indications

Trofinetide is now in clinical trial for other neurological condition such as Fragile X, Phelan-McDermid and Angelmann Syndrome.

Another compound called NNZ-2591 from Margaret’s laboratory is also now in clinical trial for Pitt Hopkins and Prader Willi Syndrome. This compound came from a collaboration between Jian Guan and Margaret. Margaret supplying this cyclic peptide to Jian. See Jian’s work here.

The Endgame

Finally, nearly 22 years after Trofinetide was first made it is now a licensed drug for sale. See the Neuren Pharmaceuticals for more details. Margaret looks back with pride that a female NZ academic scienctist has done this. This is a big part of Margaret’s life work, and it is hard to mention all the other people in this story. This is a story about what collaboration, being bold and NZ science can do. While I have only written about Margaret’s chemistry, I am sure there is another story out there about all the other NZ biological and clinical scientists that were involved too.


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