1. You’ve been in the regenerative medicine and cell therapy fields for a long time, what are the biggest developments or achievements that you’ve witnessed?
From my point of view, it has to be the T-cell CAR development. My background in regenerative medicine is from both a gene and a cell-based therapy perspective and CAR-T hits the nail on the head on both of those fronts. It came along at a point when the gene therapy translational academic field, as well as commercialisation, in North America was pretty much at a standstill. All of a sudden, these trials started to appear with retroviral gene transfection in T-cells, which had a profound therapeutic effect. It’s really changed our whole thinking when you have a therapy that’s proliferating inside the patient and actually taking over to a certain extent.
We’re still somewhat early on in terms of success as far as commercialisation goes but it seems to have lifted the whole field from a commercialisation and a venture capital point of view, focusing a lot of interest on the field of gene and cell-based therapy. It also highlights how profoundly therapeutic these types of therapies may be. I think that’s helped us all in the field.
I also think that just the amount of cell therapy trials that have taken place over the past 20 years, plus the fact that there have been very few adverse effects in these trials, has given a lot of support to the further development into clinical trials.
2. Can you tell us about the SAPPHIRE clinical trial you're currently running involving minicircle DNA plasmids and how this has been received by regulators?
To give you a little background on SAPPHIRE, first of all, it’s based on a couple of decades of preclinical work that we’ve been doing to develop cell therapies in the pulmonary hypertension field, largely in collaboration with Dr Duncan Stewart. The particular type of pulmonary hypertension we’re looking at is classically termed idiopathic pulmonary hypertension or pulmonary arterial hypertension, which is a severe chronic disease and the feeling was that the only appropriate regenerative remedy would be to revascularise the lung in some form. We took the approach of looking at ways to target angiogenesis in the lung and early on by using cells to carry important angiogenic genes to the site of interest.
We started some early studies with fibroblasts and smooth muscle cells but very quickly realised at that time (around the late 90s) there were some very interesting studies based on endothelial progenitor cells. If you grow them long enough in culture, they can be much like endothelium but the ones we chose to use were much more like a monocyte with some endothelial characteristics. Once we decided those were the cells to pursue, we started to figure out how to manufacture them to get into a clinical trial and then to figure out how to transfect the cells, which was difficult because many of the normal transfection reagents would simply kill the cells. We had to find some way to transfect the cells and get them into patients and that led to the development of our first phase I trial which was a safety trial.
We had seven pulmonary hypertension patients in a dose-escalation trial where the first doses were split into three over the course of three days and all delivered down a catheter, so these patients had a right heart catheterisation that remained in place for four days during the course of therapy. It was a rather invasive procedure and the patients should very much be credited as being heroes in this case. As it was a dose escalation trial, those first doses were very low as we were focusing on safety and had anticipated that the early doses may not be that therapeutic. However, at the end of the trial, we did see rather significant increases in six-minute walk distances, which was the primary endpoint.
There were several years between stopping that first trial and beginning the second larger phase II trial. During this time, the whole cell therapy industry evolved and I think that convinced our partners at United Therapeutics that this cell therapy may be a valuable target for pulmonary hypertension. Recently, they have made a big investment into the process and allowed us to move ahead with the design of the SAPPHIRE trial which is a phase II trial that will involve 45 patients and is placebo-controlled. There will be three arms in the trial where the patients are given four doses upfront with a primary endpoint at six months; the six-minute walk distance. It’s probably the strongest endpoint for pulmonary hypertension, although it is somewhat qualitative. There are other haemodynamic parameters, which are secondary endpoints that look at the pulmonary resistance. After the first course, all patients will be treated for another four doses for the following four months. Every patient, even if they were initially in the placebo arm, will receive active therapy over the second part of the trial, so every patient in the trial will receive a minimum of four doses of active therapy and I think that’s becoming very important in designing cardiac trials because it’s very difficult to get patients engaged and enrolled in a clinical trial if there’s the potential to be randomised into a group where they won’t get any active therapy at all. The multiple dosing is something that’s unique. We’re hoping it gives a synergistic effect because what we saw in the first trial was what seemed to be a sustained effect over several months.
3. Can you elaborate on your repetitive dosing approach and the impact of using the minicircle plasmid in implementing this approach?
During the PHACeT trial, the safety trial, there were some limitations as the cells were very difficult to transfect. We used plasmid DNA and electroporation, which, unfortunately, led to a significant loss of cells, anywhere from 90% to 60%, making it very difficult to get appropriate dosing in the patients. So, we had to go up to higher doses and grow 10 times more cells than we were actually going to apply. From a GMP perspective, it was a much more difficult and cumbersome process and was not as predictable for us in terms of finding the actual cell yield.
For the second phase of the pulmonary hypertension SAPPHIRE trial, we decided to explore the use of minicircle therapy because it had a significant advantage in that it removes all of the bacterial sequences that may be in the plasmid-based DNA, and by doing so, it would make the product less immunogenic. There would be less foreign sequences and would hopefully allow the minicircles a further length of expression. Indeed, we were able to get a very consistent minicircle transfection, which allowed us to hit most of our targets in terms of yield and transfection. In fact, the level of transfection we need is rather low-level, our bottom target is at least five-fold above what’s inside the cell already for endothelial nitric oxide synthase (eNOS) production. With the minicircle, we’re far in excess of the minimum fold increase in expression of eNOS required over baseline. So, we hope we’ll be moving ahead with the minicircle because it allows us a very consistent product as well as potentially limiting any immune responses. Since the SAPPHIRE trial involves repetitive therapy of an autologous cell, we wanted to limit immune responses as much as we could.
There were obviously regulatory implications of moving from plasmid DNA in phase I to minicircle DNA in phase II but I can give you some insight into how this was received by regulators. The phase I trial gave us some clues as to what the safe dosing may be and then we felt that we could then do repetitive dosing based on that and that’s what led us to move to the minicircle DNA. We felt there might be significant regulatory concerns with these major changes, but Health Canada did not express any significant concerns to us. They seemed to recognise that moving from the plasmid to the minicircle, if anything, was likely to produce a safer product; there’s less foreign DNA there. They seemed to feel it was a good thing and they recognised that we had done a series of animal studies to look at that as well as animal toxicology studies which they accepted. They also recognised that repetitive dosing is the likely way to go to be therapeutic and that this would be part of what the phase II trial would be about.
With Health Canada, I think the individuals in the biological and gene therapy directorate, particularly in the gene therapy directorate, are very knowledgeable. They did have questions about the quality of the product, the quality of the production of the plasmid and the sequencing of it but after that they were sufficiently knowledgeable to understand that there’s not a big difference between a piece of plasmid DNA transfected in this manner versus the minicircle from a safety point of view and the only differences are likely to be positive.
4. Engaging with clinicians and building a treatment centre network is a key factor in the success of a trial, particularly in terms of accessing patients. How have you approached this and how have clinicians’ attitudes changed towards cell-based therapy trials over the years?
From a personal perspective as a PhD scientist, if I was working simply at a university it would be extremely difficult for me to address this but, fortunately, or unfortunately, my first faculty appointment was embedded right in a clinical setting. I was hired by the cardiac surgeons at St. Michael’s Hospital in Toronto and I worked very actively with the cardiologists there. Right from the initial preclinical work, we were working very closely with the clinicians to try to address the most important unmet clinical needs in the patient population. I think it’s so important to get clinicians engaged right at the beginning, as it’s very difficult for a scientist to engage with the full clinical population without having someone who’s treating the patients and knowledgeable about how the therapy might be applied and to convince other clinicians to participate in the clinical trials. You absolutely need a clinician who’s at the forefront of this to push the therapies ahead and what really is required here is a strong teamwork approach. However, what is difficult is finding clinicians who are knowledgeable enough in the science to appreciate how important the scientific approach is. The other challenge is that many of the clinicians that you may try and engage don’t understand GMP manufacturing or anything about the manufacturing of a cell therapy product and how that may need to influence either design of the clinical trial.
Additionally, there has been a large change in the past 20 years or so, where the enthusiasm of patients who participate in these trials has waned somewhat so it’s becoming much more difficult to get patients into the clinical trials, particularly trials that may involve a placebo group only. Patients begin to wonder whether or not they are going to get any benefit from their participation. Particularly, after a life-changing event like a myocardial infarct, it can be very difficult to engage them and get them involved in clinical trials where they may be randomised to a placebo group. So, enrolment in the trials is very difficult. Also, if you're developing a therapy that is on top of an effective therapy, it’s very difficult for patients to make that decision to go on those trials and, I think that’s where we may be in the cardiac field.
So, it’s definitely a competitive landscape to get your patients into any particular clinical trial and, it’s how it’s presented to the patient and who is presenting to the patient that becomes particularly important. Once you get to a phase II and you're starting to require more and more patients, it becomes that much more difficult to convince clinicians at multiple centres that this is a very important trial and should be done.
5. Your lab at The Ottawa Hospital contains cGMP facilities. How has the perception of academic-based manufacturing and process development evolved and what is your experience of it today?
Well, we struck out 15 years ago and started developing our own GMP facility that was outside of the classic bone marrow transplant or cell therapy types of facilities, first at St. Michael’s Hospital and then at The Ottawa Hospital. The challenge for academics in Canada, and possibly elsewhere in the world, are the financial pressures. Developing cell therapies with the full cGMP is a very expensive process. The other challenge is that, from an academic point of view, we’re still locked into the single investigator type of funding scheme whereas, when you're trying to implement a cGMP trial you need strong cGMP experience and, clearly, it’s not the cGMP people who write the grants for all the disease indications. So, it really does require strong teamwork and as yet we don’t really have a teamwork-based funding approach.
The only way you can get a cGMP manufacturing facility up and running in an academic setting is through strong institutional support and a recognition from the institution that this is going to be a major strategic objective from either a research or medical perspective. So, that’s where cGMP facilities have mainly been drawn from and there’s a lot of institutional money that has gone into it, a lot of donor-specific money, philanthropic money goes into building and maintaining the facilities. Then, combine that with money derived from your standard granting process to move clinical trials ahead into phase I and phase II.
The larger the trial, the higher the risk. Therefore, your processes need to be much more rigorous and rigour requires additional expense, quality control and quality issues that you have to begin addressing, which we didn’t really anticipate in the early parts of developing this. I think our thought was if we were successful in phase I and phase II, there’s going to be an industry partner that this can take over and they’ll just go and manufacture elsewhere. Well, it turns out once you’ve developed all that experience and manufacturing in phase I and II, you're probably in the best place to move that ahead into a phase III because you have all the knowledge; this is a strongly knowledge-based industry.
Now, we have to find a way to adapt to that and apply much more rigour to GMP in our academic settings in order to meet very high quality and reproducibility standards, while still using the manufacturing facility within the hospital for a phase III trial. That becomes our biggest challenge as we move ahead because some of our facilities aren't necessarily built with a phase III trial in mind.
6. You are also the CSO of Northern Therapeutics, can you give us some insight into your scale-up and commercialisation strategy?
From a Northern Therapeutics point of view, we have a licensing agreement with United Therapeutics. We’ve developed a strong partnership with United Therapeutics and rely on them for commercialisation in the United States. As we’re developing an autologous product, it would be scaled out rather than scaled up so multiple types of platforms might require some investment. We are currently basing our manufacturing on a BioSpherix isolator unit and you could easily put a number of them in a single manufacturing facility with one dedicated to each patient. So, I don’t think that would be much of a problem, but it would come down to cost and remuneration as to what successful commercialisation looks like.
7. What would you say is the most important factor for successful commercialisation?
Well, I’m 90% an academic, so I would define successful commercialisation quite differently to how a venture capitalist might define successful commercialisation. My definition of successful commercialisation would be a very profoundly efficacious product where we have developed the capability to deliver it to as much of the patient population as we can. Obviously, if you can do that, you are likely to make money from it.
So, I would define a success as a company that’s capable of growing and being able to treat the patient population with an efficacious product.