Executive Highlights
- Mesoblast CEO Dr. Silviu Itescu discussed Mesoblast’s current priorities and future plans, the use of surrogate endpoints in clinical trials for diabetic nephropathy, and challenges facing the diabetic nephropathy field.
We recently had the pleasure of interviewing Mesoblast CEO Dr. Silviu Itescu on the company’s mesenchymal precursor cell (MPC) treatment for diabetes and its complications, including diabetic nephropathy. The enlightening conversation touched on the use of surrogate endpoints in clinical trials for regulatory approval, the challenges facing the diabetic nephropathy field, and Mesoblast’s priorities moving forward. For background, Mesoblast is investigating MPCs as a treatment for a wide range of indications, including diabetic nephropathy and type 2 diabetes (in phase 2 for both; results in type 2 diabetes recently published and results in diabetic nephropathy presented at the 2015 ADA and ASN annual meetings). To our knowledge, Mesoblast is the only company developing a stem cell-based therapy for diabetic nephropathy, and we hope this novel drug class can address the large remaining gaps in this area. Below are our top five highlights from the interview, followed by a full transcript. An overview of the diabetic nephropathy competitive landscape can be found here.
TOP FIVE HIGHLIGHTS
1. Dr. Itescu shared that Mesoblast is currently prioritizing its treatment for complications of advanced diabetes, including diabetic nephropathy. He stated that the company’s strategy is to focus on the areas of greatest unmet need – such as diabetic nephropathy – where there are few alternative therapies available. This is consistent with our sense over the past few years that the pipeline of completely novel drug classes for type 2 diabetes has grown rather thin and that companies are focusing more on making incremental improvements to existing products.
2. Dr. Itescu noted that Mesoblast plans to work with the FDA to identify a regulatory pathway for the MPC treatment in diabetic nephropathy. He noted that the FDA is considering alternatives to the traditional composite endpoint (doubling of serum creatinine, renal replacement, or death) that may allow companies to conduct shorter-duration, less costly trials with smaller sample sizes to support approval of new therapies. The debate over surrogate endpoints vs. hard outcomes is a timely one in many fields, including type 2 diabetes and dyslipidemia, but change in GFR appears to be widely accepted as a reliable surrogate marker in the nephrology field.
3. Dr. Itescu informed us that Mesoblast is working on a type 1 diabetes program for the MPC therapy. The company is currently evaluating the use of optimized proprietary technology using its MPCs to preserve endogenous beta cell function in newly diagnosed patients with type 1 diabetes.
4. Dr. Itescu stated that the diabetic nephropathy program for the MPC treatment would evaluate cardioprotective benefits in addition to potential benefits on renal function. He noted that drugs for diabetic nephropathy have failed in the past due to lack of efficacy or an association with increased heart failure risk. The ideal MPC treatment would not only demonstrate sustained renal benefit but would also show cardioprotective benefits. While we don’t want to jinx anything, it is possible that J&J’s SGLT-2 inhibitor Invokana (canagliflozin) could achieve this holy grail first, with the CANVAS, CANVAS-R, and CREDENCE cardiovascular and renal outcomes trials scheduled to complete within the next five years
5. Dr. Itescu gave us a closer look at how the MPC process works from the patient perspective. He shared that the MPCs are delivered through a minimally-invasive, outpatient intravenous injection and that based on the experience to date, a single MPC infusion holds promise for stabilizing renal function relative to placebo.
INTERVIEW WITH DR. SILVIU ITESCU
Helen Gao: Can you describe the MPC injection procedure in detail for patients? How invasive is it? What is involved?
Dr. Itescu: It’s an intravenous injection. The physician hangs up a bag of cells and the infusion takes about an hour. It’s an outpatient procedure. It’s innocuous. It’s no different from any other outpatient intravenous infusion.
Melissa An: Would the procedure need to be repeated? If so, how frequently?
Dr. Itescu: I wouldn’t call it a procedure. It’s an intravenous infusion – that’s all it is. And at this point we don’t know how frequently it would need to be repeated.
Helen: What is the planned timeline and design for phase 3?
Dr. Itescu: Right now we are in the midst of designing phase 3 to work with the FDA around including GFR decline as an endpoint. We’re working on the study designs and review by regulators.
Melissa: How much will Mesoblast need to scale up production of the MPCs for the phase 3 trials and commercialization?
Dr. Itescu: We’re already in multiple phase 3 trials and manufacturing scale-up is a major focus for Mesoblast in order to meet projected commercial demands and to be cost-effective. We have developed proprietary manufacturing processes employing 2-D technology and have made significant advances in the development of 3-D bioreactor technology.
Helen: Are you going to pursue indications in type 2 diabetes and diabetic nephropathy simultaneously or will one be prioritized over the other?
Dr. Itescu: Our general strategy as a company is to develop our product for those areas where there are a significant unmet needs and where the outcomes are profoundly poorly addressed. In patients with type 2 diabetes, the main unmet need today is that despite well-controlled diabetes, diabetic nephropathy continues to have a high rate of progression through stage 3 and 4 and on to dialysis. Of course, if we can delay the onset of the need for dialysis it will have a major impact on patients’ quality of life, let alone on the ongoing complications associated with dialysis.
Our objective is to develop a therapy to be used on top of standard of care in patients who have already progressed to stage 3 and beyond and delay the need for dialysis. In our studies to date the cells have been well tolerated in patients with type 2 diabetes. I would see that as a next phase of development – eventually a therapy that would provide a clinically meaningful and durable effect on renal function. The goal right now is to delay the onset of dialysis by maintaining or improving the glomerular filtration rate. With longstanding diabetes, the underlying inflammation persists and you end up with end-organ damage whether it’s the kidneys or the liver or the eyes, for example, that results from excessive inflammation that causes tissue destruction, fibrosis, and vascular disease. Our cells have potent anti-inflammatory immunomodulatory capabilities by releasing various factors that are able to down-modulate the monocyte T cell inflammatory processes. If you can switch off this type of immune response you have a real shot at controlling the underlying pathophysiology that drives the vascular disease and diabetes. Our approach in terms of having successful clinical outcomes and having positive interactions with regulators is to address the most advanced, difficult-to-target patient population.
Melissa: What level of efficacy would you consider a success in the phase 3 trials?
Dr. Itescu: In our 30-patient pilot study that was recently presented at the ADA meeting, we were very encouraged that the treatment was well tolerated and by the signals of efficacy that will guide future development. With a single injection of our MPCs in our patients who were stage 3 and 4 chronic kidney disease, we saw a placebo-adjusted treatment effect on glomerular filtration rate at three months and at six months that suggested stabilization of renal function relative to placebo. To see those kinds of improvements relative to placebo of relatively prolonged duration was particularly intriguing to us. We are further interested in evaluating potential biomarkers that have both prognostic and predictive value in this patient population. It’s encouraging to see that the FDA has now acknowledged that inclusion of surrogate endpoints such as decline in glomerular filtration rate is appropriate.
Helen: Does Mesoblast have plans in type 1 diabetes?
Dr. Itescu: We are interested in exploring the potential of MPC immunomodulation to change outcomes in patients with newly diagnosed type 1 diabetes, where there may be potential to rescue or regenerate the native pancreas.
Melissa: If this therapy reaches the market, how costly would you estimate it to be for patients and what would be the biggest concern for payers?
Dr. Itescu: The good news is that we have developed proprietary manufacturing processes to enable us to scale up to match our supply needs. I think that the cost to patients will be proportional to the overall benefit and will most likely consider the economic impact of chronic renal failure and associated complications.
Helen: What are your thoughts on the advantages and disadvantages of the approaches of ViaCyte and Semma Therapeutics?
Dr. Itescu: I don’t comment on other technologies, but in general I think that beta cell replacement therapy is a promising approach to type 1 diabetes. It’s an approach that assumes that your beta cells are all gone. If immunomodulation doesn’t have any benefit or end point, then replacement with cell therapy would be appropriate. I think the question is whether effective immunomodulation at a time point where you still have sufficient beta cells would obviate the need for beta cell replacement therapy. That’s a question that we are obviously considering.
Kelly Close: Do you think there’s any concern about people getting their hopes too high for where the technology stands right now?
Dr. Itescu: For type 1 diabetes, there may be a role in the foreseeable future for cell-based immunomodulatory therapies to protect endogenous beta cells, or for beta cell replacement therapies. The real question is the benefit of cell therapy with durable insulin production vs. improvements in insulin delivery. There are a lot of questions: the source of the cells, the need or no need for immune suppression therapy, the durability of the response, the mode of delivery, and the encapsulation. If cell therapy could indeed reduce the need for frequent insulin injection, that would be a big deal.
Kelly: It is a big deal. It’s really exciting.
Dr. Itescu: There are many issues to consider in developing a cell therapy product and putting it through the regulatory process, and then ultimately showing that it’s superior to other therapies. There has to be substantial rationale for why you should do this versus insulin, which works.
Kelly: No, but it’s so hard to use. This would be so much better.
Dr. Itescu: I understand that. In general, our approach to developing cell therapy products is to focus on those users where there’s no alternative. I think where there’s no alternative, there’s a lot of benefit to putting in a lot of resources. Where there are alternatives, then the bar is a lot higher to demonstrate the real benefit over the standard. And on top of that, even more importantly you have to demonstrate that you have certain efficacy benefits and you don’t have extensive risks.
Kelly: From a patient perspective, we’ve seen a lot of things go into the FDA like the anti-CD3 therapies, where it seemed like there was so much pressure not to show a lot of adverse events that maybe the dosing wasn’t optimal. It’s always easy to say after the fact…
Dr. Itescu: There are therapies that are well known to have profound and severe side effects – anti-CD3 is one of them. The last thing you want to do is to be treating people with diabetes and giving them serious side effects of immune suppression such as infection and malignancy. That’s the problem with standard immunosuppressant drugs. The immunomodulatory cell therapies, such as our MPCs, are potent at switching off pathways of immune cell activation without any demonstrable risk to date of infections or malignancies. So, it’s a good class of an approach compared to traditional immunosuppressant drugs, particularly for newly diagnosed patients with type 1 diabetes where safety has to be paramount.
Kelly: That makes a lot of sense. We were talking to a researcher the other day about the news in the Langer lab and the work with Novo Nordisk, and he was comparing it to the news about Novo Nordisk working with Richard DiMarchi’s group. He said, “One of these is such an incredibly prolific inventor and he’s working on a lot of new molecules, and the Langer lab is a big deal but they’re just trying to make one drug better.” And we said, “Yeah, but the bar is so high now to get a new molecule and there are so many problems with adherence – in both type 1 and type 2.”
Dr. Itescu: Whether one is developing a new agent for better glucose control in type 1 or type 2 diabetes, or for diabetic complications such as nephropathy, the key question is risk/benefit trade-off. Our MPCs have shown signals of efficacy in a small number of patients without any safety concerns. A major complication of progressive renal disease in diabetes is the concomitant cardiovascular risk and cardio-renal syndrome. To date our cells are well tolerated in patients with chronic heart failure, unlike other classes of agents. In fact, given the substantial competing risk between progression to end-stage renal disease and cardiovascular events in patients with diabetic nephropathy, we would plan to assess cardiovascular events in addition to renal function. Those are the kind of outcomes that the FDA is very mindful of.
Kelly: Yes, that’s so amazing and part of what we find so incredibly exciting about what you’re working on. The only time that I’ve ever cried at work was when we got that bardoxolone news. That was just tragic. There were so many high hopes for that.
Dr. Itescu: To have a drug that potentially improves or preserves renal function and also reduces the competing risk of cardiovascular outcomes would be of great value to these patients.
