Moderna - Q4 2022

Transcript

Operator (participant)

Good morning. My name is Kevin. Welcome to Moderna's fourth quarter 2022 earnings call. At this time, all participants are on a listen-only mode. Following the formal remarks, we'll open the call for your questions. To ask a question during the session, please press star one one on your telephone. If your question has been answered and you wish to withdraw your question, please press star one one again. Please be advised this call is being recorded. At this time, I'd like to turn the call over to Lavina Talukdar, Head of Investor Relations at Moderna. Please proceed.

Lavina Talukdar (Head of Investor Relations)

Thank you, Kevin. Good morning, everyone. Thank you for joining us on today's call to discuss Moderna's fourth quarter and full year 2022 financial results and business update. You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the investor section of our website. On today's call are Stéphane Bancel, our Chief Executive Officer, Stephen Hoge, our President, Arpa Garay, our Chief Commercial Officer, and Jamey Mock, our Chief Financial Officer. Before we begin, please note that this conference call will include forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please see slide 2 of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance or results to differ materially from those expressed or implied in these forward-looking statements.

With that, I will now turn the call over to Stéphane.

Stéphane Bancel (CEO)

Thank you, Lavina. Good morning or good afternoon, everyone. Welcome to our Q4 2022 conference call. Today, I will start with a quick business review of 2022. Stephen will then review our clinical programs before Arpa gives an update on our commercial progress and plans. Jamie will then present our financial results, and I will come back to share some thoughts on where we're heading. We are pleased to report today revenues of $19.3 billion for fiscal year 2022, GAAP net income of $8.4 billion, and GAAP diluted earnings per share of $20.12. Cash and investment balances of $18.2 billion at the end of the year. We continued our disciplined capital allocation policy, reinvesting first in our company.

In 2022, we invested $3.3 billion in R&D, our highest level of R&D investment ever. We invested $1.1 billion in SG&A and $400 million in capital investments. We made investments in Metagenomi for access to new gene editing enzymes and Carisma in oncology. We announced an investment in CytomX and the acquisition of OriCiro in Japan to continue to streamline our manufacturing processes. Just yesterday, we announced a collaboration with Life Edit. $3.3 billion were returned to shareholders through a buyback of 23 million shares. I am proud of the strong results by our team in 2022, as we made history with a number of outstanding accomplishments for patients.

In respiratory vaccines, we developed new products with remarkable speed, getting our mRNA-1273.214 against Omicron BA.1, the strain recommended by WHO, and mRNA-1273.222 against Omicron BA.5, the strain asked by the U.S. FDA. We developed 1273.222 in less than two months. We were able to protect millions of people from potentially severe disease resulting from new COVID strains. Our RSV vaccine went from phase I start to phase III data in 24 months and met its primary efficacy endpoint in a phase III trial. In oncology, our personalized cancer vaccine was the first demonstration of positive results from an mRNA cancer treatment in a randomized clinical trial. In rare diseases, our propionic acidemia program showed early positive clinical results in a repeat dose chronic disease setting in reducing metabolic decompensation events in patients.

We announced what we hope will become the first effective inhaled mRNA therapy in humans as our partner, Vertex, entered phase I trial using our technology in a therapy for cystic fibrosis patients who lack the CFTR protein. Finally, we held our first ESG day and published our first ESG report, providing additional transparency in how we conduct our business. I want to take a moment this morning to touch on transitions in Moderna Executive Committee. As we announced in late 2022, Marcello Damiani decided to retire as Chief Digital Officer after more than seven years with the company. Marcello joined Moderna before our first clinical trial, and we are today a digital-first company as a big testament of his ability to scale digital resources. I'm grateful to Marcello for his contribution during the early years of Moderna.

I am excited to have worked already with Brad Miller since early January. Brad brings a wealth of enterprise solution and platform organization experience in several of the top technology companies. This will be instrumental as Moderna scales into a fully integrated biotechnology company. I want to also share with you that Juan Andres, currently President of Strategic Partnerships and Enterprise Expansion, has informed me of his intention to retire and will be retiring at the end of May. Juan has played a tremendous role since joining Moderna in 2017 from Novartis, where he led all our manufacturing for them.

Juan served as Moderna Chief Technical Operations and Quality Officer when he led our manufacturing from an early-stage clinical development company to a commercial scale. I believe Juan did a historic job with his team in 2020 and 2021 to scale Moderna for global commercial launch during the pandemic. It is literally unbelievable that he led the team from having made across our entire portfolio less than 100,000 dose in 2019 to more than 800 million doses in 2021, all during the pandemic. We and hundreds of millions of people across the globe who received the Moderna COVID-19 vaccine owe Juan our gratitude. I believe very few manufacturing leaders could have led such an achievement. Most recently, Juan has focused on building out our organization to support Moderna growing pipeline, leading our efforts in producing our personalized cancer vaccine.

Jer, who used to work for Juan at Novartis, has joined us since early fall and has been leading manufacturing since then. I am thankful for Juan, who has ensured a very smooth transition, helping Jer every step of the way. Upon his retirement at the end of May, Juan responsibility will transition to Stephen Hoge, President of Moderna, to integrate PCV across all functions, with Jer leading the manufacturing of PCV for multiple phase III and of course, for getting commercial ready. On behalf of the entire Moderna team, I want to thank Juan for his continued leadership and wish him and his wife, Marina, the best of a well-deserved retirement. I am deeply thankful to have counted him for so many years as a partner at Moderna, and more importantly, for more than 20 years as a friend and a mentor. We will miss him.

The company continues to expand at a rapid pace. We now have three commercial COVID-19 vaccine products. With our four development programs in phase III, we hope to expand our commercial portfolio very soon. Overall, we have 48 programs underway with a team of 3,900 team members and now present on the ground in 16 commercial subsidiaries across Americas, Europe, and Asia Pacific. Our $18 billion of cash balance at the end of the year is enabling us to scale across research, clinical development, manufacturing, commercial, and G&A. With that, let me now turn to Stephen.

Stephen Hoge (President)

Thank you, Stéphane. Good morning or good afternoon, everyone. Today, I'll review our progress against our key clinical programs. I'll start with our respiratory vaccines. We have approved our phase III development programs against the big three respiratory viruses, COVID-19, RSV, and influenza. I'll share some additional data on these in a moment, including some presented this morning on our older adult RSV phase III trial. We're also advancing a portfolio of next-generation programs against these viruses, including mRNA-1283, which is a next-generation COVID-19 booster that is refrigerator stable. We also have multiple next-generation flu programs, which seek to increase the breadth of coverage against influenza by adding additional antigens that are not present in currently available flu vaccines.

Lastly, our respiratory portfolio includes a large number of combination vaccines to provide protection against multiple respiratory pathogens, which has advantages for many stakeholders, including healthcare providers, payers, and consumers. These include combinations of COVID flu and RSV, as well as two pediatric vaccines that include additional viruses that are important in children, including hMPV and PIV3. As we prepare for endemic COVID in 2023 and beyond, we wanted to briefly recap the recent VRBPAC committee discussions and recommendations. At the January VRBPAC meeting, the committee voted to harmonize the primary series and booster dose vaccines, which is an important step to simplify future guidance. The FDA also indicated that it expects to convene VRBPAC to determine vaccine strain composition for the 2023-2024 season in the second quarter of this year.

We believe that our mRNA platform has demonstrated its ability to deliver variant-matched vaccines on accelerated time horizons, we believe we are therefore well-positioned to deliver whatever composition updates the FDA and other public health agencies recommend. Now moving to RSV. As you know, we shared the top-line results from our phase III RSV study in older adults earlier this year. Today, we shared additional data that was presented this morning at RSVVW. The top-line results we've seen are incredibly encouraging, and we're grateful to the FDA for Breakthrough Therapy designation for mRNA-1345, which further emphasizes the significant health impact of RSV in older adults and the high unmet need. In the top-line data presented in January, mRNA-1345 demonstrated 83.7% vaccine efficacy in the primary endpoint of lower respiratory tract disease with two or more symptoms.

mRNA-1345 was found to be generally well-tolerated, and there were no safety concerns identified by the Data and Safety Monitoring Board. In the data presented today at RSVVW, we confirmed that mRNA-1345 was well-tolerated and has an acceptable safety profile. Solicited adverse reactions were mostly grade 1 or grade 2, and to date, most solicited adverse reactions were mild to moderate, with the most common adverse reactions being injection site pain, headaches, myalgia, and arthralgia. Vaccine efficacy was consistently high across all age groups and in participants with pre-existing comorbidities that are at highest risk. Please refer to the scientific and medical meeting section of the Moderna investor relations website to see the full RSVVW presentation.

We're very encouraged by these data and look forward to file a Biologics License Application with the FDA in the first half of 2023 if things proceed. With the option of using a Priority Review Voucher, we might see regulatory action on this filing in late 2023 or early 2024. Moving to flu. Last week, we shared with you data from our phase III immunogenicity and safety study in the Southern Hemisphere, study P301. In this study, our first generation vaccine, mRNA-1010, demonstrated superiority on seroconversion rates for influenza A H3 and H1 and superiority on geometric mean titers for H3, and non-inferiority on geometric mean titers for H1. mRNA-1010 did not meet non-inferiority on seroconversion or titers for the two influenza B strains.

Our separate phase III efficacy study in the Northern Hemisphere, study P302, has now accrued over 200 confirmed cases of influenza-like illness, almost all of which are influenza A. This was expected as the overwhelming majority of influenza burden in older adults is caused by influenza A, including over 95% of hospitalizations in the most recent season. Based on the case accrual in P302, we now expect the independent DSMB will review the first interim analysis of efficacy in that study in the first quarter of this year. Let's take a look at our latent vaccines on slide 14. Our CMV vaccine is in an ongoing phase III study, and we've begun dosing participants in a phase I/II adolescent dose-ranging study.

Our EBV vaccine to prevent infectious mononucleosis is in phase I, while our EBV vaccine to prevent long-term sequelae of EBV is in preclinical development. We have two HIV phase I trials ongoing, our HSV vaccine is in preclinical. Finally, our VZV program has begun dosing in participants in a phase I/II study, which I will discuss further on the next slide. The VZV study is a phase I/II randomized safety and immunogenicity study evaluating mRNA-1468 against Shingrix. This is a relatively large study, enrolling 500 seronegative older adults in multiple doses and dosing intervals, and a 12-month study follow-up. Over 35% of participants will be 70 years and older, which is in line with the largest disease burden of shingles. Now let's take a look at our therapeutics portfolio on slide 16. I'll highlight a few of the programs.

We recently reported strong top-line data for our personalized cancer vaccine, which I will talk to in a moment. In immune oncology, we are working to address disease burden beyond PCV with our checkpoint and triplet programs, both of which are in phase I trials in various tumor types. In rare diseases, our phase I/II PA program continues to enroll patients, and we are looking forward to selecting a dose of the expansion arm. I'll provide a brief update on that in just a moment. Earlier this year, our partner Vertex announced initiation of phase I trial in cystic fibrosis patients, which is our first inhaled pulmonary mRNA therapeutic program. In cardiovascular, we announced Relaxin has initiated dosing in phase I study. Both of these study initiations represent important milestones for Moderna as we expand our modalities in therapeutic areas.

In December, we shared exciting top-line data from our phase II personalized cancer vaccine program, testing the combination of PCV and Keytruda against Keytruda alone in the setting of adjuvant melanoma. Keytruda is the standard of care in that setting. In this study, we showed the addition of our personalized cancer vaccine treatment, mRNA-4157, to Keytruda reduced the risk of recurrence or death by 44% compared to Keytruda alone. This was the first demonstration of efficacy for an investigational mRNA cancer treatment in a randomized clinical trial, we are pleased to announce that 4157 has received Breakthrough Therapy designation from the FDA. Along with our partner Merck, we are excited about these results and expect to launch multiple late-stage confirmatory studies for PCV in 2023, starting with melanoma and then moving to non-small cell lung cancer.

We are planning to explore additional indications for mRNA-4157, where we believe there's a strong biologic rationale for immune-stimulating approaches. These include early-stage and metastatic standings and will include indications where Keytruda is not yet approved. We expect to release full data from our phase II study at an oncology meeting this spring and in an upcoming publication. Moving to PA. Since our update at our R&D day, the PA Paramount study has made good progress. Our fourth cohort is now fully enrolled, and we're currently enrolling patients in our fifth cohort, which doses at 0.9 milligrams per kilogram every II weeks. We are encouraged that to date, we've not observed any dose-limiting toxicities. We're also encouraged that all patients and families have opted to continue treatment electively in our open label extension study across all prior dose cohorts.

Now the next step in this trial will be to review available data and determine a dose for expansion. I'll now hand the call over to Arpa Garay, who will provide an update on our commercial activities. Arpa?

Arpa Garay (Chief Commercial Officer)

Thank you, Stephen, and good day to everyone. I will start with a review of sales on slide 20. In the fourth quarter, total product sales were $4.9 billion. In the U.S., our sales were $1 billion. Sales in Europe approximated $2.2 billion, and sales in the rest of the world were $1.6 billion. We ended the full year strong with total product sales for 2022 of $18.4 billion. Sales in the U.S. for the full year were $4.4 billion, sales in Europe were $6.7 billion, and in the rest of the world were $7.3 billion. We are reiterating approximately $5 billion in COVID sales for delivery in 2023 from our currently signed advanced purchase agreements and deferrals. We do expect additional sales from key markets such as the U.S., EU, and Japan.

Slide 21 summarizes the current composition of sales for 2023. We have advanced purchase agreements from Canada, Kuwait, Switzerland, Taiwan, and the United Kingdom. We expect these sales to be recognized upon delivery of vaccines in the second half of 2023. We expect further sales from deferrals from 2022 contracts. These deferrals are from the countries listed on the slide and are expected to be mainly recognized from deliveries in the first half of 2023. These advanced purchase agreements and deferrals total approximately $5 billion in sales for 2023. We do expect additional sales from key markets, including the U.S., EU, and Japan, as well as Australia and other countries in Asia and Latin America. In the U.S., contracting discussions with commercial customers are ongoing, and we will provide visibility into expected U.S. sales at a future date after we complete these discussions.

In our discussions with commercial customers in the U.S., it is clear to us that our customers recognize that COVID is still a substantial health burden. Throughout 2022, COVID continued to be a leading cause of hospitalizations and deaths. If you look to the chart on the left-hand side, what you'll see here is data available through September of 2022, COVID was the third leading cause of death in the United States, only after heart disease and cancer. If you look to the right-hand side for months, so the fall and winter season from October 1st, 2022 to February 2023, hospitalizations from COVID in the U.S. are nearly 450,000, more than double from flu and nearly three times higher than RSV in that same four-month period. There continues to be a clear need to protect against severe COVID infections, and our customers recognize that.

Given this need, we estimate the U.S. fall 2023 COVID market volume to be approximately 100 million doses. We based this assumption after looking at 2022 vaccination rates and including potential recommendation for 2-dose booster series for high-risk individuals. Taken together, the doses administered represent roughly 30% of the U.S. population. A few factors that can impact this volume include viral evolution, regulatory recommendations, as well as vaccine understanding and uptake by consumers. Moderna's commercial organization is prepared for the transition to a commercial market in the U.S. Let me now take you through how we have been preparing to go to market. First and foremost, we are committed to access, which I will explain in greater detail in just a moment.

To ensure coverage of our vaccine, we are engaged in discussions with private customers as well as public entities such as the VA, CDC, and the Department of Defense. We are increasing awareness and educating consumers as well as healthcare providers about the benefits of booster vaccinations in alignment with public health agencies such as CDC and the ACIP. We are reaching healthcare providers and consumers through innovative digital outreach programs. We have built the infrastructure needed to fulfill customer orders and shipments. Our commercial and medical organizations have been scaling to execute on this plan, and we are ready for the transition to a commercial market in the United States. Very importantly, as we enter the commercial phase of the endemic COVID market, we want to emphasize our commitment to vaccines access for everyone in the United States, regardless of their ability to pay.

For all insured individuals in the United States, consistent with preventive health services requirements, current reimbursement roles will be sustained. As an ACIP-recommended vaccine, Moderna's COVID vaccine will continue to be available for zero out-of-pocket costs for individuals with insurance. We are proud to say that for uninsured or underinsured people in the United States, Moderna will be launching a patient assistance program that will provide COVID-19 vaccines at no cost. Let me now summarize our COVID vaccine outlook. In 2023, we expect COVID sales of approximately $5 billion. In addition, we are expecting sales from U.S. commercial market orders, EU, Japan, and other countries. We will provide visibility into these sales after we complete ongoing discussions with governments and with customers.

We recognize COVID continues to be a burden to healthcare systems. This continues to be an important point as we discuss the value of booster vaccinations with our customers. In the U.S., we expect commercial market volumes to be approximately 100 million doses in 2023, and Moderna's commercial organization is prepared for the transition to a commercial endemic market. Last but not least, we are committed to patient access in the United States. I now want to turn to another launch in the respiratory vaccine space that the commercial team is preparing for: our RSV vaccine in 2024. As you heard from both Stéphane and Stephen earlier, we are very pleased by our phase III RSV vaccine results. Stephen's organization will be filing for the approval soon, and we expect we may be approved in late 2023 or early 2024.

With the potential approval fast approaching, I am very excited for the RSV vaccine launch. I want to provide additional color into the launch plans. The RSV launch will leverage the existing commercial infrastructure that is already in place for COVID. We will continue to invest to support it, ensuring strong execution. Both COVID and RSV markets overlap considerably as we look at our target customers as well as potential target patients and audiences. We will leverage this overlap between the two markets. We will ensure awareness of RSV disease and the associated economic burden of RSV in older adults across key stakeholders such as healthcare providers and payers. Upon approval of our RSV vaccine, we will educate consumers on key attributes of our vaccine. These planned activities will be initiated in 2023 and in full force upon approval.

We have the added benefit of an in-place commercial infrastructure built for COVID. Many of these resources can be leveraged for flu as well into the future. I look forward to keeping you updated on our progress throughout this year. With that, I will turn it over to Jamey.

Jamey Mock (CFO)

Thanks, Arpa. Hello, everyone. This morning I will cover our 2022 financial performance and provide a framework for our 2023 financial outlook. Moving to our fourth quarter results starting on slide 29. Total product sales decreased by 30% year-over-year to $4.9 billion. The decrease in 2022 was mainly driven by lower sales volume compared to overall higher demand in the prior year. Cost of sales was 39% of product sales, compared to 14% of product sales in 2021. A key driver of the increase in cost of sales as a percent of product sales was a catch-up royalty payment to the National Institutes of Health, or NIH, of $400 million, representing 8% of product sales in the fourth quarter.

In December 2022, we entered into a non-exclusive patent license agreement with the National Institute of Allergy and Infectious Diseases, an institute or center of the NIH, to license certain patent rights concerning stabilizing pre-fusion coronavirus spike proteins and the resulting stabilized proteins for the use in COVID-19 vaccine products or 2P technology. Pursuant to the agreement, we have agreed to pay low single-digit royalties on future net sales of our COVID-19 vaccines. Our cost of sales also includes a charge of $297 million for inventory write-downs related to excess and obsolete COVID-19 products, an expense for unutilized manufacturing capacity, and CMO wind down costs and related charges of $376 million, and a loss on firm purchase commitments and related cancellation fees of $281 million.

These charges, other than royalties, are driven by costs associated with surplus production capacity, overall lower demand, and a shift to our most recent Omicron BA.4/BA.5 targeting COVID-19 bivalent booster. Research and development expenses were $1.2 billion, which increased by 87% versus prior year. The increase in R&D spend continues to be driven by our clinical trial expenses, particularly with our phase III studies for RSV, seasonal flu, and CMV. The increase in R&D was also driven by the acquisition of a Priority Review Voucher and an increase in personnel-related costs due to increased headcount. Selling, general, and administrative expenses were $375 million, also reflecting an increase of 87% year-over-year. The growth in spending was primarily driven by continued investments in personnel and outside services in support of our marketed products and company build-out.

The effective tax rate was 11%, compared to 10% last year. After-tax net income decreased by 70% to $1.5 billion. Diluting earnings per share in Q4 decreased by 68% to $3.61. Now turning to our full year 2022 financial results on slide 30. Total product sales for the full year 2022 were $18.4 billion, an increase of 4% year-over-year. The growth was mainly attributable to customer mix and a higher average selling price in 2022 in certain markets. Cost of sales was 29% of product sales, compared to 15% of product sales last year. The increase was driven by higher write-downs for excess and obsolete inventory related to our COVID-19 vaccines, unutilized manufacturing capacity, and losses related to future purchase commitments for raw materials.

The key drivers for these charges are similar to the drivers in Q4. Costs associated with surplus production capacity, overall lower demand for the year, in particular from low-income countries, and rapid product demand shift from our original vaccine to Omicron-targeting COVID-19 bivalent boosters. The previously mentioned catch-up royalty payment to NIH of $400 million is also a driver of the increase year-over-year. The effective tax rate was 13%, compared to 8% last year. As a reminder, we had a net operating loss carryforward of $2.3 billion at the end of 2020, which resulted in a non-recurring benefit to the reported tax rate in 2021. After-tax net income of $8.4 billion decreased 31% versus prior year.

The decrease of net income was primarily due to higher cost of sales, higher other operating expenses, and a higher effective tax rate. Diluted EPS decreased 29% to $20.12. Turning to cash and cash deposits on slide 31. We ended 2022 with cash and investments of $18.2 billion compared to $17 billion at the end of the third quarter. The increase was driven by our commercial activity. Cash deposits for future product supply reduced from $3.8 billion at the end of the third quarter to $2.6 billion by the end of the year. Turning to slide 32. I wanted to give an update on the progress we have made on our capital allocation priorities.

Our top investment priority has been and will continue to be reinvesting in our base business across multiple areas. Research and development spending increased 65% year-over-year from $2 billion in 2021 to $3.3 billion in 2022. We are projecting an additional increase to approximately $4.5 billion in 2023. The clinical data from our PCV, RSV, and flu trials were encouraging and further validates the potential of our mRNA technology. We are also investing in our digital capabilities, the commercial build-out of the organization, as well as expanding our manufacturing footprint. We plan to significantly accelerate our CapEx in 2023 as we expand both our international and U.S. manufacturing footprint. Our second investment priority is to seek attractive external investments and collaboration opportunities that will enable and complement our platform.

We've recently announced several new transactions. I'm happy to report that we have successfully closed our acquisition of OriCiro Genomics in the first quarter of 2023. OriCiro is a great example of the companies we are evaluating to enable our mRNA platform. It will create substantial value from both a speed and cost viewpoint and impact our preclinical, clinical, and commercial pipeline for years to come. Our collaboration with Life Edit, which we announced yesterday, is another example of an attractive external investment opportunity. We believe the combination of Moderna's mRNA platform with Life Edit's proprietary gene editing technologies, including base editing capabilities, has the opportunity to advance potentially life transformative or curative therapies for some of the most challenging genetic diseases. We are in multiple active discussions regarding additional external collaboration opportunities. We will be disciplined in our approach.

After evaluating internal and external investment opportunities, we assess additional uses of cash. In 2022, we repurchased 23 million shares for $3.3 billion at an average price of $143 per share. We have $2.8 billion of share repurchase authorization remaining. Let's turn to our 2023 financial framework on slide 33. As Arpa mentioned earlier, we currently have COVID vaccine sales of $5 billion contracted for delivery in 2023. We are actively working on preparing for the private market and government contracts in the U.S. and additional contracts for Europe, Japan, and other key markets. To help you with your modeling purposes, we expect first half 2023 sales to be approximately $2 billion.

Our total cost of sales includes the cost of goods manufactured, third-party royalties, as well as logistics and warehousing costs. We expect full year 2023 reported cost of sales to be 35%-40% of sales. This includes royalties of approximately 5% of sales, which are payable to UPenn and Cellscript for modified chemistry licenses and to NIAID and NIH for the 2P license that I mentioned earlier. The increase in cost of sales as a percent of product sales compared to 2022 is primarily driven by presentation mix change as we move from a pandemic to endemic setting, with single-dose applications significantly increasing in volume. Longer term, as the endemic market normalizes and we add additional respiratory and other products, we expect our cost of sales as a percent of sales will significantly decrease from the rates we're experiencing in 2023.

For R&D and SG&A, we expect full year expenses to be approximately $6 billion, with approximately four and a half billion dollars in R&D. The increase is driven by our maturing development portfolio and the global scale-up of our company. We expect a negligible provision for income tax in 2023. Finally, we expect capital expenditures of approximately $1 billion. The increase is primarily due to investments in expanding our manufacturing footprint. This concludes my remarks concerning our financial performance. I will turn the call back over to Stéphane.

Stéphane Bancel (CEO)

Thank you, Jamey, Arpa, and Stephen. Let me now share some thoughts about where we're heading. I'm really excited to see our mRNA platform and the investments we have made in science over the last 11 years lead to such a promising pipeline. We anticipate a number of important developments. Let me start by our first franchise, respiratory vaccines. In COVID boosters, we are working for the switch to a U.S. commercial market, and we anticipate being able to quickly meet the fall of 2023 market needs for updated vaccines after VRBPAC and the FDA make their strength selection in the spring of 2023. We plan to submit our IV vaccine for regulatory approval in the first half of 2023. As you heard from Arpa, we'll be ready to launch IV vaccine in late 2023 or early 2024.

In flu vaccine for Northern Hemisphere mRNA-1010 phase III trial, the Data and Safety Monitoring Board is expected to complete its interim efficacy analysis in the first quarter of 2023. Our second franchise, latent virus vaccine. It's progressing very well with broad spectrum of programs. In our large CMV phase III study, we look to complete enrollment. For EBV, HIV, and CMV programs, our next milestone will be phase I data. Turning to slide 37, let me review the milestone for mRNA therapeutics programs. For personalized cancer treatment, we expect to start our phase III study in partnership with Merck in adjuvant melanoma. We expect to rapidly expand to additional tumor types, including non-small cell lung cancer. Full phase II data will be presented at an upcoming oncology meeting and published in a top quality medical journal.

In PA, we plan to select those and begin the expansion arm of our phase I/II study. MMA, we will have phase I/II data. The next milestone for heart failure therapeutic Relaxin will be phase I data in patients. In inhale therapeutics, our partner Vertex expects to complete its single-ascending dose study and initiate a multiple ascending dose study. To continue to build the best version of Moderna, we have established 7 priorities for 2023. Priority number 1: execute the operational and sales plan for COVID boosters for fall of 2023. Priority number 2: build an evolved seasonal respiratory vaccine franchise. Priority number 3: execute a bold campaign of cancer vaccine studies. Priority number 4: advance rare metabolic disease programs. Priority number 5: drive rapid advancement and growth of our latent vaccine portfolio. Priority number 6: deliver the next generation pipeline and platform.

As we said before, this is just the beginning. Priority number 7: build a culture of perpetual learning and strengthen our processes and digital system as we want to scale the company to another level. On slide 39, some key dates for 2023 Moderna Investor Days. April 11 will be our annual vaccine day. September 13 will be our annual R&D day, where we present development pipeline key updates. December 7th will be our second ESG day. Now that we have delivered on the promise of mRNA science with our first product launched, our mission has evolved. Our mission is to deliver the greatest possible impact to people through mRNA medicine. We are passionate about our ability to have a profound impact on humanity.

We believe we have a technology to eliminate or greatly reduce human suffering caused by respiratory viruses, latent viruses, many cancers, rare genetic diseases, and a growing list of other diseases. We believe we can have an impact on disease treatment with our therapeutic first, then with our gene editing programs. This is just the beginning. With that, the team and I are happy to now take your questions. Operator?

Operator (participant)

Thank you, ladies and gentlemen. If you have a question or a comment at this time, please press star one one on your telephone. If your question has been answered and you wish to remove yourself from the queue, please press star one one again. One moment for our first question. First question comes from Salveen Richter with Goldman Sachs. Your line is open.

Salveen Richter (Biotechnology Equity Research Analyst)

Good morning. Thank you for taking my question. Could you speak to the regulatory strategy for flu, given the miss on the B strains for immunogenicity? If you're confident into the interim efficacy analysis, given the dominating prevalence of A strains here?

Stephen Hoge (President)

Yeah, I'll take that. Thank you, Salveen, for the question. Look, I think the honest answer is we still have incomplete information to provide guidance on the regulatory strategy. At this point, we are looking to the efficacy results from the P302 study that I described, which will guide us on that filing strategy. It's important to note that efficacy, ultimate demonstration of non-inferior efficacy against an approved vaccine was always gonna be required for full approval, and that the only thing that you could do with immunogenicity would be an accelerated approval path with an obligation to subsequently demonstrate efficacy.

Right now, we are actually very encouraged that the data that we've seen from our immunogenicity and safety study, which was run in the Southern Hemisphere, P301, shows superiority on 3 out of 4 endpoints for the influenza A strains, which drive the overwhelming majority of disease in the population of interest here, older adults, and account for over 99% of the cases in our efficacy study. That first interim efficacy analysis that we're producing now in P302 will involve over 200 cases, 99% of them are influenza A, and it will be our first a chance to really see the performance of the vaccine in terms of prevention of influenza-like illness from flu A.

That is a first interim analysis, and so it's quite possible, as you would expect in any efficacy study, and we've all got some experience now with these respiratory efficacy studies, that we may end up need to go to a second subsequent interim analysis and accrue even more cases to demonstrate either non-inferiority or superiority in that study. What we'll do is we will wait for the results from the DSMB, the independent DSMB, and guidance from that. Based on those results, obviously, if we do see efficacy, that is the gold standard for proceeding with regulatory filing and full approval. If we do not yet meet that threshold, then we'll be looking forward to subsequent interim analyses in that study.

Salveen Richter (Biotechnology Equity Research Analyst)

Great. Thank you.

Operator (participant)

One moment for our next question. Our next question comes from Gena Wang with Barclays. Your line is open.

Gena Wang (Managing Director of Biotech Equity Research)

Thank you. Just quickly follow Salveen's question. Do you need to show superiority in order to receive approval regarding the efficacy study? Quickly on the revenue, did I hear correctly, the existing contract of $5 billion mainly will be in the second half 2023? If that's the case, is it fair to say that total COVID revenue in 2023 should be around $7 billion? Regarding the $2 billion in the first half of 2023, how much will be from the U.S. market, i.e., out of estimated 100 million doses in the U.S., what could be your market share?

Stephen Hoge (President)

Great. I'll take the first question. Thank you, Gena, for that. First on superiority, you do not need to demonstrate superiority to get a flu vaccine approved, that's well precedented. Non-inferior efficacy is the threshold. Our goal, though, over time, is absolutely to develop a superior influenza vaccine. If we don't see it with a first-generation product, which is mRNA-1010, I would note that we have four other programs, flu programs in development, different stages of clinical trials, that are looking to do even better than perhaps flu mRNA-1010. Our goal over time would be to demonstrate that we have a superior influenza vaccine. It is not actually required for approval. Non-inferiority should suffice. I'll turn it over to Arpa, I think, for the other questions.

Arpa Garay (Chief Commercial Officer)

Sure. Yep, I can take the second question. In terms of the total sales, we are anticipating about $2 billion of the $5 billion in the first half of the year. None of that $2 billion is coming from the U.S. market. The remaining advanced purchase agreements that we have of $3 billion will be coming in the second half of this year. That $5 billion is just a total that we have from advanced purchase agreements as well as deferrals from 2022. We do anticipate additional sales from the U.S., Japan, E.U., and other markets, and we believe the majority of these sales will be in the second half of 2023.

Gena Wang (Managing Director of Biotech Equity Research)

Your market share regarding the U.S. market?

Arpa Garay (Chief Commercial Officer)

We continue to believe in the strong, differentiated profile of our product. We do not have any updates on market share projections as we are currently in discussions with customers right now for fall of 2023 contracting.

Gena Wang (Managing Director of Biotech Equity Research)

Thank you.

Operator (participant)

One moment for our next question. Next question comes from Matthew Harrison with Morgan Stanley. Your line is open.

Matthew Harrison (Managing Director)

Great. Good morning. Thanks for taking the question. I was hoping to ask about the regulatory strategy for PCV and specifically how you're thinking about the potential for filing off the phase II data set, as well as how you're thinking about the timelines for enrollment in the phase III program and how that may impact the timeline for potentially filing off the phase II data set. Thanks.

Stephen Hoge (President)

Great. Thank you, Matt, for the question. We are obviously really pleased yesterday to announce that we received FDA Breakthrough Therapy designation therapy for the PCV program. What that allows us to do is very rapidly accelerate our conversations with the FDA and other regulators on the path forward for filing 4157. As you noted, the phase II-B study that we've run is a randomized study compared against really the standard of care, which is Keytruda alone, and has already shown a quite significant benefit, a 44% reduction of the rate of recurrence and/or death. That study is ongoing. We're continuing to follow over time and conduct additional interim analyses.

It's possible that those, in fact, we would hope that those data mature and continue to get stronger and stronger. It is entirely possible that in our discussions under Breakthrough with the FDA and others, that we will come up with a path forward for beginning the filing process based on that phase II, and potentially proceeding with an accelerated approval. As you know, in this country, and I think it's where your question's coming from, as well as globally, if there is a path forward there, which we haven't yet engaged with the FDA on, because the Breakthrough happened yesterday. If there is a path forward there, it would require us to rapidly enroll a confirmatory phase III study.

In fact, there's more and more attention on perhaps requiring that those phase III studies be enrolled prior to an accelerated approval. For that reason, ourselves and Merck are working really quickly now to try and stand up that confirmatory phase III melanoma study and enroll as fast as possible. We're not ready yet to guide on how quickly that will be, but we're fully aware of the fact that in fact, if there is a path forward for accelerated approval, the enrollment of that phase III may be gating. Therefore, we'll wanna have it enrolled as quickly as possible. At this point, we've just received the Breakthrough designation. We're engaging with regulators. We're gonna try and develop that path forward.

It is theoretically possible that there is an accelerated approval path and that we would need to enroll that phase III study based on recent regulatory guidance, more generally to the industry. We're working hard to make sure that we can do that as fast as possible here while continuing to conduct other additional interim analyses and see the maturity of this data continue to proceed, and hopefully the strength of the, of the benefit provided by the combination to be further validated.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Edward Tenthoff with Piper Sandler. Your line is open.

Edward Tenthoff (Managing Director and Senior Research Analyst)

Great. Thank you very much. Thanks for all the detail on the call today. My question had to go back to flu for a minute, just with respect to the follow on candidates, including, I think the one that's pentavalent, hemagglutinin and then fix hemagglutinin and then also into the neuraminidase, the candidates that had neuraminidase. What should be our expectation, both in terms of timing for data here and how do you ultimately see your seasonal flu product offering kind of evolving? Thanks.

Stephen Hoge (President)

Thanks for the question, Ted. Let me start with the most advanced program obviously is our 1010 program, which we've talked about. We have done a update to that vaccine that we think will increase the B immunogenicity for those populations for whom that matters. We expect to advance that in clinical study quite quickly. That in combination with the efficacy data that we were just talking about with P302-

Edward Tenthoff (Managing Director and Senior Research Analyst)

Yep

Stephen Hoge (President)

-probably is the most important information for guiding our next step on the second generation products. Our multiple or our penta and hexavalent vaccines as well as the mRNA-1020, mRNA-1030 programs which include neuraminidase, as you said, are all in various phase I studies. As we've shown repeatedly, hopefully over the last couple of years, we can proceed very quickly into subsequent phase III and pivotal studies once we select one of those candidates to move forward. The really important gating information is understanding how is our first generation product performing in terms of efficacy as a first mRNA flu vaccine. We are waiting for that information before proceeding forward. We do expect that at least one, if not multiple of those second generation products would move into subsequent pivotal studies, phase III studies.

In those cases because we would be looking to demonstrate some form of superiority either against a broader range of influenza strains or better protection against influenza-like illness because we've included additional antigens, we would expect those studies to include both immunogenicity and safety and efficacy endpoints as we move forward. We'll make a selection on which ones we might move forward based on the ongoing interim analyses of efficacy from our 1010 program.

Edward Tenthoff (Managing Director and Senior Research Analyst)

Great.

Stephen Hoge (President)

We don't have an update at this point on which one we'll move forward.

Edward Tenthoff (Managing Director and Senior Research Analyst)

Great. Thank you very much.

Operator (participant)

One moment for our next question. The next question comes from Michael Yee with Jefferies. Your line is open.

Michael Yee (Managing Director and Senior Biotechnology Analyst)

Thanks. Good morning. A couple follow up on the flu vaccines and also a PCV question for Stephen. I guess, could you clarify, do you have a hypothesis around why the B strains were not non-inferior and what the ramifications are for that, either for this flu vaccine but also for the infection study, and what that would mean for combinations? First of all just clarify what's going on there with the B strain, the ramifications for a flu vaccine. My second question is on PCV. Obviously we're excited about the adjuvant data. There's also a competitor reading out in metastatic melanoma this summer. I wanted to understand how we should compare and contrast that and if you could walk us through how to think about metastatic and what competitors might show.

Thank you.

Stephen Hoge (President)

Thank you Michael for both questions. First on the flu, on the B. We're still looking into the data, you know, develop a more complete picture of what we think happened in the Influenza B immunogenicity study. I would note a couple of things that are important. The first is these are active comparator studies when you look at non-inferiority on seroconversion or titers, it's important to note that we're going against the standard flu, standard dose influenza vaccine active comparator. Between the phase II study and the phase III southern hemisphere study, there were changes in the composition of those active comparators and the comparator used. That can drive some difference. The second thing I would note is that they were different populations.

We went from a northern hemisphere to a southern hemisphere. Obviously that can drive some differences in background, history of influenza illnesses. The third and perhaps maybe most relevant is, we did expect that the influenza B neutralizing titers were lower. As you'll remember, as we shared with the phase II data, about a year ago, we did have lower neutralizing HAI titers for the influenza B strains. For our older adult influenza vaccine, we thought that was acceptable because at the end of the day our goal was only to achieve non-inferiority, not to demonstrate superiority. For the influenza A strains we really wanted to maximize those neutralizing titers and potential for benefit because influenza A really is what drives illness in older adults, which is our first generation product.

We did focus heavily on the influenza A. We were aiming at non-inferiority on the influenza B. As you said, we did not make non-inferiority on those and we'll continue to pull apart the reasons as to why. We have already identified an update that will allow us to improve immunogenicity against the Bs to the extent that that is important going forward, not just in younger populations but perhaps from a overall regulatory perspective. We've made that update. We're actually going to be evaluating that in a clinical study very shortly here. We expect that we'll be able to address that lower immunogenicity that we saw in the Bs quite quickly. As I said a moment ago, what really matters is efficacy and efficacy against influenza disease.

In this case, we really do see that as Influenza A related for our first generation product. We will obviously be updating Influenza B strains for other subsequent generation products. It's important to note that that's really important as you get into pediatric populations where Influenza B is a burden of disease, particularly in the young. On the question of PCV, yeah, we're pretty encouraged by the adjuvant melanoma data. We do have some early metastatic data as you've as you'll note from our prior phase I studies and in the phase II, there was some stage 4 disease as well in that study. We did not conduct it only in first-line metastatic.

We're actually looking forward to understanding the performance of a competitor product in that space because it may actually identify an opportunity for us to move into earlier stages of treatment. For now, our approach has been to focus on places where checkpoint, including Keytruda, are standard of care and have demonstrated a really strong signal, which is why you see us expanding from adjuvant melanoma into adjuvant non-small cell and ultimately will go first into other adjuvant indications where we really think there's the most immediate biologic benefit or biologic rationale for potential benefit that we'll be looking to demonstrate. Obviously as others start to move into the space, if they show benefits in other lines of therapy, we will absolutely want to proceed very quickly in those directions as well.

We're looking forward to those results and we'll obviously mention them as everyone else will.

Operator (participant)

Thank you. One moment for our next question. Next question comes from Tyler Van Buren with Cowen. Your line is open.

Tyler Van Buren (Managing Director and Senior Biotech Equity Research Analyst)

Hey guys. Good morning. Thanks very much for taking the question. For RSV a few years from now, do you expect it to be a two, three, or perhaps a four-player market when including J&J? How do you believe that the tolerability profile compares to others based upon the full data presented this morning?

Stephen Hoge (President)

Sure. I can maybe I'll take the first portion of that question. You know, at this point, you know, obviously three companies that have read out their phase III pivotal efficacy studies and are proceeding right now to filing. I think I, you know, I don't have a specific view on J&J. Maybe Arpa can offer perspectives on that, but it is an adenoviral viral vector program and otherwise, still unclear about their regulatory path forward. Now on the question of reactogenicity and tolerability profile, as we presented today, or as our collaborator presented today at RSVVW, we do see, we think a favorable tolerability profile.

Grade three adverse reactions, whether local or systemic, were all below 2% for any of the individual symptoms. Actually compared relatively favorably with the placebo in that arm often, you know, maybe one and a half times as frequent as what we're seeing in placebo, which we think is a compelling overall reactogenicity profile. We think the other parts of the benefit of the product are obviously efficacy. We're incredibly pleased by if you look at the most common definition of cases, so RSV or respiratory tract disease involving two symptoms, which has been relatively consistent across the different products, we have seen very high efficacy, 83%, which really I think is among the best.

As we presented today, that efficacy actually holds up beautifully as you look at older populations, those over the age of 70, as well as those with high risk comorbidities, those that would drive the majority of the expense associated with caring for patients, older adults with respiratory disease from RSV. Overall, you know, it's very difficult obviously to do cross trial comparisons, and ultimately it will fall for public health officials to make those decisions. We are really encouraged by both the efficacy and tolerability profile of 1345, and look forward to filing and ultimately to the commercialization of that product. Arpa, would you like to add anything in terms of your perception of the market going forward?

Arpa Garay (Chief Commercial Officer)

Sure. I would say we do anticipate it being at least a three-player market, with Moderna, Pfizer and GSK. There is a possibility of a four-player market if J&J has the regulatory path forward with their adenovector virus vaccine. Nothing more to add there.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from Jessica Fye with JPMorgan. Your line is open.

Jessica Fye (Managing Director and Equity Research Analyst)

Great, good morning. Thanks for taking my question. Following up on flu for mRNA-1010, just to be very clear, if you hit on non-inferiority in the efficacy, Northern Hemisphere study, do you think that mRNA-1010 would be approvable in spite of missing on non-inferiority on the B strains? Related to that, would you envision the approval only being for older adults? On RSV, can you comment on the expectation for dosing frequency for your RSV vaccine? How do you think about the value and potential pricing of that vaccine, maybe benchmarking off of other vaccines for that age group? Thank you.

Stephen Hoge (President)

Yeah, thanks for those questions. Let me take the flu stuff first. Again, the full approval gold standard is a head efficacy study. If we demonstrate non-inferior efficacy against an approved vaccine, in the population which we're studying it, which in this case in P302 is 50-plus adults, we do believe that could form the basis of an approval. At the end of the day, immunogenicity results and in particular are only surrogates for efficacy and ultimately efficacy is the gold standard. That's what's required for traditional approval, and that's why we're running the P302 study.

It will depend upon how on conversations with regulators around that data package, but it is certainly plausible and in fact one might say, you know, likely that if we meet efficacy in the efficacy study that that would be sufficient to move forward for a full approval. That doesn't mean that there may not be questions about demonstrating non-inferior immunogenicity with influenza B strains or other things in subsequent studies, but we do believe there's a possibility there. At the end of the day, it will be dependent upon data and discussions with regulators, including the FDA. We'll wait till we have that data and have those conversations. I think it's certainly a possibility.

Now as relates to age for approval, we're currently studying mRNA-1010 only in older adults. As I said, the P301 was in 18 plus, P302 is in 50 plus. That's really where we see the broadest recommendations for seasonal influenza vaccines and where we have been most focused initially on building out our respiratory portfolio. We will evaluate our influenza vaccine, in fact, many of our respiratory vaccines in younger populations over time, but we'll have to do age via very much like what we did with COVID. Our initial filings for approval, if they proceed based on data, would be in adults and older adults principally. Eventually we would follow on with pediatric populations.

As I said a moment ago in response to Michael's question, that may involve using updated B antigens to increase immunogenicity in that population. Again, that's subsequent studies that we would do in children. Could you remind me of the second question?

Jessica Fye (Managing Director and Equity Research Analyst)

For RSV, what are you thinking for dosing frequency, and how do you think about value and potential pricing of that vaccine, maybe benchmarking off of other vaccines for that age group?

Stephen Hoge (President)

For sure. I'll let Arpa take the second part of that question. First on frequency, it is not yet clear on how frequently people will need an RSV vaccine. It's a seasonal virus, a seasonal epidemic of disease that shows up. Most of us have been exposed to RSV well over 12 times over the course of our lives. What really happens from a biology perspective is as we get older, our ability to maintain high neutralizing titers that protect us goes down, and what we have is breakthrough disease and ultimately a disease that leads to substantial cost and morbidity and even some mortality in older adults. We have not yet had approved vaccines. What, what we don't yet know is what's the frequency of vaccination.

Is it gonna be seasonal every year, or is it gonna be less than seasonal every couple or few years? What's pretty clear based, from my perspective, based on the epidemiology of RSV infection, is that we do see RSV fairly regularly as adults, and unfortunately over time it breaks through more frequency. There probably will need to be repeated boosting to protect against RSV. At the end of the day, the initial recommendations will come from ACIP, you know, as well as from regulators around that frequency.

We will have to defer to them on how they want to administer and roll out the RSV vaccines, whether they wanna follow a flu model, which would be annual to make sure that we get the broadest amount of protection, or that they wanna initially roll out RSV vaccines and then follow over time for the durability of that efficacy. At this point, none of us, none of the three products that have read out in phase III have a clear answer on the durability of that efficacy, although we would expect it to wane as it does against natural RSV infection over time in older adults. Arpa, do you wanna take the next part of the question?

Arpa Garay (Chief Commercial Officer)

Sure. Yep. I can take the question on pricing. Overall, from a pricing philosophy perspective, Moderna is committed to pricing that reflects the value of our vaccines, in terms of what they deliver to patients, to societies, and to healthcare systems, while also ensuring full access for patients regardless of their ability to pay. With that broader principle around pricing, we will be looking at the full recommendations that come out of ACIP as we get the filing and the ACIP recommendations, to look at what the full value that could be provided back is based on things, as Stephen mentioned, around dosing frequency, and the pricing will be set based on both value and access.

I'm not able to share any additional details on what sort of range that pricing might fall into, but it will be consistent with our overall pricing philosophy.

Stephen Hoge (President)

Thank you. One moment for our next question. Our next question comes from Ellie Merle with UBS. Your line is open.

Ellie Merle (Executive Director of Biotech Equity Research)

Hey, guys. Thanks so much for taking the question. Just another on flu. Just any more details on the titer levels specifically that you saw or when we'll get more details on the titer levels? Then how should we think about the importance of having titers above that 40 benchmark versus demonstrating non-inferiority? Like, I guess what if the comparator vaccine titers in your phase III say, you know, did very well and were well above 40, how should we think about the implications then, say you're at or near 40, what that would mean from a regulatory standpoint as well as a commercial standpoint in interpreting the immunogenicity data? Thanks.

Stephen Hoge (President)

Yeah, all very good questions. I think the short answer is we're looking into that data right now, and we will provide an update. I'm not exactly sure when we will have that, but we do have the Vaccines Day investor meeting coming up in either April or the spring. Then obviously be looking to publish that data and share it as it comes in and is available. You've highlighted one of the key challenges in active comparator studies in influenza in particular, which is that you can see high titers, but actually because you're looking at a ratio, you know, say for whatever reason your active comparator does really well against one of the strains that can impact your ability to achieve non-inferiority statistically.

You know, at the end of the day, the challenge is even more complicated as you look at, you know, older adults where, for instance, the Influenza B strains are not a big driver of efficacy or disease. We will look at all of that, as will regulators. I would note that it is well precedented. In fact, many of the currently approved influenza vaccines have in the past missed on non-inferiority for an Influenza B strain endpoint here or there, and still have received full approval or accelerated approvals.

The reason for that is, as we've said sort of throughout, that at the end of the day, influenza B is not a primary driver of concern, and it is known to be among the different strains of influenza in the virus in the vaccines of lower import for disease in older adults. In fact, one of the four strains, there have been active debates about the B/Yamagata strain as to whether or not it's gone extinct and even should be removed from quadrivalent vaccines in many of the recent WHO and other debates. Influenza B is a, you know, well-trodden path for many of these vaccines, as well as now for mRNA-1010, where there is differential performance.

Ultimately, there is precedent for moving forward, where you do not technically meet non-inferiority on immunogenicity or seroconversion endpoints, and still moving forward because of the lower concern about that disease in older adults. We will look at that data. We will develop our strategy. We will, obviously engage with regulators with that data, and ultimately determine a path forward. The most important thing for us, though, in the near term, is continuing with the efficacy study, trying to establish whether or not we have non-inferior or even superior efficacy for mRNA-1010 in its current form against influenza A, which is really where we think payers and public health officials will have the most attention.

It is prevention of that disease, not the immunogenicity endpoints, prevention of influenza-like illness hospitalizations, that is the primary objective of the vaccine, and that's where we're focusing our attention right now.

Ellie Merle (Executive Director of Biotech Equity Research)

Great. Thanks for the color.

Operator (participant)

One moment for our next question. Our next question comes from Joseph Stringer with Needham. Your line is open.

Joseph Stringer (Senior Analyst)

Hi. Good morning. Thanks for taking our questions. Two from us, the first one on mRNA-4157 Keytruda combo program. Just curious if you could give us a little bit more color on how we should think about the cadence of the additional trial starts. Is it something that will be more stepwise and measured approach, or should we expect sort of a full course kind of multiple trial starts approach? Secondly, on rare disease, outside of your MMA, GSD, and PA programs, what is the next rare disease program that we can expect to enter the clinic? Thank you.

Stephen Hoge (President)

Thank you for those questions. On mRNA-4157, I think, I'll just reiterate our prior guidance, and I want to expand it to say that we are trying to move into those pivotal studies, either phase III confirmatory studies for melanoma and non-small cell lung cancer, both adjuvant settings, this year. We, you know, you can look at the history of Merck and their ability to execute those studies and enroll quite quickly. Now working together with us, we hope to be able to, at least do that well. We'll look to enroll those, at, you know, at least as quickly as other confirmatory phase III studies in similar populations have been run, you know, generally.

I don't think we're gonna provide more specific guidance on enrollment time horizons except to say we want to go as fast as possible. I will also clarify too that from an accelerated approval perspective, if that pathway were to become available based on the current phase II data, which again is subject to future conversations with regulators, that we would want to have started those confirmatory studies. We wouldn't have needed to complete enrollment, but definitely we wanna be demonstrating that we're moving forward in those confirmatory studies as quickly as possible. We have double impetus for moving fast in enrolling them in the near term. In the rare disease space, programs moving out of pre-clinical into clinical.

The first I would say is we do have a clinical program for MMA, which you referenced. That MMA program is another place where we expect to see additional data following on, hopefully the continued strong performance of the propionic acid in the PA program. In the pre-clinical development space, we have programs against OTC and PKU, so phenylketonuria and a urea cycle disorder, OTC. Those are both programs that we would hope to move into clinical testing in short order. We haven't specifically guided on the timing of that yet.

Joseph Stringer (Senior Analyst)

Great. Thanks for taking our questions.

Operator (participant)

Ladies and gentlemen, this concludes the question and answer portion of today's call. I turn the call back over to Stéphane for any closing remarks.

Stéphane Bancel (CEO)

Thank you very much, everybody, for joining us and for the many thoughtful questions. We look forward to hosting you for Vaccine Day on April 11. It will be live in Boston for those of you who can join us and also, of course, virtual. Have a great day. Thank you.

Operator (participant)

Ladies and gentlemen, this concludes today's presentation. You may now disconnect and have a wonderful day.