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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

Periodic Reporting for period 2 - 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: 2018-07-01 to 2019-12-31

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 project includes also scientific research on target engagement and biomarkers to study the role of CDNF in alleviating endoplasmic reticulum (ER) stress in Parkinson's disease.

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 2017-2020.
The clinical development part of TreatER consists of two studies:

• 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.

Both clinical studies have all regulatory and ethics committee approvals in Finland and Sweden. Patient recruitment for the primary study (WP1) was completed in Q2/2019 and the study patients were surgically implanted the Drug Delivery System to enable the intracerebral administration of CDNF or placebo. The treatments in Primary study (CDNF or placebo) were completed in December 2019 . The patient recruitment in Extension study has also been completed.

Herantis Pharma Plc announced the topline results of Phase 1-2 CDNF trial on 25 February 2020. It confirms positive safety and tolerability of CDNF in advanced-stage Parkinson’s disease patients, with encouraging biological responses as measured by PET imaging in some patients. Results from the second part of trial, in which all patients will receive CDNF for an additional six months, are expected in Q3 2020.

The research on target engagement and biomarkers related to CDNF has progressed as planned. The analyses for two out of the three objectives have been completed and the scientific manuscripts are under preparation.

The business development efforts of CDNF have progressed through continued discussions with several potential partners for later stage drug development beyond the TreatER project.

Information on the project is available on the TreatER web site, https://treater.eu.
The TreatER project has already reached significant milestones with first-in-human dosing of CDNF in clinical use, especially by completing the treatments in the Primary study in December 2019. 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.
TreatER web site