Member Info for JoeyDiamond

One of the drugs is AZN mAbs, UK pre ordered 1 million doses last year. I'm sure the task force will discover it :)

Molnupiravir has just been dropped from hospital trials due to lack of efficacy.

For outpatients use, the FDA have said not enough people were recruited in their trial to prove the drug works. The effificay result was not significant. Therefore Merck need to recruit more people, estimate 4-6 months further for trials.

Molnupiravir was the front runner but has fallen at one of the fences.

Hi Matterhorn yes that is a possibility. Also it is common for people to have a new secondary viral/bacteria infection eg staph at later stage Covid disease.

Possibly using inhaled interferon may give better outcomes based on the hypothesis it reduces the negative effects of Dex and thus helps the body fight off new or persistant infections. As Scinv points out Covid viral load is low by time people get into ICU so could be other issues interferon is helping?

All theoretical at this point but interesting how interferon has gone from being blamed for cytokine storms and bad outcomes to now potentially being trialled at such late stage disease.

Dr Aurelien Mary was able to treat with inhaled IFN-ß-1b, on a compassionate basis, four patients with severe COVID-19 admitted in the intensive care unit. All 4 survived. As we know he has been given the go ahead to trial 146 patients in France albeight at early stage of disease.

https://www.frontiersin.org/articles/10.3389/fphar.2020.592543/full

Definately warrants a trial for such late stage as even a small signal would have big benefits.

I think people can see that Scinv, it is a study on the synergy between inhaled Interferon and Dexamethasone and how they compliment each other. The potential in the study would support the theory of being able to use interferon at late stage disease - ie ventilator/ICU. Hence why Synairgen and our French Dr in Amiens are interested in trialling for this stage.

Hi Aether

I believe Tom was referring to the WHO Ordinal scale of clincial improvement and the dose timings. Scale used here - https://static.politico.com/90/c8/aa11d6ef426db2fc9676e3ecc2a6/who-ordinal-scale-for-clinical-improvement.jpg

In the P2 trial SNG001 was given to people at scale 3 or 4 (I think a couple at 5 iirc). Most people would have expected stronger results from patients given SNG001 during scale 3 stage simply as the theory is the earlier interferon therapy is given the better. However in the trial it was notable the signal was stronger in patients at scale 4, ie patients in hospital who had worsened and now requiring oxygen. As you mention Tom and others were surprised they didnt' see an increase in inflammation and is a key finding.

Fast forward to the P3 trial, SNG designed the trial to target only patients at WHO ORD scale 4 ie patients who need oxygen support. So P3 will trial later stage patients and hopefully there is a stronger signal. My personal theory is a synergy between interferon and Dexamethasone could be a helping hand here. Dex is normally given once oxygen therapy starts in hospital. Outlined by this study https://www.nature.com/articles/s41392-021-00496-5

With regards to ICU trials of interferon then a compelling case can be made from same study. There is compelling data that shows patients in ICU who had both inhaled interferon and Dex had a greatly increased chance of survival than just having Dex alone.

Some text from the study -

Steroids are dual edged swords. GCs suppress the life-threatening cytokine storm in the lung and prevent inflammation-induced tissue damage. On the other hand GCs also impair the antiviral immunity which both delays viral clearance and increases the risk of secondary infections.

Despite of our findings of an IFN-GC synergy, the disruptive role of GC in IFN signaling is thought to interfere with IFN therapy in treating viral infections. We would attribute the strong synergy between IFN and GC despite of their functional conflicts partly to the use of inhaled IFN instead of intravenous or subcutaneous delivery methods in this cohort. The twice daily inhalation of IFN aerosol would deliver much higher concentration of IFN in lung epithelial cells than daily systemic GC, and the elicited IFN signaling might be sufficient to achieve clinical benefits even with the presence of GC. In fact, animal studies have shown that inhaled IFN could effectively repair the antiviral immunity impaired by GC and prevent viral infections. Another potential advantage of inhaled IFN is the low distribution of IFN to those air-impenetrable lung lesions where IFN may play a more damaging role in further exacerbating inflammation and disrupting tissue repair. Since GC is given systemically, they can still reach these regions via blood vessels to suppress inflammation. Taken together, we believe that the administration route of IFN may play a key role in achieving IFN-GC

Yes its great news and hope there is a serious push for the hospital lab test. Pretty cool you could give patients a test that predicst with 75% accuracy who will likely go on to develop severe disease after first being admitted to hospital.

This would enable Drs to change treatment courses / protocol etc to bring about better outcomes. More precision in choosing what anti inflammatory drugs would function best in a given situation or which people get interferon etc.

You also could likely manage beds / ICU better.

Hi Ghia and anyone else interested

Here is the full lancet paper - https://www.sciencedirect.com/science/article/pii/S2352396421001328

Fantastic work by these scientists creating a genetic biomarker model to predict disease severity. Will be known as the EPICOVID signature. Essentially they ran tests on people and performed a genetic test They found 20 genes were linked to severe outcomes of Covid, 7 of which were linked to interferon.

Significantly overrepresented genes (hypergeometric test, P value = 2.14e-06) associated with GO biological processes included those of “immune response”, “type I interferon signalling pathway”, “interferon-gamma-mediated signalling pathway”, “antigen processing and presentation”, “defence response to virus”, “cytokine-mediated signalling pathway” and “inflammatory response”. These processes are highly relevant to the degree of potential response to COVID-19 infection, since they are related to the capacity of the immune system to respond to viral infections. In this regard, the 20 genes containing the CpG methylation variants associated with COVID-19 severity include an overrepresentation of genes that mediate the response to interferon, a key pathway in the physiopathological pathway of the disease

* 13% of people in the population match the EPICOVID signature and in theory means they will likely develop severe Covid.

* In hospital they found between 83.5 and 90% of patients with severe Covid matched the EPICOVID signature.

Using this approach, we obtained an epigenomic signature, hereafter referred to as the EPICOVID signature, that predicted COVID-19 severity with 90.18% accuracy (mean Kappa = 0.804). Supervised hierarchical clustering using the COVID-19 signature also clearly distinguished two branches that were significantly enriched with respect to each condition: those who were asymptomatic/paucisymptomatic and those with respiratory failure. We observed that the EPICOVID-positive signature was also associated with worse COVID-19 clinical course with a specificity of 88.18%, a sensitivity of 77.78%, and positive and negative predictive values (PPV and NPV) of 84.34% and 82.91%, respectively. The accuracy was 83.5% and the mean Kappa 0.6643.

* Regards to using this testing in a hospital setting as a predictor of disease outcomes then the answer in theory is yes.

The use of more user-friendly PCR approaches, such as the described pyrosequencing technology, could facilitate the analyses at the common hospital laboratory level. In this regard, it is worth noting that, if instead of the comprehensive EPICOVID signature we selected the top five CpG sites associated with severity according to P-value (Table S2), its single differential methylation status was still ossociated with COVID-19 severity (69%-76% accuracy range). Thus, a more restricted signature derived from the heatmap and clustering analyses might be useful in future prospective multicentre studies.

New nature article - https://www.nature.com/articles/d41586-021-00958-4

The race for antiviral drugs to beat COVID — and the next pandemic. Some interesting quotes from influential people and gives a mindset.

The pandemic has been “a wake-up call”, says John Young, global head of infectious diseases at pharmaceutical company Roche in Basel, Switzerland. “It’s just a matter of time before the next one,” he says, “and we need to prepare ourselves as an industry.”

To that end, leaders of the COVID R&D Alliance, a coalition of more than 20 life-sciences companies and venture-capital firms that came together last year to tackle SARS-CoV-2 collaboratively, are now launching a side project geared at broad-spectrum antivirals for coronaviruses and influenza viruses.

The US government has similar ambitions. Antivirals for coronaviruses are “task number one”, says NIH director Francis Collins.

There is a race on it seems to get a broad antiviral to corona viruses - huge profit potential for a company that hits the spot.

hmmm Boris changing tact? https://twitter.com/northerness/status/1381923895146643461

'The reduction in hospitalisations, deaths and infections has not been achieved by the vaccination programme. It's the lockdown that has been overwhelmingly important in delivering this improvement in the pandemic'

I'm not great with politics but this seems like he is laying foundations for another lockdown and isn't showing great confidence with the AZN vaccine. I do wonder with the SA variant cases in South London are they expecting it to spread hence a new stance negative on the vaccine and promoting the lockdown benefits. Just a bit odd considering vaccines were previously the route out of the pandemic.

Will be interesting to see the next data of the variants - https://www.gov.uk/government/publications/covid-19-variants-genomically-confirmed-case-numbers/variants-distribution-of-cases-data

https://www.nytimes.com/2021/04/13/us/politics/johnson-johnson-vaccine-blood-clots-fda-cdc.html

Federal health agencies on Tuesday called for an immediate pause in use of Johnson & Johnson’s single-dose coronavirus vaccine after six recipients in the United States developed a rare disorder involving blood clots within about two weeks of vaccination, officials briefed on the decision said.

All six recipients were women between the ages of 18 and 48. One woman died and a second woman in Nebraska has been hospitalized in critical condition, the officials said.

'That would be statistically significant enough to make the Lancet'

haha that made me chuckle :)

https://twitter.com/itvnews/status/1381693476467789829

Outbreak of SA variant in South London. Surge testing in Wandsworth and Lambeth in place but already likely 74 cases.

With many going shopping and the pub today lets hope it gets contained.

Following on from last week and discussion on events in HT. From the Budesonide trial in outpatients we had this data

Among patients who had completed all 28 days of study follow up by 25th March 2021, 8.5% (59/692) in the budesonide group were hospitalised with COVID-19 compared with 10.3% (100/968) in the usual care group (estimated percentage benefit, 2.1% [95% BCI -0.7% – 4.8%], probability of superiority 0.928).

So we have a UK based population with similar entry requirements to the Budesonide trial as SNGs home trial. It will give us the likely amount of events we may see.

10% in SOC group were hospitalised from Budenside would mean around 6 in home trial placebo group on average. Hopefully none in interferon group :)

This is a cheap anti-inflammatory that masks Covid symptoms, as the trial shows people self reported they felt better on average 3 days quicker. As a treatment for symptoms its a no brainer to give people. Cheap, easy to use and used worldwide. In America its known as Pulmicort.

From trial
'Based on the interim analysis using the latest data from 25th March 2021, the results showed the estimated median time to self-reported recovery for inhaled budesonide was 3.011 days shorter compared to usual care (95% Bayesian credible interval 1.134 to 5.410 days)'

However it is not a game changer in my view as some of the media reports say.

* The trial was not a blinded placebo controlled trial, patients in the trial knew they were in the drug group or SOC group. Obviously this can influence results and have bias considering participants self reported results.

* The drug is not an anti-viral and as expected didnt do too much in the way of preventing hospitalisation.

From trial
'Among patients who had completed all 28 days of study follow up by 25th March 2021, 8.5% (59/692) in the budesonide group were hospitalised with COVID-19 compared with 10.3% (100/968) in the usual care group (estimated percentage benefit, 2.1% [95% BCI -0.7% – 4.8%], probability of superiority 0.928). Since fewer than expected people were admitted to hospital in the trial, and with COVID-19 cases and hospitalisations continuing to drop in the UK, it is not clear from this interim analysis whether budesonide reduces hospitalisations.'

So its pretty clear this drug looks to reduce symptoms and people self report they feel better quicker in people who can mount a good normal immune response to Covid.

However minimal reduction in hospitalisation as the drug doesn't do anything to stop the virus (as expected its not an anti-viral) and with the 95% CIs we can see its not conclusive which the trial researchers admit. So people who for what ever reason develop moderate/severe Covid will still likely end up going into hospital.

Yes interesting video, you see Dr Mary in it with their drug and kit in the store room :)

I tend to agree with Scinv this wasn't a great overall interview by Richard with some of his terminology however I do believe he was trying to set expectations with regards to the home trial outcomes.

Scinv you may be assuming the worst with regards to the data being already unblinded and using the clinical record modification update as evidence for new endpoints being added afterwards.

Some alternate less negative viewpoints
* You would not need to unblind the data to know how many hospital events overall there were in the trial, this would be common knowledge amongst the researchers/nurses running the small trial. People just wouldn't know if patients had placebo or drug.

* Unblinding the trial would have potential implications for recording the long covid data as it could be seen as a potential bias issue. Would various committees/regulators take a dim view of new endpoints after a trial data had been unblinded?

* SNG have often updated clinical records late after the event. Just a busy team leaving admin late?

* There was an RNS from 18/12/20 - COVID-19 Clinical Programme Update

'Following discussions with the regulatory agencies, the trial has been amended as follows:
Addition of assessments for Long COVID-19 symptoms on day 60 and day 90.'

Yes the change was listed under the SG018 trial in the RNS text, but in December it would have made sense to add the same long covid protocols to the home trial patients for a larger dataset. Surely it would have been a mistake to not record this same long covid data in the home trial patients until commencing March 19th? Last dosing was 19th Jan so you would only have a couple of patients who would qualify for the 60 day assessment on time. I checked the P2 HT and P3 trials and the same long covid endpoints are listed as per regulator discussion.

Quality of life measured using EuroQol 5-dimension 5-level (EQ-5D-5L)
General Anxiety Disorder 7
Patient Health Questionnaire - 9
FACIT Fatigue Scale
Nottingham Extended Activities of Daily Living Scale

So in general on this board maybe people are jumping to conclusions prematurely whether it be positive or negative in the absence of more information.

Alphageddon in effect they have already extended the trial for an extra 210 (IIRC) patients by inclusion to the USA Activ-2 trials. So overall we will have around 330 patients dosed in an outpatient setting where we hope there is enough signal from across the 2 trials.

https://clinicaltrials.gov/ct2/show/NCT04518410

Hi Richlist you are correct with the Oxford figures they are for the general population and is a guide to relative odds of Covid outcomes for your age group etc

Yes with a positive PCR test and Covid diagnosis then the odds shorten even further for hospitalisation. I was trying to show the difference the co-morbidities make so apologies I didn't explain it too well and left that important bit out :)

Looking at the trial design https://clinicaltrials.gov/ct2/show/record/NCT04385095 and the inclusion criteria then it is possible we could have many people over 65 who are in general good health on the trial. From the relative odds if this is the case then we would expect less events and signal than if we have a higher proportion of people signed up with a co-morbidity like obesity, heart disease or COPD for example.

From Eli Lilly trial a sub group analysis of obese patients showed 15% in placebo group went to hospital as opposed to the 7% in overall total placebo group.

My take on the interview -

The interviewer obviously knows the theory and excitement with interferon, basically the early you give interferon the better. He made a comment saying we may expect better results in the HT, Richard reigned him back in and advised caution.

In the hospital trial patients were already ill so getting a result/signal was going to be easier to see. Events in the trial were N=98.

In the home trial people are at this stage only mildly ill and statistically many in the trial will get better on their own accord and will not need hospitalisation. People who have followed SNG will know about the asthma trial which failed its primary end point due to lack of exacerbations in placebo and drug arm. From past experience he was saying it is possible again we will just not have the events in the trial to give a signal one way or the other.

So simply numbers in the trial may be too low and not enough people in the placebo arm actually go to hospital. We need to see the makeup of the patients in the trial and if any have a co-morbidity.

I have used the UK Covid calculator here to work out example odds of patients going to hospital - https://www.qcovid.org/Calculation

White 70 year old healthy man - 1 in 548
White 82 year old man (COPD/In a nursing home) - 1 in 97
Black African 75 year old woman (Obese/type 2 diiabetes/Heart Disease) - 1 in 80
Black African 78 year old man (Sickle cell disease/stroke) - 1 in 14

So to see a signal you will likely need much larger numbers in the trial ie need activ-2 people included too. Like previous trials there may not be enough events.

For reference Eli Lilly Mabs EUA needed 1035 patients. Primary endpoint was the proportion of participants who had a COVID-19-related hospitalization. Endpoint events occurred in 11 of 518 participants (2%) in the bamlanivimab plus etesevimab arm and in 36 of 517 participants (7%) in the placebo arm.

On this basis if we get around 4 or 5 events in the home trial we will have done well. So Richard was just being honest in the interview relaying what many of us already knew. The HT on its own is unlikely to give a blockbuster as its just not powered to do so unless we get very lucky with placebo events.