Community Research and Development Information Service - CORDIS

FP7

ELIMOX Report Summary

Project ID: 606528
Funded under: FP7-SME
Country: Sweden

Final Report Summary - ELIMOX (Biopharmaceutical therapy for treatment of Primary Hyperoxaluria)

Executive Summary:
ELIMOX, “Biopharmaceutical therapy for treatment of Primary Hyperoxaluria”, was a project funded by FP7-SME-2013 Research for the benefit of SMEs program. The ELIMOX Consortium had 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 was a truly international project. The project public website was www.elimox.se.

The ELIMOX project proposed to develop a new drug from Oxalobacter formigenes, an anaerobic bacterium whose only carbon source is oxalate, for the treatment of primary hyperoxaluria (PH). PH is a rare and life-threatening disease, present at birth, characterised by high endogenous levels of oxalate that damage the kidney and cause renal failure. The three SME participants utilised the expertise of the nine specialised research providers to increase the understanding of the characteristics of the sensitive, anaerobic and highly specialised O. formigenes, to implement the manufacturing process to obtain a clinically effective drug, to optimise drug delivery and to develop specialised analytical methods to monitor clinical effects following treatment. Technology advancements were confirmed by clinical studies in PH patients and by mapping the presence of the bacteria before and after treatment with the O. formigenes drug.

The project comprised 5 Work Packages; one related to management (WP1), 3 related to research and technological development (WP2-WP4) and one related to use and dissemination of the project results (WP5). There were 17 Deliverables and 14 Milestones across the 5 Work Packages.

The original ELIMOX project was a 24 month project that started on 01 October 2013 and ended on 30 Sept 2015. It had 2 reporting period (Oct 2013 – June 2015; July 2014 – Sept 2015). Due to a delay in the clinical timelines in Work Package 4, the ELIMOX consortium requested an extension to the project timelines (Amendment 1). Approval was given in August 2015 to extend ELIMOX by 12 months, primarily for WP4 (Clinical studies of Oxalobacter fromigenes). Timelines for the management work package (WP1) and the exploitation and dissemination work package (WP5) were also extended from 24 to 36 months. Timelines for WP2 (Development of Drug Product Intermediate and Drug Product) and WP3 (Development of analytical tools for development and drug delivery of Oxalobacter formigenes therapy) remained as in the original application (i.e. ended at Month 24). The ELIMOX project then ran from 01 October 2013 to 30 Sept 2016 with 3 reporting periods (Oct 2013 – June 2015; July 2014 – Sept 2015; Oct 2015 – Sept 2016).

The majority of the objectives and deliverables for the five Work Packages were achieved during the ELIMOX project. The only work package that was not fulfilled according to the Grant Agreement was the clinical Work Package, WP4. This work package had included 3 clinical studies with Oxabact OC5 in patients with Primary Hyperoxaluria. Only 2 of the 3 studies were conducted during the ELIMOX timelines. The third study the extension (pivotal) study will be conducted outside the project.

In accordance with the Grant Agreement, all objectives, deliverables and milestones for the manufacturing Work Package, WP2 (Development of Drug Product Intermediate and Drug Product) and the pharmacodynamics Work Package, WP3 (Development of analytical tools for development and drug delivery of Oxalobacter formigenes therapy) were achieved during the first 2 years of the project. All objectives and deliverables for the exploitation and dissemination Work Package, WP5 were achieved within the 3 year project. This 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.

Project Context and Objectives:
ELIMOX, “Biopharmaceutical therapy for treatment of Primary Hyperoxaluria”, was a project funded by FP7-SME-2013 Research for the benefit of SMEs program. The ELIMOX Consortium had 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 was a truly international project. The project public website was www.elimox.se.
The ELIMOX project proposed to develop a new drug from Oxalobacter formigenes, an anaerobic bacterium whose only carbon source is oxalate, for the treatment of primary hyperoxaluria (PH). PH is a rare and life-threatening disease, present at birth, characterised by high endogenous levels of oxalate that damage the kidney and cause renal failure. The treatment employs a new approach whereby bacterial breakdown of excessive oxalate occurs in the gut, inducing an alternative pathway for the oxalate, thereby protecting the kidneys from failure. Treatment with pharmacological doses of O. formigenes would facilitate enteric elimination of oxalate via the gut The O. formigenes approach to treat PH is an ideal model for bacterial treatment of metabolic disease.
The three SME participants utilised the expertise of the nine specialised research providers to increase the understanding of the characteristics of the sensitive, anaerobic and highly specialised O. formigenes, to implement the manufacturing process to obtain a clinically effective drug, to optimise drug delivery and to develop specialised analytical methods to monitor clinical effects following treatment. Technology advancements were confirmed by clinical studies in PH patients and by mapping the presence of the bacteria before and after treatment with the O. formigenes drug.
The ELIMOX project advanced current standards and methodology in i) manufacture of anaerobic bacteria for pharmaceutical use, ii) identification, quantification and tracking of microbes in the human gut and their impact on human microbiota during treatment, iii) optimisation of tools to monitor clinical effects during treatment with anaerobic bacteria.
The original ELIMOX project was a 24 month project that started on 01 October 2013 and ended on 30 Sept 2015. It had 2 reporting periods as follows:
• Reporting Period 1: 01 October 2013 – 30 June 2014
• Reporting Period 2: 01 July 2014 – 30 September 2015

Amendment 1 – Project extension from 24 to 36 months to enable inclusion of all 3 clinical studies within the ELIMOX time-frames.

Due to a delay in the clinical timelines in Work Package 4 (primarily stemming from the longer study recruitment and analyses time for the first study, OC5-DB-01), the ELIMOX consortium requested an extension to the project timelines (Amendment 1). This was discussed at depth with the REA. Following submission of an official request and updated documentation in July 2015, approval was given in August 2015 to extend ELIMOX by 12 months. This was primarily to extend the timelines for the clinical work package WP4. Timelines for the management work package (WP1) and the exploitation and dissemination work package (WP5) were also extended from 24 to 36 months. Timelines for WP2 and WP3 remained as in the original application (i.e. ended at Month 24). The ELIMOX project then ran from 01 October 2013 to 30 Sept 2016 with 3 reporting periods as follows:

• Reporting Period 1: 01 October 2013 – 30 June 2014
• Reporting Period 2: 01 July 2014 – 30 September 2015
• Reporting Period 3: 01 October 2015 – 30 September 2016

Work Packages and Objectives.
The project comprised 5 Work Packages; one related to management (WP1), 3 related to research and technological development (WP2-WP4) and one related to use and dissemination of the project results (WP5).
Work Package 1: Project Management

The objectives of the management Work Package, WP1, were as follows:
• To coordinate the project at a management level.
• To organise a project management and communication system between the partners.
• To establish a project management structure and agree on rules and mandates of the partners.
• To set up and manage the project financing, budgeting and reporting.
• To keep records of all administrative work related to the project.
• To organise regular meetings and communication mechanisms between partners and with the EU.
• To conduct regular project assessments and reviews, and address any deviations to the project plan, and mitigate any risks.
Work Package 2: Development of Drug Product Intermediate and Drug Product

The objectives of the WP2 were to transform bulk drug substance to a lyophilised drug product intermediate and then to an encapsulated clinical drug product. This involved developing the freeze drying cycle for the drug product intermediate and the encapsulation process of the drug product into its final dosage form. The drug product was to be continuously examined for quality and stability to allow release of the drug for use in the clinical trials.

Work Package 3: Development of analytical tools for development and drug delivery of Oxalobacter formigenes therapy.

The overall aim of this Work Package was to provide important tools for determination of the effects of O. formigenes in vivo. The work in this package was to result in an optimally designed capsule that would release the O. formigenes drug at the proper location in humans in vivo. Furthermore, sensitive methods for the detection and quantification of O. formigenes in complex samples were to be developed; these included real-time Polymerase Chain Reaction (PCR) and the Ion Torrent Personal Genome Machine (PGM). The overall impact of the administration of O. formigenes drug on a normal gut microbiota was also to be evaluated.

Work Package 4: Clinical studies of Oxalobacter formigenes
The objectives for WP4 were to conduct and complete three phase I/II clinical studies in patients with primary hyperoxaluria to
• demonstrate the delivery of viable bacteria to the gut and that enteric elimination has occurred,
• demonstrate the tolerability and efficacy of the probiotic drug.

The ELIMOX project was to cover 3 clinical studies of Oxabact OC5 in Primary Hyperoxaluria (PH) patients.
• Task 4.3: A phase I/II clinical study during 8-10 weeks in patients with maintained renal function and high levels of endogenous oxalate in plasma
• Task 4.5: A phase I/II clinical study during 6 weeks in patients on dialysis
• Task 4.6: A phase I/II clinical extension study during 24 weeks in patients with maintained renal function and high levels of endogenous oxalate in plasma

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. (This protocol was amended from the initial 6 weeks treatment time to allow for up to an additional 2 years of continued treatment. As a consequence the timelines for the study were significantly prolonged, such that the study was still ongoing when the ELIMOX project ended). However, the initial study design as detailed in the Grant Agreement, was performed. This covered treatment of 6-8 dialysis patients with Oxabact OC5 for 6 weeks during the first 14 weeks of the study.

Despite the revised Annex 1 there were still been problems with the clinical work package (WP4). This will be discussed in detail in the result section for WP4. It was not possible to complete the amended version of the dialysis study (with prolonged treatment periods) nor to conduct the extension study within the ELIMOX project timelines.

Work Package 5: Dissemination and Exploitation of Project Results
The objectives of WP5 were to:
• enable the results of the project to be turned into value-bearing products and services for the SME participants.
• reach all relevant interested parties, including the scientific community and the pharmaceutical industry.

Project Results:
The majority of the objectives and deliverables for the five Work Packages were achieved during the ELIMOX project. The only work package that was not fulfilled according to the Grant Agreement was the clinical Work Package, WP4. This work package had included 3 clinical studies with Oxabact OC5 in patients with Primary Hyperoxaluria. Only 2 of the 3 studies were conducted during the ELIMOX timelines. The third study the extension (pivotal) study will be conducted outside the project.

In accordance with the Grant Agreement, all objectives, deliverables and milestones for the manufacturing Work Package, WP2 (Development of Drug Product Intermediate and Drug Product) and the pharmacodynamics Work Package, WP3 (Development of analytical tools for development and drug delivery of Oxalobacter formigenes therapy) were achieved during the first 2 years of the project. All objectives and deliverables for the exploitation and dissemination Work Package, WP5 were achieved within the 3 year project.

Work Package 1: Project Management
All of the WP1 objectives and deliverables have been achieved. There were 3 tasks and 3 deliverables in WP1. The tasks were on track with all three deliverables (D1.1 “Delivery of Signed Consortium Agreement”, D1.2 “Public Communication and Website” and D1.3 “Establish and implement an effective reporting system”) having been achieved and submitted during the project.

Work Package 2: Development of Drug Product Intermediate and Drug Product

OVERVIEW
All the WP2 objectives, deliverables and milestones were achieved during the first 24 months of the project. 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 during the 1st reporting period. The second deliverable (D2.2 “Production of clinical drug product and stability studies”) was finalised and submitted in Month 25. Both milestones (MS1 “Validated Manufacturing Process” and MS2 “Release of Clinical Drug Product for the first clinical study”) were completed during the 1st reporting period. 3 GMP clinical trial batches had been produced within the first reporting period for use in the clinical studies.

The outstanding activity in the 2nd reporting period for WP2 was continued stability testing of the Oxalobacter formigenes product together with packaging, labelling and distribution of clinical trial supplies. This was reported in D2.2 and submitted in October 2015 (Mth 25).

TASKS

Task 2.1 Development of a validated lyophilisation and encapsulation process finalised
The active ingredient, O. formigenes, is a live anaerobic Gram-negative bacteria with very specific survival conditions, resulting in significant technical challenges in terms of transportation, transfer into the lyophilisation facility, freezing and lyophilisation and final encapsulation. Maintaining these conditions for the scale of process required to support clinical and in-market delivery requires significant development. It is essential to develop a lyophilisation process which will maximise survival of the bacteria, and the process parameters need to be extensively evaluated and defined.
The O. formigenes drug will be encapsulated in gelatin-based capsules. The drug needs capsule and coating for protection from gastric degradation in order to reach the small intestines, the site of action. However, as many PH patients are children, the capsule size is kept at as small as possible, size 4, for an as easy administration to patients as possible. Freeze-drying of the O. formigenes drug will be performed by participant #9, KABS Pharmaceutical. Final formulation and encapsulation will be performed by participant #8, Galenica. Technical review and quality monitoring of data will be done by SME2, Cobra.

Task 2.2 Production of clinical drug product and stability studies
The effect of O. formigenes therapy is highly dependent on the number of viable cells and the oxalate degrading capacity of those cells in the bacteria formulation. Truly quality-indicating assays will be developed to secure that the product is highly viable and presents a good oxalate degrading capability. These assays are essential for monitoring of drug stability during storage, robustness of the manufacturing process, and for the release of drug product for clinical trials. The assays will be validated and run by participant #8, Galenica. The final drug product will be manufactured, characterised and tested in detail prior to release for use in clinical trials. The test requirements set on the final drug product are stringent with regard to function, safety, purity and other properties that together define the profile of the O. formigenes drug. The testing is performed by participant #8, Galenica. Stability studies will be run by Galenica for both drug substance and drug product throughout the entire project.

WORK PACKAGE 2 RESULTS

Both tasks were successfully completed in accordance with the Grant Agreement.

KABS developed a robust and reliable lyophilisation process that converted the Drug Substance (frozen cell paste) into a stable Drug Product Intermediate (lyophilised powder). The lyophilisation process had to maintain the stability and potency of the product. The water activity level had to be carefully controlled and below a certain value to ensure stability of the DPI. Appropriate vacumn and drying conditions were tested and developed. KABS also performed in process controls and tests to better understand and monitor the process. 3 DPI batches were successfully produced at KABS.

Galenica were responsible for developing, testing and releasing a final dosage form, the Drug Product, for Oxabact OC5. This was an enteric-coated, size 4 gelatin capsule containing a suitable blend of the lyophilised DPI to ensure a specified amount of viable Oxalobacter formigenes bacteria in each capsule. In addition to developing a finalised DP, Galenica also developed and validated analytical methods for the Oxabact Drug Sustance, Drug Product Intermediate and the Drug Product. These tests included appropriate methodologies to evaluate the following; description, identity of OC5, Total cell count, Viable cell count, Non-viable cell count, Uniformity of dosage units, potency/oxalate degrading activity, formate, disintegration, water activity and microbiological quality. 3 Good Manufacturing Practices (GMP) batches of Drug Product were manufactured and released for use in the clinical studies. Study medication was shipped to 28 patients at 8 sites in 3 countries (Germany, France and the UK) in the OC5-DB-01 study. In addition, study medication was shipped to patients at 1 site in Germany in the OC5-OL-01 study. The packaging and labelling procedures were compliant with regulations for clinical trials in the EU (GMP guideline Annex 13). Appropriate stability testing was also performed on for 3 batches of DPI and 3 batches of DP. This ensured that the study drug was stable during the clinical studies.

Work Package 3: Development of analytical tools for development and drug delivery of Oxalobacter formigenes therapy.

OVERVIEW
All the WP3 objectives, deliverables and milestones were achieved during the first 24 months of the project. There were 3 tasks, 3 deliverables and 2 milestones in in WP3. D3.1 “Finalisation of assay methods and evaluation of long term impact on gut flora” was finalised and submitted 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 (during the 2nd reporting period). Deliverable D3.3 (Capsule targeting characteristics in healthy volunteers) was finalized and submitted in Month 9 (1st reporting period). This completed scintigraphy study also related to MS4 “Capsule disintegration profile confirmed”.

TASKS

Task 3.1 Assay for quantification of O. formigenes in artificial and human faecal samples and assay for determination of changes in the gut flora after administration of O. formigenes. Evaluation of the long-term impact of O. formigenes on gut microbiota. The possibility to monitor the natural occurrence of O. formigenes bacteria and the presence of the O. formigenes drug during and after pharmaceutical use is an important tool for control of the pharmacodynamics of the drug. A real-time quantitative PCR assay will be developed that permits determination of the levels of O. formigenes and and its distribution within stool, both in artificial and in human faecal samples. The method will be used to track O. formigenes both in an artificial GI tract system (see Task 3.2), and in human samples from clinical trials (see WP4). The method development will be outsourced to participant #10, MVZ Institut für Mikroökologie.
Next-generation sequencing (NGS) technologies are currently applied in a vast number of metagenomic studies, which extend the understanding of microbial communities. The recently introduced Ion Torrent’s Personal Genome Machine (PGM) constitutes a new type of next-generation benchtop sequencing platform. In this project, participant #10, MVZ Institut für Mikroökologie, will use the Ion Torrent PGM (a new NGS technology) to analyse faecal samples for shifts in the microbial community in response to the treatment with O. formigenes. The effects of O. formigenes treatment on gut flora will be analysed by participant #10, MVZ Institut für Mikroökologie. The impact on gut microbiota is important to monitor for full understanding of the clinical effects of pharmaceutical use of O formigenes.

Task 3.2 Understanding the drug release characteristics of O. formigenes formulation in a simulated GI-system
Participant #11, TNO, will be contracted to provide services for in vitro testing of drug release in a simulated gastric system, the TIM-1 system. The TIM-1 model is a multi-compartmental, computer-controlled model of the gastrointestinal tract, and will be used since it simulates the digestion of the small intestines. Primarily, the average physiological conditions of the gastro-intestinal tract for healthy, adults under fed state will be simulated. The enteric-coated capsule containing O. formigenes will stay in the stomach for one hour before transfer to the small intestine by mimicking the housekeeper wave. Coated capsules will move through 3 compartments, simulating the transit from duodenum to ileum. During transit of the test product through the stomach and small intestine it will be subjected to the digestive enzymes. Samples will be taken out at various locations along the artificial small intestine to monitor the transit of the capsule, capsule disintegration and release of the bacteria. Capsules will be investigated to identify an optimal coat for the release of O. formigenes into the upper part of the small intestines. Samples will be analysed for the occurrence of O. formigenes during transit in the simulated GI system by participant # 10, MVZ Institut für Mikroökologie.

Task 3.3 Study of capsule targeting characteristics in healthy volunteers.
To confirm disintegration of the coated capsules at the proper site in vivo, we intend to study the performance of the optimally coated capsules containing placebo in healthy volunteers in a clinical imaging setting. By radiolabelling of placebo with a stable isotope, the capsule targeting characteristics can be traced in real time by sensitive scintigraphic imaging of the small intestines in humans. It is of utmost importance that the capsule disintegrate, releasing the bacteria at the proper site in vivo. Participant #12, Bio-Images Research, will be contracted to study in vivo release of coated placebo capsules in healthy humans using the non-invasive imaging technique, gamma scintigraphy. Participant #8, Galenica, will be contracted for supply of the coated placebo capsule.

WORK PACKAGE 3 RESULTS

The three tasks were successfully completed in accordance with the Grant Agreement.

Quantification of O. formigenes
Institut für Mikroökologie developed validated a real-time quantitative Polymerase Chain Reaction (PCR) assay to quantify Oxalobacter formigenes in faecal samples. The PCR assay was a robust, fast and reliable quantification method for O. formigenes with a minimal detectable cell number of 10E+05/ g faecal sample. This method measure both living and dead bacteria and clearly shows if the O. formigenes increased in number within the faecal samples. The methodology was also able to distinguish between the two genotypes of Oxalobacter formigenes, genotype 1 and genotype 2. (Oxabact OC5 is derived from genotype 1).

Results from the OC5-DB-01 study, showed that OC5 treatment induced a statistically significant increase in the number of O. formigenes in faeces after 8 weeks of treatment compared with placebo. As compared with placebo, OC5 treatment also increased the absolute number of O. formigenes cells genotype 1 and 2 in the faeces of patients The LS mean difference from baseline after 8 weeks of treatment was 12,268,589 greater in the OC5 group than in the Placebo group (95% CI: 501,684–24,035,493; p=0.0417).

Results from the dialysis OC5-OL-01 study for the initial 6 week treatment in the majority of patients would suggest that treatment with Oxabact OC5 leads to an increase in Oxalobacter formigenes genotype 1 in stool samples. In most patients, O. formigenes levels decreased following 4 weeks with no OC5 treatment. Prolonged treatment with OC5 during the continued treatment period in the OC5-OL-01, dialysis study resulted in high and stable levels of O. formigenes in faeces.

These findings indicate that O. formigenes is successfully delivered to the gut and that OC5 treatment promotes the growth of O. formigenes within the intestine. These results confirmed that OC5 administration promoted the enteric elimination of oxalate.

Analysis of shifts in the gut microbiota
Institut für Mikroökologie developed an Ion Torrent’s Personal Genome Machine (PGM) next generation sequencing (NGS) assay to analyse faecal samples for shifts in the microbial community. In the NGS methodology, the DNA was extracted from the stool samples and relative amounts of gut microbiota detected. Inter-individual differences in shifts in phyla and family abundance (%) before and after study drug feeding and in controls were measured.

The faecal microbiota is highly variable. Strong inter-individual variations are mainly due to external factors such as diet and life style. Comparing baseline to values after 6 or 8 weeks treatment with Oxabact OC5, no significant differences could be observed. However, in most samples the phylum Proteobacteria did increase and the phylum Firmicutes decreased. Interestingly, all samples showed a very low abundance of the phylum Bacteroidetes. Comparing the treated (Oxalobacter formigenes) with the placebo group no significant changes could be observed at either the phyla or family level.

In vitro disintegration profile in the TIM-1 system
TNO, were contracted to perform in vitro testing of drug release in a simulated gastric system, the TIM-1 system. The TIM-1 model is a multi-compartmental, computer-controlled model of the gastrointestinal tract from the stomach to small intestine. The freeze-dried Oxalobacter formigenes bacteria were encapsulated. The filled capsules need to be enteric-coated to make them resistant to gastric juices and to ensure disintegration in the gut at the proper site of action further down the intestinal tract.

2 different enteric-coated capsules with different release profiles were examined in the TIM-1 system (Product #1 and Product #2). These capsules both contained O. formigenes. Product #1 had a short disintegration time and Product #2 had a normal disintegration time. Product #1 had the same enteric coating as the placebo Targeted Capsule B that was used in the Bio-Images in vivo study. Product #2 had the same enteric coating as the placebo Targeted Capsule A that was used in the Bio-Images study.

Samples were taken out at various locations along the artificial small intestine to monitor the transit of the capsule, capsule disintegration and release of the bacteria. This work parallalled the disintegration profiles from the in vivo scintigraphy study to determine when to take out samples.

For product #1 the capsule was visually intact during the transfer from duodenum to jejunum, 90 minutes after capsule intake. After 170 minutes for the triplicate run, the capsule was completely dissolved within the jejunum. Intake of O. formigenes from the capsule was 8.2x10E+09 CFU. For product #2 the capsule was visually intact during the transfer from duodenum to jejunum after 90 minutes. Disintegration of the product #2 capsule was around the 170 minute timepoint. Intake of O. formigenes from the capsule was 6.4x10E+09 CFU. Compared to product #1, product #2 showed a delayed disintegration of the capsule. In addition there was a lower release of Oxalobacter formigenes from product #2 as compared to product #1.

In vivo disintegration profile in the gamma scintigraphy system
The scintigraphy study was a single-centre, two-arm, open-label, non-randomised study in 6 healthy male volunteers conducted by BioImages. The aim of the study was to aid the optimisation of drug delivery to specific regions of the gastrointestinal tract by using only placebo enteric-coated capsules (Targeted Capsules). Targeted Capsule A was designed to mimic the behaviour of the capsules used in the successful Oxabact phase I/II study - withstand simulated gastric fluid (SGF) for an hour and then show signs of disintegration within one hour in simulated intestinal fluid (SIF). Targeted Capsule B was designed to withstand SGF for an hour and then show signs of disintegration within 10 minutes in SIF.

Each capsule was radiolabelled with approximately 4 MBq 99mTc-DTPA (dose measured at time of dose). Radiolabel was injected into the capsule and the hole was then sealed. A validation study was performed to ensure that the injection/sealing process did not affect the integrity of the enteric-coating.
Anterior and posterior images (25 s each) were acquired at dosing then every 10 minutes to 10 h post-dose. Imaging may have been stopped if complete radiolabel release was observed or capsule excretion was confirmed.

This clinical study successfully visualised the in vivo disintegration behaviour of Targeted Capsules A and B using scintigraphic methods. Both capsules were stable in the acid environment of the stomach, with no radiolabel release observed. Clear differentiation between the disintegration times of the two capsules once emptied from the stomach was achieved. Targeted Capsule A, designed to start disintegration within 1 h in SIF, started to disintegrate at a meantime of 91.6±30.6 min after gastric emptying in vivo. Comparatively, Targeted Capsule B which disintegrates after 10 min in SIF began to release its contents at a mean time of 33.3±16.3 min in the higher pH environment of the small intestine. Targeted Capsule A tended to release further along the GI tract, in the distal small intestine and proximal colon while Targeted Capsule B generally released more proximally, in the small intestine.
Targeted Capsule B exhibited faster disintegration, as evidenced by a shorter mean time from onset to complete release, as compared to Targeted Capsule A; the values being 35.0±15.2 min and 106.8±83.8 min respectively. This indicates that Targeted Capsule B provides a more immediate release of its contents compared to Targeted Capsule A, which tended to show an extended release profile.

The BioImages in vivo findings showed an expected release profile of the Oxabact clinical drug product. The TNO TIM-1 evaluation confirmed those results in vitro.

Work Package 4: Clinical studies of Oxalobacter formigenes

OVERVIEW
The ELIMOX project was to cover 3 clinical studies of Oxabact OC5 in Primary Hyperoxaluria (PH) patients.
• A phase I/II clinical study during 8-10 weeks in patients with maintained renal function and high levels of endogenous oxalate in plasma (Task 4.3)
• A phase I/II clinical study during 6 weeks in patients on dialysis (Task 4.5)
• A phase I/II clinical extension study during 24 weeks in patients with maintained renal function and high levels of endogenous oxalate in plasma (Task 4.6)

Many of the WP4 objectives, deliverables and milestones have been achieved. There were 6 tasks, 6 deliverables and 10 milestones in WP4. Apart from activities related to the third clinical study (the extension study), 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 during the 1st reporting period. 1 deliverables (D4.3 “Short term tolerability and efficacy study complete” was finalised during the 2nd reporting period and submitted in month 26.
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. However, the initial dialysis study design as detailed in the Grant Agreement was performed. This referred to treatment of 6-8 patients with Oxabact OC5 for 6 weeks during a 14 week study.

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 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).
6 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”, MS7 “Last patient completed in the MRF Phase I/II study” MS8 “Study results for the MRF Phase I/II study”, MS9 “Regulatory and Ethical Approvals for the dialysis study” and MS10 “First patient enrolled in the dialysis study”). 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.

TASKS

Task 4.1 Development of optimized clinical assays for oxalate.
Current clinical standard methods that measure urinary oxalate levels differ between clinical sites. The methods differ also in procedures, which affects the possibility to accurately compare results between sites. Pharmaceutical use of O. formigenes is expected to impact on the levels of urinary oxalate. Development work for measurement of urinary oxalate to monitor pharmaceutical effects of O. formigenes will be performed by participant #7, UCLH.

Task 4.2 - Ethical and Regulatory approvals obtained for the short-term, Phase I/II study in patients with maintained renal function.

Task 4.3 - A phase I/II clinical study during 8-10 weeks in patients with maintained renal function and high levels of endogenous oxalate in urine and plasma.
A phase I/II, placebo-controlled, double-blind clinical study in patients with primary hyperoxaluria (OC5-DB-01; EudraCT Number: 2012-005606-22) has been designed and discussed with regulatory agencies. The study aims to demonstrate a reduction of urinary oxalate during 8-10 weeks, in patients with maintained renal function. 24 subjects will be enrolled in the study and half of the subjects will receive Oxalobacter formigenes and half will receive placebo. This study will provide evidence that viable bacteria have been delivered to the gut and that enteric elimination of endogenous oxalate has occurred. The study is performed by participants #5, Universitätsklinikum Bonn (UKB), and participant #6, Hospices Civils de Lyon (HCL). Clinical analyses of the 24hr urine collections are performed by participant #7, UCLH. Faecal samples are analysed by participant #10, Institut für Mikroökologie (IFM). Participant #4, Ergomed Clinical Research Ltd, are responsible for the coordination of clinical operations and Good Clinical Practice (GCP). These tasks include regulatory submissions, project management, interactions with clinical sites, monitoring activities, safety monitoring and reporting, compilation of the Trial Master File (TMF), data management, biostatistics and medical writing.

Task 4.4 - Ethical and Regulatory approvals obtained for the dialysis study and extension study (at month 4 and 27 respectively).

Task 4.5 – A phase I/II clinical study during 6 weeks in patients on dialysis
A phase II, open-label clinical study in patients with primary hyperoxaluria who are on dialysis (OC5-OL-01; EudraCT Number: 2013-004368-74) will demonstrate a reduction of plasma oxalate during 6 weeks of treatment. 6 – 8 subjects will be enrolled in the study and they will all receive Oxalobacter formigenes. This study will provide ultimate evidence that the probiotic therapy is effective and tolerable in patients with severe clinical and morbid symptoms, and where the only remaining, however insufficient, route of oxalate clearance is through dialysis. This study is designed to demonstrate a clear clinical benefit from enteric elimination via administration of O. formigenes. The study is performed by participant #5, UKB and #6, HCL. Faecal samples are analysed by participant #10, IFM. Participant #4, Ergomed Clinical Research Ltd, are responsible for the coordination of clinical operations and Good Clinical Practice (GCP). These tasks include regulatory submissions, project management, interactions with clinical sites, monitoring activities, safety monitoring and reporting, compilation of the Trial Master File (TMF), data management, biostatistics and medical writing.

Task 4.6 – A phase I/II clinical extension study during 24 weeks in patients with maintained renal function and high levels of endogenous oxalate in plasma
A 24-week extension study (OC5-OL-02) will have the main purpose to explore the long-term effect and tolerability of O. formigenes treatment and the sustainability of reduced levels of urinary oxalate. Furthermore, the extension study will allow the gathering of exploratory data related to kidney function, such as renal function, renal injury and the degree of nephrocalcinosis. Patients from the preceding OC5-DB-01 clinical study will continue to be investigated for effect of O. formigenes treatment in this extension study, but the specimen sampling is less frequent here. This study will provide evidence that viable bacteria have been delivered to the gut and that enteric elimination of endogenous oxalate has occurred. The study will be performed by participants #5, UKB and participant #6, HCL. Clinical analyses of the 24hr urine collections will be performed by participant #7, UCLH. Faecal samples will be analysed by participant #10, IFM. Participant #4, Ergomed Clinical Research Ltd, will be responsible for the coordination of clinical operations and Good Clinical Practice (GCP). These tasks include regulatory submissions, project management, interactions with clinical sites, monitoring activities, safety monitoring and reporting, compilation of the Trial Master File (TMF), data management, biostatistics and medical writing.

WORK PACKAGE 4 RESULTS

Prior to starting the clinical studies it was necessary to have accurate and reliable clinical assays in place to measure urinary oxalate in the 24 hr urine samples. Urinary oxalate excretion was the primary endpoint in 2 of the studies. UCLH developed and validated a suitable methodology; they evaluated and controlled for the effects of pH and centrifugation on the oxalate levels in the urine samples.

The necessary Regulatory and Ethical Approvals were obtained before a clinical study was initiated. Regulatory Approvals were required from the German, French and UK Authorities (BfArM, ANSM and MHRA). In addition Ethical Approvals are required from the German, French and UK Ethics Committees. ELIMOX is only concerned with Approvals in Germany and France. In addition to the initial approvals for the Clinical Trial Application, it was necessary to make substantial amendments to the clinical protocol and the Investigational Medicial Product Dossier (IMPD). These were also approved by the requisite Regulatory Authorities and Ethics Committees before implementation.

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.

The first study, OC5-DB-01, was conducted as outlined in the ELIMOX Grant Agreement. However, the design and timelines of the OC5-OL-01 study was modified from that originally detailed in T4.4 in the Grant Agreement. The initial 6 week treatment period in the original dialysis protocol was insufficient time to see a change in the plasma oxalate levels in the PH patients on dialysis with a more severe form of the disease. The protocol was amended in Germany and France to extend the continued treatment period (24 months in Germany and 12 months in France). This prolongation meant that the study took much longer than anticipated and was still ongoing at the time the ELIMOX project ended. Revision of the protocol timelines from a 14 week to 118 week study and difficulties in recruiting such a rare patient population consequently extended the clinical timelines for the dialysis study. Since this was an open-label study (in which all patients received OC5 study drug and no patients were on a placebo-treatment) results were available throughout the study. An interim study report for the OC5-OL-01 study with information on the study progress from May 2014 to August 2016 was submitted in September 2016 to EU REA for Deliverable D4.5 (Dialysis study complete). The initial dialysis study design as detailed in the Grant Agreement was performed. This referred to treatment of 6-8 patients with Oxabact OC5 for 6 weeks in a 14 week study. The submitted Interim Study Report shows results for 8 patients who participated in the initial 14 weeks of the study.

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. No SUSARs (Suspected Unexpected Serious Adverse Reactions) have been reported during these clinical studies.

While the efficacy primary endpoint (i.e. a significant reduction in urinary oxalate) was not met in the OC5-DB-01 study, ad hoc analyses showed correlations between renal function and the effect of Oxabact OC5 treatment on urinary oxalate concentration. Furthermore, a correlation was found between the number of O. formigenes cells and change in plasma oxalate concentration. The OC5-DB-01 study showed that there was marked patient heterogeneity. There was an indication that oxalate deposits may be dissolving in OC5-treated patients. The study data yielded very interesting findings and resulted in the generation of the oxalate dissolution hypothesis.

Results from the ongoing OC5-OL-01 study regarding plasma oxalate and oxalate deposits in heart look promising in patients who have entered the continued treatment period. Total and free plasma oxalate levels have reduced and there is an indication of improved heart function in some patients. This study has provided valuable mechanistic information on the efficacy and safety of PH patients on dialysis.

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.

The results of the first and second clinical studies had been delayed and evaluation of results took some time. OxThera have had several Scientific Advice procedures with Regulatory Authorities (EMA, FDA, BfArM, MHRA and MPA) to discuss the findings from the first two studies (OC5-DB-01 and OC5-OL-01) and to design the subsequent pivotal study. These discussions have taken a long time (ranging from May 2015 to Sept 2016). It was critical that OxThera discussed these matters in detail with the concerned Regulatory Authorities before proceeding with the pivotal clinical study. For OxThera to complete this pivotal study and prepare for a Marketing Authorisation Application (MAA) to EMA, costs are expected to be approximately €25 million. This will also involve numerous clinical centres, most probably in Germany, France, United Kingdom, Netherlands and the United States of America.
Consequently no information on approvals or study outcome is available for the extension study. OxThera hope that clinical trial applications for the pivotal/extension study will be submitted in Q1 2017 and that the study will commence in Q3 2017.

A status update sent to EU REA on 09 June 2016 conveyed that the extension study would not be conducted during the ELIMOX project timelines. This update conveyed that Deliverable D4.4 would not contain approvals for the extension study and that Deliverable D4.6 would not be possible.

Work Package 5: Dissemination and Exploitation of Project Results

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 submitted at the end of the ELIMOX project (Mth 37 and Mth 38 respectively).
This 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. The WP5 results are discussed in more detail in the section “Potential impact and main dissemination activities and exploitation results”.

Potential Impact:
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.

Work Package 5 dealt with the exploitation and dissemination activities for the project. WP 5 contained 3 deliverables. Deliverable (D5.1: Interim use and dissemination plan) was submitted on 11 July 2014 (Month 10 of the ELIMOX project). Deliverable D5.2 Final use and dissemination plan was submitted on 13 October 2016 (Month 37). This deliverable, D5.3: Publication and dissemination of project information was submitted on 09 November 2016 (Month 38).

Summary of “Publication and dissemination of project information” for all 3 SMEs
The three SMEs have all gained know-how and data that can be used by each of them in different ways, to further develop the business concept of the company. For partner #1 (OxThera) this was a completed clinical trial, which will support a final pivotal clinical study to reach the market. For participants #2 (Cobra Biologics) and #3 (SymbioPharm), this could be advancement of knowledge in core areas (e.g. technology and capacity development, fulfilling regulatory requirements, or a market assessment and plan for new manufacturing services for pharmaceutical use).
The SME partners have attended relevant scientific and commercially focused meetings and conferences to inform about the project results. The project has been presented to interested key opinion leaders within the hyperoxaluria community (e.g. the Oxalosis and Hyperoxaluria foundation) and the pharmaceutical industry in general.
There has been one publication related to the evaluation of baseline urinary oxalate values in the first clinical trial, OC5-DB-01 (Clifford-Mobley et al., 2016). Another manuscript on the full OC5-DB-01 results has been submitted to the journal, Pediatric Nephrology, and has been accepted for publication (Notification for acceptance was given mid/later November 2016). It is hoped that this paper will be published during 2017. It is also the intention to prepare a manuscript for the OC5-OL-01 study in dialysis patients once the study is completed. Several results from this project are expected to redefine certain standards for the clinical treatment of primary hyperoxaluria.
OxThera has also recently filed a patent application (1650828-5) for the Oxabact OC5 product based on findings from the OC5-DB-01 study.

There were no peer-reviewed publications nor intellectual property applications on relation to WP2 or WP3.

Partner #1 OxThera AB: Publication and Dissemination
1. Publications
In relation to data from the ELIMOX clinical work package, WP4, one publication has been published during the project and one publication has been accepted for publication at a reputable journal. It is hoped this will be published in 2017.
a. Published manuscript
The published manuscript is as follows:
• Clifford-Mobley O, Sjögren A, Lindner E and Rumsby G. “Urine oxalate biological variation in patients with primary hyperoxaluria”, Urolithiasis, Vol 44, No. 4, pg 333-337, 2016 (ISSN 2194-7228: DOI 10.1007/s00240-016-0860-2).
Abstract: Hyperoxaluria is a well-recognised risk factor for urolithiasis and patients with primary hyperoxaluria(PH) gradually build up calcium oxalate deposits leading to chronic kidney disease. Efforts to improve treatment for PH have focused on reducing urine oxalate excretion and thus decreasing lithogenesis. To determine the efficacy of treatments designed to alter a biochemical parameter it is necessary to know the biological and analytical variation of that parameter. In this study, we estimated the intra-individual biological variation of urine oxalate excretion in patients with PH, and from this determined what would constitute a significant change in the form of a reference change value (RCV). Each patient collected four 24-h urines on consecutive weeks. The intra-individual biological variation of oxalate excretion calculated from these samples ranged from 0 to 36 % with a mean of 14 %. The corresponding RCVs were 4–84 % with a mean of 32 %. This result implies that, on average, a reduction of almost one-third in urine oxalate excretion is required to prove an effect from treatment. The wide range of biological variation between individuals may reflect other, as yet unknown, determinants of oxaluria in PH, as well as inaccuracies in urine collection. The data suggest that it is more appropriate to use individual RCVs established prior to treatment to determine its efficacy: a relatively small fall in urine oxalate excretion may be outside the biological variation of some patients but not of others.
The manuscript was jointly prepared by participant #7 (University College London Hospital) and participant #1 (OxThera). It was submitted to Urolithiasis because the authors felt that this journal provided the best route to disseminating the findings to clinicians who may encounter patients with PH. The information is derived from the OC5-DB-01 clinical study.
Currently this manuscript does not have open access. The article is protected by copyright and all rights are held exclusively by the publisher, Springer-Verlag Berlin Heidelberg. However, the manuscript version can be deposited in any repository and made publicly available 12 months after official publication or later and provided acknowledgment is given to the original source of publication and a link inserted to the published article on Springer's website.

b. Manuscript accepted for publication (November 2016) - not yet published
A manuscript on the findings from the OC5-DB-01 study “ A randomised Phase I/II trial to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria” has been accepted for publication at the journal “Pediatric Nephrology”.
The OC5-DB-01 study in PH patients with maintained renal function failed to meet the primary endpoint (i.e. a significant reduction in urinary oxalate). In the ad hoc analyses, correlations were observed between renal function and the effect of Oxabact OC5 treatment on urinary oxalate concentration. Furthermore, a correlation was found between the number of O. formigenes cells and change in plasma oxalate concentration. The OC5-DB-01 study showed that there was marked patient heterogeneity. There was an indication that oxalate deposits may be dissolving in OC5-treated patients. The study data yielded very interesting findings and resulted in the generation of the oxalate dissolution hypothesis.
This manuscript was submitted to the journal “Pediatric Nephrology” in August 2016. The manuscript was accepted for publication by the journal in mid/late November 2016. "Pediatric Nephrology" publishes original clinical research and new or important clinical observations pertaining to any aspect of the wide spectrum of acute and chronic diseases that affect renal function in children as well as on hypertension and fluid and electrolyte metabolism. It is a highly reputable journal and very relevant for the PH disease indication.

c. Publications that will be prepared
It is OxThera’s intention to publish a manuscript on the findings from the OC5-OL-01 clinical study in PH patients who are on dialysis once the study has been completed. This study started in May 2014 and is currently ongoing. It is anticipated that the study will end in Q4 2018 and that the publication will be available in 2019.
The OC5-OL-01 study is an open-label study in PH patient who are on dialysis. Results regarding plasma oxalate and oxalate deposits in heart look promising in patients who have entered the continued treatment period. This study has provided valuable mechanistic information on the efficacy and safety of PH patients on dialysis.

2. Conferences and Meetings
OxThera AB are an important biopharmaceutical player in the field of PH. They are well acquainted with the key opinion leaders, research organisations and have contact with patient groups. OxThera has attended or exhibited at the following industry conferences During the ELIMOX project:
• Sixteenth Congress of International Pediatric Nephrology Association (IPNA 2013). 30 August to 03 September 2013 in Shanghai, China.
• ASN Kidney Week, 05-10 November 2013, Atlanta, USA.
• Research on Calculus Kinetics (R.O.C.K) Society Meetings: 7-8 February 2014, Fort Lauderdale, USA.
• 2014 BIO International Convention, 23-26 June 2014, San Diego, USA.
• 11th Annual International PH Workshop – scientific Symposium and Patient Workshop – June 27-29, 2014, Chicago, USA.
• Anaerobe Society of the Americas. 29 June – 01 July 2014, Chicago, USA.
• 47th Annual Scientific Meeting of the European Society for Paediatric Nephrology (ESPN), 18-20 September 2014, Porto, Portugal.
• BioEurope 3-5 November 2014, Frankfurt.
• ASN Kidney Week, 11-16 November 2014, Philadelphi, USA.
• JP Morgan-33rd Annual Healthcare Conference, 12-16 January 2015, San Francisco, USA.
• OxalEuropa Meetings: 23 June 2015, Amsterdam.
• PharmaOutsourcing on 09 December 2015, Stockholm Waterfront Congress Centre.
• Research on Calculus Kinetics (R.O.C.K) Society Meetings: 11-12 March 2016, New York.
• Bio-Europe Spring 4-6 April, 2016, Stockholm.
• BioEquity, 10-11 May 2016, Copenhagen.
• OxalEuropa Meetings: 20 May 2016, Munich.
• Seventeenth Congress of International Pediatric Nephrology Association (IPNA), 20-24 September 2016 in Iguacu, Brazil.

3. Intellectual Property (Patents)
(Information on the patent application 1650828-5 is CONFIDENTIAL. The application is not public and will not be published until mid December 2017 (18 months from filing).
Partner #1 (OxThera AB) filed a patent application “Novel compositions and methods for the treatment of oxalate-related disorders”. This was submitted to the Swedish patent office on 13 June 2016 (Application number: 1650828-5). It is the intention to file a PCT application for this patent application. The foreground IP that emanated from the ELIMOX project concerned data relating to the clinical outcome of patients treated with the candidate drug, new treatment regimens, and new methodology and formulations. The patent application conveyed that Oxabact OC5 was a better formulation and had a better recovery rate which made it superior to earlier Oxabact products/formulations. This accounted for the effects seen in the OC5-DB-01 study (i.e. increased urinary oxalate excretion, reduced plasma oxalate and reduced disease progression). The combination of these results was an unexpected finding which facilitated the new patent application.
The SESAM reporting system states that a URL is mandatory in order to upload patent application information in the Final Report. The patent application 1650828-5 is still in the confidential phase and does not currently have a URL. Once the 18 month confidential period is over (in December 2017), the application would be public and it would be possible to access the public file in the Swedish patent database. Unfortunately, there is no URL at present and this means that it was impossible to upload the patent application to the Final Report. This matter was discussed with both the IT Helpdesk and Project Officer but it was not possible to resolve.

4. Exploitable Foreground
a. Commercial exploitation of R&D results - Appropriate clinical development program to led to a pivotal trial and to facilitate a Marketing Authorisation Application (MAA) for Approval and Sales of O. formigenes product.
OxThera believe that completed phase I/II clinical trials with solid clinical and supporting data will be of significant interest to the pharmaceutical industry. The data from the earlier OC5-DB-01 and OC5-OL-01 trials will enable OxThera to raise the necessary capital/investment to continue the clinical development program and to conduct a Phase III, pivotal clinical trial. This would be used as a core part of a Marketing Authorisation Application to get the product approved and on the market.
The primary impact of the ELIMOX program for OxThera was the possibility to enter a pivotal trial in Primary Hyperoxaluria. This is the final step to be fulfilled before a Marketing Authorisation Application (MAA) can be submitted to the European Medicine Agency (EMA). If EMA considers the application to be acceptable, OxThera could within 12 months from MAA submission, obtain a marketing authorization for the drug to treat Primary Hyperoxaluria in all countries in the EU. There is no treatment for PH available today, so this would constitute a tremendous beneficial impact to patients and society. Prior to marketing and sales, OxThera would need to negotiate the sales price for the drug with each individual national authority controlling pharmaceutical costs for each EU country. Prices for orphan pharmaceutical products range between 50,000 € to 1 million € per year per patient. Assuming the lower price and assuming over 1000 patients in the EU, sales of the O. formigenes drug could potentially earn revenues exceeding 50 million € per year.

b. General advancement of knowledge - Optimised the manufacturing and testing process for the O. formigenes product
OxThera’s knowledge and learning around the development and manufacturing of the O. formigenes drug product, innovative analytical methodology and assays and the disintegration and release profile of the drug product increased significantly as the ELIMOX programme progressed. This knowledge was applied to enhancing our capability in this area.

Partner #2: Cobra Biologics - Publication and Dissemination of Project Information

1. Publications
No peer- reviewed publications were published by Cobra for the manufacturing work package, WP2. The manufacturing process is confidential and important know-how for the concerned participants.
However, in relation to data from the ELIMOX manufacturing work package, WP2, Cobra created factsheets and posters for distribution at conferences and meetings, summarising the Cobra Microbiota service offering and the ELIMOX partnership.

2. Conferences and Meetings
Dissemination of extended technology services was done by SME #2 through presentation at scientific and business conferences and by providing information via their homepage and other networking forums. The Cobra commercial team attend 40+ conferences each year; examples of microbiota specific conferences attended over the last three years include:
➢ 16th European Federation of Biotech, Edinburgh (13-16 July 2014)
➢ 3rd Viruses of Microbes Meeting, Zurich (14-18 July 2014)
➢ CphI ICSE Worldwide, Paris (7-9 October 2014)
➢ BioProcess International, Boston MA (20-23 October 2014)
➢ AAPS Pharma, San Diego CA (2-6 November 2014)
➢ BioEurope Autumn 2014, Frankfurt (3-5 November 2014)
➢ 2nd Microbiome R&D and Business Collaboration Forum, London (7-8 May 2015)
➢ Biotech Builders, Stockholm (27 August 2015)
➢ 3rd Microbiome R&D and Business Collaboration Forum USA, San Diego (10-11 September 2015)
➢ 3rd Microbiome R&D and Business Collaboration Forum, London (11-12 April 2016)
➢ 4th Microbiome R&D and Business Collaboration Forum USA, San Diego (9 June 2016)

The new Microbiota ball featured on the 2016 BIO USA booth and a new Microbiota focused portable conference stand has also been printed to heighten awareness of the services offered.

3. Intellectual Property (Patents)
There were no applications for intellectual property (patents, trademarks, registered designs, etc) related to the ELIMOX manufacturing work package, WP2.

4. Exploitable Foreground
a. General advancement of knowledge - Product development and manufacturing of live biotherapeutic microbiota products
Cobra’s understanding and experience in the product development and manufacturing of live biotherapeutic microbiota products has been significantly expanded through the ELIMOX program.

Prior to the ELIMOX project, Cobra Matfors microbial experience was related to the manufacture of microbial protein based products. The ELIMOX product facilitated an increase in the scientific awareness around technical aspects of manufacturing a live biotherapeutic microbiota product. Summary of the knowledge and learning gained during the ELIMOX project.
• Large scale fermentation of live biotherapeutic microbiota product
• Handling of strict anaerobic organisms
• Additional processing requirements for maintaining viability of cells following the fermentation process
• Process Characterisation – Cobra developed significant learnings in how to map out critical processing parameters

Cobra used the ELIMOX project to develop a supply chain that enabled a ‘one stop shop’ offering for the development and scale up of live biotherapeutic microbiota vaccine products. Cobra built strong relationships with both KAB’s and Galenica, developing working practice and quality systems that are directly transferable to new live biotherapeutic microbiota product contracts.

The knowledge gained has been used to generate proposals for live biotherapeutic microbiota products, which has directly lead to commercial leads with clients at Cobra.

Partner #3 SymbioPharm: Publication and Dissemination of Project Information

1. Publications
No peer- reviewed publications were published for the pharmacodynamics and drug delivery work package, WP3.

2. Conferences and Meetings
SymbioPharm are experts in the field of probiotic drugs, and presented research findings and transpiring new products and services to the market as well as to the scientific and medical communities. SymbioPharm have attended the following conferences during the timelines of the ELIMOX project:
• 28-29 April 2014 Microbiom/ Microbiota, London, UK
• 16-19 June 2014 Rowett-INRA – Gut Microbiology: from sequence to function, Aberdeen, UK
• 27 June – 1 July 2014 Anaerobe, Chicago, USA
• October 05 - 08, 2014 4th Joint Conference of the German Society for Hygiene and Microbiology (DGHM) and the Association for General and Applied Microbiology (VAAM) 2014, Dresden, Germany
• 11 October 2014 3rd Meeting on Microbial Diagnostics, Herborn, Germany
• 1 – 6 March 2015 Gut Microbiota Modulation of Host Physiology: The Search for Mechanism“ in Keystone, Colorado, USA.
• 07 – 11 June 2015 6th Congress of European Microbiologists, Maastricht, The Netherlands
• 17 – 19 October 2015 Targeting Microbiota 2015, Paris, October 2015

3. Intellectual Property (Patents)
There were no applications for intellectual property (patents, trademarks, registered designs, etc) related to the ELIMOX pharmacodynamics/drug delivery work package, WP3.

4. Exploitable Foreground
a. General advancement of knowledge
SymbioPharm’s knowledge and expertise on the development of diagnostic readouts for microorganisms increased as the ELIMOX program proceeded. This knowledge enabled SymbioPharm
• to develop new readouts for their own probiotic strains
• to better monitor their strains in future studies, and
• to understand better the impact of their own strains on the microbiota during treatment.

List of Websites:
The ELIMOX website (elimox.se) was operational on the start date of the project and has been regularly updated throughout the project. Information on the website and press releases were uploaded as D1.2 in Month 5. The website contains information on all 3 reporting periods in the project up to project end.

Related information

Reported by

OXTHERA AB
Sweden
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