Phase 2

Neuren is using a quite different mid-stage clinical development approach for NNZ-2591 than that used for trofinetide.

For mid-stage testing of trofinetide in Rett syndrome, two studies were completed, the first a 4 week study in 67 adults and the second a 6 week paediatric study with 82 participants. Both studies were randomized, placebo-controlled and double-blinded trials. Different doses were given to separate groups in the active arms, as optimal dosing was still to be figured out. Ultimately, between these two studies with a total of 149 participants, just 27 participants in the paediatric study received the 200mg/kg bid dose, over just 6 weeks, that demonstrated statistically significant effect and was subsequently used in the 12 week pivotal Phase 3 trial. It took 4 years from the start of the first Phase 2 study until results were announced from the second Phase 2 trial, and another 2.5 years passed before the pivotal Phase 3 Rett trial commenced.

In a departure from that approach, in its mid-stage testing of NNZ-2591, Neuren is recruiting just over half the total participants of the two Phase 2 trofinetide in Rett trials (this time, 80 participants all up) and spread them across 4 indications. The studies are all open label, all single arm and all participants will receive the same dose, which Neuren appears to have already optimized. Thus, 80 participants (20 in each indication) will be treated over 13 weeks at the dose intended for use in pivotal trials.

Neuren has said that, along with the primary endpoint to confirm safety and PK in paediatric patients, their choice of trial design this time is prioritising (i) speed to data and (ii) maximising the opportunity to demonstrate effects across multiple efficacy measures to inform selection of the primary endpoint for subsequent registration trial/s.
In order to maximise the opportunity to demonstrate treatment effects, the Phelan McDermid trial is using 14 exploratory efficacy outcome measures, Pitt Hopkins and Angelman each have 16 and Prader-Willi has 17, and there is a considerable degree of overlap. This compares with just 6 exploratory efficacy outcome measures used in the first Phase 2 trial of trofinetide in Rett.

Consequently, although each of the current Phase 2 studies is small, unblinded and has no placebo control, significantly more data will be generated on efficacy at maximum dose over a longer period than in the Phase 2 Rett trials. Data from 3 of the 4 current Phase 2 trials should be available within just 2 years of start of the first trial, while Prader-Willi might lag a bit behind. Furthermore, with Neuren concurrently completing the toxicology study and manufacturing requirements of a pivotal trial, any progression to Phase 3 will be possible within a much shorter time frame than happened with trofinetide.

Together, the larger number of efficacy measures, and the much larger number of patients being dosed at a higher dose over a longer period should provide a comprehensive assessment of the drug’s potential impact over a broad range of aspects such as cognition, verbal and non-verbal communication, social, emotional and adaptive behaviours, aberrant behaviours, sleep behaviours, motor skills and ambulation and GI-associated issues.

Finally, an added twist in the NNZ-2591 Phase 2 clinical program in four separate neurodevelopmental disorders is that Neuren now has three US granted patents which cover the use of NNZ-2591 in treating symptoms of autism, autism spectrum disorders and neurodevelopmental disorders (US20170020869, 20180140601, 20200163961).
These autism/neurodevelopmental disorder patents make claim for NNZ-2591 producing an improvement in one or more of a wide range of symptoms, including many of those being assessed in the current Phase 2 trials.

Not for the first time, I wonder whether the four Phase 2 NNZ-2591 trials have not also been designed with an eye to providing Proof of Concept for the use of NNZ-2591 in the treatment of autism.