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Colin Dinney: Well, thank you the organized committee for inviting me and also Neal for inviting me to talk at this meeting and discuss the explosion of intravesical therapy for non-muscle invasive bladder cancer.

Here are my disclosures that are relevant to this presentation.

Now, if you want to understand the explosion of therapy, you got to go back to 2012. At that time the history of drug development for non muscle invasive bladder cancer was dismal. Only four agents had been approved for the treatment of this disease since 1959, and only one of those drugs, BCG, was commonly used. So in 2012, the SUO, the AUA, and the FDA launched a collaborative effort to address this deficiency. The initial focus was to define a pathway for drug registration for what is now known as BCG Unresponsive disease and stimulate activity in this space. Now at the same time, Bioniche announced the closing of the second randomized trial with Urocidin, indicating that randomized trials weren't feasible in this patient population.

Trial designs evolved over time. The FDA would accept a single arm trial with a mixed population of patients as long as they met the stringent definition of BCG Unresponsive disease. The primary endpoint for these trials was a CR rate for patients with CIS and the FDA made clear that the approval would be for CIS, but patients who had high grade Ta and T1 one disease, once the agent was approved, they could extend the label to cover those patients or they could be treated off label.

So you can see this activity was effective. And now most trials in this space have patients with BCG Unresponsive disease as part of the patient population.

A lot of alternatives to a cystectomy have been under development. Quite common is BCG plus something else. Other immunotherapies, toxins, chemotherapy such as docetaxel and gemcitabine, and gene therapy. And three intravesical agents have gone through phase three for BGC Unresponsive disease. Vicinium, the development has been halted because of issues that arose during the FDA review ALT 803 and BCG and Nadofaragene.

So first, let's talk about the QUILT 303 trial. This is the trial of N-803 in combination with BCG and N-803 is a IL-15 superagonist that induces specific subpopulations of T-cells and NK cells that enhance the activity of BCG. So the drug is given with BCG. So patients are given an induction course of the two agents and then non-responders are eligible for a second induction course, and then two years of maintenance.

The results have been pretty good. This is the results for the Cohort A, which would be the BCG Unresponsive population. A complete response rate of 71%. Very durable and well-tolerated. In fact, looks like it's better tolerated than BCG alone.

This is the results for the Cohort B, which for the most part would be their high grade Ta/T1 disease. You can see a smattering of CIS in there. And again, the 12-month disease-free survival, 55% is pretty good. See the durability there. Again, well tolerated and treatment was discontinued in 6% of the patients, but no SAEs.

Now it's interesting because the drug is relatively inactive as a single agent, but in combination with BCG, it compares favorably to other FDA-approved drugs such as pembrolizumab, which was approved in this space with a CR rate of 41%. But there are certain caveats with respect to the study design that you need to consider when comparing across these trials. First of all, it was a combination trial with BCG and there's no BCG comparator. And second, re-treatment was allowed at three months for non-responders. That improved the CR rate by 25%. And if you go back to the pembrolizumab trial, patients who were non-responders at three months were taken off trial. And it's possible if they'd been treated, you might have seen a complete response rate of about 65% there.

Now the final one that has been through phase three is Nadofaragene. The registration trial was performed by the Society of Urological Oncology Clinical Trials Consortium.

This is the primary endpoint for Nadofaragene was a 53% complete response rate for CS at three months. Again, like pembrolizumab, all complete response were at three months because those patients who didn't respond were taken off trial. But most of those patients or half those patients had a CR at three months, maintained that through a year. For patients with high grade Ta/T1 disease, 73% were high grade recurrence free at three months and 60% maintained that at one year. That's important because late recurrences beyond 12 months were rare. This study was a little bit different than others. There was a mandated end of study biopsy, which identified occult disease in about 10% of the patients that went on to the 12 month biopsy. Eight patients or 5% progressed, but six or 75% of those patients had history of T1 high grade. So it's likely that some of those patients had advanced disease at the time of the chemo trial because of the under staging that occurs in T1 high grade.

There's acceptable safety and tolerability. Only one Grade 4 treatment related adverse event. This was actually sepsis secondary of the catheterization. No Grade 5 treatment or drug or procedural related adverse events. Only three treatments, serious adverse events. And only three patients or 2% stopped treatment because of an adverse event. No pattern of immune related adverse events, and no deaths from bladder cancer. And I want to point out the convenient dosing schedule. Patients received one intravesical therapy every three months and that was especially important during the Covid pandemic when you're trying to limit the patient's visits to the hospital.

Now, when you're considering across these single arm trials, I just want to point out again that there's some specific considerations you need to take into account. First of all, the time point for defining a CR or high grade recurrence-free survival after the first dose of a study drug will determine the response rate. The complete response rate was improved as much as 25% by using a six month endpoint that allows for re-treatment of non-responders at three months. When you're comparing against trials that employ a combination therapy in which often with BCG versus those with single monotherapy, you need to consider the contribution of a second drug to the response rate. We know that even in BCG Unresponsive disease, at least 20% of patients would achieve a CR with BCG alone. I think in these trials you need to consider an end of study biopsy is it identifies occult disease and minimizes investigator bias.

Now, there's a lot of activity in this space and a lot of all these combinations are a combination of IO plus BCG or something else with BCG. I think one of these studies that looks promising is Cold Genysis' trial with their oncolytic adenovirus with pembrolizumab. The preliminary results are very, very, very promising.

Now what about BCG naive disease? Yes. Houston, we have a problem. That's the BCG shortage.

Now these are agents under development for BCG naive disease. And it was thought that and hoped that the development of these new agents would actually address the shortage, but for the most part it doesn't. Because for the most part, these trials used BCG in combination with an IO or with something else. I think the one trial that may address the BCG shortage is the PRIME study. And this is a SWOG study. Rob Svatek is the PI. Patients with high risk non-muscle invasive bladder cancer were randomized to receiving either intravesical TICE BCG, intravesical Tokyo BCG, a new strain, or they were primed first with Tokyo BCG and then received intravesical Tokyo BCG. And while there may be no difference in the high grade recurrence-free survival between these three arms, this trial may lead to the approval of another strain of BCG in the United States. That would be very, very important.

Now, there's also interest in another population. This is the BCG exposed population. These would be called the BCG failure population. And these are patients who have high grade persistent recurrent non-muscle invasive disease within 24 months of the last dose of BCG but don't meet the stringent definition of BCG Unresponsive. So they just don't meet the definition. And they were the subject of an FDA workshop in 2021. The recommendations were for randomized trials in this patient population. There are several randomized trials ongoing right now. We have Noah Hahn's ADAPT trial, multiple IO+BCG, and there's a trial with using Erdafitinib in this space as well.

So just to summarize, the explosion of drug development for BCG Unresponsive disease has extended to the naive state and the BCG exposed state. And this is really due to the active engagement and collaboration with the FDA. It wouldn't have happened without that. Most trials in the United States combined BCG with something else and won't address the BCG shortage. Approval of the Tokyo strain would alleviate the risk to patients imposed by the restricted access to BCG. I think interest continues in filling the BCG exposed space, and I think we're also going to start to see some activity in intermediate risk non-muscle invasive disease.

I finally want to leave you the words but wise man. This holds true today. "It ain't what you don't know that gets you into trouble. It's what you know for sure that just ain't so." Thank you.