Webinar: Expanding Treatment Options for Non-muscle Invasive Bladder Cancer: Introducing a novel therapy for those who do not respond to BCG

October 6, 2023

Bacillus Calmette Guérin (BCG) has long been the gold standard for treating high-grade non-muscle invasive bladder cancer (NMIBC). For those whose tumors do not respond to BCG, a newly approved gene therapy may provide a valuable treatment for BCG unresponsive NMIBC. Listen to urologist researcher Colin P. Dinney MD, Chairman of the Department of Urology at the University of Texas MD Anderson Cancer Center, as he explains this new treatment option that uses the patient’s own bladder wall cells to enhance the body’s natural defenses to fight cancer. 

With Dr. Colin P. Dinney

Year: 2023

Introduction to Adstiladrin | Gene Therapy for BCG Unresponsive NMIBC

Transcript (PDF)

Questions and Answers on Adstiladrin | Gene Therapy for BCG Unresponsive NMIBC

Transcript (PDF

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Full Transcript of Expanding Treatment Options for Non-muscle Invasive Bladder Cancer: Introducing a novel therapy for those who do not respond to BCG

Stephanie Chisolm:

Welcome to Expanding Treatment Options for Non-muscle Invasive Bladder Cancer: Introducing a novel therapy for those who do not respond to BCG.’’

Stephanie Chisolm:

Bacillus Calmette-Guérin has long been the gold standard for treating non-muscle invasive bladder cancer, and for those whose tumors don’t respond to BCG, which is the standard of care, there’s a newly approved gene therapy that may provide a valuable alternative to bladder removal surgery.

This new treatment, a gene therapy, was recently approved by the FDA, and BCAN is delighted to welcome the chairman of the Department of Urology at MD Anderson Cancer Center in Houston, Dr. Colin Dinney, a longtime member of BCAN Scientific Advisory Board and a globally recognized expert in treating bladder cancer. Dr. Dinney was the principal investigator on the clinical trials that led to this approval, and he’s going to talk about this new adenovirus vector-based gene therapy and show you how it works, how it’s administered, and who would benefit from the latest treatment options for non-muscle invasive bladder cancer.

Welcome, Dr. Dinney. It’s a pleasure to have you here.

Dr. Colin Dinney:

Thanks, Stephanie, and thank you for inviting me to speak on the development of Adstiladrin for what’s now known as BCG unresponsive disease.

Dr. Colin Dinney:

So, I’m going to start talking about BCG unresponsive non-muscle invasive bladder cancer, which really is an inherently resistant cancer. From a cancer perspective, a radical cystectomy is the safest option, but we all know there’s a tradeoff with respect to quality of life. Historically, valrubicin was approved for what’s known as BCG refractory carcinoma in situ, carcinoma in situ that was not treated by this, do not respond to BCG, with a complete response rate though of only about 10% at 12 months. Up until recently, patients had very few therapeutic options as effective second-line therapy was an unmet need for patients facing cystectomy. And Adstiladrin was developed to fill this need.

Dr. Colin Dinney:

When talking about non-muscle invasive bladder cancer, what are we talking about? We’re talking about cancers that are confined to the urothelium and the lamina propria. So, this is the bladder. This is the bladder lumen. The tumors we’re talking about are the high-grade Ta lesions. These are lesions that are confined to the urothelium, and under the urothelium is the lamina propria. We’re talking about carcinoma in situ, which is a high-grade intraepithelial neoplasm. It’s confined to the urothelium, but it’s high-grade. It can invade and it can metastasize.

And also includes these tumors, these are T1 tumors, and these tumors invade into what is called the lamina propria. That’s the tissue between the lining and the deep muscle. And it’s a misnomer to consider these to be superficial tumors, but you can see that these tumors look very much like a tumor that’s invading the muscle. The only difference is they haven’t gone as far. So, it’s very, very important that when the urologist resects these tumors that they get adequate tissue depth and they get into the muscle and get all the way around it prior to starting any treatment.

Dr. Colin Dinney:

I guess the first question you have to answer is, if BCG isn’t working, do we have time to find an alternative to cystectomies? Well, this is a recent paper that says we do, we have about 12 months until the survival of patients who don’t respond to therapy gets worse. And that corresponds to about five TURBTs.

Dr. Colin Dinney:

Now, I’m going to take it back to 2012 where the story began, and if you look back in 2012, the history of drug development for non-muscle invasive bladder cancer was bleak. Only four agents had been approved for the treatment of non-muscle invasive bladder cancer since 1959. And only one of those drugs, a BCG was being used currently.

Dr. Colin Dinney:

The grim reality was that very few drugs went beyond early-stage trials as the conventional paradigm for clinical drug development just wasn’t working. So, we recognized we needed to radically rethink our clinical trial design if we wanted to bring new agents into the clinic for our patients. We had to ensure that trials would be feasible so they could be finished, but the endpoints were clinically relevant, so we would’ve analyzed the drugs properly and foremost, that patient safety was prioritized. So, in 2012, the SUO, the AUA, and the FDA launched a collaborative effort to address this deficiency. And the initial focus was to define a pathway for drug approval for what we now call BCG unresponsive non-muscle invasive bladder cancer to stimulate drug development in this space.

Dr. Colin Dinney:

Now, back in 2014, the FDA approached a group of us and asked us to identify the patient population that would not benefit from additional BCG, and those were patients who had persistent high-grade disease after adequate BCG being defined as having induction BCG plus first maintenance.

It also included patients who initially responded to BCG but then recurred a high-grade papillary disease and individuals who had persistent or progression to T1 disease. That’s that minimally invasive tumor. So, we thought they were especially aggressive subtype.

Dr. Colin Dinney:

So, what does a registration or approval trial look like today? Well, the FDA will accept a single-arm trial. We don’t have to do a randomized trial in this disease space because it was not feasible and there really isn’t an acceptable comparator for a trial.

This is a trial of a mixed population of patients who have carcinoma in situ with or without high-grade Ta or T1 or patients with high-grade Ta and T1 disease only, providing that they meet the stringent definition of BCG unresponsive disease. Now, the FDA has made it clear that the primary endpoint will be the complete response rate for patients with carcinoma in situ, and that the approval will be for carcinoma in situ. Now, once an agent is approved, patients who have Ta and T1 high-grade only could be treated off-label or perhaps the label could be extended to include them, although that hasn’t happened yet.

Dr. Colin Dinney:

Now these efforts have been successful because today the vast majority of clinical trials for patients with non-muscle invasive bladder cancer include patients with BCG unresponsive disease.

Dr. Colin Dinney:

Now, these are the agents that recently have completed registration phase three trials. Pembrolizumab was approved in January 2020. Another drug, Oportuzumab Monatox or Vicinium went to the FDA panel in August of 2021. But issues came up and the production of this drug has been halted. The drug we’re talking about today, Adstiladrin was approved by the FDA in December of 2022. And recently, the combination of ALT 803 and BCG went to the FDA but it was not approved. And right now the company is addressing FDA issues.

Dr. Colin Dinney:

So, what is gene therapy? So, gene therapy really is the delivery of a nucleic acid that’s the building block of your DNA into a host’s cell to treat a disease. Now, gene therapy was originally developed to treat genetic disorders, but today the majority of gene therapy development is for the treatment of cancer.

Dr. Colin Dinney:

And if you think about it, the bladder is an ideal organ for gene therapy. It’s a cavity that allows for direct contact between the vector. The vector is the agent that carries the gene. In our case, it’s adenovirus, and the tumor. We have relatively easy access to urine and tissue to monitor the effects of therapy and to perform correlative studies that might link some biomarker expression to response. We have models available to optimize therapy, but despite the relative advantages of developing gene therapy for bladder cancer, the early trials were disappointing because gene delivery was a real challenge.

Dr. Colin Dinney:

So, the barrier to success was the GAG layer, a glycan layer that lines the urothelium. It’s designed to prevent infections of the bladder by bacteria and viruses, and that was the barrier to effective gene transfer across the urothelium.

Dr. Colin Dinney:

So, we were very fortunate. Early on we worked with a company called Canji. They were the gene therapy subsidiary of Schering, and they identified this drug. They discovered this drug called Syn3. It’s a detergent which made gene therapy possible. So, I’m showing you some early work that they did.

What they did was they took adenovirus containing a gene, not the interferon gene, but a gene called beta-galactosidase. If that gene is expressed by the bladder, if they can effectively transfer that gene to the bladder, it turns the bladder blue. And you can see here that when they administered that vector with the gene, with Syn3, they turned all the bladders blue. Without Syn3, there was no gene transfer. So, Syn3 made all the difference. Syn3 allowed for this gene to be transferred.

This is another experiment they did. They delivered another gene in adenovirus. This was the p53 gene, which you may have heard of. And then, they took sections, and this is with Syn3 and without Syn3. Then they took sections from that bladder and they stained them with immunofluorescent antibodies to p53. So, you can see with Syn3, you’re seeing lots of fluorescence of the cells indicating the expression of p53, not so when they didn’t use it. So, Syn3 was the difference-maker and it was the game-changer for us in developing gene therapy.

Dr. Colin Dinney:

You might ask why did we evaluate interferon alpha gene therapy for bladder cancer. Well, I mean, interferon alpha has pleiotropic antitumor activity. It can kill cells directly through releasing an agent called TRAIL. It’s anti-proliferative. That means it stops cancer cells from dividing. And recently there’s a lot of interest in its immune activities involved in antigen recognition and processing, leading to activation of T-cells that could kill the tumor cells and NK cells and macrophages. But that’s not why we started developing interferon gene therapy.

It actually started because data from Josh Fidler’s lab, he was my mentor at MD Anderson when I started. This was at the era when anti-angiogenesis therapy was in vogue, and the data from his laboratory suggests that interferon alpha had an anti-angiogenic effect in colorectal cancer. So, essentially, they were saying that interferon could actually choke off the tumor’s blood supply because the tumors grow by inducing a blood supply that feeds them nutrients and allows them to grow. If you can stop that, you can theoretically stop the tumor from growing. So, that’s how the development of this began.

Dr. Colin Dinney:

I was studying interferon as an anti-angiogenic agent using a model that we developed for metastatic bladder cancer and seeing if interferon would inhibit angiogenesis, inhibit tumor growth. So, this is histochemical staining for a protein called basic FGF, which promotes blood vessel formation. And you can see with interferon, we’re not seeing any expression of the protein. In the control we’re seeing strong expression. When we counted blood vessels, we also saw that they went down. So, what we found was that systemic interferon, inhibited angiogenesis and the growth of these bladder tumors.

Dr. Colin Dinney:

So, the next series of experiments we asked, does the schedule of interferon influence the response. So, we treated these tumors, these mice with these human tumors with a constant weekly dose of interferon, 70,000 units a week, either once a week bolus of 70,000, 35,000 units twice a week or 10,000 units daily. And we found that the daily interferon was more effective at inhibiting tumor growth.

Dr. Colin Dinney:

We asked ourselves, how can you deliver continuous low-dose interferon alpha? And the answer to that question led us to interferon gene therapy. And this is actually the first work that was published by my group where we showed that interferon gene therapy could inhibit tumor growth by inhibiting angiogenesis. We published this in 2002, 20 years before the drug was approved.

Dr. Colin Dinney:

So, based upon that work, we hypothesized that this potentially could be a new drug for treating patients with non-muscle invasive bladder cancer. We knew that the intravesical interferon protein was largely ineffective because there was insufficient exposure of the tumor to the interferon due to the transient availability after installation. So, this recombinant ad interferon with Syn3 was developed to overcome this limitation.

So, when you infect the bladder, essentially the bladder becomes a bioreactor that produces high sustained levels of interferon that you could measure in the bladder and the urine. So, we collaborated with Canji back in the late ’90s because they had Syn3 and they had vectors that we could use in our experiments.

Dr. Colin Dinney:

So, together starting in 1999, we co-developed interferon alpha gene therapy. Together we showed that ad interferon with Syn3 could inhibit the growth of human bladder cancer growing in mice, and this was accompanied by sustained high levels of interferon in the urine and the tissues.

We didn’t think that one dose would be sufficient. So, we did some experiments to see about the timing of re-dosing, and we found that we had to wait out to 90 days to re-dose these animals in order to restore urine interferon alpha levels in the urine. And this is how the schedule for the drug was developed. It came directly from this experiment, and that’s why the schedule for Adstiladrin is one intravesical therapy every 90 days or every three months. We also found that it had both a direct effect and a bystander effect. And a bystander effect is the effect of killing a tumor cell that isn’t been infected by the virus.

Now, it’s virtually impossible to infect every single cell in the bladder with the viral treatment. However, we’re very fortunate that interferon has a very rich bystander effect that’s mediated through its anti-angiogenic effect through TRAIL that’s released into the urine and can kill neighboring cells, and also by its role in signaling immune system. We did not see any major toxicity in any preclinical studies, no germline toxicities. And so, the data suggested and supported the translation of this work in the lab into the clinic.

Dr. Colin Dinney:

So, this is the vector we’re using. It’s an adenovirus type five. It’s a first generation adenovirus. We construct it so that it has the interferon alfa, it expresses the interferon alfa gene in its DNA. We then would instill this vector with a Syn3 into the bladder. The virus will penetrate a cell, either a normal cell or a cancer cell and releasing its DNA with interferon gene, which is taken up into the nucleus. The gene is then transcribed in the nucleus, and the protein is translated in the cytoplasm of the cell within the cell and released intracellularly, which can kill that cell or into the microenvironment.

Dr. Colin Dinney:

And so, using that vector, that drug, we did a phase one study.

This was sponsored by Schering, and this was a standard dose-escalating phase one trial for recurrent high-grade non-muscle invasive bladder cancer after BCG. We had not yet coined the term BCG unresponsive disease. What we found in this phase one study was that interferon alpha gene therapy was safe. We did not encounter any dose-limiting toxicity, and we were able to demonstrate effective gene transfer by measuring interferon levels in the urine. So, we were able to actually infect the bladder and have the bladder produce interferon. Now, while this was a phase one study, the clinical results were promising and together everything supported a phase two trial.

Dr. Colin Dinney:

Now there have been a lot of bumps in the road along the development of this drug. And at that point in time, Schering was brought up by Merck. Merck had other priorities and put the product on the shelf. And it sat on the shelf for about a year and a half to two years until FKD, a small gene therapy company in Finland licensed the product from Merck in 2011, after the CEO talked to me about the drug. At around the same time, the SUO, the Society of Urological Oncology, formed the SUO’s Clinical Trials Consortium (CTC). I was the founding president of that organization and I was the lead of the bladder committee.

And our goal was to develop trials for urologists to get involved in clinical research. So, we needed a clinical trial to jumpstart the SUO-CTC. FKD needed a clinical trials group to run their phase two trial. And so, I negotiated with them such that the SUO-CTC would be the exclusive site for their phase two trial.

Dr. Colin Dinney:

And we conducted a phase two trial, the SUO-CTC, and we reported a 30% complete response rate for CIS and a 50% high-grade recurrence-free survival for high-grade Ta and T1 at 12 months. And this 30% CR rate is about threefold higher than was reported with valrubicin.

We also found that the drug was well tolerated with manageable adverse events. And in fact, we published this in a high impact journal, the Journal of Clinical Oncology. And in fact, this article was selected as one of the top JCU articles for GU malignancies in 2011. And the promising data supported a phase three registration trial.

Dr. Colin Dinney:

So, this is the phase three trial of Adstiladrin. This is the trial that led to the approval by the FDA.

Dr. Colin Dinney:

And we reported as a primary endpoint, a 53% complete response rate for carcinoma in situ at three months. And in those patients with carcinoma in situ who achieved a CR, about half those patients maintained that high grade recurrence-free survival through 12 months. They didn’t recur through the 12-month period. For patients with high grade Ta or T1 disease, 73% were high grade recurrence-free at three months, and 60% maintained that status at 12 months.

And that was important because late recurrences beyond 12 months were very rare. And so, recurrence-free survival was fairly stable after that point. Now, our study differed from most of them in the same space that we’re in. We had a mandated end-of-study biopsy and we found occult disease in 10% of the patients who underwent the biopsy. These have been patients that we would’ve considered to have had been disease-free based on clinical grounds, cystoscopy and the results of cytology. So, we found disease in 10%.

Now, of the patients on our trial, eight patients are 5% progressed. That’s not a high level. No patients died from bladder cancer. But of the eight patients that progressed, six of the eight or 75% had a history of T1 high grade. And now again, that’s the lesion that’s minimally invasive, and in fact, it’s notoriously understaged. So, it’s likely that some of the patients who came on the trial had occult muscle-invasive disease at the time that they were treated, and they actually did not progress, but they had the disease when they started.

Dr. Colin Dinney:

Now of course, the other goal of the study is to avoid a radical cystectomy. Forty-three patients or 29% ultimately underwent cystectomy. And the cystectomy-free survival was 65% at two years. If you looked at those patients who underwent cystectomy on this trial, only five of 43 or 12% upstaged to having muscle-invasive disease or greater. So, I think that points to the high quality of the study and then the investigators on the trial. Because we looked at our patients who were referred to MD Anderson. So, they came to MD Anderson with BCG unresponsive disease for a radical cystectomy.

And when we did the radical cystectomy, we found that 44% were upstaged to pT2 at cystectomy. So, you can see the high quality of the investigators that did this trial because the risk of progression was much lower.

Dr. Colin Dinney:

Now, there were adverse events secondary to the treatment, and study drug, the Adstiladrin, or procedure-related adverse events occurred to about 70% of our patients. The procedure-related events are related to the catheterization. That’s the procedure.

Fortunately, most of the adverse events were minor. Only three patients or 2% had a serious adverse event, and no patients died from an adverse event secondary to the drug or procedure. And in fact, only three patients or 2% discontinued the study drug secondary to a treatment related adverse event. So, that’s pretty good. That speaks to the tolerability of the agent.

Dr. Colin Dinney:

Now, here are the most common local and systemic adverse events that were seen at least 10% of the patients on the trial. In dark, you can see the local symptoms. Majority were bladder spasms were common, or urinary urgency, blood in the urine, painful urination, urinary tract infection. We also saw systemic side effects such as fatigue, fever, chills, headache, or diarrhea. And these are likely related to the exposure to the low-dose interferon. But luckily, most of these adverse events were transient, lasting only one to two days.

Dr. Colin Dinney:

Now, there are other concerns that you might have about gene therapy, especially when we think about the last couple of years we’ve gone through. Patients and physicians alike share concerns about the safety of adenoviral gene therapy after living through the consequences of transmitted viral disease over the past several years. And there was an unfortunate death of a patient from an overwhelming inflammatory response secondary to the delivery of an extremely high dose of the adenovirus early on. And this temporarily paralyzed the field. I mean, this was an inappropriate treatment. The patient, a young man died from complications from the therapy. So, gene therapy really stopped for a while.

Subsequent studies, including our own, demonstrated that when administered correctly the therapy is safe. We don’t say you’re not at risk for an overwhelming inflammatory response. It’s much safer than you would think.

Dr. Colin Dinney:

Now why is that? Well, also, the adenoviral backbone of Adstiladrin has been changed to make it distinct from the adenoviruses that cause human disease. So, the part of the gene, the virus’s gene that controls replication has been removed so the virus can’t divide. The virus will infect the bladder, release the interferon, and then the virus is gone.  And what does this do? Well, this limits the risk for severe illnesses for patients under treatment and also transmission to close contact, to their close contacts.

Dr. Colin Dinney:

And there’s another theoretical concern, and this is the risk for insertional mutagenesis and a secondary malignancy falling incorporation of viral DNA into the patient’s DNA. Some viruses inserted into your own DNA and they can cause a problem.

A good example of that is the AIDS virus. It is a lentivirus that becomes incorporated into the host’s DNA and causes serious problems. Now, our virus is not incorporated into the host’s DNA. So, this is not a problem. And in fact, we really didn’t even measure any viral DNA in the circulation after intravesical therapy because there’s limited transmission of the virus outside the bladder. So, the virus is not getting outside the bladder. There’s also no risk for germline transmission. You couldn’t transfer the virus to, say, an offspring. That doesn’t happen as well.

Dr. Colin Dinney:

Another concern would be that patients who might have a cold or a flu might have natural antibodies in their circulation that could neutralize the adenovirus and make the gene therapy less effective. Now, this concern has not been borne out by clinical experience. And in fact, we’ve found that generating higher titers of systemic antiviral antibodies actually predicts for a favorable clinical response. So, patients who have more antibodies in their circulation have a better response to the adenoviral gene therapy, likely because they have a more profound immune response to the therapy and an inflammatory response.

Dr. Colin Dinney:

So, just to summarize, we found that on the phase three trial that, acceptable safety and tolerability of Adstiladrin. As I mentioned, most adverse events were transient, lasting one to two days. We only had one grade four adverse event, which was secondary to a urinary tract infection, no grade five drug or procedure-related events. And so, no patients died from an adverse event related to the drug. Fourteen patients or 9% had a total of 26 serious adverse events, but only three of those were drug or procedure related for 2%. And the adverse events that were considered serious, one patient fainted after getting the drug.

And I’m not even really sure this is an adverse event related to the drug, but it was quoted that way by the site PI. Therefore, that’s how it’s recorded. One patient developed sepsis and that was the patient that had the grade four adverse event and one patient had blood in their urine secondary to the catheterization.

Dr. Colin Dinney:

As I mentioned, three patients or 2% stopped treatment because of a treatment-related adverse event. Two of these were bladder spasms and one patient had this benign proliferative bladder growth. It wasn’t the cancer, but they came off the trial. We don’t see any of the immune-related adverse events that characterize drugs like pembrolizumab.

As I said, no treatment-related deaths or even deaths from bladder cancer. And I think one of the more favorable aspects to this drug is this convenient dosing schedule. Patients only need one intravesical therapy every three months. So, based on this, we concluded that Adstiladrin does provide a favorable benefit-risk profile for patients facing cystectomy.

Dr. Colin Dinney:

How does Adstiladrin compare to the other drug that has been recently approved for this indication? That’s pembrolizumab. So, the trials were quite different. So, the Adstiladrin trial, all of the patients were from the US because it was a US-based trial. The pembrolizumab trial was an international trial, and 35% of the patients only were from the US. If you look at the three-month complete response rate for CIS, we reported it to be 53%, where pembro was 41%. But if you looked at the US population, it was only 31%.

The patients that really benefited from pembro were patients that were treated in Asia, in Korea, and in Japan where they have a different definition of BCG unresponsive disease. Some of these patients may not have been considered to be BCG unresponsive in a US population. If you look at the 12-month complete response rate for patients with CIS, we reported 24% with a biopsy, 27% without a biopsy. And for pembrolizumab is 19% without a biopsy. If you look at the 12-month complete response rate in the US population, well, it’s the same. It was 24% in our trial because everybody was from the US.

And for pembrolizumab, if you estimate it based upon the CR rate at three months and the durability data, it comes out to be about 13%, and that’s not much better than valrubicin. And there’s a price to pay for that. You can see that the treatment-related adverse events, grade three and four are 5% with Adstiladrin, 13% with pembro. And serious adverse events, 2% versus 8%. Furthermore, the schedule is a benefit, one intravesical therapy every three months, and it is administered by an urologist who’s very aware of how to manage this disease.

Dr. Colin Dinney:

So, just to summarize then, the efficacy and safety of Adstiladrin was confirmed by the phase three trial. We’re very pleased with the results to date. We do feel we can do better. And how are we going to do that? We’re going to do that, first of all, by improving patient selection. So, either by identifying patient characteristics or biomarkers that predict sensitivity resistance and how will that improve response rates? It’ll improve response rate because we’ll select patients that are likely to respond to treatment.

And our focus is on the development of urine and serum biomarkers so we can avoid a biopsy. We’re also looking at alternative vectors, so other viruses or non-viral vectors that might improve the delivery of the gene and doing so might improve the response. And we’re very interested in developing novel combination strategies, targeting resistance mechanisms through Adstiladrin.

Dr. Colin Dinney:

So, finally, what did it take to get us over the line? Well, really, it took the willingness of our patients to trust us and enroll in these gene therapy trials. It took thousands of hours of work by hundreds of dedicated people, and essentially came down to an effective collaboration between clinical, scientific, regulatory, and corporate leaders at key points in the development of this drug. And of course, we could have done this with the collaboration and the support of the FDA.

Dr. Colin Dinney:

Thank you for your attention and I’d be happy to answer any questions.

Stephanie Chisolm:

All of the people on this call have a much better perspective of the many steps and at the end how many years that you have been working to get this drug as a group collectively to the patients. And I think that it’s really phenomenal because again, for patients who are non-muscle invasive, BCG had been the gold standard. There are few other options, and if that doesn’t work, it’s really challenging. So, this has been wonderful. I want to remind everybody, if you have questions, please drop them in the Q&A box and we will try to get to as many as we can.

I know that there was a question that was submitted that want to just know how do you get the drug. So, what I have is, I’m about to drop into the chat. There’s a phone number for Ferring. That’s the company that is doing this. They have what they call the Early Experience Program, and it’s available mostly at the clinical trial sites and in other places around the country. So, if you want to know more, ask your doctor to find out because they have a website. But this is the phone number you can call, 888-FERRING, F-E-R-R-I-N-G. So, I dropped that in the chat so you can pull that up and make note of it.

Now, let’s get to some of the questions. One question, are there specific mutations that Adstiladrin is more effective against? I know you mentioned CIS in the beginning, but are there other mutations that it seems to work well with?

Dr. Colin Dinney:

That’s a very good question, and it’s really something we’re just starting to look at. We only have experience with the drug in high-grade disease, and high-grade disease is characterized by a specific set of mutations such as p53, RB. There’s a mutation called TERT. There’s other mutations like FGF receptor three and PIK3CA. Those other mutations tend to be found in earlier stage disease, which we have no experience. So, right now, it’s the high-grade tumors that we know that we see responses in. And we haven’t been able yet to distinguish which mutations are prone to predict sensitivity.

We have done some work though to identify potential biomarkers of response. We’ve identified that in patients whose tumors and bladders induce cytokines such as TRAIL or IL-6 have a better response. We started our first studies with a phase two study. The only robust genomic platform we had for urine was microRNA, and there were about seven or eight microRNAs that changed, the expression changed significantly with treatment, but only one that seemed to be associated with response. And that’s let-7f.

We’ve also found that there is one potential alteration, a mutation, it’s a deletion, deletion of a gene called CDKN2A. And this gene is found at the same place in the chromosome as the interferon gene. So, the hypothesis is that these patients will have lost the interferon gene, and for them interferon treatment is gene replacement treatment. So, we are going to be looking at the phase three samples to see if we can corroborate what we found.

Stephanie Chisolm:

Yeah. That’s another good segue to another question. Should patients consider a clinical trial?

Dr. Colin Dinney:

At this point in time, I think that there are some trials that are ongoing. I think that there are drugs that are approved. I think it would depend upon what’s available right now. Generally, a patient should always consider a trial because it’s been shown that the survival of patients that participate on clinical trials is superior to those of the patients that don’t. They’re going to get closer follow-up. They’re going to get closer care and contact, and I think that that’s all associated with an approved survival. We have a couple of drugs that are available now that are approved.

I think that Adstiladrin. I’m biased. You really can’t ask me that, right? I’m biased. What I think is a positive, there’s a document response as good as or better than whatever else has been tested to this point. And it’s safe, and we didn’t see patients progressing or dying from cancer who went on treatment. If you don’t respond to it, you could always go out and try something else. But I do think it is a drug that has its place in the treatment of this disease.

Stephanie Chisolm:

Okay, great.

Dr. Colin Dinney:

But then, I’m biased. Okay?

Stephanie Chisolm:

We’re talking also all clinical trials. There may be other clinical trials that somebody could be eligible for. So, we always try to remind people that clinical trials could be a treatment option and there’s some real benefit to doing that. Not only will it change, no new drugs are approved without that clinical trial evidence, but it can expose you to something that might be more beneficial that’s not currently available. So, they are out there and BCAN does have a clinical trials dashboard that lists all of the bladder cancer clinical trials in the United States that are open and recruiting patients.

Let me move on to some more questions because we have a lot of really good questions. Is papillary mixed grade non-muscle invasive in scope for this discussion or only high grade and or CIS? What about these mixed tumors?

Dr. Colin Dinney:

Right now, even though the approval was only for CIS, the FDA did encourage us to include patients that had high-grade Ta or T1 as well, and even by itself. You have to remember that the definition of BCG unresponsive implies that all these tumors are high-grade, so they’re not low-grade tumors. You could have a mixed tumor that’s predominantly low-grade with some high-grade features. I guess they would potentially be candidates as well. There will be some studies that are going to be done, basically with low-grade tumors to see if it’s effective or not. But right now, I think that the development has been in high-grade disease.

Stephanie Chisolm:

So, if this is not as frequent an installation as BCG, there’s a question in here. Is Adstiladrin similar to BCG in that there might be a recommendation to rotate around to make sure it gets there, or is it just an installation and there’s not as much of an issue with rotating and making sure you’ve reached all the nooks and crannies in somebody’s bladder?

Dr. Colin Dinney:

Yeah, that’s a good question too, but basically, you drain the bladder, the catheter, the bladder’s collapsed. You put in, I think it could be 75 CCs at first then maybe 50 now. So, the bladder is all exposed to the drug. I don’t think it’s as important to have the patient roll around because there’s such a strong bystander effect. And the fact is we drain the bladder so we know that the bladder is being exposed to it.

Stephanie Chisolm:

Okay.

Dr. Colin Dinney:

Also, the thing is that I think it would be hard to have someone roll around with it because also the Syn3 can be a little irritating, and you wouldn’t ask someone, that would be cruel to ask them to roll around if they’re having spasms from their bladder from the Syn3.

Stephanie Chisolm:

Yeah. And is there anything that you can do to help alleviate the spasms? Is there something that you can apply?

Dr. Colin Dinney:

We found in early trials, giving anticholinergics upfront was helpful. B&O suppositories were the best. They’re not available right now, but they were the best. But now we use other drugs such as Levsin, those things. But yeah, we found that we made it more tolerable. Midway through phase one and phase two, we realized that we could improve the delivery by giving anticholinergic first to settle the bladder down, at least to some extent, and people could hold it longer.

Stephanie Chisolm:

Right. Well, here’s a really, it’s the question on everybody’s mind. How soon after you start this process with Adstiladrin is a patient going to know that the therapy’s effective? Is it usually right away? Do you have to do a couple of installations before you really see anything? Are there biomarkers or anything else that you can monitor to say, “Yeah, it’s looking good, it’s encouraging?”

Dr. Colin Dinney:

It’s interesting. We looked at a lot of biomarkers. For instance, we looked at the interferon levels to see if interferon levels corresponded with response. The interferon was generating the urine. Turned out that it didn’t because even in people who responded in those that didn’t, the majority had levels at a certain level, which was 5000 units per mil. When you got above that, we were enriched for patients that were going to respond. So, those who induce high levels are responders. It’s like anything else. We are looking at predictive biomarkers to see if they can correlate with response. So, we are doing that and we are collecting urine at sentinel moments during the course of treatment.

We found, for instance, that in our phase two trial, that if the person, if their bladder started producing a cytokine called IL-6, we can identify that by day four. And that patient was likely to have a response. I think moving forward, we’re going to have these assays that we can do in real time, and they’re likely going to be urine assays because it’s a lot easier and you don’t have to do a biopsy. And you can look at those urine assays and predict how that person could do. What goes hand in hand with that is developing combination therapies that are targeting resistance mechanisms. So, these are genes or pathways that pop up in people that don’t respond.

A very good example. So, one of the consequences of, for instance, interferon treatment is upregulation of PD-L1 on the tumor cells. Now, PD-L1 is a biomarker that can lead to immune exhaustion because what it is, is the body’s way of trying to prevent autoimmunity from the interferon. And that can be associated with resistance. What we’ve noted in preclinical studies is that combining the gene therapy with a checkpoint inhibitor such as pembrolizumab will actually improve the response and will treat those patients who are going to recur through that mechanism.

And I think we’re trying to develop assays so we can analyze this in real time and see if we can predict early on who’s likely to respond, who’s likely not. That’s just an example of a targetable alteration that comes up after treatment.

Stephanie Chisolm:

Yeah, I have a question about effectiveness as compared to… hang on one second, compares to gemcitabine and docetaxel.

Dr. Colin Dinney:

That’s a very good question. I think docetaxel and gemcitabine have activity, but they haven’t been tested at the same population. It’s a mixed population of patients that would mostly be considered to be BCG exposed. So, they look like BCG unresponsive patients, but they, for the most part, don’t fit the strict definition of BCG unresponsive disease so that their natural history is probably a little bit more favorable. But that combination does have activity, and I’ve used it when we don’t have a protocol ongoing.

We’ve used it to treat these individuals as well who don’t want to have their bladder, I mean whenever I see someone with BCG unresponsive disease, even though I’ve been involved in the development of a drug, I still recommend a radical cystectomy because from an oncologic perspective, it’s the safest treatment.

Stephanie Chisolm:

That’s a good point to make. Is Adstiladrin and this whole gene therapy similar to BCG that you might have a course, maybe you’re on there for the year, but then you need maintenance? Is it lifelong, you’re always going to have for the rest of your life quarterly treatments?

Dr. Colin Dinney:

Those are good questions. The real answer is I don’t know, but basically, we treat them once every three months. Now in our trial, I mean, we were one of the first trials out of the blocks, and I was really conservative. I didn’t want to risk somebody’s cancer progressing and patients getting metastatic disease to be on a trial that I was promoting. So, if patients had a recurrence at three months, we took them off treatment. Subsequent trials have actually used the BCG definition of refractory, and actually will not declare defeat until it had gone six months. In that case, for us, it would be two treatments.

Because if you look at the trials that are ongoing, you can improve the response rate probably by another 25% by giving a second dose. So, I think today, if I had to redo it, I would give a second dose at three months for individuals who had recurrence, not if they progressed, had a recurrence, and then go from there. And we’d evaluate the person every three months after that.

Stephanie Chisolm:

Here’s a question that came in after you were done, but if you could just reiterate what again is the definition of BCG unresponsive? How do you define that from a patient’s perspective?

Dr. Colin Dinney:

Okay. There’s three criteria. One is what’s called BCG refractory. So, these are individuals who would receive optimal BCG. They would receive induction therapy, at least five of six induction courses, and then get at least two of three of the first maintenance. And if those individuals had persistent high-grade disease, then they would be considered to be BCG unresponsive. If you take another patient and they respond to BCG but then later recur, then those patients would also be considered to be BCG. They’d be the relapse. They’d formally been considered to be relapsed.

And then, because of the concern for progression for patients with T1 disease, it also includes individuals who had three months after induction therapy only, not allowing for maintenance, have persistent T1 disease or have progressed to T1 disease. So, those are the three criteria that identify BCG unresponsive disease today, and it’s a strict criteria.

Stephanie Chisolm:

So, you still have to go through all the trouble of having BCG and seeing if it works and everything before you really could be eligible unless you enroll in one of the clinical trials that is moving you forward.

Dr. Colin Dinney:

That’s correct, yeah. At this point, that’s the indication for the drug. Obviously, there’s going to be efforts to move the drug up higher in the disease state, but those efforts are being designed.

Stephanie Chisolm:

Remember to call 888-F-E-R-R-I-N-G and speak to the team at Ferring, and they can give you information about the Early Experience Program and tell you how to share with your doctor how they can get involved. And they are working on the manufacturing facility, so I think they’re expecting.

It’s not going to take too-too long to get up to full speed, but they do have this drug and they’re making it available at most of those clinical trial sites. And there were quite a few of them. Let me see. Oh, will it be possible to have a treatment therapy with a combination of BCG and Adstiladrin? Is that something anybody’s looking into?

Dr. Colin Dinney:

That’s also a good idea. There’s a lot of trials that combine BCG with something else, and BCG would be one of the attractive drugs to combine with Adstiladrin. They may overlap somewhat in their mechanisms of action, but it would be interesting in looking at that. There are other combinations that look promising as well. For instance, a combination with a checkpoint inhibitor that looks very, very promising. I think that would be something that I would think about in individuals who don’t respond to Adstiladrin consider adding another drug onto it. You could consider adding it with chemotherapeutic agents. So, there’s a lot of different combinations to think about.

So, once the manufacturing is up to speed, then we can start pursuing some of those interesting ideas.

Stephanie Chisolm:

Great. Here’s another question for you. This comes from Canada. Are there trials going on in other countries that are using Adstiladrin?

Dr. Colin Dinney:

I believe that there is a trial ongoing in Japan, a trial of BCG unresponsive disease. I’m not aware of another trial that’s ongoing right now. Again, I think that we have to make sure we have enough drug available to do these trials, and I think the trials will start opening up shortly once the manufacturing is up to speed.

Stephanie Chisolm:

I think that this is great. We still have a lot of really good questions. I’m just trying to filter through so I can make sure I hit on all the key points. Given the BCG shortage, many non-muscle invasive patients receiving other therapies like gemcitabine, docetaxel, what if they don’t respond to those? Are they then eligible since they couldn’t get BCG to be refractory in the first place?

Dr. Colin Dinney:

That’s the same question that’s plaguing us as well, right? Right now, letter of the law would say no. It is possible that when the drug is commercially available that practitioners could prescribe it assuming that the insurance will pay for it. But yeah, those are the critical questions for individuals who recur despite our standard upfront therapies. Right now they wouldn’t be a candidate because it’s a strict approval. People can be treated off-label. And so, I think that’s possible.

Stephanie Chisolm:

So, the off-label availability’s probably going to be a little bit more accessible once they’re up to speed fully, because right now they’re still doing that Early Experience Program where they have limited supply.

Dr. Colin Dinney:

Yeah.

Stephanie Chisolm:

Okay. All right. It’s all good things to know. Somebody asked if you could explain again what the Syn3 component is in this.

Dr. Colin Dinney:

Okay. We thought that gene therapy was a slam dunk for bladder cancer because we had good exposure of the urethane, the tumor to whatever we put in the bladder. We found out that wasn’t the case, and we found out that the barrier, the glycan barrier was preventing infection. So, there was a lot of work done to try to improve infection by altering the viruses, by doing other things. And one of the approaches was by using chemicals. And so, there was a chemical that they looked at, it was called Big CHAP, and this was worked done by Schering. They used Big CHAP as a detergent and they combined it with a gene and they administered it.

And they found out that it worked to a certain extent, but there was differences in… there was two companies, Big CHAPs they looked at. And one worked and one didn’t. So, they looked at the one that worked, and this is ironic, and they actually found out that the Syn3 was actually a contaminant in the effect of a Big CHAP. And then, they had developed that. It’s a detergent. And how it works, well, we don’t really know for sure exactly how it works. We haven’t looked at mechanism, but it alters the properties of the lining of the bladder to allow the virus to infect the bladder. So, probably disrupts the GAG layer somewhat.

Stephanie Chisolm:

Okay. Let’s see. Is gene therapy an option if the patient is not eligible for BCG, maybe TA or recurrent disease? What about, again, going back to… you’ve already answered the question about comparing to non-BCG treatments, but if they’re not eligible for that, maybe they have a reaction or something else?

Dr. Colin Dinney:

I think those individuals would be a candidate for treatment off-label. I think you can make a strong claim for that because they can’t receive BCG. It hasn’t been tested in the BCG intolerant population, but you would think that it actually might even be more effective because you’re giving it early on, but we don’t have the data. But I think that you could go for an off-label usage of it in that circumstance.

Stephanie Chisolm:

Here’s a question. From what I’ve read, there appears to be a cohort of CIS patients, carcinoma in situ, maybe 15% to 20% who have very aggressive tumors with high rates of progression and metastasis. How do we determine if a patient is in this cohort, and if so, should they go directly to cystectomy bladder removal or consider one of these trials like this Adstiladrin trial?

Dr. Colin Dinney:

As I said, BCG unresponsive disease, I always recommend a radical cystectomy as the safest oncological approach, but I don’t think that there’s, I mean carcinoma in situ, we know the genetic alterations associated with them. And I don’t think you can distinguish between one and the other. We know that carcinoma in situ that’s associated with high-grade T1 disease tends to have a worse prognosis. So, in that scenario, you might be a little more cautious and I would recommend a radical cystectomy for someone in that scenario. I don’t think we have the knowledge of exactly what genetic alterations or mutations will make you unresponsive to the therapy.

Stephanie Chisolm:

Okey-doke. Well, I think we’re coming up on time. I think we have time for one more question. Let’s see. Would Adstiladrin be an option for someone who is unable to continue BCG due to severe inflammation but they haven’t yet had a recurrence? Maybe they had to truncate their BCG.

Dr. Colin Dinney:

I would tend to watch that individual. This is not an infrequent event. Our clinical practices see this all the time. And we need to look closely at whether or not those individuals actually do pretty well because they’ve had such a robust inflammatory response that the tumors have been destroyed and it’s been effective. So, my sense is that some of these people do pretty well and I would not want to treat them until we had evidence of a recurrence.

Stephanie Chisolm:

Yeah. Okay. Well, that’s really good to know. There’s great promise. There’s more work to be done to really understand how this fits into the great schema of all non-muscle invasive treatments. But the nice thing is there are options, and that is something that we didn’t have five years ago. We didn’t have 15 years ago. We’ve had BCG as the standard of care for, what, 40 something years right now, and we’re still dealing with the shortage.

I do want to say thank you, Dr. Dinney. This has been phenomenal.