Ashish Kamat: It gives me great pleasure to welcome Dr. Colin Dinney, Professor and Chair of the Department of Urology at MD Anderson Cancer Center in Houston. Dr. Dinney is a pioneer and a trailblazer in the bladder cancer field and really needs no introduction. He's also mentored countless individuals that have worked in this field including myself, and I'm really honored to have him here today to bring us up to speed on the latest data regarding gene therapy for bladder cancer. It's a pleasure to have you, Colin.

Colin Dinney: Thank you, Ashish, and thank you for the opportunity to present on behalf of the SUO-CTC the results of our Phase III trial with nadofaragene firadenovec. These are my disclosures that are relevant. I am the independent chairman of the steering committee for the Phase III nadofaragene firadenovec trial, and I have research support from the NCI and I will discuss the investigational use of nadofaragene therapy in this presentation.

So just as a preamble, we have a dilemma. BCG is our most effective therapy for treating non-muscle based disease, but we know over time most patients will eventually recur and up to 35% may actually die of bladder cancer, it's been reported. So alternative therapy is indicated, but to date or until recently only valrubicin has been FDA approved for BCG-refractory CIS with a complete response rate of only about 10% at 12 months. So clearly, effective second-line therapy is an unmet need for patients facing cystectomy and one of the approaches is a bit evaluated, has been interferon gene therapy for this indication.

Now just showing you some background, the SUO-CTC has completed a Phase II trial for rAd-IFNα/Syn3 for BCG Unresponsive disease. We published this in JCO where we reported a 30% complete response rate for carcinoma in situ and a 50% recurrence-free survival for high-grade Ta/T1 disease at 12 months. The drug was well tolerated and there was no dose-limiting toxicity, and there are promising data supported this Phase III registration trial for patients with BCG Unresponsive non-muscle invasive disease. This was a single-arm multi-center study. Steve Boojian was the PI to investigate both the safety and the efficacy of intravesical rAd-IFNα/Syn3 now known as nadofaragene firadenovec. Patients were BCG unresponsive according to the 2018 FDA guidelines. Patients received an installation of the agent at a dose of 3 x 10 to the 11th viral particles per mL. That was the dose that was found to be most effective in Phase II with the planned one hour dwell time.

Patients were monitored at months three, six, and nine with a cytology and cystoscopy and a biopsy of clinically indicated to evaluate for the recurrence of high-grade disease. Now patients that were free from high-grade recurrence were eligible for additional treatments at months four, seven, and 10. But then at month 12, all patients underwent these investigations but also a mandatory biopsy to improve the rigor of the study and again, those free high-grade recurrence with the biopsy or clinically were eligible for retreatment at three-month intervals while they remain high-grade recurrence-free for another three years.

So the data cut off for this analysis that I'm presenting was in July of 2019 when all patients had completed 12 months of follow-up. Now here's the primary objective of our trial. The primary objective was to evaluate the complete response rate in patients with carcinoma in situ disease at any time following the first installation of rAd-IFNα. The important secondary objectives which were to evaluate the durability of the complete response rate in those patients with carcinoma in situ, but also to evaluate the rate and durability of high-grade recurrence-free survival in patients with Ta/T1 high-grade disease only. And again as I mentioned, a 12-month biopsy was mandated to confirm the durability of the response.

We screened 198 patients for eligibility. Forty-one patients were excluded for one reason or another, leaving us with 157 patients who were enrolled in the trial and received at least one dose of rAd-IFNα/Syn3. That was 107 patients with carcinoma in situ and 50 patients with high-grade Ta/T1 disease. This makes up our safety population because as it turned out four patients with carcinoma in situ and two patients with high-grade Ta/T1 disease did not meet the stringent definition of BCG unresponsive non-muscle invasive disease, and that left us with 103 patients with carcinoma in situ and 48 patients with high-grade Ta/T1 disease that make up our efficacy population. I just want to show you some of the baseline patient characteristics that indicate that this is a high-risk population. For instance, if you look at the median time from diagnosis until treatment for patients with carcinoma in situ it approached two years, and the majority of our patients had received three or more courses of BCG.

Here's our primary endpoint and the incidence of complete response at any time for patients with carcinoma in situ. All CRs occurred within three months and 55 patients or 53% achieved a CR at three months. With respect to our secondary endpoints, at the beginning, the patient with disease, 73% achieved a high-grade recurrence-free survival at three months. And if you look at the durability for carcinoma in situ, 25 of 103 patients or 24.3% maintained that CR to 12 months and for patients with high-grade papillary disease, 44% remained high-grade recurrence-free at 12 months.

Now if you look at the percentage of patients with a complete response or those who are high-grade recurrence-free at three months that maintain that disease-free state at 12 months. For patients with carcinoma in situ, there are 55, 25 or 46% maintained that response out to 12 months. And for patients with a high-grade Ta/T1 disease, 21 of 35 or 60% of those patients were high-grade recurrence-free at 12 months. So really the three-month evaluation seemed to be a litmus test for those patients that will do well because if they get past that point about half the patients will remain disease-free throughout the study.

This curve shows the durability of the recurrence-free survival. It also shows you that late recurrences in patients that are high-grade recurrence-free at 12 months are very rare. We did see a drop off on month 12 and that's because of the end of study biopsy. Now as I mentioned, we included a biopsy to confirm the free for high-grade recurrence at 12 months. There were six patients that had a positive biopsy at that time point, but five of the six including three patients with carcinoma in situ would have been considered to be free from high-grade recurrence at 12 months based on clinical features alone.

If that had been the case, we would have reported a 27% complete response rate for carcinoma in situ and a 48% recurrence-free survival for high-grade papillary disease at that time point based on clinical features only. And I think this does provide a standard for the interpretation of efficacy in the absence of a biopsy. So if we had not done the biopsy and we looked again the percentage of patients with a complete response at three months that remained disease-free 12 months, we would have reported that 51% of the patients with carcinoma in situ and 66% of patients with high-grade Ta/T1 disease would have maintained that status at 12 months.

Now, one of the concerns you have in putting patients with BCG unresponsive disease on clinical trials is the risk for progression and death from bladder cancer. So we looked at that and we found that fortunately these patients were not put in a high-risk of progression over the course of the study. Eight patients or 5% showed progression, three of these showed progression clinically and five were found to be upstaged at cystectomy. But fortunately, no patients have died from bladder cancer, so it appears that patients were not placed at risk by [inaudible] on the trial.

Now we did report study drug or procedure-related adverse events and 70% of the patients, the procedure is the catheterization. Fortunately, only three patients had a severe adverse event or 2%, and only six patients or 4% had a grade three or grade four adverse event. There was one grade four adverse event. Importantly, no patients died from an adverse event, so no patients died from a complication related to the study drug or procedure and only three patients or 2% came off of study because of a procedure or drug-related adverse event. So the tolerability is pretty good. But these are the most common study drug-related adverse events and they can be broken down as systemic effects such as fatigue, chills, et cetera, GI complaints and headaches. And these are likely secondary to the interferon and irritative voiding symptoms are also very common. And these are secondary likely to the Syn3 which is the excipient used to enhance gene transfer. It's a detergent so what's irritated, it irritates the bladder. We can ameliorate this by pre-treating patients with an anticholinergic and that's what we promote, the clinicians will do that.

These are the procedure-related adverse events that overlap with what was attributed to the drug with the exception of hematuria, which is universal. Now, fortunately, median duration one or two [inaudible 00:09:38] and frequency of the median was 41 days, but we all know that urinary frequency is very common in patients with non-muscle invasive bladder cancer, especially those that are ongoing undergoing treatment. And so we weren't really concerned about the duration of these risks of the frequency.

So now just to summarize, in terms of efficacy, with respect to our primary endpoint, we reported a 53% complete response rate in patients with carcinoma in situ at three months in what is a high-risk population. With respect to our secondary endpoints, we report a 24% complete response rate for carcinoma in situ with 12 months with a biopsy, and 46% of the patients maintained the CR through 12 months. If we had not done a biopsy or the biopsy were at the investigator's discretion, 27% would've been reported to a complete response at 12 months. For patients with high-grade Ta/T1 disease, 73% of the patients were high-grade recurrence-free at three months and 60% remained high-grade recurrence-free at 12 months. And as I mentioned, late recurrences beyond 12 months were rare.

With respect to tolerability and safety, we're showing an acceptable safety and tolerability only one Grade 4 and no Grade 5 drug or procedure-related adverse events. There was only one drug-related and two procedure-related serious adverse events. And no pattern of immune related adverse events and no treatment-related deaths, and only three patients or 2% stop treatment due to treatment-related adverse events. We've had long recognized the convenient dosing schedule. Patients have one intravesical treatment every three months and so I would conclude that nadofaragene firadenovec does provide a favorable benefit-risk profile for patients facing cystectomy. Before I stop, I'd like to thank the SUO-CTC site, PIs and their staff. Shown here are some of the sites, there are 33 sites that participate in this trial and I'd also like to acknowledge our associates in Kuopio, Finland who provided the reagents for the trial. I thank you very much, Ashish, for allowing me to present this.

Ashish Kamat: Thanks a lot, Collin. That was great. That was a very concise and precise summary of all the data. To highlight a few points for our listeners and viewers, what would you say would be the three key efficacy endpoints that they should remember regarding this drug?

Colin Dinney: So I think the three key efficacy endpoints would be number one, the CR rate at three months keeping in mind that we did perform a biopsy, which others in the same disease space did not. I think that the 12-month durability is important, but also the fact that once you get beyond 12 months that late recurrences are very, very rare. So I think that once you get beyond three months, your chance of maintaining a response is about 50% or more. And then once you get to 12 months, it's very, very unlikely that someone will recur at that time point.

Ashish Kamat: Yeah, and I think that's a very important point because you hear a lot of people ask how long is it safe to try different drugs for these patients. And it seems like with the nado therapy, if you get a response at three months, more than likely that patient will retain it for about a year. Is that accurate?

Colin Dinney: That's correct. And also, the other thing that I didn't show is that first of all, nobody died from bladder cancer. And in fact, when we looked at the cystectomy, those patients that finally went to cystectomy, only 12% had been upstaged to T2 disease or greater. Most patients did not progress. And so even those patients that don't respond, we're not seeing a lot of progressions. It does seem to be safe. It either means that we're very, very good at selecting the appropriate patients or that the drug did prevent that progression. Because looking at our own data sheets that you provided, in patients that were basically unresponsive and went to immediate cystectomy, 44% were found to have T2 disease or greater and we were only seeing 12% so we're not putting patients at risk, and patients do have time to try something before moving onto cystectomy.

Ashish Kamat: Right, and that's a key thing that our listeners and viewers should remember. Because this is a very dangerous disease state and we don't want to forget the risk of progression that our patients have. So it's really encouraging to see that not only can you prevent recurrences, but also prevent progression or at least the progression that we saw in this study was much lower than what you would expect based on actual historic controls, which is really good. From a practical standpoint, if a urologist and his practice or her practices is planning to adopt this into their clinic, are there any special considerations they should be planning for as far as the viral part of it is concerned?

Colin Dinney: Well, that's a good question. They used to demand that we had [inaudible 00:14:49] to facilities, but that may no longer be necessary because there's been a change in packaging. FinVector says that the product will come and it in a closed system and you can just instill it without having to have it go to a pharmacy to be mixed. So it might be a lot simpler and it might also open up the utilization to places that don't have a specialized pharmacy available to them. So I think that's something to watch out for that. That's something that FinVector who makes the reagent has started to investigate and actually has it ready to go.

Ashish Kamat: Great. And again having put patients on the study, I can also vouch for the fact that it was very easy for patients to come in and get their installation and it was very well tolerated. But any tips for the practicing urologists that are looking into using this? What pre-medication things like that, what would you recommend?

Colin Dinney: I think that we recognize that... I think everybody should get an anticholinergic, and again, we don't really know which one is best. I would probably prefer being on suppositories if they're available. But I haven't seen the data. I asked the company for the data as to which drug, which agents were used to see if one was better with the other. The other thing that people should be reassured of is that it's not a dangerous drug. Right now, we're living in a time when the threat of transmit viral disease is taking our front page in our lives. And people might be worried about giving an animal virus because they might be afraid of being getting infected. Well, the virus that we use has been modified. The replication sequence has been removed so it's replication-deficient and it doesn't become integrated into the host genome. So the risk for insertional mutagenesis and the development of a second malignancy is essentially eliminated. So I think that people should be assured that it is safe.

Ashish Kamat: That's great. A couple of questions because as you know, ICER is planning to do a comparative review of nado with pembro and I believe with vicinium as well. Could you enlighten the readers on your take on the data? What was presented for pembrolizumab and what you know in the public domain for vicinium and highlight the key advantages of nadofaragene firadenovec as I think it's going to be called.

Colin Dinney: First, let's start with pembro. I think that the number of patients on this trial was 96. The complete response rate was about 41% at three months, which is in the ballpark of ours. What's really ironic is that only 36 patients were treated in the United States. It was approved for use here. We treat more patients on our Phase II trial than they treated in the US on their registration trial. And you really can't do a subset analysis between trials, this is really not as a statistically unsound, but I'll do it anyway. If you look at the complete response rate in the US population, it was only 31% and ours in the US population was 53%. So I think that our efficacy is as least as good as pembro in this patient population. And our durability is at least as good.

With respect to the vicinium, their CR rate at 12 months was I believe 17% which is in the ballpark. But it's a much more intensive regimen for patients and in the induction phase is much more intensive. Ours is only one treatment every three months. I think that's one of the advantages for this agent over vicinium is the ease of administration. It allows more individuals to be able to treat patients with the agent.

Ashish Kamat: Exactly. Kudos to you for being involved with this. And again, I know you've been involved with this from the very beginning. Back when I was a fellow, we were studying this in the lab and then taking it to the FDA and getting them to understand BCG and what it means to be BCG unresponsive and then seeing this to completion is really a huge feat. Before we close, where do you see gene therapy heading in the near and not so near future?

Colin Dinney: So I think like any other agent that's available, you need to try to figure out how to best treat patients with it and how to improve the efficacy of the drug. I think the first thing we need to do is to identify likely responders. Patients who are...