Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Abstract

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

IGF-1 and IGFBP-3 levels in CSF and serum pre- and post-MAD. The Mean and SE of IGF-1 and IGFBP-3 in serum and CSF are shown (P values based on Student's t test). CSF and serum samples were obtained before IGF-1 administration on day 1 and 1–2 h after dose on day 29 (n = 12). Levels of IGF-1 in serum and CSF more than doubled, indicating IGF-1 reaches the CNS compartment. IGFBP3, the main IGF-1-binding protein, did not significantly increase in serum or CSF.

Fig. 2.

(A) Serum IGF-1 concentrations show a log-linear terminal phase 4–6 h after dosing. Serum IGF-1 concentrations were analyzed by a noncompartmental analysis comparing escalating doses at days 1, 8, 15, and 29. A log-linear terminal phase was observed after 4–6 h postdosing. The slopes of decay allowed the estimation of t1/2,λ and MRTb are described in Table S1. (B) As shown, the mean and SE of the AUCt of IGF-1 suggests nonlinear kinetics. The AUCt up to the last observation lacked dose proportionality, suggesting a nonlinear kinetics. The lowest dose of 40 μg/kg BID dose elicited a mean AUCt = 2,050 ng⋅h/mL whereas the area for twice that dose (80 μg/kg BID) incremented just about 75%. When the lowest dose was tripled (120 μg/kg BID) at day 15, the increment was nearly the same. The Mean and SE of the AUCt in serum and CSF are shown.

Fig. 3.

Right-sided frontal alpha band EEG asymmetry shows a trend toward reversal. Greater relative L vs. R alpha activity has been interpreted as greater positive effect/less anxiety and greater R vs. L the opposite. Six subjects evaluated before the OLE demonstrated R > L asymmetry. Although the degree of asymmetry was variable after OLE, five of the six showed a decrease in the asymmetry index and in three there was a reversal. A paired-samples t test revealed significant group differences pre- and post-OLE.