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A pivotal phase IIb clinical trial of inhaled alginate oligosaccharide (OligoG) for cystic fibrosis

Periodic Reporting for period 4 - OligoGpivotalCF (A pivotal phase IIb clinical trial of inhaled alginate oligosaccharide (OligoG) for cystic fibrosis)

Reporting period: 2022-01-01 to 2022-12-31

The objective of the project is to advance the orphan drug OligoG through a pivotal phase IIb clinical trial, to enable a new and improved therapeutic approach for the orphan disease cystic fibrosis (CF). The study drug is an alginate oligosaccharide derived from seaweed. Several properties relevant to the treatment of CF have been demonstrated using in vitro and ex vivo models, including the release of stagnant mucus, disruption of bacterial biofilm, and increased antibiotic susceptibility. OligoG received an EU Orphan Drug Medicinal Product Designation in 2007 and an FDA Orphan Drug Designation in February 2016 for the treatment of CF.

The planned clinical trial was to include 204 CF patients from approx. 35-40 European sites in coordination with the European Clinical Trial Network. The final study design, selection criteria, procedures and endpoints will be based on results from a recently finalized phase II study. It was to follow scientific advice and protocol assistance received from the European Medicines Agency (EMA). A set of clinical and exploratory endpoints was defined to assess the various effects of OligoG, comprising lung function assessed by spirometry and Lung Clearance Index (LCI) measurements, infection status assessed by frequency of pulmonary exacerbations and non-culture-dependent microbiology, and patient-reported outcomes assessed by standardized CF questionnaires (CFQ-R).

A successful trial would enable the preparation of applications for conditional marketing authorization (cMAA) throughout Europe and a New Drug Application (NDA) in the US for the treatment of CF. In accordance with the work programme, a successful project will thus imply a new and improved therapeutic approach available for CF patients.
The Consortium consists of partners from five different European countries, with academia, medical professions, commercial enterprises, and patient organizations.

AlgiPharma AS introduced the concept of natural medicine based on seaweed to enable patients to clear sticky mucus in the lungs and combat the infections that CF patients often suffer from. The Consortium has developed a clinical trial protocol to test the drug in CF patients down to 12 years of age. There are about 35-40 sites that wanted to participate in the clinical study.

Clinical research is a very specialized field, and the Consortium also includes professionals in clinical research, Smerud Medical. They have ensured that the protocol meets all regulatory and statistical requirements that will enable the drug to be licensed and marketed. Smerud Medical would follow up on the performance of the trial to ensure good quality in all study procedures.

Manufacturing the test material has been a particular challenge, but this was finally solved in 2019.

Inviting patients to test a new drug involves challenges of an ethical nature, particularly when adolescents are involved. It is important to take great care to ensure that all patients, and in the case of children, also their guardians, understand fully what participation in the trial involves. To ensure that all patients are adequately informed and followed up, the Consortium has engaged an independent Ethics Advisor following the project closely. There is also a Data Safety Monitoring Board (DSMB), consisting of experts in medicine, clinical research, and ethics.

The clinical study is designed as a double-blind study. The patients must perform several tests to evaluate how well their lungs function to document how efficacious the treatment is. In this trial, the consortium and selected clinical sites will also be testing a new method of measuring lung function, called the Lung Clearance Index (LCI). The LCI method shows great promise of being a more sensitive tool for following up CF patients, particularly younger patients. Experts are leading this work from Imperial College London. They have set up a training programme for hospitals that are less experienced in this technique, and they will be following up the sites throughout the study.

In spring 2020, we received all ethics and regulatory approvals in all participating countries to start the OligoG-pivotal-CF study with the clinical protocol version 2. Also, a two-year extension to the project was granted by the program office. At the same time, the COVID-19 pandemic put countries in lockdown and restricted access to hospitals and patients. Although we managed to initiate a few sites, it became clear that, due to the COVID-19 pandemic, it was necessary to put the study on hold. Vaccines have been developed, but vaccination was slow due to supply restrictions. Consequently, there was significant variability in vaccine practice and status in countries where the study sites are located. For the present study, with a focus on exacerbations, a stable study population is crucial for the scientific validity of the study.

In combination, the factors mentioned above have, unfortunately, delayed the startup of the study. During this time, the CF therapeutic landscape also changed with the approval of highly effective modulator treatment, Kaftrio, in Europe which have implications for the study's recruitment.

While the landscape is slowly starting to stabilize after the initial crisis of the pandemic, the impact of the introduction of Kaftrio on our study population is still not fully known. New data from the North American CF Conference, November 2021, suggest that most patients on modulators improve lung function by 10-14% and that exacerbation rates decrease by as much as 80%.

The number of patients potentially available for a clinical trial program with OligoG appears insufficient to power a trial to show a statistically significant difference in lung function nor reduced exacerbation rate. Without reaching such clinical endpoints, bringing a drug candidate forward to launch as a CF medication appears futile, and it would be unethical to recruit patients into such a study.

In this context, advice from clinical KOLs and the Horizon 2020 program office was sought. A redesign would be necessary to meet meaningful clinical endpoints in the study. However, we learned from the program office that changing the endpoints and scope of the study would not be accepted and that a further extension to the project would be highly unlikely. Therefore, at the end of 2021, a consortium meeting was called for January 2022 to discuss the closure of the project due to futility in the present context.
The project has advanced the manufacturing of OligoG medicine for respiratory diseases significantly, so a next respiratory clinical trial would benefit from the work done under this programme. The Consortiums combined effort to consider redesign to fit the new treatment landscape of Cystic Fibrosis is a valuable source of knowledge going forward. Since more than half of the adult Cystic Fibrosis population have chronic lung infections, the need for new agents to treat this population is still there, where OligoG’s ability to disrupt bacterial biofilms would still be relevant for Cystic Fibrosis and other lung diseases involving infection. Furthermore, OligoG has shown to not be genotoxic, and as such may prove to be a very useful medicine to fight infections without causing antimicrobial resistance, so all the work put into this project may certainly have significant value for medical treatment, the healthcare systems and society-at-large going forward.
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