Regeneron Pharmaceuticals Inc (REGN) — Q3 2022 Transcript

Thank you, Towanda. Good morning, good afternoon, and good evening to everyone listening around the globe. Thank you for your interest in Regeneron, and welcome to our third 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 business, 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 competition. Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission, including its Form 10-Q for the quarterly period ended September 30, 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. Once our call concludes, Bob Landry and the IR team will be available to answer further questions. With that, let me turn the call over to our President and Chief Executive Officer, Dr. Len Schleifer. Len?

Thank you, Ryan, and thank you to everyone joining today's call. Regeneron's strong operational momentum continued in the third quarter, highlighted by important developments across our pipeline and outstanding commercial execution. Total revenues for the quarter increased by 11% compared to last year when excluding contributions from our COVID antibody cocktail. With global net sales of Dupixent and Libtayo, as well as U.S. net sales of EYLEA reaching new all-time quarterly highs and growing by double digits. Before diving deeper into our commercial results, I'd like to review some of the recent progress we have made across our pipeline, starting with the striking pivotal data that we reported in September for our investigational Aflibercept8 mg, which we believe could ultimately transform the treatment landscape for patients. With nearly 90% of DME patients and 80% of wet AMD patients able to sustain 16-weeks maintenance dosing through 48 weeks of treatment, we believe Aflibercept8 mg may shift the current treatment paradigm, with more patients receiving less frequent injections while achieving visual acuity gains anatomical improvements, and a safety profile comparable to EYLEA. It has proven to be very difficult to decrease the treatment burden beyond what we were able to achieve with EYLEA over a decade ago with many potential treatments failing either due to suboptimal visual outcomes or safety issues. A recently issued anti-VEGF agent did not demonstrate in pivotal studies that the majority of patients in either disease were able to sustain 16-week maintenance dosing throughout the first year of treatment, supporting our view that Aflibercept8 mg has the potential to become the next generation's standard of care anti-VEGF treatment, assuming regulatory approval. We plan to submit the Aflibercept8 mg pivotal data to the FDA under a single BLA at the end of this year and have decided to use a previously granted priority review voucher to expedite the FDA review process. Pre-launch planning is already underway, with a potential FDA approval by late August 2023. In addition to the pivotal Aflibercept8 mg data, Regeneron continued to make notable progress in our immunology and oncology pipelines. Starting with immunology, in September, we received FDA approval for Dupixent in prurigo nodularis, the first systemic therapy for this indication, and the fifth disease for which Dupixent is now approved. So far this year, Dupixent has received four U.S. or E.U. regulatory approvals, expanding the treatment-eligible population by approximately 225,000 patients, including in two diseases that previously had no FDA-approved systemic therapies. In the first-half of next year, we are looking forward to the E.U. regulatory decisions for eosinophilic esophagitis, prurigo nodularis, and atopic dermatitis in patients as young as six months. With these potential additional indications, approximately 200,000 more patients with these type 2 inflammatory diseases could benefit from Dupixent's unmatched clinical profile. Additionally, we expect pivotal data readouts for Dupixent in chronic inducible cold urticaria and chronic obstructive pulmonary disease in the first-half of next year. Moving to oncology, where the depth and breadth of our pipeline has positioned Regeneron to ultimately become a global leader. We presented several datasets at this year's European Society for Medical Oncology Annual Meeting, further underscoring the importance of Libtayo as the foundation for our overall oncology strategy. George will review the data in more detail during his remarks, but we were particularly encouraged by the results for Libtayo monotherapy in neoadjuvant CSCC as well as Libtayo in combination with Fianlimab, our LAG-3 antibody, in first-line metastatic melanoma. We also presented monotherapy data for our MUC16 by CD3 bispecific in recurrent ovarian cancer, which has the potential to be combined with Libtayo as well as data for our METxMET biparatopic bispecific in MET-altered non-small cell lung cancer. I'd also note the early but very exciting results for our PSMAxCD28 costimulatory bispecific in combination with Libtayo, which showed promising anti-tumor activity in patients with advanced metastatic castration-resistant prostate cancer. The patients enrolled in our study have a poor prognosis, with an expected survival of one to two years depending on their treatment history. Given prostate cancer has been largely unresponsive to PD-1 inhibition and immunotherapy in general, there is a clear need for new treatments. In 2020 alone, there were over 375,000 deaths globally from prostate cancer, and it was the second leading cause of cancer death in American men. We continue to expand our costimulatory bispecific efforts in prostate cancer with an acceleration in enrollment in our first immune study since we reported our top line results in August. And we look forward to updating you on this program in the first-half of next year. Now turning to our commercial performance, in the third quarter, EYLEA global net sales grew 8% at constant currency to $2.4 billion. In the U.S. EYLEA net sales were $1.63 billion, up 11% year-over-year, and outperforming the anti-VEGF category growth of only 4%. Despite recent branded and biosimilar entrants, EYLEA set a new all-time high for anti-VEGF category share in the United States. Dupixent continued to grow at a remarkable pace bolstered by approvals in new diseases and younger patient populations in previously approved indications. In the third quarter, global net product sales were $2.3 billion, up 45% at constant currency compared to last year, reflecting growth across all indications and all geographies. Dupixent's differentiated clinical profile and ability to effectively treat more and more patients in both currently approved indications and potentially for additional type-2 inflammatory diseases is expected to drive strong growth in the future. Libtayo total net sales grew 25% globally at constant currency, to $143 million in the third quarter, including 21% growth in United States driven by non-melanoma skin cancer indications and monotherapy non-small cell lung cancer. At the start of the third quarter, we acquired global rights to Libtayo from Sanofi, with potential future combinations including with chemotherapy in non-small cell lung cancer as well as other pipeline agents in development, we believe Libtayo is poised to become a more meaningful revenue contributor over time. We are excited about the strong commercial performance for our core products with compelling efficacy, safety, and durability data that we reported for Aflibercept8 mg, as well as the notable progress we have made advancing our pipeline, particularly in oncology. Our pipeline now includes approximately 35 product candidates in clinical development including a number of marketed products that we are investigating for additional indications, some of which George will discuss in a moment. In closing, our strategy continues to focus on investing in our internal R&D capabilities while exploring potential collaborations that will enable us to fully realize the power of our science. We remain confident in this strategy and in our growth prospects as well as in our ability to deliver breakthroughs to patients and value to shareholders. Now, I will turn the call over to George.

Thank you, Len. I will start with ophthalmology. Positive pivotal results for Aflibercept8 mg in the PULSAR and PHOTON study were recently presented at the American Academy of Ophthalmology Annual Meeting. Results of these trials in wet AMD and DME respectively demonstrated that a remarkably high percentage of patients were able to be rapidly initiated into and then successfully maintained through week 48 on 12- and 16-week dosing intervals while achieving vision gains that were non-inferior to the current standard of care, EYLEA 2 mg dosed every 8 weeks. These results suggest that Aflibercept8 mg has the potential to become the new standard of care in these retinal diseases. I think it would be helpful if we step back for a minute and try to put these results in context. What our trials did was push the limits far beyond what has been accomplished with any currently available anti-VEGF therapies. Rather than using response criteria to try to identify or slowly extend patients to longer dosing intervals, our trials tested whether all patients could be randomly assigned and rapidly initiated on extended dosing intervals of Aflibercept8 mg without compromising visual improvement or safety. These Aflibercept8 mg trials accomplished just that for the vast majority while delivering a safety profile consistent with that of EYLEA. Eighty-nine percent of DME patients and 77% of wet AMD patients were able to be rapidly initiated and maintained on a 16-week Aflibercept8 mg dosing regimen while 93% of DME and 83% of wet AMD patients were able to be rapidly initially maintained on at least a 12-week dosing interval. All while delivering efficacy similar to that of EYLEA administered every 8 weeks. We believe these are truly unprecedented and potentially game-changing results which have not been achieved using any other anti-VEGF agent. Others have speculated that PULSAR and PHOTON results were due to our dose modification criteria and even tried to theoretically extrapolate that their agent could have somehow approached these results using our criteria. We put these speculative extrapolations into the category of wishful thinking. And based on our expert analysis of the data, we conclude it is all about the drug and not the trial design. Briefly moving on to Dupixent, building on our recent approval in eosinophilic esophagitis in adults and adolescents, we are planning on submitting a supplementary BLA for eosinophilic esophagitis in 1- to 1-year-old children in mid-2023. Dupixent's ability to treat eosinophilic esophagitis highlights how important it is that our IL-4 and IL-13 blocker more completely target the entire type 2 inflammatory cascade and not only eosinophils. As you heard Len mention, the FDA label was expanded yet again in the third quarter as Dupixent became the first and only treatment indicated for prurigo nodularis, a debilitating chronic skin disease. This marks the fifth disease for which Dupixent is now approved. Our collective clinical data with Dupixent support a unifying molecular mechanism underlying these related diseases from asthma to atopic dermatitis to nasal polyps to prurigo nodularis to eosinophilic esophagitis. In this unifying hypothesis, IL-4 and IL-13 induced inflammation is driving all these related diseases in different tissue compartments. Moving to Libtayo and oncology, in the third quarter, our robust oncology pipeline has started to deliver data readout from our latest and most innovative programs. We are expecting these readouts to accelerate in the remainder of 2022 and continue into 2023. The European Society of Medical Oncology or ESMO Annual Meeting in September was a truly a banner event for Regeneron, with several notable oral presentations for assets in our oncology pipeline, which I would like to briefly summarize. Starting with Fianlimab, our LAG-3 antibody in combination with Libtayo, at ESMO, we shared data from two independent advanced melanoma expansion cohorts from our first-in-human study which importantly showed consistent efficacy and safety between the two replicate cohorts. Fianlimab in combination with Libtayo demonstrated greater than 60% response rates in each cohort. A median PFS estimated will be 24 months across both cohorts, and a median duration of response that has not yet been reached. The preliminary safety profile of the combination appears to be in line with anti-PD-1 monotherapy and potentially with less toxicity compared to anti-CTLA-4 combination. While dual LAG-3 and PD-1 inhibition has previously shown promise in advanced melanoma, response rates greater than 45% with median PFS of more than a year has not been previously reported. These initial results in melanoma suggest that the Fianlimab-Libtayo combination has the potentially best-in-class profile in the setting. We are enrolling our Phase 3 metastatic melanoma study. We intend to initiate a Phase 3 adjuvant melanoma study later this year and have additional plans in other solid tumors where Fianlimab has a potential to be first-in-class. The neoadjuvant cutaneous squamous cell carcinoma or CSCC, a Phase 2 study of Libtayo monotherapy has shown promising results. Given prior to potentially curative surgery in patients with large tumors, Libtayo was able to deliver major pathological responses to 63% of patients prior to surgery. This raises the possibility that Libtayo could decrease the burden of these major and potentially disfiguring surgeries for the many patients who require them each year. We are pleased that concurrent with the ESMO presentation, these data were published in the New England Journal of Medicine. Regarding next steps, we are talking to regulators about possible pathways to labeling and potential inclusion in the NCCN guidelines. Also at ESMO, we presented initial clinical data for Ubamatamab, our MUC16xCD3 bispecific developed for advanced ovarian cancer, our first clinical data for a CD3 bispecific in a solid tumor. In the heavily pre-treated ovarian cancer population, we observed durable responses to this MUC16xCD3 monotherapy. In a patient subset whose tumors over expressed MUC16, response rates were as high as 31%. Most of the treatment-emergent adverse events occurred with the initial step-up dosing. Ubamatamab is being developed as a monotherapy as well as in combination with Libtayo and as well as in combination with our MUC16 co-stim bispecific. We are looking forward to more data across these programs in 2023. In our ESMO investor presentation, we shared more detailed data for our PSMAxCD28 co-stim bispecific in combination with Libtayo, representing the first efficacy and safety data with this new class of bispecifics which we had initially top lined and discussed at our second quarter earnings. We have since continued to enroll patients in the study. We are planning to present updated data at a medical meeting in the first-half of 2023. Regarding our hem/onc pipeline, we are looking forward to data from Odronextamab, our CD20xCD3 bispecific as well as Linvoseltamab, our BCMAxCD3 bispecific at the American Society of Hematology or ASH Annual Meeting in December. For Odronextamab, we will present pivotal Phase 2 data for both follicular lymphoma and diffused large B-cell lymphoma in two separate oral presentations. Upon discussions with the FDA, we are now targeting a second half 2023 regulatory filing of this program. We hope to initiate combination studies with an appropriate CD28 co-stim bispecific in the near future. For Linvoseltamab, our BCMAxCD3 bispecific antibody, we remain on track with development, and we are planning to file pending discussions with the FDA in 2023. We have now completed enrollment in our potentially pivotal Phase 2 study. As I mentioned earlier, data from this study will be updated at ASH. As with our Odronextamab, we are planning on initiating combination studies for Linvoseltamab with co-stimulatory bispecifics in the near future. We believe existing standard of care therapies leave significant room for improvement in these difficult-to-treat settings. And we have been encouraged by the interim efficacy and safety data we have generated today for both Odronextamab and Linvoseltamab. Finally at ESMO, we also shared initial data for our Maftivimab bispecific antibody in MET-altered non-small cell lung cancer. Responses were rich in patients with high levels of MET expression. No dose-limiting toxicities were observed. Even the modest overexpression of MET may render lung cancer susceptible to this mechanism of action. And we are looking forward to the METxMET antibody-drug conjugate data next year. In summary, for oncology, a rich combinatorial pipeline is delivering competitive data. And with our full ownership of Libtayo, we are excited about the potential to advance standard of care in oncology with our portfolio approach. Concluding with the Regeneron genetic medicines efforts where we continue to progress our pipeline and discovery engine. In September, we and Alnylam reported promising data from our ongoing Phase 1 study of Alnylam HSD nonalcoholic steatohepatitis or NASH. We are planning on initiating a Phase 2 study shortly, which is just one part of our multi-pronged approach exploring multiple genetically validated targets for NASH. Also in September, we and Intellia announced initial data from the cardiomyopathy arm of our ongoing Phase 1 study of NTLA-2001. An investigational CRISPR-based therapy for the treatment of transthyretin amyloidosis, which shows deep and sustained mean serum TTR reductions of over 90% and was generally well tolerated. Finally, in October our collaborators at Decibel Therapeutics announced FDA clearance for an NDA application for DB-OTO, a first virally delivered gene therapeutic product candidate designed to provide hearing to individuals with otoferlin-related hearing loss. This IND provides clearance to initiate a pediatric Phase 1/2 clinical trial in the United States. With that, I will turn it over to Marion.

Thank you, George. Our third quarter performance reflects strength across our commercial portfolio. We continue to extend our leadership position in additional therapeutic categories as part of our commitment to deliver life-changing medicines to patients in need. With Dupixent's approval in prurigo nodularis, Libtayo's anticipated approval in combination with chemotherapy in the first line of non-small cell lung cancer, and recent data demonstrating the compelling profile of Aflibercept8 mg, Regeneron's commercial business is poised to deliver long-term growth. Starting with EYLEA, which reached $2.4 billion in global net sales for the third quarter, this represents an 8% increase on a constant currency basis, a remarkable achievement for a brand that launched 11 years ago. In the U.S., EYLEA net sales grew 11% year-over-year to $1.63 billion to again achieve over a million injections in the quarter. Despite the overall 2% sequential category decline in volume from the second to third quarter of 2022, EYLEA continued to grow across all indications gaining share from both branded and unbranded agents. In fact, EYLEA reached all-time highs in category share of approximately 50%, with a commanding 75% share in the branded category. We continue to strengthen and extend EYLEA's leadership position in the anti-VEGF category, as we recently announced the FDA has granted pediatric exclusivity for EYLEA, thereby extending the period of EYLEA's U.S. market exclusivity by an additional six months through May 17, 2024. Since announcing positive Phase 3 results earlier this year, there has been widespread excitement in the retina community about the Aflibercept8 mg dataset and Aflibercept8 mg's potential to become the future standard of care, if approved. Next to Libtayo, total global product sales were $143 million, growing 25% on a constant currency basis. In the U.S., net sales grew 21% to $95 million based on growth in our lung and non-melanoma skin indications. We see particular opportunity for growth in lung cancer over time. In monotherapy, there are already steady increases in prescribers and total utilization. We are launch-ready for the potential chemotherapy combination approval which significantly expands the patient opportunity. And finally to Dupixent, third quarter global net sales were $2.3 billion, up 45% on a constant currency basis. In the U.S., net sales grew 45% to $1.82 billion driven by robust demand across atopic dermatitis, asthma, and nasal polyps. Growth was also driven by a rapid launch trajectory across recent indications including eosinophilic esophagitis and pediatric atopic dermatitis where Dupixent is the only biologic to be approved from infancy through adulthood. Starting with dermatology, in atopic dermatitis, Dupixent is the leading first-line systemic therapy with strong uptake across the spectrum of moderate to severe disease and across age groups. The ongoing launch in patients as young as six months is progressing very well, providing relief to families as well as reinforcing the safety of Dupixent for all age groups. We've also expanded Dupixent's leadership in dermatology. Following its approval in prurigo nodularis, Dupixent is the only FDA-approved medicine for this chronic debilitating skin disease that affects approximately 75,000 adults in the U.S. Early launch indicators are positive with patients already being initiated on therapy. Dupixent also continues to perform well in the highly competitive asthma market, with steady growth in prescriptions and new patient starts, as well as nasal polyps. Early launch performance in eosinophilic esophagitis has been very strong, with broad adoption from both gastroenterologists and allergists. The medical community has embraced Dupixent as patients previously had very limited options. Dupixent is the only medicine indicated to treat eosinophilic esophagitis and is the only treatment shown to address the underlying causes resulting in unprecedented symptom relief. There are presently 50,000 adults and adolescent patients in the U.S., and we continue to advance our clinical efforts in younger patients where substantial unmet need remains. Outside the U.S., Dupixent net sales were $506 million, growing 44% on a constant currency basis. There is rapid uptake across approved indications, and we continue to execute on recent launches, and expand into new geographies. As part of this, Regeneron's increased presence in key international markets supports efforts to bring Dupixent to even more patients. In conclusion, our third quarter performance demonstrates strength and growth across our commercial portfolio. We are successfully executing on initiatives to deliver life-changing medicines to patients and advancing strategies to maximize new and upcoming launches. Our commercial portfolio is positioned well to drive long-term and sustainable growth. Now, I will turn the call 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 performed well in the third quarter, with growth from key brands and execution across the business continuing to drive strong financial results on both the top and bottom line. Excluding global revenues related to the COVID-19 antibody cocktail, third quarter total revenues increased 11% year-over-year to $2.9 billion, demonstrating continued growth momentum from our core business and reflecting the favorable impact of the Libtayo transaction. Third quarter total diluted net income per share was $11.14 on net income of $1.3 billion. Beginning with collaboration revenue, and starting with Bayer; third quarter 2022 ex-U.S. product sales were $817 million, up 4% on a constant currency basis, versus third quarter of 2021. Total Bayer collaboration revenue was $333 million, of which $315 million related to our share of EYLEA in those profits outside the U.S. Total Sanofi collaboration revenue was $711 million in the third quarter of 2022 and grew 22% from the prior year, driven by Dupixent. Recall that in connection with the Libtayo transaction, we increased the repayment of our antibody collaboration development balance from 10% to 20% of antibody collaboration profits. A portion of this step-up is recorded as a reduction to antibody collaboration revenues, while another portion is recorded as R&D expense. Given Regeneron is now recording its full 50% share of antibody collaboration R&D expenses incurred, previously Regeneron had only recognized a partial share of its antibody collaboration R&D expenses incurred, with the remaining share of expenses added to the antibody development balance. Also, as we highlighted last quarter, in accordance with the agreement, we recorded a one-time development balance repayment of $57 million as an incremental reduction to Sanofi collaboration revenue in the third quarter of 2022. We have posted to our website supporting materials to further explain the accounting associated with this and other elements of the Libtayo transaction. Moving now to our operating expenses, R&D increased 38% year-over-year to $817 million, partially driven by the impact of the Libtayo transaction, which affects R&D in two ways. First, Regeneron now records all R&D expenses for Libtayo, which was previously shared equally with Sanofi. Second, as I mentioned earlier, Regeneron now records its full 50% share of antibody collaborations spend for Dupixent and Itepekimab. SG&A expense increased 20% year-over-year to $467 million primarily driven due to incremental costs related to assuming global rights to Libtayo. Cost of goods sold in the third quarter was $109 million, and product gross margin in the quarter increased to 94% as compared to 90.2% in the prior year. The more favorable gross margin was driven by the non-recurrence of REGEN-COV sales in the current period and the removal of the payment to Sanofi for their share of U.S. Libtayo gross margin. Finally, the third quarter 2022 effective tax rate was 12.1% compared to 10.8% in the prior year. Shifting now to cash flow in the balance sheet, year-to-date in 2022, Regeneron has generated $2.9 billion in free cash flow and ended the third quarter of 2022 with cash and marketable securities less debt of approximately $10.3 billion. We remain focused on leveraging our strong financial position to deliver long-term value for shareholders. Over the first nine months of 2022, we have deployed in excess of $2.8 billion in capital; we have executed approximately $1.2 billion in business development initiatives including the $900 million acquisition of Libtayo rights. Additionally, we have repurchased over $1.6 billion of our shares, including over $900 million in the third quarter alone. As of September 30, we had approximately $1.2 billion remaining on our current share repurchase authorization, and we remain opportunistic buyers. As we approach the end of the year, we've made some minor changes to our 2022 guidance ranges. A complete summary of our latest full-year financial guidance is available on our press release issued earlier this morning. In addition to these changes, I would also like to provide some initial thoughts on our 2023 expense outlook. We continue to make investments to advance our pipeline and position the company for long-term growth. We expect R&D investment to grow in 2023 comparable to our slightly above the nine-month year-to-date growth rate reported earlier today. The incremental R&D investment in 2023 will be driven by advancing our immuno-oncology, hematology, immunology, and genetics medicine pipeline, as well as the continued expansion of our R&D organization. In addition, 2023 will be the first full year reflecting the impact of the Libtayo transaction where we record 100% of global R&D spend for Libtayo and our full 50% share of the Sanofi antibody collaboration R&D spend as incurred. For SG&A in 2023, we currently project growth in the mid-teens versus 2022 given we'll be recording a full-year of global Libtayo expenses along with targeted investments in the build-out of our international infrastructure. Finally, for other operating income and expense in the third quarter of 2022, we recognized the remaining $44 million of deferred income related to previously received upfront payments in development milestone for Fasinumab as a result of the program discontinuation. We do not currently expect any material other operating income or expense in the fourth quarter of 2022, in 2023, and beyond absent any new transactions. In conclusion, Regeneron has performed exceptionally well in the first nine months of 2022, and our strong financial position enables continued investment to drive long-term growth. With that, I will pass the call back to Ryan.

Thank you, Bob. So, Towanda, this concludes our prepared remarks. We'd now like to open the call for Q&A. With the number of callers in the queue, I'd like to ensure we are able to address as many questions as possible. As a result, we'll only be able to answer one question from each caller before moving to the next. So, Towanda, please open the call for Q&A.

Hi, guys. Thank you so much for taking my questions, and congrats on the progress. So, with nearly $13 billion on the balance sheet and minimal debt, can you provide more color on your capital allocation priorities? Would you consider business development on a larger scale and/or issuing a dividend?

Evan, hi, good morning, it's Bob. With regards to capital allocation, and demonstrated today by our growth in R&D in the 2023 forward guidance, we are going to continue to invest, first and foremost, in the R&D pipeline that we have. We issued our 10-Q this morning; within the MD&A, you'll see a plethora of trials that are currently ongoing. And as George mentioned in his script, we're very bullish regarding what is in the pipeline. Now, again with regards to business development, it's not an either/or, right, as you saw in what we've done in the first nine months of 2022, where we do think there are opportunities and where we believe we can do collaborations where one plus one is three, then we're absolutely going to take that opportunity, and I think Checkmate was a good example of that. And I would expect that you'd see more of that. With regards to your question on dividends, it's never a never. Obviously, that tool is in our toolbox if we do decide to play that card. As of right now, we don't have dividends in the foreseeable future in our plan. We have been very opportunistic with regard to buybacks. Again, the MD&A issued earlier today, the 10-Q will show you what we've been buying back our shares. Again, we'll remain opportunistic buyers. And we do have a remaining $1.2 billion remaining under our current $3 billion authorization.

Thanks, Bob. So, Towanda, please have the next question on, please.

Good morning, everyone. Congratulations on a successful quarter. I took a look at the Odronextamab and 5458 NASH abstracts, and I would appreciate a brief preview from you regarding what you feel is necessary to present at the conference in order to remain competitive with what others are displaying.

Yes, I don't think we want to scoop ourselves given that the conference is coming up pretty soon, Tyler. But Odronextamab has the potential of being a very important molecule. We recognize that there are some people ahead of us, and we recognize that some of the most recent timelines are pushed back a little bit based on recent regulatory feedback. The regulators have recently been focused on having Phase 3 trials substantially enrolled at the time of submission before they'll grant accelerated approval. But we are confident in the profile of Odronextamab. And as George says, there is also the future possibility of combinations with other things in our pipeline that could really even leapfrog.

Thanks, Len. Next question, please, Towanda?

Good morning. Thanks for taking my question. On EYLEA, what are you observing in the market between yourselves and Roche for the Vabysmo launch?

So, happy to give more characterization, as I mentioned, we see EYLEA continuing to perform extremely well, reaching all-time high category share of 50%, and now as well growth in the overall branded market where we participate with other branded agents, including Roche. One thing I will mention just to give a bit more insight is that EYLEA captured growth coming primarily from Lucentis and also from Avastin. And, in fact, if you put the Roche portfolio together, the growth of EYLEA obviously was positive, while there was a decline in a real market share for the Roche products combined.

Thank you, Marion. Next question, Towanda?

Great, good morning. Thanks for taking the question. George, I was wondering if you could just comment on your outlook for the COPD study for Dupixent and how you think about that market opportunity? Thanks.

Actually, COPD has been a very difficult disease for new therapies in biologics in particular. We think that there is a category of patients with COPD who have or are marked by more of what we call Th2-type inflammation. We think that, as I said in my remarks, that there's this unifying hypothesis there are a lot of Th2-type diseases that manifest in different ways. We believe that this subset of patients with COPD may fit into that category. And being able to benefit these patients in terms of either reducing their exacerbations and/or improving their lung function would really make a difference to these patients. And so, we're anxiously awaiting the data, and we're hopeful that we will have another set of patients where we might be able to demonstrate that Dupixent could really make a difference.

Thanks, George. Towanda, next question?

Thank you so much. Lilly will be launching Lebrikizumab in '23 in atopic derm, and they have data that looks comparable to Dupixent, at least in this one indication. Pretty much a direct competitor, although not identical on mechanism, they know the derma space because it halts, and the positioning is going to be that they can dose every month versus Dupixent, which is every two weeks. So, I'm wondering if you have any strong views on that product or if you think that it's going to be total nonstarter which is pretty much the consensus view I get?

Maybe Marion can comment on it. But look, there's room for competitors in this market. We're really modestly penetrated in the opportunity. I don't think that the profile that you say is actually going to be suppressed. We've seen it so far, all that's similar. We have the earliest, from infancy already to adulthood. That's a big deal, okay. In addition, the fact that many of these people have other comorbidities, whether it be asthma or nasal polyps, for example, and they can get, if they do have comorbidities, this single drug can treat both. It's a very big differentiator. So, I think that when you're the market leader, when you're so far ahead, when you have really a differentiated profile you have an advantage. Obviously, Lilly is a fine company; they know what they're doing. But as I said, there's room; frequently, when new, good drugs come to market there is a growth of the market. And we're not going after a fixed number of patients; we're actually growing those patients. Marion, I don't know if you want to add anything?

So, I would just add that most of the key opinion leaders that we speak to recognize that the dual mechanism of action, the IL-4 coupled with IL-13 is very, very important, so certainly efficacy shouldn't be assumed. There's also reinforcement on the incredible efficacy that's seen for patients with moderate-through-severe disease. And, obviously, real-world experience is compelling. The administration with Dupixent is really quite straightforward, it's self-administration, and we actually see there the active patient or parent involvement has been very helpful in establishing Dupixent. But certainly as Len mentioned, expanding the education in category to bring more atopic dermatitis patients into the treatment continuum is very positive for patients, and certainly for Dupixent.

Not to pile on, but to add to what Len was saying, the fact that IL-13 has failed in other important Th2 inflammation-driven diseases, such as asthma and COPD, suggests that they are not fully addressing Th2 inflammation. Many individuals, as Len pointed out, suffer from other allergic comorbidities. It can make a significant difference for a patient when one drug can treat a systemic disease rather than only addressing one aspect of where it manifests. Medicine should be moving towards treating systemic diseases where Th2 inflammation is likely prevalent in various parts of the body; treatment should not be limited to just one area. We have demonstrated with Dupixent that it works across different diseases, effectively addressing the underlying inflammation associated with all of these conditions.

Okay, thank you for that response. Towanda, can we go to the next question?

Thank you for taking my question, and congratulations on your progress. I would like to ask for more details about your comments on the growth of the anti-VEGF market, which you mentioned is around 4% year-over-year. This appears to be a slowdown compared to the high growth we have previously observed. Could you provide more insight into this? Do you think this is just a one-quarter occurrence? Is it possible that this is a result of the rapid growth we experienced post-COVID, which is now declining? Your clarification would be appreciated. Thank you.

I think it's very difficult to extrapolate one quarter. Certainly I did mention that there'd been a sequential decline of about 2% going from the second quarter into the third quarter in the overall anti-VEGF category. But I think it's really difficult to extrapolate from that. The numbers you shared on overall year-over-year growth of category, at about 4%, we recognize as well. I think we'll have to see as a bit more time goes by. But it's really difficult to draw conclusions on what may or may not have occurred in a one-quarter period.

There's still quite a bit of room for growth in the diabetic eye diseases area. We still see decent growth there in that category.

Helpful, thank you.

Next question.

Thank you, Len, and Marion, and Mohit. Next question, please, Towanda?

Hey, thanks. Just another question maybe on the VEGF market and EYLEA specifically, so in our checks we get a sense that there's some docs who believe that Vabysmo confers differentiated efficacy. But on the other hand, there's still a sizable amount of docs who've yet to see a patient for follow-up after the first dose. So, sort of just curious if, in the field, you're seeing a difference in perception of Vabysmo by time of experience, that is any discernable change in perception with the more patient follow-up they've had? Thanks.

I think it's probably best that Roche answer questions on what they're hearing about use. I'll just share at this point, I haven't heard characterization or that use is still at a low level, in fact quite modest. I can characterize the EYLEA performance, as I did, in terms of market leadership and the growth we see in our business in terms of market share and other parameters, and that is across indications, and certainly substantially creating EYLEA as leader in the anti-VEGF category. And, obviously, we're very enthusiastic as is the retina community, probably even more important about the possibilities and potential of Aflibercept8 mg if approved in the future.

Thank you, Marion. Next question, please.

Hey, good morning, and congrats on the quarter. So, on EYLEA, in '23, we're starting to see confirmatory updates. So, I was wondering, could you just speak to how you see the market share evolving over the course of '23 in light of Vabysmo, and then, obviously, biosimilars? And then just as we think about high-dose EYLEA in the back half of the year, anything you can say in terms of anticipated OpEx changes? Thank you.

So, as a start, we don't predict future market share performance, so I'm going to stay away from specifics in that area. Certainly, not only this quarter but over several quarters, we've been able to demonstrate continuing strong performance with EYLEA as the anti-VEGF category leader. And certainly, we'll continue to work on that. And as agents have entered the market, our competitive readiness abilities have been very strong. But most importantly, frankly, it's the profile of EYLEA; the clinical attributes, the safety of the product, the breadth of indications, ease of access for physicians and patients, but going forward, certainly we will be very much prepared to launch Aflibercept8 mg and you know, as we get into that launch potentially with an FDA approval we will be able to give more characterization, but as George and Len described today, the profile of Aflibercept8 mg and opinion leaders in the retina community confirm that this profile potentially has all the ingredients to become standard of care, and certainly that's what we work on all the benefits of vision coupled with safety, and now this potential of substantial durability that hasn't been seen before in the category.

Collin, it's Bob. Regarding operating expenses, Marion and I will approach the brands as we always do, evaluating what truly makes sense. As you know, determining the number of retinal doctors is essential. We are not venturing into entirely new territory that introduces many new points of contact. Additionally, Marion's team is currently a highly effective sales team performing at their best. Therefore, we do not anticipate any major shifts in this area, but we will ensure that we allocate funds appropriately and that the commercial aspects align with the strength of the clinical data. Thanks.

Thank you.

Okay. Next question, please?

Hey, good morning. Thanks for taking my question, and congrats on the continued execution and innovation. On Costimulatory Bispecifics, by specific, now that you have more time with the evolving data, any views on predictors of response and durability there, and I'm curious how your learnings might shape your latest thoughts on threading the therapeutic window, both for the PSMA as you accelerate the trail enrollment, as well as your other Costimulatory Bispecifics? Thanks.

Yes, our data indicates that we've seen remarkable response rates, particularly at higher doses. To remind you, at the highest dose, three out of four patients experienced very profound responses. Response predictors are not a concern, but there has been a question regarding the therapeutic window; we are observing autoimmune-related side effects associated with these responses. We are actively working to better understand the relationship between responders and these new side effects. A positive aspect is that we do not see significant autoimmune side effects in patients who do not respond. This indicates that those who benefit from the treatment are experiencing those side effects, which suggests that the drug is functioning as intended. I believe this is some of the most exciting data in immunotherapy, as we can treat what has traditionally been considered a 'cold tumor,' which typically shows minimal responses to immunotherapy, and achieve very high rates of deep, durable responses. We will continue to work on enhancing the therapeutic window. Regarding our bispecific program, I want to emphasize that there are few bispecific therapies in the CD20 and BCMA spaces that are competitive with each other, ours included. The emerging data points to effective efficacy and safety profiles among these agents. We plan to share updated data at ASH, and I foresee a limited number of competitors in this field, although there is a significant patient population in late-stage settings requiring treatment. Therefore, there will be room for these competitors. In the future, we will focus on transitioning to earlier lines of therapy, which requires careful study designs and consideration of standard co-therapies. Moving these agents into earlier treatment lines will involve a lot of skill. Additionally, aside from transitioning to earlier therapy lines with standard combinations, we will explore novel combinations. For instance, in prostate cancer, we are working with similar agents that will be combined with our CD20 bispecific in lymphoma and our BCMA bispecific in myeloma. We believe these strategies will have a substantial impact on patient care. It's essential to note that R&D will produce competitive agents in late-stage settings, all making valuable contributions to patient treatment. As we artfully introduce these agents into earlier lines of therapy, we are optimistic about the opportunities in our portfolio to elevate the treatment of cancers and improve patient outcomes, as is already evident in our work in prostate cancer.

George, there was one question about biomarkers in prostate cancer, maybe you might just comment on how quickly you can use PSA, you know, as studies after paper works is exposed to both agents?

Right. And in some of the data we have already shown, and we will continue to show, many of our patients have remarkably high PSA levels, because they have a very high burden of disease; as we all know depending on the assay and the lab and so forth, normal PSA levels are in the low single-digits, maybe one to four, consider the highest levels. We have patients who entered into our study with PSAs in the 100s, 500s, 600 and so forth. And we saw with this combination treatment, as soon as you put the combination on board essentially at the next time point that we measured within three weeks or so, we saw dramatic drops in the order of 99% reductions in the PSA. And these are really astounding results, and now where we continue to follow our patients over time we have seen that, for example, bone lesions have entirely normalized, and so forth. So, the effects are incredibly rapid as reflected in the PSA. And to the point about predicting which patients respond, it doesn’t matter whether you had patients who had relatively low burden as measured by PSA, where their PSA was measured in let's say, 40 to 50 range, or whether you had incredibly high PSAs in the 500 to 600 range; those patients seem to similarly respond in terms of very dramatic, very profound drops in the PSA within weeks of starting therapy. And as we continue to follow these patients incredibly durable responses, first patient has now been out for more than a year. Their immune side effects have resolved, whereas their complete remission has remained completely intact, and as I said, not only completely normalized the PSA levels, but the bone lesions and so forth have all normalized at least as measured by bone scans and so forth. So, this really has the potential to be so game-changing for these late-stage patients who really have at this point no other real recourse.

Thank you, Len and George. I think we have time for one more question. Towanda?

Hi. Good morning. Thank you for taking the time to speak with me. I'd like to ask Marion about the timeline for receiving a J Code for high dose EYLEA next year. We've seen quite different timelines in the past for approvals, such as with AVEVO, while Eli Lilly and Roche had a slower process. Should we anticipate that the J Code could potentially be issued around January 1, 2024, or possibly even in the later part of 2023? Thank you.

Carter, thank you for the question, and certainly we will stay very close on this. And obviously, the importance of new BLA and new J Code is important. In terms of timing, I would need a crystal ball to predict this right now; certainly would share with you, we will be working very closely with the proper organizations and officials, but at this time it's too early to give anything definitive on expectation for J Code timing.

Yes. From my perspective, I am not fully convinced that the J Code will lead to significant changes in uptake.

Okay, thank you.

I think that's all we have time for today. Thank you everyone for joining the call. As always, the Investor Relations team is standing by for any follow-up questions you may have. Have a great day, everyone.