Regeneron Pharmaceuticals - Q2 2023
August 3, 2023
Transcript
Operator (participant)
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 on a listen-only mode. Later, we will come to the 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.
Ryan Crowe (VP, Investor Relations)
Thank you, Shannon. Good morning, good afternoon, and good evening to everyone listening around the world. Thank you for your interest in Regeneron. 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 Robert 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 forecasting, 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 30, 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?
Leonard Schleifer (CEO)
Thanks, Ryan. 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 earnings 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. 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 biological 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, labeling, 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 we generally engage to complete vial filling for aflibercept 8 milligrams.
The inspection observations were noted in a Form 483 and were 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 milligram 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 milligram CRL. There is a clear understanding of the remediation work that is required to allow the FDA to resume 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, 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 3 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 milligram 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 twentieth. If not, we anticipate the FDA will act on a pozelimab and aflibercept 8 milligram BLAs before the end of the third quarter. In closing, we remain confident in our strategy of focusing investment 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.
George Yancopoulos (President and Chief Scientific Officer)
Thank you, Len. I would like to start with a recent update on aflibercept 8 milligrams data in DME that Len referred to. At the annual American Society of Retina Specialists meeting, we presented the 2-year results from our PHOTON study. These data demonstrated that the vast majority of aflibercept 8 milligrams patients 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 milligrams patients were able to maintain at least every 12-week dosing intervals for the entire 2-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 milligrams 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 milligrams and position this investigational medicine to become the future standard of care for 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 22, 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 eosinophilic 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 itepekimab and Dupixent could transform the treatment paradigm for COPD by leveraging 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%-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 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 the 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 MUC16 by CD3 bispecific, plus Libtayo in advanced ovarian cancer.
Last year, we showed encouraging ubamatamab monotherapy data in advanced ovarian cancer. We believe that combining it with Libtayo may lead to enhanced antitumor activity. Moving to costimulatory bispecifics. We're currently exploring multiple different CD28 costimulatory bispecific antibodies in early clinical trials in a variety of tumor settings, in combination with Libtayo or with corresponding CD3 bispecifics. In our phase I study of REGN5678, our PSMA by CD28 costimulatory bispecific in advanced prostate cancer in combination with Libtayo, which has demonstrated promising antitumor activity. The safety profile of this combination continues to pose a challenge, highlighted by a recently observed second grade 5 adverse event or death.
Although serious immune-mediated adverse events continue 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 antitumor 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, but with the challenge of focusing the response solely to the tumor. Our preclinical studies and mechanistic insight suggest that degree of immune-related adverse events seen when combining costims with PD-1 blockade may depend on the particular costim target and tumor type. 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 our 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 bispecific 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, U.S. and EU regulatory submissions for both relapse or refractory follicular lymphoma and diffuse large B-cell lymphoma remain on track.
Regarding linvoseltamab, our BCMA by CD3 bispecific, we recently presented updated data at the ASCO annual meeting, demonstrating early, deep, and durable responses in patients with heavily pretreated 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 6 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 of 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 the myeloma-specific co-stim 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 for 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 collaborators at 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 amyloid cardiomyopathy. 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.
Marion McCourt (EVP, Head of Commercial)
Thank you, George. In the second quarter, Regeneron delivered impressive results across our commercial portfolio. Notably, Regeneron medicines currently lead multiple disease categories. 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 mg 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, U.S. 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 this goal 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 mg, 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 $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. 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 U.S., 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 U.S. 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 U.S. 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. We are prepared to maximize opportunities from our robust pipeline with the goal of extending Regeneron's scientific innovation to even more patients. Now I will turn the call over to Bob.
Robert Landry (CFO)
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 U.S. Total Sanofi collaboration revenue was $944 million in the second quarter, improved 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 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 is related to the manufacturing of commercial supplies, for which we are reimbursed by Sanofi. As we continue to phase 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-U.S. 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 heme-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 phase-in 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 thirtieth, 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.
Ryan Crowe (VP, Investor Relations)
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 1 question from each caller before moving to the next. Shannon, can we go to the first question, please?
Operator (participant)
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Our first question comes from the line of Evan Seigerman with BMO. Your line is now open.
Evan Seigerman (Managing Director, Head of Healthcare Research and Senior Biotech Analyst)
Hi, guys. Thank you so much for taking my questions and on all the updates today. On the 8 mg CRL, do you have any idea if it's a Class 1 or Class 2 resubmission? 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.
Leonard Schleifer (CEO)
Hi, Evan. It's Len. Thanks for your question. 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. Let me remind you what happened. There was a preinsp-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 it, they will review the remediation efforts in the context of the pozelimab BLA, and therefore, whatever happens there will govern the timeline and results. 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'll be in a position to promptly make a decision on approval for the 8 milligrams. Does that answer your question?
George Yancopoulos (President and Chief Scientific Officer)
He's off the line. We'll, we'll move to the next question.
Leonard Schleifer (CEO)
Okay.
George Yancopoulos (President and Chief Scientific Officer)
Shannon?
Operator (participant)
Our next question comes from the line of Tyler Van Buren with TD Cowen. Your line is now open.
Tyler Van Buren (Analyst)
Hi there. Good morning. Thanks for taking the question. The timeline to the FDA potentially taking action by the end of this quarter on high-dose EYLEA is very encouraging. Investors are clearly surprised by the short timeline, kudos to you all for executing. As we think about the data submission in 2 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?
Leonard Schleifer (CEO)
Right. Great question. We've been in very close contact with Catalent and the FDA, multiple meetings, oral, written, and so forth. 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.
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, as soon as possible. That's why we have confidence about this getting done in this quarter. To summarize, the data has been coming in on a rolling basis. We have everything we need. The last piece of information will be rolling in and submitted by the middle of the month. The FDA will strive expeditiously to review that in turn, in time for the August 20th PDUFA date.
If not, there'll be a clock extension for up to 3 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.
George Yancopoulos (President and Chief Scientific Officer)
Okay, thanks, Len. Next question, please, Shannon.
Operator (participant)
Our next question comes from the line of Mohit Bansal with Wells Fargo. Your line is now open.
Mohit Bansal (Analyst)
Great. Thank you very much for taking my question, and, and really thank you very much for providing all the clarity on, on, on, on the filing situation right now. Just trying to understand this a little bit more. 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?
Leonard Schleifer (CEO)
Actually, the, 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. 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.
George Yancopoulos (President and Chief Scientific Officer)
Let me further say, there's 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.
Leonard Schleifer (CEO)
Yeah, that's a very good point, George. It, 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. One remediation satisfies both. All the data and information are 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 review that 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'll set the clock back three months. Notwithstanding that three months, they've told us that they will continue to prioritize our review. We're very pleased, and we're working very hard. Catalent's working very hard.
The FDA is working very hard. Everybody wants this, done properly and finished, and properly remediated.
George Yancopoulos (President and Chief Scientific Officer)
Okay, next question, please, Shannon.
Operator (participant)
Our next question comes from the line of Tim Anderson with Wolfe Research. Your line is now open.
Tim Anderson (Managing Director)
... thank you, very much. I have a question on, on the Vabysmo. Roche at Q3 said they're capturing 30% of treatment-naive patients, which seems like a, a quite high figure, frankly. Then they said afterwards that it's not the extended dosing that's driving this as much as it is the better drawing that they say docs are, seeing with their product. I'm wondering how those comments kind of line up with what you're seeing play out, in the U.S. market. Thank you.
Marion McCourt (EVP, Head of Commercial)
Sure. So Tim, I will comment on our EYLEA performance. You know, as I just shared with you, the performance in the quarter was, was strong. Certainly, we see EYLEA steadily as the standard of care in the anti-VEGF category. We continue to capture not only naive patients, but also another big source of business is switch patients from Avastin. You know, obviously, the other branded competitors are smaller in market today. I would say that, you know, beyond your comment, probably best to get more clarification from, you know, the individuals who are commercializing for aflibercept in the market.
Certainly, I do want you to know that we are seeing, you know, continued strength in EYLEA performance, and obviously, very much look forward to having the potentially game-changing opportunity of bringing aflibercept 8 mg into the marketplace, you know, 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.
George Yancopoulos (President and Chief Scientific Officer)
Thanks, Marion. Next question, please.
Operator (participant)
Our next question comes from the line of Chris Raymond with Piper Sandler. Your line is now open.
Chris Raymond (Senior Research Analyst)
Yeah, thanks. Just maybe another market, VEGF market-related question. I, I know, you know, these extended dose therapies have benefits in and of themselves on the face of, 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, for geographic atrophy patients. You know, specifically, the, you know, with the Apellis drug. Just maybe curious, how widespread was that notion before the Kevzara safety issue? Now with, with the issue, have you noticed a discernible shift among docs who are talking about that? Then maybe a related question, you guys have talked, I think, about an early effort of your own in geographic atrophy. You know, clearly, the market's sizable. When could we expect to hear more about that effort?
Marion McCourt (EVP, Head of Commercial)
You know, let me share first in terms of the market dynamic. I think the most exciting thing and most important thing about aflibercept 8 milligrams is that it gives prescribers for all of their patients, whether, you know, a naive patient, a patient currently on EYLEA, or a patient on another anti-VEGF category product, you know, the opportunity to decide if that patient is a candidate when we launch and, you know, when we have an FDA approval, if the patient is a candidate for aflibercept 8 milligrams, 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 a category that we're not directly involved in.
We are, though, very focused on making sure that we are ready for launch and certainly, you know, at the proper time, educating all stakeholders on aflibercept 8 milligrams once we have an approval.
George Yancopoulos (President and Chief Scientific Officer)
In, 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. We believe that we may have an approach that may allow potentially treatment in these retinal diseases while avoiding some of the very concerning adverse events having to do with issues like occlusive vasculitis and so forth. 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.
Operator (participant)
Our next question comes from the line of Carter Gould with Barclays. Your line is now open.
Carter Gould (Senior Analyst, U.S. Biopharma Equity Research)
Great. Good morning, and thanks for all the transparency. maybe switching gears a bit in terms of the update on your co-stim and the report of the death and the change in the dosing paradigm with REGN5678 in combination with Libtayo. George, maybe you can speak about the implications for other combination efforts of CD28s with Libtayo. Is this gonna require a lower dosing with those efforts with on the Libtayo portion, and just the broader implications there, and just so your level of confidence, you can kind of, you know, thread that, thread that needle in terms of the dosing levels. Thank you.
George Yancopoulos (President and Chief Scientific Officer)
Right, now, 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. I think that that excitement continues with the Costim platform in terms of all of the science and the preclinical modeling and predictions have really delivered in terms of showing that this new class does seemingly have the ability to really change the efficacy paradigm. Now we have to balance that, as you said, with the safety, 'cause 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 co-stim target. What you see for one co-stim doesn't necessarily apply to the other co-stim. We are, as you said, for our-... PSMA co-stim, moving at a lower doses of the Libtayo, because the full dose combination, while it seems like it has the potential to be very efficacious, also has, in some cases, these associated, only in, remember, only in the patients who are having deep responses, these associated, in, in some cases, they can be very serious, even resulting, in, in, in, in deaths associated immune adverse events.
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 co-stims. 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, co-stim in combination with Libtayo, are not seen preclinically when you combine with the CD3 bispecifics. We are very aggressively trying to move forward those programs as well, where we hope we might even have a better efficacy safety profile. It's both a very exciting time to have these very active molecules.
Remember, remind you, we have 3 classes now, 3 independent classes of very active molecules that have been individually validated in our portfolio. We have the checkpoint inhibitors, in particular, our PD-1 and our LAG-3 checkpoint inhibitors, which are validated. We have our CD3 bispecifics, which are validated, and we now have our co-stims, 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 benefit, relative to the potential adverse events we would see in the patients.
Leonard Schleifer (CEO)
Thanks, George. Next question, please.
Operator (participant)
Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is now open.
Salveen Richter (Lead Analyst, U.S. Biotechnology Sector)
Good morning. Thanks for taking my question, and nice updates this morning. You know, 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. Kind of a 2-part question here. What are the dynamics around this, and how do you, on one hand, kind of maintain and grow this switch population from EYLEA? Secondly, how should we think about the uptake of high-dose EYLEA without a permanent J-code? Thank you.
Marion McCourt (EVP, Head of Commercial)
Hi, Salveen. I'll get started. You know, certainly we're conscious of the dates and the requirement for submissions to CMS that occur at the start of a quarter. You know, 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 milligrams 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. Obviously, we wanna 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.
Leonard Schleifer (CEO)
Okay, thanks, Marion. Shannon, please move to the next question.
Operator (participant)
Our next question comes from the line of Terence Flynn with Morgan Stanley. Your line is now open.
Terence Flynn (Equity Research Analyst)
Great. Thanks so much for taking the question. Len, I know we've talked about this before, but the company's been somewhat nontraditional on pricing decisions historically. You guys priced EYLEA at a discount to Lucentis. You worked with ICER on Dupixent pricing. Just wondering why we shouldn't expect a similar approach here with high-dose EYLEA? Thank you.
Leonard Schleifer (CEO)
Thanks, Terence. If, if your comments, referencing similar mean thoughtful and appropriate, we would agree.
George Yancopoulos (President and Chief Scientific Officer)
Okay. next question, please, Shannon.
Operator (participant)
Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is now open.
Brian Abrahams (Managing Director, Senior Research Analyst)
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 reinspection would not be required? Have you had any interactions or feedback with the agency around this? Is there a defined period of time where the FDA would need to wait reinspection or not, to ensure that the remediations are sustainable before approving the BLAs? Thanks.
Leonard Schleifer (CEO)
Great. Thanks for your question. Well, we've tried to be a 1,000% transparent as usual at 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. If they can't, they said there would be a three-month clock extension.
Even with the three-month clock extension, they've been very categorical in saying that they would prioritize a 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. We've given you our best estimate at this point.
Speaker 20
Thanks, Len. Let's move to the next question, please.
Operator (participant)
Our next question comes from the line of Chris Schott with J.P. Morgan. Your line is now open.
Chris Schott (Managing Director, Equity Research)
Great, thanks so much. Can I 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.
George Yancopoulos (President and Chief Scientific Officer)
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 co-stim side, but we've been doing all of them in the context of the full dose Libtayo. Now what we're doing is we're exploring some of the doses that are active, particularly ones that are active as monotherapy. As I mentioned, there is monotherapy activity with the PSMA co-stim, now we're to try to decrease these immune-related adverse events. Let me remind you, they are in 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.
We're hoping that lowering the checkpoint inhibition may allow us to adjust the therapeutic window there. We are, as you're saying, dealing with a couple different doses of the co-stim, but now we're incorporating lower doses of the Libtayo into the program as well.
Leonard Schleifer (CEO)
I, I think what George said earlier, and 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 are, for the most part, in the patients who are benefiting with the efficacy. That's a very good position to begin to explore on how to get the therapeutic index or signal-to-noise, as George calls it, right.
Speaker 20
Okay. Let's move to the next question, Shannon. Thank you.
Operator (participant)
Our next question comes from the line of Dane Leone with Raymond James. Your line is now open.
Dane Leone (Managing Director, Senior Biotech Analyst)
Hi, thank you for taking the questions. Congratulations on the updates, and best of luck with the resolution of the reviews for pozelimab and aflibercept 8 milligrams. 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 is 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.
George Yancopoulos (President and Chief Scientific Officer)
Yeah. What we know right now is that we're gonna 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.
Speaker 20
Okay. Thanks, George. Hopefully, an update soon. Next question, please.
Operator (participant)
Our next question comes from the line of Colin Bristow with UBS. Your line is now open.
Colin Bristow (Managing Director, Biotech Analyst)
Hey, good morning, and congrats on the quarter and the progress. Just maybe one on the itepekimab interim. Can you, can you share anything on the futility thresholds? If not specifically, then could you say how these sort of fared relative to BOREAS? Thanks.
Leonard Schleifer (CEO)
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.
Speaker 20
Yeah, both we and Sanofi are, are blinded to that. We only got the go decision from the independent Data Monitoring Committee. We'll proceed to a, a final readout for both of those studies. Let's go to the next question, please.
Operator (participant)
Our next question comes from the line of Brian Skorney with Baird. Your line is now open.
Speaker 21
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.
Marion McCourt (EVP, Head of Commercial)
Thank you, Luke, and, yeah, 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. That is demand-based. It is not stocking-based.
Speaker 20
Okay. I think, Shannon, we have time for 2 more questions, please.
Operator (participant)
Our next question comes from the line of David Risinger with Leerink Partners. Your line is now open.
David Risinger (Managing Director, Senior Research Analyst)
Yes, thanks very much. Excuse me. My question is for George on the co-stims, please. You mentioned that you haven't seen the immune AE with respect to your other co-stim 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 gonna have similar problems in your other co-stim trials. Thanks very much.
George Yancopoulos (President and Chief Scientific Officer)
You know, that's a very good and fair question, and those programs are at earlier stages. We won't know until we're more advanced, whether when we get to the same sort of efficacy type levels, do we have the same sort of immune-related adverse event 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 co-stim itself. 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're in with full dose Libtayo combinations at this point.
Ryan Crowe (VP, Investor Relations)
Okay, thanks, Shannon. We have time for one more question.
Operator (participant)
Our last question is from Akash Tewari with Jefferies. Your line is now open.
Akash Tewari (Managing Director, Equity Research)
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.
George Yancopoulos (President and Chief Scientific Officer)
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. As you described, it's 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 yo-yo on and off them. That can really lead to substantial changes over time in body composition, and can be very debilitating for patients.
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. 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? We are very actively pursuing everything that we can imagine, and hopefully, we'll be providing updates on our approaches as time goes along.
Ryan Crowe (VP, Investor Relations)
All right, thanks, George. 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.
Operator (participant)
This concludes today's conference call. Thank you for participating. You may now disconnect.