Q1 2022 Regeneron Pharmaceuticals Inc Earnings Call

Gigi: Welcome to the Regeneron Pharmaceuticals first quarter 2022 earnings conference call. My name is Gigi, and I'll be your operator for today's call. At this time, all participants are in a listen-only mode.

Welcome to the Regeneron Pharmaceuticals first quarter 2022 earnings Conference call. My name is Jay and I'll be your operator for today's call. At this time all participants are in a listen only mode. Later, we will conduct a question answer session. Please note that this conference is being recorded.

Ryan Crowe: 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, Gigi. Good morning, good afternoon, and good evening to everyone listening around the globe.

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

Ryan Crowe: Thank you for your interest in Regeneron and welcome to our first quarter 2022 earnings conference call. An archive of this webcast will be available on our Investor Relations website shortly after the call ends. Joining me today are Dr. Leonard Schleifer, Founder, President, and Chief Executive Officer; Dr. George Yancopoulos, 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.

Thank you Gigi good morning, good afternoon, and good evening to everyone listening around the globe.

Thank you for your interest in Regeneron and welcome to our first quarter 2022 earnings conference call.

An archive of this webcast will be available on our Investor Relations website. Shortly after the call ends.

Joining me today are Dr. Leonard Schleifer, founder President and Chief Executive Officer, Dr. George <unk> 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.

Ryan Crowe: After our prepared remarks, we will open the call for Q&A. I would also like to remind you that remarks made on this call today include forward-looking statements about Regeneron. Such statements may include, but are not limited to, those related to Regeneron and its products and businesses, financial forecasting guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, payer coverage, and reimbursement, 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.

After our prepared remarks, we will open the call for Q&A.

Ryan Crowe: 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 March 31, 2022, 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 the reconciliation of those measures to GAAP is available in our financial results press release, which can be accessed on our website.

I would also like to remind you that remarks made on this call. Today include forward looking statements about regeneron.

Such statements May include but are not limited to those related to regeneron and its products and businesses financial forecasts and guidance development programs and related anticipated milestones collaborations finances regulatory matters payer coverage and reimbursement issues intellectual property pending litigation and other proceedings and.

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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 filings with the United States Securities and Exchange Commission, including its Form 10-Q for the quarterly period ended March 31, 2022, 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 on our financial results press release, which can be accessed on our website.

Ryan Crowe: Once our call concludes, Bob Landry and the IR team will be available to answer any further questions. This earnings call is neither an offer to purchase nor a solicitation of an offer to sell securities of Checkmate Pharmaceuticals Inc. In connection with the tender offer for Checkmate stock, Regeneron and Scandinavian Acquisitions Inc. filed with the SEC a tender offer statement on Schedule T-0 and other tender offer materials, and Checkmate filed a solicitation recommendation statement on Schedule 14-D-9 with the SEC.

Once our call concludes Bob Landry and the IR team will be available to answer any further questions.

This earnings call is neither an offer to purchase nor a solicitation of an offer to sell securities of Checkmate Pharmaceuticals, Inc.

Connection with the tender offer for Checkmate stock Regeneron and Scandinavian acquisition Sub Inc filed with the SEC and tender offer statement on schedule T O and other tender offer materials and checkmate filed a solicitation recommendation statement on schedule 14D-9 with the SEC.

Ryan Crowe: Copies of the documents filed with the SEC by Regeneron and Checkmate are available free of charge on Regeneron's website at investor.regeneron.com or on Checkmate's website at ir.checkmatepharma.com, as applicable, or at the SEC's website at www.sec.gov. You should review such materials filed with the SEC carefully because they contain or will contain important information about the tender offer for checkmate stock that holders of checkmate securities and other investors should consider before making any decision with respect to the tender offer. With that, let me turn the call over to our President and Chief Executive Officer, Dr. Len Schleifer. Len

Copies of the documents filed with the SEC by Regeneron and Checkmate are available free of charge on regeneron to website and investor that Regeneron dot com or on Checkmate Checkmates website at IR Dot checkmate pharma dot com as applicable or at the SEC's website at Www Dot FCC Dot Gov.

You should review such materials filed with the SEC carefully because they contain or will contain important information about the tender offer for checkmate stock that holders of checkmate securities and other investors should consider before making any decision with respect to the tender offer with that let me turn the call over to our President and Chief Executive Officer, Dr. Len Schleifer Len.

Len Schleifer: Thank you, Ryan. Welcome to your first earnings call. I hope all of our stakeholders will join me in giving you a warm welcome to the Regeneron team. Thanks to everyone joining the call as well. Following an exceptional 2021, Regeneron is off to a strong start in 2022. Our first quarter results were driven by execution across the entire company as we continue to realize the benefits of our sustained investment in differentiated research and development, along with our focus on commercial performance. We also continue to drive shareholder value through prudent capital allocation, including approximately $350 million of share repurchases in the first three months of this year.

Thank you, Brian and welcome to your first earnings call.

I hope all of our stakeholders will join.

Join me in giving.

Giving you a warm welcome to the Regeneron team, thanks to everyone joining the call as well.

Following an exceptional 2021 regeneron is off to a strong start in 2022.

Our first quarter results were driven by execution across the entire company as we continue to realize the benefits of our sustained investment in differentiated research and development along with our focus on commercial performance.

We also continue to drive shareholder value through prudent capital allocation, including approximately $350 million of share repurchases in the first three months of this year.

Len Schleifer: Regarding our financial performance, we delivered strong double-digit revenue and non-gap earnings per share growth. Excluding revenue contributions from our investigation of COVID antibody cocktails, revenues grew 25%, reflecting our increasingly diversified core business, which continues to thrive.

Regarding our financial performance, we delivered strong double digit revenue and non-GAAP earnings per share growth, excluding revenue contributions from our investigation Covid antibody cocktail.

Revenues grew 25%, reflecting our increasingly diversified core business, which continues to thrive.

Len Schleifer: For ILEA, global net sales grew 11% to nearly $2.4 billion in the first quarter, including $1.5 billion of revenues in the United States, up 13% versus last year, which outpaced the U.S. anti-VEGF category growth. And yet another milestone for ILEA, after more than 10 years, we recently surpassed 50 million ILEA injections globally, a testament to its well-established efficacy and safety profile. We believe ILEA continues to represent a significant long-term growth opportunity, primarily driven by an aging population, increasing utilization among a rapidly growing diabetic population, as well as the potential for investigational flibbers at eight milligrams to complement and enhance our retinal franchise.

Before I leave global net sales grew 11% to nearly $2 4 billion in the first quarter, including $1 5 billion of revenues in the United States up 13% versus last year, which outpaced the U S anti VEGF category.

And yet another milestone for Eylea after more than 10 years, we recently surpassed 50 million Eylea injections globally, a testament to its well established efficacy and safety profile.

We believe Eylea continues to represent a significant long term growth opportunities primarily.

Driven by an aging population increasing utilization among our rapidly growing diabetic population as well as the potential for investigational flip is at eight milligrams to complement and enhance our retinal franchise.

Len Schleifer: For Dupixent in Quarter 1, global revenues for the quarter exceeded $1.8 billion, an increase of 43% compared to last year, as we continue to redefine the treatment of Type 2 Inflammatory Diseases. A significant opportunity remains to reach even more patients in already-approved indications, and we look forward to potentially launching Dupixen in several new indications in the U.S. later this year and in early 2023, including pediatric atopic derma Collectively, approximately 200,000 U.S. patients are suffering from these three indications today but currently have no FDA-approved systemic treatment. In oncology, Liftyl continues to capture a significant share in FDA-approved non-melanoma skin cancer indications, where it is considered the standard of care.

So depiction in quarter, one global revenues for the quarter exceeded $1 8 billion, an increase of 43% to last year. As we continue continued to redefine the treatment of type two inflammatory diseases.

A significant opportunity remains to reach even more patients and already approved indications and we look forward to potentially launch depiction and seven new indications in the US Later this year and in early 2023, including pediatric atopic dermatitis is Senate silicon Esophagitis Emperor.

I go to the July hours.

Actively approximately 200000 U S patients.

Nothing from these three indications today, but currently have no approved FDA no F D. A approved systemic treatment options.

In oncology titled continues to capture significant share in FDA approved non melanoma skin cancer indications, where it is considered the standard of care.

Len Schleifer: Beyond dermato-oncology, we're beginning to generate momentum in monotherapy non-small-cell lung cancer in the United States, helping to build a foundation for a potential launch of Liptio plus chemotherapy later this year, which would allow Liptio to address a much larger population of non-small-cell lung cancer patients. As we have said before, we continue to consider LIBTIO to be foundational to our immuno-oncology development strategy and expected to serve as the backbone for our investigation of the clinical program in combination with various antibodies by specific, and co-stimulatory biospecifics in our pipeline, as well as other pipeline candidates, including those from our collaboration. In April, we announced our agreement to acquire Checkmate Pharmaceuticals, Regeneron's first-ever acquisition of a company.

And as a matter of oncology, we're beginning to generate momentum in monotherapy non small cell lung cancer in the United States.

Helping to build a foundation for a potential launch of <unk> plus chemotherapy later, this year, which would allow us to address a much larger population of non small cell lung cancer patients.

As we've said before we continue to consider the dio to be foundational to our immuno oncology development strategy and expected to serve as the backbone for our investigational clinical program in combination with various antibodies by specifics and coasting stimulatory by specifics in our pipeline.

As well as other pipeline candidates, including those from our collaborations.

Len Schleifer: Upon closing, we expect Checkmate's differentiated toll receptor 9 agonist, V-Dutolimod, will add a promising new modality to Regeneron's pipeline of potential approaches for difficult-to-treat cancer. Looking ahead, we remain on track for the second half of this year to share data in difficult-to-treat solid tumors such as ovarian and prostate cancers, to submit a BLA for ojonextamib, a potentially best-in-class CD20 by CD3 bispecific for refractory B-cell lymphomas, and to Advance Regeneron 5458 is BCMA by CD3 by specific.

In April we announced the agreement to acquire Checkmate Pharmaceuticals, we general its first ever acquisition of a company.

In closing, we expect checkmates differentiated C a T.

<unk> receptor nine agonists <unk> told them.

We'll add a promising new modality to a general its pipeline of potential approaches for difficult to treat cancers.

Looking ahead, we remain on track for the second half of this year to share data in difficult to treat solid tumors, such as ovarian and prostate cancers to submit a BLA for <unk> next to map, our potentially best in class CD 20 by CD three bispecific, so refractory b cell lymphomas.

And to advance Regeneron and 50 458, our B C M. A C D three by specific.

Len Schleifer: Finally, regarding our ongoing COVID-19 program, Regeneron remains committed to combating the virus as we head toward the likely endemic stage. We firmly believe that monoclonal antibodies will continue to play an important role, particularly to protect immunocompromised individuals who do not respond adequately to COVID-19 vaccines, as well as to treat infected patients for whom an oral antiviral therapy is not well-tolerated or might trigger serious drug

Finally regarding the ongoing COVID-19 response, we generally remains committed to combating the virus as we head towards the likely endemic stage. We firmly believed that monoclonal antibodies will continue to play an important role, particularly to protect immunocompromised individuals who do not respond adequately.

COVID-19 vaccines as well as the treating infected patients, whom in all events are all anti viral therapy is not well tolerated or might trigger serious drug drug interactions.

Len Schleifer: We are progressing next-generation antibodies that are designed to be active against multiple variants, including those of the Omicron lineage, and initiated a first-in-human study last month. Meanwhile, the FDA continues its review of our Regenco BLA for COVID-19 treatment and prophylaxis. We are working closely and collaboratively with them and other global regulatory authorities to establish clinical and regulatory pathways to bring additional safe and effective monoclonal treatment options to patients as quickly as possible.

We are progressing next generation of antibodies that are designed to be active against multiple bands.

<unk> those are all mcmullen lineage and initiated a first in human study last month.

Concurrently as the FDA continues their review of our Gen <unk> BLA for COVID-19 treatment and prophylaxis.

We're working closely and collaboratively collaboratively with them and other global regulatory authorities to establish clinical and regulatory pathways to bring additional safe and effective medical treatment options to patients as quickly as possible.

Len Schleifer: In closing, we are excited about the strong commercial momentum for our inline portfolio and the progress we have made advancing our pipeline so far this year. For the remainder of 2022, we anticipate up to eight additional U.S. and EU regulatory approvals, up to four additional U.S. or EU regulatory filings, pivotal data for Flivix at 8 milligrams, as well as various other data readouts from other pipeline programs. George will discuss.

In closing we are excited about the strong commercial momentum for our in line portfolio and the progress we have made advancing our pipeline so far this year.

For the remainder of 2022, we anticipate up to eight additional U S and EU regulatory approvals up to four additional U S or EU regulatory filings pivotal data for sliver at eight milligrams as well as various other data readouts from other pipeline programs, which George will discuss.

Len Schleifer: We remain confident in the long-term outlook for our business, and our pipeline continues to be highly productive, and we are in a strong financial position, all of which positions Regeneron to deliver sustainable growth and long-term value creation. Now I will turn the call over to you, Len. And I will start with ophthalmology.

We remain.

Confident in the long term outlook for our business and our pipeline continues to be highly productive and we are in a strong financial.

Addition.

All of which positions regeneron to deliver sustainable growth and long term value creation now I will turn the call over to George.

Thank you Lynn and I will start with ophthalmology today at the recent angiogenesis meeting we presented encouraging results for the phase II Candela study of a flipper set of eight milligram in patients with wet AMD Cindy element. The primary safety endpoint with no new safety signals observed through week, 44, and efficacy endpoints newmar.

George Yancopoulos: At the recent angiogenesis meeting, we presented encouraging results for the Phase II Candela study of a flibrosome of 8 mg in patients with wet AMD. Candela met the primary safety endpoints with no new safety signals observed through Week 44, and efficacy endpoints numerically favored a flibrosome of 8 mg in visual acuity, drying, and other anatomical measures through Week 44. Phase 3 studies, Photon in DME and Pulsar in wet AMD, are ongoing.

<unk> favorite of flips of eight milligram and visual acuity, drawing and other anatomical measures through week 44.

Phase III studies photon and D Army and pulsar and wet AMD are ongoing the primary objective of the phase III studies to determine whether bluebird sub eight milligram dosing can allow for more extended dosing intervals.

George Yancopoulos: The primary objective of the Phase 3 studies is to determine whether a Flibersev 8 mg dose can allow for more extended dosing intervals while maintaining efficacy and safety. Regarding phase 3 design, in both photon and repulsor studies, patients are randomized at baseline to three groups, and every 8-week ILEA 2-milligram and every 12 week, 8 mg of Flivicept arm and every 16 week, 8 mg of Fl The primary endpoint of both these studies was the mean change in best corrected visual acuity, or BCDA, at week 48.

Maintaining efficacy and safety.

Regarding phase III design in both photon and the Pulsar study patients are randomized at baseline to three groups in every eight week Eylea two milligram arm and every 12 week eight milligram Photoshop dorm. Then every 16 week eight milligram bluebird kept on following loading doses.

Primary end point of both these studies as mean change in best corrected visual acuity, where B C. D. E. At week 48. The primary end point will be met if eight milligram of Bluebird is non inferior to two milligram eylea.

George Yancopoulos: The primary endpoint will be met if 8mg of flibrosep is non-inferior to 2mg ileo while being dosed less frequently. We anticipate results for both Photon and Pulsar in the second half of this year, and if possible, we will file for regulatory approvals in the U.S. and EU by early 2022. Moving to Dupixent, which had a remarkable quarter in terms of clinical updates and regulatory progress. In January, we announced our second positive phase 3 study in Purago Nodularis, a disease with high unmet need.

<unk> dosed less frequently we anticipate results at both photon impulsion in the <unk>.

Second half of this year and if positive to file for regulatory approvals in the U S and EU by early 2023.

Moving to depict which had a remarkable quarter in terms of clinical updates and regulatory progress.

In January we announced our second positive phase III study in Prurigo Nigel era.

Disease with high unmet need at the Quad AI and AAD meeting. This year, we presented detailed data from the first positive phase III study in Prurigo Nigel Arris.

George Yancopoulos: At the Quad AI and AAD meetings this year, we presented detailed data from the first positive phase 3 study in Purago Nodularis. We also presented detailed data from our positive Phase III studies in eosinophilic esophagitis and in chronic spontaneous urticaria, or CSU, in biologic nave patients. The second phase 3 CSU study in patients refractory to omelizumab did not reach statistical significance in an interim analysis.

We also presented detailed data from our positive phase III studies in eosinophilic, esophagitis, and chronic spontaneous urticaria or CSU in biologic naive patients.

Second phase III CSU study in patients refractory to Omalizumab did not reach statistical significance in an interim analysis.

George Yancopoulos: And, as announced in March, we have completed enrollment in the first of the two phase three duplexing studies in COPD and anticipate data from this first study to read out in the first half of next year. In terms of regulatory progress, we expect an FDA decision for Dupixan in children aged 6 months to 5 years with moderate to severe atopic dermatitis by the June 9th PDUFA date. We are also excited about an upcoming trial in collaboration with the National Institute of Allergy and Infectious Diseases, or the NIAID, to assess the efficacy and safety of Dupixan for asthma in underserved populations, including black and Hispanic children in the United States.

As announced in March we have completed enrollment in the first of the two phase III studies in C. O P D and anticipate data from this first study to read out in the first half of next year.

In terms of regulatory progress, we expect an FDA decision for depiction in children, aged six months to five years with moderate to severe atopic dermatitis by the new Junior I do predict. We're also excited about an upcoming trial in collaboration with the National Institute of allergy and infectious diseases.

The N I E I D to assess efficacy and safety of two pixels for asthma in underserved populations, including black and Hispanic children in the United States.

George Yancopoulos: Additionally, we're expecting an FDA decision for our supplementary BLA and eosinophilic esophagitis in patients 12 years and older by August 3rd, and we completed a regulatory submission for Porygon Agillaris, indication with FDA acceptance of this application. Participated. Short.

Additionally, we are expecting an FDA decision for a supplementary BLA in eosinophilic esophagitis in patients 12 years and older by August 30.

We completed our regulatory submission for Prurigo, Nigel Arris indication with the FDA acceptance of this application.

Anticipated shortly.

George Yancopoulos: Moving to Leptile and Oncology. We are excited about the upcoming milestones in our oncology pipeline, including the FDA decision on our Leptile Chemo Combo application for non-small cell lung cancer, Data readouts and potential regulatory filings for our hematology bispecifics, as well as initial data readouts from our bispecific antibodies for solid tumors. In hematology, adrenaxumab, or CD20 by CD3 bispecific, has the potential for best-in-class efficacy in both follicular and diffuse large B-cell lymphoma and was recently granted fast-track designation from the FDA for these indications.

Moving to the tile and oncology.

We are excited about the upcoming milestones in our oncology pipeline, including the FDA decision on our lip Tayo chemo combo application for non small cell lung cancer data readouts and potential regulatory filings for a hematologist by specifics as well as initial data readouts from our Bispecific antibodies for solid tumors.

In hematology, our gene extra map, our CD 20 by two three by specific is the potential for best in class efficacy in both Follicular and diffuse large b cell lymphoma and was recently granted fast track designation from the FDA for these indications detailed results of our first in human study were recently published in lancet.

George Yancopoulos: Detailed results of our first incubant study were recently published in Lancet Hematology, and our registration intent programs in late-stage folliculofoam and DLBCL are expected to complete enrollment soon. Based on the safety profile we are observing from our updated step-up dosing regimen, we believe Odronexamab has the potential to be administered entirely within the outpatient setting. We look forward to filing with this updated data set later this year pending regulatory feedback from the FDA.

Hematology and our registration and 10 programs in late stage Follicular lymphoma in D. C. L are expected to complete enrollment soon based on the safety profile. We are observing from our updated step up dosing regimen. We believe <unk> has the potential to be administered entirely within the outpatient setting.

We look forward to filing with this updated dataset later this year pending regulatory feedback from the FDA.

George Yancopoulos: Development of REGEN 5458, a BCMA by C3 bi-specific investigated for relapsed or refractory multiple myeloma, remains on track and, pending regulatory feedback, we are planning to submit regulatory approval in the first half of 2023. Studies in earlier lines of the disease, as well as an umbrella study in multiple myeloma investigating 5458 in combination with various standard care products and investigational candidates, will begin In the second half of the year, we anticipate initial clinical data disclosures for three first-in-class bispecifics: our MUX16 by CD3 monotherapy for late-stage ovarian cancer, our MET by MET bispecific antibody for MET-altered non-small-cell lung cancer, as well as our PSMA by CD28 co-stem bispecific in combination with liptyle in late-stage prostate cancer.

Development of region 5458, RBC made by T. Three by specific investigated for relapsed or refractory multiple myeloma remains on track and pending regulatory feedback we are planning to submit regulatory approval in the first half of 2023 studies in earlier lines of the disease as well as an umbrella study in multiple myeloma.

Investigating 50 458 in combination with various standard of care products and investigational candidate will begin enrollment shortly.

In the second half of the year, we anticipate initial clinical data disclosures for three first in class Bispecific or must 16 by T. Three monotherapy for late stage ovarian cancer are met by net bi specific antibody for met altered non small cell lung cancer as well as our P. SMA by CD 28 coastal biases.

In combination with with time in late stage prostate cancers, where these late stage cancers patients have limited options and showing any durable response would be a promising early signs to be confirmed with additional clinical studies also involving combinations with.

George Yancopoulos: For these late-stage cancers, patients have limited options, and showing any durable response would be a promising early sign to be confirmed with additional clinical studies also involving combinations. We continue to progress our strategic approach to oncology, which starts with Liptio as our foundational anti-PD-1 therapy and is augmented by logical combinations utilizing our broad oncology pipeline, whether it involves combining Liptio with a second checkpoint inhibitor, as we are doing with our LAG-3 antibody in melanoma and other settings, with different combinations of bispecifics, or with other agents in our portfolio.

We continue to progress our strategic approach to oncology, which Josh will look tires are a foundational anti PD, one therapy and is augmented by logical combinations utilizing our broad oncology pipeline with.

It involves combining with tile with a second checkpoint inhibitor, because we are doing with our lag three antibody in melanoma and other settings with different combinations of bi specifics or with other agents in our portfolio.

George Yancopoulos: Turning to our antibodies against COVID-19, as we recently announced, the FDA extended its review of our RegenCo BLA for COVID-19 treatment and prophylaxis with a new action date of July 13th. This extension was due to ongoing discussions with additional data provided to the FDA on pre-exposure prophylaxis use of Regen-Co. As this regulatory process continues, we are advancing next-generation COVID-19 antibodies and initiated a first-in-human trial with a new candidate in April.

Briefly turning to our antibodies against COVID-19, as we recently announced the FDA extended its review of our region Cobia like COVID-19 treatment and prophylaxis with a new action date of July 13th.

This extension was due to ongoing discussions with additional data provided to the FDA on pre exposure prophylaxis use a region cope.

This regulatory process continues.

We are advancing next generation COVID-19 antibody and initiated a first in human trial with a new candidate and in April we.

George Yancopoulos: We continue to believe that a major unmet need for COVID antibodies is in chronic disease prevention for immunocompromised patients, and future development efforts will be addressing this population. Finally, closing with our Regeneron Genetics Medicine, where we and collaborators continue to advance our pipeline. For our siRNA collaboration with Elm Island, we are very excited about our first-in-class approach to combining siRNA with antibody therapeutics designed to maximize effect as well as duration of target blockade. The first of these is our C5-SIRNA antibody combination, Simgistrin plus pozolivin. Phase III studies of the combination treatment for paroxysmal nocturnal hemoglobinuria, or PNH, and myasthenia gravis are underway, but will start dosing patients shortly.

To believe that a major unmet need for Covid antibodies is in chronic disease prevention for immunocompromised patients and future development efforts will be addressing this population.

Concluding with our Regeneron genetics medicine, where we and collaborators continue to advance our pipeline.

Or S. Irna collaboration with island, we are very excited about our first in class approach to combining S. I RNA with antibody therapeutics designed to maximize the effect as well as duration of target blockade.

The first of these is our <unk> SA RNA anybody combination some distress plus puzzle loopnet phase.

Phase III studies of the combination treatment for paroxysmal nocturnal hemoglobinuria, where pn age and myasthenia gravis are underway, we'll be dosing patients shortly in teenage we're planning to test our combo in both naive and switch patients tested against standard of care therapies, including Red you lose demand and <unk> map.

George Yancopoulos: In PNH, we are planning to test our combo in both naive and switch patients tested against standard of care therapies, including Revulizumab and Eculizumab. The ONC-V several edition combination programs are in our preclinical pipeline. We continue to work with Elm Island as leaders in the use of siRNA therapeutics to address non-alcoholic steatohepatitis, or NASH, with several programs addressing novel targets discovered by the Regeneron Genetic Center. First data in NASH patients for ALN-HSD are anticipated in mid-2022.

T. But several addition combination programs are in our preclinical pipeline.

We continue to work with them on them as leaders in the use of RNA therapeutics to address non alcoholic Seattle hepatitis or Nash with several programs addressing novel targets discovered by the Regeneron genetic center first data in Nash patients for L. N HST, our anticipated mid 2022 we are progressing.

George Yancopoulos: We are progressing a second target, PNPLA-3, into the clinic later this year, and we have recently identified an additional, novel, promising target that has been validated by RGC and is awaiting peer-reviewed publication. We are also pleased to report a notable milestone, that Wheelan-Anilam initiated our first CNS-targeted siRNA clinical program targeting amyloid precursor protein, or APP, in development for both cerebral am Showing that this SRN approach can reduce levels of a target protein in the CNF has the potential to open the door to using this approach in other genetically defined neurodegenerative diseases.

A second target P. M. P. L. A three into the clinic later this year you have recently identified an additional novel promising target that's been validated by our D. C and is awaiting peer review publication.

We were also pleased to report a noble noble milestone that we own on an island initiated our first CNS targeted SA RNA clinical program targeting amyloid precursor protein or a P. P. In development for both cerebral amyloid angiopathy and Alzheimer's disease.

Showing that this S arent approach can reduce levels of the target.

Protein is C. N. It has the potential to open the door for using this approach in multiple genetically defined neuro degenerative diseases.

George Yancopoulos: In the first corner, Wayne and Talia provided an update on our joint CRISPR-based knockout program for transthyretin amyloidosis. Just to remind you, this is the first example of achieving CRISPR-based genomic editing in human beings. A recent update demonstrated a greater than 90% reduction of transthleretin, durably achieved for the follow-up observation period in patients with hereditary transthleretin amyloidosis with polyneuropathy, as well as acceptable safety observed so far. Our Genetics Medicine Portfolio now includes the diverse pipeline of sRNA candidates that we are working on with El Nylon, targeting diseases of the liver, the brain, and the eye, as well as Well, it is still early.

And the first corner waiting until you provided an update on our joint CRISPR based knockout program for transfer Eaton Amyloidosis, just to remind you. This is the first example of achieving CRISPR based genomic editing and human beings, a recent update demonstrated greater than 90% reduction of transfer.

Durably achieved for the follow up observation period in patients with hereditary transfer Eaton <unk> amyloidosis with Polyneuropathy as well as acceptable safety observed so far.

Our genetics medicine portfolio now includes the diverse pipeline of S. R&D candidates that we're working on with all now targeting the diseases of the liver the brain in the eye as well as our Crystal based approaches in collaboration with Intel and our viral targeted gene delivery programs, such as with Decibel addressing some general forms of hearing loss and other internal programs.

Marion McCourt: We think these groundbreaking approaches have the potential to change the practice of medicine. And with that, I will turn the call over to Mary. Thank you, George.

Well, it's still early we think these groundbreaking approaches have the potential to change the practice of medicine.

And with that I will turn the call over to Mary.

Marion McCourt: Our commercial performance in the first quarter reflects strong execution and the competitive strengths of our diversified and growing portfolio. Starting with Aliyah, first quarter global net sales grew 11% year-over-year to nearly $2.4 billion. Over the same period, US net product sales grew 13% to $1.52 billion as Aliyah continues to strengthen its leadership position.

Our commercial performance in the first quarter reflects strong execution and the competitive strength of our diversified and growing portfolio, starting with India first quarter Global net sales grew 11% year over year to nearly $2 4 billion.

Food period U S. Net product sales grew 13% to 152 billion as Eylea continues to strengthen its leadership position across the approved indications.

Marion McCourt: In cross-approved indications, Aliyah is the preferred anti-VEGF treatment based on its differentiated efficacy and safety profile as well as extensive real-world patient and physician experience. As Len mentioned, we are incredibly proud that Aliyah has helped improve or save the vision of patients around the world with more than 50 million treatments since launch. Category growth in ILEA market share continued to increase across all approved indications. In diabetic eye disease, we've seen notable increases across the patient continuum, from initial patient diagnosis through to receiving ongoing ILEA treatment.

Preferred anti VEGF treatment based on its differentiated efficacy and safety profile as well as extensive real world patient and physician experience.

Glenn mentioned, we are incredibly proud that Andy has helped improve were seeing it.

<unk> of patients around the world with more than 15 million treatments since launch.

Great Great and Eylea market share continued to increase across all approved indications in diabetic eye disease. We've seen notable increases across the patient continuum from initial patient diagnosis street to receiving ongoing treatment. We believe diabetic eye disease will remain an important source of future growth finally.

Marion McCourt: We believe diabetic eye disease will remain an important source of future growth for ILEA, as unfortunately, most patients remain underdiagnosed and undertreated. Additionally, beyond ILEA, our investigational Aflibricept 8 milligram clinical program continues to generate excitement and a high level of interest within the retinal community. If supported by phase 3 results, Aflibricept 8 milligram has the potential to be a major enhancement to the anti-VEGF treatment paradigm. In summary, we are confident in Regeneron's ability to maintain leadership over the long term, based on our current ILEA performance and future potential of Aflibricept 8 milligram.

Yeah. It's unfortunately, most patients remain underdiagnosed and Undertreated.

Yeah, our investigational a flipper set the eight milligram clinical program continues to generate excitement and a high level of interest within the retinal community. If supported by phase three results. Let me say at the eight milligram has the potential to be a major enhancement to the anti VEGF treatment paradigm in summary, we are confident.

And rich I know its ability to maintain leadership over the long term based on our current performance and future potential almost 9% eight milligram turning now to live Tayo, It's first quarter global net sales of $125 million in the U S. Net sales were 79 million based on steadily improving demand across FTA.

Marion McCourt: Turning now to Libtio, with first quarter global net sales of 125 million; U.S. net sales were 79 million, based on steadily improving demand across FDA-approved non-melanoma skin cancer indications. The number of prescribers has increased in our non-small cell lung cancer monotherapy indication, based on growing brand awareness, positive prescriber feedback, and an increasing number of institutions and networks that have included Libt We are working to build on this momentum ahead of the potential chemotherapy combination approval expected later this year, which would dramatically expand the patient opportunity for Libtio in lung cancer.

<unk> non melanoma skin cancer indications the number of prescribers has increased in our non small cell lung cancer monotherapy indication based on growing brand awareness positive prescriber feedback and an increasing number of institutions and networks that is included in the tie out in protocols.

Pathways, we are working to build on this momentum ahead of the potential chemotherapy combination approval expected later this year it would dramatically expand the patient opportunity from Italian with lung cancer and <unk>.

Marion McCourt: And finally, on to Dipixen, which again achieved remarkable growth for the quarter, demonstrated by a 43% increase in global net sales to over $1.8 billion. Our performance is fueled by robust uptake across all approved indications, as well as an expanding geographic footprint and potential future indications, including use in younger patients. Dipixen is a transformational medicine for patients and prescribers with significant growth potential ahead. In the U.S., net product sales grew 38% to $1.3 billion, and atopic dermatitis to Dipixen is the first-line systemic treatment in patients with moderate to severe disease. Healthcare specialists recognize Dipixen's differentiated profile, which includes a dual anti-IL-4 and IL-13 mechanism of action, compelling efficacy, rapid symptom relief, and a well-established safety profile.

Finally onto the picks and once again achieved remarkable growth for the quarter demonstrated by a 43% increase in global net sales to over $1 8 billion. Our performance is fueled by robust uptake across all approved indications as well as an expanding geographic footprint and potential future indications, including youth and young.

Patients. It takes there is a transformational medicine for patients and prescribers with significant growth potential ahead in the U S. Net product sales grew 38% to $1 3 billion in atopic dermatitis depicts it is the first line systemic treatment in patients with moderate to severe disease healthcare specialists to work.

Cognize depicts a differentiated profile, which includes the dual anti IL four and IL 13 mechanism of action compelling efficacy rapid symptom relief and well established safety profile more than 430000 patients worldwide are currently on treatment across all indications and <unk>.

Marion McCourt: More than 430,000 patients worldwide are currently on treatment across all indications, and launch preparations are underway for the June potential label expansion for children as young as six months of age with atopic dermatitis. We estimate approximately 75,000 eligible children in the U.S. could benefit from Dipixen in this younger age group. We also look forward to potentially extending Dipixen's label to include additional dermatology conditions, including Progonodularis, where patients currently have no FDA-approved medicines.

Launch preparations are underway for the June potential label expansion for children as young as six months of age with atopic dermatitis, we estimate approximately 75000 biologic eligible children in the U S could benefit from <unk> in this younger age group. We also look forward to potentially extending depicts since label to include additional.

<unk> dermatology conditions, including probably a notch allowance for patients have no currently FDA approved medicines, approximately 75000 U S patients with Pn.

Marion McCourt: Approximately 75,000 U.S. patients with PN are in need of new treatment options and may benefit from Dipixen. In the highly competitive biologic asthma indication, Dipixen continues to grow based on its compelling differentiation for healthcare professionals based on its unique dual mechanism of action, ease of administration, demonstrated safety, broad label, and use in both steroid-dependent patients and pediatric patients. There are positive prescribing trends from the recent pediatric asthma launch, and nasal polyps to Dipixen remain the preferred choice for both ENTs and allergists, with rapid growth even three years after initial launch. Many patients with type 2 or allergic disease suffer from another concomitant type 2 disease.

Need of new treatment options and they benefit from it takes it.

In the highly competitive biologic asthma indication depicts and continues to grow based on its compelling differentiation for healthcare professionals based on its unique dual mechanism of action ease of administration demonstrated safety broad label and use in both steroid dependent patients and pediatric patients.

Our positive prescribing trends from the recent pediatric asthma launch in nasal polyps depicts it remains the preferred choice for both E. N T isn't allergists with rapid growth even three years after initial launch.

Many patients with type two allergic disease suffer from another concomitant types of disease. For example, in our atopic dermatitis clinical program, 40% of patients also had asthma.

Marion McCourt: For example, in our atopic dermatitis clinical program, 40% of patients also had asthma. Dipixen is differentiated not only by its efficacy and safety profile in individual FDA-approved type 2 indications but also its potential to simultaneously address multiple type 2 diseases in the same patient. We look forward to expanding Dipixen into even more type 2 diseases. Launch preparations are underway for eosinophilic esophagitis, where there are no FDA-approved medicines and significant unmet need. Importantly, in our EOE clinical program, approximately 45% of patients also had atopic dermatitis or asthma.

It is differentiated not only by its efficacy and safety profile and individual F. D. A approved type two indications, but also its potential to simultaneously address multiple type two diseases isn't the same patient. We look forward to spending just takes it into even more types of diseases launch preparations are underway.

Send it felt like a south Florida, where there are no FDA approved medicines and significant unmet need and importantly in our E. L E clinical program approximately 45% of patients also had.

Atopic dermatitis asthma.

Marion McCourt: If approved in EOE, we estimate at least 50,000 patients in the U.S. could benefit from Dupixent and Disindication. Key opinion leaders continue to provide positive feedback on our clinical data, especially given the lack of effective approved treatment alternatives for patients who suffer from multiple EOE symptoms. Turning briefly now to Depixin in markets outside the U.S., in the first quarter, net product sales grew 61% to $485 million.

If approved in <unk>, we estimate at least 50000 patients in the U S could benefit from detection into syndication key opinion leaders continue to provide positive feedback on our clinical data, especially given the lack of effective approved treatment alternatives for patients who suffer from multiple elite, sometimes turning briefly now to the picture.

Outside the U S. In the first quarter net product sales grew 61% to $485 million over the past year Regeneron has expanded our commercial presence in several key markets outside the United States and we are encouraged with progress so far integrating our sales efforts with fantasy in summary, we see significant potential for depicts.

Marion McCourt: Over the past year, Regeneron has expanded its commercial presence in several key markets outside the United States, and we are encouraged by progress so far, integrating our sales efforts with Sanofi. In summary, we see significant potential for Depixin to continue to change the lives of patients and their families, and we will continue to advance initiatives that bring Depixin to those in need. In conclusion, we are pleased with performance across our portfolio, we continue to advance our inline brands, and are on track to deliver on future launches, positioning Regeneron for sustained and long-term growth.

And to continue to change the lives of patients and their families and we will continue to advance initiatives to bring it takes them to those who need it.

Conclusion, we are pleased with performance across our portfolio. We continue to advance our inline brands and are on track to deliver on future launches positioning weekend around Christmas day.

Aimed at long term growth now I'll turn the call over to Bob. Thank you Maryann. My comments today are on Regeneron financial results and outlook will be on a non-GAAP basis, unless otherwise noted regeneron is off to a strong start in 2022 with double digit top and bottom line growth in the first quarter driven by execution across the <unk>.

Marion McCourt: Now I'll turn the call over to Bob. Thank you, Marion. My comments today are on Regeneron's financial results and outlook, which will be on a non-gap basis. Regeneron is off to a strong start in 2022 with double-digit top and bottom line growth in the first quarter driven by execution across the business. First quarter total revenues grew 17% year-over-year to $2.97 billion.

Bob Landry: Excluding global revenues related to the COVID-19 antibody cocktail, total revenues grew 25%, demonstrating continued strength of our core business. First quarter total diluted net income per share grew 16% to $11.49 on net income of $1.3 billion. Beginning with Collaboration Revenue and starting with Bayer, first quarter 2022 XUS ILEANAP product sales were $869 million, growing 7% on a reported basis and 13% on a constant currency basis versus first quarter 2021. Total Bayer Collaboration Revenue was $385 million, of which we recorded $338 million for our share in net profits from ILEA sales outside the U.S. Total Sanofi Collaboration revenue was $631 million in the first quarter of 2022 and grew 73% from the prior year driven by Dupik's, In this quarter, we recognized a $50 million sales milestone upon achieving $2 billion of aggregate ex-U.S. sales for antibody collaboration products on a rolling 12-month basis.

Bob Landry: Finally, we recorded Roche collaboration revenue of $216 million related to Roche's sales of Ronapreve outside the U.S. We do expect additional revenue from this collaboration, primarily in the second half of 2022. Regarding Regencove in the U.S., consistent with our commentary from earlier this year, we did not record any U.S. sales for Regencove in the first quarter of 2022. Absent the execution and fulfillment of an additional government contract, we do not expect to record any U.S. sales for Regencove this year.

First quarter total revenues grew 17% year over year to $2 97 billion exclude.

Excluding global revenues related to the COVID-19 antibody cocktail total revenues grew 25% demonstrating continued strength of our core business first quarter total diluted net income per share grew 16% to $11 49 on net income of $1 3 billion.

Beginning with collaboration revenue would starting with Bayer first quarter 2022 X U S. Eylea net product sales were 869 million growing 7% on a reported basis and 13% on a constant currency basis versus first quarter 2021.

Total Bayer collaboration revenue was 385 million of which we recorded $338 million for our share of net profits from Eylea sales outside the U S. Total scientific collaboration revenue was $631 million in the first quarter of 2022 and grew 73% from the prior year driven by <unk>.

In this quarter, we recognized a $50 million sales milestone upon achieving $2 billion of aggregate ex U S sales for antibody collaboration products on a rolling 12 month basis.

Finally, we recorded Roche collaboration revenue of $216 million related to Roche, whose sales have grown approved outside the U S. We do expect additional revenue from this collaboration primarily in the second half of 2022.

Regarding Regina Covid the U S consistent with our commentary from earlier this year, we did not record any U S sales for Virgin Cove in the first quarter of 2022 absent the execution and fulfillment in the oven and additional government contract. We do not expect to record any U S sales for Virgin Cold This year.

Bob Landry: Other revenue in the first quarter of 2022 was $94 million. This includes a $30 million upfront payment from our collaborator, Ultragenyx, to market FKESA outside of the U.S. Moving now to our operating expenses. R&D increased 12% to $751 million, driven by higher headcount and clinical manufacturing costs, including for next-gen COVID antibodies, partially offset by lower clinical trial costs for regen codes. Starting in the first quarter of 2022, we are changing the presentation of our non-GAAP results to include in-process R&D acquired in connection with asset acquisitions, as well as upfront and opt-in payments related to license and collaboration agreements.

Other revenue in the first quarter of 2022 was $94 million. This includes a $30 million upfront payment from our collaborator ultra genetics to market Ftes are outside of the U S.

Moving now to our operating expenses R&D increased 12% to $751 million driven by higher head count and clinical manufacturing costs, including for Nexgen, Covid antibodies, partially offset by lower clinical trial costs for Virgin Cold.

Starting in the first quarter of 2022, we are changing the presentation of our non-GAAP results to include in process R&D acquired in connection with asset acquisitions, as well as upfront and opt in payments related to license and collaboration agreements going forward. We will now include these charges in both GAAP and non-GAAP results as a new light.

Bob Landry: Going forward, we will now include these charges in both GAAP and non-GAAP results as a new line item called acquired in-process research and development. In the first quarter of 2022, acquired IP R&D was $28 million, which includes a $20 million opt-in payment to our collaborator, Atoset. In full year 2021, there were $44 million of aggregate upfront payments excluded from non-GAAP R&D expense, all of which were recorded in the fourth quarter of 2022.

Called acquired in process research and development in the first quarter of 2022 acquired IP R&D was $28 million, which includes a $20 million opt in payment to our collaborator and upset in full year 2021, there were $44 million of aggregate upfront payments excluded from non-GAAP R&D expense.

All of which were recorded in the fourth quarter of 2021.

Bob Landry: SG&A expense increased 10% year-over-year to $389 million, primarily due to costs related to growth initiatives for ILEA and higher headcount to support our expanding organization. COCM increased 58% year-over-year to $198 million due to higher sales into PIXEN and an increase in shipments of commercial supplies of Pralulin for Sanofi outside the United States. Finally, the first quarter 2022 effective tax rate was 11.6% compared to 10.5% in the prior year.

SG&A expense increased 10% year over year to $389 million, primarily due to costs related to growth initiatives for eylea and higher head count to support our expanding organization.

Dosing M increased 58% year over year to 198 million due to higher sales of depiction and an increase in shipments of commercial supplies are probably late fourth canopy outside the United States.

The first quarter 2022 effective tax rate was 11, 6% compared to 10, 5% in the prior year shift.

Bob Landry: Shifting now to cash flow and the balance, in the first quarter of 2022, Regeneron generated $2 billion in free cash flow, inclusive of collections from the U.S. government for sales of Regencove recorded in the fourth quarter of 2021, and ended the first quarter of 2022 with cash and marketable securities, less debt of $11.4 billion. We continue to deliver on our capital allocation priorities. Last month, we announced the agreement to acquire Checkmate Pharmaceuticals for a total equity value of approximately $250 million.

Shifting now to cash flow and the balance sheet and.

In the first quarter of 2020 to Regeneron generated $2 billion in free cash flow inclusive of collections from the U S government for sales of Virgin Cove recorded in the fourth quarter of 2021 and ended the first quarter of 2022 with cash and marketable securities less debt of $11 4 billion.

We continue to deliver on our capital allocation priorities last month, we announced the agreement to acquire Checkmate pharmaceuticals with total equity value of approximately $250 million earlier. This week, we launched a tender offer for checkmate shares and expect this deal to close in mid 2022 subject to receipt of regulatory approval.

Bob Landry: Earlier this week, we launched the tender offer for Checkmate shares and expect this deal to close in mid-2022, subject to receipt of regulatory approval and other customary closing conditions. In addition, we repurchased $352 million of our shares in the first quarter of 2022.

And other customary closing conditions. In addition, we repurchased $352 million of our shares in the first quarter of 2022, we continue to be opportunistic buyers, where we see dislocation between our stock price and our intrinsic valuation.

Bob Landry: We continue to be opportunistic buyers where we see dislocation between our stock price and our intrinsic valuation. I will conclude with select updates to our full year 2022 guidance and outlook. We are updating full-year R&D guidance to be in the range of $2.9 billion to $3.1 billion. The increase in guidance is driven by clinical manufacturing costs for next-gen COVID antibodies, most of which were recorded in the first quarter, and advancing programs across our We also now expect our full year effective tax rate to be in the range of 12 to 14 percent.

I will conclude with select updates to our full year 2022 guidance and outlook.

We are updating full year R&D guidance to be in the range of $2 9 billion to $3 1 billion. The increase the increase in guidance is driven by clinical manufacturing costs for <unk> for.

For Nexgen Covid antibodies, most of which were recorded in the first quarter and advancing programs across our pipeline.

We also now expect our full year effective tax rate to be in the range of 12% to 14% a complete summary of our latest full year guidance is available in our press release issued earlier. This morning in conclusion, our core business is performing well and we continue to make investments in our R&D engine supported by our strong financial position.

Bob Landry: A complete summary of our latest 4-year guidance is available in our press release issued earlier this morning. In conclusion, our core business is performing well, and we continue to make investments in our R&D engine supported by our strong financial position, leaving Regeneron well-positioned for sustainable long-term growth. With that, I will pass the call back to Ryan. Thank you, Bob. Gigi, that concludes our prepared remarks. We'd now like to open the call for Q&A.

Leaving regeneron well positioned for sustainable long term growth with that I will pass the call back to Ryan.

Bob Landry: With more than 20 callers in the queue and to ensure we are able to address as many questions as possible, we will answer only one question from each call before moving to the next. Gigi, please go ahead. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key.

Thank you Bob G. G that concludes our prepared remarks, we'd now like to open the call for Q&A with more than 20 callers in the queue and to ensure we are able to address as many questions as possible we.

We will answer only one question from each caller before moving to the next.

Julie Please go ahead.

Yeah.

As a reminder to ask a question you will need to press star one on your telephone to withdraw your question press the pound key please standby, while we compile the Q&A roster.

Ryan Crowe: Please stand by while we compile the Q&A roster. Our first question comes from the line of Chris Raymond from Piper Sandler. Your line is now open. Hey, thanks for taking the question. Just a question, maybe for Marion if I can, on ILEA and the opinions pointed out that the drug is a highly competitive set. I know you guys have said feedback from the market on Bisvo has been somewhat muted, but it is actually kind of striking how different Roche is sort of viewing the reception of the drug. They highlight a lot of enthusiasm for stocks.

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

Hey, Thanks for taking the question.

Just a question maybe for Mary and if I if I can.

And sort of the competitive set.

I know you guys have said feedback from the market.

Digital has been somewhat muted but.

But it was actually kind of striking how different roche is sort of viewing the reception of the drug.

A lot of enthusiasm.

And I know, there's a lot of talk about you know what will happen after a permanent J code, but I know you guys have a lot of levers to pull here.

Marion McCourt: I know there's a lot of talk about what will happen after a permanent J-code, but I know you guys have a lot of levers to pull here, not least of which is launching the high-dose format of ILEA. Can you talk a little bit about the rebates, how they are playing into your counter-strategy?

Not least of which is launching the high dose format of Eylea, but can.

Can you talk a little bit about the rebates, how they are playing into your counter strategy and maybe near to intermediate term and how we should be thinking about.

Marion McCourt: in the early intermediate term, and how we should be thinking about net pricing going forward. [inaudible] I'm just happy to give you some characterization of the market. First, let me comment on ILEA, and as we reported today, our performance certainly with ILEA in a very competitive marketplace is quite strong across indications. And certainly, we see very strong performance, not only in capturing more than our fair share of the market growth but also competitive share gains across indications. As a reminder, in the overall market, we have about 50% of the VEGF category market share with ILEA, and in the branded marketplace, over 75% of the branded market share.

Pricing going forward. Thanks.

Chris happy to that to give you some characterization of the market first let me comment on Eylea and there's we reported today our performance certainly with Eylea in a very competitive marketplace.

It's quite strong across indications and certainly we see very strong performance not only in capturing more than our fair share of the market growth, but also competitive share gains across indications as a reminder, in the overall market. We have about 50% of the Dutch Act category market share with Eylea.

And then the branded marketplace over 75% of the branded market share I really do think it's probably best to let British comments on uptake of their new product in the marketplace.

Marion McCourt: I really do think it's probably best to let Roche comment on uptake of their new product in the marketplace. I'll share that prescribers and key opinion leaders have commented to us on the importance of the demonstrated safety they see with ILEA, the efficacy, and these are the included, including the source of your profile that we have. And certainly the extensive consideration across indications and in-market use that has been incredibly robust. As it relates to your pricing and things of that sort generally, you don't comment that I certainly will say is that you are looking ahead. We see strong leadership with Alia and a profile that is certainly leading the category in terms of experience. Thank you. Next question.

Sure that prescribers and key opinion leaders come in to us on the importance of the demonstrated safety basi with Eylea.

The patience.

Profile that we have and certainly the extensive.

Consideration across indications and in market niche that has been incredibly robust.

As it relates to other items on pricing and things of that sort of generally we don't comment, but I certainly will save that child. You know looking ahead, we see strong leadership with Eylea and a profile that is certainly beating the category in terms of experience uptake and use.

Thank you next question Judy.

Marion McCourt: Thank you. Our next question comes from the line of Corey Kasimov from J.P. Morgan. Your line is now open. Great. Good morning, guys.

Thank you. Our next question comes from the line of Cory <unk> from Jpmorgan. Your line is now open.

Marion McCourt: Thanks for taking my question. To follow up on Eilidh, I wanted to ask about the high-dose formulation. Assuming the results read out as you anticipate, how do you think this product potentially slotting into the treatment landscape? Is it possible that this could broadly take over from your current dose, or would you expect it to be primarily used in certain segments of the market? So I think at this point, we'll want to wait and look at the product profile as the clinical data matures.

Great. Good morning, guys. Thanks for taking my question to follow up on Idly I wanted to ask about.

The high dose formulation and assuming the results read out as you anticipate how do you think about this product potentially slotted into the treatment landscape is it possible that this could broadly take over from your current dose or would you expect it to be primarily used in certain segments of the market. Thank you.

So I think at this point will want to wait and look at product profile as the clinical data matures and then certainly as we move into launch preparation planning will be considerate of how the profile matches up against patient need and opportunity.

Marion McCourt: And then certainly as we move into launch preparation, planning will be considerate of how the profile matches up against patient need and opportunity. So I think more to come on specifics on uptake. We remain optimistic, but, of course, we need to wait and see how the clinical data matures and the profile of the product is clarified. Gigi, next question, please.

So I think more to come on specifics on uptake, we remain optimistic but of course, we need to wait and see how the clinical data matures and the profile of the product is clarified.

Thank you <unk> next question please.

Marion McCourt: Thank you. Our next question comes from the line of Evan Seigerman from BMO Capital Markets. Your line is now open.

Thank you. Our next question comes from the line of even Sugarman from BMO capital markets. Your line is now open.

Len Schleifer: Hi guys, thank you so much for taking the question. I'd love if you could expand on some of the rationale behind acquiring or proposing to acquire Checkmate Pharmaceuticals. Anything in the data that was particularly notable when you were doing your diligence that piqued your interest?

Hi, guys. Thank you so much for taking the question and I'd Love if you could expand on some of the rationale behind acquiring are proposing to acquire checkmate pharmaceuticals anything in the data that was particularly notable when you were doing your diligence that picture interest and do you expect to go forward combining their asset with the pile versus.

Len Schleifer: And do you expect to go forward combining their asset with Liptyle versus, say, Nivolumab or Pembro as they have in their prior trials? Thank you. I'm sure George would love to expand upon the thinking, but unfortunately, because we just launched the tender offer, we're really not committed to having that discussion. We'll look forward to that discussion, assuming that the deal closes around the middle of the year, as we anticipate. Fair enough, Len.

Second of all the mab or Pembroke as they had on their prior trials. Thank you.

I'm sure I'm sure George would love to expand upon that.

But unfortunately, because we just launched the tender offer we're really not permitted to have that discussion I will look forward to that discussion, but assuming that the deal closes around the middle of the year as we anticipate.

Len Schleifer: Fair enough. Thank you. No, it's all right.

Fair enough fair enough.

Alright, but what because we couldn't answer that question. If you go back in the queue will come back to you for another question.

Len Schleifer: But because we couldn't answer that question, if you get back in the queue, we'll come back to you for another question. Fair enough. Thanks, Evan. Gigi, next question. Our next question comes from the line of Salveen Richter from Goldman Sachs. Your line is now open.

Fair enough.

Thanks, Kevin G. G next question.

Our next question comes from the line of Halloween right. There from Goldman Sachs. Your line is now open.

George Yancopoulos: Good morning, thanks for taking my question. On these initial bispecific data sets and solid tumors in the second half, could you just speak to what exactly we're going to see initially and then what you would like to, what you would want to see from the data set in terms of being clinically meaningful? Well, as I indicated in my, Thank you all for your important remarks. Basically, we're going into late stage patients, heavily pre-treated. We're hoping to actually be able to report on objective responses, and the number and the duration of the responses are what we're looking for.

Good morning, Thanks for taking my question on these initial bispecific datasets in solid tumors in the second half could you just speak to what exactly we're going to see them. Initially and then what you would like this.

Would want to see from the data set in terms of being clinically meaningful.

Well as I indicated in my.

George Yancopoulos: We would love to be able to see significant numbers of durable responses showing that each one of these novel agents is really making a difference in the latest stage patients. That, of course, would open up for each one of them, we think, very important opportunities in terms of both those late stage settings but also, particularly with logical combinations going back into earlier and earlier stage patients. So each one of them could then become a significant program, not only in monetary terms but in combination with logical other agents.

Remarks.

Basically we're going into late stage patients.

Heavily pretreated, where.

We're hoping to actually be able to report on seeing objective responses.

And the number and the duration of the responses is what we're looking for we would love to be able to see significant numbers of durable responses showing that each one of these novel agents is really making a difference in the latest stage patients data.

Of course, we'd open up for each one of them rethink.

We think very important opportunities.

In terms of both of those late stage settings, but also particularly with logical combinations are going back into earlier and earlier stage patients. So each one of them could become then a significant program.

Not only in monetary but in combination with a logical other agents. So as I said responses with duration is what we're looking for in all three of those programs.

Len Schleifer: So, as I said, responses with duration are what we're looking for in all three of those. Just to amplify a little bit, to make sure nobody missed what George just said, it seems to be the case that with these types of reagents, much as it is the case with other anti-cancer drugs, that while you start in the latest, most difficult patients, there is better activity in earlier lines with these kinds of immune reagents. So finding activity in late, heavily pre-treated soil would be very encouraging. Terence Flynn and George Gigi. Next question, please.

Just to amplify a little bit but to make sure nobody missed what George just said is that it seems to be the case with these types of reagents much. It as is the case with other anti cancer agents.

While you start in the latest most difficult patients.

Or activity.

Earlier lines with these kinds of immune reagents, so finding activity in the late heavily pretreated, we'd be very encouraging.

Thanks, Len and George G. G. Next question. Please.

George Yancopoulos: Thank you. Our next question comes from the line of Brian Abrahams from RBC Capital Markets. Your line is now open.

Thank you. Our next question comes from the line of Brian Abrahams from RBC capital markets. Your line is now open.

George Yancopoulos: Good morning, congratulations on all the progress, and thanks so much for taking my question. Can you elaborate a little bit more on the safety benefit that you're seeing for Otronextamab stepped-up dosing, and I guess what it means in terms of differentiating versus other bispecifics in development, and ultimately CAR-T, and then your confidence that you'll retain similarly strong efficacy with this dose? Thanks. Yeah, we actually initiated the concept for by specifics in general, as we were very early players in the field of this concept of step-up dosing and what it seems to be.

Good morning, Congrats on all the progress and thanks, so much for taking my question can.

Can you elaborate a little bit more on the safety benefit that youre seeing for ultra and extra mab stepped up dosing and I guess, what it means in terms of differentiating versus other bi specifics in development and ultimately car T. And then your confidence that you'll retain similarly strong efficacy with this dose.

Yeah, we actually had initiated the constant for bi specifics in general as we were very early players in the field of this concept of step up dosing and.

What it seems to be.

George Yancopoulos: , and the other thing that's being confirmed by our own data and other people's data is that when you give them initially at low doses and gradually step up to your optimal dose, you are reducing the incidence of severe side effects and particularly cytokine release syndrome. We actually had pretty low rates with our original.

Being confirmed by our own data and other People's data is that when you give them initially at low doses and gradually stepped up to your.

Optimal dose you are reducing the incidence of severe side effects and particularly cytokine release syndrome, we had actually pretty low rates with our original so our original.

George Yancopoulos: So our original dosing regimen was also a step-up dosing regimen. But in collaboration with the FDA, we redefined the step-up dosing and came up with an even more gradual program. It only extends the timing to get to the maximum dose by one week, and we're still obviously getting to that same dose.

Dosing regimen was also a step up dosing regimen, but in collaboration with the FDA, we redefined the stepped up dosing and came up with a even a more gradual program you'd only extends the timing to get to maximum dose by one week.

And we're still obviously getting to that same dose and what we're saying is that from the early read from the new step up dosing, which presumably will give you the detailed data at some point in the future.

George Yancopoulos: And what we're saying is that from the early read from the new step-up doses, which presumably will give you detailed data at some point in the future, the results are looking very promising. The already low rate of significant cytokine release syndrome that we were seeing looks like it's depressed even further down to rates where we think, as I stated, we will be able to use this regimen in this setting in the outpatient setting.

The results are looking very promising.

Already low rate of a.

Again cytokine release syndrome that we were seeing it looks like it's depressed even further.

Down to rates, where we think as I stated, we will be able to use this regimen in this approach.

In the outpatient setting so it's just very promising that we've come up with the safe.

George Yancopoulos: So it's just very promising that we've come up with the safe. It looks like it could be a safe protocol that could be used in outpatient settings, and it's getting to the same maximum dose in a pretty short period of time as well. Thanks so much.

Well it looks like to be a safe protocol that can be used in outpatient settings.

And it's getting to the same.

Maximum dose.

In a pretty short period of time as well.

Thanks George.

George Yancopoulos: Gigi, next question please. Thank you. Our next question comes from the line of Carter Gould from Barclays Capital. Your line is now open. Great. Good morning. One for me.

G. G next question please.

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

Great Good morning.

For me.

Hum.

George Yancopoulos: I want to understand, I guess, how you're thinking about your broader CVE effort. You know, we've heard from a number of larger pharma and biotech companies sort of rededicating themselves to CVE recently. And when you map out the indications and products, I'd argue you have one of the broader pipelines across CVE, but you don't really get much credit for it. And Praluen and Avkiza remain relatively small contributors to your sales.

I want to understand I guess, how you're thinking about your broader CV effort. You know we've heard from a number of large pharma and biotech companies.

Dedicating myself for TV recently, and when you map out the indications in products that argue you have one of the broader pipelines across TV, but you don't really get much credit for it and probably you want enough keesler remain relatively small contributors to yourselves. So do you see this being a major commercially relevant area for regeneron going forward I'd, just like to understand your ambitions here a little bit better. Thank you.

George Yancopoulos: So do you see this being a major commercially relevant area for Regeneron going forward? I'd just like to understand your ambitions here a little bit better. We have not obviously realized what we think is the full potential of our CV expertise and capabilities, and we are exploring ways to do that. Some of which may require us to rethink combinations of both types of reagents and targets, and hopefully, you'll hear more about that. But we would agree that right now it's not a major contributor to our near-term performance.

We have not.

Obviously realize what we think is the full potential of our C V expertise and capabilities.

We are exploring ways.

To do that.

Some of which may require us to rethink our com.

Combinations.

Both types of reagents and targets and hopefully you'll hear more about that but we would agree it's right now it's not a major contributor.

To our near term performance.

Okay. Thank you <unk> next question please.

George Yancopoulos: Okay, thank you. Gigi, next question, please. Our next question comes from the line of Brian Skorney from Baird. Your line is now open. Hi, this is Luke Herman. I'm on behalf of Brian Skorney.

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

George Yancopoulos: Could you talk a bit more about 5458? Maybe your confidence that the currently enrolling Phase 2 study will support a filing? Any timeline granularity and combinations you're particularly excited about there? Thanks.

Hi, This is Luke Harman on for Brian Scorning.

Could you talk a bit more about 50 458, maybe your confidence that the currently enrolling phase II study will support a filing any timeline granularity and combinations you are particularly excited about there. Thanks.

Yeah well.

George Yancopoulos: In small numbers, we have very competitive response rates with deep responses and duration that we think for these late-stage patients should be able to support registration if we can replicate it in the larger phase two registrational study that we're undertaking. We continue to see a very acceptable safety and tolerability profile. And as you said, this is just sort of the first step in the whole program. We are very excited about combinations, and we're also very excited about moving to earlier lines of therapy.

In small numbers, we have very competitive response rates with a deep responses and duration that we think for these late stage patients should be able to support registration.

If we can replicate it in the larger phase III Registrational possible study that we're.

Undertaking we continue to see a very acceptable.

Safety and Tolerability profile.

And as you said this is just sort of the first step in the whole program. We are very excited about combination and we're also very excited about moving to earlier lines of therapy in terms of combinations.

George Yancopoulos: In terms of combinations, As we've talked about before, it's very logical and the preclinical data are very compelling that combinations with so-called co-stimulatory bi-specifics that also bind to a target on the same myeloma cells but now activate what we and others refer to as single two will be very exciting and have really the potential to enhance responsiveness and deepen responsiveness and deepen duration. We have a series of additional next-generation candidates as well that we could layer on top of that next series of logical combinations. Bob these co-stimulatory molecules.

As we've talked about before it's very logical and the preclinical data are very compelling that combinations with so called co stimulatory bi specifics, but also buying to a target on the same myeloma cells, but now activate what we referred to as a single.

Two.

We will be very exciting and has really the potential to earn.

Hans responsiveness, and deepen responsiveness and deepen duration.

We have a series of additional next generation.

Generation candidate as well that we could layer on top of that next series of logical combinations, which in.

Evolve these co stimulatory molecules and we're also thinking that obviously as Len already mentioned.

George Yancopoulos: And we also think that, obviously, as Len already mentioned, going to earlier lines of therapy is only going to increase responsiveness and the opportunities to get longer and longer responses and, dare I say, even potentially cures. So that's the basic summary of our programs. Get registration in the late setting by replicating the data that we've seen with our ongoing registration, possible phase two study, adding combinations to enhance responses, deepen responsiveness and duration, and three, going into earlier lines of therapy as well. George, Gigi, next question, please.

Mentioned go into earlier lines of therapy is only going to increase the responsiveness and the opportunities to get longer and longer responses and dare I say, even potentially tours.

So that's the basic summary of our programs get registration in the late night late late setting by.

Replicating the data that we've seen with our ongoing registration possible phase two study are adding combinations to enhance responses deepened responsiveness and duration.

And three going into earlier lines of therapy as well.

Thanks, George G. G. Next question please.

George Yancopoulos: Thank you. Our next question comes from the line of Brittany A. Woods from Cowan & Company.

Thank you. Our next question comes from the line of Britney and Wood from Cowen and company. Your line is now from.

George Yancopoulos: Your line is now open. Good morning, everyone. This is Brittany on behalf of Tyler.

George Yancopoulos: Congratulations on another strong quarter. And thanks for taking our questions. So, a multi-part question related to the Regenco cocktail. For the ongoing studies of the next-gen candidates, and you expect that you will be filed for approval, what does the regulatory path forward look like? And also, if we continue to be at a relatively low case period as we enter the endemic phase, what could a pivotal trial ultimately look like there?

Good morning, everyone. This is Brittany on for Tyler Congrats on another strong quarter and thanks for taking our question. So a multipart question related on the re janco cocktail for Dion.

Boeing studies of the Nextgen candidate.

The fact that you'll be file for approval with the regulatory path forward look like.

And also if we continue to be at a relatively low key period as we entered the endemic Jade what pivotal trial ultimately it looked like there.

George Yancopoulos: These are all really great questions, and we are continuing to discuss our regulatory path both for getting hopefully full approval for our existing cocktail but also the regulatory path going forward for next generation cocktails with the FDA. That's an ongoing discussion that has the potential to change, and obviously, associated studies to support that program have the potential to change, so we're not at this point talking about the details of either. Great questions. Suffice it to say the complexities are increased when you have to start thinking about supply as well.

These are all really great questions and we are continuing to discuss a regulatory path both for getting our Oh, hopefully full approval for our existing cocktail, but also the regulatory path going forward for <unk>.

Next generation cocktails with the FDA, that's an ongoing discussion.

Has potential to change and obviously associated studies to support that program has the potential to change so where we're not at this point.

Talking about the details of either.

But great question suffice.

Suffice it to say the complexities of increase when you have to start thinking about supply as well so as George said work in.

Len Schleifer: So, as George said, we're in discussions with the agency about what it would take to get an authorization, but you're always chasing the next variant. And we have probably what we think is the greatest end-to-end capabilities in this space as there are, but still knowing which variant to manufacture for which antibody and how to keep chasing that. It's a fairly complex situation, but we're committed to trying and make monoclonals an important part of the solution. And I think they can be, but it is going to require some artful science.

Our discussions with the agency about what it would take to get an authorization, but you're you're.

Chasing the next variant.

We have probably what we think is the greatest end to end capabilities in this space.

Out there, but still knowing which varian to manufacturer for which rich antibody and how to keep chasing that it's a fairly complex situation, but we're committed to try and make monoclonal is an important part of the solution.

And I think they can be but it is going to require some artful.

Science so to speak.

Thank you D. G. A next question please.

George Yancopoulos: Thank you. Gigi, next question. Our next question comes from the line of Dane Leone from Raymond James. Your line is now open. Hi, thank you for taking the questions and congratulations on all the progress across all of your programs. One question for me on the Photon and Pulsar outcomes.

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

Alright, Thank you for taking the questions and congratulations on all the progress across all of your programs.

One question for me on the photon impulse or outcomes.

George Yancopoulos: It's been interesting to hear your narrative over many years now, through ILEA, and your team's generally been right in terms of next generation efforts that have kind of failed to replace ILEA as the standard of care. And to that point, I'm a little interested in your commentary on the Candela readout and how that impacts your interpretation of a photon and pulsar, meaning what does your team really think ends up being a differentiated outcome for those patients that are able to treat and extend the high dose out to Q16 week?

It's been interesting to hear your narrative over the many years now.

Through Eylea and your team has generally been right.

Terms of next generation efforts that kind of thing.

To just displace eylea.

Standard of care.

And to that point I'm interested from your commentary on the Candela readout.

And how that impacts your interpretation of our photonic pulsar, meaning.

Meaning what is your team really think ends up being a differentiated outcome for those patients that are able to treat and extend on the high dose out to Q16 week.

George Yancopoulos: And does that have to be a comparison to what read out with first map studies to make it a compelling, you know, drug option or higher dose option in the market to complement ILEA? And the context for this, I guess I'd put it this way, you guys have generally contended that a lot of these studies comparing against per-label ILEA are not actually fair studies to be running for us. Now, obviously, you use a natural loading dose, but in the real world, the treatment extent of ILEA versus any of these other agents is actually quite equivalent.

And does that have to be a comparison to what read out with tourists map studies to make it a compelling.

Drug option or a higher dose option in the market.

To complement Eylea.

And the context for this I guess I'd put it in as you guys have generally contended that a lot of these studies comparing against per label Eylea or not it's really fair studies to be running.

For us and obviously use the extra loading dose, but in the real world the treat and extend of Eylea versus any of these other agents is actually quite equivalent.

George Yancopoulos: So I'd be just interested to hear how the contextualization of these high dose liver studies really informs who should get the higher dose if and when it becomes available. Thank you very much.

So I'd be just interested to hear how you think that the contextualized Asian of these high dose <unk> studies really inform us who should get the higher dose if and when it becomes available. Thank you very much.

You know.

George Yancopoulos: That's going to be, obviously, a choice for clinicians to decide once they've seen all the data. But I think an important consideration is still going to be not only the duration, because duration does matter, efficacy, and efficacy matters, but safety. And I think the distinct advantage we have with high-dose ILEA is that from a molecular point of view, whether you're having immunologic reactions and those sorts of things. ILEA is a very well-known entity.

That's going to be obviously, a choice for clinicians.

Decide once they've seen all the data.

But I think that was an important consideration is still going to be not only the duration because duration does matter efficacy efficacy matters, but safety and I think the distinct advantage, we have with high dose eylea is that from a molecular point of view.

Whether you're having immunologic reactions and those sorts of things I believe is very well known entity. If we can transition to a higher dose with the same kind of safety and allow for longer duration I think that is a more attractive paradigm in switching.

George Yancopoulos: If we can transition to a higher dose with the same kind of safety and allow for longer duration, I think that is a more attractive paradigm than switching to a new molecular mechanism of action with unproven safety and 50 million injections behind it. And frankly, I do think even the FDA views when you're changing dosing paradigms of the same molecule as different when you're bringing in a new molecule. So we can't say, and we wouldn't dare to speak for what clinicians will do once they see the data.

To our new molecular mechanism of action with unproven safety.

50 million injections.

And frankly, I do think even the FDA views.

The when you're changing dosing paradigms of the same molecule is different.

You're bringing in.

New molecule. So we can't say we wouldn't.

So you have to speak to what clinicians will do once they see the data, but we do feel strongly that having the same.

George Yancopoulos: But we do feel strongly that having the same idea back is better than having to start again. If we get the safety that we anticipate thus far from this small candela... And we get the kind of extension of duration, perhaps with more drawing, we'll look at the actual numbers, I think that sort of transition is more efficient than transitions that may occur with new reagents. Thank you. GG, I think we have time for two more questions. Thank you. Our next question comes from the line of Charlie Yang from Morgan Stanley. Your line is now open. Thanks for taking the question. This is Charlie Yang for Matthew.

I believe our backbone if we get the safety that we anticipate thus far from the small and Dallas Saturday.

We get the kind of extension of duration, perhaps with more dry well look at the actual numbers I think that's sort of a transition as more efficient transitions.

Transitions that may occur with new reagents.

Thank you Lynn Thank you.

Judy I think we have time for two more questions.

Thank you. Our next question comes from the line of Charlie Yang from Morgan Stanley . Your line is now open.

Yeah.

George Yancopoulos: I just want to follow up on the Region 5458 BCMA. By specific, I guess my question here is, you know, given the competitor is ahead and potentially kind of getting approval later this year, and they are kind of already testing in combination with Darzalex, for example, I'm just curious about your confidence in, you know, the 5458, kind of in terms of its outlook, and maybe just provide some thoughts on the competitive landscape and the, you know Thank you.

Thanks for taking the question. This is Charlie young for it on for Matthew.

I just wanted to follow up on the region of 5458, so it would be seeing me.

Specific I guess my question here is you know given the competitive is a head and potentially kind of getting approval.

Later this year and they are already testing it in combination with <unk>.

Dogs are X for example, I'm just curious about kind of your confidence.

You know the five four or five age cow in terms of its outlook and maybe just provide some thoughts on the competitive landscape and the.

The commercial opportunity across a different line of upsetting. Thank you.

George Yancopoulos: Yeah, we think being, you know, marginally ahead or behind here isn't really going to mean all that much. It's how good your actual agent is. And also, of course, what opportunities you have for combinations. And so, as we said, if we can reproduce the efficacy we've seen in our initial studies in our potentially pivotal phase two program, they'll make it a very, very competitive agent in terms of efficacy. And that's obviously what really matters.

Yeah, we think being you know marginally ahead or behind here isn't really.

Meanwhile, that much it's how good your actual agent is.

And also of course, what opportunities you have for combinations.

So as we said if we can reproduce.

The efficacy we've seen you know our initial studies in our potentially pivotal phase II program don't make it a very very competitive.

<unk> agents in terms of efficacy and that's what obviously it really matters, but also in terms of combinations.

George Yancopoulos: But also, in terms of combination, uh... we do believe that we have some of the most interesting and potentially game-changing combinations with novel agents such as these co-stimulatory biocivics that are whole different opportunities than combinations with traditional, more traditional agents, so we can take the efficacy that hopefully we will see with monotherapy both in the late stage setting but just as if not more importantly in the earlier stage setting and really extend and take it to We think it's really, you know, whether you can really come up with something and you have in your portfolio very interesting, logical combinations that can really be game changing. And we think that we have those opportunities, which is why we're so excited about this program.

We do believe that we have some of the most interesting and potentially game changing combinations with novel agents such as these coast inventory by Civic center whole different opportunities than combinations with traditional more traditional agents. So we can take the efficacy that hopefully we will see.

With the monotherapy both in the late stage setting, but just as if not more importantly in the earlier stage settings, and really extend and take it.

To another level.

So.

No.

Being a little bit of ahead or behind here is not going to be as important as producing really good data combinations. We think it's really you know whether you can really come up and you have in your portfolio very interesting logical combinations that can really be game changing and we think that we have those opportunities which is why.

We're so excited about this program.

Great. Thanks, George G. D last question. Please.

George Yancopoulos: Thanks, George. Gigi, last question, please. Thank you. Our next question comes from the line of Mohit Bansal from Wells Fargo. Your line is now open.

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

George Yancopoulos: Great, thank you for squeezing me in. Maybe a question on ILEA, high-dose ILEA. Hey George, I would love to get your take on the design of the DME trial. It seems like there are five monthly doses in the two milligram arm, just like the label, but only three for the eight milligram arm.

Great. Thank you for squeezing me in a maybe a question on <unk>.

Yeah high dose Eylea, Hey, Josh I would love to get your take on the design of the D. E trial. It seems like there are five monthly doses. The two milligram arm just like label, but only pay for the eight milligram arm.

George Yancopoulos: Could you please walk us through the rationale behind this difference and whether it wouldn't put high-dose ILEA at a disadvantage? Thanks. Yeah, well, certainly, the whole goal of the high-dose ILEA is to deliver the same efficacy and safety, as Len said, safety being very important, but with a reduced injection schedule. And so, obviously, it is, as you said, more challenging to accomplish the results in photon with less loading injections than for the 2-mg ILEA, but that is the goal with the high-dose of flibrocepts.

Could you please walk us through the rationale behind this person wouldn't it.

Hydro is eylea at a disadvantage thank you.

Yeah, well certainly the whole goal of the high dose eylea used to deliver the same efficacy.

Safety as Len said safety being very important.

But with the reduced ejection schedule and so honestly. It is as you said more challenging to be accomplishing. The result in in photon with less loading injection then for the two milligram eylea.

But that is that is the goal with the high dose.

George Yancopoulos: So, it is challenging, but it is the higher dose, that's what the goal is, and I guess the data will speak. Yeah, I think we can eliminate if we get too high of a loading dose, obviously, it might complicate some of the efficacy readout. But as George said, I think based on what we know when we designed it, it looks like it could, and we're optimistic.

A flipper set so well.

It is challenging but it is the higher dose and that's what the goal is in and I guess the data will speak.

Yeah.

If we can elaborate if we get too high of a loading dose obviously.

It might complicate some of the efficacy readouts.

But as George said I think he's right.

On what we know what we designed it.

It looks like it could.

Right.

Yeah.

George Yancopoulos: Thank you. I think we're done. Thanks. That's Mohit.

Alright, Thank you Ed, but I think we're done.

Thanks.

Thanks, Mohit G D. We conclude the call.

Ryan Crowe: Gigi, we are ending the call. This concludes today's conference call. Thank you for participating. You may now disconnect.

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

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