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. 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. 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. 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 forecasts and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, payor coverage and reimbursement issues, intellectual property, pending litigation, and other proceedings and competition.

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

A more complete description of these and other materials 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 on our financial results press release, which can be accessed on our website. 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 Acquisition Sub Inc.

filed with the SEC and tender offer statement on Schedule TO and other tender offer materials, and Checkmate filed a solicitation recommendation statement on Schedule 14(b)(9) with the SEC.

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?.

Thank you Ryan. Welcome to your first earnings call. I hope all of us stakeholders will join me in giving you a warm welcome to the Regeneron team. Thanks for 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 continued to realize the benefits of our sustained investment in differentiated research and development along with our focus on commercial performance.

We also continued to drive shareholder value through proven capital allocation, including approximately $350 million of share repurchases in the first three months of this year. Regarding our financial performance, we delivered strong double-digit revenue and non-GAAP 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.

For EYLEA, 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.

In 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 opportunity primarily driven by an aging population, increasing utilization among the rapidly growing diabetic population, as well as the potential for our investigational aflibercept 8 milligrams to complement and enhance our retinal franchise.

For Dupixent in quarter one, global revenues for the quarter exceeded $1.8 billion, an increase of 43% to last year as we continued 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 Dupixent in seven new indications in the U.S. later this year and in early 2023, including pediatric atopic dermatitis, eosinophilic esophagitis, and prurigo nodularis. Collectively, approximately 200,000 U.S.

patients are suffering from these three indications today but currently have no FDA-approved systemic treatment options. In oncology, Libtayo continues to capture significant share in FDA-approved non-melanoma skin cancer indications, where it is considered the standard of care.

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 potential launch of Libtayo post-chemotherapy later this year, which would allow Libtayo to address a much larger population of non-small cell lung cancer patients.

As we have said before, we continue to consider Libtayo to be foundation to our immune-oncology development strategy and expect it to serve as the backbone for our investigation of clinical programs in combination with various antibodies, bispecifics and co-stimulatory bispecifics in our pipeline, as well as other pipeline candidates including those from our collaborations.

In April, we announced our agreement to acquire Checkmate Pharmaceuticals, Regeneron’s first-ever acquisition of a company. Upon closing we expect Checkmate’s differentiated toll receptor 9 agonist, vidutolimod will add a promising new modality to Regeneron’s 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 Odronextamab, our potentially best-in-class CD20xCD3 bispecific for refractory B-cell lymphomas, and to advance Regeneron 5458, our BCMAxCD3 bispecific.

Finally regarding our ongoing COVID-19 response, 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-drug interactions.

We are progressing next-generation antibodies that are designed to be active against multiple variants, including those of omicron lineage, and initiated a first in human study last month concurrently as the FDA continues their review of our REGEN-COV BLA for COVID-19 treatment and prophylaxis.

We’re 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.

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 aflibercept 8 milligrams, as well as various other data read-outs from other pipeline programs, which George will discuss.

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 George..

our MUC16xCD3 monotherapy for late stage ovarian cancer, our METxMET bispecific antibody for met-altered non-small cell lung cancer, as well as our PSMAxCD28 costim bispecific in combination with Libtayo in late stage prostate cancer.

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 Libtayo as our foundational anti-PD1 therapy and is augmented by logical combinations utilizing our broad oncology pipeline, whether it involves combining Libtayo 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.

Briefly turning to our antibodies against COVID-19, as we recently announced, the FDA extended its review of our REGEN-COV BLA for COVID-19 treatment and prophylaxis with a new action date of July 13. This extension was due to ongoing discussions with additional data provided to the FDA on pre-exposure prophylaxis use of REGEN-COV.

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.

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. Concluding with our Regeneron genetics medicine, where we in collaboration are continuing to advance our pipeline.

For our siRNA collaboration with Alnylam, 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, cemdisiran plus pozelimab.

Phase III studies of the combination treatment for paroxysmal nocturnal hemoglobinuria, or PNH, and myasthenia gravis are underway and we’ll be dosing patients shortly. In PNH, we are planning to test our combo in both naïve and switch patients tested against standard of care therapies, including ravulizumab and eculizumab.

Beyond C5, several additional combination programs are in our pre-clinical pipeline. We continue to work with Alnylam 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 mid-2022. We are progressing a second target, PNPLA3 into the clinic later this year and have recently identified an additional novel promising target that has been validated by RGC and is awaiting peer review publication.

We are also pleased to report a novel milestone, that we and Alnylam initiated our first CNS target siRNA clinical program targeting amyloid precursor protein, or APP, in development for both cerebral amyloid angiopathy and Alzheimer’s disease.

Showing that this siRNA approach can reduce levels of the target protein in the CNS has the potential to open the door for using this approach in multiple genetically defined neurodegenerative diseases. In the first quarter, we and Intellia 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.

Our recent update demonstrated greater than 90% reduction of transthyretin durably achieved for the follow-up observation period in patients with hereditary transthyretin amyloidosis with polyneuropathy, as well as acceptable safety observed so far.

Our genetics medicine portfolio now includes a diverse pipeline of siRNA candidates that we are working on with Alnylam targeting diseases of the liver, the brain and the eye, as well as our CRISPR-based approaches in collaboration with Intellia and our bio-targeted gene delivery programs, such as with Decibel addressing congenital forms of hearing loss and other internal programs.

While still early, we think these groundbreaking approaches have the potential to change the practice of medicine. With that, I will turn the call over to Marion..

Thank you George. Our commercial performance in the first quarter reflects strong execution and the competitive strength of our diversified and growing portfolio. Starting with EYLEA, first quarter global net sales grew 11% year-over-year to nearly $2.4 billion. Over the same period, U.S.

net product sales grew 13% to $1.52 billion as EYLEA continues to strengthen its leadership position. Across approved indications, EYLEA 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 EYLEA helped improve or save the vision of patients around the world with more than 50 million treatments since launch. Category growth and EYLEA market share continued to increase across all approved indications.

In diabetic eye disease, we have seen notable increases across the patient continuum from initial patient diagnosis through to receiving ongoing EYLEA treatment. We believe diabetic eye disease will remain an important source of future growth for EYLEA as, unfortunately, most patients remain under-diagnosed and under-treated.

Beyond EYLEA, our investigational aflibercept 8 milligram clinical program continues to generate excitement and a high level of interest within the retinal community. If supported by Phase III results, aflibercept 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 EYLEA performance and future potential of aflibercept 8 milligram. Turning now to Libtayo, with first quarter global net sales of $125 million, in the 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 Libtayo in protocols and pathways.

We are working to build on this momentum ahead of the potential chemotherapy combination approval expected later this year that would dramatically expand the patient opportunity for Libtayo in lung cancer.

Finally onto Dupixent, which again achieved remarkable growth for the quarter, demonstrated by a 43% increase in global net sales to over $1.8 billion. Our performance was fueled by robust uptake across all approved indications as well as an expanding geographic footprint and potential future indications, including use in younger patients.

Dupixent 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, Dupixent is the first line systemic treatment in patients with moderate to severe disease.

Healthcare specialists recognize Dupixent’s differentiated profile, which includes dual anti-IL4 and IL13 mechanism of action compelling efficacy, rapid symptom relief, and well established safety profile.

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 biologic eligible children in the U.S.

could benefit from Dupixent in this younger age group. We also look forward to potentially extending Dupixent’s label to include additional dermatology conditions, including prurigo nodularis where patients have no currently FDA-approved medicines. Approximately 75,000 U.S.

patients with PN are in need of new treatment options and may benefit from Dupixent.

In the highly competitive biologic asthma indication, Dupixent continues to grow based on its compelling differentiation for healthcare professionals based on its unique dual mechanism 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 recently pediatric asthma launch. In nasal polyps, Dupixent remains 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.

For example, in our atopic dermatitis clinical program, 40% of patients also had asthma. Dupixent 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 Dupixent 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.

If approved in EOE, we estimate at least 50,000 patients in the U.S. could benefit from Dupixent in this indication. Key opinion leaders continue to provide positive feedback on our clinical data, especially given the lack of effective approved treatment alternatives for their patients who suffer from multiple EOE symptoms.

Turning briefly now to Dupixent in markets 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 Sanofi.

In summary, we see significant potential for Dupixent to continue to change the lives of patients and their families, and we will continue to advance initiatives that bring Dupixent 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. Now I’ll turn the call over to Bob..

Thank you Marion. My comments today on Regeneron’s financial results and outlook will be on a non-GAAP basis unless otherwise noted. Regeneron 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.

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 ex-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 Sanofi collaboration revenue was $631 million in the first quarter of 2022 and grew 73% from the prior year, driven by Dupixent. In this quarter, we recognized the $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’s sales of Ronapreve outside the U.S. We do expect additional revenue from this collaboration primarily in the second half of 2022. Regarding REGEN-COV in the U.S., consistent with our commentary from earlier this year, we did not record any U.S.

sales for REGEN-COV 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 REGEN-COV this year. Other revenue in the first quarter of 2022 was $94 million.

This includes a $30 million upfront payment from our collaborator, Ultragenyx to market Evkeeza 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-COV.

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 line item called Acquired In Process Research and Development. In the first quarter of 2022, acquired IPR&D was $28 million, which includes a $20 million opt-in payment to our collaborator, Adicet.

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

COCM increased 58% year-over-year to $198 million due to higher sales in Dupixent and an increase in shipments of commercial supplies of Praluent 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.

Shifting now to cash flow and the balance sheet, 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 REGEN-COV 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 total equity value of approximately $250 million.

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.

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 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, 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. 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 caller before moving to the next. Gigi, please go ahead..

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 EYLEA and the competitive set. I know you guys have said feedback from the market on Vabysmo has been somewhat muted, but it’s actually kind of striking how different Roche is viewing the reception of the drug.

They highlight a lot of enthusiasm from docs and I know there’s a lot of talk about what will happen after a permanent J-code.

I know you guy have a lot of levers to pull here, not least of which is launching the high dose format of EYLEA, but can you talk a little bit about the rebates, how they are playing into your counterstrategy in the maybe near to intermediate term, and how we should be thinking about net pricing going forward? Thanks.

Chris, happy to give you some characterization of the market. First let me comment on EYLEA.

As we reported today, our performance certainly with EYLEA 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 EYLEA and in the branded marketplace over 75% of the branded market share. 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 comment to us on the importance of the demonstrated safety they see with EYLEA, the efficacious profile that we have, and certainly the extensive consideration across indications and in-market use that has been incredibly robust.

As it relates to other items around pricing and things of that sort, generally we don’t comment; but I certainly will say that looking ahead, we see strong leadership with EYLEA and a profile that is certainly leading the category in terms of experience, uptake and use..

Thank you. Next question, Gigi..

Thank you. Our next question comes from the line of Cory Kasimov from JP Morgan. Your line is now open..

Great, good morning guys. Thanks for taking my question. To follow up on EYLEA, I wanted to ask about the high dose formulation.

Assuming the results read out as you anticipate, how do you think about this product potentially slotting into the treatment landscape? Is it possible 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..

I think at this point, we’ll want to wait and look at product profile as the clinical data matures and then certainly as we move into launch preparation planning, we’ll be considerable 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 product is clarified..

Thank you. Gigi, next question please..

Thank you. Our next question comes from the line of Evan Siegerman from BMO Capital Markets. Your line is now open..

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, and do you expect to go forward combining their asset with Libtayo versus, say, nivolumab or pembro as they had on their prior trials? Thank you..

I’m sure--it’s Len here. I’m sure George would love to expand upon the thinking, but unfortunately because we just launched a tender offer, we’re really not committed to have 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. Fair enough. .

Sorry..

No, it’s all right..

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..

Good morning, thanks for taking my question.

On these initial bispecific data sets in solid tumors in the second half, could you just speak to what exactly we’re going to see initially and then what you would want to see from the data set in terms of being clinically meaningful?.

Well, as I indicated in my remarks, basically we’re going into late stage patients heavily pretreated. 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.

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 to earlier and earlier stage patients.

Each one of them could become then a significant program, not only in monotherapy but in combination with logical other agents. So as I said, responses with duration is what we’re looking for in all three of those programs. .

Just to amplify a little bit, to make sure nobody missed what George just said, is that it seems to be the case that with these types of reagents, much as it is the case with other anti-cancer agents, 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 the late heavily treated would be very encouraging.

.

Thanks Len and George. Gigi, next question please..

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

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

Could you elaborate a little bit more on the safety benefit that you’re seeing for Odronextamab 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..

Yes, we actually had initiated the concept for bispecifics in general as we were very early players in the field of this concept of step-up dosing, and what seems to be 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 had actually pretty low rates with our original, so our original 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 an even more gradual program.

It 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 we’ll give you the 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 and this approach in the outpatient setting.

It’s just very promising that we’ve come up with a safe, what looks like to 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 George. 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 from me - I want to understand, I guess, how you’re thinking about your broader CV effort.

We’ve heard from a number of larger pharma and biotech companies rededicating themselves to CV recently, and when you map out the indications and products, I’d argue you have one of the broader pipelines across CV but you don’t really get much credit for it and Praluent and Evkeeza remain relatively small contributors to your sales.

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..

We have not obviously realized what we think is the full potential of our CV expertise and capabilities, and we are exploring ways on how 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 that.

But we would agree - right now, it’s not a major contributor to our near term performance..

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 Hermann on for Brian Skorney. Could you talk a little bit more about 5458, maybe your confidence that the currently enrolling Phase II study will support a filing, any timeline granularity, and the combinations you’re particularly excited about there? Thanks..

Yes, well 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 II registrational possible study that we are undertaking.

We continue to see a very acceptable safety and tolerability profile, and as you said, this is just 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 terms of combinations, as we’ve talked about before, it’s very logical and the preclinical data are very compelling.

The combinations with so-called costimulatory bispecifics 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 has 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 which involve these costimulatory molecules, and we’re also thinking that obviously, as Len already mentioned, going to 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 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 II study, adding combinations to enhance responses, deepen responsiveness and duration, and three, going into earlier lines of therapy as well..

Thanks George. Gigi, next question please..

Thank you. Our next question comes from the line of Brittany A. Woods from Cowen & Company. Your line is now open..

Good morning everyone, this is Brittany on for Tyler. Congrats on another strong quarter and thanks for taking our question. A multi-part question a bit related on the REGEN-COV cocktail.

For the ongoing studies of the next-gen candidates, when do you expect that you’ll be able to file for approval and what will the regulatory path forward look like; and also, if we continue to be in a relatively low case period as we enter the endemic phase, what could a pivotal trial ultimately look like there?.

These are all really great questions, and we are continuing to discuss our regulatory path both for getting our 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 potential to change, and obviously associated studies to support that program have the potential to change, so we are not at this point talking about the details of either, but great questions..

Suffice it to say the complexities are increased when you have to start thinking about supply as well, 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 is out there.

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 try and make monoclonals 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. Gigi, next question please..

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 from me on the PHOTON and PULSAR outcomes.

It’s been interesting to hear your narrative over many years now through EYLEA, and your team’s generally been right in terms of next-generation efforts that have failed to displace EYLEA as the standard of care.

To that point, I’m a little interested from your commentary on the CANDELA readout and how that impacts your interpretation of 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 on the high dose out to Q 16-week, and does that have to be a comparison to what read out with studies to make it a compelling drug option or a higher dose option in the market to complement EYLEA? The context for this, I guess, I’d put in is you guys have generally contended that a lot of these studies comparing against per label EYLEA are not actually fair studies to be running - obviously used an extra loading dose, but in the real world the treatment extended EYLEA versus any of these other agents is actually quite equivalent, so I’d be just interested to hear how you think that the contextualization of these high dose aflibercept studies really inform who should get the higher dose, if and when it becomes available.

Thank you very much..

You know, 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 - 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, EYLEA is a 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 than switching to a new molecular mechanism of action with unproven safety with 50 million injections behind it.

Frankly, I do think even the FDA views the--when you’re changing dosing paradigms of the same molecule is different than when you’re bringing in a new molecule.

We can’t say, and we wouldn’t dare speak for what clinicians will do once they see the data, but we do feel strongly that having the same EYLEA backbone, if we get the safety that we anticipate thus far from the small CANDELA study and we get the kind of extension of duration, perhaps with more drying, 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 Len. Gigi, 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 on for Matthew. I just want to follow up on the REGEN5458 BCMA bispecific.

I guess my question here is given the competitor is ahead in potentially getting approval later this year, and they are already testing in combination with darsivax , for example, I’m just curious about your confidence on the 5458 in terms of its outlook, and maybe you could just provide some thoughts on the competitive landscape and the commercial opportunity across different line settings.

Thank you..

Yes, we think being 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.

As we said, if we can reproduce the efficacy we’ve seen in our initial studies, in our potentially pivotal Phase II program, that will make it a very, very competitive agent in terms of efficacy, and that’s what obviously really matters.

But also in terms of combinations, we do believe that we have some of the most interesting and potentially game changing combinations with novel agents, such as these costimulatory bispecifics that are a whole different opportunity than combinations with traditional, more traditional agents.

We can take the efficacy that hopefully we will see with the monotherapy, both in the late stage settings but just as, if not more importantly, in the earlier stage settings and really extend and take it to another level, so being a little bit ahead or behind here is not going to be as important as producing really good data.

Combinations, we think it’s really 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. Gigi, last question please..

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

Great, thank you for squeezing me in. Maybe a question on EYLEA, high dose EYLEA. George, would love to get your take on the design of the DME trial. It seems like there are five monthly doses in the 2 milligram arm, just like label, but only three for the 8 milligram arm.

Could you please walk us through the rationale behind this difference, and wouldn’t this put high dose EYLEA at a disadvantage? Thank you..

Yes, well certainly the whole goal of the high dose EYLEA is to deliver the same efficacy and safety, as Len said, and safety being very important, but with a reduced injection schedule.

Obviously it is, as you said, more challenging to be accomplishing the results in PHOTON with less loading injections than for the 2 milligram EYLEA, but that is the goal with the high dose aflibercept. It is challenging, but it is the higher dose, that’s what the goal is, and I guess the data will speak..

Yes, and I think we can eliminate if we get too high of a loading dose, obviously, it might complicate some of the efficacy readouts; but as George said, I think based on what we know when we designed it, this looks like it could--we’re optimistic..

All right, thank you. I think we’re done. Thanks Mohit.

Gigi, can we conclude the call?.

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