Periodic Reporting for period 3 - 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: 2020-01-01 to 2020-12-31 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 deliveryMore than 10 million people worldwide suffer from Parkinson’s disease (PD). In PD dopamine neurons gradually deteriorate, which typically causes movement related symptoms like tremor and slowness. As the disease progresses also non-motor symptoms like anxiety and dementia are common. The symptoms appear gradually, and slowly get worse. As yet there is no cure for PD, standard therapies aim at alleviation of symptoms. 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 dopamine neurons in the brain. The clinical development of CDNF builds on this extensive nonclinical research, as well as an excellent safety profile based on the toxicology studies. The two objectives of the TreatER project were: 1) Proof-of-concept of CDNF protein therapy for disease modification in PD. The treatment with CDNF aims at slowing or even stopping the progression of PD 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 was to conduct two clinical studies to evaluate the safety and efficacy of intracerebrally administered CDNF protein therapy in patients with PD, using a neurosurgically implanted Drug Delivery System (DDS):• A first-in-human study in which 1/3 of the patients received monthly infusions of placebo and 2/3 of the patients received monthly infusions of CDNF for a period of 6 months. • An extension study for the patients who participated in the first study. In this study all patients received monthly infusions of CDNF for a period of 6 months.The project included also research on target engagement and biomarkers to study the role of CDNF in alleviating endoplasmic reticulum (ER) stress in PD. TreatER project brought together both public and private sector partners from 5 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 patient organization: European Parkinson’s Disease Association EPDA• 2 pharma companies: H. Lundbeck A/S, Orion Corporation• Engineering company: Renishaw plc/ Renishaw Neuro Solutions (RNS)• SME drug development company: Herantis Pharma PlcTreatER project was executed during 2017-2020. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far TreatER clinical studies:• Primary study: 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: 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.Patient recruitment for the Primary study was completed in Q2/2019 and the 17 study patients were surgically implanted with the DDS to enable the intracerebral administration of CDNF or placebo. The Primary study treatments were completed in Dec 2019. The patient visits in the Extension study were completed in Jul 2020. Herantis Pharma announced the topline results of Primary study in Feb 2020. It confirmed positive safety and tolerability of CDNF in advanced-stage PD patients, with encouraging biological responses as measured by PET imaging in some patients after a 6-month treatment. The topline results from the Extension study, in which all patients received CDNF for an additional 6 months, were communicated in Aug 2020. The primary endpoint of safety and tolerability was achieved also in this study. In addition, improvements were observed in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score as well as an indication of a biological response compared to the baseline, which may be clinically relevant. The results also indicated predictable and accurate placement of the DDS as well as its positive performance throughout the study treatments, as announced by Renishaw.The research on target engagement and biomarkers related to CDNF has also been completed. The results of CDNF, MANF and α-synuclein levels as well as ER stress markers in brain samples will be presented in a scientific article titled “Human-specific levels of CDNF, MANF and ER stress in the pathological progression of Parkinson’s disease”, the submission of the manuscript in spring 2021. The business development actions of CDNF have progressed through continued discussions between Herantis and potential partners for the drug development beyond TreatER project. For RNS, the performance of DDS in TreatER clinical studies has demonstrated its possibilities in the treatments of many neurological conditions.Information on the project is available on the TreatER website, https://treater.eu. 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) CDNF for the treatment of PD, has successfully achieved its primary endpoint of safety and tolerability in the TreatER 12-month Phase I-II study. The adverse events were generally mild and transient, and reduced compared to the first study period. Similarly, serious adverse events were also less frequent during the second study period, and all patients who previously experienced SAEs have since recovered.The study also gathered preliminary data to support an assessment of the product’s potential efficacy. This included measuring the severity of motor symptoms using the UPDRS. Although patient responses varied, at the 12-month the data suggests an overall improvement. This may suggest a potential slowing of disease progression in some patients.An additional exploratory assessment evaluated biological signals in the brain, as measured by Dopamine Transporter Positron Emission Tomography imaging which provides an indirect measure of dopaminergic function in the brain. Responses again varied, but a promising biological signal was seen in some patients where significant increases in DAT PET signaling was observed in the target infusion area of CDNF.Based on the encouraging results from TreatER project, the research and drug development of CDNF is continuing strongly both on academic and business fronts, the goal remaining in developing a disease-modifying treatment for PD and other neurodegenerative conditions. As to the drug delivery system, the data gained from the TreatER programme advanced the understanding of direct drug delivery into the brain. Further data required for market approval of the device is currently being generated by RNS.The TreatER consortium is deeply thankful to the skillful personnel in three hospitals who made it possible to carry out the demanding study as well as to the study patients, whose regular participation in numerous study visits was the key to successful completion of the studies – especially during the COVID-19 period, which made the execution challenging from time to time. TreatER web site
