A visit to the Brimble Lab to see where Trofinetide (NNZ-2566) was discovered
Distinguished Professor Margaret Brimble of the University of Auckland has given two lectures at the Rett NZ Conferences.
In May 2016 Professor Brimble invited our Rett NZ Trust Chairman Dugald MacBrayne and Rett NZ Coordinator Gillian Deane to visit her laboratory to see how the drug NNZ-2566 or Trofinetide was discovered and to meet the staff members who helped with its discovery. There are no current approved medicines for the treatment of Rett Syndrome.
In visiting the lab, Dugald being an engineer, understood the complexities of the laboratory equipment and the need for very careful measurement of the results. We were both greatly impressed with the devotion and intelligence of the group of scientists we met. They were an exciting and heart-warming team.
Trofinetide is currently being trialled with a view to commercialization by an Auckland registered and Australian listed company, Neuren Pharmaceuticals, which in November 2014 announced that the Phase 2 trial under FDA auspices in the US was successful in demonstrating clinical benefits for patients with Rett Syndrome. The trials were also designed to test the safety of the drug.
The benefit observed in the trial encompassed many of the core symptoms of Rett Syndrome and was observed in both clinician and caregiver assessments.
In February 2015 the FDA granted Orphan Drug designation to the drug for Rett Syndrome, having earlier granted this status also for Fragile X, a form of autism. The drug also has FDA Fast Track status in the US and Orphan Drug designation in Europe.
Neuren is now testing Trofinetide in higher dosages and in younger patients under a Paediatric Phase 2 trial and working towards commercial manufacturing scale-up.
The origin of this exciting drug was in the Brimble Group laboratory at the University of Auckland. The group is led by Distinguished Professor Margaret Brimble CNZM, FRSNZ, FRSC, FRACI, FNZIC. Margaret has an impressive array of awards and honours including the international L’Oréal Women in Science Award and three of NZ’s most prestigious science awards, the Rutherford, McDiarmid and Hector Medals. It was great to be able to see these on her desk!
The Brimble Group’s work concentrates on organic and medicinal chemistry and peptide chemistry. To quote from their web site:
Natural products have long been regarded as ‘nature’s medicine chest’ providing a rich source of lead compounds as invaluable platforms for developing front-line drugs. Our research focuses on making and modifying naturally occurring bioactive compounds that have been isolated from plants, animal tissue, microbes or marine and soil organisms, which are rare or hard to isolate in abundance. These compounds provide rich and diverse chemical structures that challenge the synthetic chemist to develop new flexible synthetic methodology for their construction.
The preparation of synthetic analogues of the natural compound may improve the biological activity and provide an understanding of the mechanism of action of the naturally occurring compound.
With specialist interests in asymmetric synthesis, heterocyclic chemistry and organocatalysis, the research group use their extensive expertise to synthesise complex bioactive natural products. The synthesis of complex glycopeptides, lipopeptides, labelled peptides, peptidomimetics and long peptides is readily undertaken within the research programme, often in collaboration with biotechnology companies and institutes.
The group have a proven track record in the field of peptide chemistry, with peptide-based drug candidates now in clinical trials. Trofinetide (NNZ-2566) is currently in Phase 2 clinical trials for traumatic brain injury, concussion, fragile X syndrome and Rett syndrome (see Neuren Pharmaceuticals). The group also involved in the synthesis of melanoma vaccines under cGMP which is currently in Phase 1 trial.
The research is facilitated by rigorous structure determination using nuclear magnetic resonance, mass spectrometry and X-ray crystallography. Our peptide laboratory is also equipped with several fully automated solid phase synthesisers, semi-preparative HPLC and LCMS.