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

Periodic Reporting for period 3 - OligoGpivotalCF (A pivotal phase IIb clinical trial of inhaled alginate oligosaccharide (OligoG) for cystic fibrosis)

Reporting period: 2021-01-01 to 2021-12-31

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. 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 model systems, 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 February 2016 for the treatment of CF.

The planned clinical trial will include 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 will follow scientific advice and protocol assistance sought at the European Medicines Agency (EMA). A set of clinical and exploratory endpoints will be 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 will 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 notably, patient organizations.

AlgiPharma AS brought in the concept of natural medicine based on seaweed to enable patients to clear sticky mucus in the lungs and to combat the infections that CF patients often suffer from. The Consortium developed a robust clinical trial protocol to test the drug in CF patients down to 12 years of age. The CF patient community and their networks have been instrumental in recruiting the best hospitals and medical institutions to participate in the clinical trial.

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 will 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 at Brompton Hospital. 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 (UK, Ireland, Austria, Germany, Poland) 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 Horizon 2020 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. COVID-19 represents an extra burden for CF patients. 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 cystic fibrosis therapeutic landscape also changed with the marketing authorization of the 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 Cystic Fibrosis 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%. Also, data suggest that patients not eligible for modulator therapy show some benefits.

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. Therefore, at the end of 2021, a consortium meeting was called for January 2022 to discuss the potential closure of the project due to futility in the present context.
The expected results are documentation of the safety and efficacy of OligoG, which will lead to conditional marketing authorization in Europe for a new drug as an outcome.

Approximately 80.000 people worldwide suffer from CF. Most patients are regularly followed up at their respective clinics throughout their lives. Combined with the time spent in hospital for exacerbations, or awaiting lung transplants, the burden on individual patients, relatives, CF clinics, healthcare services, and society at large is significant.

Benefits for society include:
• A unique new treatment alternative improving quality of life and life expectancy for CF patients, enabling them to maintain activities and duties including job, earn income, pay tax, etc.
• Reduced exacerbation rate will imply less frequent hospital admissions.
• Reduced infection burden implies reduced need for prescribed antibiotics, as an additional valuable contribution.
• Reduced time to market for new CF medicines, due to the establishment of LCI as a new clinical endpoint with lower variability.
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