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TOPIC: MOAKS- the objective judge on OA

MOAKS- the objective judge on OA 06 Aug 2016 14:03 #7551

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I listened to the part on OA from the CC a few times - read and corrected the transcript of Seeking Alpha on the same topic and believe that all chances are still there that OA will be a major application for Cytori going forward.

The key statement from the call- I believe to be this one here-

In general, the magnitude of the mean changes observed in the trial from baseline to the various time points were substantial, consistent with placebo effect or saline effect as reported in recent med analysis. In comparison, the difference between active and placebo at various time points, were all consistent, was relatively small.


This means simply that if your nil hypothesis for placebo is that one does NOT see a therapeutic impact, however that impact is defined, and the placebo still delivers a good impact albeit lesser that treated, you never ever will have statistical significance. At least what I vaguely remember from statistic seminars at the University was that the Gaussian curves and all that jazz is totally against you.

Certainly when your primary endpoint is pain after x meters walking at 12 weeks, when placebo - the power of the mind- is still the strongest. Lets say- everybody in the trial was happy.. that is good isnt it?? :grin: :grin: The control patients were and the treated patients even better. :vegas:

Anyway- I am really-, really glad Cytori spent a lot of money on MRI´s and the resulting data could mean a lot to the Company going forward-

so - here MOAKS should be introduced-

File Attachment:

File Name: 2014-SubregionalOAProgressionUsingMOAKS.pdf
File Size: 176 KB


Excerpt from the paper:

Recently, the MRI Osteoarthritis Knee Score (MOAKS), a new semi-quantitative magnetic resonance imaging (MRI) scoring tool, was introduced by a panel of experienced researchers in osteoarthritis (OA). The MOAKS is primarily applicable to quantify OA status, since the interpretation of change in the MOAKS features was not described. In order to enable longitudinal evaluation, we propose definitions for progression and improvement of the main MOAKS features.


and the ensuing remarks of Hedrick should be self explanatory- since here we see OBJECTIVE-, QUANTIFIABLE BENEFITS, we should give them the time to continue their analysis and discussion with partners.

I am confident somebody will take the bate based on hard positive data...

Some comparisons between active and placebo for patient reported outcomes approach in some cases reached statistical significance. While the ECCO-50 showed signals as to improvements in patient reported outcomes, as a potential regenerative therapy for these patients, the use of living cells, MRI valuation of joint pathologic changes were an important aspect of safety and exploratory analysis of this trial.
To that effect, we use blinded expert MRI readers to evaluate the MRI Osteoarthritis Knee Score in this case MOAKS to evaluate a possible effect of the overall disease severity of the knee. The MOAKS analysis system device in the 15 anatomic subunits and measures various parameters that correlate with both early and late joint dysfunction. And longitudinal studies to detect changes MOAKS is generally used to follow patients out well beyond two years to establish trends and it can also be used as a prognostic tool for the need for total knee arthroplasty.

This trial showed consistent trends in all six pre-specified MOAKS classification score and it’s important to note and in particular emphasize, that while preliminary and further analysis is warranted, this suggests that the therapy may result in an effect on the target need joint pathologic features like 48 weeks from treatment, for the treated group relative to placebo control group after single administration of the therapeutic. Specific anatomic subunit analysis is important here and correlation with symptom improvement data is ongoing to further characterize the nature of any cell effect. For the record, specifically the six features we assessed for – and trended positively, were in patients were the number of bone marrow lesions, the percent of bone marrow size, the size of bone marrow lesions as a percent of the sub-region, the percent full thickness cartilage loss, the cartilage loss as a percent of surface area and the size of the largest osteo site.

The safety profile coupled with observed trends in patient reported outcomes and joint – favoring cell therapy in its first trial in patients with this indication are encouraging and particularly intriguing in the context of the potential imaging benefits in the joint itself, but correlation is key though. So what are the next steps? Our advisors have recommended further and deeper examination of the data in particular correlations of the patient reported outcome in MRI data and looking at specifically the anatomic sub-regions which requires a stick of – raw data set and those analysis are being considered. We have an awful lot of data here. So, from a strategic perspective, what is the preliminary data meaning for the company in terms of our overall plans? Well as mentioned previously, our corporate focus remains on targeting niche orphan indications that can be brought to market quickly and cost effectively, scleroderma is the prime example there.

However, knee OA is a compelling opportunity and building on this trial with further development, we feel it’s warranted but will require partner support. Our intention is to reach out to those with whom we’ve been in contact, that have had interest or may be interested in this data and we’ll share the full dataset with them. But also and I think this is an important point, we will work with our current commercial partners in Japan that have obtained approval to treat OA patients under provisions, under the new regenerative medicine law and are interested in the clinical use of this product and moderately severe osteoarthritis patient. The safety and feasibility data will use to help support that effort. Finally, we intend to detail the study results via academic presentation and publish that in a peer review journal if and when accepted.

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MOAKS- the objective judge on OA 06 Aug 2016 22:07 #7552

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You are certainly reading this result in a far more positive light than I am Fas !

Let's see who comes running with a check !!!!!

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MOAKS- the objective judge on OA 07 Aug 2016 01:00 #7553

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However, knee OA is a compelling opportunity and building on this trial with further development, we feel it’s warranted but will require partner support.


I feel the glass is half-full :write:

For me the judgement of a partner is key criteria -- show me the money...

holdi

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MOAKS- the objective judge on OA 07 Aug 2016 03:04 #7554

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myownhedgefund wrote: You are certainly reading this result in a far more positive light than I am Fas !

Let's see who comes running with a check !!!!!


Yes- as Holdi also points out- this is the key.

But we knew that all along- OA has to wait like everything else until money is there from Japan or scleroderma patients treated. The famous extra 20 Mio.
But the partner solution is preferred of course. Based on the above- I think that possibility is still there.

Time will tell.
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Board moderator and Site-owner. I still regret the day I started analysing the prospects of MacroPore (now Cytori) back in 2004- a left-over from the tech-bubble at that time from the century change in my portfolio- and became addicted to Cytori´s fat cell technology. :cry:

MOAKS- the objective judge on OA 07 Aug 2016 11:03 #7555

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fas wrote: I listened to the part on OA from the CC a few times - read and corrected the transcript of Seeking Alpha on the same topic and believe that all chances are still there that OA will be a major application for Cytori going forward.



Fas, I, too, edited the transcript and with all the mistakes, it took hours! After listening to the conference call, I was wondering if the data would be enough to attract a partner. After editing and reading the transcript, I am a bit more positive, but clearly the jury is still out. Perhaps WST can help us remember what happened with Athersys with their stroke data. Initially, the data looked weak, but after more time and further examination, the beneficial effects became more apparent and the data did attract a partner from Japan.

Fas has sighted one of the positive statements from Hedrick. Here is a potentially offsetting statement made by Hedrick when speaking about the IV administration and its future implications. "The fingers are a great delivery site for cells because they stick around, but maybe the joints not such a great place. So maybe intravenous delivery can beneficially affect that as well." I think this statement underscores the company's stance that this trial was exploratory in nature as it will help with the design of the phase 3 trial. Certainly, Cytori has learned a few things NOT to do in the next trial. To plug Okyanos a little bit, they discovered early on that being able to hold the cells in the joint for a longer period of time would yield better results. Cytori's ACT-OA trial simply injected the cells into the fluid of the knee.

Another observation: it seemed to me the questions were planted in advance. Jason got Marc to downplay the 12 week primary endpoint of pain on walking and then got Tiago to remind shareholders that the cash on hand should last until after Phase 3 results are out for scleroderma and the ATM was available to ensure that. Then Steve got Marc to emphasize the results of investigator initiated trials around the world. They both asked questions so Marc could emphasized the therapy platform, while the trials measure a single dose of the stem cells, the eventual scleroderma therapy may include IV injections as well as follow-up treatments from cryopreserved cells harvested during the initial liposuction procedure.

I have updated my spreadsheet with very minor reductions in 2016 product revenues due to comments about the Idis program. I will send the spreadsheet to Fas because I do not know how to post it so all can access it.
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MOAKS- the objective judge on OA 07 Aug 2016 20:11 #7557

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***Another observation: it seemed to me the questions were planted in advance***

One could say scripted !
Something I have always complained about and why they would never dare open calls to real investors !!!!!!!!!!!

Let me be clear....the OA results stunk. Another piss poor trial design that perhaps highlights what may be one giant placebo effect worldwide !
We simply don't know. We have proved absolutely NOTHING for our millions ! There will be no partner based on the data they reported last week. This is beginning to sound like the cardiac app. For those who are relying on the editing...what about the mention of looking up to 2 years out at this data ? Anyway, as I said on my first call review, a tip of the hat to mix this in with the full Q call. Everyone should have known there was no, or at least next to no chance of a data from this trial. Only the 48 wk MRI had a chance but it seems wishy washy right now.

OK...now that this OA stuff is over with. On to the next danger zone !
IDIS revenues will be short. I don't mean DOV's small adjustment for 2016. They will need to raise money in 2017 ! PERIOD !!!!! This will be a slow process not only for approvals but also for serious patient recruitment and treatment.

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MOAKS- the objective judge on OA 07 Aug 2016 21:12 #7558

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DOV,

The Athersys stroke program has an extensive amount of preclinical science behind it. In fact, I'm working on an article that will extensively cover it. The mechanism of action is also well understood. Regarding the 90 Day post-hoc stroke analysis that you asked about, I covered it extensively in this article . One main point was that the treatment window played a role in efficacy. 24-36 hours worked better than 36-48 hours. Furthermore, the One Year results reached statistical significance for "Excellent Outcome", the same measurement used in the approval of tPA (the only approved stroke drug that can only be used within the first few hours)for ALL patients!!. I don't think there is enough in the OA data to be optimistic. No dose related response for example and no details to look at. Had this been something worth getting excited about, don't you think we would have seen a separate press release??? No therapy will be approved unless it can soundly beat the placebo effect, nor should it be.

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MOAKS- the objective judge on OA 08 Aug 2016 07:43 #7559

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If Cytori cannot raise any money from a partnership on Scleroderma, OA, wound healing, or anything else, they most certainly will need to raise capital in 2017. The question is how much.

Hedge, I have never seen you be so definitive. Congratulations on that!

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MOAKS- the objective judge on OA 08 Aug 2016 08:36 #7560

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The insights provided by the OA data have been purposely kept at a high level. They do not want to be premature in giving misleading data. Perhaps they do not want to give further marketing material to all the unlicensed clinics? . We know that the primary objective of pain at 12 weeks did not reach statistical significance. Do we know how it was at 48 weeks? Placebo does not last for 48 weeks.

We do know that there is MRI data that suggests remodeling of the joint. How significant is yet to be determined/disclosed. That is HUGE. If there can also be shown to be a positive correlation between the remodeling and patient improvement then we will have something that is truly significant. I believe that they have all the data to undertake this analysis.

Management realize that this is a trial that if it is to be done correctly will require significant funds and capacity. That they are consciously aware of this and will seek a partner is positive.

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MOAKS- the objective judge on OA 08 Aug 2016 11:21 #7561

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One thing is very clear. Either Cytori finds a partner willing to put up the $20 million necessary to conduct a Phase 3 trial or they don't. The partner must be large enough to pay the $20 million necessary for a fully powered trial. Upfront cash to Cytori would be nice, but not a deal breaker.

The only funds budgeted for OA for the next few years are those necessary to further analyze the data and perhaps some T&E in the pursuit of a partner.

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MOAKS- the objective judge on OA 08 Aug 2016 12:29 #7562

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Key to this all is, as Rongside also stated, we now have objective analyzable data, which apparently are in favor of the treatment group. I assume - despite the power of the mind- one can spiritually feel that pain is reduced, but surely one can not remodel your own tissue micro-infrastructure of the knee. :grin:

So- any pivotal primary endpoint can be set up according to those objective parameters, which - as you can read in the paper I attached- also gives wonderful quantitative assessment numbers.

Nobody believes or trusts Hedrick anyway and his statements were very general and useless for the common shareholder, so maybe its best the way it is and wait as Hedge says, until someone comes running with the check.

I am quite positive someone will- despite Hedrick and his funny statements. :bang:

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MOAKS- the objective judge on OA 09 Aug 2016 16:39 #7569

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Mesoblast had a dose related response and encouraging data in Rheumatoid Arthritis, yesterday. Formatting is screwed up here for the table so I advise readers to look up the press release online. This will give you a comparison to what Cytori was able to report in OA. Unlike Fas, I see no partner putting up any cash for OA.


NEW YORK and MELBOURNE, Australia, Aug. 08, 2016 (GLOBE NEWSWIRE) -- Mesoblast Limited(MESO) today announced that a single intravenous infusion of its proprietary allogeneic Mesenchymal Precursor Cell (MPC) product candidate, MPC-300-IV, was well tolerated and demonstrated a dose-related improvement in clinical symptoms, physical function, and disease activity relative to placebo through the 12 week primary endpoint in its Phase 2 trial in biologic refractory rheumatoid arthritis.

Dr Allan Gibofsky, Professor of Medicine and Public Health at Weill Cornell Medical College and Attending Rheumatologist at Hospital for Special Surgery in New York, commented: “The safety and efficacy results of this study are very encouraging and suggest that Mesoblast’s cell therapy has the potential to fill the major unmet medical need of the biologic refractory RA population, where agents that provide consistent durable effects without the risk of opportunistic infections or malignancies are sorely needed.”

Mesoblast’s Phase 2 trial recruited a total of 48 patients with active RA who were on a stable regimen of methotrexate and had an inadequate prior clinical response to at least one anti-Tumor Necrosis Factor (TNF) agent. Of the 48 patients, 30 (63%) had previously received 1-2 biologic agents. Patients were randomized to a single intravenous infusion of 1 million MPCs/kg (1M/kg, n=16), 2 million MPCs/kg (2M/kg, n=16) or placebo (n=16). The study was comprised of a 12 week primary study period with a 40 week follow-up for a study total duration of 52 weeks.

The primary objective of the study was to evaluate safety and tolerability of a single intravenous MPC infusion in these biologic refractory RA patients through a 12 week primary endpoint. Additional objectives were to evaluate clinical efficacy at the primary 12 week endpoint and to assess the durability of effects and safety profile through the full 52 week study. Pre-specified efficacy endpoints included the American College of Rheumatology (ACR) composite clinical response, which is an endpoint used in RA clinical trials to measure improvement in signs and symptoms of the disease in terms of 70%, 50% or 20% improvement from baseline, the health assessment questionnaire-disability index (HAQ-DI), a standardized measure of functional status, and the DAS28 composite measurement of disease activity. Analyses were performed for the whole study population and for the pre-specified exploratory subgroup based on whether the subjects had previously received 1-2 or more than 2 biologic agents.

Key results at week 12, shown in detail in the table below, were:

1. Safety:

Cell infusions were well tolerated with no infusion-related adverse events. There were no serious adverse events, and the safety profile over 12 weeks was comparable among placebo and MPC treatment groups.
2. ACR70/50/20 composite scores measuring degree of clinical responses to treatment:

There was a dose-related improvement in many of the individual components of the ACR composite following MPC treatment; the 2M/kg group who had previously received 1-2 biologics showed significant improvement over placebo in each of the following categories: swollen joint counts, investigator global assessment, patient global assessment, and patient pain scores.
ACR70 responses overall showed a dose-related effect after a single MPC infusion, with the greatest effect seen in the 2M/kg group who had previously received 1-2 biologics (36% vs 0% placebo).
ACR50 responses overall showed a dose-related effect after a single MPC infusion, with the greatest effect seen in the 2M/kg group who had previously received 1-2 biologics (55% vs 11% placebo).
ACR20 responses were greater in both the 2M/kg and 1M/kg group who had previously received 1-2 biologics than placebo (55% and 60%, respectively, vs 33% placebo).
3. HAQ-DI score measuring functional improvement following treatment:

A single MPC infusion resulted in a dose-related improvement in function, based on reduction in mean HAQ-DI levels as early as week 4 and sustained reduction in mean HAQ-DI through 12 weeks; maximal effect was seen in the 2M/kg group who had previously received 1-2 biologics (-0.7 vs -0.1 placebo).
At 12 weeks, MPC treatment resulted in a dose-related increase in the number of patients achieving a minimum clinically important improvement in physical function, defined as a reduction of at least -0.22 in the HAQ-DI; the greatest effect was seen in the 2M/kg group who had previously received 1-2 biologics (91% vs 33% placebo).
4. DAS28 composite score measuring overall disease activity following treatment:

A single MPC infusion resulted in a dose-related reduction in the mean DAS28 activity score relative to placebo, and in an increase in the number of patients achieving the biologically-meaningful target of low disease activity state, defined as DAS28-CRP <3.2.
Summary of Key Efficacy Responses at Week 12:

All Subjects Subgroup with Prior Use of 1-2 Biologics
Placebo 1M/kg 2M/kg p-value
2M/kg vs placebo Placebo 1M/kg 2M/kg p-value
2M/kg vs placebo
N=16 N=16 N=16 N=9 N=10 N=11
ACR70 0 % 20 % 27 % 0.04 0 % 20 % 36 % 0.09
ACR50 19 % 27 % 31 % >0.1 11 % 30 % 55 % 0.07
ACR20 50 % 47 % 50 % >0.1 33 % 60 % 55 % >0.1

HAQ-DI <-0.22 38 % 53 % 93 % 0.003 33 % 60 % 91 % 0.02
HAQ-DI LS mean change from baseline -0.2 -0.3 -0.6 0.02 -0.1 -0.4 -0.7 0.03

DAS28-CRP LS mean change from baseline -1.4 -1.3 -2.0 >0.1 -1.1 -1.8 -2.4 0.06
DAS28-CRP <3.2 19 % 27 % 36 % >0.1 22 % 30 % 40 % >0.1


Major advances in the treatment of RA using biologic agents have resulted in a $15 billion global market in 2015, which is projected to grow to over $18 billion in 2024. Over two million patients were treated for RA in the United States alone in 2015, with three million more people in the five major European markets and Japan. Despite the substantial advances in RA treatment using biologic agents such as anti-TNF agents, approximately one third of patients either do not respond sufficiently or cannot tolerate these agents due to infectious or other complications. In the United States, the anti-TNF refractory population is the fastest growing branded market segment, projected to increase by 8% annually and potentially higher with the expected market entry and greater availability of anti-TNF biosimilars.

Mesoblast Chief Executive Silviu Itescu said: “The Phase 2 trial results have indicated a strong efficacy signal and consistent effects of a single MPC infusion on clinical symptoms, functional abilities, and disease activity, without any serious adverse events. These results support the potential of our allogeneic cell therapy to be positioned as a first-line treatment option for biologic refractory patients, where there is a clear need for safe and effective treatments. Given the large market opportunity, our Tier 1 product candidate, MPC-300-IV, is well-positioned to advance through a strategic partnership into Phase 3 development for biologic refractory rheumatoid arthritis.”

About Rheumatoid Arthritis
RA is a chronic autoimmune disease of unknown etiology, affecting approximately one percent of the global population. The disease is attributed to chronic inflammation affecting the synovial membrane of multiple joints, which eventually leads to cartilage and bone destruction. The health-related quality of life in patients with RA is significantly impaired by pain, fatigue, and decline in musculoskeletal function. RA is associated with an increased risk of cardiovascular disease and mortality.
Standard criteria established by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) are used to assess the effectiveness of RA treatments. The ACR70/50/20 response is a composite measure based on achieving 70%/50%/20% improvement in tender joint or swollen joint counts plus improvement in three of the following:

Patient global assessment
Physician global assessment
Patient pain assessment
Physical function/disability questionnaire (HAQ-DI)
Acute phase reactant (sedimentation rate or high-sensitivity C-reactive protein)
The patient and physician global assessments and pain assessment are measured using a visual analogue scale on a scale of 0-100. The HAQ-DI assesses physical function in performing a variety of activities of daily living and yields a score ranging from 0-3 (lower is better). A reduction in the HAQ-DI score of -0.22 is the minimal clinically important difference.

The DAS28 is another validated RA disease activity index based on a 28 joint count. The derived DAS28 scores are comprised of tender joint count; swollen joint count; acute phase reactant (hsCRP or ESR) and the subject’s global assessment of disease but do not include measures of pain or physical function. High disease activity is defined as DAS28 score >5.1; moderate disease activity is defined as DAS28 scores between 5.1-3.2; low disease activity and remission are defined as DAS28 scores of <3.2 and <2.6, respectively.
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MOAKS- the objective judge on OA 09 Aug 2016 17:19 #7570

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We are a scleroderma company now WST...they screw that up and we go to zero.
I took OA out of my calculations when CYTX reported its 12 week data. DOV will come around and make corrections to his spreadsheet in time...he always does.
We will see if his IDIS scleroderma updates were enough.
I will reestablish my arguments on his overly optimistic 2020 burn treatments again at another date. Lets first see if the revised IDIS numbers are closer to reality from Cytori 's (pre-rights offering) claims.

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