Novo Nordisk A/S

CSE:NOVO B

Earnings Call Transcript 2021-Q1

[Operator]

Hello, and welcome to the Q1 2021 Novo Nordisk A/S earnings conference call. [Operator Instructions] Today, I'm pleased to present Lars Fruergaard Jørgensen. Please go ahead with your meeting.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you very much, and welcome to this Novo Nordisk Earnings Call for the first 3 months of 2021 and outlook for the year. I'm Lars Fruergaard Jørgensen, the CEO of Novo Nordisk. With me I have our Chief Financial Officer, Karsten Munk Knudsen; and Executive Vice President and Head of Development, Martin Holtz Lange. Also present and available for Q&A session is Executive Vice President and Head of Commercial Strategy and Corporate Affairs, Camilla Sylvest. Today's earnings release and the slides for this call are available on our website, novonordisk.com. Please note that this call is being webcasted live and this call -- and the recording will be made available on Novo Nordisk's website. The call is scheduled to last 1 hour. The presentation is structured as outlined on Slide 2. Please note, all sales and operating profit growth statements will be at constant exchange rates unless otherwise specified. The Q&A session will begin in about 25 minutes. Please turn to Slide 3. As always, I need to advise you that this call will contain forward-looking statements. Such forward-looking statements are subject to risk and uncertainty that could cause actual results to differ materially from expectations. For further information on the risk factors, including the uncertainties related to COVID-19, please see the company announcement for the first 3 months of 2021 and the slide prepared for this presentation. Please turn to the next slide. In the past 3 months, Novo Nordisk has progressed on all 4 dimensions of our strategic aspirations. We want to continue to add value to societies while we are taking steps on prevention and access. We have announced 2 partnerships where we invest in healthier urban populations as well as support frontline health care workers in low and middle-income countries to improve access to diabetes care. As part of our Circular for Zero environmental strategy, we are pleased to note that several suppliers have already committed to the zero carbon emission target by 2030 when supplying Novo Nordisk. This is expected to eliminate an estimated 15% of Novo Nordisk supplier carbon emissions. Martin will come back to key milestones within innovation but firstly, I want to mention that while we had an initial setback for Ozempic 2.0 milligram in the U.S. with the FDA issued refusal to file letter, we are working towards a resubmission in the second quarter. Furthermore, I'm happy to share with you that Ozempic has been approved for type 2 diabetes treatment and established cardiovascular disease in China. For commercial execution, we have progressed on all 3 strategic aspirations. Lastly, within financials, despite a tough comparator, which has been partly offset by inventory changes and timing of shipments in the first quarter of [ 2029 ], sales grew by 7%, while operating profit increased by 3%, both measured at constant exchange rates. Please turn to Slide 5. The sales increase of 7% was driven by 9% sales growth in international operations and North America operations growing by 5%. The negative impact for COVID-19 related stocking in the first quarter of 2020 is primarily offset by inventory changes and timing of shipments in this quarter. All therapy areas contributed to growth, with diabetes care sales growing by 9%, driven by GLP-1 sales growth and unchanged insulin sales. GLP-1 sales increased by 23%, driven by North America growing by 19% and international operations growing by 31%. The unchanged insulin sales were driven by 5% growth in international operations, offset by 10% sales decline in North America. The U.S. insulin sales declined by 10%, driven by declining in volume, rebate enhancement, while partially offset by channel mix. Diabetes care sales grew by 9% as international operations grew by 18%, and North America operations grew by 2%. Biopharm sales increased by 1%, driven by North America operations. Please turn to Slide 6. In line with our [ strategic ] of reaching 1/3 of the diabetes value market by 2025, we have improved our market share by 0.6 percentage points to 29.3%. The increase reflects GLP-1 market share gains in both operating units. We have increased our insulin volume market share to 47.3%, driven by market share gains in international operations, supported by all 3 areas. Please turn to Slide 7. The U.S. GLP-1 volume market is around -- sorry, the US GLP-1 volume market growth is around 20% in the first quarter of 2021 driven by once-weekly injectable as well as oral GLP-1 products. Novo Nordisk market leadership is now 58%, driven by the uptake of Ozempic and supported by Rybelsus. Measured on total scripts, Novo Nordisk is the market leader with more than 50% market share. Please turn to Slide 8. In the U.S., Rybelsus increases its volume market share, both in terms of total scripts and new patient starts despite 2 lockdowns with no face-to-face interactions between Novo Nordisk and the prescribers. We have secured broad market access for Rybelsus while the majority of Rybelsus scripts are now reimbursed, and more than 80% of new patients are from outside the GLP-1 class. Outside of the U.S., Rybelsus has now been launched in 14 countries with one key market being Japan. 2.5 months into the launch, Rybelsus has captured 0.5% of the all anti-diabetes market. The OAD market in Japan constitutes around 80% of the diabetes market. Please go to Slide 9. In international operations, diabetes care sales increased by 10%, driven by all geographies. The continued rollout of new generation insulins and focus on the GLP-1 product portfolio has resulted in an increased diabetes market share, which is now 23.6%. This is driven by share -- market share gains in both GLP-1 and insulin. The value share of the GLP-1 class of the total diabetes market has increased 1.8 percentage points to 11.2%. Please turn to Slide 10. Obesity care sales increased by 9% with 2% growth in North America operations and 18% growth in international operations. Throughout 2020 and into '21, fewer patients have started treatment with Saxenda due to COVID-19 lockdown and reduced access to health care providers. In the U.S., we have since the start of the year seeing an upward trend in the new patient starts on Saxenda, indicating early signs of recovery in patient flow. Please turn to Slide 11. Biopharm sales grew by 1%, driven by 3% sales growth in North America operations and unchanged sales in international operations. Rare blood disorders grew by 2%, driven by new product launches with Esperoct and Refixia. The 2% NovoSeven sales decline was more than offset by Hemophilia A product growing by 16% and Hemophilia B sales increasing by 18%. Rare endocrine disorders grew by 2%, driven by new indications and global rollout of next-generation device for Norditropin. Now over to you, Martin, for an update on R&D.

[Martin Holst Lange]

Thank you, Lars. Please turn to Slide 12. We continue to progress our late-stage pipeline, aiming at initiating Phase III activities across all of our therapy areas over the next year. In other serious chronic diseases, we in April initiated the Phase IIIa trial called Essence, evaluating subcutaneous once-weekly semaglutide 2.4 milligram for treatment of non-alcoholic steatohepatitis, or NASH. The trial will enroll around 1,200 people with NASH in Stages 2 and 3 of fibrosis. The trial is planned in 2 parts. Part 1 will assess the effect of semaglutide 2.4 milligram versus placebo, both on top of standard of care. The primary assessment will be based on liver histology after 72 weeks of treatment. Part 2 will be an extension of part 1, thereby preserving the randomization and assessing the effect of semaglutide 2.4 milligram on liver-related clinical outcomes after a total of 240 weeks of treatment. The regulatory submission is expected to be based on part 1 of the trial, combined with the already completed and reported results from the Phase II trial for which we have been granted breakthrough designation by the U.S. FDA back in 2020. Please turn to the next slide. In obesity, our strategic aspiration is to develop a leading portfolio of superior treatment solutions. Consequently, we've decided to complement our injectable therapy portfolio with an oral option. From market research, we know that the majority of people with overweight seeking care with health care providers are not referred to an anti-obesity medicines prescriber. Further, research has shown that a number of patients as well as their prescribers have a preference for tablet-based treatment. Consequently, we expect to be able to address a substantial unmet need by developing a broader palette of obesity offerings as we enable announced our decision to enter into Phase III in obesity with all semaglutide 50 milligram. This decision follows the completion of the step Phase IIIa clinical program for once-weekly subcutaneous semaglutide 2.4 milligram which is currently under regulatory review in the U.S. as well as in the EU. The global 68-week program, also called Oasis, will enroll around 1,000 people with obesity or overweight with at least one weight related comorbidity in a total of 3 trials. As usual, weight related comorbidities are defined as hypertension, dyslipidemia, obstructive sleep apnea and cardiovascular disease. We expect to end the second half of '21 to initiate the first of the 3 trials, which is expected to enroll around 650 trial participants. The objective is to confirm superiority of oral semaglutide 50-milligram versus placebo on weight loss in people with obesity or overweight. Please turn to the next slide. Now turning to the broader R&D high-level milestones in '21. As Lars mentioned earlier, we have in U.S. in March received a refusal to file letter for the label expansion for 2.0 milligram of Ozempic for the treatment of diabetes. The regulatory file was based on the SUSTAIN FORTE trial. The U.S. has requested additional information mainly related to additional manufacturing data. And it is our belief that no additional clinical data will be needed for the resubmission. We're currently in a constructive dialogue with the FDA and work to resubmit during the second quarter of '21. Moving on, also in the first quarter of '21, we have initiated a Phase III, 52-week clinical trial with once-weekly semaglutide 2.4 milligram in people with obesity related heart failure with preserved ejection fraction, also called HFpEF. In the second quarter, we also expect to initiate the Phase III program for oral semaglutide in Alzheimer's disease, and we look forward to receiving the feedback from the U.S. FDA on the application for semaglutide 2.4 milligram in obesity. Moving to the second half of '21, we expect to see Phase I results within our insulin innovation. And we also expect to initiate the Phase III outcomes trials for ziltivekimab within cardiovascular disease. Towards the turn of the year, we expect a decision from the EU on semaglutide 2.4 milligram in obesity as well as for Ozempic 2.0 milligram within diabetes. And within biopharm, we expect to have results from the Phase III program for somapacitan in children. Lastly, for the ongoing combined Phase I and II trial with Mim8, we expect to see results from the different cohorts during the coming 3 quarters. With that, over to you, Karsten.

[Karsten Munk Knudsen]

Thank you, Martin. Please turn to Slide 15. In the first 3 months of 2021, sales were unchanged in Danish kroner and grew by 7% at constant exchange rates. The gross margin declined to 82.8% compared to 84.1% in 2020. The decline reflects negative currency impact and lower realized prices in the U.S., partly offset by positive product mix and productivity. Sales and distribution costs increased by 9% in Danish kroner and 16% at constant exchange rates. The increase is driven by launch activities and promotional spend for Rybelsus and Ozempic, market development investments for obesity as well as sales force expansions in China. Research and development costs increased by 4% in Danish kroner and 7% at constant exchange rates. The cost increase is driven by a higher activity level as we progressed the early-stage pipeline within other serious chronic diseases as well as the ongoing cardiovascular outcome trials, SOUL and SELECT. Administration costs increased by 1% in Danish kroner and 3% at constant exchange rates. Operating profit decreased by 8% in Danish kroner and increased by 3% at constant exchange rates. The negative currency impact on operating profit is partly offset by around DKK 1 billion in hedging gains under net financial items. This compares to a loss of DKK 1.3 billion in 2020. The hedging gains are a consequence of the U.S. dollar trading 9% lower compared to last year. Net profit increased by 6% and diluted earnings per share increased by 8% to DKK 5.45. Free cash flow was DKK 9.5 billion compared to DKK 7.7 billion in 2020. The increase reflects the higher net profit and the favorable impact from changes in working capital. Please turn to Slide 16. In the first quarter of 2021, we have realized a negative currency impact on sales and operating profits. The currency headwinds are driven by most major currencies and emerging market currencies trading at lower levels in 2021 than in 2020. Some of the negative currency impact from major currencies on operating profit is, as mentioned, partly offset in net financial items as they are hedged. Please turn to the next slide. Based on the strong underlying performance seen in the beginning of 2021, we now expect 2021 sales growth between 6% and 10% at constant exchange rates. This guidance reflects continued diabetes care growth, mainly driven by Ozempic and Rybelsus as well as obesity care growth. Also embedded is intensifying competition both within diabetes care and biopharm and continued pricing pressure, mainly within diabetes care in the U.S. Operating profit is now expected to grow between 5% and 9%, reflecting the sales growth outlook and continued investments in current growth drivers as well as pipeline assets to secure future growth. As previously mentioned, we expect negative currency impact for the full year. Consequently, reported sales and operating profit growth is now still expected to be 4% and 6% lower than at constant exchange rates, respectively. The current COVID-19 pandemic causes uncertainty to the outlook regarding new patient initiations and societal impacts. Financial items is still expected to be a gain of around DKK 0.7 billion. Due to minor timing changes, we now expect capital expenditure to be around DKK 7.5 billion in 2021. Lastly, free cash flow is parallel shifted upwards by DKK 1 billion and now expected to be between DKK 37 billion and DKK 42 billion. As a consequence, the ongoing share buyback program is expanded with DKK 1 billion to DKK 18 billion. Now back to you, Lars, for final remarks.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Karsten. Please turn to Slide 18. We are very encouraged with the start of the year. Sales growth was driven by all therapy areas and across geographical areas within international operations as well as North America operations, where growth was accelerated in the U.S. We were also pleased to announce plans to develop oral semaglutide as a convenient and effective treatment option for people with obesity, complementing our injectable obesity medications. The solid financial performance in the first 3 months of 2021 has enabled us to raise our outlook range for the full year. We're now ready for the Q&A, where I kindly ask all participants to leave for her or himself to 2 questions. Operator, we're now ready to take the first questions.

[Operator]

[Operator Instructions] Our first question comes from Emmanuel Papadakis from Deutsche Bank.

[Emmanuel Douglas Papadakis, Research Analyst]

Emmanuel Papadakis from Deutsche Bank. Since I'm early, perhaps I'll start with a guidance question. Seems majority of the Q1 revenue beat was stocking related. Perhaps you could just quantify that. And you notably raised guidance regardless. So if you could just talk about the confidence in that stocking you saw in Q1, the revenue side will not reverse through the course of this year? And whether there are any other factors driving your increased confidence for the full year outlook or indeed any other swing factors we should be thinking about in terms of the range for this year. And then perhaps I'll take a question around the outlook in China. What have you assumed, if anything, at present in your guidance for potential VBP incident impact? It appears possible it still could come within 2021. What are your latest expectations around timing and price impact? And what options would be available to you to mitigate that at the EBIT level were it to arrive?

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Emmanuel. 2 questions related to guidance. One linked to the stocking we saw and what more to say about the guidance lift. And then outlook for China also in -- linked to guidance and volume-based pricing. So Karsten, over to you.

[Karsten Munk Knudsen]

Yes. Thank you for those questions, Emmanuel. And clearly, some movements on Q1 results, that's important to take into account when providing full year guidance. So just to reiterate, our 7% sales growth in the first quarter should be considered in the light of the DKK 2 billion stocking we saw in the first quarter last year. So if adjusting for that would take us to 14% sales growth. And then what we saw in the first quarter of this year between wholesaler stocking in the U.S., partly related to launch of Ozempic with the 3 ml cartridges as one piece. And then timing of shipments in [ IO and tenders ] as well, would basically adjust the [indiscernible] sales growth down to 9%. So in adjusted terms, our Q1 underlying sales growth is 9% and that's basically in the high end of the guidance range we issued back in February, where we said from 5% to 9%, and being in the high end was one of the key indicators for us to increase our full year guidance. On top of that, linking to your China impact to guidance question. Then, of course, when assessing the proper guidance for the remainder -- for the full year, of course, that also takes into account the risk picture we're looking into. And what we see in China specifically is that we do see an impact from volume-based purchasing on NovoNorm, so the so-called [ VBP 4 ], where we'll see an impact on NovoNorm starting from May and onwards. So that's fully included into our guidance. In terms of pursuing VBPs in China, we do not expect insulin to be included in VBP 5, which is happening now with effect from some time in Q3. And hence, any potential impact from insulin on volume-based pricing in China would be later in the year. So truly quantifying that is hard because we don't know the exact structure and timing. But that's also why we're working with guidance ranges. So it can be bigger, smaller, but we do expect a negative impact in the time to come from insulin in China.

[Operator]

Our next question comes from Peter Verdult from Citi.

[Peter Verdult, Managing Director]

Pete Verdult, Citi. Two Questions. Mads -- sorry, Karsten. Simple one, just tax, what the implications would be if U.S. goes to 28%? Realize it won't have an impact on '21, but just going forward, any sort of sensitivities there would be helpful. And then assuming Camilla is on the line. Could you just remind us how big the current U.S. Saxenda sales force is and your current approach to the launch? Should we be thinking sort of omnichannel approach? Or are you particularly focusing on either widening the prescriber base, getting patients to seek treatment initially or to improve the reimbursement access? Or are you trying to do all things at the same time? So anything you're willing to share at this juncture would be appreciated.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Pete. So first, Karsten, on impact from potential change in tax structure in the U.S. And then later on, Camilla?

[Karsten Munk Knudsen]

Yes. Thanks, Pete. That's clearly something we're looking at. So -- and as you know, it has not been concluded in Congress at this point. But I'll say the simple sensitivity measure on tax impact is that a -- and what we saw when the Trump administration reduced rates some years back, was that on the U.S. corporate income tax rate, if a reduction or a movement of 10 percentage point on that moves our global group effective tax rate by 1 percentage point. So taking the U.S. rate from 21% to 28%, that would move our group rate by some 50 basis points or something like that. There are a number of other potential elements in the rule-making process. And I'm sure you read about global minimum taxes and so on. At this point, it's simply too early to assess whether it has an impact or not. But the simple sensitivity is around 0.5 percentage point from the U.S. corporate income tax.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Karst. And then Camilla, what can you share in terms of tactics for the obesity commercial efforts in the U.S.?

[Camilla Sylvest]

Yes. So in terms of tactics for the obesity in the U.S., we are, of course, focused on driving the expansion in the commercial segment. But we're, of course, also working longer-term to get into the Medicare segment. This, of course, is not -- there is no sort of -- an immediate timeline to that. But what we can say about the access in the commercial segment is that there is -- we are working on making sure that there is opt into the gross coverage, meaning that we can improve also on our net coverage. And of course, we also expect that over time, when we launch our next product, semaglutide 2.4, subject to approval, that, that will also, of course, be of -- effectful in terms of getting coverage. So coverage continues to be important. And in terms of sales reps, we are complementing our efforts from sales reps with omnichannel approaches. And of course, also working to see if we can expand what we call the direct care approach. Which means that since there are very few physicians that are prescribing obesity products at this point, it might be easier to enable that with an omnichannel approach, meaning online diagnosis potentially over time and online scripts. So that's something that we are working on, but it's not in full force at this point in time.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Camilla. Thank you, Pete. Next set of question please.

[Operator]

Our next question comes from Wimal Kapadia from Bernstein.

[Wimal Kapadia, Research Analyst]

Wimal Kapadia from Bernstein. Can I just first ask on GLP-1 pricing, please? It seems that the net price of Rybelsus in the U.S. in 1Q was around $13.50 per day. That compares to closer to 20% -- $20 per day for Ozempic. So just curious if we now believe this is at a steady state from which future declines will appear. Or is there still some co-pay impact in Rybelsus, which will mean that the net price could be slightly higher for the rest of 2021? And then my second question is just following up on China and VBP again. I just wanted to get a sense of what is your current base assumption? When we eventually do see a VBP, how will it be implemented? Would it be the more traditional approach like the typical wave 5 and 6 in the future? Or could it be a Wuhan star VBP, which was clearly very different? And then just tied to that, any thoughts on a potential GLP-1 VBP at some point in the future? Would the Chinese government actually consider all GLP-1s in the same class like they did with the different incident classes?

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Wimal. So first, Karsten, on GLP-1 pricing?

[Karsten Munk Knudsen]

Yes. So on Rybelsus and GLP-1 pricing. So Wimal, it's always dangerous to do this value per script on a quarterly basis. But I would say, in trying to make it as simple as possible then, when you compare Ozempic and Rybelsus, then there's a delta of 11% on a list price per day, simply due to the size of the script between a weekly and a daily treatment. So that's one delta. Then furthermore, we do see continued use of affordability programs for Rybelsus. So there's both a bigger co-pay buy down compared to that of Ozempic since we're competing in the oral segment, down to $10. And then we still see a sale of some of the affordability programs from 2020, where you have some runway before that ends. And then, of course, there's the usual channel mix dynamics, where you start out in the higher-margin channels and then over time, products are available in more channels also in lower-margin channels. So I'd say in short the affordability piece with the tail going out on some of the launch programs, that should be beneficial. But the channel mix, as we've seen it with other products, should be negative going forward on an ARP per script basis, but on a net value, it will be positive.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Karsten. And on China, volume based pricing, we cannot really go in and speculate about what will happen in the future. I'll just say that I believe it's slightly more complicated to handle biological medicines for physicians and patients. If you go into these type tender situations compared to small molecules, while it's not really possible for us to speculate on how this will play out in the future. Thank you, Wimal.

[Operator]

Our next question comes from Jannick Lindegaard from ABG.

[Jannick Lindegaard Denholt, Research Analyst]

It's Jannick Denholt from ABG. Can I ask a little about your maneuver room right now in the U.S. in terms of getting Rybelsus on the road? Essentially now this is the, what, third time you're trying to launch it with the field force coming in. So can you talk a little more about your field force interaction? So I understand that you are approaching some 85% or so of the core interactions with ACPs are face-to-face. How does that translate into productivity, i.e., in terms of usual number of calls that you make? And then secondly, also on Rybelsus rollout, then in Japan, obviously there's this 14-day limitation for the first year on prescription. So how should we think about the uptake in Japan this year? Because, obviously, longer term, this is a huge opportunity.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Jannick. I'll pass on both questions to Camilla.

[Camilla Sylvest]

Thank you, Jannick. Yes, correct, that we are quite optimistic around when we get back into the field, we see that the -- that the NBRx curves of Rybelsus comes back to similar slopes of the curve, so to say. Of course, we are not fully, as you say, back in the field yet so there's still some room. But we are, of course, constantly increasing our presence in the field also. So -- and in 2020, we also got quite some experience on how to supplement our in-field presence with other types of multichannel engagement parameters. So that's the way that we try to do this. But over time, this constantly should increase also with the U.S. opening up. Then on Japan and Rybelsus rollout, we are quite satisfied with the uptake so far, especially when we look at also our share of voice, where we, together with Merck, have the highest share of voice in the OAD segment in Japan at this point in time. So despite the sort of special conditions in Japan with the 2-week prescription rules, then we feel that on a comparative note, we are tracking quite well in Japan following the very recent launch of Rybelsus.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Camilla. And thank you, Jannick. So also as you can hear, we're very confident and very pleased with how Rybelsus is performing both in the U.S. and Japan, and we are very optimistic about the future for Rybelsus.

[Operator]

Next question comes from Simon Baker from Redburn.

[Simon P. Baker, Head of Pharmaceutical Research]

Two, please. Firstly, on phasing. I wonder if you could give us any pointers as to the phasing of R&D and SG&A costs across the remaining 3 quarters? Is there any things we should remember in terms of trial starts and launch costs? And also on phasing, if you could remind us on the COVID stocking, destocking for last year. Obviously, it was DKK 2 billion in Q1, DKK 500 million destocking in Q2. If you could just remind us what the Q3 and 4 impact was. And then secondly, on obesity, I wonder, as you're moving into supplement injectable with oral, if you could give us any thoughts on the potential payer and reimbursement challenges of oral versus injectable. There's long been a suggestion in some quarters that payers are probably more [ receptible ] to an injectable because it's seen as a "more serious medical intervention" then a pill. Is that your belief? And are there any things we should be thinking about in the future?

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Simon. First, Karsten, on phasing, both on cost and stocking.

[Karsten Munk Knudsen]

Yes. Thank you, Simon, for that set of questions. So on phasing, I would say the key aspect we'll be looking out for in terms of comparables versus last year, is in Q2, where we saw quite significant destocking last year, taking our Q2 sales growth last year, down to basically 0. So of course, that will impact the comparator as we saw impacting the comparator in the first quarter of this year, the other way around. So that would be the main on sales growth. I think on the other partial destocking between Q3 and Q4 last year, I think it will be on the decimal. So I wouldn't be [ haunching ] that vis-à-vis other impacts on top line. In terms of our spending, I would say you should not expect any significant changes to our spending pattern this year. So the way it happens, I would say, if I take R&D first, then we're basically phasing our spending vis-à-vis the trial execution. So there's a start-up cost and a close down cost, and the remainder of the spending on trials are basically spread over the lifetime of the trial. And hence, it's being phased rather gradually. Then there would only be significant bumps in case of, you could say, any impairments to intangible assets. And as you know, we don't have a lot of acquired assets in Novo Nordisk, so don't expect significant bumps on -- in terms of R&D spending. S&D, what you saw here in the first quarter with S&D being up 16%, that was an artifact of us both pushing Rybelsus and Ozempic, especially in the U.S. market from the beginning. So we're basically running parallel DTC campaigns behind the brands. So we've front-loaded the spending. But more granularity in terms of the phasing I would not want to give at this point in time because that also indicates some of our commercial tactics vis-à-vis, for instance, DTC programs in the U.S.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Karsten. And on payer reception of oral sema in obesity, we're starting the trial now. So maybe it's a bit early to start talking about market access. But I would just make the comment that we see that for Rybelsus, which is an oral version of sema, we see pricing similar to what we see on Ozempic. So I think this is all about efficacy. And bear in mind that the obesity market is, say, a market to be opened up. And I think there is plenty of opportunity to segment that market. And I'm sure that there's a very large segment who would prefer an oral treatment. So for us, that's a significant opportunity.

[Operator]

Our next question comes from Trung Huynh from Credit Suisse.

[Trung Chuong Huynh, Research Analyst]

It's Trung Huynh from Credit Suisse. Three questions, if I can. First one, oral sema and obesity. The 50 mg dose that you're going for is a 25x more than the injectable sema dose for obesity. So I know you're working on improvements in yield, but how should we think about the gross margin impact of this in the short-term but also the long term? Secondly, you initiated the study of sema in obesity with HFpEF. So perhaps, can you discuss some of the rationale for starting this study, maybe the commercial opportunity you have there? Is there any opportunity to move beyond the obesity in diabetes patients? And then finally, just on Mim8, the Phase I/II results now are listed as 2Q to 2H. Just seeing if that's somewhat a slight delay there? Or are we expecting multiple data sets throughout this year?

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

So thank you, Trung Huynh. So first, Karsten, on the 50 mg gross margin impact.

[Karsten Munk Knudsen]

Yes. Thank you for pointing to that trial, Trung, because that's actually one of my favorite trials these days. Because actually, what you're looking at is a Phase III asset that only takes 1,000 patients in clinical trials -- in the clinical trials to get to a regulatory decision. So our cost to get to market is, in the first place, relatively manageable compared to most other Phase III programs. Then in terms of commercialization, you know all about the volume opportunity in obesity and the attractiveness of having an asset with an efficacy in the magnitude of what we see with the sema 2.4 and up to 18% weight loss as we saw in the STEP program. And of course, before entertaining such a trial, then we do a lot of financial modeling, including cost of goods and manufacturing. And I would say with the scaling we're doing in our manufacturing setup and the process improvement we are entertaining in manufacturing, first of all, we do see improvements in our cost of goods, as we've also been discussing with Rybelsus early on. Furthermore, what we're also doing is that we're looking at the formulation of the tablets in the 50-milligram version, thereby also looking at certain opportunities in terms of improving our gross margin profile for the product. So all in all, we expect to see an attractive product on -- also on a gross margin level if and when we get to market.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Karsten. And Martin, combined answer to make it sound like one answer to the second question on semi HFpEF and Mim8.

[Martin Holst Lange]

That's going to be a tall order, combining obesity and hemophilia, but I'm going to give it a try. On HFpEF, we see obviously a great number of patients suffering from heart failure, and there's no treatment specifically for HFpEF out there. These patients have a severe impact on their everyday life: on their function, on their quality of life and obviously on their outcomes. And we have indications that semaglutide may be an impactful treatment in this space, specifically because 80% of people with HFpEF suffer from obesity. And we have clear indications that weight loss will improve the outlook, the quality of life and the activity of daily living with these patients. So we see this as an opportunity to serve some patients with currently no treatment and a potential for a label expansion of the obesity label for semaglutide. Moving fastly then to the Mim8 question, we will see a readout from different cohorts throughout the next 3 quarters. We will combine our assessment of those readouts and report on the efficacy and safety of Mim8 later this year, as based on these data.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Martin. So really no change to Mim8 compared to previous quarters' comments.

[Operator]

Our next question comes from Sachin Jain from Bank of America.

[Sachin Jain, Managing Director]

I've got a 2-parter on obesity, if I may. I understand your midterm excitement build in the market, but I wonder if you could indulge and just give some color on launch expectations. I'm going to frame the question versus consensus. So consensus has sema launching 50% faster than the initial Saxenda launch, layering on top of Saxenda for [indiscernible] perspectives on the speed of sema launch versus prior Saxenda? What factors should we be thinking about as we think about this launch versus prior in terms of pricing, payer familiarity, where education is? And then the second is how to think about the 2 products in combination; what short-term dynamics should we be thinking of in terms of potential sema cannibalization of Saxenda patients? I understand your state on dynamic debate, but I expect takes time to manifests in terms of patient build.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Sachin Jain. While we do not kind of guide on launch trajectory, et cetera, for products or comment on consensus estimates, Camilla, what can we say on this?

[Camilla Sylvest]

Yes. So what we are trying to do in many countries, but also of course in the U.S., is to build the market, as you rightly said. And with the launch of semaglutide 2.4 with a much higher efficacy, we know from our early discussions with payers in general, that weight loss in the magnitude of what we are seeing with 2.4 is of course of high relevance. So it will feed into our attempts to build the market in terms of making sure that more patients seek treatment for obesity care because obesity care has such a -- obesity has such a big influence on the health care system and the cost. So of course, with higher efficacy, we are more likely to see a strong uptake of 2.4. But that is, of course, early days to say, but we are basing this just on efficacy. But we're also launching into a market that is more mature than what it was when we launched Saxenda. So in the meantime, of course, we have built the awareness around obesity. We're working to have it recognized as a disease in many countries around the world. We have launched new websites, Truth About Weight, for patients where they can learn about obesity and also rethink obesity for physicians, where they can also obtain more information about obesity in general. So a bigger sort of base to build on for a more effective product. So that's basically the difference in the situation compared to Saxenda, where we started very much from scratch. In terms of cannibalization, it's difficult for us to comment on, and we cannot give details on that. But of course, we are launching a product that has more than twice the efficacy into the market.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Yes. Thank you, Camilla. So it's, of course, still early days, but looking at the reports that come out from the medical community observing, say, the early payer dialogue, I think this is a significant different trajectory than what we have seen in the past. And I think, in my view, this is the first time there's a real solution to managing obesity with medical intervention. So I think it's really, really exciting.

[Operator]

Our next question comes from Michael Novod from Nordea.

[Michael Novod]

It's Michael from Nordea. Two questions also. Maybe you could elaborate a bit on the sales differences between Q4 and Q1 in terms of Rybelsus in the U.S., which, of course, looks quite dramatic. I know you've been talking to the general volatility between quarters, but this looks very dramatic, so it would be great to get an update on that in more detail. And then secondly, on the 2.0 milligram refuse to file letter from the FDA in diabetes, and what kind of feedback you're getting on the 2.4 milligram sema obesity file? And also whether we should see a potential risk on sort of any type of read across between the 2 on the manufacturing side?

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Michael. First, Karsten, on Rybelsus sales Q4 last year versus Q1 this year.

[Karsten Munk Knudsen]

Absolutely. And I recognize that it looks odd that actually Rybelsus sales being a launch product is lower in Q1 this year compared to Q4 last year. I would say there are a couple of technicalities that explains basically all of it. And then I think we should talk to the underlying kind of dynamics of the products, which are 100% intact. So on the technicalities, so let me just start out by 2 pieces. First of all, looking at quarterly sales on a launched product is always super dangerous. And we've seen that again and again for different dynamics. The 2 key dynamics you should take into account here is, first of all, that's a so-called [ ex-factory ] ratio. So basically, the ratio between what we sell to wholesalers and scripts being written to patients. And there's quite some volatility on launch products in that ratio since that -- we are building pipeline in the supply chain when you're launching a product. So basically, product going into rural pharmacies and distribution centers across a nation. So we saw that in the fourth quarter of last year, that there's quite a high [ ex-factory ] ratio and where we see a more normal [ ex-factory ] ratio in the first quarter of this year. So that would be kind of a natural launch supply chain volatility. And then the second piece to take into account is on adjustments to rebates as we've also seen on launched products. So being a launched product, you don't know exactly how much is being utilized through cash programs and co-pay and different insurances. And there, of course, with the lag we have, there will be some adjustments over time. And that was what we talked to in Q4, that we had a favorable impact to our GLP-1 business. And I would say for Rybelsus, it's in isolation. We didn't call it out on the brand. It's less than DKK 100 million in the fourth quarter. But of course, for a launch brand with somewhat limited sales, then, of course, it's a bigger piece. So [ ex-factory ] ratio and changes to rebates and estimates in the fourth quarter. Adjusting for that, 20% volume increase from the fourth quarter to the first quarter. But Camilla, on the underlying fundamentals on Rybelsus?

[Camilla Sylvest]

Yes. On the underlying fundamentals, we track on a number of parameters to understand, of course, our uptake and launch with Rybelsus. And all of that is in line with our ambition. So it means that the -- that means the number of prescribers is continuing to progressing well. And we also see that awareness and preference is improving over time. Especially on the preference to prescribe Rybelsus, that has increased significantly and looks very strong also compared to other branded OADs in the market. So what we are working on right now is to increase our awareness of the brand, and that comes with us and the reps coming back into the market and as we continue the launch trajectory. So we are quite confident with that path. We also continue to see that the source of business and the positioning is working out so that the sourcing is 80% outside the GLP-1 class, as we have talked to before also. So it means that we continue to be very confident in Rybelsus and the commercial strategy. But of course, we also see that it's a very promotion sensitive launch product, and we have -- and as we talked to before, whenever we have reintroduced the product, we see that we get back on a very strong trajectory. We continue to support Rybelsus, of course, also with DTC. And of course, also with reps more and more in the field, as we just talked about before.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Karsten, Camilla. Strong confidence from our side in the launch trajectory for Rybelsus. And with that, over to Martin on read across from the refusal to file letter from the FDA to 2.4 milligram.

[Martin Holst Lange]

Yes. Thank you very much. So broadly speaking, I don't think I will speculate on an ongoing regulatory review. But maybe just say that the FDA has accepted the submission of the 2.4 milligram. It's under review, and we currently have no indications of that file being impacted by the refusal to file on the Ozempic 2.0 milligram.

[Operator]

The next question comes from Michael Leuchten from UBS.

[Michael Leuchten, Co]

It's Michael Leuchten from UBS. Just 2 quick ones, please. Just in terms of the mix -- price/mix effect on the insulin side, there seems to be quite a few things going on in the U.S. at the moment, with patient access coming out, [ 340Bs ] playing a part. As we think about this beyond 2021, would you be able to give a bit of a feel for what the underlying conventional price/mix effect is? And what is sort of 2021 specific? And then the second question, just going back to the tax question. It doesn't look like there will be any manufacturing offset in terms of tax rebates in the U.S. Does that have any relevance in terms of how you think about your manufacturing setup as you increase your oral manufacturing platform?

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Michael. Two questions for you, Karsten, on price/mix effect on insulin and also looking a bit into the future. And then, again, on taxes in the U.S., combined with manufacturing footprint in the U.S.

[Karsten Munk Knudsen]

Yes. Thank you for those questions, Michael. So first of all, all on insulin and insulin dynamics, you see our North American business being down 10% in the first quarter on insulin. Which is a function of both lower volumes. It's enhanced rebates and then an offset from positive channel mix. So what you should expect going forward is that, of course, there will be competition in the market for volumes with potentially more biosimilars entering into the market. So that will intensify. But of course, we'll be defending our leading position in the market in terms of market share. With competition comes also pressure on rebating and pricing. So the dynamic around pricing and rebating, we do expect to continue for those reasons. And as to channel mix, the positive factor on channel mix is mainly related to 340B, where we are basically -- we stopped our shipments as [ just ] with the full year. We stopped our shipments to contract pharmacies, which enables us to avoid double dipping of rebates and hence, a better channel mix impact on our insulin sales. That is, of course, only something one can do one time. I would have to say that on 340B, while comfortable in terms of what we included in the first quarter, of course, there's still some uncertainty vis-à-vis legal cases and legislative impacts around future rule-making on a prospective basis. Then to your question on taxes and manufacturing offsets, then I would say the starting point, when we look at our manufacturing footprint is that we look at the supply chain backup and redundancies and closeness to markets. So of course, we take taxes into account, but tax is not a prime criteria for when we decide where to put our manufacturing footprint. So what we're looking at now is that we're just in our final stages of finalizing documentation on our U.S. API expansion project. So project running according to plan. So we -- now we're moving into a ramp-up phase. And the CapEx ramp up we've been signaling with now DKK 7.5 billion CapEx spend this year, is mainly driven by expansions in Denmark. So I'd say no implications for our CapEx manufacturing strategy from the changes in U.S. tax legislation.

[Operator]

Our next question comes from Carsten Madsen from SEB.

[Carsten Lønborg Madsen, Research Analyst]

Maybe I'll actually only take one question here for Martin. It's in relation to the NASH Phase III trial with sema. You mentioned that there are 2 binary histology endpoints. What does this actually mean? In Phase II, you showed the resolution of NASH. But with no worsening of fibrosis, do you now also need to show an improvement in fibrosis and not only no worsening of fibrosis?

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Carsten. Over to you, Martin.

[Martin Holst Lange]

Yes. It's a super relevant question. And the regulatory guidance basically stipulates that you have to win on 2 counts. You had to show improvement in steatohepatitis. and you had to show improvement in fibrosis. Just to clarify, of course, being a Phase II trial, this trial was not powered to look at fibrosis. However, numerically, we did see an improvement in fibrosis as well as the sort of stopping in worsening of fibrosis. If we see the same numerical change in the Phase III trial, we will actually be in a place where we are not only clinically relevant but also statistically significant and thereby living up to the regulatory guidance. So what we need is for our Phase III trial to confirm what we saw in Phase II.

[Carsten Lønborg Madsen, Research Analyst]

And then...

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

The second question?

[Carsten Lønborg Madsen, Research Analyst]

Yes. I had a second question that was just for the other Karsten. In terms of the gross margin development, 80 bps of the 130 bps lower gross margin this quarter versus last year's FX, how is the remaining 50 bps divided between amortizations and price pressure on your price mix, you can say?

[Karsten Munk Knudsen]

Yes. So that's what is for other Karsten. And I think when -- what we disclosed upon acquiring Emisphere was that we do expect a negative impact here in the first year of less than 1% of OP simply due to the delta between the royalty payments under the previous contract and then the amortization profile, having acquired the company. So if you take that 1% or less than 1%, then that will make you into -- that corresponds to less than 50 bps on the margin. So the main driver is in reality amortization related to Emisphere. You can look in the cash flow statement on the step-up in depreciation and amortizations also, just to get a feel for it. But that's the main driver. The other effects remains the same. We continue to drive productivity. We continue to get the product mix gain from GLP-1, and we continue to see some negative impact from prices in the U.S.

[Lars Fruergaard Jorgensen, President, CEO & Member of Management Board]

Thank you, Carsten, and thank you, Karsten. With that, we thank you for the attention today at our conference call. And if you have more questions, feel free to contact our Investor Relations officers. And with that, we wish you a good day. Thank you. Bye-bye.

[Operator]

Thank you. This now concludes our conference call. Thank you all for attending. You may now disconnect your lines.