Analysis of the EAP, page-201

@aquazul, I like your question so I'll put Europe on hold for a bit to talk about it.

Based on the outline for competitors I gave above, the short answer is "no", I don't consider FDA-approved Xpovio to be a competitor that could displace rem-L from the ICU. Even if we jump two years ahead that's not going to happen. We can add this one to my list of, "give us your vaccines, your anti-virals, your JAK inhibitors, etc etc.". In other words, rem-L will treat this medicine's failures, no doubt about that. Could it somehow beat us to the finish line for bragging rights as the "first FDA-approved therapeutic for C-19?" It's going for a label extension (like hydroxychloroquine, Jakafi and others), so I can't entirely rule that out, though unlikely as I'll explain. If it does beat us to the C-19 finish line, the C-19 ARDS trophy will still be up for grabs, still a major prize, so no harm done. This is not an ARDS medication.

I suspect you've done more exhaustive research on this than I have based on your knowledge of its rocky approval pathway. Perhaps you're invested there? or taking the medication under duress of illness? I spent maybe 20 minutes on it this morning, so I'll let you critique my analysis or fill in gaps or take an opposing view. By looking at meds like this perhaps we can learn something about our own therapeutic (and come to appreciate it all the more).

Here's how I analyze it, and no intention to speak down to any experts, but for a general audience: First, let's try to classify the molecule itself. There are many ways to categorize medications. One way is to think about meds that work outside a target cell vs meds that work inside a target cell. If we think of a cell as a factory, does our medicine "cut the phone lines" so to speak, or does it sneak in the back door and try to throw a klinker in the gear works? We are told this one is a "Selective Inhibitor of Nuclear Export" (SINE). I like selective, but nuclear tells us it's getting inside the cell. We also find it's being taken orally. So, I haven't looked up the chemistry, but I'll wager 99.9% it's a synthetic small molecule. It's approved for MM (multiple myeloma), a type of cancer. So, it's a chemotherapy agent. Let's be frank and call it a poison. We're going to try to treat patients by poisoning fast growing cancer cells (it induces apoptosis through the unique SINE mechanism) without poisoning other cells too much... if I had MM, I'd take it if prescribed by my oncologist. Given the alternative. If I had C-19 I would be very hesitant... unless I also had MM or a malignant brain tumor (glioma) for which it is also in trials. Those patients are more vulnerable to C-19 and don't appear to be excluded by entry criteria. So, two birds one stone. And signing up for the Xpovio trial does not exclude you from later entry into the rem-L trial, UNLESS... unless the side effects of this medication trigger an exclusion criterion via your kidneys, or liver, or sepsis from your low white count or bleeding from a low platelet count... and the list goes on. And don't think about having a baby for at least 3 months, even if you're a man... that's an unusual proviso. This med has toxicities. That's why I would hesitate to sign up: the only thing good to be said about this medication's side effect profile is that it's better than Jakafi's, another small molecule,... but that's starting with a very low bar indeed.

For general reference, there have been advances in oncology towards "targeted" medicines. Often the target is a surface receptor or a SIGNALING molecule that activates the receptor. Remember that word SIGNALING. All things equal and this is a big generalization and I'm risking a lot of blow back here, but medicines that work outside the cell tend to be less toxic. Monoclonal antibodies, for example, all work outside the target cell. They may have toxicities but usually your hair doesn't fall out. Most of the medicines on my competitor list above are mAbs. Now think about our therapeutic, rem-L. Remember what Dr Caplan said. MSC's are Medicinal SIGNALING cells...yes, with multiple mechanisms of action that may include secretion of exosomes which in some cases might directly act on the inside of a target cell... but rem-L is working to calm the storm mostly from outside cells. And even any exosomes would be found in the organic section of your grocer, not the synthetic insecticide aisle. All things equal, rem-L has a much better side effect and safety profile... because it acts on chemokines and surface markers and inflammatory mediators largely outside the target cells. As an investor that has more appeal to me... perhaps a bias in my analysis.

Second, we can look at the trial(s), Karyopharma looks reputable. $1.5B market cap. They are going after noble targets for which we need better therapies... MM, GBM, etc. But for C-19 I think it's a long shot. Still, they are throwing a lot of money at C-19 and must have confidence in their molecule. Two trials are registered, both are phase 2, and there are some curiosities, all probably related to a concern about toxicities. The first trial is a 230-patient placebo controlled multi-national trial with most centers in the US, but some in Europe and Israel. Only the patient is blinded to the medication (suggesting they want the doctor to be on her toes and to know what to do in case of toxicities). The target illness is Covid-19 pneumonia. Intubation is an exclusion. Oxygen by nasal canula up to a P/F of 300 gets you in, so these patients are situated well before rem-L would be considered. Following the FDA Guidelines we discussed, they are targeting "severe C-19" cases and excluding "Critical" cases. One of their secondary endpoints is "Overall Death Rate", not very optimistic.

The dosing of this toxic medication is interesting. The usual dose in MM is 80 mg twice a week = 160 mg per week. In the 230-patient C-19 trial they are giving 20 mg 3 x per week or 60 mg total per week, again the lower dose is a reflection of toxicity concerns. They have a second trial set up to enroll 80 patients for an open-label comparison of 60 mg per week vs an 80 mg per week dose. That trial is not yet recruiting... so that too is a bit strange. Normally before launching into 230 patients a company would perform the dose-finding part of a trial first... here perhaps the opposite or they'll run it in parallel? Strikes me as unusual, again probably logic borne of toxicity concerns.

And finally what are the toxicities? The most common at the 160 mg dose is a low platelet count, which occurs in 75% of patients. That can provoke bleeding if it gets too low. Not good in a population where clotting abnormalities are a big part of the disease and heparin is routinely given in those hospitalized for any length of time, certainly those going to the ICU. Next is a low white count, not good when the disease is infectious and the hospital exposes patients to antibiotic-resistant organisms in addition to the virus they bring in. Will the lower doses avoid those problems.? I would look for a lot of drop outs and failures on this one. I don't see it as a threat in any way.

I walked through this in some detail to give a general framework for analyzing potential competitors. Any feedback or opposing viewpoints are most welcome. So far, I haven't found anything that makes me want to sell MESO in order to buy KPTI, quite the opposite.

@Nydem, echoing a bit what @Ricky H said, would a Catholic person in Spain or Italy object to a corneal transplant or a kidney transplant or a heart transplant? MSC's are perhaps closer to a blood transfusion because they don't graft... but if the person would accept a corneal transplant the only difference here is that the cells have been sorted and allowed to divide before the transplant. And the transplant is done with a liquid infusion, easier. Some great discussions on this thread. Thanks to all.