Abstract Background Respiratory viral infections are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon-β is naturally produced in response to viral infection, limiting replication. This exploratory study aimed to demonstrate proof-of-mechanism, and evaluate the efficacy and safety of inhaled recombinant interferon-β1a (SNG001) in COPD. Part 1 assessed the effects of SNG001 on induced sputum antiviral interferon-stimulated gene expression, sputum differential cell count, and respiratory function. Part 2 compared SNG001 and placebo on clinical efficacy, sputum and serum biomarkers, and viral clearance. Methods In Part 1, patients (N = 13) with stable COPD were randomised 4:1 to SNG001 or placebo once-daily for three days. In Part 2, patients (N = 109) with worsening symptoms and a positive respiratory viral test were randomised 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation [i.e., acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids]). Results In Part 1, SNG001 upregulated sputum interferon gene expression. In Part 2, there were minimal SNG001–placebo differences in the efficacy endpoints; however, whereas gene expression was initially upregulated by viral infection, then declined on placebo, levels were maintained with SNG001. Furthermore, the proportion of patients with detectable rhinovirus (the most common virus) on Day 7 was lower with SNG001. In Group B, serum C-reactive protein and the proportion of patients with purulent sputum increased with placebo (suggesting bacterial infection), but not with SNG001. The overall adverse event incidence was similar with both treatments. Conclusions Overall, SNG001 was well-tolerated in patients with COPD, and upregulated lung antiviral defences to accelerate viral clearance. These findings warrant further investigation in a larger study. Trial registration EU clinical trials register (2017-003679-75), 6 October 2017.

Background: Interferon beta (IFN-β), a key host antiviral mediator, can be suppressed by virus or host factors locally at the site of infection. Inhaled SNG001 (IFN-β-1a nebuliser solution) aims to restore lung IFN-β levels. In a Phase 2 trial hospitalised COVID-19 patients receiving SNG001 were more than twice as likely to recover, supporting progression to the Phase 3 SPRINTER trial in hospitalised patients and inclusion of SNG001 in the ACTIV-2 Phase 2/3 trial in non-hospitalised volunteers (Figure 1). The SPRINTER study did not meet its primary efficacy endpoints, hospital discharge and recovery, likely due to improved standard of care reducing the window to show a treatment effect. An encouraging signal for the key secondary endpoint, prevention of progression to severe disease or death (26% RRR;OR 0.71(0.44,1.15);p=0.161), was observed and supported by post hoc analyses of at risk groups. Results: In ACTIV-2 there were no statistically significant differences between SNG001 and placebo for the primary outcomes of safety (SNG001 was well-tolerated), symptom resolution, or virology. However, fewer participants required hospitalisation following SNG001 treatment (N=1/110, [1%]) compared to placebo (N=7/110, [6%]), 86% RRR (P=0.07). IDSMB recommended progression to Phase 3. Conclusions: SNG001 was well tolerated across trials and should continue to be investigated for COVID-19 in the home and hospital settings.

Background Despite the availability of vaccines and therapies, patients are being hospitalised with coronavirus disease 2019 (COVID-19). Interferon (IFN)-β is a naturally occurring protein that stimulates host immune responses against most viruses, including severe acute respiratory syndrome coronavirus 2. SNG001 is a recombinant IFN-β1a formulation delivered to the lungs via nebuliser. SPRINTER assessed the efficacy and safety of SNG001 in adults hospitalised due to COVID-19 who required oxygen via nasal prongs or mask. Methods Patients were randomised double-blind to SNG001 (n=309) or placebo (n=314) once daily for 14 days plus standard of care (SoC). The primary objective was to evaluate recovery after administration of SNG001 versus placebo, in terms of times to hospital discharge and recovery to no limitation of activity. Key secondary end-points were progression to severe disease or death, progression to intubation or death and death. Results Median time to hospital discharge was 7.0 and 8.0 days with SNG001 and placebo, respectively (hazard ratio (HR) 1.06 (95% CI 0.89–1.27); p=0.51); time to recovery was 25.0 days in both groups (HR 1.02 (95% CI 0.81–1.28); p=0.89). There were no significant SNG001–placebo differences for the key secondary end-points, with a 25.7% relative risk reduction in progression to severe disease or death (10.7% and 14.4%, respectively; OR 0.71 (95% CI 0.44–1.15); p=0.161). Serious adverse events were reported by 12.6% and 18.2% patients with SNG001 and placebo, respectively. Conclusions Although the primary objective of the study was not met, SNG001 had a favourable safety profile, and the key secondary end-points analysis suggested that SNG001 may have prevented progression to severe disease.

BACKGROUND:Effective therapeutics given early to high-risk ambulatory patients with coronavirus disease 2019 (COVID-19) could improve outcomes and reduce overall healthcare burden. However, conducting site visits in non-hospitalised patients, who should remain isolated, is problematic.AIM:To evaluate the feasibility of a purely remote (virtual) study in non-hospitalised patients with COVID-19; and the efficacy and safety of nebulised recombinant interferon-β1a (SNG001) in this setting.DESIGN & SETTING:Randomised, double-blind, parallel-group study, which was conducted remotely.METHOD:Eligible patients aged ≥65 years (or ≥50 years with risk factors) with COVID-19 and not requiring hospital admission were recruited remotely. They were randomised to SNG001 or placebo once-daily via nebuliser for 14 days. The main outcomes were assessments of feasibility and safety, which were all conducted remotely.RESULTS:Of 114 patients treated, 111 (97.4%) completed 28 days of follow-up. Overall compliance to study medication was high, with ≥13 doses taken by 89.7% and 92.9% of treated patients in the placebo and SNG001 groups, respectively. Over the course of the study, only two patients were hospitalised, both in the placebo group; otherwise there were no notable differences between treatments for the efficacy parameters. No patients withdrew owing to an adverse event, and a similar proportion of patients experienced on-treatment adverse events in the two treatment groups (64.3% and 67.2% with SNG001 and placebo, respectively); most were mild or moderate and not treatment-related.CONCLUSION:This study demonstrated that it is feasible to conduct a purely virtual study in community-based patients with COVID-19, when the study included detailed daily assessments and with medication administered via nebuliser.

Abstract Background Respiratory viral infections (RVIs) are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon beta (IFN-β) is key in host defence against viruses but can be suppressed by virus or host factors locally at the site of infection. Inhalation of SNG001 (IFN-β-1a nebuliser solution) aims to restore lung IFN-β levels. SG015 (NCT03570359) was a randomized, placebo-controlled Phase 2 clinical study of inhaled SNG001 conducted in COPD patients. Here we describe lung antiviral biomarker and sputum viral clearance data from Part 2 of the study which was conducted in patients with a confirmed RVI. Methods 109 COPD patients with worsening symptoms and a positive respiratory viral test were randomized 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation [i.e.,acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids]). Sputum samples were collected on days 1, 4, 7, 10, 13, 17 and 28 for analysis of lung antiviral biomarker responses (interferon-stimulated genes (ISGs): Mx1, OAS1 and CXCL10) and lung viral load by RT-qPCR. Results Mx1 and OAS1 sputum cell gene expression were significantly upregulated on day 7, 10 and 13 (p< 0.05) overall and in Groups A and B with SNG001 treatment compared to placebo. CXCL10 sputum cell gene expression was significantly upregulated in the overall population with SNG001 treatment compared to placebo on days 7 and 10, in Group B on days 7, 10 and 13, and there was no significant difference in Group A. Patients had a broad range of RVIs, the most common being human rhinovirus. A post-hoc analysis was therefore conducted in the subgroup of patients who had detectable rhinovirus viral load in sputum. By Day 4 the proportion of patients receiving SNG001 who had detectable rhinovirus reduced to 40.0% (compared to 94.7% of patients receiving placebo; p=0.052), with a further reduction to 20.0% on Day 7 (versus 89.5% receiving placebo; p=0.014). Conclusion Inhaled SNG001 upregulated lung antiviral defenses as assessed using sputum cell biomarker responses and accelerated viral clearance, supporting the proposed mechanism of action as an antiviral treatment for severe viral lung infections. Disclosures Phillip D. Monk, PhD, Synairgen Research Plc: Employee of Synairgen Research Plc and has options on shares|Synairgen Research Plc: Stocks/Bonds Jody L. Brookes, BSc, Synairgen Research Ltd: Share options Victoria J. Tear, PhD, Synairgen Research Ltd.: Stocks/Bonds Marcin Mankowski, MD MFPM (Dis), Multiple companies: Advisor/Consultant|Synairgen: Advisor/Consultant Michael G. Crooks, MBChB (hons), MD, FRCP, AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|AstraZeneca: Honoraria|Chiesi: Advisor/Consultant|Chiesi: Honoraria|Gilead: Honoraria|Synairgen: Advisor/Consultant Dave Singh, MD, AstraZeneca: Advisor/Consultant|Chiesi: Advisor/Consultant|gsk: Advisor/Consultant|Novartis: Advisor/Consultant|Orion: Advisor/Consultant|Pulmatrix: Advisor/Consultant|Sanofi: Advisor/Consultant|Synairgen: Advisor/Consultant|Synairgen: Grant/Research Support|Therevance: Advisor/Consultant Rekha Chaudhuri, MD, AstraZeneca: Grant/Research Support|AstraZeneca: Honoraria|Chiesi: Honoraria|GSK: Honoraria|Novartis: Honoraria|Sanofi: Honoraria|Teva: Honoraria Sarah Dudley, N/A, PhD, Synairgen Plc: Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc|Synairgen Plc: Stocks/Bonds Felicity Gabbay, MbChb, Synairgen: Board Member Stephen T. Holgate, FMedSci, MD, Synairgen Research Plc: Board Member|Synairgen Research Plc: Stocks/Bonds Ratko Djukanovic, MD, GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Honoraria|KyMab: Advisor/Consultant|Sanofi: Advisor/Consultant|Synairgen: Advisor/Consultant|Synairgen: Stocks/Bonds Tom Wilkinson, PhD, PhD, Synairgen: Advisor/Consultant|Synairgen: Grant/Research Support|Synairgen: Honoraria

People with post-COVID conditions can have a wide range of symptoms lasting months and it can affect as many as one in five infected people. Interferon beta (IFN-β) is key in host defence against viruses but can be suppressed by virus or host factors locally at the site of infection. Inhalation of SNG001 (IFN-β-1a nebuliser solution) aims to restore lung IFN-β levels. SPRINTER (NCT04732949) was a RCT of inhaled interferon beta in hospitalised COVID-19. There was no effect of SNG001 on the primary endpoints of time to discharge or recovery most likely due to improvements in the standard of care. However, there was an encouraging signal for the key secondary endpoint of prevention of progression to severe disease or death (ITT 26% relative risk reduction [RRR]; Odds Ratio [95% CI]: 0.71 [0.44, 1.15]; Per Protocol 36% RRR; OR 0.63 [0.35, 1.13]). Post hoc analyses showed enhanced effects favouring SNG001 in subgroups at higher risk of progression. We report on the impact of SNG001 on long COVID symptoms in SPRINTER. Patients requiring low-flow oxygen were randomized to receive SNG001 (314) or placebo (309) once daily for 14 days, plus standard-of-care. Long COVID symptoms were assessed as a secondary endpoint at follow-up visits via telephone/video call on Day 60 and Day 90. The following patient reported outcome (PRO) measures were also assessed: General Anxiety Disorder 7 Questionnaire (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale and Brief Pain Inventory (Short Form). When compared to placebo, SNG001 reduced the relative risk of common symptoms of long COVID (fatigue/malaise [RRR=35.4%]; dyspnoea [RRR=28.3%]; loss of smell and/or taste [RRR=61.4%]). Analysis of the PROs is ongoing. Assessment of COVID symptoms at Day 60 and 90 follow up visits Effect of SNG001 treatment on long COVID symptoms Long COVID can leave patients with lingering cognitive, respiratory, and functional symptoms months after a SARS-CoV-2 infection. Given the shift from pandemic to endemic status for COVID-19 and the need for new treatments then these findings, suggesting SNG001 may be impacting common long COVID symptoms, provide additional support for the further investigation of SNG001. Phillip D. Monk, PhD, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Board Member|Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Victoria J. Tear, PhD, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Jody L. Brookes, BSc, Synairgen Plc (Employed by Synairgen Research Ltd which is a subsidiary of Synairgen Plc, Stocks/Bonds): Stocks/Bonds Marcin Mankowski, MD, MFPM (Dis), CytoDyn: Advisor/Consultant|Entasis: Advisor/Consultant|ImmuPharma: Advisor/Consultant|Menarini: Advisor/Consultant|Pfizer: Advisor/Consultant|Synairgen: Advisor/Consultant|Venatorx: Advisor/Consultant Ratko Djukanovic, MD, Synairgen: Advisor/Consultant|Synairgen: Honoraria|Synairgen: Stocks/Bonds Stephen T. Holgate, FMedSci, MD, Synairgen: Board Member|Synairgen: Non executive board director, patent on inhaled interferon beta|Synairgen: Stocks/Bonds chris brightling, FMedSci, Synairgen: Advisor/Consultant|Synairgen: Grant/Research Support Tom Wilkinson, PhD, PhD, AZ: Grant/Research Support|AZ: Honoraria|My mhealth: Board Member|My mhealth: Ownership Interest|My mhealth: Stocks/Bonds|Synairgen: Grant/Research Support|Synairgen: Honoraria.

Rationale: Interferon beta (IFN-β) is key in host defence against viruses but can be suppressed by virus or host factors locally at the site of infection. Inhalation of SNG001 (IFN-β-1a nebuliser solution) aims to restore lung IFN-β levels. Methods: Adults hospitalised due to COVID-19 requiring low flow oxygen were randomized to receive SNG001 (314) or placebo (309) OD for 14 days, plus standard-of-care. Efficacy was assessed by change in clinical condition using the WHO 9-point Ordinal Scale for Clinical Improvement (OSCI). Primary endpoints: time to discharge (OSCI ≤2) and time to recovery (OSCI ≤1). Key secondary endpoints: progression to severe disease or death (OSCI ≥5), progression to intubation or death (OSCI ≥6), and death. Results: Most patients were discharged rapidly from hospital and there was no effect of SNG001 on time to discharge or recovery. However, there was an encouraging signal for prevention of progression to severe disease or death (ITT 26% relative risk reduction (RRR); Odds Ratio (95% CI): 0.71 (0.44, 1.15); Per Protocol 36% RRR; OR 0.63 (0.35, 1.13)). Post hoc analyses supported this observation with enhanced effects favouring SNG001 in subgroups at higher risk of progression (≥65 years; ≥1 comorbidity; oxygen saturation ≤92% and/or respiratory rate ≥21 breaths/min on oxygen). Conclusion: If the encouraging signal in the relative risk of disease progression or death (~30% reduction) observed in this 300 patient/arm trial were confirmed in a larger trial, SNG001 could become a useful treatment option for hospitalised COVID-19 patients.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection carries a substantial risk of severe and prolonged illness; treatment options are currently limited. We assessed the efficacy and safety of inhaled nebulised interferon beta-1a (SNG001) for the treatment of patients admitted to hospital with COVID-19.MethodsWe did a randomised, double-blind, placebo-controlled, phase 2 pilot trial at nine UK sites. Adults aged 18 years or older and admitted to hospital with COVID-19 symptoms, with a positive RT-PCR or point-of-care test, or both, were randomly assigned (1:1) to receive SNG001 (6 MIU) or placebo by inhalation via a mouthpiece daily for 14 days. The primary outcome was the change in clinical condition on the WHO Ordinal Scale for Clinical Improvement (OSCI) during the dosing period in the intention-to-treat population (all randomised patients who received at least one dose of the study drug). The OSCI is a 9-point scale, where 0 corresponds to no infection and 8 corresponds to death. Multiple analyses were done to identify the most suitable statistical method for future clinical trials. Safety was assessed by monitoring adverse events for 28 days. This trial is registered with Clinicaltrialsregister.eu (2020-001023-14) and ClinicalTrials.gov (NCT04385095); the pilot trial of inpatients with COVID-19 is now completed.FindingsBetween March 30 and May 30, 2020, 101 patients were randomly assigned to SNG001 (n=50) or placebo (n=51). 48 received SNG001 and 50 received placebo and were included in the intention-to-treat population. 66 (67%) patients required oxygen supplementation at baseline: 29 in the placebo group and 37 in the SNG001 group. Patients receiving SNG001 had greater odds of improvement on the OSCI scale (odds ratio 2·32 [95% CI 1·07–5·04]; p=0·033) on day 15 or 16 and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment (hazard ratio 2·19 [95% CI 1·03–4·69]; p=0·043). SNG001 was well tolerated. The most frequently reported treatment-emergent adverse event was headache (seven [15%] patients in the SNG001 group and five [10%] in the placebo group). There were three deaths in the placebo group and none in the SNG001 group.InterpretationPatients who received SNG001 had greater odds of improvement and recovered more rapidly from SARS-CoV-2 infection than patients who received placebo, providing a strong rationale for further trials.FundingSynairgen Research.