@Grainger, sorry for the delay getting back to you due to time zones... and I've been busy accumulating a few more MESO shares at these attractive prices.
Itolizumab has been around for awhile... It's apparently been approved in India since 2013 to treat psoriasis... so it's use to treat C-19 in that country amounts to a "label extension" to now include cytokine release syndrome.
Itolizumab is not approved in the US. The situation would be somewhat comparable to tocilizumab, which is approved in the US for RA and also has a label extension for CRS.
Equillium has phase 1/2 trials underway to test itolizumab in lupus nephritis and aGvHD (patients above the age of 12). There's also a phase 1 study underway in Australia to test it for "uncontrolled asthma".
Here's a review article from a few years ago that makes some interesting points:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407739/So, I agree with many of your statements, except "it only targets T-Cells". It's a bit more complex than that because the target surface protein CD6 is also found on subsets of B-cells and even some neural tissues. Itolizumab binds to CD6 and modulates immune synapses. It modulates interaction with antigen presenting cells and it modulates immune cell proliferation. In chronic inflammatory conditions like psoriasis and RA, T-cell modulation is an important part of its mechanism of action... but the full MoA in Covid-19 will probably require further study. It's generally safe, but note the precautions given in the review article on risk of susceptibility to other infections, risk of reactivating latent infections such as TB and risk of tumorgenesis.
We have limited information out of India on details of the study conducted there by Biocon (certainly a curious name). Reportedly, it was open label, twenty patients with moderate to severe C-19 ARDS received the medication and 10 patients received placebo. So, a small, unblinded study. Open label, I would regard this as somewhat comparable to an EAP, here involving 20 patients who received the medication as opposed to 12 in the Mesoblast study. We are told all who received the medication survived and 3 of 10 who received placebo perished. And we're told that was "statistically significant".
The devil is in the details and it would be good to know exactly what parameters they used to enroll patients. I'm always concerned when a company reports "100% success" and doesn't give full details on entry criteria or sided effects encountered. What co-morbidities did patients have? Did those co-morbidities randomize equitably to both arms of the study? I haven't seen those details presented anywhere. Drawing a conclusion of "statistical significance" based on numbers this small seems premature especially with open label. We know that "Bayesian predictive analysis" requires a double blinded trial of at least 90 patients for this illness, and that analysis was probably based on a mortality rate higher than 30% in the control arm.... If you read earlier posts in this thread we discussed that statistical significance using small numbers of patients requires a high mortality rate in the control arm. The lower the baseline mortality rate, the greater number of patients one needs to prove statistical significance. The approval in India is based on smaller numbers and a lower mortality rate than we saw with the Mesoblast EAP. So, while itolizumab may have emergency authorization in India, a more robust trial will almost certainly be required by the FDA for anything beyond an IND.
Yes, I am adding itolizumab to my watch list of potential competitors though I consider it to be far behind on the regulatory pathway. Recall that my May 21 list was based on therapeutics undergoing phase 3 (or large phase 2) trials in the US. This molecule does not meet that criterion, though I suspect Equillium will not have trouble getting an IND to begin a trial in the US. They certainly didn't lose any time getting an S-3 filed to raise up to $150M on the back of yesterday's press release. That's also become a familiar pattern, but the time to run from the clinic over to the investment banker's office may establish a new land speed record here.
As for undermining faith in the investment thesis for MSB, that's for each investor to decide. I look at this as just another piece of confirmation that there may indeed be something to this idea of "immune modulation" in cytokine storm. If we see any pattern emerging it could be that mAb's targeting cell receptors (itolizumab, leronlimab) might do better than mAb's targeting cytokines (tocilizumab and other anti-IL-x inhibitors)... but even that is too soon to tell. Time and trials will ultimately tell. Has your faith in rem-L been undermined by tocilizumab which has also conducted at least 4 studies of GvHD? How about leronlimab then? Of course not. Announcing a study and actually posting a BLA are two very different things - if for no other reason than the many years that separate them.
From my opening post on May 19: "
Comparing the rem-L phase 3 to other trial designs shows this cell-based therapeutic is being positioned to occupy a most special niche: medicine of last resort. It's a great place to be: give us the patients who have failed your vaccines, anti-virals, convalescent plasma, IL-x Inhibitors, monoclonal antibodies, JAK inhibitors, nitiric oxide, HCQ, zinc, Super Factor XYZ, or combinations of any or all of the above, whatever. Try those first and when they're stopped due to toxicities, drug interactions or side effects - or when they fail to cure - give us those patients." I have no changes to offer to that statement. Will itolizumab or any of the others replace remestemcel-L or displace it from its niche? I see NO evidence for that. These mAbs all target one limited aspect of the immune cascade... they all have potential toxicities, side effects and adverse drug interactions.... they all must be carefully titrated in critically ill patients where "over modulation" can become a problem, where nosocomial infections can become a problem... and history tells us that while they may work for some patients, they will all have failures in this complex illness with a wide spectrum of severity and co-morbidities.
An MoA based on living MSC's that can home directly to areas of inflammation and size up millions of unique micro-enviroments in multiple organs of the patient and modulate each one "just the right amount" will prove superior in the most difficult-to-treat patients. That's my investment thesis, and I've seen nothing yet to shake it. No medication to my knowledge is positioning itself downstream from rem-L. (ECMO may prove to be the ultimate last resort in that rem-L will no doubt be used prior to ECMO. But I don't consider that a medication - and in maxed out rationing ICU's it may not be available). Remestemcel-L will be the LAST hope for many patients.
"Medicine of last resort" is a great niche to occupy. Under-appreciated and under-valued. Someone may try to displace us, but it's not going to be itolizumab.
Awaiting news, exciting times ahead, glta
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