Neuren Pharmaceuticals (NEU: $15.57) announced last week top-line Phase II results for NNZ-2591 in Angelman syndrome (AS). NNZ-2591 is a synthetic peptide that maintains the bioavailability of IGF-1 which promotes synaptic connections in the brain. It is the follow-on compound from trofinetide (DAYBUE) which has been approved and is being sold by Acadia Pharmaceuticals.
Trial design
The open-label Phase II study involved 16 children aged 3-17, investigating safety, tolerability, and the pharmacokinetic profile of NNZ-2591. Also examined as secondary endpoints were a basket of clinician- and caregiver-assessed measures, as well as non-AS-specific tests.
The study lasted 13 weeks, in addition to four weeks of screening and two weeks of follow-up evaluation. Sixteen subjects began the trial, with two discontinuing due to COVID and one was unable to complete the safety monitoring procedures. NNZ-2591 was administered as an oral liquid twice daily, escalating to 12mg/kg during the first six weeks.
Trial Results
Results showed statistically significant increases (from baseline) in impression of improvements from the clinician perspective with mean CGI-I scores of 3 (minimally improved), with improvements observed in 11 of the 13 subjects (p=0.001). Two of the subjects were considered to have shown 'much improvement'.
From a caregiver's perspective, the mean CIC score was 3.2 (with 4.0 being no change). Eight of the 12 subjects showed improvement. (p=0.027)
As seen in previous studies, there were no serious adverse effects related to NNZ-2591, nor were there any meaningful trends in all other safety parameters.
Of interest, in the 3-12 age group, all eight subjects showed improvement, particularly in motor abilities, communication, behaviour, and cognition. "The hypothesis as to why younger children do better could be because of CNS plasticity. Young brains can adapt more, and are more likely to improve," said Liza Squires, Chief Medical Officer of Neuren.
About Angelman syndrome
Angelman syndrome (AS) is a rare disorder affecting around one in 15,000 people. It's caused by a mutation in the maternal UBE3A gene, which impedes brain development. Patients with AS present in infancy with neurodevelopmental complications, including minimal speech, issues with their gastrointestinal tract and balance, and characteristic frequent laughter.
NNZ-2591 MoA
NNZ-2591 is a synthetic analogue of cyclic glycine proline, a naturally-occurring brain peptide that restores normal connectivity between neurons.
Discussion
Whilst the results in AS were not as strong as seen in the two previous studies, this latest study reinforces NNZ-2591 as a platform drug candidate. In the last 12 months Neuren has also delivered positive results in Pitt Hopkins syndrome and Phelan-McDermid syndrome. (See table below)
Neuren is prioritising NNZ-2591 for the treatments of Pitt Hopkins and Phelan-McDermid syndromes, with stronger competition in Angelman syndrome (see Summit coverage below).
Neuren is capitalised at $2.0 billion. Its share price fell by 9% on the result, noting there is a current 2.6% short position in the stock.
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