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Safety, efficacy, and exposure-response of NNZ-2591, a synthetic analog of an IGF-1 metabolite, for Phelan-McDermid syndrome in children and adolescents

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
Phelan-McDermid syndrome (PMS), a rare genetic condition associated with delayed neurodevelopment, currently has no approved treatments. The treatment effects and pharmacokinetics (PK) of NNZ-2591, a synthetic analog of cyclic glycine-proline (cGP), a metabolite of IGF-1, were evaluated in a phase 2, multisite, open-label clinical trial of children and adolescents with PMS.

 

Methods:
Participants aged 4–13 years with PMS (n = 18) received oral NNZ-2591 twice daily for 13 weeks (dose titrated from 4 mg/kg to 12 mg/kg over 6 weeks). Safety and tolerability, efficacy measures evaluating clinically important symptoms of PMS, PK, and exposure‑response relationships were assessed.

Results:
Participants receiving NNZ-2591 experienced statistically significant improvement from baseline for 10 of 14 efficacy outcomes, including both clinician- and caregiver-assessed outcomes (Wilcoxon signed rank test P < .05). NNZ-2591 was well tolerated with a good safety profile. Most AEs were mild or moderate; there was 1 serious AE (gastroenteritis unrelated to the study drug, which occurred during the post-treatment safety follow-up period). Linear PK was observed over the titrated dose range. A one-compartment linear population PK model was developed. Apparent clearance of 1.89 L/h, apparent volume of distribution of 20.2 L, half-life of 7.4 h, and 24-hour steady-state area under the curve (AUC24) of 381 μg·h/mL were estimated for a child with PMS who weighs 30 kg. All 15 participants who received 13 weeks of treatment with NNZ-2591 had an AUC24 > 300 μg·h/mL and showed symptomatic improvement on the PMS-anchored Clinical Global Impression-Improvement scale. Exposure projections indicate > 80% of children are expected to achieve the target minimum exposure of 300 μg·h/mL at a dose of 12 or 13 mg/kg twice daily for children weighing > 20 or ≤ 20 kg, respectively.

Conclusion:
NNZ-2591 appeared safe and well tolerated in children and adolescents with PMS. Both clinicians and caregivers observed improvements in clinically important aspects of PMS, including communication, behavior, cognition/learning, and socialization. The efficacy of NNZ-2591 is supported by exposure-response modeling that shows the target minimum exposure can be achieved with the evaluated dosage.

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