The background of our study is that there has been a significant unmet need for patients with BCG-unresponsive bladder cancer. We have not had any recent intravesical FDA approvals in decades and, as a result, this is a trial looking at a combination of BCG with a unique molecular compound in patients that have BCG-unresponsive CIS as well as papillary disease, Ta and T1 disease.
The methodology was a phase II trial looking at patients with persistent recurrent CIS following BCG that was deemed as adequate. This would be at least 5 out of 6 installations of BCG as well as at least 2 out of 3 of the maintenance course and for papillary disease, Ta and T1 disease, they would have to have disease within 6 months of the adequate BCG. The primary endpoint was looking for a complete response for those patients with CIS and then also a disease free rate at 12 months for patients with papillary disease.
In a heavily treated group of patients, the median number of BCG doses were 12 to a mean as high as 16 receiving that number of BCG doses. The key findings were for both CIS patients as well as papillary patients a significant response to the combination of BCG with the N-803, which is the unique molecular compound that’s an IL-15 superagonist, cytokine agonist. As a result, what was found was for CIS there was a complete response rate that was quite significant and long-lasting. So for CIS at 12 months the complete response rate was more than 60% and there was significant durability with a complete response rate at 24 months being more than 50%, actually 52%.
When looking at patients actually with papillary disease, this is disease we find as Ta and T1 disease, a similar response rate that we think is clinically significant and durable. That is, basically, a 12 month disease free rate of more than 50% and at 24 months actually that being maintained with 48% of patients actually disease free without evidence of papillary disease.
So a combination of this unique IL-15 cytokine agonist, N-803, in combination with BCG seems to show significant response rate as well as durability of response.
Importantly, there are several key findings. First is the fact that this is an intravesical treatment, so not a systemic treatment, not anything out of the ordinary. This follows a familiar kind of treatment regimen that urologic surgeons are used to when treating patients with bladder cancer. That’s number one. Number two – it’s incredibly well tolerated. So there were no grade 4 or grade 5 significant adverse events or no patients that had issues with actually falling off the study due to adverse events. If you look at the grade 1 and grade 2 most common side effects they are lower urinary tract symptoms that are actually related to treatment-induced intravesical side effects that are quite common such as urinary frequency and haematuria and dysuria. In fact, when measuring serum levels of this N-803 IL-15 agonist there were no levels within the plasma. So this was a localised treatment to the bladder, so a familiar mode of administration, a very safe administration and one which has significant response rates that do occur and seem to be durable.
How we think this combination works is based upon trained immunity. Our hypothesis and the thought process is we know that BCG is effective when one of the mechanisms seems to be inducing this trained immunity. These innate immune cells actually depend upon a response to BCG that requires natural killer cells, that requires immune cells. What N-803 does is it uniquely revs up, activates, and helps the proliferation of natural killer cells’ trained immunity. So we think this combination of BCG being the actual induction and starting this trained immunity response that is augmented by N-803 and that explains why patients that do respond tend to have a durable response.
So this combination of agents seems to be the most effective in terms of bringing about a complete durable response.