Treatment of Chronic Infective Disease with Alginate Oligomer based formulations.

AlgiPharma is developing a novel drug (OligoG) to combat excessive mucus accumulation and chronic multi-drug resistant infections in the lungs of cystic fibrosis patients. OligoG is formulated as a dry powder for inhalation (DPI) and is delivered to patients by use of a CE-marked and FDA-approved inhalator device. The OligoG-Formulate project has provided valuable knowledge on whether OligoG could eventually be administered continuously to patients to maintain a better lung mucus clearance, help combat chronic debilitating lung infections, and ultimately reduce the need for prolonged antibiotic treatment. CF patients spend many hours each day undergoing treatment to prevent disease progression, and it is anticipated that any therapeutic advances that reduce this medication burden would be welcomed by CF patients, doctors and caregivers alike. Long term safety and formulation studies have been performed for the approval of extended duration of OligoG treatment needed for fighting a chronic disease like CF. Existing and new drug formulations have been examined with the objective of securing optimal effect. Optimized test formulations were studied in mucus and microbial biofilm models for screening and monitoring drug absorption. One formulation has already been shown to improve secondary manifestations of CF, which could lead to improvements in patient wellbeing. The work was performed by an international consortium including, SINTEF, NTNU, and Cardiff University and carefully selected sub-contractors, each providing key expertise for delivering the project aims. The project has reached most of its pre-defined milestones. The finalized DPI formulation for stability studies was achieved at the end of 2015, an LC-MS/MS method for detection of OligoG has been developed, and a 4 week Maximum Tolerated Dose (MTD) study has been performed well in advance of schedule and with very good results. This method was further developed and validated in a second independent CRO. However, we discovered that plasma concentrations of OligoG from the MTD study were not high enough to permit further characterization. Nevertheless, the nature of the improved detection assay provided a partial characterization/validation of the OligoG circulating in the plasma. Although the low circulating level of OligoG in the plasma is especially good news for the pharmacodynamics of the drug candidate, it means that we are unable to address the full characterization studies that were outlined and planned. A large data set on formulations and interaction studies in vivo and in vitro were obtained, some of which has led to implementation of changes to the ongoing planning of human clinical trials. A long-term (6 months) animal toxicity study in rat was performed in 2018 that confirms that the product has an exceptional safety profile. The data from the animal tox study forms an important part of a data package to support a submission for Conditional Market Authorization (cMA) for early entry to the European CF market. However, this milestone could not be met in full as it is also dependent on human clinical activities not supported by this project: While previous clinical studies have demonstrated clear efficacy in specific CF patients, additional clinical trials are required to establish optimal dosing and thus we will not be able to coordinate these activities to meet the final project milestone of an application for a cMA. This cMA will therefore be delayed until we have completed the additional clinical trial (ongoing work). Nevertheless, the project has provided essential data for the development of related products for cystic fibrosis and other chronic respiratory diseases.

Outcomes: Competence development at research partners, based upon access to challenges in drug development. Enabling and competence building of AlgiPharma relating to requirements in terms of documenting formulations for approval as new medicinal products. Impact: A new class of medicine available to a broad range of patients with the inherited disease Cystic Fibrosis (CF).

AlgiPharma is developing a novel drug to combat excessive mucus accumulation and chronic multi-drug resistant infections in the CF lung. The drug is in phase 2b clinical trials and is formulated as a dry powder for inhalation (DPI). The major new elements of the OligoG-Formulate project include the investigation of OligoG absorption in animal tissues after more prolonged drug administration. This planned program of work will provide valuable knowledge on whether OligoG could eventually be administered continuously to patients to maintain a better lung mucus clearance, help combat chronic debilitating lung infections, and ultimately reduce the need for prolonged antibiotic treatment. The regulatory authorities require completion of long term safety studies in animals in order to approve the extended duration of OligoG treatment that is needed for fighting a chronic disease like CF. Materials from the animal safety studies will be investigated to evaluate the mechanisms of drug absorption and how that may be enhanced by formulation changes. Optimized test formulations will be studied in mucus and biofilm models in vitro and ex vivo for screening and monitoring of drug absorption, as well as in appropriate animal models. The key partners in the project include, SINTEF, NTNU, and Cardiff University. Results obtained in the OligoG-Formulate project will be valuable and required to make a submission for Conditional Market Authorization for early entry to the European CF market. CF patients spend an estimated 3 hours each day undergoing treatment to prevent disease progression. It is anticipated that any therapeutic advances that could potentially reduce this medication burden would be welcomed by CF patients, doctors and caregivers alike. Indeed AlgiPharma has already received assurances from patient interest organisations in Europe and America that an improved medicinal product for this patient population would expect rapid approval and market uptake.