Leonard Schleifer: Well, we certainly believe that when you are in something where there is tremendous medical need and no alternative, that there will be opportunities to move for accelerated approval. We are all aware of the new FDA guidelines that they want you to be underway with your pivotal studies are well underway, I think is a phrase they use. So, we are taking that into account. But there is no question that if we can reproduce the efficacy that we saw in these late-stage prostate cancer patients. There is not only the need, but there will be a mechanism to get that to patients as quickly as possible. Remember, the main issue as you referred to, is being mindful of the safety. And of course, we are doing everything we can to mitigate that.
But remember, thus far for the most part, there has been an extremely tight linkage of safety and efficacy. That is the adverse events occurred in those patients who were having the substantial benefit. So, that makes the risk/reward even more attractive from a regulator’s and doctor’s and frankly, a patient’s perspective. But the short answer is we think we are not going to go too fast where one would be reckless. We have to be careful. But we do think there is an opportunity for an accelerated approval if we follow the new approach the FDA has laid out.
Ryan Crowe: Thanks Len. Last question, please, Shannon.
Operator: Our last question comes from the line of Robyn Karnauskas with Truist. Your line is now open.
Robyn Karnauskas: Great. Thank you for squeezing me in. So, just a follow-up on the prior question. So, for your MUC16, CD28 and MUC16 is a great combination, what are you expecting regarding the safety profile and how do you think about that type of combination efficacy and safety vice versa as CD28-CPI combo? And just a follow-up to that, I know the FDA was concerned back in the day about dosing up with CD28 is superagonist, like do you think that your initial data might alleviate some of the needs of the low doses for CD28 bispecifics? Thanks.
George Yancopoulos: Well, a lot of good questions in there. I will start from the end first. For sure, when we started the program, there was very serious concerns about previous experience with general CD28 activators that activated all over the body that resulted in really horrific situations for patients, which almost killed the field. We invented this new approach to tightly limit where we were limiting CD28 activation right at the tumor surface and so forth. And of course, there was a concern from the FDA, which is why, as you said, they made us employ a very, very conservative dose escalation program. We had to go through five or six dose levels just to get to where we thought were the active dose levels where we then start to see the rather dramatic antitumor activity that we began to report.
We are hoping that as we get more experience and show that what we had demonstrated pre-clinically is really holding true in humans. In fact, the side effects that Len was talking about immune-related adverse events are totally unrelated to the sort of toxicities that were seen with non-specific CD28 superagonist in the past. They were really much more on target and on mechanism that is we were generating a presumably a polyclonal T-cell response against the tumor and some of that cross-reacted to tissues in the patients, and that’s what we were seeing. So, we are hoping that increasingly we might be able to move a little bit more quickly through some of these dose escalation stages to get to the active doses with these other agents. What we are seeing so far, as we have presented in our posters on MUC16xCD3 that right now it’s having an acceptable safety margin.
