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Sam Chang: Hi, my name is Sam Chang, and I'm a urologist in Nashville, Tennessee. We're actually quite fortunate to have Mark Tyson from the Mayo Clinic in Scottsdale. Mark is going to go over the presentation he's giving at the AUA 2024 plenary session, which is the practice-changing, paradigm-shifting plenary session, looking at the BOND-003 trial. So Mark, thank you for spending some time with us. Give us some highlights of this important presentation that you'll be giving.

Mark Tyson: First of all, thank you for having me, Dr. Chang. I'm delighted to be here with you. At a top level, I think it's worth reviewing the mechanism of action for creto. Cretostimogene grenadenorepvec is the drug that's being studied in BOND-003. It has a dual threat of action. The mechanism works by directly killing tumor cells through exploiting a biological mechanism, specifically Rb pathway-deficient tumor cells, which most bladder cancer tumors are. In those cells, the creto can replicate, resulting in direct tumor killing from replication. And then there's also a secondary immunotherapeutic mechanism of action where these antigens are released, and it potentiates this immunotherapeutic effect.

Sam Chang: So you have a combination of cell kill as well as actually increasing your immune response.

Mark Tyson: Right. Yeah. And then, actually, the complementary DNA for GM-CSF is encoded as well, so that transgene is expressed—

Sam Chang: Which stimulates—

Mark Tyson: Right. So it kind of potentiates it. At a top line, we observed a complete response rate at any time point for all comers based upon central path review of 75.2%. The confidence interval is pretty tight, 65-83%. So, pretty impressive data there.

Sam Chang: For BCG unresponsive?

Mark Tyson: BCG unresponsive CIS.

Sam Chang: Monotherapy with cretostimogene.

Mark Tyson: Correct, yeah. So BCG unresponsive monotherapy, intravesical therapy, with cretostimogene. Pretty impressive complete response rates at any time points. Also, durable. We observed that of the 35 complete responders who had hit that 12-month time point, 29 of them, or 83% of them, maintained their CR beyond 12 months. Another really interesting finding, 'cause that's what the FDA cares about, really. I mean, it's nice to have a complete response at any time point of 75%, but if that response isn't durable, then it's really not meaningful.

Sam Chang: And then, tell us the treatment schedule then with the cretostimogene.

Mark Tyson: Right. It's once a week for 6 weeks, followed by a repeat induction for non-responders, and then maintenance for responders. And the maintenance is like BCG every 3 weeks, or once a week for 3 weeks at—

Sam Chang: Month 3, month 6, and then—

Mark Tyson: 12, 18, and then from there, it's every 6 months. The other really interesting thing, observation we observed with creto relates to that secondary induction. We found that 54% of patients who didn't initially respond to that first induction course went on to respond to that second induction course.

Sam Chang: So, basically half.

Mark Tyson: Yeah. And it speaks to that oncolytic immunotherapy mechanism, that dual threat, where like with re-induction of BCG, the immune system switches from innate to adaptive.

Sam Chang: And truly, I wouldn't even call them non-responders to the drug. It really should be that initial course followed by, if there's that initial evaluation, if there is or isn't disease, that second course will be important, because that really helps determine down the line who's going to respond or who doesn't.

Mark Tyson: That's right.

Sam Chang: And then, importantly then, just like you said, the [inaudible 00:03:20] response of basically three-quarters of the CRs, basically the vast majority of them, 80% plus, continue to have that at the 12-month mark, right?

Mark Tyson: Yeah. Well, the data set's not entirely mature. So, there are 22 patients still pending. So, we'll see how the data matures.

Sam Chang: Sure. At this point, it is variable. It could go actually much longer at this point.

Mark Tyson: Right. And so, I'm really only speaking to those 35 complete responders for which we have hit that—

Sam Chang: At that one-year follow-up.

Mark Tyson: Yes.

Sam Chang: Got it. Got it. And then, so, when you look at this intravesical medication, tell me about the side effect profile.

Mark Tyson: Right. So, it's mostly urinary symptoms, grade 1, grade 2 urinary symptoms, frequency, urgency, sometimes pain with urination, or hematuria. We didn't observe any grade 3 treatment-related adverse events. There were a couple of grade 2 serious events, cystitis in one patient that resolved with some antibiotics, and hematuria in another. And there was only one patient that discontinued the trial, and that was due to an unrelated adverse event.

Sam Chang: So, very well tolerated it seems. The safety profile, obviously, looks quite good.

Mark Tyson: Yeah.

Sam Chang: And an agent that may cause symptomatology that we have seen with multiple other intravesical agents.

Mark Tyson: Right.

Sam Chang: So nothing that seems to be outlying. Yeah.

Mark Tyson: Right. 94.5% of patients in BOND-003 completed all of their treatment or protocol-directed treatments.

Sam Chang: Okay. And was that a one-year or 18 months? What was the goal then in terms of treatment length?

Mark Tyson: So, up until their recurrence—

Sam Chang: Sure.

Mark Tyson: ... Or up until they completed the protocol.

Sam Chang: Okay. And the protocol was up to 18 months?

Mark Tyson: Up to 18 months.

Sam Chang: 18 months.

Mark Tyson: But we do have a treatment extension phase now, years 2 and 3, and I have a few patients entering this now where they get maintenance every 6 months in years 2 and 3. So we've extended the maintenance protocol for complete responders. The other thing too, you asked about side effects during the instillation process. Most patients, during the actual instillation and dwell, no, pretty much all of them, tolerated it. There weren't any people that could not tolerate the instillation and dwell.

Sam Chang: And so, nitty-gritty granular placement of this agent historically has required some pontification or pre-treatment of the bladder.

Mark Tyson: Right.

Sam Chang: But this is now a single type of treatment? Is that correct?

Mark Tyson: Right.

Sam Chang: Okay.

Mark Tyson: So, it's been simplified. For BOND-003, it was a DDM wash and then a DDM dwell, followed by a saline wash, and then the creto dwell, so the process was actually quite laborious.

Sam Chang: Right.

Mark Tyson: We've implemented changes for PIVOT-006 and BOND-003 moving forward—

Sam Chang: Yes.

Mark Tyson: —where, in Cohort P, which we haven't talked about yet, it's much simpler. It's a 15-minute DDM dwell and then a creto dwell.

Sam Chang: And then creto dwell. With the same catheter?

Mark Tyson: It can be instilled by nurses, it can be instilled by medical assistants. It's pretty easy. The workflow is very familiar for urologists.

Sam Chang: Great. Well, Mark, this trial, everybody has been quite anxious to see the results. Clearly, there are other trials ongoing. Some of those will be presented at this year's AUA as well—

Mark Tyson: Yeah.

Sam Chang: —in terms of trials in progress. Really, really appreciate all your efforts in terms of moving the field ahead with non-muscle invasive bladder cancer therapies. And thanks for spending some time with us. Very exciting times.

Mark Tyson: Well, I appreciate you including me, and I have you to thank for the mentorship and getting me to where I am, so I appreciate you.

Sam Chang: Yeah.

Mark Tyson: Thank you very much.

Sam Chang: Thanks very much, Mark. All right, take care.