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Chronic Obstructive Pulmonary Disease (COPD) is a lung condition characterised by airflow limitation that is not fully reversible. This airflow limitation is normally progressive and is associated with an abnormal inflammatory response of the lung to pathogenic stimulus. The majority of COPD is associated with long-term cigarette smoking. Symptoms of COPD include cough, excessive sputum production, and shortness of breath.
Exacerbations of COPD are defined as the worsening of COPD symptoms beyond normal day-to-day variations and are associated with irreversible loss of lung function and, therefore, accelerated disease progression. Exacerbations severely impact on the patient’s quality of life (patients typically take a number of weeks to recover) and are a major healthcare burden and are the second most common cause of emergency admissions to hospital in England1. Exacerbations are currently treated with oral corticosteroids and antibiotics. Systemic administration of corticosteroids is associated with unwanted side effects and there is a drive to reduce antibiotic usage.
Respiratory viral infections, such as the common cold and flu, are a major driver of exacerbations in patients with lung disease when infections spread from the upper respiratory tract to the lungs to worsen pre-existing lung inflammation. Furthermore, particularly in COPD, there is growing evidence that virus infections increase susceptibility to follow on bacterial infections. Therefore, there is a strong rationale to develop antiviral treatments to prevent or treat exacerbations of COPD.
Interferon beta is a naturally-occurring protein that orchestrates the body’s anti-viral defences. We have shown in in vitro models (see Figure 1 below) that interferon beta protects the lung cells of COPD patients when infected with viruses that cause exacerbations. SNG001 is a formulation of interferon beta delivered to the lung using a nebuliser.
Figure 1: IFN-ß treatment of lung cells from smokers/COPD patients cultured in the lab protects them from infection with the common cold virus.
Two Phase II trials (SG005 and INEXAS) in asthma, conducted by Synairgen and AstraZeneca respectively, suggest that SNG001 boosts antiviral responses in the lungs, has a beneficial effect on lung function and, in more difficult to treat patients, improves asthma control during cold infections. However, the unexpectedly low exacerbation rate (<10%) in the INEXAS trial population suggests that the economic viability of the drug in an asthma indication would be limited.
Studies in COPD patients published in 2017 suggest that looking at all colds in the study period, the risk that a cold will cause an exacerbation of COPD is much higher at around 50%7 and could be even higher in particular at risk patients8, making COPD a very attractive market.
However, up until now, our ability to identify those patients who may benefit from an inhaled anti-viral therapy made the design of a prospective study challenging. This is because exacerbations of COPD can be caused by other factors such as bacterial infections.
Recently, a novel point of care diagnostic tool has been developed which enables rapid confirmation of the existence of a respiratory viral infection when patients present themselves at the hospital or trial site. This has enabled Synairgen to only treat patients who are infected with a virus, significantly reducing the number of subjects required to show the potential effect of SNG001. This has significant benefits in the future, allowing accurate prescribing of antiviral therapy quickly to patients who could benefit from treatment.
SG015 Clinical Trial
In February 2018, Synairgen commenced a two-part Phase II trial to evaluate the potential of SNG001 in COPD, called SG015.
In part one of the trial, SNG001 was well tolerated in patients with moderate to severe COPD, and biomarkers of antiviral activity were significantly elevated 24 hours following IFN-β inhalation.
Part 2 of the trial, was designed to study the efficacy and safety of inhaled SNG001 in up to 120 COPD patients with a confirmed respiratory viral infection, commenced in October 2018, and recruitment into the trial commenced in earnest in January 2019.
In March 2019 the Data Safety Monitoring Committee (DSMC) completed its planned safety review of Part 2 of the trial. In its review, the DSMC did not identify any safety concerns for patients currently enrolled and it endorsed a pre-planned broadening of the patient population to allow patients with more severe COPD to participate in the trial.
The trial was progressing well until the emergence of SARS-CoV-2, which made it difficult to test this vulnerable patient population for virus and dose patients without potentially exposing them and research staff to SARS-CoV-2. Hence, in March 2020, the trial was paused with 109 out of the targeted 120 patients recruited. Synairgen shortly after received approval from the Medicines and Healthcare products Regulatory Agency (MHRA) to run an unplanned interim analysis on the grounds that data from 109 COPD patients with confirmed viral infection could generate data to support Synairgen’s ongoing trials of SNG001 in COVID-19 patients, SG016.
SG015 Interim Analysis
On 8 September 2020, Synairgen announced positive data from the interim analysis of its Phase II clinical trial of inhaled SNG001 in COPD patients with a confirmed respiratory viral infection. The full announcement can be read here.
Key findings included
SNG001 was well tolerated during the treatment period in a study population that was elderly (mean age 66 years) and suffering from reduced respiratory function, as measured by forced expiratory volume in one second (FEV1) (59% of predicted value).
The percentage of on-treatment adverse events was similar in the placebo and SNG001 treatment groups (48.1% versus 45.6%, respectively), with treatment-related adverse events being more frequent in the placebo group (25%) compared to the SNG001 group (15.8%). This safety data adds to the safety database for SNG001, supporting Synairgen’s interactions with regulatory agencies in respect of COVID-19, where older age and poor lung function are risk factors.
During the treatment period, lung antiviral responses to viral infection were significantly enhanced in patients receiving SNG001 when compared to those receiving placebo, as assessed by measuring increases in the gene expression of interferon beta-dependent antiviral biomarkers MX1 (p=<0.001) and OAS1 (p=<0.001) in lung (sputum) cells.
The impact of viral infection on COPD patient participating in the trial was most evident on peak expiratory flow rate (PEFR), a measure of lung function, and patient-reported symptoms assessed using the Breathlessness Cough and Sputum Score (BCSS), and was particularly apparent in exacerbating patients already requiring treatment with oral corticosteroids and/or antibiotics at the time of randomization, and who represented one third of the patients enrolled.
Importantly, exacerbating patients (patients already requiring treatment with oral corticosteroids and/or antibiotics), experienced significantly better lung function during the treatment period. Although there was no significant difference in total BCSS in this group over the treatment period, there was a trend for the breathlessness component of the score, suggesting that patients may have recovered more rapidly if they received SNG001 rather than a placebo.
Patients recruited in this trial all had a confirmed respiratory virus, which is relevant for Synairgen’s SG016 trial in COVID-19 patients, as these patients can be coinfected with other respiratory viruses such as influenza, and SNG001 demonstrated antiviral activity against multiple viruses in cell-based assays.