About Elimox

This is ELIMOX

ELIMOX, Biopharmaceutical therapy for treatment of Primary Hyperoxaluria, is a project funded by FP7-SME-2013 Research for the benefit of SMEs program. The project is co-ordinated by OxThera AB, Stockholm, Sweden.

The ELIMOX Consortium has three SME-partners; OxThera AB, Cobra Biologics Ltd and SymbioPharma AG; and nine RTD-partners; ErgoMed Clinical Research Ltd, Universitätsklinik Bonn, Hospices Civils de Lyon, University College London Hospitals, Galenica AB, KABS Laboratories Inc., MVZ Institut für Mikroökologie, TNO and Bio-Images Research Ltd. The project is a truly international project.

This research has received funding from the European Union´s Seventh Framework Programme managed by REA-Research Executive Agency http://ec.europa.eu/research/rea (FP7/2007-2013) under grant agreement no FP7-SME-2013.

About Primary Hyperoxaluria

Primary Hyperoxaluria (PH) is a rare autosomal recessive inborn error of glyoxylate metabolism, with a prevalence of 1-3 per million. The disease is characterised by severe hyperoxaluria, i.e. excessively high levels of oxalate in the urine of the patient and excessively high oxalate levels in the plasma of patients suffering from chronic renal failure. The disease is present at birth, and most patients develop kidney stones and nephrocalcinosis at very young ages, most often under the age of 10.
Progression of renal failure is followed by systemic deposition of CaOx and premature death. Overall, the risk of end-stage renal disease (ESRD) is 50% by age 15 and 80% by age 30. The median age at death is around 30. (Hoppe et al., 2009). There is currently no approved pharmaceutical therapy for this devastating disease. The only curative therapy, applicable for PH type I, is eventually a combined kidney and liver transplantation at end stage renal disease (Hoppe, 2009).

There are no existing anticipated business agreements which may impose limitations on the subsequent exploitation or information or inventions generated as a result of the project.

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» The partners in this project will be pioneers in this area of research and technological development.« Elisabeth Lindner, OxThera

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Project description

The use of naturally occurring bacteria from the human gut as pharmaceutical drugs has gained increased interest, as knowledge about the human microbiota and its role in health and disease has advanced considerably with new technology and computational techniques.
The primary aim of the ELIMOX project was to develop an innovative and unique bacterial pharmaceutical product for the treatment of a severe and debilitating inherited disease, Primary Hyperoxaluria (PH).

Our approach was to use the metabolic potential of a naturally occurring microbe, Oxalobacter formigenes to eliminate toxic compounds from the blood. The potential clinical applications for such a probiotic drug are many, including treatment of disorders where enteric elimination would be an alternative metabolic pathway as well as for malabsorptive disorders. The SME’s in this project were pioneers in this area of research and technological development.

To achieve this, the following was implemented:
1. The manufacture of an anaerobic bacterial product for administration in the gut.
2. The development of analytical tools to verify the quality, delivery and activity of the bacterial product.
3. The clinical development of the bacterial product to verify the clinical benefit.

Work Package 1 - Project Management

OxThera AB will coordinated the ELIMOX project. The coordinator is an important player in the hyperoxaluria community and has a close relationship with key opinion leaders and researchers in the field. OxThera has demonstrated success in early clinical studies using experimental drug formulations of O. formigenes.

Work Performed and Results achieved during the 1st Reporting Period
(01 October 2013 – 30 June 2014).

A considerable proportion of the WP1 objectives and deliverables were achieved. There were 3 tasks and 3 deliverables in WP1. The tasks were on track with the first two deliverables (D1.1 “Delivery of Signed Consortium Agreement” and D1.2 “Public Communication and Website”) having been achieved and submitted in a timely manner. The third deliverable (D1.3 “Establish and implement an effective reporting system”) also progressed well.

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 2nd REPORTING PERIOD (01 JULY 2014 – 30 SEPT 2015).

Good progress with work package 1. Deliverable D1.3 will be submitted at end of the 3rd reporting period (Sept 2016).

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 3rd REPORTING PERIOD (01 OCT 2015 – 30 SEPT 2016).

All of the WP1 objectives and deliverables have been achieved. The third deliverable (D1.3 “Establish and implement an effective reporting system”) was submitted at the end of the 3rd reporting period (Month 37).

Overall all objectives for WP1 in the ELIMOX project were achieved. An effective project management and communication system was set up between all partners and with the EU REA. There has been extensive communication between the ELIMOX beneficiaries particularly between the co-ordinator, OxThera AB, and all other participants.

WORK PACKAGE 2 - Development of Drug Product Intermediate and Drug Product

Cobra Biologics Ltd were responsible for manufacturing of the drug and will lead this Work Package. Most activities were outsourced: freeze-drying to partner #9, KABS Laboratories Inc., and the capsule filling, coating, analysis and stability studies to participant #8, Galenica AB.

Work Performed and Results achieved during the 1st Reporting Period
(01 October 2013 – 30 June 2014).

A considerable proportion of the WP2 objectives, deliverables and milestones were achieved. There were 2 tasks, 2 deliverables and 2 milestones in in WP2. The tasks were on track with the first deliverable (D2.1 “Development of a validated lyophilisation and encapsulation process finalized”) having been achieved and submitted. The second deliverable (D2.2 “Production of clinical drug product and stability studies”) also progressed well. Both milestones (MS1 “Validated Manufacturing Process” and MS2 “Release of Clinical Drug Product for the first clinical study”) were completed. 3 GMP clinical trial batches were produced within the first reporting period for use in the clinical studies. The outstanding activity in the 2nd reporting period for WP2 is continued stability testing of the Oxalobacter formigenes product.

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 2nd REPORTING PERIOD (01 JULY 2014 – 30 SEPT 2015).

The outstanding activity in the 2nd reporting period for WP2 was continued stability testing of the Oxalobacter formigenes product together with the packaging, labeling and distribution of clinical trial supplies. The second deliverable (D2.2 “Production of clinical drug product and stability studies”) was finalised in Month 25.

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 3rd REPORTING PERIOD (01 OCT 2015 – 30 SEPT 2016).

Not applicable here. All the WP2 objectives, deliverables and milestones were achieved during the first 25 months of the project.

WORK PACKAGE 3 - Development of analytical tools for development and drug delivery of Oxalobacter formigenes therapy

SymbioPharm GmbH led the identification and quantification of O. formigenes, analysis of changes in the gut microbiota as well as in vitro and in vivo drug release studies. The development work relating to identification and quantification of O. formigenes in complex gut samples, together with studies on changes of the gut microbiota was outsourced to participant #10, the MVZ Institut für Mikroökologie GmbH. In vitro drug release testing was outsourced to participant #11, TNO and the in vivo capsule disintegration characterisation was outsourced to participant #12, Bio-Images Research Ltd.

Work Performed and Results achieved during the 1st Reporting Period
(01 October 2013 – 30 June 2014).

A considerable proportion of the WP3 objectives, deliverables and milestones were achieved. There were 3 tasks, 3 deliverables and 2 milestones in in WP3. The tasks were on track. D3.1 “Finalisation of assay methods and evaluation of long term impact on gut flora” was not due until month 24. However, two sub-deliverables (notably “Validated assays for quantification of O. formigenes and for changes of gut flora” (i.e. MS3) were both completed by month 9. Deliverable D3.2 (Drug release characteristics in a simulated GI system) was delayed. This largely stemmed from some structural re-organisation with TNO and a subsequent delay in the contracts and technical plans. A contract was agreed and work was performed early Sept 2014. Results would be expected late September 2014 (Month 12). Deliverable D3.3 (Capsule targeting characteristics in healthy volunteers) was finalized and submitted on 24 June 2014. Bio-Images completed the study during May 2014 and finalised the clinical study report in June 2014. The results were extremely promising and confirmed that capsules with the same enteric-coating as the clinical OC5 drug product survived in the stomach and started to disintegrate in the small intestine. This completed study also related to MS4 “Capsule disintegration profile confirmed”.

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 2nd REPORTING PERIOD (01 JULY 2014 – 30 SEPT 2015).

Deliverable D3.1 “Finalisation of assay methods and evaluation of long term impact on gut flora” was finalised in month 26. Two sub-deliverables (notably “Validated assays for quantification of O. formigenes and for changes of gut flora” (i.e. MS3) were both completed by month 9. Deliverable D3.2 (Drug release characteristics in a simulated GI system) was finalised and uploaded in Month 15.

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 3rd REPORTING PERIOD (01 OCT 2015 – 30 SEPT 2016).

Not applicable here. All the WP3 objectives, deliverables and milestones were achieved by Month 26 of the project.

WORK PACKAGE 4 - Clinical studies of Oxalobacter formigenes

OxThera AB were also responsible also for clinical development of the product. All operational activities and analytical services in this Work Package were outsourced. The CRO was participant #4, Ergomed Clinical Research Ltd. The clinics that were contracted was participants #5 and #6, Universitätsklinikum Bonn and Hospices Civils de Lyon. The central laboratories were participants #7, UCLH NHS Foundation Trust and participant #10, the Institut für Mikroökologie.

Work Performed and Results achieved during the 1st Reporting Period
(01 October 2013 – 30 June 2014).

Many of the WP4 objectives, deliverables and milestones were achieved. There were 6 tasks, 6 deliverables and 10 milestones in WP4. The tasks were generally on track. 2 of the deliverables (D4.1 “Clinical assays for oxalate finalised” and D4.2 “Ethical Clearance for first study”) were completed and submitted in a timely manner. 2 deliverables (D4.3 “Short term tolerability and efficacy study complete” and D4.5 “Dialysis study complete”) are ongoing (with expected delays). The 2 remaining deliverables (D4.4 “Ethical Clearance for dialysis and extension studies” and D4.6 “Long term extension study complete”) relate largely to the extension study which will not commence until the second Reporting Period. 4 of the 10 milestones have been completed (MS5 “Ethical and regulatory approvals for the first Phase I/II study”, MS6 “First patient enrolled in the MRF Phase I/II study”, MS9 “Regulatory and Ethical Approvals for the dialysis study” and MS10 “First patient enrolled in the dialysis study”). 6 milestones relating to completion of the Phase I/II and dialysis studies and to the initiation and completion of the extension study remain to be achieved in the 2nd and 3rd Reporting Periods. MS8 “Study results for Phase I/II study” forms a “Go/No Go decision for the extension study.

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 2nd REPORTING PERIOD (01 JULY 2014 – 30 SEPT 2015).

Deliverables (D4.3 “Short term tolerability and efficacy study complete” was finalised during the 2nd reporting period. Deliverable D4.5 “Dialysis study complete”) was ongoing (with expected delays). The 2 remaining deliverables (D4.4 “Ethical Clearance for dialysis and extension studies” and D4.6 “Long term extension study complete”) relate largely to the extension study that will not commence until the third reporting period. Milestones MS7 “Last patient completed in the MRF Phase I/II study” and MS8 “Study results for the MRF Phase I/II study” were completed during the 2nd reporting period. 4 milestones relating to completion of the dialysis study and to the initiation and completion of the extension study (MS11, MS12, MS13 and MS14) remain to be achieved in the 3rd Reporting Period.

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 3rd REPORTING PERIOD (01 OCT 2015 – 30 SEPT 2016).

Deliverable D4.5 “Dialysis study complete” is currently ongoing. Revision of the protocol timelines from a 14 week to 118 week study and recruitment issues extended the clinical timelines for the dialysis study. An interim study report for the dialysis study was submitted in September 2016 (month 36) in lieu of D4.5. The 2 remaining deliverables (D4.4 “Ethical Clearance for dialysis and extension studies” and D4.6 “Long term extension study complete”) relate largely to the extension study which did not commence during the third Reporting Period. Regarding D4.4, all initial Regulatory and Ethical approvals were in place by month 7. All approvals throughout the dialysis study to date were detailed in D4.4 that was submitted in September 2016 (month 36). 4 milestones relating to completion of the Phase I/II and dialysis studies and to the initiation and completion of the extension study (MS11, MS12, MS13 and MS14) were not achieved in the 3rd Reporting Period. The delay in the clinical work package necessitated an extension for the ELIMOX project timelines from 24 months to 36 months. Amendment 1 was approved by REA in August 2015. While considerable effort was put into the clinical work package, particularly in trying to initiate the third study (the extension study), it was not possible to achieve this during the ELIMOX project timelines. OxThera have had many discussions with clinical experts and Regulatory Agencies on the design of the pivotal clinical study. It is hoped that clinical trial applications can be submitted Q1 2017 and that the study will commence in Q3 2017.

During the ELIMOX project timelines the first 2 clinical studies were conducted. These were the:
• OC5-DB-01 study in PH patients with maintained renal function
• OC5-OL-01 study in PH patients who were on dialysis.

Results from these studies demonstrated that viable Oxalobacter formigenes bacteria were delivered to the gut and that enteric elimination of oxalate occurred. Both of these studies confirmed a favourable tolerability profile for the drug.

WORK PACKAGE 5 - Dissemination and Exploitation of Project Results

This Work Package was dedicated to the exploitation and dissemination of the results that will emerged from WPs 2-4. The work was driven by all three SME partners.

Work Performed and Results achieved during the 1st Reporting Period
(01 October 2013 – 30 June 2014).

There were 3 tasks and 3 deliverables in WP5. Only one task and deliverable related to the 1st Reporting Period. This deliverable (D5.1: “Interim use and dissemination plan”) was submitted in Month 9. The other 2 deliverables D5.2 “Final use and dissemination plan” and D5.3 “Publication and dissemination of project information” were not required until the end of the ELIMOX project.

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 2nd REPORTING PERIOD (01 JULY 2014 – 30 SEPT 2015).

Work package 5 progressed well. The 2 remaining deliverables D5.2 “Final use and dissemination plan” and D5.3 “Publication and dissemination of project information” are not required until the end of the ELIMOX project (months 34 and 36 respectively in 3rd reporting period).

WORK PERFORMED AND RESULTS ACHIEVED DURING THE 3rd REPORTING PERIOD (01 OCT 2015 – 30 SEPT 2016).

D5.2 “Final Use and Dissemination Plan” and D5.3 “Publication and Dissemination of Project results” were submitted in month 37 and month 38 respectively. These showed how the results of the project had been turned into value-bearing products and services for the SME partners. Information was widely shared with relevant parties in the scientific and medical community and with the pharmaceutical industry.

Table 1 ELIMOX Deliverables as of November 2016

ELIMOX Deliverables: Status as of November 2016 (End of the Project)
Deliverable Subject
Date to be submitted
Status
Deliverables Submitted
D1.1 Consortium Agreement delivered Mth 2 (Nov 2013) ✓ (Mth 2)
D4.2 Ethical Approvals for OC5-DB-01 Mth 2 (Nov 2013) ✓ (Mth 3)
D1.2 Public communication & website Mth 3 (Dec 2013) ✓ (Mth 5)
D4.1 Clinical oxalate assay report Mth 5 (Feb 2014) ✓ (Mth 5)
D2.1 Lyophilisation & Encapsulation Development Report Mth 5 (Feb 2014) ✓ (Mth 6)
D3.2 In vitro characterization in TIM-1 system Mth 9 (June 2014) ✓ (Mth 15)
D3.3 In vivo characterization – Scintigraphy study Mth 9 (June 2014) ✓ (Mth 9)
D5.1 Interim Use & Dissemination Plan Mth 9 (June 2014) ✓ (Mth 9)
D2.2 Clinical Drug Product & Stability Studies Mth 24 (Sept 2015) ✓ (Mth 25)
D3.1 Assays & Evaluation of impact of OC5 on gut microbiota Mth 24 (Sept 2015) ✓ (Mth 26)
D4.3 OC5-DB-01 completed Mth 24 (Sept 2015) ✓ (Mth 26)
D4.4 Approvals for the dialysis & extension study Mth 27 (Dec 2015) Approvals for dialysis study only
(Mth 36)
D4.5 OC5-OL-01 completed Mth 24 (Sept 2015) Dialysis study ongoing in Sept 2016.
Interim study report submitted Mth36
D5.2 Final Use & Dissemination Plan Mth 34 (July 2016) ✓ (Mth 37)
D1.3 Effective Reporting Structure Mth 36 (Sept 2016) ✓ (Mth 37)
D5.3 Publication & Dissemination of Project Results Mth 36 (Sept 2016) ✓ (Mth 38)
Deliverables NOT achieved during the project
D4.6 Extension study completed Mth 36 (Sept 2016) Not possible within the project timelines

Expected final results and potential impact and use.

The ELIMOX project aimed to optimise drug manufacture and delivery, and demonstrate safety and efficacy of the Oxalobacter formigenes drug product for treatment of Primary Hyperoxaluria. For all three SME participants, there were clear economic and capacity-building benefits to be gained as a result of the proposed programme. These benefits were predicted to result in significant economic impact for the SMEs and to expand their competitive position in: 1) manufacture and delivery of probiotic drugs 2) further development towards a final Phase III clinical trial, for further development and marketing of the O. formigenes drug, and 3) capacity building in terms of enhancement of manufacturing processes and new assays and 4) increased market opportunities and revenues. The field of biopharmaceuticals is highly international and a successful project will open up a global market for the participants.

Contact us

Work Package 1

wp1@elimox.se

Work Package 2

wp2@elimox.se

Work Package 3

wp3@elimox.se

Work Package 4

wp4@elimox.se

Work Package 5

wp5@elimox.se

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OxThera AB

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Phone +46 8 660 02 23