Sam Chang: Hi, this is Sam Chang from Nashville, Tennessee. I'm a urologist at Vanderbilt University Medical Center, and we're quite fortunate to have Dr. Sandeep Bobby Reddy, who's the Chief Medical Officer at ImmunityBio. This company has had a recent FDA approval of an agent called Anktiva, which is a super agonist IL-15. When combined with BCG, it has been approved in the BCG-unresponsive space. So it's an exciting time for this company and for this agent, and we've asked Bobby Reddy to join us to actually talk about other clinical trials, other next steps, and possible indications for this medication. So Bobby, thanks so much for spending time with us. I need to disclose that I've been an investigator using this agent and obviously I'm excited about it, but we really look forward to seeing what the science holds for the next iterations of this drug.

Bobby Reddy: Well, thank you, Sam, I appreciate it. I appreciate the invitation and I'm happy to present some of the data that was presented at AUA recently. What we're talking about today is, as Dr. Chang mentioned, the combination of Anktiva or N-803 with BCG for patients with BCG-naive non-muscle invasive bladder cancer, both carcinoma in situ and papillary disease. This trial is called QUILT 2.005, and the underlying rationale is that we're very aware that BCG has effectiveness. It is obviously the standard of care and has been for quite some time. One of the problems, of course, is that ultimately a good number, perhaps up to 50%, 40 to 50% of patients who receive BCG will recur at some point, some early, some late, but will ultimately recur, and what can we do to try to prevent that recurrence?

When BCG is delivered to the bladder, what we know now is that there is the establishment of trained immune memory. Certainly, when I was in school what we were taught is that it is a non-specific immune activation, but that's actually not true. It's a highly specific immune activation, acting through stimulation of trained immune memory of natural killer cells, monocytes, macrophages, basically the innate immune system as well as the adaptive immune system, both parts coming together to be effective in clearance of the bacteria and then, as a result, clearance of the tumor as well. What's the rationale for the combination of the two? How does Anktiva work?

Well, it's a first-in-class IL-15 super agonist. The green egg portion here that you can see on the top of the molecule is the cytokine, the IL-15, but it has a mutation and this mutation, this N72D single point mutation, gives it a tenfold greater binding affinity to the target receptors, the native IL-15. And then, the IL-15 receptor alpha presents the cytokine to the receptors in such a manner that stereo-chemically it only binds to the activating receptors, i.e., the IL-2 beta gamma receptors which are present on NK cells and T cells, and it does this without activating regulatory T-cells. So you can see in the bottom figure from a paper where this was given subcutaneously, from a paper in Blood, where you see an eightfold increase in NK cell activity, a fourfold increase in CD-8 positive T-cell activity, but no increase in regulatory T-cells.

So consequently, what's really happening is that on the far left what we can see is that in nature when we have, say, a BCG stimulus or some other stimulus, some other infectious stimulus or cancer stimulus, dendritic cells will become activated. And certainly with a BCG infection we will see stimulation of the dendritic cell through the toll-like receptor, at which point cytokines will be released. Cytokines such as interferon gamma, and that will directly stimulate the natural killer cells to proliferate. In addition, in the case of, say, an activated dendritic cell, that bacteria will be chopped up into pieces, the antigens will be processed on its surface through MHC and will then engage with the T-cell receptor activating the T-cells.

So how does Anktiva help with this? Well, as you can see from the structure, it's very similar to the receptors that are present on the activated dendritic cells that are presenting IL-15 to the immune effector cells. So in the third column, what's happening is that the Anktiva is mimicking the dendritic cell and the immune effector cells, they don't know the difference. And so, in a normal process what would happen is that the dendritic cell would activate these cells to proliferate and they would do their thing and, in this circumstance, the Anktiva effectively does the same thing. The NK cells, the T cells, they both see the Anktiva and they believe that this is effectively an activated dendritic cell, and so their natural response is to proliferate and activate, and as a result, we have an enhancement of that immune function.

So, BCG alone can enhance the immune function through the activation of dendritic cells, but the addition of Anktiva can cause a further and more significant enhancement. So based on this concept, it seemed logical to combine this with BCG in the setting of non-muscle invasive bladder cancer, and what we see here is the Phase I experience. And, I think what's obviously quite striking is that we have 100% of the patients being treated, so at all dose levels a response. We have both papillary and carcinoma in situ here, but, importantly, it's durable. We know that BCG is an effective therapy, and so having responses at six months would not potentially be that unusual, but to have them all be durable, 100% durable at 24 months is rather striking. And, we now have close to nine years of follow-up data and six of the nine patients remain in a 100% disease-free status.

Two died of natural causes and one was lost to follow-up, so truly of the six that are known in terms of follow-up, six out of six remain disease-free nine years later. There are early interim data, and this is a bit unusual when you have an ongoing randomized trial, but the reason that we can present this is that this was part of a request by the FDA when we submitted for breakthrough designation. And so, I show this just to give potential investigators some, I think, comfort in knowing that there is an underlying efficacy signal and, hopefully also, patients who would be enrolled in this trial. So what we see is there's a difference between the BCG alone arm, which is in gray, and the BCG plus Anktiva arm in blue, at CR at any time. And actually, this reaches statistical significance at nine months, so small numbers, early data, I think just provocative, but also to give comfort that there seems to be an efficacy signal that could be very meaningful for these patients.

The design is pretty straightforward. This is a one-to-one randomization. There are two arms. One arm is BCG alone, the other arm is BCG plus N-803. In addition, there are two cohorts, so there's a cohort A, which is carcinoma in situ and cohort B, which is high-grade papillary disease. The current state of affairs is that we are enrolling these cohorts sequentially because there's a BCG shortage and we are supplying all of the BCG, so we're prioritizing cohort A first, then cohort B. The schedule is the standard SWOG schedule, so this is the Don Lamm SWOG schedule of induction and maintenance, and patients are allowed re-induction if they fail to have an adequate response after their primary induction. The inclusion and exclusion criteria, I think, are not terribly controversial; this is what we usually see, patients over 18 years of age. The cohort A is, as I mentioned, CIS with or without papillary disease, and cohort B is pure papillary disease alone without CIS.

Patients are required to have a biopsy within three months to show that they had no additional disease. The outcome measures, this is important. There are two different outcome measures. For carcinoma in situ, it is complete response at six months, and this is in line with the recent recommendations from the IBCG. And then, for papillary disease, it's disease-free survival at 12 and 24 months. Importantly, I think it's critical to note that we are in an ongoing BCG shortage. I was going to say the new world order, but it's the old world order where we've been experiencing this for quite some time. When this trial first enrolled in October of 2015, we had to put an enrollment pause because, as a sponsor, we were providing all of the BCG and there was limited supply. So that is why we actually are lucky in that we have data that's long-term from people in the trial, and we've seen a good safety profile and of course the efficacy profile that I showed.

But what's important to note now is that we have the opportunity to move forward and enroll more aggressively because the BCG supply has improved. We've completed our BCG unresponsive trial, and so those supplies can be directed in this direction. As of April, there were 121 of 366 planned subjects in cohort A and 74 of 230 in cohort B. Now, those numbers are for the first interim analysis with the option to increase, so for sites that may be interested, I would strongly suggest that they reach out because by no means do we know that there's only 240 slots left; there may be more slots. Lastly, last week we did announce a partnership with the Serum Institute of India to use a new supply of BCG, including the recombinant strain of BCG in our bladder cancer trials. This is important because, number one, it will allow us to save some of that TICE BCG which we had been providing for the trials in the United States because perhaps the trials outside of the United States could use the other strains of BCG, which are approved in those countries.

And second, we haven't yet had that conversation with the FDA but we would welcome that conversation about the possibility of bringing these strains into the United States for trials, thus expanding our capability to run these trials.

Sam Chang: Bobby, thank you so much for that overview. When you look at those long-term responses from that initial cohort, remind us, did those patients get to kind of the full three years? Was it a year, year and a half? I know the trial spells out the SWOG protocol but for those original nine how much did they receive of the combination?

Bobby Reddy: Yeah, that's a really good question. So they received full BCG induction and maintenance, but for the 803 they only received it through the first basically two cycles because it was a Phase I. So even, and I think it's a really exciting potential, which is that even a limited exposure had long duration. We believe that this is because of the memory component, which is where when you engage the memory T-cell and you have that T-cell, it will not only be working while you're receiving the therapy which, for example, with chemotherapy it's obviously working while you're receiving the therapy. But if you can train the immune system and you can engage that memory T-cell long after the therapy has been completed, just like any other vaccine, it will persist and be durable and be meaningful.

Sam Chang: So as you look at this data with the combination upfront, it's always tempting that we know BCG is effective, we know the combination is actually effective in patients that have actually had tumor recur while they've gotten BCG or just soon afterwards. It doesn't make some sense that this combination upfront would be effective, and I know that's what you're studying and you're evaluating. As we then try to weigh combination versus single agents, say BCG monotherapy, obviously we worry about side effects and the combination of the two drugs, is it worth a small, say, difference? Although statistically you already see a difference but is it worth a difference in terms of side effects? So tell us a little bit from what you know now regarding the side effect profile.

Bobby Reddy: Sure, and I think that's absolutely an important question, all patients entering a clinical trial are going to ask about that. So what's intriguing is that we do not see a difference in the side effect profile. Basically what we're seeing, certainly in the second line and what's in the FDA label, shows a label that's very consistent in terms of adverse events as BCG monotherapy. And in this trial, when we do the comparison from a safety aspect, we're seeing no difference. There's no statistically significant difference between the two arms. At first glance, that might seem unusual or hard to fathom but it actually makes perfect sense. And the reason is that what's happening with BCG is a pure cytokine-mediated event and so you're having those side effects.

When you add Anktiva, you're driving more of the NK cell because we showed it's more proliferative for NK cells, more tropic to NK cells than T cells. And so, when you're driving more NK cells to clear the tumor you're not driving cytokines because NK cells are killing through direct cell-to-cell mediated contact. And so, you're not seeing a big appreciable change. It may be that with BCG you have a threshold event where you have enough cytokines and pushing them up another 10% really doesn't lead to a clinical change for the patient.

Sam Chang: Yeah, no, I think that's a really important point and as you gather more data I think that'll be really important. With the original data that came out looking in the BCG unresponsive group, many were surprised. How come you don't have more side effects? Where are the side effects? And I think the mechanism you spelled out was important. The other point that I brought up and others as well is, if you look in the BCG unresponsive group the median number of treatments of BCG was 12. That was the median number so this was a heavily treated population that still was anxious, interested, et cetera, in receiving more treatment. Already you've pre-selected the group out that can't tolerate more therapy, and so the fact that adding the IL-15 super agonist, the Anktiva, did not simply change the side effect profile made sense to me. Now, even more importantly, upfront there doesn't seem at this point to show a signal I think is really important. I guess the last question is, what about invasive disease? What about those patients that we may be able to find clinically organ-defined? Is there enough of a robust response where we can actually see an impact on invasive disease, Bobby, or do we not even know yet?

Bobby Reddy: Well, it's a great question and we don't know yet. It's something that we're certainly interested in looking into. The drug has been studied extensively in other tumor types, solid tumors, showing efficacy in pancreatic cancer and lung cancer. And in those circumstances, it's given subcutaneously. And I'm thinking in the bladder, in invasive disease, we have a special opportunity where we can give it both intravesically but also subcutaneously to have both a systemic and local effect. It's well tolerated. We don't see cytokine storm or cytokine release, and so therefore I think it could be combined with the agents that are being studied now. So there are plans to study it with EV and Pembro and also with GemSys and Nevo, which are both being, I think, looked at in that setting, and we believe it would have synergy and benefit in those patients.

Sam Chang: Wow. Exciting times for sure in urologic oncology, with a real uptick in clinical trials, interest, and options for our patients. So, Bobby, thank you so much for spending some time with us, and we look forward to enrolling more patients as we get more data and then being able to see longer-term data with bigger numbers. Thanks again for spending some time with us.

Bobby Reddy: I appreciate it, thank you so much.