I appreciate all the feedback and I think the analysis by Treed of the trial design is spot on (judging posts as of 3 hours prior to this one). Mesoblast clearly sat down with the FDA and worked out the best design given a number of variables specific to the therapeutic and its previous safety and efficacy profile. Having looked at a lot of clinical trials I've had nothing but confidence there since day 1. Key elements are number of patients to be enrolled, enrollment criteria, primary endpoint, interim readout points, and number (and prestige) of centers participating. The FDA wants reliable data. I have no doubts on the design of this one. Mesoblast has set the bar high for challengers to follow.
I still some concerns on the HC formatting, haven't figured it out yet, will do the best I can. I'm here because I tend to compose long, a fault. If I compose on the site I risk losing work if there's a computer problem. Appreciate all the feedback.
So, today I thought I'd shift gears just a bit, still on the general topic of the EAP and progression now into the phase 3. Yesterday ecool2 raised the remote possibility of M&A so I thought I'd scan the field a bit and see what the competition looks like. I think an acquisition is remote... but I thought that about Osiris too. Any company can be bought, officers reach a point after years of non-stop gruel, and we're into a situation where the large walruses might start looking for a US$2-20+B niblet or two. Whether that happens or not, as investors we should always be looking at what the competition is doing. That STARTS by knowing who the true competitors are. On Yahoo also, I see people worrying about things I don't worry about. Before I tell you what I do worry about (not that you care), I'll tell you what I don't worry about...
If you search the clinical trials web site for Covid-19 there are some 4000 trials that come up. If you narrow that down to therapeutics the number goes down to about 1000. In other words we take out observational trials, vaccines and prophylaxis. For example, should we worry about a vaccine coming along next year or even tomorrow and suddenly eliminating our patient base?? I don't worry about things like that. If we look at other examples, influenza is a good one, there's a vaccine, perhaps not an ideal one, but there's a vaccine and 30,000 deaths still occur in the US during a typical winter. People think it's because the vaccine isn't effective, but that's only part of the story. For some people the vaccine is indeed not effective because they can't mount a good immune response. A lot of those patients are in the target population already for rem-L, the older and the weaker prone to get ARDS. Then there are a lot of people who are convinced a vaccine will cause autism. Even though they're 70 years old. Others say, "I never get sick". Some of the patients in the refrigerator truck said that until they stopped saying it. Bottom line: Many won't take a vaccine, many won't respond to a vaccine, some have legitimate allergies to a vaccine... I don't worry about a vaccine coming along - which may never happen as some have mentioned.
What about an anti-viral? I don't worry about those either. Again looking at influenza as an example, we have oseltamivir (Tamiflu), and we still have lots of ARDS in cases where it doesn't work, has side effects or most importantly gets started too late. This is a potential problem with Gilead's remdesivir. As with many (not all) anti-virals, it looks like it will work better if started early, within 48 hours of symptom onset. Unfortunately, that doesn't rhyme with IV administration, which is required due to the chemistry of the compound. And daily IV admin is recommended for 5 to 10 days, (even though 10 days hasn't been shown to convey any benefit over 5 days). That means an expensive hospitalization just for an anti-viral, which means sicker patients less likely to respond. There's a nice 2019 paper by J Chen et al that talks about their experience in China using MSC's to treat avian flu in the epidemic that occurred in 2013. 100% of patients in their study received anti-virals prior to getting MSC's for their advanced pneumonitis. The paper is important also for the 5-year follow up. As in that study, rem-L will get the anti-viral failures. Anit-virals are not competitors in our space. They may reduce the number of patients who get ARDS, that's good, but they do not treat ARDS (for the most part). And they all have toxicities, adverse drug interactions and side effects. I don't worry about anti-virals.
What about prophylactic medicines? President Trump is taking hydroxychloroquine as a preventative. Probably it's ok... the medicine has an excellent safety profile, UNLESS it doesn't protect you from the virus. In other word, if it does its job as a prophylactic you're ok. But if you get the virus and keep taking the medicine, there's at least a theoretical possibility you'll have an SAE. The medicine, along with some others in this space like azithromycin, is known to cause Q-T prolongation on an EKG. That can become a problem if the medicine fails, the heart is attacked by the virus and becomes "irritable". I'm sure the President had an EKG and is being monitored carefully. But the average Joe the Plumber is probably not being monitored that carefully. It's the kind of situation where a small percentage can wake up dead, and it will be chalked up to "natural causes". There are some FDA-approved medications that reliably kill a small percentage who use them. Chlormycetin the antibiotic is an example. About 1 out of 20,000 to 40,000 who take it will die. That's enough to restrict its use greatly among humans (the vets use it a lot because animals don't seem to have the problem). In any event, I don't worry too much about prophylactic meds somehow eliminating all rem-L cases. Same as with vaccines and anti-virals, they may help some, that's good, but rem-L will get the failures. Large trials are needed to sort all this out and are underway.
Likewise, there are any number of medications being "re-purposed" for Covid-19, or that are being tried at an earlier stage of illness, namely "Severe Covid-19", per FDA Guidelines. This is the bulk of the 1000 I mentioned above. Human ingenuity is mind-boggling just in terms of the variety of ideas. I have little doubt that many of these are trying to catch funding updrafts if you can get the public to believe you've found the magic bullet for C-19. Everything is being tried. Feeling strange or starting to hear voices because you've been locked in so long due to the virus? May be time to go back on your Thorazine... and you can join a trial for C-19 at the same time. Two birds with one stone. Same if your gout has flared, there's a colchicine study for C-19. There are studies for vitamin C, vitamin D, or BCG vaccine. In India they're trying a less expensive alternative to that by autoclaving readily available TB bacilli and injecting them. If you're an Australian diver you can join a hyper-baric oxygen study... bring your mask, but no snorkels allowed. There are sequential oxygen schemes and inhaled nitric oxide... and if any of that gives you a headache there's a trial using plain old aspirin. Of course...
One or some of these COULD beat rem-L over the finish line for bragging rights to becoming the first FDA-approved therapeutic for C-19. That's OK. They're still not competitors. All companies have competition and we need to survey the true competitors or potential competitors in our space, which is the treatment of CRITICAL cases of Covid-19 that progress to intubation and a ventilator. To narrow the list from a 1000, I selected only those companies and therapies with large trials actively recruiting patients in the US to treat C-19 pneumonia or ARDS. That narrows the list quite a bit. These are the therapeutics that bear watching imo, either because they might position between us and a suitor or they might beat us to the finish line for an FDA-approved therapeutic for C-19 pneumonitis/ARDS. I list them is no special order, formatting being limited. Please feel free to add or subtract:
1. Ruxolitinib (Jakafi). As many of you may know, this is the small molecule that has FDA-approval to treat adult GvHD. It's manufactured by Incyte, a Delaware company on the move in terms of pipeline and market cap, which is $21B. Jakafi started a 500-patient phase 3 trial on May 8 with an estimated primary completion date of July 29... hard to believe they'll get done that soon because so far they have only 1 recruiting site listed - in Pittsburgh of all places. Nevertheless, Incyte is clearly in the race. The biggest drawback for their molecule is the long, long list of side effects that will not play well in the C-19 ARDS population: Serious infections, anemia, low platelet counts, low white cell counts, liver toxicity, the dreaded neuro complication PML, and even cancers. Plus there are a host of meds that can't be given concomitantly, and no grapefruit juice - which eliminates the study for me even if I'm unconscious. They're taking patients with a higher P/F than rem-L, anything under 300, suggesting they're trying to recruit patients before they get too, too sick and can't tolerate the medicine. INCY is always listed as an acquisition target and management is aggressive and savvy. I consider them a competitor. Worth keeping a watch on even if their molecule is a long-shot for this particular indication (they're also a competitor in the adult GvHD space, obviously).
2. Athersys MultiStem. The company has a market cap of $596M and has started an open-label lead-in phase 2 to their planned pivotal phase 3 which will enroll up to 400 patients. They're using an adaptive design which allows "sequential enrollment" and more frequent interim review. As I mentioned before, they are considered number two in the cell-based therapeutic space. Their phase 2 began on April 29. They have two hospital centers listed for recruitment, both in Cleveland where they are headquartered (and where MSC's got their start with Dr. Caplan). If they match Mesoblast's speed they should move in to phase 3 tomorrow. I'll be surprised, Athersys has been a slow-walker getting in to phase 3, may have less potent cells (MAPC's), may be stepping on Mesoblast IP. Their enrollment criteria pretty much match Mesoblast's, so they're in our space, but well behind now due to failure to do an EAP. They just did a $50M cap raise through BoA/Merrill Lynch so will probably be getting analyst support on that front. The sequential design is the one variable to consider... doubt FDA would let them undercut our 90 patient interim review, they may not have enough cumulative patients for safety (global total) but we're in the Age of Covid-19. Surprises are always possible if they show exceptional results during the lead-in... Worth watching.
3. Biohaven Vazegepant. The company has a market cap of $2.8B. This is a different one. It's an intra-nasal administration of a "Calcitonin Gene-Related Peptide" resceptor blocker that's in trials to treat migraine headache. They've gotten FDA authorization to do a phase 2/3 trial and list two prestigious recruiting centers: Georgetown Hospital in the nation's capital and Thomas Jefferson University in Philadelphia. They're recruiting patients with pneumonia prior to intubation with a goal of preventing intubation. Not directly in our space but off-beat enough that I thought I'd mentionn it. Ease of administration and a larger potential population base could allow faster recruitment. It's made my watchlist.
4. Roivant Gimsilumab This is a Swiss company founded by Vivek Ramaswamy. Still private as far as I can tell. The molecule is an anti-GM-CSF mAB, so targeting as an immune modulator "to reverse cytokine storm". They have 11 prestige medical centers recruiting patients on HFNC or within 72 hours of intubation. Phase 2, 270 patients. So, they're putting a lot of dollars into this. The trial started on 4/12 and lists an expected primary completion date of July/2020. Most interesting are the trial endpoints: Mortality at 43 days, and all the secondary endpoints are measured at 43 days... The company is said to have raise $1B in PE in 2019. Definitely on my watchlist, though I think the molecule is only part of the solution to CS. Trials will tell.
5. Cytodyne Leronlimab The company has a market cap of $1.55B. The molecule is an anti- CCR5 inhibitor for which they just filed a BLA after 13 years of testing against HIV. FDA acceptance for priority review pending. They are now moving aggressively in to the C-19 space with two trials, one for mild to moderate C-19 and one for severe to critical C-19. The latter is a phase 2b/3 390 patient trial with 11 centers listed, only 3 actively recruiting as I write. It's an interesting mAb targeting the well-know CCR5 T cell receptor, a genetic deficiency of which confers immunity to HIV without other apparent health problems. The company ran an EAP and boasted "remarkable" results saving the lives of 4 or 11 patients, 7 of whom were immunosuppressed organ transplant patients. They followed that up with a paper documenting reduction in RANTES (CCL5) and viral copies. They are recruiting critical patients, limiting patients to a P/F of 150 or higher, but accepting patients in shock or on ECMO, which is unusual. Yesterday they announced a third trial in Mexico. Management has come under criticism due to its handling of the BLA and some insider sales of stock. A company worth watching, all of their results need to be verified imo. Potential drawbacks of the molecule are liver, adverse interactions and ?increased risk of infection in this acute population. I find it MOST surprising that Pfizer (Maravoc, which targets the same receptor) has been very quiet on re-purposing to Covid-19. In any event, CYDY is definitely on my watch list, eventual synergies with rem-L cannot be ruled out.
6. Humanigen Lenzilumab The company has a market cap of just $100M. I mention it because they have a mAb directed at the same target as gimsilumab. Despite their small size they've managed FDA authorization for a full phase 3 trial with 238 patients. They have 9 centers participating including the most prestigious Mayo Clinic. They are targeting C-19 pneumonia just prior to intubation... bigger pool of potential patients, smaller recruitment size and the phase 3 means they could beat us to the finish line for FDA first-mover bragging rights - while we get to treat their failures. Ouch. Still, MoA has to be proven for all of these molecules that target only part of the storm problem... I think live cells will win at the end of the day. On my watch list.
7. Regeneron Sarilumab (Kevzara) The market cap is $64.2B. Another mAb, this one an IL-6 inhibitor being re-purposed from RA. So, the advantage is that it already has FDA approval for that indication. The company has deep pockets and has 63 medical centers enrolling. The trial started April 30 with an anticipated primary completion date in September. They are targeting pneumonitis patients with a primary endpoint of progression to ARDS/ventilator at 28 days. I think the mAb will prove weak for this indication, trials will tell. It has toxicities and carries black box warnings for serious infection and oppotunistic infection, not ideal for ICU patients. Still, on my watch list.
8. Roche/Genetech Tocizilumab (Actemra) Another anti-IL-6 mAb already approved for RA. This one also has approval for Cytokine Release Syndrome related to treatment with CAR-T cells. There was a report in the NEJM on May 12 reporting favorable experience using this molecule in China to treat 21 patients with C-19 lung illness. 15 of 21 had a decrease in O2 requirements. Genentech is pursuing this vigorously with 44 different trials registered phase 2 and phase 3 in multiple countries. So, very deep pockets... will they beat us to the finish line - or take other action if their molecule stumbles due to reasons I listed above? Trials will tell.
9 Celularity CYNK-001 I believe the company is private. Not really a competitor but I mention them briefly because they got some publicity a few weeks ago from Rudy Giuliani, the former Mayor of New York City who interviewed the CEO on his podcast. The company is developing Natural Killer cells, so a cell-based therapeutic that would not interact well with MSC's if given at the same time. They are targeting pre0intubation patients. So, a lot of publicity but it didn't get them too far with the FDA. They'll be doing and 86-patient trial at 5 different centers targeting patients not too sick with a PO2 above 95. And they'll be starting in phase 1.
10. Pluristem... not yet actively recruiting at this time.... I add them to the list just to round it out. They're number 3 in terms of cell based therapy, bogged down in phase 2 testing and dose finding as I mentioned before. I have grave doubts about administering 15 IM injections x 2 to unconscious ICU patients. But the FDA approved it, so let's see. Still waiting for a good explanation of how the cells will traverse hill and dale from the butt to the lungs in time to take action... their entry criteria are a bit looser, the only requirement is "ARDS".
Well, there are a couple of others I'm watching, but that's enough for now. Appreciate any feedback or refinements to the list. I'm invested in Mesoblast because I thing the available evidence points towards cells working better than molecules in these ACUTE illnesses where time is of the essence and molecular dosing can over or under-modulate. I like the concept of cells going in, sizing up the problem so to speak and applying just the right amount of modulation at the right points, using servo mechanisms feedback loops in the cellular micro-environment to fine tune exactly what is needed. We see it in aGvHD... will we see it in ARDS, where the "A" stands for acute in both conditions. And I also think any of the companies above can stumble and we'll beat them to the FDA finish line. Exciting times ahead.
Disclosure: I have no investment in any of the 10 companies listed above. GLTA, Left-e
TEST FORMATTING, duplicate text:
Well, there are a couple of others I'mwatching, but that's enough for now. Appreciate any feedback orrefinements to the list. I'm invested in Mesoblast because Ithing the available evidence points towards cells working better thanmolecules in these ACUTE illnesses where time is of the essence andmolecular dosing can over or under-modulate. I like the conceptof cells going in, sizing up the problem so to speak and applyingjust the right amount of modulation at the right points, using servomechanisms feedback loops in the cellular micro-environment to finetune exactly what is needed. We see it in aGvHD... will we see it inARDS, where the "A" stands for acute in both conditions. And I also think any of the companies above can stumble andwe'll beat them to the FDA finish line. Exciting times ahead.
(20min delay)