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. 2024 Nov 2;15(1):47.
doi: 10.1186/s13229-024-00626-0.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile X syndrome

Jordan E Norris  1 , Elizabeth M Berry-Kravis  2 , Mark D Harnett  3 , Scott A Reines  3 , Melody A Reese  4 , Abigail H Outterson  2 , Claire Michalak  2 , Jeremiah Furman  2 , Mark E Gurney  3 , Lauren E Ethridge  5   6
Affiliations

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile X syndrome

Jordan E Norris et al. Mol Autism. .

Abstract

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. These EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding post-period 1 of the study, participants who received BPN14770 in period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770 measured at the end of period 1. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of a significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Keywords: Biomarker; EEG; Fragile X syndrome; Pharmacokinetics; Zatolmilast.

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Conflict of interest statement

J.E.N, E.M.B.-K., L.E.E., M.A.R., A.O., C.M. and J.F. declare no competing interests. M.D.H.and S.D.R. are paid consultants to Tetra Therapeutics. M.E.G. is an employee of TetraTherapeutics, which is a wholly owned subsidiary of Shionogi & Co., Ltd that has a financial interest in BPN14770.

Figures

Fig. 1
Fig. 1
A Channel map for all 32 electrodes of the 32-channel BioSemi Cap with the frontocentral channels denoted by boxes. B The ERP waveform (N = 22 BPN14470 and N = 23 placebo participants) for both stimuli in the habituation pair from Berry-Kravis et al. (2021). Stimuli are identified by dashed vertical lines where S1 is the first stimulus and S2 is the second stimulus
Fig. 2
Fig. 2
Post-Period 1 PK – N1 Correlation Plot for the First ERP Peak. A Correlation plot for post-period 1 PK values and N1 amplitude. All PK values at 0 are individuals who received placebo during period 1. The trend line reflects the relationship for the Zatolmilast group only. B Correlation plot for N1 amplitude values change from baseline and post-period 1 PK values. The trend line reflects the relationship for the Zatolmilast group only. Starting values were all negative, so negative values are not representative of participants having more negative N1 amplitudes on BPN14770 C Box plot with individual datapoints for the baseline N1 amplitude values between groups to show the spread of the N1 amplitude for individuals who went on placebo compared to those who went on BPN14770
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References

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