NNZ-2591 is a synthetic analogue of cyclic glycine-proline, which occurs naturally in the brain and is related to IGF-1.
IGF-1 is produced by both of the major types of brain cells – neurons and glia - and is critical both for normal development and to maintain or restore the biological balance required for normal functioning. While the various neurodevelopmental disorders that Neuren is targeting with NNZ-2591 are caused by different genetic mutations, they all share the feature of impaired signalling between neurons, with abnormal length and density of the dendritic spines that connect the neurons via synapses. Hence, despite different genetic causes, these disorders share many common symptoms.
The aim of treatment with NNZ-2591 is to restore the natural balance of brain function by reducing inflammation, restoring the normal functioning of microglia, improving the dendritic structure of synapses and normalising the levels of IGF-1 in the brain.
NNZ-2591 is an oral drug, taken twice daily. As well as having high oral bioavailability, it has very good penetration of the blood-brain barrier.
Biochemical testing in a Phelan-McDermid mouse model has shown that the abnormal length of dendritic spines between brain cells, excess activated ERK protein (pERK) and the depressed level of IGF-1 in the knockout mice were all normalised after treatment with NNZ-2591.
In Phelan McDermid syndrome, as well as in multiple other disorders (Neuren suggests there could be up to 100 potentially treatable disorders), NNZ-2591 exerts diverse effects rather than exerting a specific effect on a specific target.
In contrast, PYC’s drug candidate for Phelan McDermid syndrome, PYC-002, specifically targets the insufficient functional SHANK3 expression that is the cause of Phelan McDermid syndrome, by increasing SHANK3 expression of the remaining healthy copy of the gene to compensate.
NNZ-2591 has now successfully completed Phase 2, demonstrating statistically significant effect on 10 efficacy endpoints that cover a broad range of symptoms of the disorder, following three months treatment with the drug. These are not “anecdotal” effects. These are effects measured by both independent, trained clinicians, as well as carers, using similar clinical endpoints to those proposed by PYC (see Slide 11 of PYC’s PMS presentation, June, 2023).
Neuren expects to meet with the FDA with their Phase 3 plan for NNZ-2591 in Phelan McDermid syndrome in Q2 next year. PYC-002 is still in preclinical and PYC still needs to decide which of two assets it has been developing it will proceed with. In the latest company presentation, it is estimated that Phase 1 might be completed in 3 years’ time. This suggests that PYC’s drug candidate is 4-5 years behind Neuren’s candidate.
Advantages of PYC-002 over NNZ-2591, as I see it, are that if the drug works as intended, it will likely demonstrate greater effect on symptoms of the disorder than NNZ-2591. Also, there may well be a preference by some for a procedural intervention a few times each year rather than a twice-daily oral medication. Finally, as a drug intended for a single orphan indication, it would be exempt from IRA price negotiation after orphan and patent exclusivity protections expire. I regard PYC-002 as an ideal out-licensing opportunity for PYC. I believe there will be multiple parties interested in this asset.
NNZ-2591’s relative advantage is in its incredibly broad potential application as well as its first-to-market standing in this indication, if approved.
I am a long-term shareholder in both Neuren and PYC and am keen on both assets and the prospects of both companies.
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