Objective: To test if intermittent intraputamenal monthly infusions of CDNF have an effect on striatal dopamine transporter (DAT) binding, as measured by PET, in subjects with advanced idiopathic Parkinson’s disease (PD).

Background: CDNF is an unconventional neurotrophic factor shown to protect dopaminergic neurons and improve both motor and non-motor functions in rodent and primate models of PD via a unique multi-modal mechanism of action.

Method: A phase I-II clinical trial with 17 subjects with idiopathic PD of moderate severity enrolled in a placebo-controlled, double-blind six-month main study (the main study) followed by a six-month active treatment extension study. Patients randomized to placebo (n=6) or incremental CDNF dosage (n=6 for low-mid dose and n=5 for low-mid-high dose) groups received doses every four weeks via an intraputamenal drug delivery device (Renishaw). Primary endpoint was safety and tolerability. Secondary endpoints were clinical effects. PET imaging was performed at baseline, at 6 months (end of main study) and at 12 months (end of extension study) using DAT radioligand [¹⁸F]FE-PE2I. PET scans were performed using high-resolution research tomography. List mode data were acquired for 81 minutes and reconstructed into 35 frames as previously reported (Fazio, 2018). Parametric images of binding potential (BP_ND) were generated and coregistered to the structural MRI. Regions of interest (ROI) were caudate, putamen (the location of the catheter tips) and n. accumbens using FreeSurfer 6.0 and substantia nigra using an in-house template (Fazio, 2018).

Results: In the main study, the average BP_ND in the infused putamen decreased by ~6% from baseline to end of main study scan in the placebo group, as expected. Two subjects who had received CDNF showed a significant increase (37-51%) of BP_ND in the infused putamen. The analysis of the treatment extension study data is on-going and will be completed by August 2020. The analysis of the active treatment extension study data is on-going and will be completed by August 2020.

Conclusion: Preliminary analysis of the DAT PET data from the first 6-month placebo-controlled treatment period suggests that some CDNF-dosed subjects showed signs of biological response in the putamen, the target area of CDNF infusions.

References: Patrik Fazio, Per Svenningsson, Zsolt Cselényi, Christer Halldin, Lars Farde, Andrea Varrone. Nigrostriatal Dopamine Transporter Availability in Early Parkinson’s Disease. Mov. Disord. 33(4): 592-599, 2018.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phase-i-ii-first-in-human-clinical-study-of-intraputamenal-cdnf-in-parkinsons-disease-exploratory-pet-imaging-endpoints-of-the-12-month-treatment-period/