Periodic Reporting for period 2 - Calcivis CAIS (Validation of clinical performance and pre-commercial development of a novel diagnostic for dental caries assessment)
Periodo di rendicontazione: 2016-07-01 al 2017-06-30
Untreated caries (tooth decay) in permanent teeth was found to be the most prevalent condition evaluated in the entire 2010 Global Burden of Disease Study (Murray et al, The Lancet 380), affecting 35% of the global population. In the EU, while there has been significant progress in recent decades in the prevention of caries in children, ‘the bad news is that having damaged, missing or filled teeth is still the norm rather than the exception in Europe’ (The State of Oral Health in Europe, Patel et al, 2012). The same report identified that the cost of traditional curative dental care to the EU 27 countries ‘is close to €79 billion, and if the trends continue, this figure could be as high as €93 billion in 2020’. Improvement of oral health and containment of the associated costs requires a shift away from the curative ‘drill and fill’ paradigm, which locks patients into a cycle of recurrent tooth restoration and progressive age-related loss of tooth structure, and towards preventive dentistry. While this requires changes in health care practice, it also needs the introduction of enabling new technologies.
Calcivis is developing a globally competitive, disruptive technology that addresses a major unmet need in general dentistry. Fundamental to the effective management of caries is 1) the ability to detect caries early (before cavitation when the disease process can still be reversed) and 2) to identify which lesions are active i.e. likely to progress, and those which are inactive and therefore unlikely to progress. Until now, the assessment of caries activity has relied primarily on subjective visual and tactile inspection, which leads to active caries lesions going untreated, and the unnecessary treatment of inactive lesions.
The Calcivis Imaging System will, for the first time, allow the real-time detection and visualisation of calcium ions released by active demineralising caries lesions, in routine patient dental examinations. Early detection and assessment of caries activity with the Calcivis System will allow for tailored, rational, evidence-based treatment in line with dental best practice. It will accelerate the ongoing development of preventive dentistry and the move away from the ‘drill and fill’ paradigm.
This overall objective of the project was to get the Company to the point where the Calcivis System is clinically validated in preparation for launch, thereby accelerating commercialisation and enabling the company to raise the substantial funding and form the industry partnerships required to realise the full global potential of the technology.
The broad objectives of the project are as follows:
1. Validate the clinical performance of the Calcivis System through two clinical studies
2. Scale up manufacturing in preparation for EU launch
3. Create and submit a regulatory filing to FDA to enable US market access
Calcivis is developing a globally competitive, disruptive technology that addresses a major unmet need in general dentistry. Fundamental to the effective management of caries is 1) the ability to detect caries early (before cavitation when the disease process can still be reversed) and 2) to identify which lesions are active i.e. likely to progress, and those which are inactive and therefore unlikely to progress. Until now, the assessment of caries activity has relied primarily on subjective visual and tactile inspection, which leads to active caries lesions going untreated, and the unnecessary treatment of inactive lesions.
The Calcivis Imaging System will, for the first time, allow the real-time detection and visualisation of calcium ions released by active demineralising caries lesions, in routine patient dental examinations. Early detection and assessment of caries activity with the Calcivis System will allow for tailored, rational, evidence-based treatment in line with dental best practice. It will accelerate the ongoing development of preventive dentistry and the move away from the ‘drill and fill’ paradigm.
This overall objective of the project was to get the Company to the point where the Calcivis System is clinically validated in preparation for launch, thereby accelerating commercialisation and enabling the company to raise the substantial funding and form the industry partnerships required to realise the full global potential of the technology.
The broad objectives of the project are as follows:
1. Validate the clinical performance of the Calcivis System through two clinical studies
2. Scale up manufacturing in preparation for EU launch
3. Create and submit a regulatory filing to FDA to enable US market access
The total project lasted 24 months. This reports concerns the second 12 months of activity. Overall the project has gone largely according to plan; we have made excellent progress in the development of the technology and the Company. The project is divided into five main research and development work packages (WP). A brief summary of each is shown below.
WP1 Camera applicator design and manufacturing scale up. The design of the new Calcivis Imaging System has been completed and the pre-commercial devices manufactured and tested. An EU based, medical device contract manufacturing organisation (CMO) has been selected for commercial supply. The technology transfer process to the CMO is complete and devices are now being shipped for a beta test launch in the UK.
WP2 Photoprotein manufacturing and scale up. The biological manufacturing process has now been optimised to improve process yields dramatically. The bulk manufacturing process has been successfully conducted at commercial scale in a GMP (Good Manufacturing Practice) environment as required by the regulatory authorities.
WP3 Clinical studies of Calcivis Imaging System. All the preparation work and ethical approvals for the two planned clinical studies has been completed. The pivotal study was developed in consultation with FDA and has now finished, achieving its primary and secondary endpoints.
WP4 Laboratory studies of Calcivis System. A programme of experiments has been designed in collaboration with our external scientific/clinical advisers to optimise the utility of the System in imaging demineralisation. Specific experiments have focused on the imaging of artificially created erosive lesions as well as caries and the effect of remineralisation therapies. The experimental plan has completed and the results reported as part of the project.
WP5 Regulatory activity to support EU/US market access. The Calcivis Imaging System is regulated as a class II Medical Device in the EU and has received a CE mark. The main focus of this work package has been the preparation of the regulatory filing for the FDA, specifically a PMA (Premarket Authorisation). This is now close to complete and we intend to submit the PMA to the FDA in September this year.
WP1 Camera applicator design and manufacturing scale up. The design of the new Calcivis Imaging System has been completed and the pre-commercial devices manufactured and tested. An EU based, medical device contract manufacturing organisation (CMO) has been selected for commercial supply. The technology transfer process to the CMO is complete and devices are now being shipped for a beta test launch in the UK.
WP2 Photoprotein manufacturing and scale up. The biological manufacturing process has now been optimised to improve process yields dramatically. The bulk manufacturing process has been successfully conducted at commercial scale in a GMP (Good Manufacturing Practice) environment as required by the regulatory authorities.
WP3 Clinical studies of Calcivis Imaging System. All the preparation work and ethical approvals for the two planned clinical studies has been completed. The pivotal study was developed in consultation with FDA and has now finished, achieving its primary and secondary endpoints.
WP4 Laboratory studies of Calcivis System. A programme of experiments has been designed in collaboration with our external scientific/clinical advisers to optimise the utility of the System in imaging demineralisation. Specific experiments have focused on the imaging of artificially created erosive lesions as well as caries and the effect of remineralisation therapies. The experimental plan has completed and the results reported as part of the project.
WP5 Regulatory activity to support EU/US market access. The Calcivis Imaging System is regulated as a class II Medical Device in the EU and has received a CE mark. The main focus of this work package has been the preparation of the regulatory filing for the FDA, specifically a PMA (Premarket Authorisation). This is now close to complete and we intend to submit the PMA to the FDA in September this year.
The Calcivis System has the potential to support a new standard of care in the management of tooth decay. Uniquely in dentistry, it uses biotechnology to move beyond the current state of the art in the diagnosis and management of demineralisation caused by caries and erosion. It will accelerate the movement towards preventive dentistry and the move away from the ‘drill and fill’ paradigm.
No other approach provides this type of information on the pathological process of ongoing demineralisation. Its novelty has been recognised by the European Patent Office which granted our Detection of Demineralisation patent in 2014.
Scientifically this represents a totally new approach to the problem of assessing the activity of tooth decay. For the first time dentists will be able to directly detect and localise the products of demineralisation on the tooth surface (using a bioluminescent protein to detect free calcium) during a clinical examination. The resulting demineralisation map image will be shared with patients to explain and support the proposed course of treatment. Current state of the art relies on subjective visual and tactile inspection. Radiographs can help to stage the extent of caries but are of limited use for the diagnosis of early disease and do not provide information on the activity of caries lesions.
The Calcivis System will enable dentists to manage patients with caries based on this new class of evidence. This will help avoid unnecessary restoration (move away from automatic drill/fill response to lesions) and enable broader use of secondary preventive therapies (e.g. sealants and fluoride varnishes). It is also important that the System is quick and easy to use; essentially the product is used like an intraoral camera (of which dentists already have experience) with the application of the photoprotein automated, allowing the whole application and imaging process to be completed in less than a second at the press of a button, once the device is positioned over the tooth surface of interest.
This project has been a major stepping stone on the path to making the potential benefits of the technology real for dentists and patients. It has provided clinical validation of the Calcivis System and scaled up the necessary manufacturing capability in advance of launching the product in the EU and US.
No other approach provides this type of information on the pathological process of ongoing demineralisation. Its novelty has been recognised by the European Patent Office which granted our Detection of Demineralisation patent in 2014.
Scientifically this represents a totally new approach to the problem of assessing the activity of tooth decay. For the first time dentists will be able to directly detect and localise the products of demineralisation on the tooth surface (using a bioluminescent protein to detect free calcium) during a clinical examination. The resulting demineralisation map image will be shared with patients to explain and support the proposed course of treatment. Current state of the art relies on subjective visual and tactile inspection. Radiographs can help to stage the extent of caries but are of limited use for the diagnosis of early disease and do not provide information on the activity of caries lesions.
The Calcivis System will enable dentists to manage patients with caries based on this new class of evidence. This will help avoid unnecessary restoration (move away from automatic drill/fill response to lesions) and enable broader use of secondary preventive therapies (e.g. sealants and fluoride varnishes). It is also important that the System is quick and easy to use; essentially the product is used like an intraoral camera (of which dentists already have experience) with the application of the photoprotein automated, allowing the whole application and imaging process to be completed in less than a second at the press of a button, once the device is positioned over the tooth surface of interest.
This project has been a major stepping stone on the path to making the potential benefits of the technology real for dentists and patients. It has provided clinical validation of the Calcivis System and scaled up the necessary manufacturing capability in advance of launching the product in the EU and US.