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Impressive Results from Neuren's NNZ-2591 Phase II Clinical Trial in Phelan- McDermid Syndrome

Last month, Neuren Pharmaceuticals (NEU; $24.65) announced impressive top-line data from its Phase II trial of NNZ-2591 conducted in 18 patients with Phelan-McDermid Syndrome (PMS).

neuren p2 topline results

Last month, Neuren Pharmaceuticals (NEU; $24.65) announced impressive top-line data from its Phase II trial of NNZ-2591 conducted in 18 patients with Phelan-McDermid Syndrome (PMS).

The result marks the potential for a first-ever FDA-approved treatment for this cumbersome neurodevelopmental condition. CEO Jon Pilcher announced that the Phase II trial results have exceeded expectations. This is despite entering the clinical trials with high confidence given positive and consistent pre-clinical results.

This development carries great significance for the PMS community. As highlighted in the 'Voice of the Patient' report published by the research advocacy organisation CureSHANK, PMS has an "overwhelming unmet medical need" with its "severely debilitating manifestations."

Neuren is leading the race in this area to secure a safe and effective treatment for this disorder, with only two other companies believed to have products in clinical development, both in Phase I.

PMS is a congenital neurodevelopmental disorder resulting from the deletion of or variation in the SHANK3 gene located on chromosome 22, impacting the formation, maintenance and function of dendrites and synapses. PMS exerts a broad and severe impact on life including intellectual and behavioural impairment, language deficits, and motor delays. PMS patients are at high risk for frequent hospitalisations and accidents.


Clinical Trial Design

Neuren's Phase II PMS trial was open-label, conducted across four different sites in the US over a 13-week treatment period in children 4-13 years of age. Subjects received NNZ-2591, twice daily. Of the 18 participants who were initially enrolled and dosed in the trial, 15 children completed the study. Despite withdrawals from the trial, safety and efficacy data for all 18 patients was recorded and analysed.

Reasons for the three discontinuations of the trial were assessed as unrelated to the drug NNZ-2591 (two participants contracted COVID-19, and one experienced seizures associated with their existing epilepsy). The primary endpoints of the trial were safety, tolerability, and pharmacokinetics. The 14 secondary endpoints assessed a number of categories, including quality of life, behaviour, sleep, and symptom-specific endpoints.


Phase II Trial - Safety Data

NNZ-2591 exhibited a very favourable safety profile. It is considered by Neuren as a low-risk drug. The majority of Treatment Emergent Adverse Events (TEAEs) were mild to moderate with one severe case (gastroenteritis) in the follow-up period deemed unrelated to the study drug. There were no clinically significant changes in laboratory values such as ECG or other safety parameters.


Phase II Trial - Efficacy Data

The trial, being the first of its kind, had no pre-determined efficacy endpoints, seeking to find the most appropriate endpoints to be used in a registration study. Impressively there was a statistically significant improvement (p<0.05) in 10 of the 14 efficacy measures assessed across clinically important aspects of PMS. It should be noted there was no placebo group, with the outcomes compared to the baseline levels of the study subjects. The results for CGI-I and CIC were highly statistically significant. (See table)

On the CGI-I (Clinician Global Impression of Improvement) measure, a result of 1.0 represents very much improved, 2.0 represents much improvement, 3.0 correlates with minimal improvement and 4.0 with no change. The only difference for CIC (Caregiver Overall Impression of Change) is that 3.0 is categorized as an improvement rather than minimal improvement.

All 7 domains assessed under CGI-I demonstrated improvement. Importantly, four areas ranked as a high concern by caregivers – being self-care, communication, behaviour, and social interaction – were areas that improved most throughout the trial. Additionally, quality of life and aberrant behaviour demonstrated significant improvement, along with sleep habits and GI health which are not considered central primary endpoints.


NNZ-2591 Phase II Results in Phelan-McDermid Syndrome

  CGI-I measure CIC measure
Assessed by Clinicians Caregivers
Mean score 2.4 2.7
Number of children (out of 18) showing improvement 16 15
P-value p<0.0001 p=0.0003


Some of the testimonials from clinicians included:

  • An improvement in ability to focus
  • "Significant improvement in using more complex phrases"
  • "Teachers noted improvement in new learning skills"
  • "Marked improvement in expressive language and moderate improvement in socialisation"
  • Improvement in gross motor skills


Comparison with Trofinetide in Rett Syndrome

Whilst PMS and Rett syndrome are different genetic neurodevelopmental diseases, it may be of interest to compare the results of NNZ-2591 in PMS with trofinetide in Rett syndrome, given both studies included the CGI-I assessment. It should be noted that the CGI-I measure was tailored for the PMS disorder in this study.

For CGI-I in PMS with NNZ-2591, the mean result was 2.4, which compares to 3.0 in a Phase II study with trofinetide in Rett syndrome (3.5 for placebo). In the Phase III study with trofinetide, the results was 3.5 versus 3.8 for placebo. All results were statistically significant.

In the Phase II study with trofinetide in Rett syndrome (82 participants), 22% of subjects registered a much improved result (compared to 4% for placebo); in the PMS study with NNZ-2591, 56% achieved a much improved (2.0) or very much improved (1.0) results (eight and two patients respectively).

As with trofinetide for the treatment of Rett syndrome, more extended treatment may even improve the results. The Phase III Rett syndrome study with trofinetide involved a 13 week treatment period.

On the safety profile, whilst diarrhea and vomiting was recorded in 82% and 29% of patients respectively in the Phase III Rett study with trofinetide, with NNZ-2591 the incidence was only 11% in both of these measures.


Opportunities in the PMS market

Neuren notes that there is a trend of increasing identification and diagnosis of PMS. The recent assignment of an ICD (International Classification of Diseases) code to PMS is expected to drive increased diagnosis and disease-tracking, as it provides globally-recognised criteria for diagnosis. This is in addition to a rising awareness of the condition and enhanced genetic technologies.

Additionally, Neuren estimates up to 208,000 potential PMS patients across select countries, with up to 73,000 patients in the US and Europe (calculated according to current prevalence rates of 1/8,000-1/15,000 and UN-published population data in 2022). Almost half (up to 95,000) of patients are estimated to reside in China.


Next Steps for NNZ-2591 in PMS

On a recent investor call, the company was asked about the next steps for NNZ-2591 for the PMS indication. Neuren needs to put together a data package for the FDA prior to its end of Phase II meeting with the regulator. Pilcher would like to see this therapy available for PMS patients as soon as possible.

One consideration is whether the company should conduct a Phase IIb study with a placebo arm before a registration study is conducted. However with the consistency of the results across multiple measures, the company could arguable progress directly to a registration study. This will likely be a major discussion point with the regulator.

Another question is whether the company will partner or conduct the registration study on its own. Pilcher said that each avenue is an option for the company. A registration study would likely be between 100 - 200 patients. The protocol is likely to be less onerous in the registration study, resulting in faster recruitment of patients.

With regards to drug pricing for PMS, this is far from being determined, but it is expected to be similar to DAYBUE for Rett syndrome.



In addition to PMS, Neuren is exploring other possibilities for NNZ-2591 for Prader-Willi, Pitt-Hopkins and Angelman syndromes. With investigations of NNZ-2591 in four indications, no trials for additional diseases are expected to commence in the near future, although Neuren possesses a patent for the use of NNZ-2591 in Autism Spectrum Disorder (ASD) which expires in 2034. Because ASD does not receive orphan designation or exclusivity, clinical trials may introduce additional challenges.

Neuren's partner also has rights to progress NNZ-2591 in the treatment of Rett and Fragile X syndromes. Results from the Phase II study in Pitt-Hopkins syndrome are expected in the next quarter with results from the Angelman syndrome study expected soon after.

Neuren is in a strong financial position with $230 million in cash at the end of September and an ongoing royalty stream from DAYBUE sales currently tracking at around $30 million a year.

What is particularly encouraging with NNZ-2591 is the consistency of results from the preclinical stage, through to this Phase II trial where the dosage selected from the preclinical data delivered very good efficacy outcomes. The consistency of results across most efficacy measures is also an excellent signal.


Neuren is capitalised at $3.2 billion.


Bioshares recommendation: Hold




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