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No, it is the hyper-enhanced host immune response (cytokine storm) kills patients, not covid-19 virus. In the early stage of infection, anti-viral drug (remdesivir)/ anti-virus antibodies (bamlanivimab) do reduce viral load and reduce the risk of patient becoming hyper inflammatory. However, in the middle-late stage of covid-19 infection, the immune response is already being triggered, and you need to reduce the risk of deadly cytokine storm, allowing patients to recover. That's why immune modulators like dexamethasone or lenzilumab work in the middle-late stage of infection, and why anti-viral therapy failed to show efficacy in the late stage of infection.
It's a benefit/ risk issue. Since vaccines will be used on large number of healthy subjects, vaccines need to be very safe, without side effects, and you need a large trial to prove it. You don't need thousands of people to show efficacy.
Well, I just want to point out that Humanigen is relatively slow to finish the phase III study. For example, Roche start a 450 patients IL-6 study (NCT04320615) on April 3, and complete the trial on July 28. If Humanigen could have such speed, the phase III study could be completed in August. Also, Humanigen is heavily betted on COVID-19 trial, if the trial fails, I don't think Humanigen could raise enough money for another indication (~100M).
1. Humanigen spend 4 months (5-9) to recruit 150 patients from US sites in the phase III trial. Even with the help of Brazil sites, how do Humanigen manage to enroll another 150 patients in one month?
2. If humanigen managed to finish enroll patients before the end of september, it means that they can push the speed to about 2.5 patients per day in the US. But they didn’t do that, and it delays the phase 3 trials to a point that hurt the share price. Do humanigen have a good explanation for this?
Since this is not a randomized, double blind clinical trial, they try to compared the treatment response of lenzilumab with a control group, which was created from sex/age matched patients.
" A control cohort of patients who did not receive lenzilumab (untreated) was identified from an electronic registry of more than 1900 COVID-19 patients in the same healthcare centers as the lenzilumab-treated patients, and were matched to cases on sex and age within a tolerance of 5 years "
Slow to start, but they are careening along at a hellish pace now, with 5(!) new trials listed at clinicaltrials.gov, mostly beginning in July and August.
I would suggest you to check this paper: https://doi.org/10.1038/s41577-020-0357-7 If a company have anti-GMCSF in their pipeline, they will start a covid-19 trial, suggesting that GMCSF is a recognized target for covid-19.
What's the distinction between their respective actions? Is there anything to commend one over the other?
Since GMCSF only binds to GMCSFr, and these antibodies blocked the same interaction pair, I would expect little differences between anti-GMCSF and anti-GMCSFr antibodies in the treatment of covid-19.
can HGEN keep up with Kiniksa
I think the sample size and inclusion criteria of HGEN trial are more reasonable. Again, if humanigen hit the right target, the market of covid-19 pandemic is probably big enough to accommodate two anti-GMCSF or anti-GMCSFr antibodies.
Do you know anything specific about Kd for lenz? Has there been any PK/PD work with lenz-specific parameters, or would that not be necessary?
I remembered that KD for lenzilumab is about 20 pM (10-11 M). If you inject 600 mg (10 mg/kg) antibody, you will get ~70 nM (thousand fold over KD), assuming that antibody distribute equally in the body. I think that`s enough to neutralize every GMCSF.
Although both are small POC trials, but they share the same MOA, and are from two independent clinical trials. Therefore, I think anti-GMCSF will show efficacy in P3 trials.
if GM-CSF is rapidly "consumed" by cells, some (potentially large) proportion of GM-CSF would be able to bind to the cell and do its job before being disabled by lenzilumab
> It will go back to the basic of antibody biology, generally speaking, therapeutics antibodies are excellent neutralizers to their targets (KD: nM-pM), and are very stable (halflife: 1-3 wks). Considering PK/PD of the anti-GMCSF antibody, they are using overkilled doses of anti-GMCSF in the COVID-19 trial, and GMCSFs probally have no chance to exert their biological function. In other anti-GMCSF trials (RA), they used a much lower dose, and still observed clinical benefits.
Will it be effective for mild, moderate, severe, critical cases?
> From the MOA of anti-GMCSF, I think lenzilumab will work in mild/ moderate cases, preventing some patients progressing into severe/ critical stage. Once you have cytokine storm induced tissue damage, it is probably very difficult to recover.
What are people thinking about the BET trials in combo with remdesivir? It seems like remdesivir should be easy to beat
> It is a logical combination, remdesivir inhibit virus replication, and anti-GMCSF prevent lethally consequences of virus infection (cytokine storm).
Since GMCSF is rapidly consumed by target cells, the plasma level of GMCSF is not reliable. You have to use the increase of GMCSF production cells, or the downstream cytokines of GMCSF as markers of upregulation of GMCSF signaling pathway.