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  • Periodic Reporting for period 1 - TreatER (Clinical study in Parkinson's disease with two unique goals: 1) Proof-of-concept of CDNF protein for disease modification; 2) Validation of clinically tested device for intracerebral drug delivery)
H2020

TreatER Report Summary

Project ID: 732386
Funded under: H2020-EU.3.1.3.

Periodic Reporting for period 1 - TreatER (Clinical study in Parkinson's disease with two unique goals: 1) Proof-of-concept of CDNF protein for disease modification; 2) Validation of clinically tested device for intracerebral drug delivery)

Reporting period: 2017-01-01 to 2018-06-30

Summary of the context and overall objectives of the project

TreatER - Clinical study in Parkinson’s disease with two unique goals:
1) Proof-of-concept of CDNF protein for disease modification;
2) Validation of clinically tested device for intracerebral drug delivery

Estimated 7 million people worldwide suffer from Parkinson’s disease (PD), which affects dopamine-producing nerve cells in the brain. In PD, those dopamine neurons gradually deteriorate and die, which typically causes movement related symptoms like tremor, rigidity of muscles and slowness. As the disease progresses also non-motor symptoms like anxiety, depression and dementia are common. The symptoms appear gradually, and slowly get worse. As yet there is no cure for Parkinson’s disease; standard therapies aim at alleviation of symptoms by a variety of medications.

CDNF (Cerebral Dopamine Neurotrophic Factor) was discovered in 2007 at the University of Helsinki. In nonclinical studies CDNF has protected and restored the function of degenerating and dying dopamine neurons in the brain. A consistent efficacy of CDNF has been shown in several PD models as improvements in both motor and non-motor functions. The clinical development of CDNF builds on this extensive nonclinical research, as well as an excellent safety profile based on acute and chronic toxicology studies.

The two independent objectives of the TreatER project are:
1) Proof-of-concept of CDNF protein therapy for disease modification in PD. The treatment with CDNF aims to slow or even stop the progression of Parkinson’s disease and provide symptomatic relief.
2) Clinical validation of DDS, an already clinically tested approach for accurately targeted intracerebral infusion in PD patients.

The main focus of TreatER project is to conduct two clinical studies to evaluate the safety and efficacy of intracerebrally administered CDNF protein therapy in patients with Parkinson’s disease, using a neurosurgically implanted Drug Delivery System (DDS):
• A first-in-human study in which one-third of the patients will receive monthly infusions of placebo and two-thirds of the patients will receive monthly infusions of CDNF for a period of 6 months. More information at https://treater.eu/clinical-study/ and https://clinicaltrials.gov/show/NCT03295786 .
• An extension study for the patients who have participated in the first-in-human study. In the extension study all patients will receive monthly infusions of CDNF of different concentrations for a period of 6 months (no placebo).

The TreatER project brings together both public and private sector partners from five European countries (FI, SE, UK, BE, DK):
• 3 universities: University of Helsinki (TreatER coordinator), University of Oxford, and Karolinska Institutet
• 3 hospitals: Karolinska University Hospital, Helsinki University Hospital, and Skåne University Hospital
• Parkinson’s umbrella organization: European Parkinson’s Disease Association EPDA
• 2 mid-sized pharmaceutical companies: H. Lundbeck A/S, Orion Corporation
• Engineering company: Renishaw plc
• SME drug development company: Herantis Pharma Plc

The TreatER project will be executed during 2017-2019.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the clinical development part of TreatER, the project has obtained regulatory and ethical approvals for the clinical study in both planned countries (Sweden and Finland) and initiated the two clinical studies described in the Grant Agreement:

• Primary study (WP1): A Phase I-II, Randomised, Double-Blind, Placebo Controlled, Safety and Tolerability Study of Intermittent Bilateral Intraputamenal Cerebral Dopamine Neurotrophic Factor (CDNF) Infusions Administered via an Investigational Drug Delivery System to Patients with
Idiopathic Parkinson’s Disease (PD) of Moderate Severity.
• Extension study (WP2): A Randomised, Double-Blind, Multi-centre, Active Treatment, Extension and Safety Study for Patients with Idiopathic Parkinson’s Disease (PD) Who Previously Completed the CDNF/DDS Main Study HP-CD-CL-2002.

The patient recruitment was launched at Karolinska University Hospital in the Primary study - the first clinical study where the patients are implanted the sophisticated Renishaw drug delivery system in a neurosurgical procedure. The first two patients with Parkinson's disease were monitored through the first CDNF infusions in the Primary study. Since there were no safety concerns, the independent Data Safety Monitoring Board for the study recommended continuing the clinical study as designed. Subsequently patient recruitment was opened in the other two sites, the University Hospitals of Helsinki and Skåne. By the end of the reporting period (6/2018) the first two patients have now completed the Primary study and have entered the Extension study. Several other patients have been recruited in the Primary study, the device successfully implanted, and CDNF or placebo infusions started at all three sites. The target remains to complete the patient recruitment by having all 18 patients consented by the end of 2018.

The research on target engagement and biomarkers related to CDNF has progressed as planned. Biobank samples have been obtained and CDNF, MANF, and alpha-synuclein levels and an ER stress marker in progressive stages of PD pathology and controls have been analysed in three brain regions including a control region. The research has now proceeded into a more detailed statistical analysis.

The TreatER web site, https://treater.eu/, has been launched disseminating information on the project and the clinical studies to the public. The web site also contains an explanatory video on CDNF and the drug delivery system.

The exploitation of CDNF has progressed through continued discussions with several potential partners for late stage drug development beyond the TreatER project (international pharmaceutical companies).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The TreatER project has already reached significant milestones with first-in-human dosing of CDNF in clinical use. If shown as efficacious as in disease models of Parkinson's disease, CDNF has the potential to introduce a new therapeutic strategy in Parkinson's disease addressing the two major unmet clinical needs: Disease modification, and improving non-motor symptoms in addition to motor symptoms. This would have significant impacts on two European companies (Herantis Pharma, Renishaw) with commercialisation of their novel, innovative medical products. In addition, it would bring major economic benefits in terms of controlling Parkinson's disease, a very expensive brain disease for Europe, in addition to alleviating the human suffering it causes in millions of patients.

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