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

Periodic Reporting for period 1 - OligoGpivotalCF (A pivotal phase IIb clinical trial of inhaled alginate oligosaccharide (OligoG) for cystic fibrosis)

Reporting period: 2018-01-01 to 2019-06-30

The objective of project is to advance the orphan drug OligoG CF-5/20 (OligoG) through a pivotal phase IIb clinical trial, to enable a new and improved therapeutic approach for the orphan disease cystic fibrosis by 2020. 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 release of stagnant mucus, disruption of bacterial biofilm and increased bacterial susceptibility to antibiotics. OligoG received an EU Orphan Drug Medicinal Product Designation in 2007 and an FDA Orphan Drug Designation February 2016, for the treatment of cystic fibrosis.

The planned clinical trial will include 120 CF patients from approx. 35 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 and 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 questionnaires, including standardised CF questionnaires (CFQ-R).

A successful trial will enable preparation of international applications for conditional marketing authorisation (cMAA) throughout Europe and a New Drug Application (NDA) in the US, for the treatment of cystic fibrosis lung disease. In accordance with the work programme, a successful project will thus imply a new and improved therapeutic approach within cystic fibrosis available for CF patients by 2020.
The Consortium consists of partners from five different European countries, with backgrounds from academia, medical professions, commercial enterprises, and importantly, from the patient organisations. Each of the partners brings their special expertise to the table, and together we have made significant progress, although there are still important challenges to handle on the way to our goal.

AlgiPharma AS brought in the concept of a 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. With the help of leading specialists in pediatric and adult lung diseases, the consortium has developed a robust clinical trial protocol to test the dug 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. There are now about 40 sites that will 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 requirements that will enable the drug to be licensed and marketed. Smerud will follow up the performance of the trial, to ensure good quality in all study procedures.

Manufacturing the test material in a large scale has been a particular challenge, but after a few setbacks this has been solved, and the clinical supplies are now being manufactured so that the first study patients can soon be enrolled.

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. In order to ensure that all patients are adequately informed and followed up, the Consortium has involved an independent Ethics Advisor, who is following the project closely. There is also a Data Safety Monitoring Board (DSMB), consisting of experts in medicine, clinical research, and ethics. In case any suspicion of medical safety issues should arise, the DSMB will convene to decide on actions to be taken. In cases where there is a concern, the DSMB may be unblinded in order to determine if specific actions must be taken to ensure patient safety.

The clinical study is designed as a double blind study, where some of the patients receive the active drug, and some receive a placebo, or dummy drug. Neither the patients nor the doctors or hospital staff know which drug a patient is taking. In order to find out how efficacious the treatment is, the patients much must perform several tests to evaluate how well their lungs are functioning. In this trial, the consortium and selected clinical sites will also be testing a new method of measuring lung function, called Lung Clearance Index (LCI). The LCI method shows great promise of being a more sensitive tool for following up CF patients, particularly the younger patients. This work is being led by experts 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.
The project has yet to generate clinical data. The expected results are documentation of 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, but it is a disease that reaches beyond the individual, to caregivers and family members. 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, and further contribute to shift the role of the CF patient from a “burden” for society to a “contributor” to society with activity and income
• 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.

A new and better treatment option to address this unmet medical need is clearly highly desirable. A successful trial resulting in a new treatment slowing the decline in lung function for CF patients, triggered by chronic infections and degeneration of lung tissue, will potentially improve quality of life for CF patients in general. Prolonged active patient participation in work life and society in general will benefit health economics, reduce social costs, and increase potential for tax income. Moreover, development of a new medicinal product addressing lung clearance, infection and antibiotic potentiation while being safe and tolerable also has great potential as a potential new treatment option for other respiratory complications including COPD, non-CF bronchiectasis, chronic sinusitis and diseases made complicated by bacterial biofilms.
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