Carter Gould: Great, good morning. And thanks for all the transparency. Maybe switching gears a bit, in terms of the update on your costim and report of the death and the change in the dosing paradigm with 5678 in combination with Libtayo. George maybe you can speak about the implications for other combination efforts of CD28 with Libtayo, it’s going to require lower dosing with those efforts with Libtayo portion and just the broader implications there and just fill your level of confidence you can kind of thread that needle in terms of the dosing levels? Thank you.
George Yancopoulos: Great question. Obviously, as you know, in cancer, the biggest hurdle is actually coming up with approaches and new classes of agents that have the ability to really change the efficacy paradigm to really bring new ability to address cancers that have previously been untreatable or refractory to treatment. So I think that, that excitement continues with the costim platform in terms of all of the signs and the preclinical modeling and predictions have really delivered in terms of showing that this new class does seemingly has the ability to really change the efficacy paradigm. But now we have to balance that as you said with the safety, because with more efficacy, which is often seen in the cancer field comes more safety concerns to what you just said, what we’ve seen preclinically and we’re now beginning to see it in the clinic that the amount of associated immune adverse events is related to the particular costim target.
So what you see for one costim doesn’t necessarily apply to the other costim. So we are, as you said for our PSMA costim moving out of lower doses of the Libtayo because the full dose combination, while it seems like it has the potential to be very efficacious, but also has in some cases these associated only, remember only in the patients who are having deep responses, these associated in some cases, it can be very serious even resulting in death associated immune adverse events. So we’re moving away from full dose combinations there and we’re going and hoping that we can maintain some level of the efficacy, but avoiding these very serious immune-related adverse events. We’re not doing that yet, because we’re not seeing these sort of immune-related adverse events with our other costims.
And the other very, very important thing just to remind you from our preclinical modeling, these types of immune-related adverse events that we’re seeing with the PSMA in combination costim in combination with Libtayo are not seeing preclinically when you combine with the CD3 bispecific. And so we are very aggressively trying to move forward those programs as well, where we hope we may have a better efficacy, safety profile. So it’s both a — very exciting time to have these very active molecules, remember or remind you, we have three classes now, three independent classes of very active molecules that have been individually validated in our portfolio. We have the checkpoint inhibitors, in particular, our PD1 and our LAG-3 checkpoint inhibitors, which are validated.
We have our CD3 bispecifics which are validated and we now have our costims which are validated from the efficacy perspective, very exciting time to be mixing and matching them. The challenge is to mix-and-match them appropriately to maximize the signal-to-noise, the therapeutic benefits relative to the potential adverse events we see in the patients.
Ryan Crowe: Thanks, George. Next question, please.
Operator: Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open.
Salveen Richter: Good morning. Thanks for taking my question and nice updates this morning. Clearly the possibility of a permanent J-code now has moved to April and it shortens the runway for patients switching from EYLEA ahead of potentially loss of exclusivity in May. So kind of a two-part question here. What are the dynamics around this and how do you, on one hand kind of maintain and grow the switch population from EYLEA? But secondly, how should we think about the uptake of high-dose EYLEA without a permanent J-code? Thank you.
Marion McCourt: Hi Salveen. So I’ll get started. Certainly, we’re conscious of the dates and the requirement for submissions to CMS that occur at the start of a quarter. So we would estimate potentially the time frame that you’re referencing, if we have an approval in the third quarter. What I would share is that we anticipate use of aflibercept 8 milligram after approval and launch before we have the permanent J-code. Retina specialists are sophisticated in their reimbursement capabilities at the office level. They are experienced with newer products coming into the marketplace on a fairly regular basis and how to make certain that they validate reimbursement for products prior to having the permanent J-code under a temporary J-code. So obviously, we want to have the permanent J-code that will be a positive. But certainly, we do see the opportunity for uptake across patient types prior to that situation with CMS.
Ryan Crowe: Okay. Thanks, Marion. Shannon, please move to the next question.
Operator: Our next question comes from the line of Terence Flynn with Morgan Stanley. Your line is now open.
Terence Flynn: Great. Thanks so much for taking the question. Len, I know we’ve talked about this before, but the company has been somewhat non-traditional on pricing decisions historically. You guys priced EYLEA at a discount to Lucentis. You worked with ICER on Dupixent pricing. So just wondering why we shouldn’t expect it similar approach here with high-dose EYLEA. Thank you.
Leonard Schleifer: Thanks, Terrence. If your comments referencing similar, I mean, thoughtful and appropriate, we would agree.
Ryan Crowe: Okay. Next question please Shannon.
Operator: Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open.