Check out Amy Lightners clinical trial at the Cleveland...

Check out Amy Lightners clinical trial at the Cleveland Clinic.


https://clinicaltrials.gov/ct2/show/NCT04543994


Criteria

Inclusion Criteria

1. Males and Females 18-75 years of age.
2. Ulcerative colitis of at least 6 months duration with medically refractory symptoms

3. Exposure to corticosteroids, 5-ASA drugs, thiopurines, methotrexate, anti-TNF therapy, anti-integrin and anti-interleukin in the past are permitted but a washout period of 4 weeks for any monoclonal antibody is necessary.

   1. If receiving conventional immunomodulators (ie, AZA, 6-MP, or MTX), must have been taking them for ≥12 weeks, and on a stable dose for at least 4 weeks.
   2. If AZA, 6-MP, or MTX has been recently discontinued, it must have been stopped for at least 4 weeks.
   3. If receiving oral 5-ASA compounds, the dose must have been stable for at least 4 weeks.
   4. If receiving oral corticosteroids, the dose must be ≤20 mg/day prednisone or its equivalent and must have been stable for at least 4 weeks.
   5. If receiving budesonide, the dose must have been stable for at least 2 weeks.
   6. If oral 5-ASA compounds or oral corticosteroids (including budesonide) have been recently discontinued, they must have been stopped for at least 2 weeks.

4. The following medications/therapies must have been discontinued before first administration of study agent:

   1. TNF-antagonist therapy (eg, infliximab, etanercept, certolizumab, adalimumab, golimumab), vedolizumab, ustekinumab for at least 4 weeks.
   2. Cyclosporine, tacrolimus, or sirolimus, for at least 4 weeks.
   3. 6-thioguanine (6-TG) must have been discontinued for at least 4 weeks.
   4. Rectal corticosteroids (ie, corticosteroids [including budesonide] administered to the
   5. rectum or sigmoid colon via foam or enema or suppository) for at least 2 weeks.
   6. Rectal 5-ASA compounds (ie, 5-ASAs administered to the rectum or sigmoid colon viafoam or enema or suppository) for at least 2 weeks.
   7. Parenteral corticosteroids for at least 2 weeks.
   8. Total parenteral nutrition (TPN) for at least 2 weeks.
   9. Antibiotics for the treatment of UC (eg, ciprofloxacin, metronidazole, or rifaximin) for at least 2 weeks.

“Inflammation of the gut in Crohn’s disease and ulcerative colitis closely resembles the most severe manifestation of advanced-stage, life-threatening acute graft versus host disease (aGVHD). Mesoblast’s objective is to confirm the potential for remestemcel-L to induce luminal healing and early remission in a wider spectrum of diseases with severe inflammation of the gut, in addition to steroid-refractory aGVHD,” said Dr Fred Grossman, Mesoblast Chief Medical Officer
https://www.europeanpharmaceuticalreview.com/news/131213/first-in-human-trial-to-study-remestemcel-l-as-crohns-disease-therapy-launched/


I think the shorters are attempting a final shakedown . They better get on with it because I suspect Amy Lightner will have plenty to say at the forthcoming virtual congress of ECCO between the 16th-19th 2022. If normal protocol is followed I suspect that Mesoblast who are co sponsoring the trial at the Cleveland Clinic , are embargoed on releasing the initial findings …so this little abstract is a gem…thanks@Stellowe
Great find.
Mesoblast must be delighted with these initial findings (albeit a phase 1/2a) which I believe show superior potency in comparison to previous trials using Prochymal…this should not be too surprising as we have seen with the potency enhancements from the sr aGVHD clinical trials.
I will be very interested to see how the patients taking the placebo fared when they were allowed to cross over to our cells at 3 months. Assuming a successful application for Ryoncil I would not be surprised to see a supplemental investigator led NDA/BLA shortly afterwards. The successful healing of the gut mucosa to serosa also has some bearing on the similar issues faced in the treatment of GVHD.
Local administration of our cells combined with well documented improvements in cell potency appear to be very successful if these initial findings are supported by similar progress with the balance of patients in this 2 for 1 RCT.

A potted history of Prochymal trials in the IBD space was summarised in the extract below …link provided.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913333/
”In addition to local injections of MSCs, there have been significant advances in systemic infusions of MSCs for luminal CD. Unique to MSCs, an ‘off-the-shelf’ product (Prochymal) has been developed by a third-party laboratory Osiris Therapeutics Inc. (USA) These cells are isolated from the BM of healthy donors and expanded ex vivo. The MSCs purified by Osiris are cultured and packaged. Remarkably, up to 10,000 dosages can be obtained from a single donor [Rattue, 2012]. Several phase I–II studies included the Prochymal MSC product for transplant. The first human trial of systemic MSCs was carried out by Onken and colleagues and evaluated nine patients with active CD, who previously failed immunosuppressants and a course of steroids [Onken et al. 2006]. Patients were randomized to intravenously receive Prochymalallogeneic MSCs in varying doses. A total of 3 of 10 patients achieved clinical remission by day 14 following transplantation. No serious adverse events occurred during treatment in all groups, and infusions were well tolerated. Duijvestein and colleagues continued to show that autologous BM MSCT appeared to be well tolerated and feasible in the treatment of refractory luminal CD [Duijvestein et al. 2010]. Additionally, no serious adverse events occurred during harvesting and IV administration.

A phase II study, carried out by Forbes and colleagues measured clinical response at 42 days after a 4-week course of allogeneic infusions of MSCs [Forbes et al. 2014]. Among the 15 patients, a reduction in the CDAI score was seen along with 8 patients entering clinical remission. Currently, a large (330 enrolled patients) multicenter, randomized, double-blind, phase III trial is underway with an expected completion in late 2018 [Raina, 2007]. The purpose of the study is to evaluate the safety and efficacy of Prochymal MSCs at different IV doses for moderate-to-severe CD. Two preliminary analyses have been performed thus far. Of the 207 patients, 148 have successfully reached the 28-day primary endpoint assessment of an absolute CDAI score <150, signifying a clinical remissive state [Meldrum, 2014].

Notwithstanding the promising improvement of clinical outcomes, it is necessary to consider the current hazard and safety before enrolling a patient for MSCT. A few studies isolated various modes of MHCs to verify there is no risk for chromosomal aberration development after long-term culturing or induction of tumors during in vitro and in vivo experiments [Bernardo et al. 2007; Macias et al. 2010; Tarte et al. 2010]. Culture standards need to be perfected, and all possible hazards in the cell sample need to be eliminated before administration. Several phase I–III trials were carried out with historical or concomitant immunomodulating therapy. A study by Duijvestein and colleagues investigated the effect of immunosuppressive drugs (i.e., azathioprine, methotrexate, 6-MP, and anti-TNFα) on the MSC phenotype, survival, and differentiation or immunosuppressive capacity. Their results confirmed mesenchymal stromal cell function is not affected by common drugs used to treat refractory IBD patients [Duijvestein et al.2011]. Moreover, 6-MP and anti-TNFα antibodies enhanced the inhibitory effect, suggesting clinical safety and usefulness of combination therapy.

As discussed in existing literature, there is a complex variety of pathways and mechanisms through which MSCs respond to damaged inflamed tissue in the gut. Future studies should focus on the exact mechanism in which MSCs operate, providing vital information to improve current therapeutic strategies. It is also valuable to look into initiating combination therapy following transplantation to improve remission rates [Duijvestein et al. 2011]. Continuing exploration of other stem-cell sources in preclinical animal models is essential. In addition to an understanding of basic science, the protocols for isolation and administration should improve as we move forward towards stem-cell therapies for refractory CD patients and other autoimmune diseases”

When looking at remission times of other therapies, remember that the patients administered Remestemcel in this trial are already refractory to at least 1 anti TNF therapy..so we are achieving remission in some of the most difficult to treats patients that have already exhausted most other non surgical options. Remission times themselves can also be deceiving in that you need to take into account a full 12 months durability as patients go in and then out of remission …and there are normally horrendous side effects associated with existing treatments. It is well known that many patients become refractory to anti TNF treatments over time, so the market is much larger than for sr GVHD. I enclose some interesting background links for further information on remission times of the main competing products in this area. I think Stelara is one of the most recent approvals so it might be a good therapy for head to head comparison.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643264/
https://www.medscape.com/viewarticle/951681#vp_2
https://pubmed.ncbi.nlm.nih.gov/28484890/

I believe that this extract, posted in a well respected journal , concerning the study at the Cleveland Clinic, is a serious breakthrough for Mesoblast. If Amy Lightner in just over two weeks time decides to provide more colour as to how a larger subset of the patients enrolled have performed …we can seriously start to add significant potential value for these indications (which have been ignored by most analysts) .

The clinical evidence supporting our applications grows stronger by the day….I seriously believe that Silviu needs to do a roadshow to US investors and this share will start to fly. Sadly , I am starting to think that the ASX is not the right place to have the primary listing .
This Company has potentially first in class therapies in five major indications . I cannot believe the market cap…the shorters are taking everyone for fools. There will be an additional need for further funds looking past the next 12 months …but with all the phase 3 results to date , that should be relatively straightforward. The only real question is how much of a royalty interest will need to be given away to fund a series of additional trials ? I believe the whole process of refinancing will allow the Company to prove how valuable its IP is. The shorters would have you believe the only option is new equity..but obviously they have short memories . Remember the Tasly and Grunenthal deals ? They didn’t see those coming either …and we are arguably in a far stronger position now than when those deals were consummated. One day they will get well and truly shafted …and they sure have it coming. OP




Please do not rely on the facts or opinions expressed in this post. Do your own research and due diligence.