Welcome to the Regeneron Pharmaceuticals Second Quarter 2023 Earnings Conference Call. My name is Shannon and I will be your operator for today's call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. Please note that this conference is being recorded.

I will now turn the call over to Ryan Crowe, Vice President, Investor Relations. You may begin..

Thank you, Shannon. Good morning, good afternoon, and good evening to everyone listening around the world. Thank you for your interest in Regeneron and welcome to our second quarter 2023 earnings conference call. An archive of this webcast will be available on our Investor Relations website shortly after the call ends. Joining me on today's call are Dr.

Leonard Schleifer, Board Co-Chair, Co-Founder, President, and Chief Executive Officer; Dr. George Yancopoulos, Board Co-Chair, Co-Founder, President and Chief Scientific Officer; Marion McCourt, Executive Vice President and Head of Commercial; and Bob Landry, Executive Vice President and Chief Financial Officer.

After our prepared remarks, we will open the call for Q&A. I would like to remind you that remarks made on today's call may include forward-looking statements about Regeneron.

Such statements may include, but are not limited to those related to Regeneron and its products and business, financial forecast and guidance, revenue diversification, development programs, and related anticipated milestones, including anticipated regulatory actions, collaborations, finances, regulatory matters, payer coverage and reimbursement issues, intellectual property, pending litigation and other proceedings, and competition.

Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement.

A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission, including its Form 10-Q for the quarterly period ended June 30th, 2023, which was filed with the SEC this morning.

Regeneron does not undertake any obligation to update any forward-looking statements whether as a result of new information, future events, or otherwise. In addition, please note that GAAP and non-GAAP measures will be discussed in today's call.

Information regarding our use of non-GAAP financial measures and a reconciliation of those measures to GAAP is available in our financial results press release and our corporate presentation, which can be accessed on our website. Once our call concludes, Bob Landry and the IR team will be available to answer further questions.

With that, let me turn the call over to our President and Chief Executive Officer, Dr. Len Schleifer.

Len?.

Thanks, Ryan, and thanks to everyone joining today's call. Regeneron delivered strong results across the organization in the second quarter of 2023, while continuing to make progress toward our long-term objective of growing the business while simultaneously diversifying its revenue and earning streams.

Total revenues increased by 11% compared to the prior year quarter, primarily driven by Sanofi collaboration revenues and Libtayo net product sales, which grew by 39% and 49% respectively.

Non-EYLEA revenue contributions were 41% of total revenues, the highest proportion for any quarter in the last 10 years excluding those with COVID antibody revenue contributions. Overall, we were pleased with the trajectory of the business and believe the company continues to be well-positioned to deliver long-term growth.

In a few minutes George, Marion, and Bob will provide commentary on pipeline developments, commercial execution, and financial results that we achieved during the second quarter. For the remainder of my remarks today, I will focus on aflibercept 8 milligrams.

We are very excited about the emerging clinical profile including the compelling two-year data from the pivotal PHOTON study in patients with diabetic macular edema which George will discuss in more detail. Now I will summarize the progress that has been made toward getting this important product candidate approved by the FDA.

As we announced in late June, the Complete Response Letter or CRL that we received from the FDA regarding our Biologics License Application for aflibercept 8 milligrams for the treatment of patients with wet age-related macular degeneration, DME, and diabetic retinopathy did not identify any issues related to aflibercept 8 milligrams clinical efficacy, safety profile, trial design, labelling or drug substance manufacturing nor has the FDA requested any additional clinical data.

The CRL was entirely based on unresolved observations, resulting from the May 2023 FDA pre-approval inspection of a third-party contract manufacturing organization, Catalent, that Regeneron engaged to complete vial-filling for aflibercept 8 milligrams.

The inspection observations were noted in a Form 483 and related to a manufacturing line in Catalent's facility that is used to fill vials with aflibercept 8 milligrams, as well as our C5 antibody pozelimab for the ultra-rare CHAPLE disease, which has a PDUFA date of August 20th.

The inspection was conducted as part of the FDA review process for both the aflibercept 8 milligrams BLA and the pozelimab BLA. Broadly speaking, the observation cited production and process control procedures, equipment validation, and facility maintenance.

We, Catalent, and the FDA have had multiple discussions since the aflibercept 8 milligrams CRL. There is a clear understanding of the remediation work that is required to allow the FDA to assume approving BLAs that involve manufacturing on this line.

Catalent has already provided data and information to the FDA that could satisfy some of these requirements and expects to be able to provide the remaining required data and information by mid-August. The FDA said they will strive to complete their review expeditiously prior to the August 20th PDUFA date for pozelimab.

However, if they are unable to complete their review before this date, the FDA said that they may need to extend their review by up to three months. If they do extend the review, FDA has stated that they will continue to prioritize the review and complete it as early as possible.

Importantly, the FDA has also stated that their review of the Catalent manufacturing data in the context of the pozelimab BLA will support actions for both the pozelimab BLA and the aflibercept 8 milligrams BLA resubmission, which has already been submitted.

In summary, we and Catalent expect to submit by mid-August all of the Catalent manufacturing data and information required to address the observations resulting from the pre-approval inspection. The FDA has stated that they will strive to complete their review expeditiously, prior to August 20th.

If not, we anticipate the FDA will act on pozelimab and aflibercept 8 milligram BLAs before the end of the third quarter.

In closing, we remain confident in our strategy of focusing investments on our internal R&D capabilities while exploring potential external collaborations as well as in our ability to deliver breakthroughs to patients and value to shareholders. With that, let me turn the call over to George..

Thank you, Len. I would like to start with our recent update on aflibercept 8 milligram data in DME that Len referred to. At the Annual American Society of Retina Specialists meeting, we presented the two-year results from our PHOTON study.

These data demonstrated that the vast majority of aflibercept 8 milligram patients were randomized to the 12-week and 16-week dosing intervals continued to sustain vision and anatomic improvements through 96 weeks.

89% of all aflibercept 8 milligram patients were able to maintain at least every 12-week dosing intervals for the entire two-year period, while 84% of patients assigned to every 16-week dosing at baseline, were able to maintain that interval or extend beyond it.

On that point, many patients met the criteria for extension to longer intervals, with 44% meeting the criteria for greater than 20-week dosing intervals, including 27% who were eligible for 24-week dosing intervals. The safety profile of aflibercept 8 milligram remained consistent with EYLEA.

Sustaining vision and anatomic improvements while maintaining such extended dosing intervals over two years is unprecedented in the field. Our results further strengthen the clinical profile of aflibercept 8 milligram and position this investigational medicine to become the future standard of care retinal diseases.

Later in the third quarter, we and Bayer are planning to share initial results from the second year analysis of the PULSAR study in patients with wet AMD. Moving to our immunology and inflammation pipeline on Dupixent.

We look forward to the FDA decision for our sBLA in chronic spontaneous urticaria by October 22nd, 2023, in terms of Dupixent in patients with COPD. We and Sanofi are pleased to announce that Dupixent was granted breakthrough designation for uncontrolled COPD with an eosiniphilic phenotype based on the positive results of the Phase 3 BOREAS study.

Based on ongoing discussions with the FDA, we expect that in addition to the BOREAS study results, we will need to provide data from the replicate Phase 3 NOTUS study to support a BLA and such data requirements remain under discussion with the FDA. We continue to expect final results for the NOTUS study by mid-2024.

Moving to Itepekimab, our anti-IL-33 antibody, which is being evaluated for COPD in former smokers. In May, Sanofi announced that the Phase 3 AERIFY-1 and 2 studies had passed an interim futility analysis. These studies remain on track for readout and regulatory submissions in 2025.

Both the Itepekimab and Dupixent could transform the treatment paradigm for COPD by levering their distinct mechanism of action in reducing different types of inflammation that contribute to COPD. Moving to oncology and combinations with Libtayo.

In June, in an oral presentation at the ASCO conference, we presented data for the combination of fianlimab, our LAG-3 antibody plus Libtayo, which showed consistent response rates ranging from 56% to 63% across three independent cohorts of advanced melanoma patients, including a new cohort of patients who had received prior anti-PD-1 therapy in the adjuvant melanoma setting.

These response rates represent about double the rate historically seen with anti-PD-1 monotherapy in similar settings and clinically meaningful responses were observed in Post Hoc analysis of various populations of interest, including patients with poor prognosis factors and varying tumor PD-L1 expression levels.

The safety profile of fianlimab and Libtayo combination in these cohorts appears to be generally consistent with the safety profile of Libtayo monotherapy and other anti-PD-1 or PD-L1 agents, except for the higher rates of adrenal insufficiency, which were Grade 2 or lower in the majority of cases, with all cases successfully managed with steroid replacement.

Our fianlimab plus Libtayo Phase 3 studies in metastatic and adjuvant melanoma are enrolling patients as are the Phase 2 portions of the Phase 2/3 studies in advanced non-small cell lung cancer. Next on to bispecifics for solid tumors, which are being investigated in combination with Libtayo and other modalities.

Later this year, we are planning to share initial clinical data for the combination of ubamatamab, our MUC16xCD28 bispecific plus Libtayo in advanced ovarian cancer. Last year we showed encouraging ubamatamab monotherapy data in advanced ovarian cancer and we believe that combining it with Libtayo may lead to enhanced anti-tumor activity.

Moving to costimulatory bispecifics.

We are currently exploring multiple different CD28 costimulatory bispecific antibodies in early clinical trials in a variety of tumor settings, in combination with Libtayo well with corresponding CD3 bispecifics in our Phase 1 study of REGN5678, our PSMAxCD28 costimulatory bispecifics in advanced prostate cancer in combination with Libtayo, which has demonstrated promising anti-tumor activity.

The safety profile of this combination continues to pose a challenge, highlighted by the recently observed second Grade 5 adverse event or death.

Although serious immune-mediated adverse events continued to be highly correlated to patients who experience profound responses, we have decided to discontinue enrollment of new patients with the full dose Libtayo combination and explore PSMAxCD28 combination with lower doses of Libtayo.

We also will continue to explore PSMAxCD28 as a monotherapy, where we have seen anti-tumor activity in some patients and we will explore PSMAxCD28 in combination with other immunotherapy modalities.

We believe our prostate cancer data support the exciting potential of costimulatory bispecifics both the challenge of focusing the response solely to the tumor.

Our preclinical studies and mechanistic insights suggest the degree of immune-related adverse events seen when combining costims with PD1 blockade may depend on the particular costim target and tumor types. Moreover, combining costims with CD3 bispecifics may not result in these types of severe immune-mediated adverse events.

Along these lines, our other costimulatory bispecific programs continue, including our MUC16xCD28 costim with Libtayo and MUC16xCD28 costim with ubamatamab both in ovarian cancer as well as our EGFRxCD28 costim with Libtayo in colorectal and other cancers.

In these early dose-escalation studies, we have observed limited immune-mediated toxicities to-date. We are also excited about combining our costimulatory bispecifics with our CD3 bispecifics in our hem/onc programs, which continue to progress.

We have initiated dosing of our CD22xCD28 costimulatory bispecifics with odronextamab, our CD20xCD3 bispecific in relapsed/refractory diffuse large B-cell lymphoma, which we hope can improve on the impressive efficacy demonstrated by odronextamab alone in that setting.

In terms of odronextamab monotherapy, US and EU regulatory submissions for both relapsed or refractory follicular lymphoma and diffuse large B-cell lymphoma remain on track.

Regarding linvoseltamab, our BCMAxCD3 bispecific, we recently presented updated data at the ASCO Annual Meeting demonstrating early deep and durable responses in patients with heavily pre-treated multiple myeloma, with 71% objective response rate and 59% of patients achieving a very good partial response or better at the recommended 200-milligram dose with a median follow-up of only six months, with the data potentially improving as they mature.

We believe these data support linvoseltamab's best-in-class potential with differentiated efficacy, safety, hospital requirements, and favorable dosing schedule. In the fourth quarter this year, we are planning to present additional data with longer follow up and to submit regulatory applications for linvoseltamab.

We also plan to start combination studies with myeloma-specific costim next year. Next to genetic medicines.

In the second quarter, we and Alnylam jointly announced the first human data suggesting that a siRNA can be used to silence pathological genes in the brain, which may open up an entirely new approach to fighting back against neurodegenerative and other central nervous system diseases.

We plan to initiate additional clinical programs for CNS diseases next year. As announced by our collaboration with Intellia, we plan to initiate the first in-vivo CRISPR-based Phase 3 clinical program by year-end, subject to regulatory feedback in patients with transthyretin amyloidosis cardiomyopathy.

And in terms of our targeted gene delivery pipeline, we hope to initiate our first clinical program in 2024 for Hemophilia B. In conclusion, Regeneron's R&D engine continues to grow and deliver differentiated late and early-stage opportunities and we are looking forward to several important clinical milestones in the second half of this year.

With that, I will turn the call over to Marion..

Thank you, George. In the second quarter, Regeneron delivered impressive results across our commercial portfolio, notably Regeneron medicines currently lead multiple disease categories and our future is promising with short and longer-term scientific innovations on the horizon.

As Len mentioned, we eagerly await the anticipated approval of aflibercept 8 milligram for retinal diseases, beyond that our robust late-stage pipeline supports additional commercial opportunities that we anticipate will continue to drive growth. Starting with EYLEA, the anti-VEGF category leader in retinal diseases.

US EYLEA net sales were $1.5 billion, down 7% year-over-year and up 5% quarter-over-quarter. EYLEA total category share remained stable at 46% over the last two quarters and at approximately 70% for branded share.

At the end of the second quarter, there was minimal sequential change in wholesaler inventory levels compared to the levels at the end of the first quarter. Our strategic focus is to maintain and grow Regeneron's anti-VEGF leadership and we're well-positioned to deliver on the score in an increasingly competitive category.

Last week at ASRS, we presented our two-year data in diabetic macular edema which further confirmed the unprecedented durability of aflibercept 8 milligrams, with 44% of patients assigned intervals of at least 20 weeks at the end of their second year.

Market enthusiasm remains high for this important innovation and our commercial team is ready and excited to launch aflibercept 8 milligram upon approval. Moving now to Libtayo. Global net sales were $210 million, up 49% year-over-year on a constant currency basis.

In the US, net sales were $130 million, up 43% driven by steady growth in non-melanoma skin cancer and strong growth in lung cancer. In lung cancer, Libtayo use in new patients share is accelerating, both monotherapy and in combination with chemotherapy with an expanding base of prescribers in the community and academic settings.

Outside the US Libtayo, net sales were at $80 million, a 58% increase on a constant-currency basis. Growth was driven by demand in the non-melanoma skin cancer indications and initial launches in lung cancer.

We expect to drive accelerated performance as we build Regeneron's presence in key international markets and secure access and reimbursement for lung cancer indications. And lastly to Dupixent, which continues to revolutionize the lives of patients with type 2 diseases.

Global net sales were approximately $2.8 billion, up 34% year-over-year on a constant currency basis and up 12% compared to the first quarter of 2023. In the US, net sales grew 33% year-over-year to $2.1 billion driven by growth across all indications and age groups.

Once again, Dupixent is the number one prescribed biologic medicine for new-to-brand patients across all approved indications and is the category leader in total prescriptions in four out of five indications. We see impressive uptake across our recent US launches with significant opportunity for future growth.

In eosinophilic esophagitis, well over 15,000 patients have been initiated since launch and we are actively investing in disease awareness initiatives to empower patients to seek diagnosis and treatment for this debilitating disease.

Our prurigo nodularis launch is off to a fast start with physicians rapidly recognizing Dupixent as the go-to treatment for this often underdiagnosed dermatologic condition. Additionally, we look forward to our October 22nd PDUFA date in chronic spontaneous urticaria, where we estimate Dupixent could benefit up to 300,000 US patients.

We also continue to generate impressive growth across atopic dermatitis, asthma, and nasal polyps, Dupixent's three largest indications.

There is robust demand among all indicated age groups with a significant opportunity for future growth beyond the hundreds of thousands of patients around the world, whose lives have already been transformed by Dupixent.

In summary, we delivered a strong commercial performance in the second quarter with Regeneron's medicines positioned for sustained growth.

We continue to demonstrate industry-leading execution across our current portfolio and we are prepared to maximize opportunities from our robust pipeline, with the goal of extending Regeneron's scientific innovations to even more patients. Now I will turn the call over to Bob..

Thank you, Marion. My comments today on Regeneron's financial results and outlook will be on a non-GAAP basis unless otherwise noted. Regeneron's second quarter results demonstrate continued growth and strong financial performance across the organization.

Second quarter 2023 total revenues increased 11% year-over-year to $3.2 billion, driven by strong Dupixent sales growth coupled with improving profitability within our Sanofi collaboration and continued momentum from Libtayo. Second quarter diluted net income per share was $10.24 on net income of $1.2 billion.

Moving to collaboration revenue and starting with Bayer. Second quarter 2023 ex-US EYLEA net product sales were $886 million, up 4% on a constant currency basis versus second quarter 2022. Total Bayer collaboration revenue was $377 million, of which $350 million related to our share of EYLEA net profits outside the US.

Total Sanofi collaboration revenue was $944 million in the second quarter and grew 39% versus the prior year. Our share of profits from the commercialization of Dupixent and Kevzara was $751 million, an increase of 51% from the second quarter of 2022, reflecting higher volumes and an improving margin profile for Dupixent.

We expect further margin expansion from the collaboration driven by continued Dupixent global sales growth coupled with higher gross margins due to significant drug substance yield improvements resulting from dupilumab manufacturing process enhancements.

These factors are also contributing to a gradual increase in the rate in which we are repaying the antibody development balance to Sanofi. Once this balance is fully repaid in the next few years, we expect a meaningful step up in our share of Sanofi collaboration profits.

Recall that a portion of our Sanofi collaboration revenue was related to the manufacturing of commercial supplies, for which we are reimbursed by Sanofi.

As we continue to face in the higher yield manufacturing process for Dupixent, we expect these second half reimbursements to be approximately 25% lower than the first half of 2023, with the fourth quarter expected to be the lowest of the year. Other revenues were $69 million in the second quarter, up 17% versus the prior year.

We continue to expect other revenue to be higher in the second half of 2023 as compared to the first half.

Recall that other revenue primarily includes reimbursements for the manufacturing of certain Regeneron discovered products commercialized by other companies, including ex-US Praluent, ARCALYST, and ZALTRAP, as well as royalties for Alaris and our share of global profits for ARCALYST. Moving now to our operating expenses.

Second quarter 2023 R&D expense was $974 million, representing continued investment in our robust pipeline.

Year-over-year R&D growth was primarily driven by higher headcount and related costs and funding of the company's pipeline which encompasses approximately 20 late-stage or potentially registrational studies including our ongoing aflibercept 8 mg studies.

Phase 3 studies in earlier lines of therapy for our hem/onc product candidates and our advancing fianlimab development program.

The increase in R&D expense was also driven in part by the impact of the 2022 amendments to the Sanofi collaboration agreements and increased manufacturing activity associated with the company's earlier-stage product candidates.

SG&A was $562 million in the second quarter, reflecting the ongoing build-out of our ex-US operations following the acquisition of global rights to Libtayo last year, higher headcount and related costs, and higher contributions to an independent not-for-profit patient assistance organization.

Second quarter 2023 COCM was $213 million up 44% versus the prior year driven by manufacturing costs associated with higher Dupixent volumes.

As we progress the phasing of the improved manufacturing process for Dupixent, we expect COCM in the second half of this year to decline versus the first half as our unchanged 2023 COCM guidance reflects with the fourth quarter expected to be the lowest of the year. Now to cash flow and the balance sheet.

In the first half of 2023, Regeneron generated approximately $2.1 billion in free cash flow. We ended the second quarter with cash and marketable securities less debt of approximately $12.6 billion. We continue to opportunistically deploy cash towards share repurchases throughout the second quarter, buying back $723 million of our shares.

At current levels, we remain buyers of our shares, and as of June 30th, approximately $2.3 billion remained available for repurchases under our existing authorization. Finally, we've made some minor changes to our full year 2023 guidance ranges based on our first half results and our latest outlook for the remainder of the year.

We have tightened guidance ranges for 2023 SG&A and R&D spend and provided updated guidance ranges for our effective tax rate. A complete summary of our latest full year guidance is available in our press release issued earlier this morning.

In conclusion, Regeneron delivered positive financial results in the second quarter of 2023 and we remain excited for the potential upcoming launch of aflibercept 8 mg in the third quarter. With that I will now pass the call back to Ryan..

Thank you, Bob. This concludes our prepared remarks, we will now open the call for Q&A. To ensure we are able to address as many questions as possible, we will only be able to answer one question from each caller before moving to the next.

Shannon, can we go to the first question, please?.

Thank you. [Operator Instructions] Our first question comes from the line of Evan Seigerman with BMO. Your line is now open..

Hi, guys. Thank you so much for taking my questions and on all the updates today. So on the 8 milligrams CRL, do you have any idea if it's a Class 1 or Class 2 resubmission? And you say that FDA is going to take action in the third quarter or could take action.

What does that mean? Are they going to provide an approval decision or is that just going to be acceptance of a refiling? Thank you..

Hi, Evan. It's Len. Thanks for your question. So just to clarify, the FDA has not classified the resubmission as Class 1 or Class 2 because they have said that the timeline for pozelimab will be governing what happens with our 8 milligrams. So let me remind you what happened, it was a pre-approval inspection for both products.

The pozelimab is for our ultra-rare disease -- CHAPLE disease and it has a PDUFA date of the 20th. What the FDA has said is that they will review the remediation efforts in the context of the pozelimab BLA and therefore, whatever happens there will govern the timeline and results.

And when we say we expect them to take action, we mean, we expect them to make an approval or not decision. If they find the manufacturing remediation acceptable for the pozelimab, then we think they will be in a position to promptly make a decision on approval for the 8 milligrams.

Does that answer your question?.

He is off the line. We will move to the next question Shannon..

Our next question comes from the line of Tyler Van Buren with TD Cowen. Your line is now open..

Hi, there. Good morning. Thanks for taking the question. So the timeline to the FDA potentially taking action by the end of this quarter and high-dose EYLEA is very encouraging and investors are clearly surprised by the short lines. So kudos to you all for executing.

But as we think about the data submission in a couple of weeks, what additional detail can you provide regarding the manufacturing data and other information that are required from Catalent? And how feasible it is to review this in a few days prior to the pozelimab decision date on August 20th?.

Right. Great question. So we've been in very close contact with Catalent and the FDA, multiple meetings, oral, written, and so forth, and we have a clear understanding of what's required from an information point of view and from a data point of view.

The submissions have been on a rolling basis that as Catalent has completed work, they've submitted data and information already to the FDA. There is very little that will be left for the last submission at the middle of August, and that's why the FDA has told us and they know what's coming that they will strive to expeditiously review that.

And if they can't get that done by the few days before the pozelimab PDUFA date, they have told us that they will prioritize our review and do that as soon as possible. That's why we have confidence about this getting done in this quarter. So to summarize the data has been coming in on a rolling basis.

We have everything we need, the last piece of information that we'll be rolling in and submitted by the middle of the month, the FDA will strive expeditiously to review that in time for the August 20th PDUFA date. But if not, there will be a clock extension for up to three months, but they have told us that they will prioritize our review.

And that's why we believe it will get done, if not in time for the pozelimab PDUFA date in the near future thereafter..

Okay. Thanks, Len. Next question, please Shannon..

Our next question comes from the line of Mohit Bansal with Wells Fargo. Your line is now open..

Great. Thank you very much for taking my question. And really thank you very much for providing all the clarity on the filing situation right now. Maybe taking -- so just trying to understand this a little bit more.

So is it fair to say you have already submitted everything for pozelimab and the remaining part is related to high-dose EYLEA only? Is that fair?.

Actually, the way you should think about it, we've submitted everything we need for pozelimab except for the final remediation of the pre-approval inspection, which applies both to pozelimab and to the 8 milligram EYLEA. So it's a single pre-approval inspection same data and information required for both.

Once that is in then we will have completed everything necessary for pozelimab and for the EYLEA 8 milligrams. They are linked together. The FDA has clearly stated to us that the review of this remediation in the context of the pozelimab BLA will govern what happens to the 8-milligram remediation..

And I think there is nothing specific to either pozelimab or aflibercept about the data. This has to do as Len said with general manufacturing processes and operations at the Catalent manufacturing facility, particularly with this one manufacturing line..

Hey, that's a very good point, George. So that's why the single pre-approval inspection applies to both products. It wasn't the product specifically, it was the processes and validation on the line that fills the two products.

So one remediation satisfies both, all the data and information that is being submitted on a rolling basis, the last piece comes in, in the middle of August, the FDA is aware of this. They've told us in writing that they will strive to do that as expeditiously. If they get it done before the end of the PDUFA, an original PDUFA clock, that's great.

If they don't, they'll consider an amendment that will set the clock back three months. But notwithstanding that three months, they've told us that they will continue to prioritize our review. So we're very pleased and we're working very hard.

Catalent is working very hard, the FDA is working very hard, everybody wants this done properly and finished and properly remediated..

Okay. Next question please, Shannon..

Our next question comes from the line of Tim Anderson with Wolfe Research. Your line is now open..

Thank you very much. I have a question on the Vabysmo. So Roche at Q3 said they're capturing 30% of treatment-naive patients which seems like a quite high figure frankly. And then they said afterward, that it's not the extended dosing that's driving this as much as it is the better drawing that they say docs or seeing with their product.

I'm wondering how those comments kind of line up with what you're seeing play out in the US market. Thank you..

Sure. So, Tom, I will comment on our EYLEA performance. And as I just shared with you the performance in the quarter was strong, certainly we see EYLEA steadily as the standard-of-care in the anti-VEGF category. We continue to capture not only naïve-patients, but also another big source of business is switch patients from Avastin.

Obviously, the other branded competitors are smaller in market today. But I would say that beyond your comment, probably best to get more clarification from the individuals who are commercializing faricimab in the market.

But certainly, I do want you to know that we are seeing continued strength in EYLEA performance and obviously very much look forward to having the potentially game-changing opportunity of bringing aflibercept 8 milligrams into the marketplace and where the profile of efficacy, safety and durability has so many KOLs and prescribers excited based on what they've seen recently in the clinical data presented at ASRS..

Thanks, Marion. Next question, please..

Our next question comes from the line of Chris Raymond with Piper Sandler. Your line is now open..

Thanks. Just maybe another market-related question. So I know these extended dose therapies have benefits in and of themselves on the face of them. But there's been some decent level of market chatter around docs, looking to free up injection capacity specifically to make room for geographic atrophy patients and specifically with the Apellis drug.

Just maybe curious how widespread was that notion before the Syfovre safety issue. And now with the issue have you noticed a discernible shift among docs who we're talking about that? And then maybe a related question, you guys have talked I think about an early effort of your own in geographic atrophy.

Clearly, the market is sizable, when could we expect to hear more about that effort?.

So let me share first in terms of the market dynamic.

I think the most exciting thing and most important thing about aflibercept 8 milligram is it gives prescribers for all of their patients whether a naïve-patient, a patient currently on EYLEA or a patient on another anti-VEGF category product, the opportunity to decide if that patient is a candidate when we launch and when we have an FDA approval, is the patient is a candidate for aflibercept 8 milligram, that does have benefit to the patient and prescriber and potentially to the office capacity and patient flow.

I think it's premature to comment on the category that we're not directly involved in. We are though very focused on making sure that we are ready for launch and certainly at the proper time, educating all stakeholders on aflibercept 8 milligram once we have an approval..

And in terms of our own efforts, as I'm sure many are aware we've been very active with what we feel are very innovative approaches in the complement blockade field. And we believe that we may have an approach that may allow potential treatment in these retinal diseases.

While avoiding some of the very concerning adverse events having to do with issues like inclusive vasculitis and so forth, and you'll be hearing much more about those efforts in the short-term..

Okay. Thanks, Marion and George. Shannon, please move to the next question..

Our next question comes from the line of Carter Gould with Barclays. Your line is now open..

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..

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..

Thanks, George. Next question, please..

Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open..

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..

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..

Okay. Thanks, Marion. Shannon, please move to the next question..

Our next question comes from the line of Terence Flynn with Morgan Stanley. Your line is now open..

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..

Thanks, Terrence. If your comments referencing similar, I mean, thoughtful and appropriate, we would agree..

Okay. Next question please Shannon..

Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open..

Good morning. Thanks for taking my question. Congrats on all the progress and appreciate all the details. Maybe just another clarification on 8 milligram aflibercept.

Can you characterize your level of confidence that a re-inspection would not be required? Have you had any interactions or feedback with the agency around this? And is there a defined period of time where the FDA would need to wait re-inspection or not to ensure that the remediations are sustainable before proving to BLAs? Thanks..

Great. Thanks for your question. Look, we've tried to be 1,000% transparent as usual Regeneron. And this is really, let me just see if I can summarize it, again, what we know. We've been in close contact with the FDA as has Catalent. We know what the remediations required are and we've been submitting them on a rolling basis.

We expect to submit the last requirement by the middle of August and that will be several days before the PDUFA date for the pozelimab BLA. The FDA has been very clear that they will strive to expeditiously review that. If they can, great. They can't, they said there would be a three-month clock extension.

But even with a three-month clock extension, they've been very categorical in saying that they would prioritize our review and try and get it done as soon as possible. Those facts are what led us to believe it would be done during the third quarter.

In all of this, is the fact that there has been no need, no discussion, no indication whatsoever that a re-inspection would be necessary. The FDA of course is free to make those decisions, but we have not seen any indication of that in our very detailed and close contact. So we've given you our best estimate at this point..

Thanks, Len. Let's move to the next question, please..

Our next question comes from the line of Chris Schott with JPMorgan. Your line is now open..

Great. Thanks so much. Can you just come back to the CD28 PSMA update? Maybe just elaborate a little bit more in terms of the approach of lowering the PD-1 exposure to address the safety issues here and taking that approach versus trying to work to further adjust the dosing of the bispecific piece of the equation? Thanks so much..

Well, we should say that we are adjusting both doses. We have been already exploring a variety of doses from very low doses to the highest active doses on the costim side. But we've been doing all of them in the context of the full dose Libtayo.

So now what we're doing is we're exploring some of the doses that are active, particularly ones are active as monotherapy, as I mentioned, there is monotherapy activity with the PSMA costim. And now we are -- to try to decrease these immune-related adverse events.

Let me remind you, they are on the same sort of class of immune-related adverse events that you do see with checkpoint inhibitors in general. We're just seeing them in some patients, the one with the biggest responses in some cases to a greater extent.

So we're hoping that lowering the checkpoint inhibition may allow us to adjust the therapeutic window there. But we are as you are saying dealing with a couple different doses of the costim, but now we're incorporating lower doses of the Libtayo into the program as well..

I think what George said earlier, just maybe it bears repeating, is that he said that we're starting with the good position of having very impressive efficacy, one.

And two side effects that for the most part in the patients who are benefiting with the efficacy, that's a very good position to begin to explore and how to get the therapeutic index or signal to noise as George calls it right..

Okay. Let's move to the next question, Shannon. Thank you..

Our next question comes from the line of Dane Leone with Raymond James. Your line is now open..

Hi. Thank you for taking the questions. Congratulations on the updates and best of luck with the resolution of the reviews for pozelimab and 8 mg aflibercept. I actually want to ask you to expand a bit on your discussions with the FDA and potential filing or early filing on Dupixent for COPD.

The point I'd like a little bit more clarity on specifically what you may be able to have from NOTUS before the final readout of that study that you could potentially include in a package with the BOREAS results to get the FDA comfortable with an accelerated review for that indication. Thank you..

Yeah. What we know right now is that we're going to need data from NOTUS. And right now, as we said, we are still in discussions on what that data could be. And so right now, we don't have any details to give you..

Okay. Thanks, George. Hopefully an update and next question, please..

Our next question comes from the line of Colin Bristow with UBS. Your line is now open..

Hey, good morning, and congrats on the quarter and the progress. Just maybe one on the itepekimab interim. Can you share anything on the utility threshold? And if not, specifically, could you say how the sort of Fed relative to BOREAS? Thanks..

I don't think we have anything specific. This was handled by the Data Safety Monitoring Committee sort of a standard approach. We're pleased that we passed it. And we will look forward to further data at the end of the study..

And both we and Sanofi are blinded to that. We only got the go-decision from the Independent Data Monitoring Committee. So we will proceed to a final readout for both of those studies. Let's go to the next question, please..

Our next question comes from the line of Brian Skorney with Baird. Your line is now open..

Hey, this is Luke on for Brian. Thanks for taking the question. Can you just provide a little bit more color on what drove the Libtayo growth this quarter? Was there any stocking or was it largely demand-based? Thanks..

Thank you, Luke. And I'm pleased to share it is demand growth. Certainly, we see continued and steady performance across our skin indications both cutaneous squamous cell carcinoma and basal cell carcinoma.

In addition to that, it is exciting that we are seeing not only an increase in the number of prescribers for our lung cancer indications, but the depth of prescribing is improving and increasing in both the community and also academic settings. But that is demand based, it is not stocking based..

And I think Shannon we have time for two more questions, please..

Our next question comes from the line of David Risinger with Leerink Partners. Your line is now open..

Yes, thanks very much. So my question is for George, on the costims, please. You mentioned that you haven't seen the immune age with respect to your other costim trials.

Could you please comment on whether the dosing step-ups at this point are close to the higher dosing levels that you're stepping back from in the PSMA trial? I'm just trying to contextualize whether you really have advanced those other trials to the point to really know whether you're going to have similar problems in your other costim trials? Thanks very much..

That's a very good and fair question. And those programs are at earlier stages, so we won't know until we are more advanced, whether when we get to the same sort of efficacy type levels, do we have the same sort of immune-related adverse events associations or not.

What I was referring to is in the preclinical studies, the amount of this associated T-Cell activation that can lead to these sorts of immune-related adverse events varies depending on the tumor class and on the costim itself. So based on that we would expect to see different ratios of immune-related adverse events.

Those other programs though right now are all-in stages where they are in with full dose Libtayo combinations at this point..

Okay. Thanks, Shannon. We have time for one more question..

Our last question is from Akash Tewari with Jefferies. Your line is now open..

Hey, thanks so much. I'll switch it up. I guess maybe for your obesity program, you had data at the ADA showing synergy with your myostatin inhibition program when combined with the GLP-1. I guess the natural observation here is Regeneron doesn't currently have a program in development.

Is there any interest in acquiring one externally via BD or partnership at this time? Thanks..

Well, what we would say is, we do think that obviously, there's a lot of focus on obesity and particularly these new agents that are causing a large amount of weight loss.

But as you described is being increasingly recognized that the quality of this weight loss may prove challenging that many patients are actually losing muscle or lean body mass which is -- can be very detrimental particularly if they stay on these therapies or yoyo on and off them, that can really lead to substantial changes over-time and body composition can be very debilitating for patients.

And as you said, we've had long investment in programs that can maintain muscle mass in various settings and we've shown that they can maintain or even grow muscle mass in the setting of these types of obesity treatments in our preclinical modeling.

So obviously it is a very exciting opportunity to think about which is, can we combine some of our muscle preservation or growth strategies and biologics to prevent these concerning side effects that are being seen with the new class of profound weight loss agents. And so we are very actively pursuing everything that we can imagine.

And hopefully, we'll be providing updates on our approaches as time goes along..

Okay. Thanks, George, and thanks for everyone who dialed in today and for your interest in Regeneron. We apologize to those remaining in the queue that we did not have a chance to hear from. As always, the Investor Relations team is available to answer any remaining questions. Thank you once again and have a great day..

This concludes today's conference call. Thank you for participating. You may now disconnect..