Welcome, and thank you for joining the financial statement for the first six months of 2023 of H. Lundbeck A/S. Throughout today's recorded presentation, all participants will be in listen-only mode. The presentation will be followed by a question and answer session. If you would like to ask a question, you may press star followed by one on your touch-tone telephone. Please press the star key followed by zero for operator assistance. I would now like to turn the conference over to Deborah Dunsire, President and CEO. Please go ahead, madam.
Thank you, operator. Welcome, everybody, to the first half, report for Lundbeck. Thank you for dialing in. It's going to be a good conversation. May I have the next slide, please? You've seen our forward-looking statements many times before, so I won't go over them in detail. I'm sure you'll be glad to know. The first half for Lundbeck has been an outstanding performance across all of our business. We have broken records in revenue, achieving the highest first half revenue for Lundbeck ever in its history, achieving approximately DKK 10 billion, with a reported growth rate of 13%, 10% in constant currencies. I know there's a lot of focus on Vyepti, and I'm very proud of the growth rate of Vyepti at 91% in constant currency.
Of course, that's on the back of the US and the global rollout, and you'll hear more about that from Jacob and Tom, who are with us to talk to you about that. The strategic brands generally across the world have performed extremely well and achieved DKK 6.6 billion, which are now 66% of the total revenue for Lundbeck. In aggregate, the strategic brands grew 18%. We are also going to be talking to you about promising early uptake with the launches of Rexulti in agitation in Alzheimer's disease or agitation associated with dementia in Alzheimer's disease, I should say, given that is our FDA label, and of course, Abilify Asimtufii, the 2-monthly version of aripiprazole long-acting. The profit has also grown commensurately with the EBITDA margin reading, reaching 33.4%.
We do know that there is lower planned spending in the first half than the second half for a variety of reasons that we'll talk about. The pipeline has delivered very strongly in the first half of this year. Of course, the approvals are the biggest milestones. We were delighted to achieve the priority review approval of Rexulti in agitation in May on time. Of course, Abilify Asimtufii being approved at the end of April. Those launches went into effect late May and early June. Johan will be taking you through the results of the DELIVER trial, the long-term follow-up of that trial, which confirms the efficacy of Vyepti over a longer period of time.
Of course, we were very, very excited to announce the proof of concept achieved in a new mechanism of action in migraine prevention with our anti-PACAP. Next slide, please. You'll see here that all regions are growing strongly, and the strategic brands in all regions are growing strongly, and that's, of course, the engine that is going to be driving Lundbeck forward to steady growth in the coming years. On the right-hand side, you can see which regions are growing from which brands because it is a mix. Next slide, please. Let's talk more about VYEPTI. We've got very strong momentum for VYEPTI, with strong demand in the US, and we can see that demand on a continuing growth curve with a 78% growth in constant exchange rates, first half of 2023 versus first half of 2022.
There are a number of factors underlying that growth. We've fueled it with new patient starts, and that's coming from both physicians who've prescribed VYEPTI before and who are prescribing more of it because it's working well for their patients, and adding new prescribers. So that's a very good construct to be able to see for the future growth prospects of VYEPTI. The number of prescribers has increased significantly. The DELIVER trial, we'll talk about more. That was presented at the American Headache Society, we continue to expect strong growth in the second half of 2023. The market share now has reached 7% in the first half, looking at the US migraine prevention market, or at least the branded market of the CGRPs and the Gepants. Next slide, please.
VYEPTI is becoming a global brand, and we're seeing more and more countries launching. All told, VYEPTI's global revenue is up 91%. When we look externally, of course, it's off a small base, but we've got incredible growth coming for VYEPTI with the global rollout extending. We've launched seven markets already in 2023, and nine more launches are expected in the second half. We're seeing really good uptake. If you look at the left-hand curve, we can see a strong market penetration in a number of markets. UAE, over 14% market share in the prevention market, the branded prevention market in the 21st month. Switzerland close to 13% in its 13th month, and Canada in its seventh month at 11.6%. Germany's very early, but we're looking very favorably upon the growth in Germany.
I'd like to remind you that this is the first global brand that Lundbeck has launched independently. It's always exciting to see the not only the US growing strongly, but the global markets contributing to the growth of Vyepti. Next slide, please. Brintellix. Trintellix is on a great growth trajectory. The principal contributors here are, of course, continued growth in Japan, a really great market share together with our partner, Takeda. Europe has been a standout with extremely strong growth. As we've seen the market shift, there's more GP prescribing, but we've had a slightly increased footprint over the last few years as we've experimented with promoting two GPs, and that has paid off and has driven strong uptake within Europe. In the US, Trintellix has grown a little slower.
First of all, the market, it's has fragmented more. There's a lot more nurse practitioners, physician assistants, GPs prescribing in the MDD segment than there were before COVID. We do have a well-aligned sales force with Takeda, we are working strongly together, focusing on the efficacy of Trintellix, both through our sales force channel and the omnichannel approach to our customers. We are seeing new-to-brand prescriptions growing in Q2 versus Q1 of 2023. I'd remind you that during 2022, we did experience some disruption in promotion on this brand as we, together with Takeda, resized the sales force. Takeda was experiencing a loss of exclusivity on Vyvanse, both of us reduced the total number of reps that are promoting, but increased the profitability of this brand. Next slide, please.
Rexulti has been a tremendous performer for us in the first half. The US obviously has been the biggest market for a long time, given the approval in both schizophrenia and MDD, which we also have in Canada. We've seen that MDD growth, and we've talked about it in prior quarters, continuing in the US and Canada, and Brazil, but we are seeing some green shoots from the launch of Rexulti in agitation. The first, let's say, green shoot coming up in the spring is an increased utilization that we're seeing in the 65-year-old and older patient group. We don't get fully claims data until there is a lag in us getting that data, so this is the data that we have on hand to date.
We're also getting significantly interested prescribers and some prescribers who've already used Rexulti, reporting that they're seeing a tremendous change to the positive for their, for their patients and the caregivers. We're very encouraged about how this launch is progressing. The unbranded DTC was launched in the second quarter. The branded DTC campaign will launch in the fall, once approved through the FDA. Next slide, please. Abilify Asimtufii is launched in the US, and the overall franchise for Abilify Maintena and Abilify Asimtufii has grown strongly, and it's grown in all regions. The LAI market growth has continued, but we are penetrating that market with Abilify Maintena, and you see good growth in all our regions of the world. The Asimtufii launch was...
Abilify Asimtufii was really put into the market in June of 2023, we're very early in the process of that launch. We can already see that having that franchise together is lifting the overall aripiprazole long-acting business for us in the United States. I think with that, I'm going to be handing over to the first of my colleagues that's here with me today, Johan Luthman, our head of R&D. You take it away, Johan.
Thank you very much, Deborah. Let's take a look at the further information R&D. During the first half of 2023, and particularly during the second quarter, we had a rich flow of important positive R&D events. It has indeed been a very productive year so far. As Deborah already mentioned in her introductory comments, we had two approvals with FDA in the first half year, both of those together with our partner, Otsuka. The one I'd like to start with is the May 10 approval of the sNDA for Rexulti for the treatment of agitation associated with dementia due to Alzheimer's disease, for short, AA-DAD. This approval was preceded by a very supportive FDA external expert advisory committee discussion on April 14.
This approval constitutes a critical milestone since it's 20 years since FDA last time granted a full approval of any NME for the treatment of Alzheimer's disease. Moreover, this is the first ever approved treatment for agitation associated with dementia, and in fact, for any behavioral psychological symptoms of dementia. An FDA-approved treatment of agitation is a very important addition to the care of this devastating disease. In particular, since agitation is one of the most bothersome symptoms for patients to cope with, and not in the least their caregivers. In addition to the US, we have ongoing regulatory authority reviews of brexpiprazole for the treatment of agitation and dementia due to Alzheimer's disease in Canada, with the S ND S review with Health Canada expected to be concluded by the first quarter 2024.
Submissions have also been done in Singapore, Australia, and Switzerland through the so-called Access Consortium process. Approval in those three countries is anticipated during mid-2024. The second approval we had during the spring was on April 27 for aripiprazole 2-month ready-to-use long-acting injectable suspension for intramuscular administration. As you heard, it is now marketed in the US under the name of Abilify Asimtufii for the treatment of schizophrenia in adults or for the maintenance monotherapy treatment of bipolar I disorder in adults. Thus, the same population as for Abilify Maintena. The basis for that approval was a large and robust 32-week pharmacokinetic bridging study, while the efficacy of this product builds on adequate and well-controlled studies of Abilify Maintena.
As previously reported, this new extended-release formulation of aripiprazole has also been submitted to EMA for the indication on maintenance treatment of adult schizophrenia patients. The MAA review is progressing in Europe following resubmissions, a resubmission, which allows the CHMP to follow what they consider a more appropriate regulatory procedure. We have a current estimate for H1, first half of the year 2024, for finalization of that review. The S ND S review of this product submitted to Health Canada is ongoing, but with an extended review period. The product has also been submitted to Australia and Korea. The other major event during the first half of 2023, as Deborah mentioned in the introduction also, was the announcement on April 19th that we had a very encouraging positive readout of the first-in-class anti-PACAP monoclonal antibody 222 in the HOPE trial in migraine prevention.
I will get back to that in more detail. The next step for this exciting program is to progress to a phase two B trial in order to better establish dose range and route of administration. Finally, I like to highlight that we had released the new data on Vyepti from the DELIVER trial. The data further demonstrates not only the powerful action of the treatment of Vyepti, but also very nicely confirms its long-lasting migraine preventive effects. Let's take some further look at that data. Next slide, please. The phase three B DELIVER trial was evaluating the safety and efficacy of Vyepti in hard-to-treat patients with 2 to 4 previous treatment failures. The trial included an open-label extension phase. The patients had chronic or episodic migraine.
We have previously reported the placebo-controlled part of the trial, which showed a robust effect of the drug in patients that have been on other migraine prevention treatments. The open-label extension phase of the trial confirms the long-lasting migraine preventive effects of Vyepti and an excellent tolerability profile. As you can see on the graph to the left, at the time of switching all patients to active treatment, the time point, as you see here, indicated by a dotted line, there is a clear and rapid onset of the therapeutic effect on the number of migraine days in patients previously treated with placebo. This is followed by clear-cut therapeutic effects throughout the Vyepti treatment period, up to 18 months. In addition, the treatment during the open-label part of the DELIVER trial also reduced severity of headaches and reduced the use of acute medication.
Next slide, please. Naturally, we are very pleased with the performance of Vyepti as a fast onset of action migraine prevention treatment and how well it works in patients that have failed to respond well to previous treatments. However, with the results from the HOPE trial with our first-in-class anti-PACAP monoclonal antibody 222, we are looking forward to further build our efforts to deliver therapies for patients suffering from migraine, that not always find therapies that work well for them. It's not often in R&D that you get the chance to be part of a positive proof of concept readout, but the robust readout in the HOPE phase 2A trial is indeed a breakthrough for a new mechanism of action. 222 is a humanized IgG1 antibody against the receptor ligand PACAP, which is known to act through at least 3 different receptors.
The PACAP biology is quite broad. This program certainly adds an opportunity for Lundbeck to further expand not only our migraine franchise, but also may lead to us to contemplate the molecule's potential in other pain indications. The HOPE trial studied prevention of episodic and chronic migraine patients not helped by 2 to 4 prior treatments, quite similar to the DELIVER trial in design. The patients received IV infusion of low and high doses in a 12-week trial. The primary readout, which measures the number of migraine days at 4 weeks, showed clear statistical separations, separation against placebo. Both doses tested appear to work. The secondary endpoints were also supportive. 222 was also well tolerated.
The HOPE trial data will be presented at the International Headache Congress in mid-September, so we'll have the possibility to see more from this trial very soon. The path toward the HOPE trial was facilitated by early experimental medicine studies characterizing the target engagement in humans of 222. Moreover, we have previously shown good pharmacokinetic properties of 222 when given subcutaneously. We have the potential optionality in terms of route administration. A phase 2B study is currently being designed and planned to start in early 2024. Key aims of this upcoming trial is to establish subcutaneous efficacy and further explore the optimal dose range. Next slide, please. In this call, I also like to highlight 2 programs in phase 1 that are progressing well towards the possibility to initiate phase 2 proof of concept trials in the coming year.
First, some words about our differentiated CD40 ligand antibody-like drug candidate, 515. The role of CD40 ligand is well documented. It's assumed to play a key role in autoimmune diseases in which activated T and B cell cause pathology. The CD40, CD40 ligand interactions mediate T cell priming and T cell-dependent B cell responses and promote pro-inflammatory activities. By blocking the CD40 ligand and its interactions with CD40 and their co-stimulatory signaling, you can block the downstream effects on immune cells. Our drug candidate, 515, is a recombinant bispecific fusion protein that is not only binding to the CD40 ligand, but also the human serum albumin through the so-called SAFA technology platform. 515 aims to provide a long half-life. It's expected to show an improved safety profile due to the albumin binding.
The clinical development program for 515 was initiated in March 2022 and is progressing swiftly throughout the target engagement and dose escalation studies. phase 2 is expected to commence in 2024, where we'll explore several potential neuroimmune indications. We're really excited to bring forward this differentiated CD40 ligand binder. Next slide, please. I also like to talk a bit more about our D1/D2 agonist program in Parkinson's disease. It's a legacy program from our strong background in monoamine neuropharmacology. The new chemical entity, 996, is an innovative, orally available prodrug for the generation of a broad-acting D1/D2 receptor agonist. Through this mechanism of action, we aim to provide continuous dopamine receptor stimulation.
This is expected not only to lead to improved efficacy on reduction of off-time in comparison to other D2 agonists, but also improved tolerability against L-DOPA and obviously, substantially improved convenience compared to pump administration of the D1/D2 agonist apomorphine. 996 is progressing very well, and it's concluding its phase 1 this year with a solid data set that includes regular healthy volunteer studies, but also an open label experimental medicine investigation of its profile in patients with Parkinson's disease. We are planning to commence phase 2 trials next year with 996. Yeah, next slide, please.
Regarding other pipeline programs, I just like to remind you that I have previously announced that we finalized the recruitment into the two trials, Trial 071 and Trial 072, that are exploring the efficacy and safety of brexpiprazole in combination with sertraline in post-traumatic stress disorder. We are therefore looking forward to obtaining the data from the evaluation of the PTSD indication within this ongoing quarter. You hear that we are expecting to progress well also in the second half of the year with several interesting programs. This is naturally facilitated by our transformed R&D organization. We have now a strong presence in our four biological clusters. We are also fully employing experimental medicine studies supported by biomarker-driven clinical readouts for stringent go, no-go decisions and early de-risking.
Obviously, obviously, we are very happy that we have this year already been able to deliver on several critical late stage lifecycle management programs, such as Abilify Asimtufii and Brexpiprazole, in a new impactful indication for Alzheimer's disease patients. We are also importantly advancing very well in the further build up our mid-stage pipeline, with the potential to move 2 to 3 assets into phase 2 during 2024. With that, I'd like to hand over to Jörg.
Thank you, Johan. We have new microphones. Okay. Thank you, Johan. We continue to deliver an excellent performance with the strongest first six months revenue H. Lundbeck A/S has ever delivered. The +13% of reported revenue growth is driven by a growth of 10% in constant exchange rates coming from the strong underlying performance of all of our strategic brands. The positive FX effect is driven predominantly by the increase of the US dollar. The positive contribution from hedging is due to a narrowing of hedging rates versus actual rates year-over-year. Our gross margin is 1.3 percentage points lower compared to 2022, negatively impacted by the additional amortization of product rights related to the EU approval of Vyepti, as well as by the provision for Vyepti inventory obsolescence of DKK 245 million, recognized in the first half of 2023.
For that reason, it's much more insightful to look at the development in our adjusted gross margin. Adjusting for the aforementioned provision and the amortization and depreciation linked to sales, the adjusted gross margin in the first half of 2023 is higher by 2 percentage points, reflecting the positive sales volume development. Sales and distribution costs grew +14% at constant exchange rates. The increase is driven by higher Vyepti sales activity in the US, along with its global rollout in approximately 15 countries this year, as well as costs for the launch preparation of Rexulti, AAD. R&D costs declined by -14% at constant exchange rates, mainly impacted by the planned lower late development and reduced pace phase 4 activities for Rexulti and Brintellix, Trintellix so far in 2023 compared to 2022.
All of these effects contributed to an EBITDA growth of +19% at constant exchange rates. Our adjusted EBITDA that eliminates the provision for Vyepti inventory obsolescence actually grew by +32%, improving the margin by 7.5 percentage points to 33.4% compared to last year. Please bear in mind that approximately 3 percentage points of the margin improvement relates to the lower R&D costs as expected. Next slide, please. Our EBIT grew by +38% in reported rates, reflecting the high revenue growth and strong operating leverage, improving our margin by +3.9 percentage points. Our net financial expenses decreased for the first half to DKK 138 million.
The lower expenses are mainly driven by the non-recurring DKK 278 million fair value adjustment of the CVR to all the shareholders in Q1 last year, triggered by the Vyepti EMA approval and of course, lower debt levels. These are partially offset by higher foreign currency exchange effects. The effective tax rate has increased to 23.5% compared to last year's 22%, in line with full year expectation, reflecting the reduced deduction from the Danish R&D incentive. Net profit increased by +61% to DKK 1.5 billion. Adjusted net profit increased by +36% to DKK 2.5 billion. The adjusted EPS growth is in line with the underlying performance after adjustments relating primarily to the amortization of product rights and the fair value adjustment of CVR to former Alder shareholders in Q1 2022. Next slide, please.
The cash flows from operating activities landed at an inflow of DKK 1.6 billion in the first half of 2023, compared to an inflow of DKK 711 million last year. The operating cash flow is, of course, a reflection of the strong EBIT performance, further benefited by higher adjustments for non-cash items of DKK 1.4 billion, which is driven by higher amortization in 2023 and the provision for Vyepti inventory obsolescence, negatively impacted by higher change in working capital of DKK 1.5 billion. This is mainly driven by increased receivables, driven by higher sales and increased inventory, primarily driven by Vyepti inventory buildup due to the fixed term agreement that expired mid-year 2023, partially offset by changes in short-term liabilities. The cash flow from investing activities were an outflow of DKK 265 million, driven by paid out sales milestones.
Just for your reference, the first 6 months of 2022 in comparison, included an outflow of DKK 1.2 billion for the CVR payment to all the shareholders. The cash flow from financing activities were an outflow of DKK 1.3 billion in the first half, compared to an inflow of DKK 480 million in the same period last year. This is primarily driven by the continued repayment in 2023 of the last part of the 2022 loan connected to the CVR payment to all the shareholders, and of course, the higher dividend payment in 2023 connected to the improved net results in 2022.
Our net debt position continues to develop very favorably lands at DKK 1.4 billion in the first half of 2023, compared to DKK 4.3 billion the same period last year, reducing the leverage to 0.3 for the rolling four quarters, continuing our progress of deleveraging the company. Next slide, please. Lundbeck raises its full year guidance on revenue to DKK 19.5 billion-DKK 20.1 billion, while at the same time increasing the adjusted EBITDA to DKK 5.2 billion-DKK 5.6 billion. The raised guidance is reflecting the strong momentum of our strategic brands, which is expected to continue in the second half, despite the continued erosion of the mature brands. We expect at current exchange rate levels, a positive hedging effect of approximately DKK 135 million due to more favorable hedging rates in the second half.
We have some timing effects in the first half of this year from which the mature brands benefited. However, we see, especially around Cipralex, Lexapro in Japan, Deanxit in China, and Sabril in the US, a bit more of a faster erosion in the second half of this year. From a profit perspective, let me reiterate the following: The forecast of amortization of product rates remains unchanged at approximately DKK 1.6 billion for the full year. The expectations on sales and distribution costs reflect the necessary investments in the important launches of Vyepti in approximately eight additional markets, Rexulti for ADHD, and the Abilify LAI franchise. R&D full year costs are expected to be broadly stable, considering higher investments in the second half of 2023, mostly to develop clinical material ahead of planned initiation of clinical study.
Finally, as previously mentioned, the provision of approximately DKK 300 million of Vyepti inventory obsolescence is reflected in the guidance for 2023. With that, I hand over to Deborah.
Thank you, Jörg. It's great to be able to report such strong momentum in the business. We have made progress in maximizing our strategic brands. Those four brands... grew in aggregate 18%, and it's great to see momentum across the world and across the brands. The Vyepti global rollout is on track with 9 more markets to come in the second half of this year, and we're looking forward to the momentum building in those recent launches in the US I think it's fair to say that R&D has had the most productive first half in, I'm sure Lundbeck's history. We look forward to the PTSD results coming in the balance of the third quarter, 2023.
We've made good progress with a very high potential early development portfolio, rebuilding the phase 2 pipeline and potentially more molecules entering that in, in 2024. Also some very interesting additions to the phase 1 portfolio coming in. That is coming out of the transformed and highly innovative research portfolio. We've seen an improved profitability in the first half, but as Jörg has said, we do expect higher spending in the second half, given that we have the full load of the launches, the costs coming in the second half, and we anticipate the startup costs for some of our phase 1 and 2 trials, notably the, the preparation of the monoclonal antibodies, to make R&D costs higher in the, in the second half than the first, given that we finished a large number of phase 3 clinical trials during the first half of 2023.
We have been able to raise the financial guidance, given the strong momentum in the strategic brands, in spite of some headwinds on some of the mature brands in the second half of the year. Lundbeck is extremely well positioned to deliver sustainable, profitable growth for some years into the future. It is with great pride that I look back at the five years that I've had with Lundbeck. As you know, next slide, please. We have announced that I will be leaving Lundbeck at the end of August. Charl van Zyl will join us as of the 1st of September 2023. He brings a lot of experience in the neurosciences from various experiences within the industry, most recently at UCB. Of course, he has to be good because he's South African. With that, I, gonna bring this to a close. A great, great first half for Lundbeck in 2023.
Now we'll open the floor to questions, and in addition to Johan and Jörg being with us, we also have Jacob Tolstrup, who you know, very well, and Thomas Gibbs from the US, who you're getting to know very well, who I'm sure you will have many questions for. With that, let's have the first question.
Ladies and gentlemen, at this time, we will begin the question and answer session. Anyone who wishes to ask a question may press Star followed by 1 on the touchtone telephone. If you wish to remove yourself from the question queue, you may press Star and 2. If you are using a speaker equipment today, please lift the hand before making your selections. Anyone with a question may press Star and 1 at this time. Our first question comes from Michael Novod from Nordea. Please go ahead.
Thank you very much, Michael Novod from Nordea. 2 questions, please. 2 in opposite directions. First of all, on Trintellix. It's sort of a never-ending story around continued slow sales performance, and still you're trying to do whatever it takes to amp up your efforts with the Takeda and reorg on the sales force, et cetera. How should we be thinking about this in sort of the next 2 to 3 years? Is it just that it's at best flat or perhaps even gradually declining in the US? On the other side of with regards to Rexulti in Alzheimer's agitation.
I recall you've been saying, something like $500 million-$800 million in alliance sales or up to $1 billion, but your partner is saying significantly higher numbers if you calculate on their assumptions for penetration rates in AD in the US. Are you willing to sort of give a bit more flavor to how you see Rexulti in AD develop over the next five, six years? Thank you very much.
Thank you, Michael. Tom, would you like to start on Trintellix?
Sure. Sure, Deborah. Thank you, and thank you for the question, Michael. As you saw, the top-line number was a 7% decline during the first half of 2023 versus first half of 2022. However, I think it's important to recognize that there is some noise in the revenue line with some gross-to-net adjustments that did occur. What I'd like to do is focus on demand, which I believe is the most important element to understand brand performance. Demand for the first half of 2023 did decline by 3% versus the previous year.
As Deborah had stated, and I think it's important to put into context, back in the first half of 2022, our alliance partner, Takeda, who is responsible for 80% of the promotion for Trintellix, did downsize their sales and marketing investment in Trintellix in response to the Vyvanse going off patent, and this was with a goal of increasing profitability for Trintellix. Lundbeck also adjusted the promotional levels of our sales and marketing efforts to reflect the revised sales and marketing investments of our partner. These type of adjustments, as we've talked about previously, do cause some disruptions, especially when you're looking at it through the lens of our customer-facing model. As Deborah had stated, the strategic choice did achieve the intended objective of increasing profitability of the brand.
However, not surprising, this strategic choice has created some pressure on the top-line demand, which you normally see for a late lifecycle product emerging at 6 to 12 months, and that's what we're seeing now. As we've talked about, Lundbeck is working very, very closely now with our partner, Takeda, to ensure that we have our rebased resources optimally deployed from a sales point of view, from an omnichannel point of view, to reignite growth from these levels. We're starting to see some positive signs, albeit early, when we look at first quarter 2023 to second quarter 2023, where we did see an increase in both TRx and NBRx.
Great. Thanks, Tom. On Rexulti, what we have said is that we believe that across the alliance, gross sales, this product in this indication will achieve over $1 billion. We see this as an immense opportunity for the brand. We're investing as a big opportunity, and we intend to grow it as far as possible. Can it be bigger than that? Possibly. This is a very high unmet medical need, and we certainly will do all that we can to grow the market. Maybe, Tom, I'll hand over to you to talk about how we're thinking about that growth and how things are going.
Yeah. Thank you, Deborah. I think if we look at it based upon the work that we did pre-launch to understand the market and our experience in the market since approval, we believe that there is a substantial unmet need that exists within the AAD market, and we are aligned with Otsuka that there is a significant opportunity for this brand with AAD/AD. Lundbeck, along with Otsuka, are committed to investing the necessary resources to maximize this opportunity. When we think about our first priority to be able to deliver on this opportunity, it's really about driving market penetration of Rexulti in the current diagnosed and treated patient population for AAD/AD.
This is gonna take significant efforts, as we've talked about, in terms of raising awareness and appreciation from both physicians as well as caregivers about the prevalence, the disability associated with this disease, and most importantly, now that there's an FDA-approved agent to treat this debilitating disease.
Thanks, Tom, and thanks, Michael. Next question?
The next question comes from James Gordon from JP Morgan. Please go ahead.
Hello, James Gordon, JP Morgan. Thanks for taking my two questions. First question was R&D spend, and maybe one for Jörg. You reiterated the guidance for broadly stable R&D in 2023, but I noticed R&D was down 14% in H1, and I heard the comment about preparing some antibody trial material for H2, but that, that seems like a lot for R&D to be stable. Can you break out how much extra spend is there gonna be on preparing trial material in H2? Could it be the guidance is also including room for you to do some in-licensing and spend a lot more on R&D on projects that you don't yet have?
It's the first question, if you can help us better understand where this extra R&D is gonna come from in the second half, please. Then the second question for Deborah, as you retire from Lundbeck, thanks for humoring all my questions over the last few years. My question is, you've given a guidance for strong medium-term performance in the company, how are you seeing the company position longer term, so beyond the next 3 or 4 years? Do you think the growth can be maintained, or should we be thinking of a significant slowdown? What do you think the key challenges are gonna be for trial, please?
Okay, thanks, James. I'm gonna hand over to Jörg first.
Thank you, Deborah. Well, I think we don't break out specifically what is the CMC element out of clinical trials. I think if you go back to the presentation from Johan, we talk about a very promising pipeline with a number of projects that basically we bring forward. You talk in the end of the day on starting of trials as well as starting on clinical material. Plus, on top, don't only think that, you know, investment is tied to clinical trials and CMC. You also have ongoing significant trials that also have quite some milestones to achieve in the second half of the year, especially around our Vyepti in Asia program.
Great. Thanks, Jörg. James, looking a bit. Thank you for the question. You always have entertaining questions, and this is a good one. Lundbeck is well-positioned as we go forward with these four strategic brands, and we are gonna be growing mid-single digits through the middle of the decade. We have a pipeline now that is building to bring in a number of opportunities that have multi-indication potential. From within our own pipeline, we would see towards the end of the decade, some of those coming into play. We have always said that our business will be built in both internal and continued external licenses, partnerships or M&A. With a preference for the sort of bolt-on M&A. That's, nothing has changed about that.
I think what you've seen over the years at Lundbeck, before I arrived and since I arrived, is that the management working together have been very successful bringing in good assets through the years. From, you know, the Ovation acquisition, the Chelsea acquisition, the Otsuka partnership. There's a number of successes. We've had I, I believe, a great success with the Alder acquisition. Of course, that's still growing and adding to our portfolio. The future will, in some ways, be that of the past, that our business will build from the inside and the outside, which the company has successfully done over many years. I would say, bet on Lundbeck to continue growing.
Next question, please.
The next question comes from Marc Goodman from Leerink Partners. Please go ahead.
Hey, guys, First, can you give us an update on 909 and how you see that product differentiated versus some of the competition that's a little bit ahead? Then can you just give us a little more color on the agitation indication and you know, just the confidence that you're actually seeing some uptick because of that indication. You mentioned something about some data that you had. I was wonder if you can go into a little more detail on it. Thank you.
Sorry, you were a little hard to hear there, Marc, but I'm going to ask Tom to start on the agitation question. Did you hear it adequately, Tom?
Yep.
Then, Johan, you can comment on the pipeline asset.
Thanks for the question, Marc. As we all know, it's still very early in the launch, I would say that the launch is progressing as we expected. I'll first speak from a quantitative perspective. As I stated during the last earnings call, the best data that we have to look at until the claims data become available is the 65 plus weekly TRX data, which Deborah spoke about during her presentation. These data suggest there's a meaningful uptick in this segment, which is having, in my view, a positive impact on the overall brand performance. I think as you probably have seen, for the week ending July 21st, Rexulti achieved its highest record to date, TRX share, highest NRX share, and we also achieved our highest recorded new-to-brand prescriptions.
All very positive signs, both from the 65+, but also, more importantly, on the overall brand performance. I think from a qualitative perspective, our experience is that to date, is that it confirms that the AAD, AAD market is a large opportunity with significant unmet need. However, and we've talked about this, it's also a nascent market that's going to require developing this market both from a Lundbeck and also with our partner, Otsuka, and we are committed to making those necessary investments to make the... this a truly substantial opportunity for Lundbeck and Rexulti.
Thanks, Tom. Over to you, Johan.
Yeah, I believe you asked about 909. Can you confirm that? Yep. Okay. That's the program I didn't talk about in, in this presentation today. That's the anti-ACTH antibody that we got through the Alder acquisition, and we're taking that into man. It's being evaluated in congenital adrenal hyperplasia patients right now, and we are progressing well with the dose panels there. It's a really exciting program. I couldn't talk about everything we do in phase I. It's little behind the ones I talked about that are more closer to phase II starts. It's not so substantially behind because this is obviously a mechanism going for the so-called HPA axis and going for hormonal modulation. We go quite quickly into patient studies and expanding patient studies.
What we've seen so far in the very early, early data we obtained are actually very promising findings. It looks like it's very much a molecule that is alive.
Thanks, Johan. Next question, please.
The next question comes from Dominic Lunn from Credit Suisse. Please, go ahead.
Hi, thank you. Following on from the earlier question on costs, clearly the adjusted EBITDA Q2 was much better than the market expected, and guidance was raised only modestly. That kind of implies a step up of cost into the second half. Would it be fair to assume that the second half cost level is a good proxy for next year, given you'll still be needing to support the launches and fund R&D? Could you also provide an update on the timing of the transition to the lower cost cell line for Vyepti production? Secondly, on the overall Abilify franchise, there are a number of moving parts looking forward.
We'll see the team of formulation ramping up, the European LOE for the Maintena version, kicking in from 2025, and then, you know, US LOE potentially after that. How could we think about the sales profile for the rest of the decade, given the moving parts, i.e., can we expect continued year-on-year growth for the franchise? Or should we factor in some erosion in the latter part of the decade from the generics? Thank you.
Great. Jörg, would you comment on the cost profile?
Yes, absolutely. I think you, you had a couple of questions. I think the, the, the first one was, why is the adjusted EBITDA in the first half better than consensus and probably growing a bit stronger than EBIT. First of all, keep in mind, we have booked DKK 245 million of inventory obsolescence. We originally guided towards more than DKK 200 million for the first two quarters. We're not changing the full year guidance that remains in place at DKK 300 million, but you had a bit of higher adjustments than originally anticipated in Q2 around the Vyepti inventory obsolescence. The second piece is we also had pretty much DKK 15 million of restructuring costs we booked, due to the closure of a sterile plant in France. These adjustments you have probably not to the full extent, factored in.
The second part of your question was, I think, around phasing. We've always talked about fully supporting the launch of ADAD in the US, and having had launch commencing in May, you see predominantly the full launch costs in the second half of this year. Of course, you have a little bit as well in H1 because you start to hire reps, et cetera. Of course, the guidance reflects, as originally communicated, more of a spent level in the second one. I don't think we give further guidance on SG&A ratios next year. With that, I would hand over to Johan around your question on the transition.
Yeah, if it's a more technical- Yeah, if it's more a technical scientific question, I can answer. It's also of course, a cost estimate in this, but I think it's very important to say that we're progressing well with this. The CHO cell switch from Pichia pastoris, which is the yeast cell manufacturing platform we have right now, to the Chinese hamster ovary platform, is a critical one because that brings us into a much more established type of cell platform to work on. We have generated very, very strong in vitro data, The pharmacocataract characterization of the drugs are really supporting very much what we're doing, but at the end of the day, it's really a data-driven and regulatory-driven switch. When I say this is all going well, I think we are looking forward to see that switch occurring in the coming year.
Yeah, one thing I would, I would add on, on that switch. Remember, we have this contract that delivered all of the Pichia supply within 5 years, that is just sunsetting now. It is our intention to utilize as fully as possible, that Pichia supply before transitioning to delivering on the CHO supply. I think, I think you should also bear that in mind. And then on the Abilify franchise, would you like to comment from the US and perhaps you from the ex-US perspective, Jakob?
Sure. Thank you, Deborah, and thank you for the question, Dominic. As we see the Abilify long-acting injectable franchise, we see this as a important growth lever for the US over the coming years. The addition of Abilify Asimtufii has really enhanced the overall clinical value proposition that we bring to physicians and patients. We see this as an important contributor to growing the overall franchise.
Great. Over to you, Jakob.
Yes, similar comment also from my side. It's an excellent addition to our franchise, and I think there will be many patients that will be suitable and will benefit from a 2-month version. Longer term, I think that was also part of your question. We have had tremendous success with the Abilify Maintena 1-month, and I think it would be too much to hope for that you can expect the total franchise to continue to grow once we see generics on the 1-month, when and if that happens.
Next question, please.
The next question comes from Charles Pitman from Barclays. Please go ahead.
Hi, Charles Pitman from Barclays. Thank you very much for taking my question. Could I just ask on Rexulti, as we're coming up to the readout of the PTSD trial, whether or not you could just give us any more insight into how confident you are on the potential for a positive result from this trial, what you're really looking forward and for in terms of a benchmark result? And maybe if you could speak to what your expectations could be in terms of any sort of commercial opportunity for the indication relative to the other indications Rexulti was already approved in. And then just secondly, on Vyepti, looking at that global...
The geographic rollout chart, I was wondering if you could just dive a little bit more into the key differences of growth for Vyepti share in Europe and why Germany and UK share gains seem a little bit more limited, whether or not there's kind of anything we need to appreciate here in terms of increased competition and whether or not you can really get to that same level of share seen in those other geographic areas. Thank you.
Thank you. I think, Johan, you can start on the PTSD clinical side, and then Tom on the opportunity, and then Jakob will take, the Vyepti question.
I've been commenting on this before several times, obviously, I can add a little bit more element to it, but not much. As I said, we finished the enrollment, and we are just waiting for getting the results. It's really, it's too late to speculate. It could be 0%, it could be 100%, and nothing in between, right? There could be a gray zone version, of course, because there are two trials ongoing. Important for all these kind of estimates, what could work out and not work out is prior information, and that's what I've been talking about before.
For the Alzheimer's agitation indication, we had a substantial prior information and very, very solid data package already from two prior big trials. Here we are working with much less from an exploratory phase two trial, so it's definitely coming with higher risk as it does when you have less prior information.
Over to you, Tom.
Thanks, Deborah. If the data are positive, we do see PTSD as a meaningful opportunity to really enhance the overall value proposition of Rexulti. If we think about the magnitude of the opportunity, I think we start with the prevalence of PTSD, which is about the annual prevalence, about 3.5% in the US, and that compares to an annual prevalence of 8.3% for MDD, and then something right around 1% if you look at schizophrenia and schizoaffective disorder. We see the magnitude of this opportunity between that of the schizophrenia indication as well as the MDD indication.
Great. Thanks, Tom, and over to you, Jakob.
Yep, on Vyepti, we've been showing the volume market share is always good to give an indication of the progress and the performance in the different markets. It's also important to say that every market is different, and a volume market share can be distorted in different ways. One example being Germany, where our competitor, Aimovig, had an expansion of the market due to a clinical trial they did, and that means that the whole market has grown tremendously in Germany, but it also mean that our market share looks more depressed than, than for other markets. I would say both for the UK, and Germany, we are ahead of our internal plans.
Great. Thank you. Next question, please.
The next question comes from Michael Leuchten from UBS. Please, go ahead.
Thank you. 2 questions, please. Deborah, just interested in your comment on the US rep count. Do you think that is a Lundbeck Takeda specific issue, or is this actually more broad across the industry as everybody try to go down the digital path and is now figuring out that boots on the ground is actually the, the more effective way of, of marketing products in the US still, whether we like it or not? A question for Johan, PACAP, you're very firm that this is a phase 2B that you're thinking about. So is that a plain vanilla phase 2B dose range study, or is this a potential phase 2B/phase 3 trial design that would still allow you to accelerate the program? Thank you.
Thanks a lot, Michael. I'm actually going to ask Tom to comment on the Trintellix and the sales force question.
Sure.
for you.
When we look at Trintellix, we may have talked a little bit about the rebasing of our overall sales force footprint, I see that as more of a surrogate for the overall promotional spend that we put behind the brands. I think philosophically, what we do know is that the sales force continues to be an important element to the overall marketing mix, but it is, it is not sufficient, and we are seeing greater efficiencies and effectiveness with complementing sales force efforts with omnichannel customer engagement.
Thanks, Tom, over to you, Johan.
Yeah, thanks for the question. Yeah, we call it phase 2B because we're actually shifting the exploration now from an IV dose that we had prior in the POC, HOPE POC trial, and now to a sub-Q exploration. It's an element of sort of technical transition here. Of course, we have good data to support that transition, but there is a certain element in this, so we're not rushing into a pivotal trial directly based on that shift. Obviously, we need to find the dose range that is most fitting for the product. Whether we're going to have 1 or 2 doses eventually in a phase 3, that's still up for discussion, but we really like to make sure we're picking the right doses. That's why we call it 2B. The shift.
I mentioned that we're still sort of working on the design, so the shift between the two could be within the same protocol or two different protocols. That's always possible. I think we like to have a clean data set first on the sub-Q and the dose range before we really make any further decisions.
Great. Thank you. Next question, please.
The next question comes from Vineet Agarwal from Citi, please. Go ahead.
Yeah, hi. Thanks for taking my question. Just one more on Rexulti. I think in the past, you said that the transactional data shows that the utilization for ages about, you know, 65 and above, has been pretty consistent around 12%-14%. I was just curious if you can, you know, share some, any sort of, utilization data for the AD indication launch. The second question was just on Vyepti. Wanted to check if you can provide us any sort of updates on the SUN studies and the ALLEVIATE cluster headache trial. When should we expect to hear more on these 2 trials? Thank you.
Hey, hey, Vineet, we were really having trouble hearing you. I make out that there's a question on ADAD and one on Vyepti, but we really can't tell what the questions were. I don't know whether you're on a headset and you can take it to get a better connection, but could you try to repeat your question?
Is it better now?
Yes.
Yes.
I, I was just checking on the. In the past, I think you said that the transnational data shows the utilization for ages 65 and above to be pretty consistent, around 12%-14%. I was just curious if you can share any part of, you know, utilization data for the AD indication launch. Secondly, on Vyepti, I was wondering if you could provide any sort of update on the SUN studies and the ALLEVIATE cluster head trials in terms of, you know, when should we expect to hear more on them?
Great. I'm gonna have Tom start on the update on the ADAD.
Thank you for the question, and you're right. If we looked at the overall utilization for 65-plus prior to the indication, it was teetering between 12% and 14%. What I can say, and you saw within the data that was shown by Deborah, is that there's been a meaningful and significant increase in the overall 65-plus utilization.
Johan, when can we expect to hear data from the cluster, CHRONICLE and ALLEVIATE?
If for the cluster indication, which obviously is an attempt to have an indication expansion, really go into new indication, which has been a really, really hard indication to crack the nut on. Several of our competitors have struggled with this, and it's also a hard indication to run, quite frankly, trials in. But we have 2 trials ongoing, the CHRONICLE and ALLEVIATE trial. The CHRONICLE is in chronic cluster headache and the ALLEVIATE in episodic. Both trials are basically ongoing. We're waiting for data to see out of some of these trials. That's going to guide us in the future.
Next question, please.
The next question comes from Manos Mastorakis from Deutsche Bank. Please go ahead.
Thank you for taking my question. Question on the CD40 asset. I want to clarify if that is going to be a single trial, but a basket trial, including multiple indications, or if it's going to be multiple phase IIs? Basically, what are you, what are you thinking in terms of which indications that will include, in general as well on CD40, what can we expect in terms of readouts? Thank you.
Thanks, Johan.
Thanks for that question. As you heard, we are very excited about this molecule. When, when it comes to technically progressing this forward, we are contemplating a number of new immunology indications and, yeah, I'm a big fan of the basket trials if it's possible. When you go through the indications we are contemplating, they are pretty distant from each other. In basket trials, you have generally a benefit of when you have similar readouts and a similar sort of disease course. That's the benefit of doing basket trials when you have very closely associated indications. Here we're contemplating more distant from each other, so it's most likely going to be separate patient studies that we're going to initiate. In terms of what indications, we are going to gradually look through a big box of various things.
As you know, there are prior information in this field that we obviously take care of and look at carefully, but, we also like to explore new indications here.
Great. Last question, please.
The last question comes from Susanna Kreckburna from SHB. Please go ahead.
Hello, Susanna Kreckburna, Handelsbanken. I'd like to ask about the monthly fluctuations that you have in your Vyepti sales. When you look at the US hospital data, is this down to hospital purchasing patterns, or is there any seasonality when, when patients actually seek treatment in hospitals? Perhaps you can give us a bit more than insight here on Vyepti. The second question relates to the mature brands. You said that you're seeing fast erosion in the second half. Perhaps you could expand on this and specifically how we should think about that going forward.
Great. Tom, will you take the Vyepti question and Jörg, the mature brands?
Sure. When we look at the performance of Vyepti over the course of the last seven months, what we have seen is a continuing strong momentum upwards in terms of overall demand. Now, there could be some fluctuations, for example, when a price increase is taken, where you could see some additional purchasing prior to a price increase, but as it relates to any seasonality, we just don't see that in the, in the data.
Jörg?
Well, your question regarding mature brands, I think it has in, in principle, 2 components. The first component is that, yes, we see a bit faster erosion, especially in Cipralex, in Lexapro in Japan, in Sabril and in Deanxit in China. Then, of course, mature brands are always a bit impacted by timing effects. Timing effects related to governments tendering a full year volume already in the first half or changes you have in your distributor structure. There are certain timing effects also in the Q2 numbers. I think if we would specify a number here, we would probably talk around DKK 100 million-DKK 200 million, that we may not see materializing in the second half besides the topics I just mentioned on Sabril, Cipralex, Lexapro, and Deanxit.
Great. With that, I'd like to thank you for your questions, for attending the Lundbeck first half results. It has been my privilege and pleasure to work with this team at Lundbeck and also to meet and answer your questions over the years that we've interacted. I appreciate your continued interest in Lundbeck and bet on Lundbeck to drive the frontier in neuroscience and to grow.