Community Research and Development Information Service - CORDIS

FP7

CARDIMMUN Report Summary

Project ID: 601728
Funded under: FP7-HEALTH
Country: Netherlands

Final Report Summary - CARDIMMUN (A new therapeutic antibody with a personalised medicine approach in cardiovascular disease)

Executive Summary:
The aim of the CARDIMMUN FP7 project was to pursue development of the scientific findings from the FP6 project CVDImmune. The scientific base is patented discoveries that low levels of anti-PC (antibodies to phosphorylcholine) indicate risk for future development of cardiovascular disease (CVD), as well as complications in patients who already have CVD. Athera, the lead SME in CARDIMMUN, has developed a candidate drug and a diagnostic test, CVDefine kit. The candidate drug, PC-mAb, is an innovative fully human monoclonal antibody that can block vascular inflammation. Together, the product concepts form a unique opportunity for a personalised medicine approach, with a companion diagnostic and a targeted intervention in an area that is still in great medical need, despite recent advances in therapy. CARDIMMUN was set up to take the candidate drug PC-mAb into clinical development, and thereby enable industrial partnering of PC-mAb to a larger pharmaceutical company, that is capable to take on later clinical development and market registration. Thus, the overall objective of CARDIMMUN was to take PC-mAb to a commercially viable stage, with the documentation needed to enter a clinical phase 2a (Proof-of-Concept) trial.

A First-in-Human Phase 1 study was successfully completed in 2015. The double-blinded study with 48 healthy volunteers, randomized to administration of PC-mAb or placebo, supported that the antibody was generally safe and well tolerated with no serious adverse events related to study drug administration, as well as having desired antibody properties for once-monthly administration.

The second Phase 1b study, included 12 patients receiving a single dose of PC-mAb or placebo. Conclusions from this study in severe PAD (peripheral artery disease) patients undergoing revascularisation were positive; showing good safety and tolerability, as well as antibody properties supporting once monthly dosing also in patients. The study data confirms that there are generally low levels of endogenous anti-PC in PAD patients, indicating a window for reconstitution therapy with PC-mAb. PAD patients also have markedly reduced limb arterial functionality. The results give a good base for succinct definitions of clinically relevant endpoints in the planned phase 2a study in this patient group.

The overall impact of the CARDIMMUN projects is:
- Data supports further clinical development of the drug candidate PC-mAb, reporting good safety profiles and desired antibody properties, from two studies in man and from a Phase 2a-enabling toxicology study
- This new therapeutic concept has been advanced into clinical development for a first indication with great medical need.
- The commercial viability of PC-mAb has been confirmed and work to secure a business partner for later clinical development has greatly progressed
- Support for additional indications outside severe PAD have been developed, as part of a broader development program with an industrial partner. The indications presented are both in CVD and outside, including CABG (coronary bypass graft), hemodialysis patients with chronic kidney disease, and heart failure
- New clinical and preclinical data supporting the broader therapeutic concept and the companion diagnostics opportunity has been reported and communicated, both to the scientific community and the industry, as well as in press releases to general public.

In conclusion, the business attractiveness and value of the PC-mAb candidate drug has been greatly increased during the CARDIMMUN project and the possibility to reach a business agreement and secure the plans to initiate a next Proof-of-Concept study in 2017 is promising. Additionally, further co-funding from current and new investors, as well as from further EU grants (H2020 etc.) is evaluated.

Project Context and Objectives:
The aim of the CARDIMMUN project is to pursue development of the scientific findings from the FP6 project CVDImmune. The scientific base is patented discoveries that low levels of anti-PC (antibodies to phosphorylcholine) indicate risk for future development of cardiovascular disease (CVD), as well as complications in patients who already have CVD.

Athera, the lead SME in CARDIMMUN, has developed a candidate drug and a diagnostic test, CVDefine kit. The candidate drug is an innovative fully human monoclonal antibody, PC-mAb, that can block vascular inflammation. Together, the product concepts form a unique opportunity for a personalised medicine approach, with a companion diagnostic and a targeted intervention in an area that is still in great medical need, despite recent advances in therapy. Athera’s PC-mAb is initially targeting the market of reducing secondary cardiovascular events, focusing on high-risk patients with low anti-PC levels. According to plan, the data will enable a business agreement with Athera and a partner (probably big pharma) to enter into larger scale clinical trials by early 2017. PC-mAb could then be launched on the market as a new drug, with clear block-buster potential.

CARDIMMUN was set up to take the candidate drug PC-mAb into clinical development, and thereby enable industrial partnering of PC-mAb to a larger pharmaceutical company capable to take on later clinical development and market registration. Thus, the overall objective of CARDIMMUN is to take PC-mAb to a commercially viable stage, with demonstrated proof of activity in patients and with the documentation needed to enter a clinical phase 2a (Proof-of-Concept) trial. To reach this overall objective, we performed activities to deliver support to:
• Demonstrate efficacy of PC-mAb in preclinical disease models in a way that allow translation from preclinical models to secondary prevention in CVD patients
• Demonstrate good safety profile of PC-mAb in preclinical toxicity studies
• Demonstrate good safety and acceptable pharmacokinetic profiles (supporting once monthly dosing) of PC-mAb in phase 1 clinical studies in healthy volunteers and target patients
• Form a basis for generation of proof of activity data in patients, in a selected target patient group.

For the work towards Proof-of-Concept Phase 2a studies with PC-mAb, a niche indication with great medical need was selected during the early project work, as the first indication for this new therapeutic concept (First in Class). It was confirmed that PC-mAb could provide an opportunity to address the need for improved secondary prevention after revascularization in severe PAD patients and reduce the associated risks for complications and new vascular disease events. PAD is a chronic disease that severely restricts the mobility of the patients and therefore their quality of life. It affects about 5% in ages 45-50 and 19% in ages 85-90. With severe PAD the disease is causing extensive pain also at rest, leading to further morbidity. The risk for severe events like heart attack and stroke is high, as well as the risk for amputation of the affected limbs. The work during CARDIMMUN has fully focused on developing documentation and data to support the planning of a Proof-of-Concept Phase 2a study in PAD patients, as the selected first niche indication. However addition of other indications for broader market expansion with a partner has been evaluated, to maximize the future value of this new therapeutic concept.

Project Results:
The project has been progressed by bringing together SMEs and selected academic partners, and integrating preclinical and clinical studies into a commercially viable clinical stage drug candidate in a selected niche indication, but also exploring this novel therapeutic concept for broader market opportunities in additional indications. The partners of the consortium included:

Athera Biotechnologies AB, Sweden (SME)
Athera was founded to exploit breakthrough innovations in cardiovascular disease made at Karolinska Institutet. PC-mAb is a fully human antibody and the lead project for the company. Athera owns the IPR covering the therapeutic candidate PC-mAb. Athera is the leading SME in CARDIMMUN and was a major partner in the FP6 project CVDImmune. Athera has formed a virtual pharmaceutical development company with experienced people covering the critical competences needed for the early development of PC-mAb.

CTC Clinical Trial Consultants AB, Sweden (SME)
CTC is a CRO conducting early clinical trials, and has shared operational responsibility for the clinical trials within CARDIMMUN. The focus is on the clinical conduct of hospital-based early phase trials (0/I/IIa) through their own GCP certified center (including logistics, recruitment and study conduct with dedicated doctors and research nurses including qualified competence in intensive care which is required in safety studies). The clinic is inspected and approved by Swedish MPA for First in Human studies.

Leiden University Medical (LUMC), The Netherlands
LUMC has developed and validated preclinical models for cardiovascular inflammation and was a strong contributing partner in the EU FP6 project CVDImmune. The main objective of LUMC in CARDIMMUN is to deliver information on the efficacy of PC-mAb in preclinical disease models of translational value. Demonstration of efficacy of PC-mAb in a vein bypass grafting model is an important task that will add strength to the use of PC-mAb to prevent graft failure in patients with severe peripheral arterial disease (PAD). LUMC will also carry out studies to investigate effects of PC-mAb on functional and biochemical markers of systemic and vascular inflammation in preclinical disease models.

Smerud Medical Research AS, Norway (SME)
Smerud is a CRO primarily focused on clinical project management and monitoring of phase I/II – III studies and regulatory affairs. Since 1993, Smerud has been involved in more than 800 clinical trials and over 400 regulatory projects. Smerud has over the last 5 years invested heavily in self-funded clinical research, and has vast experience from participating in and leading various EU funded clinical development programs, partly in FP7 but mainly through the EUROSTARS program. Smerud is responsible for regulatory management of the clinical studies included in CARDIMMUN, and shared operational responsibility for the clinical trials in CARDIMMUN.

Turku University PET Centre
Turku University PET Centre has developed clinical imaging using PET technology that improves the usefulness of these technologies for cardiovascular studies. Their technology uniquely enables measurements of glucose uptake by FDG-PET in coronary arteries and coronary flow reserve (CFR) both in patients and in mice. This means that the technologies to be used in the clinical development can be validated in preclinical studies. A major objective in CARDIMMUN is to validate the intended clinical development of PC-mAb and the strategy is to perform preclinical experiments in disease models that resemble the patients that are to be treated with PC-mAb, and to use technologies in these studies that are similar to what we intend to use in future clinical studies.

The project has generated data evidencing therapeutic activity of PC-mAb in relevant in vivo models, through concept testing in preclinical in vivo models using biomarkers applicable also in human disease. This include left ventricular dimensions after MI, coronary flow reserve and glucose uptake in inflamed arteries. These results provide solid support for a potential therapeutic activity also in humans. Additional long term preclinical in vivo studies aimed at investigating the effect of PC-mAb on atherosclerotic plaque development and restenosis following vein graft in mice have been initiated. Bioassay for analysis of PC-mAb and anti-drug antibodies in animal and human sera, respectively, have been developed. The clinical trial material for the planned human studies has been developed and produced under cGMP regulated manufacturing. Following performance of the regulatory required toxicity studies in two species without any unwanted findings, initial two clinical studies in man (both with healthy volunteers and cardiovascular patients) that explores safety, pharmacokinetics, and pharmacodynamics of PC-mAb have been performed.

A First-in-Human study was successfully completed in 2015. The double-blinded Phase 1a study with 48 healthy volunteers, randomized to administration of PC-mAb or placebo, supported that the antibody was generally safe and well tolerated with no serious adverse events related to study drug administration, as well as having desired antibody properties for once-monthly administration. Conclusions from the second clinical Phase 1b study in severe PAD patients undergoing revascularisation were positive, showing good safety and tolerability, as well as antibody properties supporting once monthly dosing also in patients. The study, completed in 2016, was performed at Karolinska University Hospital in Stockholm, and included 12 patients receiving a single dose of PC-mAb or placebo. The study data also confirms that there are generally low levels of endogenous anti-PC in PAD patients, indicating a window for reconstitution therapy with PC-mAb. PAD patients have markedly reduced limb arterial dynamic functionality, measured by magnetic resonance imaging (MRI) methods; an important observation for future clinical study designs. These results give a good base for succinct definitions of clinically relevant endpoints in the planned Phase 2a study in this patient group, selected as the target for generation of Proof-of-Concept data in man for this new therapeutic concept.

Furthermore, during the CARDIMMUN project support for additional indications outside severe PAD have been developed. We have proposed additional indications, as part of a broader development program once the candidate drug has been partnered. The indications presented are both in CVD and outside, including:
- Patients undergoing revascularisation for MI, i.e. CABG (coronary bypass graft)
- Hemodialysis patients with CKD (chronic kidney disease)
- Heart Failure

These indications have been explored and discussed with potential partners, as opportunities for broader market expansion.

Potential Impact:
The overall impact of the CARDIMMUN projects is:
- Data supports further clinical development of the drug candidate PC-mAb, reporting good safety profiles and desired antibody properties, from two studies in man and from a Phase 2a-enabling toxicology study
- This new therapeutic concept has been advanced into clinical development for a first indication with great medical need. PAD is a chronic disease that severely restricts the mobility of the patients and therefore their quality of life and causes further morbidity. The risk for severe events like heart attack and stroke is high, as well as the risk for amputation of the affected limbs
- The commercial viability of PC-mAb has been confirmed and work to secure a business partner has greatly progressed
- Support for additional indications outside severe PAD have been developed, as part of a broader development program with an industrial partner. The indications presented are both in CVD and outside, including CABG (coronary bypass graft), hemodialysis patients with chronic kidney disease, and heart failure
- New clinical and preclinical data supporting the new therapeutic concept and the companion diagnostics opportunity has been reported and communicated, both to the scientific community and the industry, as well as in press releases to general public

Overall, there has been a large number of dissemination activities during CARDIMMUN, with 23 reported activities including oral presentations and posters at scientific meetings, press releases and interviews with press, as well as participation at industry business conferences and exhibitions. Internet based activities has also been done at websites, as well as via LinkedIn and industry communication channels. One scientific peer-reviewed publication is reported, however a number of manuscripts are still under preparation for submission to peer-reviewed scientific media. Three new patent applications have been filed by Athera.

Work in the consortium has been very active from all partners and focused on delivering the objectives of the CARDIMMUN project, with extensive communication and generous sharing of ideas and experience. Further work between partners is actively planned at the end of the project, including new EU grant applications (e.g. H2020).

In conclusion, the business attractiveness and value of the PC-mAb candidate drug has been greatly increased during the CARDIMMUN project and the possibility to reach a business agreement and secure the plans to initiate a next Proof-of-Concept study in 2017 is promising. Additionally, further co-funding from current and new investors, as well as from further EU grants (H2020 etc.) is evaluated.

List of Websites:
www.cardimmun.se
Athera Biotechnologies AB
S:t Eriksgatan 117, 113 43 Stockholm, Sweden
c.schmidt@athera.se

Contact

Jaco De Graaf, (Financial adminstrator)
Tel.: +31715265150
E-mail

Subjects

Life Sciences
Record Number: 192504 / Last updated on: 2016-12-13
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