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TOPIC: MesoBlast Type 2 Diabetes Phase II results

MesoBlast Type 2 Diabetes Phase II results 23 Dec 2013 06:53 #1148

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I had a discussion at the Cell therapy Industry Gruop at LinkedIn on the above topic- fits exactly with some of my earlier comments

Fas Kuiters- Digger for the investment holy grail and of course- the fountain of youth. Thereto publisher of several regen websites.
I have not been here for a while but could not find anything on these reported results on the fly. They were reported on December 4 and I have my specific ideas about that.
Anyone that can shed some light on these lets say- meager results?
Download PDF here -http://www.mesoblast.com/news-and-media/news-announcements

Chris Centeno-CEO at Regenexx
These results are about what one would expect to see with changing the patient to a high fiber diet ( www.ncbi.nlm.nih.gov/pubmed/24330576 ) or less than one would see using dirt cheap drugs like Metformin ( www.ncbi.nlm.nih.gov/pubmed/23522121 ). Of concern is that in at least one small data set, the effect on the HBA1c didn't last. Nobody came close to being cured of diabetes. Again guys, "aint" no insurance company going to pay for a very expensive and hard to handle vial of cells when a $5 Walmart script for generic metformin will do it better or even the same with less expense and hassle. So this is two disappointing trials for MSB where they didn't meet the "wiz bang" endpoint that would justify the big bucks the regulations will force them to charge-disc and diabetes. It will be interesting to see when Wall Street starts to notice the hype vs. reality...

Richard D. Hammer- Associate Professor of Clinical Pathology and Anatomical Sciences at University of Missouri
Fas, these results are minimal at best, and thats being generous. Of course there is not enough info here to even know what diet they placed them on, which by itself could have resulted in these changes. Or exercise or anything else that can effect these results. Too small a group, minimal results, etc. One of the hats I wear is medical director of the Diabetes Lab which is the national reference lab and standard for HgA1c testing, and I am not impressed. It seems to be a trend in the clinical trials I've seen recently that any result is deemed a success. These are often minimal effects, small numbers, and short durations. Yet they seem to allow these companies to move on to the next phase. Studies designed to be successful.I can improve my HgAIc .5-1% by nothing other than lifestyle changes. I have to agree with above, metformin is the drug to beat, and they got a long way to go.

Fas Kuiters- Digger for the investment holy grail and of course- the fountain of youth. Thereto publisher of several regen websites.
Thank you both for your insights. I admit being totally illiterate on type 2, but I do remember that lifestyle and cheap drugs can reduce HbA1c by 1 or 2 points, which than obviously is a bit more than 1-2%.. I still believe cell therapy can make a difference in diabetes. The study from Diane Mathis et al provided some pointers (2009- Fat Treg cells: a liaison between the immune and metabolic systems) and there were some anecdotal reports from the practice of medicine in Japan that smelled like a cure from the same year (going from 73 to 67). But than the law cracked down in 2010. With the new opening for regenerative medicine in Japan forthcoming, I suspect this app to be a part of that drive.

Reinout Hesselink- PhD Manager Business Development at Eufets GmbH
It may be my ignorance on mesenchymal cells, but I o not see the MoA aimed for. Type II diabetes is hallmarked by a systemic insulin resistance, resulting in constant high bloodglucose and high insuline levels. Increasing insulin levels only helps to a certain extend, and in patients suffering of TIID for over a decade, even that usually has limited effect. What way could mesenchymal cells revert this systemic insulin resistance? I would expect that after being exposed to the high glucose high insulin environment for a while, also the infused cells would become insulin resistant. This could explain the fact that after a period of 12 weeks the observed effect (if any) diminishes.
Being trained as an exercise physiologist in a department that was focussed on TIID, I would expect bigger effects if the study subjects would have taken the stairs instead of the elevator over a period of 12 weeks rather than being infused with mesenchymal precursors.

I am convinced that cell based therapies can have an added value to the current treatments in a number of diseases. It will however not be the magic bullet that will cure all diseases that some people advertise it to be. Type II diabetes may well be one of the indications where cell therapy will not have an impact
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MesoBlast Type 2 Diabetes Phase II results 23 Dec 2013 07:03 #1149

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Chris Centeno-CEO at Regenexx
Fas, I agree that a type 2 DM cell therapy may be feasible, but this would have been a good application for an inexpensive SVF machine that was registered as a device rather than turned into a BLA/IDE like Cytori's Cellution was here in the US. This then would have allowed doctors on the ground to figure out the best ways to accomplish the therapeutic goals.

Chris Centeno-CEO at Regenexx
Reinout, the theory behind why MSCs might work is that at some point systemic inflammation plays a big role in disease propagation. However, you're right in saying that whatever you down regulate, up regulate, or repair will be chewed up by the same factors that caused type 2 DM in the first place. This is why an inexpensive cell based solution may be a game changer, but a cell drug is a non-starter due to regulatory and production costs.

However, there's a bigger trend here to date that should have all in the "Cell Therapy Industry" pretty spooked. I have yet to see any trial or an approved or in process cell therapy meet it's therapeutic goals in such a way that it will justify it's huge cost. These companies, even if you keep the regulatory cost the same as for other drugs, are creating the world's most expensive to manufacture drugs. If they meet their hyped end points (i.e. making old low back discs new or curing type 2 DM), they are worth their high cost. However, if these trends continue, it's doubtful that any of these first or second round cell drug "products" will be financially successful. Remember, squeaking out 1-2 killer applications out of a field of 20 cell drug candidates won't mean success for the "industry", quite the contrary, it could spell disaster as the private funding will head for the exits.

Richard D. Hammer- Associate Professor of Clinical Pathology and Anatomical Sciences at University of Missouri
I think there is a potential in type 2 DM but we have a ways to go. This recent study is encouraging and along the lines I think it would need to go to be effective. Assuming we are ok with genetically manipulated cells. link.springer.com/article/10.1007%2Fs10238-013-0266-1?elq=4053230db2b949f7b4a53a82585240c7&elqCampaignId=4

There has been some work here also on regenerating islet Beta cells, but again a long road to hoe.
I have to agree with Chris that the therapeutic goals/results to date in many of these trials are not that impressive. Not to change the subject, I was reviewing the release from Mesoblast today regarding their stroke trial and this caught my eye.

"Using anatomical MRI, MPC-treated animals had a 17% reduction in infarct volume compared with controls (p<0.05). This effect was not seen in the overall group using post-mortem histologic assessment, which may be a less sensitive measurement."

There is obviously a disconnect here and marketing "spin". Maybe they were seeing something on MRI (edema?), but histologic assessment is the gold standard here and significantly more sensitive if done properly. If I was an investor I might be wanting to reconsider.

Fas Kuiters- Digger for the investment holy grail and of course- the fountain of youth. Thereto publisher of several regen websites.
Chris- with all due respect (to me you are the voice of reason in many aspects)- one aspect you do seem to ignore. The US and its regulatory systems are NOT the center of the universe. There are plenty of sick people outside its borders that are looking for cures too. After going through a lot of research I think I know how the most important regulatory systems outside the US tick and work i.e in markets # 2,3 etc etc. My vision is that there will be a thrust from "outside" based on example and success in cost effective regenerative medicine and acceptance accordingly. One will not be able to ignore the obvious.

Richard D. Hammer- Associate Professor of Clinical Pathology and Anatomical Sciences at University of Missouri
Fas, you are so right. It is a bit sad to watch the US fall behind here, but its not he whole world. I truly expect those other markets will take the lead, and we will be playing "catch up"--or buying plane tickets!

Chris Centeno-CEO at Regenexx
Fas, I agree 100%. We are not the center of the cell therapy universe (although as an American, we could have been...). Yes, more practical innovation about how to make cell therapy reach it's full potential won't come from the bench scientists, but from physicians ex-US who are figuring out how to make it all work.
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MesoBlast Type 2 Diabetes Phase II results 23 Dec 2013 07:33 #1150

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Actually the link that Richard Hammer provided is an interesting study- shows you, there is a lot going on around the world-

also in India- :nice:

Abstract
Insulin-dependent diabetes mellitus (IDDM) is a metabolic disease usually resulting from autoimmune-mediated β-cell destruction requiring lifetime exogenous insulin replacement. Mesenchymal stem cells (MSC) hold promising therapy. We present our experience of treating IDDM with co-infusion of in vitro autologous adipose tissue-derived MSC-differentiated insulin-secreting cells (ISC) with hematopoietic stem cells (HSC). This was an Institutional Review Board approved prospective non-randomized open-labeled clinical trial after informed consent from ten patients. ISC were differentiated from autologous adipose tissue-derived MSC and were infused with bone marrow-derived HSC in portal, thymic circulation by mini-laparotomy and in subcutaneous circulation. Patients were monitored for blood sugar levels, serum C-peptide levels, glycosylated hemoglobin (Hb1Ac) and glutamic acid decarboxylase (GAD) antibodies. Insulin administration was made on sliding scale with an objective of maintaining FBS < 150 mg/dL and PPBS around 200 mg/dL. Mean 3.34 mL cell inoculums with 5.25 × 104 cells/μL were infused. No untoward effects were observed. Over a mean follow-up of 31.71 months, mean serum C-peptide of 0.22 ng/mL before infusion had sustained rise of 0.92 ng/mL with decreased exogenous insulin requirement from 63.9 international units (IU)/day to 38.6 IU/day. Improvement in mean Hb1Ac was observed from 10.99 to 6.72 %. Mean GAD antibodies were positive in all patients with mean of 331.10 IU/mL, which decreased to mean of 123 IU/mL. Co-infusion of autologous ISC with HSC represents a viable novel therapeutic option for IDDM.
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MesoBlast Type 2 Diabetes Phase II results 23 Dec 2013 10:25 #1151

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Glimmers of hope but far from a slam dunk so far imho. (India study )
Overall discussion more clearly indicated this is years and years away to me.
Insulin is dirt cheap....so if patients still need daily insulin we are, on the surface, more talking some quailty of life benefit in lower doses?
That would leave me with the same feeling and the SUI study.
On the other hand if they can show benefit in reduced complications from this disease due to overall better disease management, then we have something...this possibility did not seemed to be discussed in your discussion post

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MesoBlast Type 2 Diabetes Phase II results 23 Dec 2013 11:31 #1152

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I do not think that is right Hedge- my example which was the Mitsuo anecdotal treatment from back in 2009.
There the LT glucose measurement (HbA1C) went from 73 to 67 which is 6 points but that is from here to the moon for a diabetic.
That is about 8% just as the Indian study with engineered cells.
65 is regularly regarded as where you have Type 2, but at that level not severe.

We will see- things can go fast in japan when the benefit is "substantial". :grin:

Than again- the discussion was basically on MesoBlast- that was the key learning and what I have been saying all along. The same conclusion I have already drawn on their cardiac results.

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MesoBlast Type 2 Diabetes Phase II results 23 Dec 2013 12:22 #1154

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***There the LT glucose measurement (HbA1C) went from 73 to 67 which is 6 points but that is from here to the moon for a diabetic.***

To be honest I am not used to seeing HbA1c reported this way but I am assuming its the same as 7.3 to 6.7 and if memory is correct sub 7 is goal for diagnosed diabetics
The A1C result from the India abstract was impressive *** Improvement in mean Hb1Ac was observed from 10.99 to 6.72 %.*** I felt that further analysis on reduced complications vs reduced insulin usage would add far greater weight than simply the latter. Besides how a individual patient manages his/her disease on a day to day basis in a non-controlled enviroment
can vary greatly so I feel the reduced complications would also show better overall management...less spiking of glucose levels, ect. This reinforces a main selling point...better outcomes at cheaper cost !!!
All of this would take time to prove, get reimbursement, and ramp. Japan is indeed a special case that we still dont fully know how quickly things will unfold starting in 2015.

I think clearly Mesoblast isnt living up to who was thought to be a leader with recent results.

All the above said...put in a call to brush up on DM and some of the comments posted for another opinion...I'll take any help I can get. No word back yet !

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