Mesoblast Ltd

ASX:MSB

Earnings Call Transcript 2021-Q3

[Operator]

Hello, and welcome to the operational highlights and financial results for the period ended March 31, 2021, for Mesoblast. An announcement and presentation have been lodged with the ASX and are also available on the home and investor pages at www.mesoblast.com. [Operator Instructions] As a reminder, this conference call is being recorded.Before we begin, let me remind you that 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 in the company's filings with the SEC which could cause actual results to differ materially from those in 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 now like to turn the call over to Dr. Silviu Itescu, Chief Executive of Mesoblast. Please go ahead.

[Silviu Itescu]

Thank you very much, operator, and good morning and good evening. With me today is our Chief Financial Officer, Josh Muntner; and our Chief Medical Officer, Dr. Fred Grossman. Today, we will be updating you on the operational highlights and financial results for the period ended March 31, 2021. A detailed slide deck will be available on the ASX website.To remind you all, we have 2 technology platforms: our first-generation remestemcel platform and our second-generation rexlemestrocel platform. Remestemcel is being developed for acute graft versus host disease in children as well as adults and for acute respiratory distress syndrome due to COVID-19 and potentially other causes. It is also being developed for refractory inflammatory bowel disease. In Japan, acute graft versus host disease is partnered with JCR. And for acute respiratory stress syndrome and other causes, we -- there is an agreement that remains subject to certain closing conditions, including the time to analyze the results from the COVID-19 ARDS trial together with Novartis.With respect to our rexlemestrocel platform technology, which is being developed for advanced heart failure and end-stage ischemic heart failure as well as chronic low back pain, the relationship with Tasly in China is for advanced heart failure and with Grunenthal in Europe and Latin America is for chronic low back pain.Our global IP estate provides the substantial competitive advantages with over 1,100 patents and patent applications across all major jurisdictions covering compositions of matter, manufacturing and therapeutic applications of mesenchymal lineage cells. We -- this IP provides strong global protection in areas of our core commercial focus against cell-based competitive product. And when outside of our core commercial areas, we may consider granting rights to third parties who require access to our large patent portfolio for commercialization.In terms of our commercial-scale manufacturing capabilities, we have scalable allogeneic, off-the-shelf cellular platforms, with manufacturing that meets stringent criteria for international regulatory agencies including FDA, EMA and others. We develop to robust quality assurance processes, ensuring final product with batch-to-batch consistency and reproducibility.Our projected increase in capacity requirements for our maturing pipeline involves proprietary technologies that are xeno-free or free of animal products in order to increase yields and output as we move toward bioreactors in 3-dimensional cultures to reduce labor and improve manufacturing efficiencies. These innovations will significantly reduce cost of goods as well as meet the commercial objectives of the company. Now I'd like to move to our financial results, and I'd like to ask our Chief Financial Officer, Josh Muntner, to take you through those, please. Josh?

[Josh Muntner, Chief Financial Officer]

Thank you, Silviu. Getting into the financials. Our cash at quarter end on March 31 was $158 million. This figure includes the proceeds from capital raise conducted in March that was led by principals of SurgCenter Development.

[Silviu Itescu]

I think we may have lost Josh.

[Josh Muntner, Chief Financial Officer]

I want to take a moment to thank our new and existing investors for their ongoing support. The capital we raised provides funds as we prepare for and conduct important meetings with the U.S. FDA in the coming quarters. Funds will also support our ongoing manufacturing initiatives as we invest in commercial supply of remestemcel-L ahead of a potential approval in GVHD to treat children as well as scale our manufacturing to be able to serve larger market opportunities in the future.We also appreciate the ongoing support of our lender, Hercules, who have extended the interest-only period of their loan to October 1. Our balance sheet cash provides us with sufficient funding through the next 12 months. And as we complete ongoing business development activities or make further changes to our Hercules loan, we anticipate having adequate cash that should bring us through multiple key milestones in the future. Moving to the income statement. We saw continued recovery of our commercialization revenue returning to largely the same level as a year ago. Our commercialization revenue for the period primarily consist of royalties from JCR Pharmaceuticals for sales of TEMCELL to treat GVHD in Japan but also includes royalties from Takeda for sales of Alofisel to treat fissures in patients with Crohn's disease in Europe. We're glad to see that our Japanese partner, JCR Pharmaceuticals, resumed robust sales of TEMCELL after instituting a temporary shutdown in production as they expanded their capacity to meet increasing demand. Total revenue was lower due to a onetime milestone recognized in the quarter in the period in the year prior.On the expense side, we see total expenses for the 3 months coming in about $1 million less than in the year earlier period. We do see a drop in R&D expenses, which may continue in near term as our key clinical trials have been completed. This reduction was offset in part by an increase in management and administration expenses related predominantly to one-off expenditures in legal and professional fees associated with financing and FDA regulatory activities. The additional information as well as the deck will be able to be found with the ASX as well as the SEC.I'd like to now return the call to Silviu, who will provide an operational update.

[Silviu Itescu]

Thank you, Josh. First, I'd like to provide an operational update on remestemcel-L for the 2 lead indications of acute graft versus host disease and acute respiratory distress syndrome, ARDS. I'd like to just reiterate that the graft versus host disease itself is a serious and fatal complication of an allogeneic bone marrow transplant. It's due to activation of multiple arms of the immune system leading to a so-called cytokine storm due to cytokines produced by T cells and macrophages. And ultimately, these cytokines result in destruction -- damage and destruction of the gut, the liver, which is a very fatal stage of the disease itself.The children with steroid-refractory acute graft versus host disease are extremely high risk of death. The children particularly under 12 years of age have no approved therapies for steroid-refractory GVHD. And in these children, once you've gone past failure to respond to steroids, mortality rate can be as high as 70% to 90% when involving the gut and the liver. It's a devastating complication with no approved therapies in children under 12.So we have established a substantial body of clinical data across 309 children from 3 different studies that have demonstrated both the safety and efficacy of remestemcel-L. The 3 bodies of data include a randomized controlled trial in a subset of children -- 27 children where remestemcel was used as first-line therapy. The second body of data was in an expanded access program of 241 children with steroid-refractory GVHD, 80% of whom had Grade C/D disease and had failed institutional standard of care. And the third body of data, of course, was our open-label Phase III trial in 54 children with steroid-refractory GVHD, 89% of whom had the most severe forms of Grade C/D disease. And across these -- each of these 3 trials, day 28 response, the primary endpoint, was very similar and was achieved by between 64% to 69% of children. In contrast, in the contemporaneous cohort of children with the sustained degree of severity and we met the inclusion criteria of the Phase III trial, a cohort called the MAGIC cohort in 30 children, the day 28 overall response was only 43%. Day 28 response is a very, very close surrogate that reflects subsequent survival. And in fact, we have seen good survival outcomes across each of our trials with remestemcel.In the most extensive analysis of survival in children with steroid-refractory acute graft versus host disease, 6 months out in the steroid-refractory pediatric population with best available standard of care, survival is only 49%. And by 2 years in these very sick children, survival is only 35%. In contrast, in our Phase III trial with remestemcel in the 54 children who received the remestemcel treatment, survival at 6 months was 69%, substantially higher level of survival. And we believe that this is the basis for why this product should be made available more broadly.So let me update you all with the regulatory update on steroid-refractory GVHD product for remestemcel. In August, as you all recall, the results from 309 children that I've just talked about were presented to the Oncologic Drugs Advisory Committee, the ODAC, of the FDA. The ODAC panel voted 9:1 that the available data support the efficacy of remestemcel in pediatric patients with steroid-refractory acute GVHD. Despite that overwhelming ODAC vote, on September 30, the FDA provided Mesoblast with a complete response letter. Mesoblast continues to be in discussion with the FDA for a well-established regulatory process that may include a resubmission with a 6-month review with the aim of achieving approval of remestemcel in the treatment of steroid-refractory acute GVHD in children.As part of this process, Mesoblast recently met with the FDA's Center for Biologics Evaluation and Research, CBER. Following CBER's recommendation after this meeting, Mesoblast, as a next step, will discuss with CBER's review team at the Office of Tissue and Advanced Therapies, OTAT, our approach to addressing certain outstanding chemistry manufacturing and control, CMC, items, which include potency assay validation. And we will, of course, continue to update the market as we have these meetings and as we progress the process for approval potentially of remestemcel for children with steroid-refractory acute graft versus host disease.Moving on to the potential to use remestemcel for acute respiratory distress syndrome due to COVID-19 now. ARDS is a major unmet need. It is a severe inflammatory lung disease that is due to a number of different agents, including viruses such as COVID-19 and influenza; including bacteria such as pneumonia, pneumococcal pneumonia or gram-negative bacteria; and trauma. And effectively, the primary cause of ARDS is an unbridled immune response to these inciting agents. Multiple arms of the immune system are activated as CF cytokines is initiated, and the end result is damage to the lung tissue flooding with fluid. And the end result is failure -- respiratory failure and death, high degree of mortality.The clinical experience that we have established with remestemcel in ARDS, in particular COVID ARDS, is twofold. One is the pilot data under an emergency IND that was established about 12 months ago. And second is the data that has been generated from a Phase III randomized controlled trial across the U.S. With regard to the emergency IND pilot data established about 12 months ago, 11 patients, 10 of whom were under the age of 65, with moderate/severe ARDS on ventilators received 2 infusions of remestemcel, 2 million cells per kilogram, within 5 days at New York's Mount Sinai Hospital. This was in the midst of the pandemic around March of last year.Nine of these patients successfully came off ventilators and were discharged from the ICU. And the experience under the emergency IND informed on the dosing regimen that we moved forward with in the randomized controlled trial. Notably, the data that was generated in patients who were predominantly under 65 years of age, 10 out of 11 patients. The dosing regimen was based on the dosing that we use in GVHD patients, where 2 doses of 2 million cells per kilogram per week for 4 weeks are generally given here in the patients with COVID ARDS. We established a dosing regimen of 1/4 of that dose -- 2 doses within the first 3 to 5 days only.The Phase III trial was a multicenter, randomized, controlled, double-blind trial in the moderate to severe ARDS patients on ventilator dependency. It was intended to enroll up to 300 patients. However, it was stopped early after 222 patients were enrolled since the Data Safety Monitoring Board, after the third interim analysis, decided that the primary end point of 43% overall mortality reduction was unlikely to be met.The median age notably of this trial during the pandemic increased substantially from 59 in the first half of the trial to 67, almost a decade older in the second half of the trial. And that was a highly significant difference. So that was part of the change in the type of patients who are enrolled, together with the fact that there were many changes to standard of care during this period, which meant that the patient population had shifted quite dramatically from the first half to the second half of the trial. And the type of drugs that had been exposed to and that potentially had failed had also changed. Importantly, a prespecified analysis of results stratified by age less than or greater than 65 was initiated because age is the number one risk factor for mortality in patients with COVID ARDS. And particularly a threshold of 65 and above has been shown to be a major predictor of severe mortality. In fact, in matter analysis of many studies, as many as, I think, 69 studies across the U.S. and globally, age as a predictor of mortality has been the single principal factor that predicts outcome once a patient has ARDS on ventilators. And mortality in patients over 65 approaches 71% to 85%, with mortality below age 65 is of the order of about 48% to 59%, still very high but clearly demarcated by age.Notably, in periods of epidemics from influenza over the past 10, 15 years, majority of patients in ICUs on ventilators are under the age of 65, although mortality rates are highest in those above 65. And in steady-state situation with COVID ARDS, we believe and being seen now across the U.S. that the majority of patients now are under the age of 65 in the ICUs on ventilators.Now when we looked at mortality in this study at day 60 in the control population older or younger than age 65, we saw a highly significant difference, being 0.005, with the older patients above 65 having a mortality rate of about 70% compared to those under 65 having a mortality rate of 42% through 60 days. And this was highly significant and confirms the robustness of the study and its consistency with other trials looking at ventilated COVID-19 patients.Overall, the trial did not meet its primary end point of reduction in mortality of 43%. In fact, we saw a positive trend with a hazard ratio of 0.86, but this did not meet statistical significance in terms of mortality through 60 days. However, when looking at the outcomes by age less than or greater than 65 years old in the 123 patients who were the majority of the trial who are under the age of 65, we saw a significant mortality benefit of approximately 46%. The controls had a 42% mortality through day 60, whereas the remestemcel-treated patients had a 26% mortality. The hazard ratio was 0.54. In contrast, no benefit on mortality was seen in those patients above 65 years old. The hazard ratio there was 1.05.Our interpretation is that there are age related differences in the older population that mean potentially that the dosage that was chosen was insufficient to achieve the mortality reduction. And in the future, we will certainly be exploring potentially higher doses or more prolonged dosing regimen for those patients who are older than 65 with higher viral loads and poor immune systems.Now in exploratory analysis, what we were extremely intrigued about was the potential of combining remestemcel with dexamethasone. Whilst in the first 50 patients in this study, dexamethasone was used in only 2% of patients, midway through the study in the subsequent 150-odd patients, dexamethasone was used in 84% of patients, and it is now the standard of care in patients in intensive care units.When we looked in the exploratory analysis in just those patients who were on dexamethasone, in fact, we saw what appears to be a highly synergistic effect where remestemcel on top of dexamethasone resulted in a 75% reduction in mortality with a hazard ratio of 0.25. Overall mortality on dexamethasone alone was 45% at day 60, whilst the combination of remestemcel plus dexamethasone resulted in only 14% mortality. These are striking results and warrant confirmation as we move forward.So the conclusion for our next steps for the COVID ARDS program is that addition of remestemcel to dexamethasone appears to be synergistic in those patients under the age of 65. And our plan is to meet with the FDA to discuss potential steps including a confirmatory Phase III trial in patients under 65 years of age combining dexamethasone with remestemcel on reduction of mortality.Now moving to the 2 other lead programs, heart failure and back pain. Our chronic heart failure program focuses on the leading cause of death from cardiovascular disease, heart failure with low ejection fraction. This is a severe disease that's increasing in incidence with a mortality that approaches 50% at 5 years. And whilst new therapies for chronic heart failure reduce recurrent hospitalizations due to volume overload, they do not materially improve mortality from cardiac disease or major ischemic events such as heart attacks and strokes.The inflammatory -- the anti-inflammatory effect of the cells in the myocardium as well as on the peripheral vasculature, we believe, have a unique benefit in terms of reducing both cardiac mortality and reduction in major vascular events outside of the heart.And when you look at the results that we achieved in 537 patients in a randomized, controlled trial, we see that we reduced large vascular events, heart attacks, recurrent heart attacks, recurrent strokes by 60% from 13% to 5% over a 3- to 4-year follow-up period. And we reduced the 3-point MACE, an endpoint that is used by the FDA to approve drugs in parallel conditions, 3-point MACE being a composite of cardiac death, heart attack or stroke, we see a 30% reduction, a significant reduction p equals 0.027 between rexlemestrocel-treated patients versus controls. The greatest benefit was in the Class II patients, where we see a 55% reduction in the 3-point MACE, p equals 0.009, indicating that the earlier we use the therapy, the greater the treatment benefit.And we believe that a single delivery of our cells in advanced Class II patients may be a very significant addition to the armamentarium of these very sick patients with advanced heart failure in combination with existing therapies that will include sacubitril/valsartan or SGLT2 inhibitors.With respect to our back pain program, we -- the randomized Phase III trial achieved significant and durable reductions through 24 months in back pain across the entire evaluable study population, with greatest pain reduction observed in those patients who had shorter duration than the median for the study, 68 months, again, indicating that the earlier that we can intervene with our therapy, the greater the treatment benefit. There's a very interesting parallel between this observation in both back pain and heart failure patients.In addition, there was a significantly greater pain reduction in the prespecified subset of opioid users at all time points compared with saline controls. And by 24 months, it was a 40% reduction in opioid use. So we conclude that rexlemestrocel may provide a safe, durable and effective opioid-sparing therapy for patients with chronic inflammatory back pain due to degenerative disc disease.Our key initiatives and upcoming milestones for the next 2 quarters are significant. And they are divided in terms of those milestones for remestemcel and those for rexlemestrocel. For remestemcel, in the treatment of steroid-refractory GVHD in children, we plan to discuss with CBER's review team at the OTAT our approach to addressing certain outstanding CMC items, including potency assay validation.In the regulatory pathway for remestemcel in patients with COVID-19 ARDS, we intend to meet with FDA to discuss potential next steps based on the observed reduction in mortality in patients under 65 in the recently completed trial. In addition, we continue to work closely with Novartis in the license and collaboration agreement for development, manufacturing and commercialization of remestemcel with an initial focus on the development of the treatment for ARDS. The collaboration remains subject to certain closing conditions, including time during this period to analyze all the results from the COVID-19 trial.For rexlemestrocel, we intend to meet with FDA and EMA to discuss a potential pathway for approval of rexlemestrocel in patients with chronic discogenic lower back pain based on the Phase III trial results and to meet with FDA to discuss the potential next steps in the regulatory pathway in patients with chronic heart failure based on the observed reduction in mortality as well as mobility in the Phase III trial. So on that note, I think I'll stop. And operator, if you could open the call for any questions, please.

[Operator]

[Operator Instructions] Your first question is from Louise Chen with Cantor.

[Louise Alesandra Chen, Senior Research Analyst & MD]

So first question I have for you is when will you have an update on your Novartis agreement and the go-forward strategy for ARDS. And then secondly, what does the ARDS COVID-19 data mean for your broader ARDS program? What is the read-through there? And then do you have any update on your bowel disease franchise or pipeline that you're working on there?

[Silviu Itescu]

Sure. Thank you. Look, as I noted, we're in very close discussions with Novartis -- the Novartis team. And as we analyze the data from the COVID ARDS trial, they analyze it with us or they received both our analysis and our detailed data sets. And we remain in very close discussions, and I would expect that in a very short term, we will be able to update the market on exactly the time lines around that collaboration.With respect to the read-through on non-COVID ARDS, I think those items become clearer as we see more and more data. So first and foremost, as I mentioned earlier, the majority of patients, as many as 70% to 80% are ventilated patients with influenza ARDS even in epidemic times are under the age of 65. And so the fact that we have seen such a striking mortality benefit in COVID ARDS patients under the age of 65, I think, speaks to the target population for us in other viral ideologies of ARDS as well as, as we start to look at bacterial ARDS, including caused by pneumococcal pneumonia or gram-negative sepsis.So I think age is a very important predictor of both who is in the intensive care and the likely outcome. And I think it's a reflection of the strength of the immune response of the individual. And I think we've learned a lot in terms of dosing strategies from this trial that we can apply to the broader infectious ARDS patient population.I think secondly, the potential to understand the mechanism of action based on biomarker data which is currently coming through to us is -- will allow us to make sort of translational conclusions about the relevance of inhibition of cytokines, inhibition of various damaging factors that more broadly be ARDS population in general.

[Louise Alesandra Chen, Senior Research Analyst & MD]

And what about the bowel?

[Fred Grossman, Chief Medical Officer]

The bowel update, yes. It's Fred. We'll be reviewing very soon the initial pilot data with the initial cohort of patients, Crohn's and ulcerative colitis, who had direct application of the MSCs. And based on that evaluation, we'll determine the next steps. We're enthusiastic about this. This is an area of very significant unmet need, and we're really looking forward to reviewing that pilot data to determine our next steps.

[Operator]

Your next question comes from Kennen MacKay with RBC Capital Markets.

[Kennen B. MacKay, MD & Co]

Hoping for a little bit more color on the anticipated dialogue with the OTAT division of the FDA here. Specifically on the sort of manufacturing controls, are those potency assays directed more sort of batch-to-batch variability? Or is that more relating to extension of the manufacturing process?

[Silviu Itescu]

Yes. No, I think it's very important. So really what we're talking about is, and as we've said, as part of the CRL letter, the FDA is looking for us to demonstrate that our potency assay can show -- not -- can show that the consistency of the product that we have in the Phase III trial continues to demonstrate consistency going forward into the commercialization phase.In other words, a potency assay that is reliable, that measures a consistent product is obviously critical when you're making large lots for commercial use. And so I think that's really the issue at hand that we need to be aligned with OTAT that our potency assay measures reproducibly the consistency of the product. And we're obviously very confident that we'll be able to come to agreement on that.

[Kennen B. MacKay, MD & Co]

And just a follow-up on that. Obviously, as it relates to CRL and the letter following that and the follow-up meeting, very clear sort of regulated processes there, regimented processes. As it relates to the follow-up conversations, do you have any sense of time lines there?

[Silviu Itescu]

Yes. Yes. We expect to be meeting with OTAT in the next couple of months, relatively short order. I think it's clear to us what are the discussions to focus on. And it's primarily aimed at getting agreement on the approach and then moving forward with what potentially would be a resubmission.

[Operator]

Your next question comes from Tanushree Jain with Bell Potter Securities.

[Tanushree Jain, Healthcare and Biotech Analyst]

Just a couple of quick ones for me. Just on the GVHD process, I think you mentioned that this could be a resubmission with a 6-month review time line. Would that resubmission be under a formal accelerated pathway? Has that been clarified during your discussions with the FDA?

[Silviu Itescu]

Well, it -- we have a priority review ready for the product, so it would fall under that process.

[Tanushree Jain, Healthcare and Biotech Analyst]

Right. Okay. And in terms of time line with your discussions with OTAT, are we looking at that happening over the next quarter?

[Silviu Itescu]

That's the plan.

[Tanushree Jain, Healthcare and Biotech Analyst]

All right. And then just moving on to the back pain product, with the European trial and getting a protocol approved, there were discussions with Grunenthal and the EMA. Could you give us an update on what we are waiting for on that before we have those discussions with the EMA?

[Silviu Itescu]

Certainly. First and foremost, we need to have agreement with the FDA on endpoints. And the plan is to meet with the FDA, get agreement on the endpoints and then take those to EMA subsequently. There's no point in doing things independently. The 2 regulatory bodies have to be aligned.

[Tanushree Jain, Healthcare and Biotech Analyst]

Right. Now just a quick question on that. So obviously, the opioid reduction that we saw in the -- in your U.S. Phase III trial, which was quite profound, that's more applicable, I guess, in the U.S. kind of scenario and not so much in the European scenario. So I guess thinking forward as to having an agreement with both the FDA and EMA on the next approvable trial, how would that kind of play in terms of differentiation?

[Silviu Itescu]

Well, again, I think the first bar to get agreement with is FDA. And as you say, the opioid reduction component was a very important one. And it may have greater importance to the FDA, but I think it also has importance to EMA. But I think that the driver of the proposal to EMA will be based on how FDA reviews the data. And so I think the sequence is clear to us. First, the FDA meeting.

[Tanushree Jain, Healthcare and Biotech Analyst]

Right. And then just lastly, with regards to Novartis, I think as part of your collaboration with them, I think one of the advantages there that we had seen was their expertise in the CAR-T therapy space, which could kind of help you guys in dealing with addressing some of those potency assay questions on the GVHD product. Could you maybe perhaps shed some light on whether they have been actually helpful in that regard?

[Silviu Itescu]

I think we are very clear in the discussions with the FDA what needs -- what we would need to propose. And as a team, we feel comfortable that we've got the appropriate approach and we've got the data that gives us confidence to meet with OTAT and discuss the appropriate potency assay. And I think you can imagine that those discussions and data being shared with the Novartis team. The next question is how appropriate are these data and potency assays for the product in general, how do they relate to the ARDS application and indication. And that's an area that, of course, we would be working closely together with Novartis moving forward.

[Operator]

[Operator Instructions] Your next question comes from Jason McCarthy with Maxim Group.

[Jason Wesly McCarthy, Senior Managing Director]

If you can talk just a little bit about heart failure and maybe walk us through the time that, that trial had started so many years ago and what was expected of approved or then subsequently approved heart failure medications on volume reduction versus mortality because there's a very key difference between what your cell therapy does and those drugs that you found in December. And I'm wondering if you'll take that data and that "argument" to the FDA to plot out your path forward?

[Silviu Itescu]

Yes. Thanks, Jason. That's a really important observation. And I think very much like in the COVID ARDS pandemic era, where so many new drugs or repurposed drugs were thrown at the patients and outcomes evolved over time, in the same way, I think, during the course of our Phase III trial, there were some new drugs that were introduced. And notably, there were drugs around SGLT2 inhibitors and the sacubitril drug that had an impact on recurrent hospitalizations from volume overload, as you pointed out.And those drugs got approved during the course of our trial. They're now -- some of them in any event are becoming the standard of care. And nonetheless, those drugs have minimal, if any, impact on cardiac mortality or on the major vascular events, all of which are related to inflammation. And what we found is that despite the introduction of these new drugs, we had a major impact on those outcomes less so, of course, on the volume-related hospitalizations.But outcomes that are extremely important are perhaps more so important given that no other therapies address cardiac mortality in the way that we've addressed it or the vascular -- large vascular events like recurrent heart attacks. And so those form the basis now of the way we will be addressing the discussions with the agency. And Fred, maybe you could speak to how you see our upcoming interactions with the FDA on this product.

[Fred Grossman, Chief Medical Officer]

Yes. I think as you mentioned, what's critical here is what we saw in our trial on the 3-point MACE, the composite of cardiac death, MI or stroke. That really is a critical endpoint. And the durability that we saw over 3 or 4 years after a single application, we believe, is very significant and is hitting an area of unmet medical need. And that's going to be the basis of the discussion that we have with the FDA.We have a large number of patients where we saw this significant effect and reduction in the 3-point MACE. The 3-point MACE is a well-accepted and understood endpoint, particularly by the FDA and other health authorities, and that's going to be the basis of the discussion. We're really enthusiastically embracing this because this is important data moving forward that can have a big impact. And we believe the FDA will agree with that approach. And we'll come up with a plan to move this forward because of these results.

[Jason Wesly McCarthy, Senior Managing Director]

And are there still continued plans to move forward in Class IV using GI bleeds or another secondary endpoint that looks like it had really good data in the prior trial? Or is the focus going to be on Class II and IIIs and maybe doing another pivotal study or both?

[Silviu Itescu]

I think, Jason, look, we've got a number of shots on goal right now. I mean, the last 3 or 4 months has really been a very busy period for us to analyze the data across each of our products in the portfolio. And in a sense, we've seen strong data emanating out of each of our programs. So in the short term, we need to prioritize our cash position, be very clear about what we allocate to which programs in terms of near term to approval, market launch, commercialization, et cetera, and then think about broadening out.I think with respect to cardiac, we have to focus whether we go first and foremost for the largest market opportunity, which is Class II, III heart failure or whether we focus on more niche opportunities like end-stage Class IV with the bleeding. But I think before we commit to those programs, we need to have discussions with the agency. We need to focus on the nearest opportunities such as GVHD to market, et cetera. So I think the prioritization is the next step in the Mesoblast review.

[Jason Wesly McCarthy, Senior Managing Director]

Great. And just last...

[Fred Grossman, Chief Medical Officer]

I would add that...

[Jason Wesly McCarthy, Senior Managing Director]

Go ahead.

[Fred Grossman, Chief Medical Officer]

Yes, I was just going to add that we're at an exciting nexus point right now. In the next several months, we're going to have clarity on potential GVHD pathway towards approval. We're going to have clarity on our COVID ARDS program and, as mentioned, clarity on chronic low back pain and heart failure. So we're hoping to have regulatory paths for all of them in the next several months. So this is a real nexus point for this company, and we're really excited about this.

[Jason Wesly McCarthy, Senior Managing Director]

Right. And just briefly, and I don't think -- I don't know if I'd actually get an answer for this. But I know all the focus of Novartis is on ARDS and that cell therapy. But just given that our company's presence in heart failure, is there an opportunity to work with them in that space as well as you start looking forward to what comes next in the heart failure program?

[Silviu Itescu]

Look, we look forward to building a strong partnership with Novartis. And moving forward into the respiratory and pulmonary space, it would be a first step as we build out that relationship over time. So we'll update the market in short order.

[Operator]

Your next question comes from John Hester with Bell Potter Securities.

[John Hester, Senior Healthcare Equities Analyst]

I just want to come back to the upcoming meetings with CBER and the assays that are going to be developed for the consistency of the remestemcel product. If you can just -- how do the Japanese regulators approach this problem? And why do you think that the FDA is so concerned about the potency of the product relative to what the Japanese regulators have determined?

[Silviu Itescu]

Well, I don't think there's any difference, really. So the product in Japan, TEMCELL, is measures of particular factors that the cells make as its potency assay to determine both bioactivity as well as consistency. And we will be proposing a very similar potency assay measuring a single factor that describes both the activity and the consistency of that process. And I think we've had initial discussions with the agency around the proposed potency assay. And we've generally had alignment, and we'll be more specific about our proposal when we meet in the coming months.

[John Hester, Senior Healthcare Equities Analyst]

Okay. Again, then on the potency assay you said -- do you think the number one roadblock to approval? Or I recall, is there going to be a requirement for a randomized trial, I mean, that sort of comes down to?

[Silviu Itescu]

Well, we believe that our clinical data has -- and supported by the conclusion of the ODAC panel, has already demonstrated that there is clinical effectiveness of the product in children with steroid-refractory acute graft versus host disease. So we are planning to meet with the review team to discuss really the plan of the potency assay. And assuming that we have alignment between our approach and what they consider to be sufficient, then we would resubmit the documentation.

[Fred Grossman, Chief Medical Officer]

Okay. Yes. I would underline the fact I think you used the word roadblock. I don't -- we don't see it as a roadblock. I think potency assays, it's not uncommon for any health authority, particularly the FDA, to focus on this. And we welcome that focus, and we'll work with them to move this forward.

[Silviu Itescu]

Well, especially that this would be the first approval for mesenchymal lineage cell therapy of any type for any indication, so it is understandable that the FDA wants to ensure that our manufacturing demonstrates consistency beyond what we showed just in our Phase III program, that all of our commercial batches continue to show exactly the same potency and activity. I think that's natural, and we welcome it. And we are working towards documentation that supports that.

[John Hester, Senior Healthcare Equities Analyst]

And just with the documentation, Silviu, have you got to generate new data for that to prove your case? Or is it really just are you reworking the data from the existing data that you already have?

[Silviu Itescu]

We have generated new data, and we will be presenting the new data together with data that we've had previously been in place that supports the critical attributes of the product. So it's a combination of existing data plus new data that has been generated and will continue to be generated.

[Operator]

Your next question comes from Tanushree Jain with Bell Potter Securities.

[Tanushree Jain, Healthcare and Biotech Analyst]

Just a quick follow-up for Josh. Josh, just on the Hercules capital contractual amendment, can you just remind me of the extensions that we spoke in the last quarter? If I recall, it was supposed to be interest-only period till the loan maturity, which was in March 2022. So we're talking about an interest-only period extension until October 2021. Can you just clarify that for me, please?

[Josh Muntner, Chief Financial Officer]

Sure, Tanu. I think at the last time we had a call like this, the extension may have gone to July of 2021 with the potential to extend to March 2022. And the potential to extend to March 2022 still exists. But at the time, and if you check our disclosure, it was to July at that time. And now it's been extended to October.

[Tanushree Jain, Healthcare and Biotech Analyst]

Right. But the potential is still there to extend it to March 2022?

[Josh Muntner, Chief Financial Officer]

Yes.

[Tanushree Jain, Healthcare and Biotech Analyst]

Right. Okay. And then just quickly on the OpEx side of things, obviously, R&D expenses are coming down, and you did highlight that we could see a decrease moving forward in that. Just on the manufacturing and G&A expenses side, how should we look at costs moving forward?

[Josh Muntner, Chief Financial Officer]

Sure. So keeping in mind that manufacturing is an investment that we continue to make particularly towards potential commercial product for remestemcel for a potential launch as well as the other manufacturing that I discussed, so that will continue at pace. It's a little bit lower this quarter, but that's just due to slight fluctuations in payments. Management administration, as I mentioned, did tick up a little bit. And that is largely due to some one-off expenditures and legal and professional fees associated with regulatory activities around the FDA as well as the financing activities. So yes.

[Tanushree Jain, Healthcare and Biotech Analyst]

And how much was this one-off expenditure?

[Josh Muntner, Chief Financial Officer]

We're not going to break down -- Tanu, we're not going to break down each line through here. But there were a number of one-offs in there that otherwise would have put it largely in line with what it was a year ago.

[Tanushree Jain, Healthcare and Biotech Analyst]

Okay. Okay. Cool. Great.

[Josh Muntner, Chief Financial Officer]

You're welcome.

[Operator]

That brings us to the end of today's call. I'll now hand back to Dr. Itescu for closing remarks.

[Silviu Itescu]

Great. Thank you very much, operator, and thank you, everybody, for joining us on this call. We're very excited about, as Fred said, the nexus that we're at right now with the regulatory discussions that have taken place and will continue to take place in the shorter term as well as with our strategic collaborations. We look forward to updating the market in due course. Thank you very much, everybody.