The latest Investing Matters Podcast with Jean Roche, Co-Manager of Schroder UK Mid Cap Investment Trust has just been released. Listen here.
https://www.fnih.org/sites/default/files/2021-10/ACTIV-2_v7.0-wLOA%20073021.pdf#page43
Master protocol link above. Nasopharyngeal swabs at entry and day 3 in phase 3. They will have the ability to do this and I think they will. I haven’t read all the way through to see if they have said they are doing it.
Ndn. The effect size was no bigger than the trends we saw- RR 0.82. Over 2000 patients though and a much more powerful trial to detect small differences. I may be clutching at straws but I don’t think synairgen have anything to lose by bundling results together and submitting an EUA. Who knows they could do that and as part of EUA enter a large platform trial. FDA do that for diabetes drugs- approve on basis of surrogate end points and ask for CVOT trials to be done! Maybe a takeover by big pharmaceutical company would be in best interests of all- they would have clout and resources to deliver the knockout large trial.
PS the magnitude of harm if steroids given before oxygen needed is about the same as benefit if oxygen needed (Absolute harm 3.8% absolute benefit 2.9%). The biggest benefit was in those on mechanical ventilation (12% absolute benefit and RR 0.64).
Thanks Rich.
I ran ITT. That may explain it. In any case SNG is in the ball park.
This is not great science but there has been a lot of bad science get through approvals under EUA and the evidence on the ground is that these therapies are working. Here’s a brief summary.
Steroids- overall no benefit. Probably harmful if taken too early, benefit if on O2. It took several studies and a meta-analysis to show this.
Il6-antagonists- again several studies and conflicting results but approved for specific sub groups.
Mabs also failed late disease studies benefit in early. Approved now on basis of mainly lab evidence!
SNG is the only therapy that appears to work in early and late stage. It’s not great science statistically but I think SNG should bundle the results all together and make EUA. Collectively the evidence points to it working with a fairly powerful effect size. We are in a pandemic and the science isn’t perfect but judgements on the basis of available evidence have been made, and continue to need to be made. I think Synairgen are trying to get data from ACTIV2 and hopefully will bundle this and make EUA. In the meantime polygon (Big pockets) are averaging down). I think takeover…. Sadly I can’t afford to risk more on this but will stay the course. I can’t afford to crystallise loss either! Like many on this board stuck in the middle and hoping??
I ran a brief chi sq test on combining p2/3. It came out as p=0.06 for end points of severe illness or death. To be precise it would need individual patient level data. I think company will do this but what it can be used for im not sure. For EUA I think they would take a global look at all data. For peer reviewed journal I think this would be rejected- not great science. Similarly I think extending trial not an option. Some trials are now designed as event driven rather than a priori power calculations and enrolment numbers to avoid this problem. That bird has flown and I don’t think on SNG resources it would have been feasible. I suspect they really needed more than 1000patients. They also went for the wrong primary end point. Again easy with hindsight.
https://clinicaltrials.gov/ct2/show/NCT04518410
Last update to the protocol was 2nd Feb 2022 and regeneron still there.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00676-0/fulltext
To emphasise the issue of power and outcome look at the tocilixumxab trial. Over 2000 patients randomised to the treatment arm and an effect size smaller than that seen with SNG001 and the outcome was statistically significant. This is what the RNS meant by large platform trial.
SNG imo would be a suitable candidate.
Hope is not lost but the question is whether or not time is on synairgens side. £25m in the bank does give a reasonable cash runway but I think buyout more likely. I’m holding and keeping fingers crossed. I’ve lost too much to walk away from a product that holds promise.
That fat lady hasn’t sung yet on synairgen. Looking at the data as a whole SNG001 appears to work. The p3 study was underpowered because of the improvement in general care. Pooling p3 and p2 data from in hospital studies gives very close by my back of envelope calculations to the magical p<0.05 significance for the most meaningful of all outcomes- death or severe disease. My calculation is p=0.06 on intention to treat basis. Given that the landscape of trial and therefore power was changing during trial there may be a logical case to pool the data. One would need accurate individual patient level data to be able to do this. There will be statistical purists who would reject this but it would certainly be worth a serious statistician looking at the pooled data to see what could be made if it. Remember molnupavir got EUAd with a study that was a game of two halfs - first half of study effective, second little better than placebo. I think this will be considered by synairgen scientists.
Activ2 p3 will be active competitor (regeneron-drug known in uk as ronapreve) or placebo, not both to the same patient at the same time. To blind the patient it will therefore be ronapreve or placebo infusion plus SNG001 or placebo of SNG001.
The standard of care now (and for a year) includes steroids for patients needing oxygen. Activ2 is an outpatient study so nobody will be on oxygen and there would be no indication for oral steroids.
Tough call today. Hope investors can carry on.
I agree improving treatments decreased the power of the study. Water under the bridge now and I agree; last chance is with ACTIV-2. Fingers crossed this will salvage something.
My thoughts are with you all.
Clutching at straws but day 90 results not yet published as far as I can see. Difficult to see how that could change things, though some are intubated and ventilated for longer than 35 days reported.
Here’s another analysis.
Results in line with p2 and evidence of benefit in at home and in hospital setting would make this the most valuable therapy the world has ever known with a paradigm shift in treatment for severe viral respiratory infections.
There are already huge vested and powerful interests in current therapeutics. These will be aligned to pick any holes in data to maintain their market positions for as long as possible.
Delay at this stage could be dotting every i and crossing every t in anticipation of the scrutiny this will come under.
Current price trends not foment but fear of success. My advice is be driven by the data we know and it is very powerful. The objective parallel story of developments in appointments etc supports this analysis.
On the original thread here was a quote about us being close to the end of the pandemic and close to endemic. That may well be true- the exponential growth of infection rates are being replaced by stable BUT very high levels of infection. The end of the pandemic absolute does not mean little need for therapeutics. If SNG works as we expect there will be massive need for this for a good few years to come- both for stockpiling in event of further pandemic waves and for lots for more predictable use during endemic phase.
Fingers crossed that p3 reads out as predicted based on the 3 x p2 trials we know were successful (p2 in hospital, p2 at home and p2 in ACTIV2). It feels like we know much more about SNG than would be usual for a pre-p3 therapy and it’s all good.
I suspect 90 day data being awaited. It will make it easier to demonstrate benefit against QALY criteria if 90 data significant. Meanwhile time appears to be being well used building top class usa team and establishing partnerships.
I’m not sure if still blinded. Previous post implied that they would have access to the data from day 35.
Thanks guys. I feel very comfortable with steady output of positive tweets and developments knowing that Synairgen team know the day 35 data. Only mystery is why the share price is still languishing circa £2. Once results available we won’t be caring about this intermediate period.
I’ve slightly lost the thread here but my original point was that ronapreve doesn’t work on omicron and their protocol allows changes with a lesser burden of statistical evidence than would full FDA approval. There could therefore be positive news for SNG long before the trial is due to complete. If Sprinter successful and EUA granted for in hospital use it won’t be long until pre-hospital approval follows.
There is a potential big boost around the corner. In ACTIV2 the standard of care against which SNG and all the other mabs are judged is ronapreve. The omicron wave is breaking across USA with high hospitalisation rates. Ronapreve doesn’t work against omicron (it is no longer used by clinicians in uk unless proven non-omicron) and most other mabs have very little efficacy. The adaptive design of ACTIV2 builds regular data safety monitoring. Page 29 of the protocol suggests that agents “if demonstrating non-inferiority, inferiority or superiority” would result in “early termination or modification” of the study. This is on page 29 & 81 of the master protocol below. I think there DSM board will be looking very carefully at the data and SNG could easily end up in the hot seat in place of ronapreve. If recruitment is rapid that news could break in the next 6-12 weeks.
https://www.fnih.org/sites/default/files/2021-10/ACTIV-2_v7.0-wLOA%20073021.pdf#page80