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Final Report Summary - NRT (Phase II clinical trial of PDGF-BB for the neurological regeneration and recovery in Parkinson´s disease)

Executive Summary:
The NRT project and Consortium was put together to develop a first in class treatment for Parkinson´s Disease (PD), a degenerative disease of the human brain and to provide supportive information for the clinical development up to drug registration, sales and marketing. The treatment involves the delivery of a naturally occurring protein (PDGF-BB) direct into fluid filled space in the brain, by means of a chronically implanted medical device consisting of a small pump placed under the skin of the abdomen and a catheter leading into the brain. Based on data obtained in animal models of PD, the drug has the potential to stimulate the regeneration and improve function of nerve fibres that have degenerated in people diagnosed with PD. A regenerative drug for PD would represent a significant breakthrough in the treatment of PD and have immense impact for people who suffer from the symptoms of PD and reduce societal costs for the treatment of the disease. The importance of patient information and education of patients about participation in a clinical trial with a novel advanced therapy was addressed specifically. Critical aspects relating to the ethical conduct of all project activities were ensured. Further studies related to the drug´s detailed mechanism of action were also performed.
To reach these project objectives, project participants consisted of a biopharmaceutical company (co-ordinating organisation), five hospitals with experience in treating people diagnosed with PD, a patient organisation, a team of researchers specialised in biological mechanisms involved in PD, a leading academic group in ethics and a communications firm.
The main objectives were broken down into separate deliverables. Most of the deliverables were finalised and reported with many important conclusions drawn, but the conduct of the clinical trial which was the core piece of the NRT project, suffered from delays in its initiation and finally had to be discontinued. The reason for this was initially a re-focus of the clinical study plan and patient population to be included in the trial, based on feedback from regulators, and later the project suffered from a significant setback related to the use of the medical device needed to deliver the drug into the brain. The significant delays, and ultimately, challenges related to the medical device for the development and commercialisation of the therapy led the biopharmaceutical company to discontinue the development of the therapy. In spite of this setback, the achievements relating to the drug’s mechanism of action, the importance of communication and information to patients and understanding the patients´ perspectives on clinical trial participation will support the development of similar advanced therapies. The project results have been and will be disseminated further.

Project Context and Objectives:
Clinical Trial Objectives (WP1)
The objective is to establish a safety, tolerability profile and preliminary efficacy for sNN0031/PDGF-BB at a dose of 6 µg/day administered for 14 days in two treatment cycles with a drug free interval of 10 weeks between cycles. Multiple methods to assess clinical effects on PD-related symptoms will be used, including brain imaging. A statistically different efficacy of PDGF-BB vs placebo-treatment for a medically important clinical end-point cannot be anticipated but the various assessments used will form an important basis for designing the single pivotal study. Medical experts (Clinical Advisory Board and Consortium Participants) have proposed and discussed a clinical trial design that would be acceptable to the five very experienced clinical trial sites engaged in the NRT consortium. A realistic patient recruitment plan is presented to ensure that the consortium can deliver a final clinical trial report within the timeframe of the project. Efficient management of the clinical sites by the internal Newron Sweden and Newron Pharmaceuticals (Bresso, Italy) staff as well as a contracted professional clinical research organisation (CRO) ensures efficient execution of the plan to meet the objective. Study information (type, design, key primary and secondary endpoints, inclusion and exclusion criteria and contact information) is provided at

Preclinical objectives (WP2)
The objectives under WP2 are led by an expert team at University of Lund, Sweden, and comprise a) to demonstrate if a shorter term treatment would have similarly beneficial effects in animal models of PD, supporting the possibility to shorten and simplify the method of drug delivery in the future clinical tests b) if biological responses in brain tissue and cerebrospinal fluid of rats can be translated into biomarkers to be used in the clinic c) if dyskinesia (unwanted involuntary uncontrollable movements) is positively or negatively affected by rhPDGFBB treatment, which may indicate whether certain patient sub-populations are good or less appropriate candidates for future treatment. These objectives will be met by testing the hypotheses in pre-clinical animal studies. We will compare the currently successful 14 day delivery with a shorter term delivery in pre-clinical study endpoints. We will also perform d) analyses of brain tissue and cerebrospinal fluids of PD model rats undergoing PDGF treatment to identify responsive cell types and differential expression of protein markers that can be used to further understand the mechanism of action and possibly to be used to detect a response in patients. The studies will be performed in a well-established research laboratory with all necessary pre-clinical animal models in place and with a vast experience from planning, executing and publishing pre-clinical research.
The real impact of the findings are when they have been translated into 1) testing a novel treatment paradigm (e.g shorter term treatment) 2) incorporating the aspect of L-dopa induced dyskinesia in a clinical trial or 3) using the identified biomarkers in a clinical setting.

Clinical development and commercialisation objectives (WP3)
The objectives are a) to establish a clear regulatory pathway/strategy and clinical development path and b) to establish a level of socio-economic impact of net clinical endpoints and c) to ensure a best product patent protection possible. Importantly, since there is no existing restorative therapy for PD, guidelines that describe what endpoints will ultimately support a product registration are also not at a fully mature state. This warrants an active reach-out towards agencies and regulators to ensure that the objectives are met.
• the work will be conducted with a focus on the regulatory framework developed by the European Medicines Agency (EMA) to ensure that the path chosen complies with regulatory guidelines. Newron, which has an SME status with the EMA, has internal staff staff/consultants that will plan and execute meetings with regulatory agencies to get as clear guidance as available during the timeframe of the NRT Consortium.
• the objectives are met when sufficient regulatory guidance have been received and verifiable/measured as minutes from meetings with regulatory agencies. As discussed above, Newron has met with the EMA (2012) and FDA (2013) and obtained sufficient regulatory advice to partially re-structure the clinical development plan.

• we are using Newron staff and consultant firms with expertise in analyses of how various European countries, in particular the U.K., Germany and Sweden, apply health economic parameters to establish a reimbursement level for this type of product, in this case a product which involves an active drug that can provide potentially long term symptomatic relief and a device as a delivery tool.

The objectives are met when a written report is available that provide a clear understanding of the cost to society and models for reimbursement in the above mentioned countries. Such a report will be available towards the end of the NRT Consortium.

• a successful commercialisation of the product will be highly dependent on the Intellectual Property position. The work under c) will focus on ensuring that any patentable results emanating from the work performed by the NRT consortium are captured and filed as patent applications. In parallel, but not funded by the NRT, Newron Sweden will prosecute its underlying pre-existing IP and together this will lead to a strong IP position for the product. Newron Sweden has internal staff with many years of international experience in IP licensing, patent portfolio development and management to ensure that this objective will be met.
The objectives will be met when sufficient background IP rights has been granted to Newron Sweden and when any foreground IP that can strengthen the commercial value of the rhPDGF treatment has been patented and licensed on an exclusive or non-exclusive basis to Newron Sweden. The timelines for such events lies outside the control of the Consortium and will depend on e.g., the European Patent Office but also on un-foreseeable novel patentable findings.

Ethics objectives (WP4)
This work package will ensure that a) the development of rhPDGF-BB therapy meets the highest ethical standards b) the patient perspective on invasive PD therapies is brought to the attention of the NRT Consortium during the project
The work under WP4 is led by staff from the Life Science Governance Institute in Vienna, Austria and is focussed on making sure that ethical concerns related to this type of early stage development project, in particular since the trial involves a surgical component and placebo patients, are taken into consideration and that governance of the project meets all ethics guidance standards. This will be ensured by establishing an ethics committee with full insight into the progression of the clinical trial and reviewed documentation will be distributed to local ethical committees, e.g. as regards patient information documents. An experienced and independent ethics committee will be established very early in the project, and the NRT consortium will ensure that this objective can be met.
To best establish how a typical PD patient, who starts to suffer from the shortcomings of current medical treatments, would perceive the proposed rhPDGF-BB therapy as well as other invasive therapies for PD, the methodology of using patient “focus groups” will be employed. The experts within the NRT consortium has substantial experience in ethics committee leadership and performing patient focus group work in multiple European countries and subsequent data analyses that will allow us to ensure a successful meeting of these objectives.

Dissemination objectives (WP5)
The objectives are to a) disseminate results from WP1, WP2 and WP4 to a broader audience by presentation of pre-clinical and clinical data at relevant meetings and in peer-reviewed scientific journals, and b) to reach out to patients and inform them about the existence of many different invasive therapies currently under clinical development, including but limited to rhPDGFBB therapy. These objectives will be effectively monitored by appointing the European PD Association (EPDA) to lead a work package that will oversee all dissemination activities. WP1, 2 and 4 will apply highest standard of scientific methodology and present the results via peer reviewed publications. WP3 will generate reports and descriptions for internal use. The use of focus groups and what has been coined “Parkinson’s Cafés” will effectively ensure that patient related information reaches the consortium and that the consortium provides a broad and objective perspective of novel invasive treatment opportunities to patients. Other dissemination activities (e.g. scientific publications) will be monitored and reported by Newron Sweden.
The objectives are met based upon dissemination activities 1) within the consortium and 2) outside the consortium. The establishment of a Website for both external and internal communication is one important deliverable that will be addressed within the first 6 month period from the initiation of the project. The WP will deliver reports regarding dissemination activities in front of each Consortium Meeting and as a final report. We have not set specific criteria for the number of publications or other external communication sessions yet.

Management objectives (WP6)
Coordination and management will be headed by Participant 1 (Newron Sweden). The main objectives and tasks of the management activities are described in WP6. In order to implement these objectives we have developed a management and organisational structure, and a set of procedures that will support the successful development of the project. The project’s main objectives are to demonstrate efficacy of a drug in a Phase II trial and to integrate various other perspectives. The implementation of the project thus concentrates on how best to achieve these objectives. The figure below illustrates that the NRT Consortium will have an internal and WP based Executive decision structure based on leadership within each WP. Importantly the WP1 will have the NRT Ethics Committee overseeing ethical aspects on a continuous basis. Strategic Committees are the Steering Committee and the Clinical Advisory Board. The Steering Committee composition ensures that all WP leaders and Participants are invited to take part in the decision making process within the NRT Consortium. Importantly, definitions of responsibility and further details of the decision-making structures and procedures, as well as agreements on ownership of knowledge (IP issues) will be defined in a Consortium Agreement that shall be signed by all participants prior to the start of the project.

Project Results:

Work Package 1: Clinical phase I/II study

The clinical study sNN0031-004 was a phase I/II study intended to evaluate the safety and tolerability (primary outcome parameters) and efficacy (secondary outcome parameters) of sNN0031 (PDGF) when administered by intracerebroventricular (directly into the brain) infusion in patients with Parkinson’s disease. The study would recruit 20 patients in 5 clinical sites located in Sweden (2 sites), UK (2) and Germany (1).
Start-up activities were completed up to the level of finalising the Clinical Trial Protocol and the submissions of applications for approval by Competent Authorities and Ethics Committees in each member state. Furthermore, full preparations were made for and at each site as regards contracts will CROs, hospital and pharmacy contracts and various vendors with a role in the forthcoming trial.
The Intention of the Clinical Study sNN0031-004
Patients would continue their normal treatment with L-dopa or a dopamine agonist. After enrolment patients would receive an implant of an Infusion System [consisting of a pump and an intracerebroventricular (i.c.v.) catheter during general anaesthesia. After a recovery period of at least 14 days without complications, infusion of study drug would be initiated and continue for 12 days. During this time period patients would have daily contact with the study site by phone for collection of adverse event information. The pump content would thereafter be switched to saline, and the patients will be followed for three months at which time a second infusion cycle would be administered. After the second cycle, the pump would be refilled with saline and the infusion system would be kept implanted for the remainder of the study.

The primary objective of the trial was to assess the safety and tolerability of i.c.v. administration of sNN0031 for two treatment cycles, separated by 3 months, of 70 μg each, at a constant daily dose, delivered via an implanted infusion system. The secondary objective was to explore the concentration profile of sNN0031 in the cerebrospinal fluid (CSF) and to assess the performance and tolerability of the infusion system. Several efficacy endpoints were introduced as an exploratory evaluation in a small sample size, aiming to guide the best choice for the primary efficacy variable in a larger pivotal efficacy trial. These include scales and measurements to collect the investigator’s assessment of motor function, the patient’s own assessment of their symptoms, Quality of Life, psychological and psychosocial assessments and potential PD biomarker evaluation.

In the Phase I/IIa sNN0031-001 trial we evaluated the binding of a PET-ligand (11C-PE2I) based on the positive DAT-data from pre-clinical studies. We would carefully asses if this technology and data supports the interpretation of the clinical data. PET studies can add important data but are also expensive and cumbersome to the patients. DaTSCAN was chosen to replace PET, for budgetary reasons, in a subset of patients. The data from the Phase I/II clinical trial described above indeed suggest that DaTSCAN investigations might add valuable information. We were planning to carefully assess this during a Clinical Advisory Board meeting.

Ratings of mood and cognitive function would have been performed at regular intervals. Vital signs, laboratory parameters and ECGs would have been followed. MRI would be performed at baseline and during the study for the assessment of possible structural changes in the brain. CSF samples would be collected in connection to the treatment period and thereafter every 3 months for assessment of PDGF-BB levels and the possible development of antibodies to PDGF-BB. CSF samples would also be used for exploratory studies aiming at identifying potential biomarkers for a drug-induced improvement of clinical rating scales. Study participation was planned to be 12 months for each patient. An independent Data Safety Monitoring Committee would review the combined safety data every 6 months after start of study and recommend whether to proceed according to protocol or implement and changes. Based on the results and after regulatory approvals, all placebo patients would be offered active drug or explantation of the drug delivery system.
At the time of the premature termination of the project, full approvals were obtained in Sweden only, and one patient was recruited at one site and the infusion system was implanted in January 2015.


On October 28, 2015, Newron Pharmaceuticals SpA took the decision to terminate the sNN0031 project, including all clinical trials, of which sNNN0031-004 was one. This action was based in part on the previously communicated quality system issues related to the device manufacturer identified by the US FDA, which prevents it from commercialising the catheter or engaging in new manufacturing of the catheter until the quality system issues are resolved. Additionally, the review of the protocol sNN0031-004 was on hold by the Health Authority in Germany pending submission of a separate Investigational Device Investigator’s Brochure. There were additional outstanding questions from the ECs in Germany and UK. Furthermore, the device manufacturer was not able to supply new catheters to replace the current ones which will expire early 2016 and, as outlined above, new developments were prohibited by the FDA. The above mentioned, led the company to conclude that the recruitment, implantation and treatment of patients in sNN0031-004 without seeing a continuation of the development program would be unethical.
Regulatory agencies, ethics committees, clinical study sites and patients were duly informed that there will be no further patient recruitment or administration of sNN0031 and Investigators were asked to initiate a discussion on options regarding post study management of the device, which may include explantation of the device. Full close out activities were initiated, contracts with third parties were terminated and a clinical safety update, in the format of a report was provided.

Work Package 2: Studying mechanism of action of PDGF-BB in animal models

Summary on work progress: The results obtained in this work package has been reported as short reports. The most interesting and significant data has been published or in preparation for publishing. Therefore, in the summaries below, only brief statements regarding the results are presented not to pre-maturely present detailed data publically and thereby reducing the chances for publications (meeting abstracts and full articles).
The mechanistic studies related to PDGF-BB induced effects in rodents (w. or w.o. lesions to the dopaminergic system) were examined by using novel methods incl. animal models: Several challenges were experienced in establishing robust lesion models, which caused some delays and limitations in the analysis and interpretation of the data. A new model (MPTP-induced lesions in mice) was established and published (Paul et al. Behavioral Brain Research, 2015 May 1).
Effects of a single bolus dose of PDGF-BB on the plasticity of dopaminergic substantia nigra neurons in a rat model of PD: The results showed that a single bolus dose had no effect or the same the same potential to reduce dopamine deficiencies in the rat 6-OHDA model of PD in comparison to a 14 day treatment cycle. The results were summarised in a short report.
Influence of PDGF-BB on L-dopa-induced dyskinesia in a rat model of PD: PDGF-BB was administered at the time of development of L-Dopa induced dyskinesia. In conclusion, PDGF-BB infusion for 2 weeks does not seem to influence L-dopa-induced dyskinesia in the animal model. The results are summarised in a short report.
PDGF-BB modulates pericyte and glia-related protein expressions in the striatum:
The gene expression analysis showed no significant differences between treatments, either on short term or long term. We therefore decided to examine the protein expression level instead, so as to verify possible changes between groups. Thus we analysed pericyte markers, including NG2, GFP, Platelet-derived growth factor β (PDGFRβ) and CD13, together with the dopaminergic neuron marker Tyrosine hydroxylase (TH). The expression of those pericytes markers was normalized to similar levels as the sham group after PDGF-BB treatment on lesioned animals, but only as a trend.
Mouse and human CSF samples:
Mouse CSF samples were collected and stored at -80°C. However, the small size of the animal rendered the CSF extraction procedure more difficult. Therefore the respective volume of extracted CSF per animal was relatively small and often contaminated with blood and analysis could not reliably be performed.
Initially it was planned to utilize human CSF from patients included in the clinical study sNN0031-004 within this trial (NRT). In preparation for the sNN0031-004 clinical study and to mitigate the risk that little clinical data would generated from the sNN0031-004 study by the end of the project period, we analysed the CSF from six patients in a previous trial (sNN031-003). Patients treated with PDGF-BB had their CSF sampled at baseline, directly after end of treatment and 3 month later. We chose to analyse the CSF to guide further analysis and to look for similar patterns when exposing pericytes to PDGF-BB in vitro.
Samples have been analyzed using mesoscale and show a pattern of modulation of inflammatory molecules and growth factors.
PDGF-BB induced growth factors release by pericytes in vitro:
Our findings indicate that PDGF-BB increases pro-inflammatory molecules and angiogenic molecules as well as NGF in the CSF of patients treated with PDGF-BB, and this effect might be mediated by pericytes.
PDGF-BB induces microvesicle release by pericytes in vitro. Our results showed that after PDGF-BB treatment, pericytes release a higher number of MVs compared to the other stimuli.
PDGF-BB is a promising growth factor for treatment for Parkinson’s disease. We showed that a single dose of PDGF-BB was not as effective as a 14 day treatment and that PDGBF-BB could not hinder the development of L-Dopa induced dyskinesia. Because PDGF-BB main receptor is present specifically on pericytes in the brain, we wished to examine whether pericytes contribute indirectly to the restorative effect observed in vivo in Parkinson’s disease rodent models, and also in patients.
In vivo, we showed that the expression a pericyte related protein, a marker for more activated pericytes, is increased in response to 6-OHDA-induced dopaminergic depletion in the striatum, which seems to be reversed upon PDGF-BB treatment. This indicates that, while pericytes become activated in response to the lesion, PDGF-BB would make the pericytes switch from an active to a more resting state.
CSF analysis of patients treated with PDGF-BB intracerebroventricularly in a previous trial indicates a release of pro-inflammatory factors and growth factors in response to PDGF-BB. Therefore, in vitro, we triggered human brain pericytes with PDGF-BB, in order to test further the potential contribution of pericytes in the restorative properties of PDGF-BB, Interestingly, we show that, upon PDGF-BB treatment, pericytes increase the secretion of (i) neurorestorative and neuroprotective growth factors, (ii) angiogenic factors and (ii) microvesicles.
Our data support the hypothesis that the restorative effect of PDGF-BB observed on the dopaminergic nigrostriatal system in vivo could be at least partially, mediated by pericytes.

Work Package 3: Clinical development and commercialisation of the treatment

Summary on work progress: The deliverables related to WP3 have been further developed during M37-48 and summarised in a report. Since the clinical study was not completed during the period, little proactive regulatory work has been performed. The regulatory work has focussed on obtaining regulatory approvals for the sNN0031-004 trial. The plans that were presented as part of the M19-M36 report are summarised below.

Regulatory Plan: Following the meeting with EMA which occurred in June 2012 a meeting with the FDA took place in July 2013. Critical questions for discussions with the FDA was prepared in the format of a pre-IND meeting which included questions related to the quality of drug, pre-clinical safety studies and the clinical development and regulatory pathway that the NRT project intends to pursue. The combined EMA and FDA feedback resulted in a changed clinical development and regulatory plan that was followed during the development of the clinical study protocol. In summary of the regulatory feedback, the revised patient target population can be defined as an orphan size population and the Sponsor of the clinical study (Newron Sweden) should seek medical and epidemiological evidence in support of defining such a population. A summary report is provided.

Sales & Licensing: The marketing of sNN0031 (PDGF-BB to treat PD patients) has continued to be considered by the business experts of Newron. A preliminary and relevant pricing structure was obtained by data from other orphan medications, such as apomorphine pumps and Duo-dopa, currently marketed in several countries and the latter is recently approved in the US. Deep brain stimulation represents another potential benchmark as regards pricing also because the cost of the surgical implantation will be similar (stereotactic neurosurgery). Ultimately, health economic data will have to be established for the effect of the drug. Also, during the course of the project a number of partnering options were considered: a. full license to a global partner that will cover all territories; b. full license to separate local partners; or c. sales and marketing by Newron with co-promotion rights in certain territories. Each option will require comprehensive assessment based on study results from a pivotal clinical study before a potential licensing deal will be executed. In principal, Newron plans to become an integrated biopharmaceutical company so option c was favoured.

The discontinuation of the clinical study has several consequences that impacts the future potential sales and marketing. However, should Newron be successful in its attempts to out-license the program to an external partner that is willing to invest in medical device and clinical development, such a partner may also assume the responsibility for the manufacturing and sales of both the drug and the device. The final commercialisation decisions will be taken after finalisation of the NRT-related work. The considerations regarding Sales and Marketing are summarised in a separate report.

Intellectual Property: The composition of matter patent has expired in 2012, Newron has built up a strong patent portfolio to protect the use of sNN0031 in CNS disorders and, more particularly, in Parkinson’s disease. Other valid and enforceable patents are in place to protect the delivery devices and the manufacturing process of the compound. Additional product exclusivity options are represented by the regulatory data protection and market exclusivity granted in all major countries upon approval and the potentially achievable exclusivity under orphan drug designation. It is expected that the overall effect of the above patent and regulatory exclusivity options will allow exclusive commercialization of the product beyond 2025. Currently, no new Intellectual Property has been generated under the NRT project but all potentially patentable claims developed during the course of the project will be evaluated. The IP related to the product is summarized in a separate report.

Work Package 4: Ethical guidelines

Summary on work progress: The appointed WP leader has worked with the NRT Ethics Committee and has conducted the six focus groups at the Klinikum Bremerhaven in Germany. The findings from the focus groups, that include both people diagnosed with PD and their spouses/relatives, have given important insights into the biosocial world of PD, that include getting the diagnosis, perspectives on participating in clinical trials in general and towards the sNN0031/PDGF-BB therapy in particular. The results have been reviewed by the Ethics Committee. The findings are summarised in a separate report.

Operate an ethical governance strategy for the project: The NRT internal Ethics Committee was established during the first reporting period and has since then been fully operable. The work has consisted of enabling and facilitating a continuous communication flow between the Ethics committee and the NRT project to enhance the overall self-reflexivity of the project and permit to address the ethical issues in a systematic way. The ethical monitoring throughout the project was in the form of electronic exchange, site visits, and meetings. The WP leader has also been in touch with the members of the ethics board and has known them personally from other academic and professional backgrounds. Finally senior staff representing the European Parkinson’s Disease Association (EPDA) joined the internal ethics board as originally proposed. It is also planned that the ethics board will attend any upcoming scientific meetings in the near future in order to discuss ethical issues in detail and to further contribute to the project’s overall self-reflexivity. Following the decision by Newron to discontinue the development of sNN00031 for PD, the leader of WP5 interacted with the Ethics Committee, Consortium Participants and clinical sites to oversee the ethical conductance of the study closure. The work conducted is described in a separate report.
Contribute to the ethical governance of the project by open transparent interaction with patient groups and publics: Being in continuous contact with the NRT project the internal Ethics Committee has been working on upcoming ethical issues. As such the committee has analysed and studied patient information forms and informed consent forms. For example the ethics board looked into the patient information sheet as provided by WP 1 leader and his team.
Conduct focus groups with patients in order to identify treatment preferences and ethical concerns: A detailed topic guide for the focus groups research has been developed on the basis of a systematic literature review and a secondary document research during [M1-18]. The clinical approval for the empirical study in Germany was submitted in autumn of 2013 and subsequently accepted.
The first focus groups with PD patients and their partners/carers were conducted at the Klinikum Bremerhaven in Germany with the Clinical Principal Investigator. With the great support from the Clinical Principal Investigator his team, with a trained clinical and health psychologist conducted six focus groups in 2014. There have been 54 focus group participants in total, consisting of 32 PD patients and 22 spouses and caregivers. All focus group interviews were tape-recorded and consecutively transcribed, which produced more than 300 pages of text. The findings are summarised in a report with the title “Public understandings of clinical research”.

Work Package 5: Public dissemination

Summary on work progress: WP5 has completed conductance of the three Parkinson-Café meetings was done in and the development of professional information material with regards to the NRT project was accomplished. A third and final article that will be submitted at the end date of the NRT project in [M48].
Arrange ‘Parkinson-Café’ meetings: Three ‘Parkinson-Café’ meetings have been arranged and the task is thereby completed. The first meeting was held on July 3 2013 in Oxford, UK and the remaining two were arranged in Lund, Sweden on November 15 2013 and in Germany on April 3 2014.
Summary articles from the Parkinson-Café meetings: The dissemination work has to date resulted in two articles and one report. The article is a summary of the NRT project presenting the project aims, progress, outcomes and future ambitions aimed at national Parkinson’s organisations, people with Parkinson’s, the general public and other stakeholders with and interest in Parkinson’s disease. The articles and report does provide a good summary of the NRT project and its ambition.
Development of professional information material about the NRT project: This task has been completed and was reported in the half time reporting period. The final article that has been submitted at the end date of the NRT project, disseminated via EPDA website and to all EPDA member organisations and prompted in Parkinson’s Life online magazine. The article has been sent to all consortium partners for dissemination and sharing.

Comment related to the Background and Foreground: The respective particpant´s background was initially described as part of the Consortium Agreement. Background, in terms of intellectual property (IP) was presented by Newron Sweden AB, relating to the drug to be used within NRT (PDGF-BB). The identification, dissemination and exploitation of foreground was the responsibility of all Participating organisations with an obligation to allow Newron Sweden to, if interested, exploit new potentially patentable findings. No patentable foreground was generated or communicated to Newron Sweden by the Participants. No foreground was generated by Newron Sweden during the course of the project.

Potential Impact:
The primary expected impact was to see the proposed regenerative therapy tested in the clinic and adopted in practice. The proposed NRT project would establish rhPDGF-BB treatment as a part of the therapeutic options for PD and the results will be published and presented to a wider clinical audience and the biopharmaceutical company would on its own and in partnerships with other commercial actors market and sell the therapy, available to clinics treating PD patients in Europe and worldwide. This would ultimately lead to better quality of life for people with complicating and disabling symptoms of Parkinson’s Disease. As a consequence of the pre-mature discontinuation of the clinical study, this will not become the case, unless a third party actor is willing to make the necessary investments to continue the work.
The impact of the findings from WP2, which have been and will be published, will contribute to the understanding of how PDGFB-B and potentially other related growth factors may act to counteract the nerve degeneration seen in PD and possibly other related diseases.
The impact of the results from WP3 regarding the regulatory path has generated a greater understanding how regulatory agencies considers an advanced therapy, i.e. that even if the therapy has potential groundbreaking disease modifying effects, the path to demonstrate that is challenging and should possibly be avoided until demonstrating a more standard relief of symptom effect. It also shows that advanced medical therapies must be developed on a case-by-case basis following close interactions the drug regulators.
The impact of the results from WP4 and 5, including successful reach-out and dissemination activities, clearly shows the importance of improving the understanding among patients what participation in a promising and exciting, but demanding and quite complex, clinical study means. It shows that biopharmaceutcial industry, the clinical centers and ethics groups can work together with patient organisations to continuously inform and interact with patients and their families and friends to leverage awareness of principles involved, opportunities and risks involved in drug development. The results also show the importance of a continuous discussion about the ethics in performing drug development for advanced therapies in patients who suffer from disabling symptoms from a degenerative brain disease.
Objectives and comments to originally presented plans for exploitation of results
Comment related to the exploitability of the results: The respective particpant´s background was initially described as part of the Consortium Agreement. Background, in terms of intellectual property (IP) was presented by Newron Sweden AB, relating to the drug to be used within NRT (PDGF-BB). The identification, dissemination and exploitation of foreground was the responsibility of all Participating organisations with an obligation to allow Newron Sweden to, if interested, exploit new potentially patentable findings. No patentable foreground was generated or communicated to Newron Sweden by the Participants. No foreground was generated by Newron Sweden during the course of the project.
Objectives were:
• To develop a strategy for commercialization of the treatment
• Comment: The pre-mature discontinuation of the clinical study makes the results generated by the NRT not applicable for exploitation. The pre-existing patents, know-how and clinical data previously generated by Newron Sweden AB can be exploited by third parties. Newron Sweden is seeking interested among potential buyers of the technology for further exploitation.

• To plan the future use and development of the results obtained during the project for the use for other diseases
• Comment: This is not applciable

• To maintain relevant IPR for the treatment
• Comment: The pre-existing patents will remain protected by Newron Sweden, possibly until patent expiry.

• To secure relevant IPR for any eventual new methodologies or products that may be developed as a consequence of and during the lifetime of the project, including patent searches and analysis of patentability of new formulas.
• Comment: Not applicable

• To make use of the experience and contacts with patient groups and other networks for dissemination.
• Comment: The results obtained have been made pubically available via artciels and posted on websites.

• To investigate and define the terms for new partnerships for continued development of the methods
• Comment: Not applicable

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