So, for those of you who hang on every word coming out of Mesoblast, but don't have time to go back and listen to the webcast yet again, I have prepared a transcript. It is accurate to the best of my ability, but I can't guarantee that I captured every word accurately.
Moderator:
During today's conference call, the company will be making forward-looking statements that represent the company's intentions, expectations or beliefs concerning future events. These forward-looking statements are qualified by important factors set forth in today's announcement and the company's filings with the SEC which could cause actual results to differ materially from those and such forward-looking statements. In addition, any forward-looking statements represent the company's views only as of the date of this webcast and should not be relied upon as representing the company's views of any subsequent date. The company specifically disclaims any obligations to update such statements.
With that I would like to hand the call over to Dr. Silviu Itescu, please go ahead.
Dr. Silviu Itescu:
Thank you very much, and thank you for joining us. Today on the call, we have Dr. Fred Grossman, our chief medical officer, and Josh Muntner, our Chief Financial Officer.
We're very excited today to present the top line, 60-day results from our randomized, controlled trial of Remestemcel-L in patients with moderate to severe covid-19 acute respiratory distress syndrome. Today we announced the 60-day results from data obtained in 222 ventilator-dependent covid-19 patients with moderate to severe ARDS. This trial had been halted after the third interim analysis, as we previously announced. Remestemcel-L reduced mortality through day 60 by 46% in the pre-specified group below age 65, but not in patients 65 or older. Remestemcel-L reduced mortality by 75%, and increased days alive off mechanical ventilation in those patients under age 65 when combined with dexamethasone, in comparison with controls on dexamethasone. The reduction in mortality in mechanically ventilated patients under 65 remains a critical unmet need since as many as 72 percent currently hospitalized patients across the U.S. with covid-19 are in this age category. This is very similar to what's seen with other causes of viral ARDS, such as influenza where 70 to 80% of patients in intensive care units are under the age of 65. The reduction in mortality seen with Remestemcel-L in this age group highlights the potential to make a meaningful difference in the treatment of diseases of excessive inflammation.
The trial enrolled 222 mechanically ventilated patients with covid-19 who had moderate to severe ARDS across the U.S. Of these, 217 were randomized in a one-to-one fashion and received either standard of care alone or standard of care plus two intravenous infusions of Remestemcel-L at a dose of two million cells per kilogram, three to five days apart. This is the same dosing regimen that is used over a four week period in children with acute steroid-refractory GVHD and is also the same Remestemcel-L dosing regimen used in the earlier compassionate use program where 11 of 12 patients were younger than 65 and 75 percent of whom successfully came off ventilatory support.
During the course of the trial, as the pandemic evolved, numerous changes occurred in the treatment regime. As a result, the referral pool of patients into the trial became progressively older with comorbidities and refractory to treatment. The median age in the trial increased substantially from 59 in the first half to 67 in the second half. This was highly significant. This may have impacted the outcome over all of the trial and in the third interim analysis, which resulted in the trial's early conclusion. It is possible that to achieve mortality reduction in patients over 65 with comorbidities will require a different dosing regimen than that which may be effective in patients under 65.
Key findings in the trial are that Remestemcel-L reduced mortality by 46% through day 60 in the pre-specified population of a hundred twenty-three treated patients under the age of 65. Remestemcel-L had similar treatment effects on mortality in these patients who had either moderate ARDS or severe ARDS. And, importantly, given that standard of care substantially changed during the conduct of the trial, notably in the use of dexamethasone, which was only used in two percent of patients in the first 50 patients, but in 84 percent of the subsequent hundred seventy two patients, we were able to explore additional analyses of Remestemcel-L treatment in combination with dexamethasone as part of the standard of care.
In these exploratory analyses, Remestemcel-L reduced mortality through day 60 by 75 percent compared to controls in patients under 65 who received dexamethasone as part of their standard of care, from 45 percent mortality rate at day 60 to 14%. Remestemcel-L also increased days alive off ventilators within 60 days, and reduced the time to discharge from initial hospitalization, compared to controls in patients under 65 who received dexamethasone. The mortality benefit observed in this ventilator-dependent group of patients younger than 65, particularly when combined with dexamethasone, has the potential to change the treatment regimen in this very critical patient population and given the continued surge in patients with this condition across the U.S., we plan to meet with the FDA to discuss next steps.
With that as a background, I'd like to now open the discussion and if there's any questions, please, address them.
Moderator:
The first question today comes from Louise Chen from Cantor, please go ahead.
Louise Chen, Cantor Fitzgerald:
Hi, congratulations on the data, and thanks for taking my questions here. So, first question I have for you is how do you see the opportunity for covid ARDS with vaccination rollout under way? I know there are still a lot of sick people in the hospital, and then how do you look at the opportunity outside the U.S., where covid is still raging in many parts of the world. And then, second question I had was on manufacturing and distribution. If you are granted an emergency use authorization, how will you manufacture and distribute the product. And then maybe last question I had for you was there have been a lot of failures in the hospital ARDS studies and you actually have a successful trial here with successful data. So where do you think you would fit into the treatment paradigm if you received emergency use authorization, thank you.
Dr. Silviu Itescu:
Thanks Louise, those are critical questions. So I think first of all, let me address your last question, where do we think we would fit in the treatment paradigm. I agree there have been many failures of therapies targeting these very, very sick, critical in-hospital population on ventilators. I think, what is particularly noteworthy is the complementarity of the effect with what is now standard of care, dexamethasone, and Remestemcel-L. And that probably goes to the heart of the mechanism of action with both Remestemcel-L and dexamethasone act to target the inflammatory cytokine process driven by inflammatory macrophages and T-cells to a lesser extent. And so mechanistically, there is an understanding of synergy between the two and that probably in part explains why we're seeing such exciting results in mortality reduction.
Midway through this trial, the standard of care changed, and now everybody on mechanical ventilation is treated with dexamethasone, and that's because of a larger data set from the UK, the Recovery trial, which demonstrated a degree of reduction in mortality overall with dexamethasone. However, the further reduction by 75%, when our cells were used in conjunction with dexamethasone suggests that moving forward, if we can confirm the data in a further confirmatory study, or through other means, that the cells ought to be used together with dexamethasone as standard when patients who have moderate or severe ARDS, which is defined on the basis of severe respiratory dysfunction on ventilators, are put on, in the ICUs. So we're pretty excited and that would be the, we would expect that patients would get both therapies, prominently.
With respect to meeting the potential demand should this product be approved, we have plans for manufacturing scale up. We have proprietary media that contains recombinant cytokines that enable substantial yield improvements and potentially we could move from two-dimensional to three-dimensional bioreactor production. Those plans are all in hand, under way. And really, we are preparing ahead of the curve, should we be in a position to launch such a product particularly in the U.S.
I think you make a very good point about the role of vaccines in this space, of the vaccine role, as showing the overall new infections cases particularly in across the U.S. and in other jurisdictions like Israel can be very effective in terms of reducing new cases by as much as potentially 80%. Nonetheless, the continued emergence of variants, particularly from third world countries, the continued social interaction, particularly in younger people who in the northern summer now will be outdoors and enjoying life, I think means that there will be continued endemic cases of this virus in various pockets. There'll be continued surges, resurgences, etcetera, and there will be a steady state of patients who will need ICU care, mechanical ventilation and treatments for the worst outcomes and the highest mortality risks of covid-19 ARDS.
So we clearly see that this is a potential therapeutic for the steady state, even in the setting of large numbers of patients being vaccinated with, we're talking about in the last 12 months in the U.S. alone, 560,000 cases of deaths have occurred, even if an 80% reduction in infectivity is a success through vaccination, that still will result in a large number of potential fatalities that could be prevented by the use of Remestemcel-L together with dexamethasone. So we're preparing for that steady state situation. Influenza ARDS is a parallel scenario where again as many as 70,000 patients a year are dying from moderate to severe ARDS and through similar mechanism of action, we believe that Remestemcel-L has the potential to be used in that patient population as well. So, this is a very important program and opportunity for Mesoblast, and these results indicate that this is a major focus for the company as we move forward, and prepare for manufacturing scale, yield, and allocation of product.
Louise Chen, Cantor Fitzgerald:
Thank you.
Moderator:Thank you. The next question comes from Jason Kolbert from Dawson James. Please go ahead.
Jason Kolbert, Dawson James:
Silviu, Josh. Thank you very much, very exciting data. Louise asked some great questions. I'd like to ask you, given the fact that you have such prominent people on your board like Dr. Eric Rose, who's pretty connected with the United States government and BARDA, and DOD, what kind of discussions have been going on there? How aware, you know, is the government of this data?
Dr. Silviu Itescu:
Jason, I think, I think it's very early days given that the trial was halted in November in the third interim analysis, and I think we've only just unblinded the data and have had an opportunity to see the top level results. And of course given the materiality of the mortality reduction that we have observed, it was important that we get this information out there. The objective over the next short period will be of course to meet with the FDA, to talk at a higher level with governmental agencies, and I guess the real question is going to be how robust are these data and what degree of confirmation needs to be observed in order for the next steps to be placed.
I guess, when we talk about BARDA, we talked earlier about contractual arrangements for manufacturing scale up. In order to think about those type of things, we need to have our plans in place, and that will require FDA discussions as well as further discussions with our potential strategic partner Novartis.
Jason Kolbert, Dawson James:
And given this data and given its demonstrated efficacy in an inflammatory disorder, does data like this support you in the GVHD program?
Dr. Silviu Itescu:
Yeah, absolutely. That's a great question. We were very careful to use a dosing regimen that had already been established from a perspective of efficacy and safety in GVHD, a regimen that in patients who had the most severe inflammatory condition and clinical symptoms, required two doses a week for four weeks. We adjusted that regimen, in this disease, which while also extremely inflammatory in nature, is even more acute than GVHD. So, our objective was to see whether a lower dose than is used generally in GVHD could be effective in these patients within several days of administration. I think that the conclusion we have is that in those patients with disease limited to the lung and without comorbidities in other organs, that acute administration of two doses or 1/4 of the dosing regimen that we use in GVHD appears to be effective in reducing mortality in patients under 65 who have really very limited comorbidities, if any, other than the lung disease.
In contrast, it is clear from these data that in the substantially older population, with a lot of comorbidities including renal disease and cancer, which accounted for up to as many as 20% of the older population, in that population, this dosing regimen did not appear to be effective and of course, we will explore other dosing regimens in those patients, at the time, including more frequent administration, or maybe more prolonged administration along the lines of the regimen that we use in GVHD. But I think the mechanism of action and the safety data and the outcomes are very similar between these populations. And we also look forward to getting a lot of our biomarker data in due course to see whether we see similar biomarker changes as we've seen in GVHD.
Jason Kolbert, Dawson James:
And I think you already answered my next question which was, when I look at inflammatory disorders and cytokine syndrome and I see T-cell therapy, you know, I see a little bit of an unmet medical need particularly where there's something benign, that's not going to shunt the immune system completely like steroids would, and so I'm just wondering if that's not on the horizon, just because there's so much big pharma, big biotech interest in pioneering T-cell therapies, but cytokine syndrome hasn't really been addressed and I'm wondering if there isn't crossover utility here.
Dr. Silviu Itescu:
Well, the way we look at these cells and their mechanism of action, is that they are being defined as targeting both T-cells and macrophages, and both of those arms of the immune system are critical to the severity of acute graft versus host disease, and macrophages perhaps even more than T-cells to the severity of viral ARDS, such as covid-19. So the similarities between these diseases, the mechanism by which they cause immune activation are close, and we understand, we believe we understand how these cells control those aspects of the immune system. And the selectivity of the control of the immune system is really what makes the cells much safer than various therapies that non-selectively target either T-cells or macrophages or other arms of the immune system without being able to be turned off. And so we're extremely pleased by the safety profile of these cells, while at the same time the selective nature of their ability to turn off aspects of the immune system critical to diseases of inflammation involving lungs and other organs like the gut in GVHD.
Jason Kolbert, Dawson James:
Thank you for holding this call on short notice, Silviu, we really appreciate it.
Dr. Silviu Itescu:
Thank you, appreciate your support.
Dr. Fred Grossman:
This is Dr. Grossman, I was going to answer a question that you asked as well. We're focusing very much on areas of the greatest unmet medical need, and from a development perspective, we're focusing right now on GVHD, on Covid ARDS, we're also are working with our potential partners at Novartis, and, as you know, we released data on lower back pain and heart failure. So, there are numerous areas that we can go into, but at this point our teams are focusing on moving past key milestones in these indications.
Jason Kolbert, Dawson James:
That makes a lot of sense and focus is something that the industry has lacked, so I can appreciate the importance of the message. Thank you.
Moderator:
The next question comes from John Hester from Bell Potter, please go ahead.
John Hester, Bell Potter:
Good morning Silviu and Dr. Grossman, thank you for taking my questions. Silviu, would you please recap on the key points from the Novartis deal, and what this data will now mean for your negotiations with them? And then I have a follow-up after as well. Thank you.
Dr. Silviu Itescu:
Thanks. Well, we've entered into a strategic collaboration with Novartis and the details of that are already out in the public domain. That collaborative agreement, license and collaborative agreement covers development, manufacturing, commercialization of Remestemcel-L focusing initially on the treatment of acute respiratory distress syndrome, including covid-19, and the agreement remains subject to closing conditions, including having sufficient time to analyze the results from this trial, top line results of which we've just announced today, but the companies are working closely together to complete analysis of a variety of secondary endpoints, including days in intensive care, other end-organ damage, potentially recovery, and measurement of circulating cytokines and biomarkers. So we expect to be able to update the market in due course, but we look forward to continuing our close collaboration with Novartis.
John Hester, Bell Potter:
And, you say in due course, is that this calendar year?
Dr. Silviu Itescu:
Oh, over the next few weeks, we expect.
John Hester, Bell Potter:
Okay. Okay. And you've alluded to confirmatory studies, but the reality is, you've now got data from a 222 patient, randomized study. And at the time of the GVHD decision from the FDA they were indicating that they wanted data from a randomized study, to what extent do you think this will go towards satisfying that requirement?
Dr. Silviu Itescu:
That's a very very good question. We are in ongoing discussions with the FDA with respect to this very product, Remestemcel-L, and its pathway to approval for children with the most severe forms of acute, steroid-refractory GVHD. This trial certainly provides evidence of biologic activity of the product in a randomized, controlled trial. Again, it's important to note that the trial was relatively small, and we see a treatment benefit in the pre-specified population under 65, but not in those older than 65. So there continues to be the requirement for confirmation and more studies. But nevertheless, in this randomized, well-controlled, well conducted study, we see strong biologic evidence of activity in patients as defined by reduction, substantial reduction in mortality. Dr. Grossman would you like to add to that?
Dr. Fred Grossman:
I think you covered most of the points. I think we're very pleased with the very strong signals that we've seen in this patient group younger than 65, particularly those who are on dexamethasone. I think the GVHD program in and of itself is a separate program and the discussions with the FDA are moving forward. So we hope to continue that.
John Hester, Bell Potter:
Cool. And Silviu, is it your intention now to pursue an emergency use authorization with the FDA?
Dr. Silviu Itescu:
Look, I think I think it's still early. We haven't yet completed our data analysis. We, again, we needed to provide the data to the market as soon as we had sufficient conclusions at hand on the most material finding which is reduction in mortality. But I think we need to be complete in terms of our analysis of the secondary findings and have a meeting with the FDA to discuss all possible paths going forward. Fred, would you like to add to that?
Dr. Fred Grossman:
Yeah, I think as noted this study was stopped before its completion. And the signal detection work that we've done has revealed something that's very, very important and significant enough to warrant these discussions with the FDA for a suitable path forward. There's such a great need as noted before for potential therapeutics, particularly those that treat mortality, and as Dr. Itescu mentioned before, there's going to be breakthrough of the virus, of the vaccine such that patients will wind up in the ICU on ventilator, and at this point there are no treatments that substantially reduce mortality. So the finding in this, signal detection analysis is such that it warrants discussion with the FDA to find a path forward for a potential therapeutic in particular, and in combination with dexamethasone.
John Hester, Bell Potter:
Silviu, outside of the U.S. we're seeing that mortality rates are probably higher than what they are in the U.S. What about the Europeans? Have they expressed any interest or indeed other regulatory bodies, in approaching Mesoblast about potentially approval outside of the U.S.?
Dr. Silviu Itescu:
So there's no doubt that the data from this randomized controlled trial will be applicable to submissions both in the U.S. and in Europe and in other jurisdictions and you are right that the European territories continue to have a terrible plight, despite the vaccines, and mortality rates are just horrendous in many countries and of course other third world countries are even worse, including India. So we will no doubt be performing additional studies to confirm precisely what we've seen, the survival benefit in this target population with this dose regimen. I think we need to do that in combination with the only drug out there that has demonstrated any improvements of ARDS survival, being dexamethasone or potentially other steroids. Having said that together with our potential strategic partner Novartis, we will be looking very closely at how to make this drug available in the U.S., in Europe, in other jurisdictions, it will require obviously scale-up and manufacturing investment and that will be the focus now of the company as we move forward. Thank you very much.
Moderator:
Thank you. That brings us to the end of today's call, I'll now hand back to Dr. Itescu for closing remarks.
Dr. Silviu Itescu:
Thank you everybody for having joined us today. These top line results we think are very important and require a full understanding by the markets, by the regulators and by our strategic partners, and I think we look forward to having the full data analyzed and presented at a later date. Thank you everybody for joining us today.
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