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expert reaction to announcement by Synairgen that their drug SNG001 has had positive results in initial trials on COVID-19 patients

The UK drug company Synairgen, founded by academics from the University of Southampton, have announced in a press release that their drug SNG001 has had positive results on COVID-19 patients in initial trials.

 

Prof Dave Singh, Professor of Clinical Pharmacology and Respiratory Medicine, University of Manchester, said:

“There is plenty of evidence that interferon beta is a key component of human immune defence against viral infection. As a scientific concept, using SNG001 to increase interferon beta levels as a treatment for COVID-19 makes a lot of sense.

“This is a phase 2 study where limited numbers of patients are enrolled in order to quickly acquire enough data to analyse whether the drug has beneficial effects. In such studies, one usually looks across the whole range of results, rather than putting excessive focus on the primary endpoint; this allows us to understand whether the effects are consistent or could be spurious false positive artefacts due to a small sample size. It is extremely encouraging to see positive results across different endpoints, and in the subgroup of more severely affected individuals who needed oxygen at the time of hospital admission. The most important result appears to be a reduction in the number of patients requiring ventilation. While some caution should be applied until we see the full publication of data, these results suggest that interferon beta urgently warrants further evaluation as a treatment for COVID-19.

 

Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:

“Synairgen have released the first analysis of the SG016 trial of inhaled interferon-beta-1a (SNG001) in patients in a press release this morning. The trial design has changed from that published on clinicaltrials.gov and the data presented are from a revised phase II trial in 100 patients hospitalised with COVID-19.

1. What unanswered questions are there from the study?

“The data presented are preliminary information only from patients requiring hospitalisation. A parallel study is recruiting patients ill with COVID-19 in the community. Baseline features of each arm demonstrated that the proportion of patients with diabetes was three times higher in the placebo arm (9/50, 18%) than among those taking interferon (3/48, 6.3%). There was also an imbalance in the proportion of patients with cardiovascular disease between those taking placebo (8/50, 16%)and those taking interferon (5/48; 10.4%). These differences could have affected the outcome, although at a press conference today the company commented that the analysis was adjusted for baseline risk factors.

“The primary outcome reported by the company emphasised a reduction in death/need for ventilatory support over the first 16 days of the study of ~79%; however only the number of deaths was given (3 patients, all on placebo). The company stated that this difference was also noted to day 28, but has not provided the number of patients with these outcomes in either arm. The proportion of subjects with a post baseline score of 0 (no clinical/virological evidence of infection) or 1 (ambulatory no limitation of normal activities) on the WHO ordinal scale was also significantly higher throughout most of the post treatment window among patients receiving interferon, with ~60% of subjects on interferon achieving this outcome by day 28 compared to ~30% of those on placebo.

“The results of the study, and of the statistical methods used to compare the outcomes, now need to be fully published to enable the scientific community to review these more comprehensively. The study is small, and the imbalance in high risk factors across the two populations suggest that more information would be needed to confirm these preliminary results.

2. What should the next steps be?

“The company would be well advised to mount a larger multinational study in countries with an ongoing epidemic to confirm these preliminary findings. In particular, any new study should balance the populations at baseline for factors known to increase mortality.

3. How do the results compare to dexamethasone?

“This did not include patients requiring ventilatory support which is the population which derived greatest benefit from dexamethasone treatment. Receipt of corticosteroid may overwhelm the effect of inhaled interferon in patients treated in ICU, and this needs to be further investigated.”

 

Dr Nick Cammack, COVID-19 Therapeutics Accelerator Lead at Wellcome, said:

“Having a wide range of effective COVID-19 treatments is essential. Once the results reported by Synairgen are confirmed, then the signs look promising and could be a significant step forward in COVID-19 treatment research. But we should remain cautious with our expectations until we see the data published in full.

“In just a few months, we already have two treatments that are proven to reduce hospital stays and mortality from COVID-19 – dexamethasone and remdesivir. But we need many more. Investing in research into a wide range of treatments, alongside vaccines and testing, and ensuring all advances are fairly available globally, is our only exit from this pandemic.”

 

Prof Martin Landray, Professor of Medicine and Epidemiology, University of Oxford, said:

“This trial is too small to draw firm conclusions. The headline reduction in progression to severe disease comes with huge statistical uncertainty. It is good to see new treatments being developed and evaluated – but there is a big difference between encouraging early results and definitive evidence that transforms clinical practice. A much larger randomised trial is needed to assess whether this treatment really has an impact on important clinical outcomes, including survival. The treatment is not licensed or available.”

 

Prof Steve Goodacre, Professor of Emergency Medicine, University of Sheffield, said:

“We still need the researchers to confirm that these are the relevant registration details for their trial and comment on discrepancies between the registration details and the press release. Specifically:

1. “The registration details specify 400 participants, while the press release states 101 were recruited. Was the trial stopped early? If so, why? Stopping a trial as soon as a treatment appears to be effective can be likened to stopping a race and declaring your horse the winner as soon as it takes the lead.

2. “The primary outcome in the registration details is Ordinal Scale for Clinical Improvement. The outcome measures reported in the press release are measures of clinical improvement, which is reassuring, but I would like to know what result there is when the primary outcome is analysed as an Ordinal Scale for Clinical Improvement, as specified in the registration details. This is the primary way of determining whether a trial has a positive or negative result.

“We should base our opinions on published peer-reviewed papers, considered alongside a protocol that was made publicly available before analysis. I appreciate the need for urgent communication of potentially life-saving findings, but I can’t see any reason why the press release should not reference the trial registration details and protocol and should not explain the issues I have noted. They could easily have included a link to the trial protocol in their press release. I am concerned they have not done this.”

 

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine (LSTHM), said:

“This announcement is a requirement of stock market rules rather than a proper, even preliminary, scientific report. It does suggest that this new inhaled treatment of a drug that has been used in an injectable form for many years in multiple sclerosis, giving moderate symptomatic benefit in that condition.

“The primary outcome of this phase II study (as described in the trial protocol) was stated to be an ordered scale for clinical improvement from a minimum of 0 (patient is well) to a maximum of 8 (death), which is similar to that used for other clinical trials in COVID-19. It was intended to be measured over the 14 days during which a patient received treatment.

“The press release relates to this outcome but may not be quite what was the outcome defined in the protocol. The company state ‘The odds of developing severe disease (e.g. requiring ventilation or resulting in death) during the treatment period (day 1 to day 16) were significantly reduced by 79% for patients receiving SNG001 compared to patients who received placebo (OR 0.21 [95% CI 0.04-0.97]; p=0.046).’

“The treatment is targeted at those in a very early stage of their clinical disease in that they had to be within 24 hours of their positive test for the SARS-CoV-2 virus. It was intended that patients could be treated at home as well as in hospital, but the press release only refers to hospitalised patients. It is not clear whether the reported data are a sub-group or whether they did not recruit sufficient patients to be treated at home. The intended number was 400, but this report is based on 101 patients.

“It is clear that this seems to be a promising treatment for the early stages of COVID-19 but should definitely be regarded as preliminary – it is a phase II study, though it has some aspects of a phase III trial in that it considers clinical outcomes and is randomised with a placebo control. From this point of view the study has definite strengths.

“It is sad that stock market rules seem to militate against proper scientific release of at least a preprint of a scientific paper. It is also not clear whether a data monitoring committee was involved in advising release of the data publicly. The adage that says “beware of small studies claiming large benefits” should be borne in mind here. There are reasons to believe it could well be an effective treatment, but these results, while encouraging, should not be taken to mean that the treatment is so dramatic that everyone should be given it. There is a need for many more patients to be recruited and for any adverse effects to be carefully evaluated. Thrombotic microangiopathy was a rare but severe coagulation complication associated with an injectable form of the drug, and, given the coagulation problems associated with COVID-19, great care will be needed to ensure that such problems do not occur with the inhaled form of the drug.”

 

Dr Gillies O’Bryan-Tear, Chair, Policy and Communications Group, Faculty of Pharmaceutical Medicine, said:

“This study of an inhaled form of interferon beta, from Synairgen, a UK company, and carried out by several hospital sites in the UK led by Southampton University Hospital, shows interesting preliminary results in COVID-19. Interferon beta is licensed for use in multiple sclerosis and is produced naturally by the body in response to viral infections.

“The study, in patients hospitalised with COVID-19, was placebo controlled and randomised, and included a little over 100 patients. The primary endpoint was progression from requiring oxygen support, to requiring ventilation or death, during the treatment period (Day 1 to 16). Deaths or ventilation after this time were therefore not included in the endpoint. Although there was a large proportionate decrease in this endpoint, of 79%, it was barely significant because of the small sample size.

“Clinical decisions to progress patients from oxygen support to ventilation are complex, multifactorial, based on a holistic assessment of the patient’s status, and subject to the interpretation of clinical guidelines. An endpoint such as this is therefore subject to considerable variability both between patients and between study centres. In a study of this modest size, a chance finding is therefore quite likely, and interpretation should be cautious.

“What is encouraging from the data, however, is that all the endpoints went in the same direction: recovery rate was greater (again limited to the treatment period only, which is artificial), and breathlessness was markedly reduced (highly significant statistically). There were three deaths on placebo and none on the active treatment arm. However, if there were differences in the patient prognostic factors at baseline, this advantage (in this case for the treatment arm), would be carried through all the endpoints. Although the authors comment that the patients were well matched at baseline, the number of prognostic factors identified already in this condition indicates that a larger study would be required to ensure matching groups.

“I would regard this study as encouraging early stage data which needs to be followed up with a larger study using more robust endpoints such as overall survival.”

 

Prof Naveed Sattar, Professor of Metabolic Medicine, University of Glasgow, said:

“The results seem very impressive, and although accepted that the trial is small with just over 100 participants, a 79% reduction in disease severity could be a game changer. It would be good to see the full results once presented and peer-reviewed to make sure they are robust and the trial conduct was rigorous. Also, with small numbers comes less certainty on the true level of benefit, or whether benefits vary between people with differing risk characteristics. Such work would require a larger trial but, even so, these results are very exciting.”

 

 

https://www.synairgen.com/wp-content/uploads/2020/07/200720-Synairgen-announces-positive-results-from-trial-of-SNG001-in-hospitalised-COVID-19-patients.pdf

 

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/COVID-19

 

Declared interests

Prof Dave Singh: “I have received sponsorship to attend and speak at international meetings, honoraria for lecturing or attending advisory boards, from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Synairgen, Teva, Therevance and Verona. I was part of the data monitoring and safety committee for the SNG001 study in COVID-19 patients. I am an investigator in the ACCORD study.”

Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”

Prof Martin Landray: “Prof Landray is co-chief investigator of the RECOVERY trial of potential treatments for COVID-19 (funded by UKRI and NIHR). Research funding to University of Oxford received from Novartis, Boehringer Ingelheim, and Merck Sharp & Dohme. Infrastructure and core funding received from Health Data Research UK, NIHR Oxford Biomedical Research Centre, UK Biobank Ltd, MRC Population Health Research Unit, and British Heart Foundation Centre for Research Excellence.”

Prof Stephen Evans: “No conflicts of interest. I am funded (1 day/week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator or any grants obtained from them. I am the statistician to the “meta-Data Safety and Monitoring Board” for CEPI. I will probably be paid for my attendance at meetings and expenses for travel.”

Dr Gillies O’Bryan-Tear: “No conflicts of interest.”

Prof Naveed Sattar: “No conflicts of interest.”

None others received.

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