Excellent commentary from ImaScientist, dplane, sailnyssa, and also JonesingPanda (sorry, it was a quick response on my cell phone). I'm going to use this post by ImaScientist to launch further analysis of the EAP and the press release from yesterday. The Company is opening a window to its thinking... here's why I attach a lot of significance to the specific wording in the PR...
There are many ways to classify diseases, and from 30,000 feet we can divide them into two broad categories, "A" and "C" for acute and chronic. The major "A" illnesses the company has pursued to date are aGvHD and the recently added ARDS. Also recently added, we are told JCR is interested in HIE, an "A" disease associated with cerebral palsy. The "C" illnesses are cGvHD, Crohn's Dz, CHF, CLBP and COPD. At an earlier clinical trial stage we see EB, RA and Diabetic Nephropathy. Notice that the A list is (a lot) shorter than the C list... And the A list is where we have some pretty good evidence with the BLA and the EAP (on top of other cell-based studies that have been done).
So, dplane and ImaScientist, I agree, the economics and regulatory impact of advancing a therapy for an A disease are different than for a C disease...It's not an accident, at least in terms of filing a first BLA, that Mesoblast is starting with a horrible A disease, imo. And IF the company is developing what amounts to a $75K Z-pack to treat COPD, it's probably not going to fly with regulators and insurers... which is why I think the PR is telling us something much more significant. Yes, A diseases can take you out quickly. But they often start on a foundation of healthy tissues, meaning if given half a chance the body can heal itself and return to a state of excellent function. C diseases represent illnesses that make long-term existence miserable... and expensive. COPD is death by slow suffocation tethered to an oxygen machine clutching a collection of pills and inhalers that provide "symptomatic" relief. Unfortunately, A vs C tells us nothing about therapeutic efficacy of any proposed treatment. However, with respect to MLC's...
.... We have good evidence that MSC's can do something for an A disease, especially aGVHD. We're told they can cure with just a few infusions. CURE, particularly in doomed children, is a compelling argument to bring to the FDA and insurers when you present your $$treatment. But look how long it's taken even for an A disease where outcomes are more clear cut. Up to present I'm hopeful but more skeptical on the C diseases; we're waiting for further confirmation on some this year. There's a huge patho-physiologic difference between "modulating a cytokine storm", a tornado-like event that comes on suddenly and attacks a baseline of relatively healthy tissues, and "slowing the progression of, or even reversing, illnesses like COPD", which is a smoldering bulla-forming, scarring, fibrotic mess fed by an ongoing gemisch of cigarette smoke, pollution, pollen, bronchitic infections, and immune reaction. Scars and bullae are macro-anatomical structures that yes make the lungs more susceptible to insults like a bacterial infection causing quick decompensation. But like I said, if the only thing the cells can do is to function as a Z-pack, that's probably not going to fly. Can they do something more fundamental to reverse or ameliorate the underlying disease?? Can they provide a "regenerative" therapy for a C disease? That's a FUNdamental question in stem cell therapy. And with growing evidence that C-19 ARDS can actually devolve into a C disease marked by pulmonary fibrosis, it becomes all the more important.
In fact, the evidence that impresses me the most on C diseases comes from our CHF studies, but more so from what we're literally able to SEE with Alofisel. Can stem cells reverse/heal a chronic MACRO-anatomical defect? That's asking the cells to do a whole lot. We have this from a 2019 review of compassionate use by Dr. Garcia-Olmo, perhaps the leading clinical researcher on fistulae in Europe:
"
Regarding perianal Crohn’s-related fistula, we treated 13 patients; they received a first dose of ASC and 5 of them were healed. Three patients received a second dose and healed all of them. Later, 2/13 patients received a second dose to treat another fistula, different to the one already cured, and they both healed. Therefore, 53% of the patients were cured after a first injection of ASC, and the patients treated with a second ASC injection were cured 100%. As we did not treat all patients with a second dose, we cannot assert but we can estimate a healing increase around 30% with the second dose of ASCs, which is consistent to previously published results [19,20]. Five of the 13 Crohn’s patients were not cured; 1 is waiting for a second ASC treatment, 3 are enrolled in a new ASC CT, and 1 refused a second dose of stem cells."
So, not a controlled study but those have been done also, see the ADMIRE-CD trial. The key point is that an anatomical structure visible to the naked eye is healed... probably through a mechanism addressing the underlying auto-inflammatory state.
From Ciccocioppo and Corazza:
"Thepotential to dampen activity of T-helper-1 and T-helper-17 cells andincrease the apoptotic rate of effector T cells while favouring theexpansion of cell populations with regulatory functions is ofbiological relevance"
Crohn's is very different than COPD, but for starters, we weren't even thinking of pulmonary diseases just two months ago. The COPD study was done by Osiris some 10 years ago, the results were published in 2013 and a bit forgotten. Here's a link to the abstract where you can download the full paper:
DrWeiss: https://pubmed.ncbi.nlm.nih.gov/23172272/
In the study 30 patients received rem-L and 32 received placebo (5 of the rem-L patients were still smoking stocksa;-)
The bottom line conclusion of the study left many investors disappointed:
"No significant effects of MSC infusions were observed on pulmonary function or QOL indicators.Further larger-scale trials will be necessary..."
The authors did note the fall in CRP levels in some patients and made this perhaps PROPHETIC statement:
"More acute diseases of lung inflammation (eg, ARDS) may be more amenable to the intense, short-lived, anti-inflammatory effects of administered MSCs."
So, let's review what has happened - and note the evolution in the Company's presentation - in the course of 2 short months. On April 6 we are told the Company has filed an IND to study rem-L in C-19 ARDS. The rationale for this new indication is based on two facts: one, evidence the "cytokine storm" of C-19 ARDS is similar the one in aGvHD where rem-L is known to work, and two a re-visit to the COPD study of 10 years ago where data mining reveals evidence of rem-L efficacy in those cases where an inflammatory marker, C-RP, is elevated.
Here's the link to the presentation by Dr. Grossman again, let's take a look at the details quickly:
https://www.celltherapyjournal.org/article/s1465-3249(20)30570-3/fulltext
It took me a minute to figure out what Dr. Grossman et al actually did - They essentially converted 1 study of 62 patients into 3 studies of the same 62 patients. In each of the 3 sub-studies the patients are sorted differently depending on their CRP values. Here's the table, take a look at the 3 groups.... If you look at each group, CRP gt 2, CRP gt 3, CRP gt 4, you can see that the same 62 patients are sorted differently. And in the right hand column, we see that the p-values for those who received rem-L fall, especially on the 6-minute walk test. As we go from CRP gt 2 to CRP gt 4 that p-value goes from 0.159 to 0.004, an enormous change... suggesting increasing statistical significance for the conclusion that rem-L is the cause for the difference in observed outcomes. In other words, for the 12 patients out of 30 who received rem-L and had a CRP above 4, there was a big difference in exercise capacity compared to the 17 placebos out of 32 who also had a CRP above 4.
So, it provides evidence that targeting COPD patients with higher inflammatory markers may be of interest. But it's a marker, not an anatomical change, and so there may be other factors based on long-term follow up that we don't know. If I were going to write a headline for the presentation it would be along the lines of "Remestemcel-L improves outcomes in patients with COPD who have Elevated Inflammatory Markers". Accuse me of over-reach, but what strikes me the most in yesterday's PR is the change in emphasis on indications. Yes, I understand it's the formal announcement of the presentation at ISCT on the COPD paper. It's just that to date the emphasis has been on the COPD study playing a supporting role to justify the study of C-19 ARDS.
Look again at the Headline:
"REMESTEMCEL-L IMPROVES RESPIRATORY AND FUNCTIONAL OUTCOMES IN PATIENTS
WITH INFLAMMATORY LUNG DISEASE"
OK. Let me make this bold statement and give me your feedback and criticism: Most pulmonary specialists would not classify either C-19 ARDS or COPD as primarily "Inflammatory Lung Disease". Of course, they both have inflammation as a component of the illness. So, do asthma, spontaneous pneumothorax, tuberculous pleural effusion and a gunshot wound to the chest. But if I told you, "I'm studying inflammatory diseases of the lungs", those would not be the primary things you would think of. Nor would C-19 ARDS, which most would classify PRIMARILY as an infectious disease, nor COPD, which most would classify PRIMARILY as an obstructive disease, it's right there in the title. It's not called Chronic Inflammatory Lung Disease for a reason. Even though yes, there's lots of inflammation in COPD. When I hear Inflammatory Lung Disease, I'm thinking of all those things plus a much broader category of illness marked PRIMARILY by inflammation. Diseases like Idiopathic Pulmonary Fibrosis; Usual Interstitial Pneumonia; Interstitial Pneumonitis related to RA, lupus, sarcoidosis or other auto-immune diseases; various pneumoconioses like asbestosis or silicosis and a host of other problems. These lung problems have a common denominator: they cause SCARRING of the lungs for which there is often NO good treatment. And they are all C diseases that can slowly suffocate by causing "irreversible" damage.
So, I'm very pleased to see this first announcement of a shift in indications. I see it as a claim to the UMBRELLA under which a host of chronic illnesses reside. C diseases that slowly kill and impair the joy of living. The question remains, can the cells get the job done? Let's continue to look for signals, subtle or otherwise. KEY question right now for anyone to be asking of SI, FG and even themselves as investors: Do we have evidence that rem-L prevents or reverses the FIBROSIS often seen with C-19 ARDS? A YES answer to that key common denominator question will open up a vista of illnesses and partnership opportunities in the months and years ahead.
Exciting times on the way. Left-e
PS, I'll save sepsis for another post
(20min delay)