Q4 2021 Pharming Group NV Earnings Call

I have here with me our CFO , Jeroen Wackermann, and our Chief Medical Officer, Anurag Rellom. We will be taking you to a conference, to a short presentation. Of course, there's questions and answers afterwards. But before I do that,

I have here with me.

Our CFO , Don will come on and our Chief Medical Officer underwriting.

We will be taking you to our conference to a short presentation of course is <unk>.

<unk> announces afterwards, but before I do that I would.

I would like to take a look at the next slide with the forward-looking statements, as we will be making some forward-looking statements that are based on our current beliefs and assumptions and expectations. And those can obviously, as you know, change.

Like to look.

You take a look at the next slide over to forward looking statements as we will be making some forward looking statements that are based on our current beliefs assumptions and expectations and those can obviously as you know change.

So let's just move on to the next slide and then there you see some pictures of of us and maybe we can move on to slide number four there as well so that.

So, let's just move on to the next slide and then there you see some pictures off.

Of us and maybe we can move on to slide number four as well so that.

And what are we? We are a well-funded business, and we are very happy, of course, that we are supported by a strong commercial sales operation on both sides of the ocean, of the Atlantic Ocean. And we have a growing pipeline for rare and ultra-rare diseases with a medical need. And our lead product, as you have seen from the press release, recorded $199 million of sales in 2021.

And.

What are we are we are a well funded business.

And we are very happy of course that we are supported by a strong commercial sales operation.

Both sides of the ocean of the Atlantic Ocean.

And we have a growing pipeline for rare and ultra rare diseases with unmet medical need and our lead product as you have seen from the press release and a recorded $199 million of sales in 2021.

and we see that, so we continue to see over the years, that more doctors are prescribing Rukines, and that was again the case in 2021, and more patients are using Rukines, so there is definitely a positive underlying continuing trend in the use of Rukines. And then we are very excited because we're at this point

And we see that so we continue to see over the years that more doctors are prescribing <unk> and it was again the case in 2021 and more patients are using <unk>. So there is definitely.

Positive underlying.

<unk> trends in the use of and the use of <unk> and then we are very excited because we are at this point in time for.

For the second time in our company's history, the last time was in 2013, we are in position

For the second time in our company's history.

Last time was in 2013.

In position.

of positive results from a pivotal trial for a new compound. So that means that we are looking to actually be able to, within a year from now, subject, of course, to approval of the product, to go into the market with our second product, Laniolisib, for the treatment of another orphan disease, APDS, which, of course, is a significant change for the company. Because last time when we had this, the company was in dire straits, and we did not have the product in our own hands.

If positive the results from our pivotal trial.

<unk> new compounds. So that means that we are looking to actually be able to within a year from now.

Subject of course to approval of the product to go into the market with our second product <unk> for the treatment of another orphan disease, a pds, which of course is a significant change for the company because last time when we had this the company was in dire Straits and we did not have the product in our own hands.

Now we have this commercialization capabilities on both sides of the ocean. We have a very strong balance sheet and we can actually have been already as you have seen from the results investing seriously into the preparations for launch because we can do it ourselves now.

Now we have this commercialization capabilities on both sides of the Ocean. We have a very strong balance sheet and we can actually have been already as you have seen from the results investing seriously into the preparations for launch because we can do it ourselves now and the good news is when you have a commercialization operation already the marginal cost, albeit star Sigma.

And the good news is, when you have a commercialization operation already, the marginal costs, albeit are significant, are not nearly as significant as when you have to do this the first time. So we're very excited about this prospect and Anna Ragwell, especially here, we'll talk a lot more about Lenny-Elizabeth later in the presentation.

Are not nearly as significant as when you have to do is the first time. So we're very excited about this prospect and anorectal Allen, especially here will talk a lot more about <unk> later in the presentation.

Anna Ragwell: We are, in addition to that, we are able to, because of our strong commercialization results and the continuation of that, we're able to actually leverage in-house expertise to drive further R&D, including continuing to hunt for additional in-licensing opportunities that are around for late-stage compounds, and also we're able to work on early-stage compounds, for

We are in this in addition to that we are able to because of our strong a commercialization.

<unk> and the continuation of <unk>, we're able to actually leverage in house expertise to drive further R&D, including.

Continuing to hunt for additional in licensing opportunities.

Around for late stage compounds and also we're able to work on early stage compounds for instance, OTR 105, which we in licensed from <unk> Therapeutics, a potentially curative gene therapy for Terry Angioedema, Twitch and record revenue.

Anna Ragwell: OTR 105, which we in-licensed from Orchid Therapeutics.

Speaker Change: a potentially curative gene therapy for Erythraea angioedema, to which Anurag Reland will talk a little bit later as well.

A little bit later as well.

Speaker Change: So we're very pleased with both results and with where the company is. And we think this is a historical moment for the company as we turn into, we start turning into a different a different company that is not only relying on this one product, one market combination, but is looking forward to build a business in the European side of the ocean as well.

So we're very pleased with both results and with where the company is and we think this is a historical moment for the company as we turned into start turning into a different a different company that is not only relying on this one product one market combination, but as looking forward to build a business in the European side of the ocean as well.

Speaker Change: And how are we going to do that? And then the next slide you see three pillars here.

And how are we going to do that and then the next slide you see the three pillars here.

Speaker Change: The left one is the commercialization pillar, where, of course, not only Rukiness will continue to be rolled out in additional countries, as you have seen earlier this year, but also where commercialization of APDS.

The last one is the commercialization pillar we're of course, not only <unk> will be continue to be rolled out in additional countries. As you have seen earlier this year, but also where commercialization of Aps is important with with linear obviously and then in the middle you see that importance.

Speaker Change: is important with Lemionis. And then in the middle, you see that important pillar here, where we look for near-term expansion of the portfolio.

An important pillar here, where we look for near term expansion of the portfolio with rare or ultra rare diseases with in licensing or acquisition of late stage assets.

Speaker Change: with rare or ultra-rare diseases within licensing or acquisition of late-stage assets in the rare or ultra-rare.

Rather ultra rare diseases.

Speaker Change: But also, of course, the development of C1 inhibitor in subsequent indications, but also PI3 kinase delta, i.e. laniolacep, has some interesting prospects of additional indications where the compound could be developed for, because there was already a lot of research done by Novartis in research collaborations to look at additional indications for this compound. So we believe there could be potentially more in the future for laniolacep as well.

But also of course the development of C. One inhibitor in subsequent indications, but also <unk>.

<unk> kinase Delta E Lenny ownership.

<unk> has some interesting prospects of additional indications where the compound could be developed for because that was already although the research done by Novartis.

And research collaborations to look at additional indications for this compound. So we believe that could be potentially more in the.

And in the future, Florida for linear ownership as well and then we have an interesting genetic testing effort going on before identification of <unk> patients and we are building gradually building up a database of genetic genetic profiles of patients that have undergone this genetic test so where we can see patterns in other.

Speaker Change: And then we have an interesting genetic testing effort going on for identification of APDS patients and we're building, gradually building up a database.

Speaker Change: of genetic profiles of patients that have undergone these genetic tests, where we can see patterns in other genetic mutations and other primary immune diseases.

<unk> genetic mutations and other immune disease other primary immune diseases, which have not been.

Speaker Change: which has not been properly diagnosed yet that can direct them and that's the third pillar for the long term our business development efforts into the direction of new identification of new primary immune deficiency opportunities and direct our colleagues and business developments to look for such assets.

Pretty diagnosed yet that can direct and then thats a third pillar for the long term.

Our business development efforts into the direction of new identification of new primary immune deficiency.

Opportunities and direct to our colleagues and business development to look for such assets.

Speaker Change: or develop them ourselves in the very long term. And then you see under that pillar as well.

Or develop them ourselves in a very long term and then youll see on the doctor as well.

Speaker Change: development of OTL 105, the ex vivo and potentially revolutionary hematopoietic stem cell gene therapy for hereditary angioedema. And last but not least, from our own platform, the alpha-glucose-based program for pompous disease.

The development of <unk> 105, the ex vivo and potentially revolutionary here, how much worth extend cell gene therapy for <unk> and lost northeast from our own platform.

After glucose today's program for complex disease.

Speaker Change: So let's just take a look back at what happens during 2021. And you can see that on the next slide.

So, let's just take a look at I look back at what happened during that 2021, and you can see that on the next slide.

Speaker Change: You see, we've been able to expand the reach of Ruknest. Now, we all know that in Heritage and Jodima, because of historical reasons, outside of the United States, the commercial opportunity is not so significant, but we believe investing in extending the presence of Ruknest is not only helpful to be able to sell more Ruknest, albeit for relatively

You see we've been able to expand the reach of <unk> now, we all know that inheritor angioedema because of historical reasons.

Outside of the United States, the commercial opportunity is not so significant because we believe investing in extending the presence of <unk> is not only helpful to be able to sell module goodness, albeit for rare disease.

Speaker Change: modest commercial returns outside of the U.S., but also to put our organization down and build networks in the markets ahead of the launch of Lanyosit, because that will be a very different story, there will be no price referencing, there will be no additional

Modest commercial returns outside of the U S. But also to put our.

<unk>.

Our organization down and build networks in the markets ahead of the launch of <unk> because that will be very different story, there will be no pricing price referencing there will be no.

Speaker Change: there will be no competition in that market and basically you know when we are in that market it's easier to access. So do you see North Africa, the Middle East, Spain that we actually reached out and we're further we're working still on further expansion of the farming presence in some of the other European markets in 2022.

<unk>.

There will be no competition in that market and basically when we are in that market is easier to access. So do you see North Africa, the middle East, Spain that we actually reached reached out and were further we are working still on further expansion of the roof of the farming presence in some of the other European markets in.

2022.

Speaker Change: We renewed our strategic manufacturing agreement with Sanofi, we're very pleased with that. Sanofi has been our excellent partner for the last, I would say, 12 years already, and we were very glad to be able to renew that.

We renewed our strategic manufacturing agreement with Sanofi, we're very pleased with us and <unk> has been our excellent partner for the last I would say 12 years already and we were very glad to be able to renew that and that gave US also the opportunity to take a sharp think about whether we wanted to build their own drug substance.

Speaker Change: and that gave us also the opportunity to take a sharper think about whether we wanted to build our own drug substance plant and we decided to step away from that which is going to save us some 40, 40 million dollars going forward which can be good to good use in for investment in LanioliCip but also for in licensing or helping in M&A transactions.

And we decided to step away from that which is going to save us from $44 million going forward, which can be put to good use and for your investment in linear leadership, but also for in licensing or helping them in an M&A transactions.

Speaker Change: So then we took a look at the late stage pipeline. We saw the positive, we already referred to that earlier, the positive top line data of the pivotal study for leni-only chip.

So then we took a look at the late stage pipeline. We saw the positive we already referred to that earlier the positive top line data of the pivotal study for any ownership.

Speaker Change: And then, of course, as I was referring to, we already started significantly investing in Lenny Olisip ahead of the anticipated global regulatory filings, which will start later on in this quarter.

And then of course as I was referring to we already started significantly investing in any ownership.

<unk> ahead of the anticipated global regulatory filings, which will start later on in this in this quarter and then of course the launch of that Jeanette.

Speaker Change: And then, of course, the launch of that genetic testing program that Navigate APDS, that collaboration with Avitae, what I was referring to, which will be significantly stepped up later on this year, as and when we deploy significantly more people in the US market to actually find APDS patients ahead of the launch of the product.

<unk> testing program that navigate Aps that collaboration with every day without what I was referring to which will be significantly stepped up.

Later on this year as and when we deploy significantly more people in the U S market to actually find <unk> patients ahead of the launch of the product and then last but not least here. We've received a positive decision from the EMA on the pediatric investigation plan for <unk> in Europe , which is important because that mean.

Speaker Change: And then last but not least here, we received this positive decision from the EMA on the periodic investigation plan for leniocip in Europe , which is important because that means that there is a clear pathway to approval in Europe as well, as the EMA accepted the primary endpoints that are exactly the same for the periodic study as for the pivotal study and also.

That there is a clear pathway to approval in Europe as well as the EMA accept that the primary endpoints that are exactly the same for the pediatric study as for the for the pivotal study and also as.

Speaker Change: as Ima brought into this whole thing, and, you know, this is a pediatric investigation plan that covers patients up to 80 years of age, whereas our study already includes patients from 12 years up to age. So we already, in a way, have done some of this work for the pediatric development program by means of the pivotal trial.

<unk> bought into this whole thing.

This is a pediatric investigation plan that covers patients up to 80 years of age, whereas our study already includes patients from 12 years up to age. So we already in a way has done some of this work for the pediatric.

<unk> development program by means of the pivotal trial.

Speaker Change: Then we, I was already referring to it earlier, we in-licensed OTR-105, this potentially curative candidate for AHA for orchid therapeutics. We also finally got our phase 2B study going for the prevention of acute kidney injury with recombinant C1, S-rays inhibitor, and we had some interesting top-line results from a clinical trial in severe pneumonia as a result of the COVID-19 infections. So, we had a very, very busy year in 2019.

Let me I was already referred to it earlier, we in licensed OTR 105, this potentially curative scheduled date for HLA for Orchard Therapeutics. We also finally got our phase II <unk> study going for the prevention of acute kidney injury with recombinant <unk> inhibitor and we have some interesting top line results from a clinical trial in severe <unk>.

Pneumonia as a result of the COVID-19 infections. So we had a very very busy year in 2019.

Speaker Change: And then we move on to the to the next slide, because of course you all want to know what's going on, what's underlying Rucanest and how does it look like in the Heritier-EU and Giba markets. And then on the next slide, you will see a picture of how we see.

We move on to the next slide because of course, you all want to know what's going on what's underlying <unk> and how does it look like in the heritage <unk> markets and then on the next slide you will see it.

A picture of how we see.

Speaker Change: the market for the proprietary engine demand, which Ruknash has placed.

The markets, Florida for hereditary Angioedema, which you can ask places.

Speaker Change: Traditionally, and of course, that's a big difference. As I was already referred to earlier, we were late to the market with Ruconest. There was a lot of competition already around. And this is not the case with APS. But when you are late, of course, to the market, then you need to have a very efficacious product. And we have a very efficacious product. And that is, on the right hand side, you see that a severely effective patient. And that has been our natural position for Ruconest from the beginning onward.

Additionally, and of course, that's a big difference as I was already referred to earlier, we were late to the market with <unk>. There was a lot of competition already around.

And this is not the case with Aps, but when you are late of course through the market.

Then you need to have a very efficacious products and we have a very efficacious product and it is on the right hand side you see that are severely affected patients that has been our natural position for <unk> from the beginning onwards.

Speaker Change: You know, of course, when you come to the market and there's already products available, you get patients that can't get by on other products. And they found the place in Rucanest, Rucanest's highly dosed protein replacement therapy.

Of course, when you come to the market and Theres already products available you got patients that can't get by on other products and they found a place where you can ask is highly dose protein replacement therapy actually covers all of the three pathways that are that are.

Speaker Change: actually covers all the three pathways that are actually involved in hereditary angioedema.

At RFG.

Evolved inherit Terry angioedema attacks, whereas the bradykinin concreting products, albeit efficacious.

Speaker Change: whereas the bradykinin and colliquinin products, albeit efficacious, suffer consistently from breakthrough attacks because they only cover one of the three pathways. And that is where Ruconest found its place.

<unk> suffered consistently from breakthrough attacks because they only cover one of the three pathways. So that is my recognition duplex.

Speaker Change: And then the good news for the patients was, of course, that this market.

And then.

The good news for the patients of course that these markets.

Speaker Change: was offered a lot more possibilities for prophylactic therapies. And prophylactic therapies have become significantly more popular in the United States. However, all these prophylactic therapies, albeit that there was great advances made in efficacy, and that is very good for the patients, obviously,

It was offered a lot more possibilities for prophylactic therapies and prophylactic therapies have become significantly more popular United States. However, all of these.

But productive therapies, albeit that it was great great.

Great advances made in efficacy and there is very good for the patients obviously.

Speaker Change: There is still a consistent, consistently, almost half the patients from time to time, or sometimes highly frequently, suffer from breakthroughs.

There is still a consistent consistently almost half the patients from time to time or sometimes highly frequently suffer from breakthrough attacks.

Speaker Change: And as the paradigm for prophylaxis shifted from the original C1 inhibition towards the bradykinin colloquial inhibition, it has become natural to actually have a C1 inhibitor, Rucanest, available as breakthrough therapy.

And is the paradigm for prophylaxis shifted from the original <unk> inhibition to wisely bradykinin <unk> inhibition. It has become natural to actually have a C. One inhibitor <unk> available as breakthrough therapy.

Speaker Change: There's also the reason why we see consistently more patients being treated with Ruconest because we see that Ruconest is increasingly also prescribed as breakthrough medication when these patients get the new prophylactic therapies.

There is also the reason why we see consistently more patients being treated with.

You can ask because we see that <unk>.

Is increasingly also prescribed as breakthrough medication when these patients get the new prophylactic therapies prescribed. So therefore, we're very confident as <unk> continues to serve in a unique position in the heritage Angioedema market I E on the right hand side.

Speaker Change: So therefore, we're very confident that Ruconess continues to serve in a unique position in the hereditary angioedema market, i.e. on the right-hand side where the severe patients are that cannot get by with the existing therapies and also increasingly so in the breakthrough attack segment there on the left-hand side of the market where Ruconess is prescribed as breakthrough medication for patients that continue to have a breakthrough attack.

Where the severe patients that cannot get by with the with the existing therapies and also increasingly so in the breakthrough attacks segment. There on the left hand side of the market. We're looking at is prescribed as breakthrough medication for patients that continue to have a breakthrough attacks.

Speaker Change: So that's why we are guiding for the first time in our history, we have given some guidance on sales for Ruknest. And we've guided for single-digit growth, return to single-digit growth for 2022 versus 2021 for the sales of Ruknest on the basis of these trends that we see underlying in the market.

So that's why we are guiding for the first time in our history, we have given some guidance on sales for <unk> guidance for.

Single digit growth return to single digit growth for 2021 versus 2000.

For 2022 versus 2021 for the sales so from a recognition on the basis of these trends that we see underlying in our markets.

Speaker Change: The next slide illustrates that point that I was making that prophylaxis has basically shifted the market from, you know, in the beginning it was like 60-40 and now it seems to have stabilized at 70 percent of the patients in the U.S. market get prophylaxis, whereas 30 are being served with the acute therapy.

And the next slide.

Illustrates that point that I was making that prophylaxis is basically shifted the market from the beginning it was like 60 40 and now it seems to have stabilized at 70% of the patients in the U S market get prophylaxis, where <unk> are being served with the acute therapies, but as you have seen on the bottom line there <unk>.

Speaker Change: But as you have seen on the bottom left there, Rukiness market share has stayed consistent over all those years.

Market share has stayed consistent over all those years and.

Speaker Change: And therefore, we strongly support the idea, we strongly believe in the idea that Rukinesh has this stable position in that Eritrea and Judima market for the time.

Therefore, we have.

We strongly support the idea we strongly believe in the idea that <unk> has this stable position in that <unk> market for the time to come.

Speaker Change: So this is what I wanted to share with you about Rukiness, and I would like to now switch over, switch gears, and share with you some of the excitement about the possibility to help patients with APDS with the product Laniolensib, hopefully coming to the market soon. And I hand over now to my colleague, our Chief Medical Officer, Dr. Anurag Rao. Anurag, over to you, please.

So this is what I wanted to share with you about <unk> and I would like to now switchover switch gears.

And share with you some of the excitement about the possibility to help patients with <unk> with the product Lenny ownership coming hopefully coming to the market soon and I'll hand over now to my colleague, our Chief Medical Officer, Dr. <unk> <unk> over to you. Please.

Anurag Rao: Thanks, Simon. And yes, we are very excited about the possibility of helping these patients with APDS. APDS is a serious, unmet need. It's a patient population that's currently underserved. It's a patient population that, as we see on the next slide, that we think that there's more than 1,350 across the U.S., Europe , and Japan that live with APDS. Many of these patients obviously are still undiagnosed.

Thanks, Simon and yes, we are very excited about the possibility of helping these patients with Etfs at PBF has a serious unmet need.

Patient population that is currently underserved.

<unk> population.

Unless we see on the next slide that we think that there's more than 1350 across the U S Europe , and Japan with live with PBF.

Many of these patients obviously are still on diagnosed.

Anurag Rao: We have actually identified through our own efforts, and really just beginning with these efforts, we've identified more than 350 patients across these areas.

We have actually identified through our own efforts and really just beginning with these efforts we have identified more than 350 patients across these areas and as we get a better understanding of primary immune deficiencies of which <unk> is one of them we have.

Anurag Rao: And as we get a better understanding of primary immune deficiencies of which APDS is one of, we have the potential to identify even

The potential to identify even more patients.

Anurag Rao: Again, these patients, because of their symptom complex, they end up seeing numerous specialists. And because the condition itself has only been described for less than 10 years, there is still a lot of unawareness about the disease.

Again these patients.

Cancel their symptom complex they end up seeing numerous specialists and.

Because the condition itself has only been described for less than 10 years.

A lot of an awareness about the disease.

Anurag Rao: As a genetic disease, the symptoms begin in childhood and disrupt their school and social development. There's a significant impact on their quality of life. These patients undergo numerous surgical procedures as part of this workup and evaluation, again seen by numerous doctors impacting their mental health. And when we look at the symptom complex, it's really across the body we see.

As a genetic disease the.

Since it was began in childhood and disrupt their school and social development.

A significant impact on their quality of life. These patients undergoing numerous surgical procedures as part of this work up in evaluation.

<unk> seen by numerous doctors impacting their mental health.

And when you look at the symptom complex, it's really across the body, we see damage from recurrent infections, we see gastrointestinal disease, we see really the hallmark of the disease, though is the swollen lymph nodes and now the resultant also.

Anurag Rao: damage from recurrent infections. We see gastrointestinal disease. We see, really, the hallmark of the disease, though, is the swollen lymph nodes and, as a result, also enlarged spleen and liver.

And large screen to deliver.

Anurag Rao: We also see autoimmune phenomenon because there is not only this immune deficiency because of the disease, but we also have activation of the immune system, and these patients can get anemias and other cytopenias. And unfortunately, many of these patients go on to develop lymphoma because of this hyperactivation of this PI3K delta pathway. And

We also see autoimmune phenomenon because there is not only miss immune deficiency because of the disease, but we also have activation of the immune system and these patients can get.

As another side of pools and unfortunately, many of these patients go on to develop lymphoma because of this hyper activation of this pi three kinase Delta pathway.

<unk>.

Anurag Rao: Unfortunately, the truth is that right now the treatment options for these patients are quite limited. It's management of infections that they develop, trying to prevent infections with immune globulin replacement therapy, trying to control the hyperactivation of their immune system with nonspecific inhibitors.

Unfortunately, the truth is that right now the treatment options for these patients are quite limited.

To manage its management of infections that they develop trying to prevent infections with immune globulin replacement therapy trying to control the hyper activation of the immune system.

With non specific inhibitors and then in rare cases patients go on to receive stem cell transplantation with all of the developing complications.

Anurag Rao: And then in rare cases, patients go on to receive stem cell transplantation with all of the resulting complications.

Anurag Rao: Again, there are no approved treatments available for these patients and so this is why based on all of the things that we see with Laniolacib so far, we're quite excited about the possibility of being able to help these patients and really potentially dramatically transform their lives.

Again, there are no approved treatments available for these patients and so this is why based on all of the things that we see with Lenny ownership. So far we're quite excited about the possibility of being able to help these patients really potentially dramatically transform their lives.

Please.

Anurag Rao: And one of the first things that we're doing is really going out there and working with physicians on education and understanding the disease. And we built a network of physicians who are experts in APDS. And on top of that, now, as we're doing that, we're beginning to understand.

And one of the things that we're doing is really going out there and working with physicians on education and understanding of the disease and we built a network.

Physicians, who are experts in atvs and on top of that now as we're doing that we're beginning to understand.

Anurag Rao: the clinical phenotype of these patients and using that clinical phenotype to potentially identify additional patients. And a big part of that was this program that we launched last year called Navigate APDF. And this is a partnership that we have with Invitae to provide sponsored genetic testing. So

The clinical phenotype of these patients.

Using that clinical phenotype to potentially identify additional patients and a.

A big part of that was this program that we launched last year called navigate Atvs and this was a partnership that we have with <unk>.

To provide sponsored genetic testing so instead of testing that is no cost to the patient that allows for patients with primary immune deficiencies, who have the features of Aps to obtain genetic testing to obtain an ultimate diagnosis, we know that there are barriers.

Anurag Rao: genetic testing that is no cost to the patient, that allows for patients with primary immune deficiencies who have the features of APDS to obtain genetic testing, to obtain an ultimate diagnosis.

Anurag Rao: We know that there are barriers currently to obtain genetic testing, especially in the U.S., and by having this program in place, we hope to eliminate those barriers and really allow these patients with any primary immune deficiency to get a specific diagnosis, not only APDF. And the feedback that we have so far from allergists, immunologists, and others who are using this program has been quite tremendously positive.

Lead to obtain genetic testing, especially in the U S and by having this program in place we'd hope to eliminate those barriers and really allow these patients with any primary immune deficiency to get a specific diagnosis not only a PBF and the feedback that we have so far from the from allergists and Immunologists and others who are using this.

Program, that's been quite tremendously positive.

Next slide please.

Anurag Rao: But then on to Laniolacib. And what we see with Laniolacib is that we have an effective PI3K delta-selective orally bioavailable inhibitor. And really, the goal here is to use this PI3K delta inhibitor to take care of the hyperactivation in the PI3K pathway and address the root cause.

But then onto <unk> and what we see with <unk> is that we have an effective.

We take delta selective orally bio available inhibitor and really the goal here is to use this.

<unk> Delta inhibitor to Richard to take care of the hyper activation.

<unk> K pathway.

The address the root cause.

Anurag Rao: By addressing the root cause, we hope to address the issues that this hyperactivation causes. And really what that hyperactivation results in is abnormal development of the immune system, abnormal maturation of B and T cells and other immune cells in the immune system. And because of that abnormal maturation, we see all of the clinical phenomenon that I've been talking about.

By addressing the root cause we hope to address the issues that this hyper activation causes and really what that hyper activation resulted in us.

Normal development of the immune system abnormal maturation of BNP cells, and other immune cells and the immune system and because of that abnormal maturation, we see all of the clinical phenomenon.

Then I have been talking about.

Anurag Rao: With the genetic test that we have, we hope to be able to allow patients with primary immune deficiency to obtain this diagnosis.

With the genetic test that we have we hope to be able to.

Now patients with primary immune deficiency.

Obtained this diagnosis or feedback in working with regulatory agencies. So far has been quite positive.

Anurag Rao: Our feedback and working with regulatory agencies so far has been quite positive.

Anurag Rao: As Simon already mentioned, we received the Pediatric Investigation Plan approval from EMA. We also have Orphan Drug designation, both in the U.S. as well as in Europe . And really, the other nice part about this is that we continue to work with the same doctors that we have been working with for the past 20 years in HAE. These are immunologists who also see patients with HAE, and now we're adding on to that capability by allowing them to work with us.

Simon already mentioned, we received in pediatric investigation plan approval from EMA.

Where can drug designation both in the U S as well as in Europe , and really the other nice part about this is that we continue to work with the same doctors that we happen to working with for the past 20 years in HIV, either Immunologists, who also see patients with HIV and now we're adding on to that capability.

Ability by allowing too.

Anurag Rao: to work with them in the field of primary immune deficiency.

To work with them in the field with primary immune deficiency.

Next slide please.

Anurag Rao: I'm going to talk a little bit now about the pivotal trial design, and the design really was in two parts. Part one was the dose-finding part, and this was in six patients that received three doses of Leni-Olson over, of course, a total of 12 weeks. The patients were individually dose-escalated, and again, these were patients with the confirmed diagnosis of APDS.

I'm going to talk a little bit now about the pivotal trial design and the design really in two parts part one was the dose finding part and this was a six patients that received.

Three doses of millennial suite over a course, a total of 12 weeks.

Patients were individually dose escalated and again these were patients with the confirmed diagnosis.

Anurag Rao: We looked at the typical outcomes in this type of study, safety, tolerability, pharmacokinetics, and the ability to actually stop that hyperactivation in this path.

We looked at the typical outcomes in this type of study safety Tolerability pharmacokinetics and the ability to actually stop that hyper activation.

In this pathway the dose that was selected based on these results.

Anurag Rao: The dose that was selected based on these results was the 70 milligram twice daily dose, and that was then used in the placebo-controlled part, the randomized placebo-controlled part two of the study, in which patients were randomized two to one to receive Laniolacib at the 70 milligram twice daily dose.

Was the 70 milligram twice daily dose and that was been used in the placebo controlled.

The randomized placebo controlled part.

Two of the study in which patients were randomized two to one to receive lineal at a 70 milligram twice daily dose.

Anurag Rao: And this study then had the following co-primary endpoints, looking really at the hallmarks of the disease, namely lymphadenopathy, or swollen lymph nodes, and normalization of the immunophenotype. And what I mean by that is that these are the features of the disease that define the disease. These patients have, because of that hyperactivation in that pathway.

And this study then had the following co primary endpoint looking really at the hallmarks of the disease, namely lymphadenopathy or swollen lymph nodes and normalization of the immuno phenotype.

What I mean by that is that these are the features of the disease that define the disease. These patients have because of that hyper activation in that pathway. They have.

Anurag Rao: they have immune cell issues with development and maturation. And because of that, their lymph nodes swell up and their B cells and other immune cells don't develop properly. So we specifically looked at those features as the primary endpoints in the study.

Immune cell.

Issues with development and maturation and because of that their lymph nodes swell up and they are linked and then b cells and other immune cells don't develop properly. So we specifically looked at those features.

The primary endpoints from the study.

And then of course, there were safety assessment.

Anurag Rao: On top of that, all of these patients then had the ability to go on into an open label extension study. And we're actually in quite a unique position here with a therapy lineal.

On top of that all of these patients then have the ability to go on into an open label extension study and we're actually in quite a unique position here with a.

Therapy, let me say that we have not only randomized double blind placebo controlled data in a rare disease, but we have data in these patients going on for several years.

Anurag Rao: we have not only randomized, double-plying, placebo-controlled data in a rare disease, but we have data in these patients going on for several years. We have some patients, including patients from Part 1, that have been on the therapy for more than five years and continue to be on the therapy. And I'll share with you some of those results, because I think when we think about the totality of the data, when we look at all of the data that we have with retinopathy,

Some patients including patients from part one.

On the therapy for more than five years and continue to be on the therapy and I'll share with you. Some of those results because I think when we think about the totality of the data when you look at all of the data that we have with letting the auction.

Anurag Rao: what really shows us what this drug is doing, is not only that we can say, okay, you've improved how these patient's immune cells work, you've improved their clinical features of

What really shows US with this drug is doing it's not only that we can say okay.

Proved how they are these patients' immune cells work you've improved there.

Our clinical features.

Anurag Rao: swollen lymph nodes, but you also can show that you can do this over many years. And again, I think that's a unique position for a therapy that's been developed for a rare disease.

Swollen lymph nodes, but you also can show that you can do this over many years and again I think that's a unique position for a therapy that's been developed for a rare disease.

Next slide please.

Anurag Rao: And in part one, what we saw was that when you also was well tolerated at these doses and then again, we selected the 70 milligram twice daily dose.

And in part one what we saw was that when you answer was well tolerated at these doses and then again, we selected the 17 milligram twice daily dose.

Anurag Rao: And what we saw also was that there was significantly less disease activity and patients felt better. There was suppression of this pathway. We were able to normalize some of these things that I mentioned about in terms of the biochemical aspects demonstrating the improper maturation of their immune system. And as a result, we also saw reduction in the swelling of their lymph nodes and spleen. And you see those reductions in the table on the left.

And what we saw also was that there was significantly less disease activity in patients felt better.

Oppression of this pathway, we were able to normalize some of these things that I mentioned about in terms of the biochemical aspect demonstrating the improper maturation.

Their immune system and as a result, we also source reduction in the swelling of the roof note and screen and you see those reductions in the table on the left.

Anurag Rao: 40% reduction in just 12 weeks of therapy with Laniolacib. And on the right figure at the bottom, you can see that these patients who would have an enlarged spleen for years and then immediately go on Laniolacib, which is labeled there as CDZ173, you can see their spleen size decrease. And that's just one example. And we have data now on all patients showing very similar.

40% reduction in just 12 weeks of therapy with lineal hosted and on the right figure at the bottom you can see that these patients who would have on an enlarged spleen for years and then immediately go on Windows, which is labeled Aaron's CDC 173, you can see the screen size.

Decrease and that's just one example, and we have beta now.

All patients showing very similar phenomenon.

Next slide.

Anurag Rao: And here, what we can see is the long-term results. Now, see, this is the result from those initial six patients that were part of the dose-finding study. And these are their IgM levels. IgM is an antibody that's produced early in the immune response. And because these patients' immune cells don't mature properly, don't develop properly,

And here, what we can see as the long term results and you'll see this is the result from those initial six patients that were part of a dose finding study and these are their IGF levels. IGN is an antibody that's produced early in the immune response.

And because these patients immune cells don't mature property don't develop properly.

Anurag Rao: In essence, they have a problem with what's called class switching, or they have a problem with transitioning to produce a IgG response. Instead, they continue to produce this high levels of IgM antibody. And you can see each of these six patients, when they went on linoleucine for those first 12 weeks, and those are those bolded lines, their IgM

In essence, they have a problem with what's called cost switching or they have a problem with transitioning to produce a <unk> response instead, they continue to produce with high levels of AGM antibody and you can see each of these six patients when they went online you're also for those first 12 weeks and those are those bolden.

<unk>.

IGN levels dropped.

Anurag Rao: What's even more interesting is that, because of some logistical issues, not all patients could continue on the Oliciv immediately in the extension study, so they had to stop. And you see those are those dash lines. And unfortunately, their IgM levels started to go up when they went off of the Oliciv. And in some cases, you can see for one patient who was off the drug for almost two years, her levels went up significantly.

Even more interesting is then because of some logistical issues not all patients could continue and you also are immediately.

The extension study so they had to stop and you see those are those dash line and unfortunately their ITM levels started to go up when they went off of the ownership and in some cases you can see for one patient that was off the drug for almost two years her levels went up significantly.

Anurag Rao: But again, once these patients resumed linoleucine again in the.

Again once these patients resumed leg ulcer, beginning with bold section, you'll see those levels start to come back down again. This is a clear sign.

Anurag Rao: bold section, you see those levels start to come back down again. This is a clear

Anurag Rao: sign to us of the effect of the drug, not only in the short term, but that's also a durable effect that these patients continue to tolerate the drug well and that their IgM levels come down.

And to us of the effects of the drug or not.

Not only in the short term, but that's also a durable effect that these patients continue to tolerate the drug well and that they were IGF levels come down, but you say, okay. So the ICM levels come down you might be wondering well what does that mean and those are those symbols that youll see above the numbers and those symbols indicate our.

Anurag Rao: But you say, OK, so their IgM levels come down. You might be wondering, well, what does that mean? And those are those symbols that you see above the numbers. And what those symbols indicate are these patients were able to reduce or sometimes completely eliminate the need.

These patients were able to reduce or sometimes completely eliminate the need for.

Anurag Rao: for IG supplementation or replacement therapy. Again, indicating that these patients, physicians felt, okay, your immune system is functioning normally. I don't need to give you antibodies from someone else's immune system to fix your own immune system. So.

<unk> supplementation.

<unk> a replacement therapy again, indicating that these patients physicians felt okay. Your immune system is functioning normally I don't need to give you antibodies from someone else's immune system.

To fix your own immune system.

Anurag Rao: It's all coming together quite nicely when we look at this kind of information.

It's all coming together quite nicely when we look at this kind of information where.

Anurag Rao: where we see the immune phenotype or the immune system functioning properly. We see reduction in their lymph nodes and spleen sizes. And then we see that they are actually having to use less immune globulin replacement therapy. Again, a clear indication that their own immune system is functioning.

Where we see.

The immune phenotype, where the immune system functioning properly, we see reduction in their lymph nodes and screen sizes and then we see that they are actually having to use less.

<unk> globulin replacement therapy, again, a clear indication that their own immune system dysfunction.

Excellent.

Anurag Rao: And what we have now also is the data from part two of the study, and this was the double blind placebo controlled part of the study where we showed both a reduction in their lymph nodes.

And what we have now also is the data from part two of the study and this was the double blind placebo controlled part of the study where we showed both a reduction in there with notes.

Anurag Rao: as well as a normalization of that immune dysfunction. And we saw these results and we'll be presenting these results. Actually, the physician from the NIH, Dr. Kennedy Rao, will be presenting these results later this month at the Clinical Immunology Society meeting.

Slowing as well as a normalization of that immune dysfunction and we saw these results and we will be presenting these results actually.

Physician from the NIH, Dr. <unk> will be presenting these results later this month.

Clinical Immunology Society meeting.

Kennedy Rao: And we're quite excited to have those results presented and we'll be continuing to share the results from this study, as well as from the other patients who were in the open label extension study throughout the course of this year.

And we're quite excited to have those results presented and we'll be continuing to share. The results from this study as well as from the other patients who were in the open label extension study throughout the course of this year.

Excellent.

Kennedy Rao: And where does that lead us? Well, that leaves us with these results now that we are in regulatory discussions, and we hope to be able to file with FDA later this quarter, or excuse me, later in this first half of the year.

And where does that lead us well.

That leaves us with these results now that we are in regulatory discussions and we hope to be able to file with FDA later this quarter or excuse me later this first half of the year and and then eventually also across Europe with EMA and in the UK.

Kennedy Rao: And then eventually also across Europe with EMA and in the UK, because we know that this condition also affects children and we've talked about this pediatric investigation plan, we want to begin our pediatric studies in the second half of this year.

Because we know that this condition also X children and we've talked about this pediatric investigation plan, we want to begin our pediatric studies in the second half of this year, we have had discussions with the Japanese regulatory authorities also and look forward to beginning a study in Japan. Because they are also there are patients there and physician to contact with us there.

Kennedy Rao: We've had discussions with the Japanese regulatory authorities also, and look forward to beginning a study in Japan, because they're also, there are patients there, and physicians have contacted us there and say, look, we'd like to be able to use leniolacid in these patients and test

We'd like to be able to use millennials are in these patients.

Kennedy Rao: lineals have been in our Japanese population of APDS patients, so we've begun that.

And test when he also.

Japanese population of <unk> patients. So we've begun that work and then as Simon said, we'd hope to be able to obtain regulatory approval in the U S as well as other territories across.

Kennedy Rao: And then, as Simon said, we hope to be able to obtain regulatory approval in the U.S., as well as other territories across the United States.

Okay.

23.

Next slide please.

Kennedy Rao: Now I'm going to turn and talk a little bit about the partnership that we have with Orchard Therapeutics, and this is the compound called OTL-105.

Now I'm going to turn and talk a little bit about the partnership that we have with Orchard therapeutics and this is a compound called <unk> 105.

Advance to the next slide.

Kennedy Rao: Really, the reason we looked at this and the reason that we eventually licensed in the compound, one, of course, we saw the potential benefits to offering.

Really the reason we looked at this one of the reason that we are.

Eventually licensing the compound one of course, we saw the potential benefits to offering.

A cure to these patients.

Kennedy Rao: But on top of that, we really have been working in H.A.E. for 20 years. And the commitment that we have to H.A.E. is real. And we wanted to be able to move when we look forward to say, OK, what can we eventually offer these patients that could completely change their lives? And that's that's what led us to this partnership.

But on top of that we really have been working in HIV for 20 years.

And the commitment that we have to HPE.

Is real and we wanted to be able to move when we look forward to say, okay. What can we eventually offer these patients that could completely change their lives and that's what led us to this partnership.

Kennedy Rao: And the concept here is to use an ex vivo autologous stem cell gene therapy for HNE. The lentivirus that is going to be developed by Orchard Therapeutics will be able to insert a copy of the SERPEN G1 gene into patients, into their own cells, and do this outside of their body.

And the concept here is to use an ex vivo autologous stem cell gene therapy for <unk>.

The lentivirus that there's going to be developed by Orchard therapeutics will be able to insert a copy of the serpent <unk> gene into patients into their own cells and do this outside of their Bobby Audi and then put those cells back into their body to get their own.

Kennedy Rao: and then put those cells back into their body to get their own.

Kennedy Rao: blood cells can then produce C1 inhibitor and can really hopefully cure their disease.

Blood cells can then produce C. One inhibitor and really hopefully cure their disease.

Kennedy Rao: In terms of what we've seen so far, we've seen that we can express the protein and that the protein works.

Terms of what we've seen so far we have seen that the we can express the protein and the protein works and that we're able to measure that.

Kennedy Rao: and that we're able to measure that in a validated way. The study, you know, all of this development is still early stage, but based on the expertise that Orchard have and that we have in HIE, we're quite motivated and positive about the prospects here. And I look forward to providing further updates during later this year.

In a validated way.

The study all of this development is still early stage, but based on the expertise that Orchard house and we have an HSA.

White and motivated and positive about the prospects here.

Forward to providing further updates during later this year.

Speaker Change: And I will turn it over to your room now to give us a little bit more on the financial.

And I will turn it over to your room now to give us a little bit more on the financials.

Speaker Change: Yeah, thank you very much, Anurag. In terms of revenue, the revenues for the full year of 2021 landed at 198.9 million, which is a 6% decrease versus the previous year.

Yes, thank you very much.

In terms of the revenue the revenues for the full year of 2021 landed at $198 9 million, which is a 6% decrease versus the previous year.

Speaker Change: And as you can see on the graph, we had a very good Q4 in 2020. And that was because basically, because of COVID at the time, patients were pre-filling Ruconest prescriptions. And that hit us in Q1.

And as you can see on the on the graph.

We have a very good Q4 in 2020 and that was because basically because of COVID-19 at the time patients were pre filling.

Refinished prescriptions and that hit us in Q1.

Speaker Change: So, in Q1 2021, as we have reported before, we had lower prescription refill rates and also a reduction in the new patient enrollment, and I'm very happy to

So in Q1 2021, as we have reported before that we had lower prescription refill rates and also a reduction in new patient enrollment.

I'm very happy to sell.

Speaker Change: tell that over the year it recovered. And in Q4, for example, we had a 3% growth in the US. So that also brings hope for the remainder of 2022.

So that over the year.

Covered and in Q4 for example, we had a 3% growth in the U S. So so that also brings hope for the remainder of 2022.

Next slide please.

Speaker Change: So the revenues from sales in the US in 2021 were 193.4 million which is a decrease of 5% previous versus the previous year and we saw ongoing recovery in sales following the the COVID impact in the at the beginning of the year.

So the revenues from sales in the U S. In 2021 were $193 4 million, which is a decrease of 5% previous versus the previous year and we saw ongoing recovery in sales following the COVID-19 impacts in the at the beginning of <unk>.

A year.

Speaker Change: In 2021, the sales in Europe decreased to 4.9 million from 8.2 and that was caused by a number of issues but mainly phasing of ordering. For example, we got a very big order at the end of 2020 in one of the countries where we deliver and that was not really caught up in the remainder of 2021. And the rest of the world revenue decreased to half a million from 1.3 million in the year before.

In 2021, the sales in Europe decreased to $4 9 million from $8 two and that was caused by a number of issues with mainly phasing of ordering for example, we got a very big order at the end of 2020.

And one of the countries, where we deliver.

That was not really caught up in the remainder of 2021.

Rest of the World revenue decreased 201 million from $1 3 million in the year before.

Speaker Change: Looking at the gross profit, it was $177.7 million, a decrease which is in line with the revenues. But it's also good to say that the gross margin was very healthy at 89.4%. And that was an improvement of 50 basis points versus the year before.

Looking at the gross profit it was.

177 points.

<unk> 7 million, a decrease which is in line with our revenues, but it's also good to say that the gross margin.

It was very healthy at 89, 4% and that was an improvement of 50 basis points versus the year before.

Next slide please.

Speaker Change: Looking at the operating profit and the operating costs in 2021, the operating profit was $36.9 million before one-off cost of $23.3 million. And it's important to note that because they had an important impact on the operating cost and therefore on the operating profit. And that $23.3 million of one-off costs

Looking at the operating profit and the operating costs into 2021, the operating profit.

Was $36 9 million before.

One off costs of $23 3 million, it's important to note that because they had an important impact on the operating costs and therefore on the operating profit and $23 3 million of one off cost was related to.

Speaker Change: was related to the Orchard Therapeutics transaction, we paid them 13.1 million for the in-licensing of the compound that Anurag just told you about.

The Orchard Therapeutics transaction, we paid them $13 1 million.

For the for the in licensing of the compound that underwriting just to just told you about.

Speaker Change: And we had impairment costs, impairment losses on assets.

And we had impairment cost impairment losses on assets.

Speaker Change: uh two assets really one was on on panda and that was a project to modify

The two assets really one was on <unk> and that was a project to modify the current products Ruger and asked for more convenience forms of administration for use by the patients. So we can pay up $4 7 million, there, which is a non cash item obviously.

Speaker Change: current product recognized for more convenient forms of administration for use by the patient. So we impaired 4.7 million there, which is a non-cash item, obviously. And we also impaired 5.4 million on the development of our downstream processing facility, which we canceled at the end of last year.

And we also Embeds, a $5 4 million on the development of our <unk>.

Downstream processing facility, which we which we consoles at the end of last year.

Speaker Change: The operating profit after the one-off cost, so the real operating profit were $13.6 million, and, well, we continued significant investment in the farming's long-term growth.

The operating profit after the one off costs. So the real operating profit were $13 6 million.

And while we continued significant investments in the farming so long term growth.

Speaker Change: and that ranges across including increased R&D expenditure but also increased costs from Leni Olusep so that is pre-launch marketing preparations about three million and additional manufacturing costs for that for that compound of about nine million.

And that.

The ranges across including increased R&D expenditure.

But also increased costs from Lenny ownership. So that is our prelaunch marketing preparations about $3 million and additional manufacturing costs for that for that component of about $9 million.

Speaker Change: So in total, 11.6 million Laniolus have got.

So in total $11 6 million within the ownership cost.

Speaker Change: We also increased the employee numbers to support the future growth of the company. Cost increased by 8.2 million and the number of FTEs went from 239 FTEs to 300 at year-end. So an increase of 61 FTEs.

We also increased the employee numbers to support the future growth of the company.

<unk> cost increased by $8 2 million and the number of Ftes went from 239 Ftes to three <unk> at year end, So an increase of 61 ftes.

Speaker Change: And lastly, we had additional insurance costs because of the NASDAQ listing, and also there were some other costs related to the NASDAQ listing to further professionalize the internal organization.

And lastly, we have additional insurance costs because of the of the NASDAQ.

And also there were some other costs related to the NASDAQ listing to further professionalize the internal organization.

Speaker Change: Net profit was 16 million, which is a 58% decrease and that was because of the increase that I've just mentioned in the operating expenses, and it was partly offset by favourable currency effects.

Net profit was $16 million, which is a 58% decrease and that was.

Because of the increase that I've, just mentioned and the operating expenses and it was partly offset by favorable currency effects.

Speaker Change: Then on the next slide we see the developments, the key items in profit before tax from 2020 to 2021.

Then on the next slide we see the developments the key items profit before tax from 2022 2021.

Michigan yet okay.

Speaker Change: Sorry for that. So moving on to cash and cash equivalents.

Sorry for that so moving on to cash and cash equivalents.

Speaker Change: which decreased by 13.7 million from 206.7 million at the end of 2022 193 million and that was driven by mainly a positive cash flow from operating activities of 37.8 and again that includes the licensing fee paid to Orchard Therapeutics.

Which decreased by $13 7 million.

From.

Two a $6 7 million at the end of 2000 $20 million to $193 million and that was driven by.

Mainly a positive cash flow from operating activities of 37 point.

H and again that includes the <unk> licensing.

Fee paid to Orchard therapeutics.

Speaker Change: They were upset by negative cash flow from investment and financing activities of in total 49 million and more than half of that negative cash flow in investments and financing activities was because of the payment, the milestone payment the last milestone payments to health in relation to the re acquisition of the North American recognized commercialization rights, which was a transaction done in 2016.

They were offset by negative cash flow from investments and financing activities of in total $49 million and more than half of that.

Negative cash flow in the investments in financing activities was because of the.

Payment the milestone payment the last milestone payments to Bausch health in relation to the re acquisition of the North American <unk> commercialization rights, which was a transaction done in 2000.

2016.

If we then go to the next slides.

Speaker Change: That's the profit before tax so that's the development from 2020 to 2021.

That's the profit before tax.

So thats the development from forward from 2022 2021.

Speaker Change: We started off last year, we ended last year in 2020 with a profit before tax of 44.1 million and in 2021 we had a decline in underlying business gross profit as I've just mentioned by 10.9 million. We had the OTL 105 investment of 13.1 million. We had the impairment that I've just mentioned.

We started off last year, we ended last year and starting in 2020.

With a profit before tax of $44 1 million.

And in 2021 rehab.

A decline in underlying.

Business gross profit as I've, just mentioned by $10 9 million.

We have the OTR 105 investments of $13 1 million, we have the impairment that I've. Just mentioned we have an increase in R&D expenditure. This is mainly related to gilenya ownership development and manufacturing costs.

Speaker Change: We had an increase in R&D expenditure. This is mainly related to linealisib development and manufacturing costs.

Speaker Change: We had an increase in SG&A expenditure, and that is mainly the insurance costs related to the NASDAQ listing that I've just mentioned. And we have increased marketing and sales expenditure, and again, a big part there was also from Laniolacip.

We had an increase in SG&A expenditure and that is mainly the insurance costs related to the NASDAQ listing that I've just just mentioned.

We have increase.

Marketing and sales expenditure and again, a big part there was also from <unk>.

Speaker Change: and then we had a very positive effect related in 2021 versus 2020 and that was 34.1 million positive and because we had a negative foreign exchange impact of 19 million in 2020.

And then we had a very positive effects related.

In 2021 versus 2020, and that was $34 1 million positive and because we had a negative foreign exchange impact of $19 million in 2020, and a positive foreign exchange effect of $15 million in.

Speaker Change: and a positive foreign exchange effect of 15 million in 2021.

In 2021 and that was all related to the cash.

Speaker Change: And that was all related to the cash that we have on the balance sheet.

That we have on the balance sheet.

Speaker Change: and the Eurodollar moving from...

The eurodollar moving from.

Speaker Change: 1.23 at the beginning of the year to 1.13 at the end of last year.

One point 23 at the beginning of the year to $1 30 at the end of last year. Although elements are cost that we had last year for a settlement of a loan.

Speaker Change: Other elements are a cost that we had last year for a settlement of a loan and some other costs and that brought us to a profit before tax in 2021 of 23.1 million.

Some other costs that brought us to a profit before tax.

In 2021 of 23 1 million.

And then going to the next slide please.

Speaker Change: Yeah, that's the cash flow development in 2021. We started off with the 205.2. This is the cash excluding the restricted cash, by the way.

Yes, that's the cash flow development in 2021, we started off with the 205. Two this is the cash excluding the restricted cash.

Speaker Change: We have the operating cash flow before changes in working capital of 42.3, so a very positive operating cash flow. Negative impact of changes in working capital, that was a mixed of increased inventory, reduced debtors and reduced payables.

Right away.

The operating cash flow before changes in working capital of $42 three so a very positive operating operating cash flow.

The negative impact of changes in working capital and that was a mixed in of increased inventory reduce debtors and reduced payables.

Speaker Change: and 21.3 million in investing activities and that was 11 million, 10.7 to be exact, was related to the downstream processing facility but also we built and finalized a third upstream production facility and that was delivered on time and in budget.

And $21 3 million in investing activities and that was.

11 million some seven to be exact the most related to the to the downstream processing facility.

But also we build and finalized a third upstream production facility and that was delivered on time and in budget.

Speaker Change: Same goes for a ERP implementation that was 3.4 million intangible asset investments and that was also delivered on time and in budget and we went live with this ERP system SAP on the 1st of January 2022.

The same goes for a ERP implementation that was $3 4 million of intangible assets.

Investments and that was also.

<unk> delivered on time and in budget and we went live with the ERP system SAP.

On the first of January 2022.

Speaker Change: We invested 4.6 million in the Orchard shares which was part of the licensing transaction in the year and we paid 2.5 million on the Laniolisip license in this year so that's totaling the 21.3 cash flow for investing activity.

We invested $4 6 million in the Orchard shares, which was part of the licensing transaction in the year and we paid $2 5 million.

Lenny ownership licensing this year, so thats totaling 21 point.

Three cash flow for investing activities.

Speaker Change: The cash flow used in financing activities has got two buckets. One is the 2.9 million is related to interest and lease costs.

The cash flow used in financing activities has got two buckets. One is at a $2 9 million is related to interest and lease costs.

Speaker Change: And the 25 million is, as I mentioned, the Bausch final payment for the reconnaissance license. So we won't have that anymore in the future. And then we have some smaller exchange rate effects and brings us to a cash and cash equivalents at the year end of 192 million US dollars. So a very strong financial position that we have. And it also provides a great opportunities for future growth. And with that, I would like to hand over to Simon.

$25 million is as I mentioned, the Bausch final payment for the <unk> license. So we won't have that anymore in the future and then we have some smaller exchange rate effects and brings us to a.

Cash and cash equivalents at year end of 192.

<unk> million dollars U S dollars, so a very.

Strong financial position that we have and it also provides great opportunities for future growth and with that I would like to hand over to Simon. Thank you very much. Your room then yes that is the final part of our presentation I would like to share the outlook here for the for 2022 as I was saying before.

Simon: Thank you very much, Jeroen. And yes, as the final part of our presentation, I would like to share the outlook here for 2022.

Simon: As I was saying before, this is the first time in our company's history that we're guiding on sales levels that we are expecting for Rucanest.

For the first time in our in our company's history there'll be guiding on sales.

Levels that we are expecting for <unk>.

Simon: driven by the US and EU operations but also subject still to the progression of this COVID-19 pandemic. As I was referring to earlier, everything is far from normal in the clinics so far but we travel hopefully going forward. Obviously quarterly fluctuations and revenues are expected as before.

Driven by the U S and EU operations, but also subject still to the progression of this COVID-19 pandemic because that was referred to earlier everything is far from normal in India, India.

The clinics, so so far but we travelled hopefully going going forward, obviously quarterly fluctuations in our revenues are expected.

As before.

Simon: As I was sharing in the beginning, we're very excited, and Anurag told you about some of the interesting features that Plenio has to bring the regulatory fines to FDA and EMA with, you know, subject, of course, to these approvals. Commercial launch is expected from early on in 21 and Q1, so within a year from now, we expect that that could happen, of course. We expect to start in the United States with launch.

As I was sharing in the beginning we're very excited that <unk> you.

About.

Some of the interesting features that <unk> have to bring the regulatory filings to FDA and EMA.

With.

Subject of course to visa approvals commercial launches expected from early on in 'twenty, one and in Q1, so within a year from now we expect that that could happen of course, so do you expect to start in the United States with the launch.

Simon: and this is a market where you can immediately go on the market and get reimbursed.

And this is a market where you can immediately go into market and get reimbursed.

Simon: But as I was saying also before, although we have this commercial infrastructure in place, we still have to significantly invest in the preparations for the launch of Leni-Odyssey. And that is, for us, a very important point. We want to do this.

But as I would say also before.

Although we have this commercial infrastructure in place.

We still have to significantly invest in this in the preparations for the launch of our Lady ownership.

That is for us very important.

I wanted to do this.

Simon: We want to get this opportunity to, you know, bring this product to the market in a proper way. We can now, this is historical for our company, we can launch a product for ourselves and we will therefore significantly invest.

We want to get this opportunity to bring this product to the marks in a proper way. We can now this is historical for our company. We can launch a product direct ourselves and we will therefore significantly invest on the launch preparations and the focus clinical development and Iraq was mentioning the pediatric studies.

Simon: on the launch preparations and the focus clinical development, and Anurag was mentioning the pediatric studies, for instance, for lenioleucine, and that will significantly increase and will also significantly have an impact on our profitability for this year.

For instance for lending ownership and it will significantly increase and we're also significantly have an impact on our profitability, Florida for this years, but with the continued cash flows as union was alluding to from <unk>.

Simon: But with the continued cash flows, as Jeroen was alluding to from Rukiness.

Simon: these investments will be funded from our own sources so there's no need to anticipate any additional financing to support our current business. I think that's an important statement to make here.

These investments will be funded from our own sources. So there will there is no need to do we anticipate any additional financing to support our current business I think that's an important statement to make here.

Simon: However, we also will look for, continue to look for potential acquisitions and in-licensing of new late-stage compounds.

However, we also.

We'll look for continue to look for potential acquisitions and in licensing of new late stage compounds.

Simon: to actually be able to launch additional products within the timeframe between now and three years time in rare and ultra rare diseases. And there, of course, depending on the size of the deal, we do have a strong balance sheet, of course.

To actually be able to launch additional products within the timeframe between now and three years time in radar ultra rare diseases and there of course, depending on the size of the deal. We do have a strong balance sheet of course, we do have access to capital by means of raising debt for instance, but theres also a possibility of course.

Simon: We do have access to capital by means of raising debt, for instance, but there's also a possibility, of course, that we could actually raise...

That we could actually raised.

Simon: equity money or pay in equity money and most notably we of course have the NASDAQ listing put up in place for that occasion to be able to part pay such acquisitions in issuing ADSs in the future.

Equity money or pay in equity money and most notably we of course have the NASDAQ listing up would have in place for the application to be able to pass base such acquisitions in issuing ads's into future.

Simon: That is, of course, the exception here, but otherwise we do not expect any additional financing needs to support our current business. But for the expansion, there might be that opportunity.

No.

That is of course, the exception here, but otherwise we do not expect any additional financing needs to support our current business, but for the expansion there might be the path that opportunity. So we really continue to focus on our strategic development in and ensuring that our growth and are potentially expanded pipeline.

Simon: So we really continue to focus on our strategic development and ensuring that our growth and our potentially

Simon: pipeline to provide further life-saving therapies for patients with those unmet medical needs and and we do look for increased returns for our shareholders and especially in the long term here because this is the name of the game at the moment of course when you're standing in front of a possible launch for a new product.

To provide further saving.

Saving therapies for patients with unmet medical needs and we do look for increased returns for our shareholders and especially in the long term here because that's the name of the game at the moment of course, when you're standing in front of a possible launch for our new products that.

Simon: that will transform our company. Because as we stated before, because this is a new disease, because there's no competition and we're first to market, we believe that, and the numbers of patients that we are starting to identify, we believe that Lenio is a significantly larger commercial opportunity than Rupines for this company.

That will transform our company because as we stated before because this is a new disease, because there's no competition and were first to market. We believe bots and the numbers of patients that we are starting to identify we believe that video is a significantly larger commercial opportunity than bedroom permits for this company.

Speaker Change: And that continues the presentation part of this conference. Operator, I would now like to open the floor, please, for questions, and we will provide answers. Thank you very much.

And that continues the presentation part of this.

This conference operator, I would now like to open the floor. Please for questions and we will provide to ounces. Thank you very much.

Speaker Change: Of course, as a reminder, if you'd like to register a question, please press star followed by one on your telephone keypad.

Of course as a reminder, if you'd like to register a question. Please press star followed by one on your telephone keypad.

Speaker Change: If you change your mind please press star followed by 2 and please ensure you're unmuted when speaking.

Have you changed your mind. Please press star followed by two am please ensure you're on mute when speaking.

Speaker Change: Again, that's star followed by one to register a question.

Again, not star followed by warm to register a question.

Speaker Change: Our first question comes from Hartaj Singh with Oppenheimer. Hartaj, please go ahead.

Our first question comes from potash, saying with Oppenheimer. Please go ahead.

Hartaj Singh: Great. Thank you for the question and also all the transparency on the slides. You know, I just want to ask a question of Anurag, going back to the long term data that he presented for Lenyelisib on slides.

Great. Thank you for the question.

And also all of the.

The transparency on the slide.

Just wanted to ask a question on Iraq going back to the long term data that he presented for millennials.

On slide 16.

Anurag: You know, it seems you're having benefits for these patients as they go along or out on therapy.

It seems youre, having benefits for these patients.

As you go longer out on therapy.

Anurag: Does that help you in terms of getting patients on therapy? For example, Vertex, when they presented their long-term data with their CFTR modulators, they've seen increased uptake by patients, physicians, and actually even the payer community likes it because from a pharmacoeconomic background, it's actually pretty useful. Just any thoughts there, and then second question would be, what's the long-term follow-up data you will have by the time assuming you get approval and let you.

Does that help you in terms of getting patients on therapy.

For example, vertex when they presented their long term data with their CF care modulators, they've seen increased uptake by patients physicians and actually even the payer community likes it because from a farmer economic background, it's actually pretty useful. So just any thoughts there and then how much just second question would be what's the long term follow up data you will.

By the time, you get assuming you get approval I'd like I was asking a question.

Speaker Change: So thanks, Arpaj. No, absolutely. I think this long-term data is critical, not only for regulators.

No absolutely.

I think this long term data is critical not only for regulators, but for physicians and essentially payers team because they can see the clear benefits that the drug is having in these patients' lives.

Speaker Change: but for physicians and eventually payers too, because they can see the clear benefits that the drug is having in these patients' lives.

Speaker Change: And the data that we have seen so far is quite encouraging. I shared some of that with you today. And again, that's data from patients going out.

And we are.

The data that we have seen so far.

It's quite encouraging I shared some of that with you today and that's data.

And some patients going out.

Speaker Change: That's two years of data there, but we have data going out for more than five years in some patients.

Two years with data there, but we have data going out more than five years in some patients.

Speaker Change: Um, with respect to your second question, we will have data. We currently have data on more than half of patients for at least two years and then for the other half, even farther, even further out. So I think we have.

With respect to your second question, we will have data. We currently have data on more than half of patients for at least two years and then for the other half even harder.

Further out so I think we have this unique situation where before we're even.

Speaker Change: this unique situation where before we're even applying for approval, we have significant long-term data, plus a double-blind placebo-controlled study in an ultra-rare population. And I think that's quite a good position to be in, and it gives me a lot of confidence when we look at this, again, the totality of the data.

<unk>.

Applying for approval, we have significant long term data plus a double blind placebo controlled study.

And then the ultra rare population and I think.

That's quite a good position to be in and it gives me a lot of confidence when we look at this again the totality of the data.

Great. Thank you Hey, Rob Thanks for the question.

Speaker Change: Our next question comes from Joe Pandagenas with HC Wainwright. Joe, please go ahead.

Our next question comes from Joe <unk> with H C. Wainwright Joe. Please go ahead.

Joe Pandagenas: Hey guys, good morning. Thanks for taking the question. Simon, I wanted to start with first. Hey there. You made some interesting comments that I'm happy to hear regarding Rukiness market share, you know, in the 70-30, you know, prophylactic versus acute. So do you think it's

Hey, guys. Good morning, Thanks for taking the question.

Simon I wanted to start with first Hey, there you made some interesting comments that I'm happy to hear regarding <unk> market share.

70, 30 prophylactic versus acute so do you think it's.

Simon: it's a fair statement to say that you're not being fully appreciated that while the treatment landscape continues to change, your market share remains stable. That's the first part. And then the second part is, how would you define your primary or beyond initiatives to be able to grow that market share?

It's a fair statement to say that youre not being fully appreciated that while the treatment landscape continues to change your market share remained stable. That's the first part and then the second part is how would you define your primary or beyond initiative to be able to grow.

That market share.

Speaker Change: Yeah, thanks, Joe. I concur with that statement. Indeed. So that's the first one. Secondly, how do we grow? Well, you know, we keep on keep working on it. And as I was saying, we see positive, continuing positive trends. Year on year on year, and including in 21, we see more doctors prescribing Ruconest, and we see more patients being treated with Ruconest. So that gives us the confidence.

Yeah, Thanks, Joe I concur with that statement.

Indeed.

So that's the first one secondly, how do we grow.

We keep on keep working on it and as I was saying, we see positive continuing positive trends.

Year on year on year, and including in 'twenty, one we see more doctors prescribing <unk> and we see more patients being treated with <unk>. So that gives us the confidence.

Speaker Change: But this, and I was already alluding to that, this, under this changing prophylactic landscape, you know, the hypothesis that we positioned years ago that, you know, although, you know, the patients have got a lot better prophylactic options now, they're all bradykinin-calocrine inhibitors, and they're all still suffering from

<unk>.

And I was already alluding to that.

This changing a prophylactic landscape.

Note that the hypothesis that we positioned years ago that although.

Patients have got a lot better prophylactic options now.

They're all <unk> inhibitors, and Theyre, all still suffering from breakthroughs.

Speaker Change: And, you know, that is, that means that it is, we have become very rational with that paradigm change to bradykinin and coliclin away from C1 for prophylaxis.

That is that means that it is we have become very rational with our paradigm change to <unk> color screen away from C. One for prophylaxis to have the C. One inhibitor, because if you're already blocking fully that pathway and you still get a breakthrough attack it doesn't make much sense to put additional bradykinin concrete ambition in place right <unk> is a breakthrough and I think that.

Speaker Change: to have a C1 inhibitor because if you're already blocking fully that pathway and you still get a breakthrough attack, it doesn't make much sense.

Speaker Change: to put additional bradykinium-chloroquine inhibition in place, right, as a breakthrough. And I think that we positioned that a long time ago, and we see that actually gradually happening. And of course, this is something that, you know, is a slow process because, as you know, in markets when products are established, you know, it takes a lot to actually move market share away. That's why we feel very confident.

We positioned at a long time ago, and we see that actually gradually happening and of course. This is something that is a slow process because as you know in markets. When products are established it takes a lot to actually move market share away. That's why do you feel very confident.

Speaker Change: Now, this is a relatively stable market and we should be able to actually continue to grow gradually into this market going forward. And that's why for the first time, as I said, you know, we're guiding for, you know, a single digit, continued single digit growth or a return actually better to single digit growth because, you know, of these underlying trends. I hope that answers your question, Joe.

This is a relatively stable market and we should be able to actually continue to grow gradually into this market going forward and thats why for the first time as I said.

Guiding for.

Single digit continued single digit growth or return actually better to single digit growth because you know all of these underlying trends I hope that answers your question Joe.

Joe Pandagenas: No, it certainly does as the market dynamic continues to change. So thanks for that. And I guess, you know, my next question, I guess, you know, not necessarily looking for, you know, guidance, but when you consider your R&D expense going forward, you obviously have the cost savings from the recent Santa Fe announcement. And, but, you know, you have the potential for portfolio expansion. So I guess when you link these potential in-license products.

No. It certainly does as the market dynamic continues to change so thanks for that and I guess my next question I guess not necessarily looking for.

Guidance, but when you consider your R&D expense going forward you, obviously have the cost savings from the recent Santa fee announcement, and but you have the potential for portfolio expansion. So I guess when you link these potential in license products too.

Joe Pandagenas: to either your current manufacturing? Is this something that you would look to do in-house or sort of, you know, add on to what you're doing with Sanofi and the overall impact to your, you know, your R&D, you know, for manufacturing especially?

Either your current manufacturing is this something that you would look to do in house or sort of add on to what youre doing with Santa fee and the overall impact to your.

Your R&D for manufacturing, especially.

Speaker Change: Yeah, yeah, manufacturing, you know, lady only ship obviously is a is a small molecule. So that's a different, quite a different animal. Son of fee is our long term partner for, you know, a reconnect, which is, of course, biological. And we feel very confident and very, very happy with them. And it's mutual. So basically, manufacturing is not our game, right? We decided. So that's why, you know, we have also outsourced

Yeah, Yes manufacturing.

Let me ownership, obviously is there is a small molecule. So that's a different quite a different animal.

Sanofi is our long term partner for Loopnet switches of course a biological.

And we feel very confident and very.

Very happy with them and as mutual.

So basically manufacturing is not our game rights, we decided so.

That's why we have also outsourced.

Speaker Change: Although we are responsible for the manufacturing of the OECIP that was tech transferred by Novartis to us.

We are responsible for the manufacturing of Randy you always sit there was a tech transfer by Novartis to us, but we are of course outsourced. The manufacturing also lending ownership to a contract manufacturer that can do these things much more efficient and much better.

Speaker Change: But we have, of course, outsourced the manufacturing of Lanyonisip to a contract manufacturer that can do these things much more efficient and much better and with a lot lower risk than if we were to engage in this, although we have expertise in-house.

Lower risk than if we were to engage in this although we have expertise in house, it's better to actually you don't do that stick to your strengths and our strengths are really the clinical development of compounds in rare and ultra rare diseases and of course, the commercialization of a rare and ultra rare diseases, you really understand that that's why it's relatively easy to bolt on these.

Speaker Change: better to actually not do that and stick to your strengths. And our strengths are really, you know, the clinical development of compounds in rare and ultra-rare diseases, and of course, the commercialization of rare and ultra-rare diseases. We really understand that. That's why it's relatively easy to

Speaker Change: these additional opportunities for portfolio expansion from in licensing or acquisition. But also, I think, Joe, what we also see is

Opportunities for portfolio expansion.

From in licensing or acquisition, but also I think Joe what we also see is Novartis has a very solid company and they have done some very solid research collaborations on <unk> in additional indications with renowned institutions.

Speaker Change: You know, Novartis is a very solid company and they have done some very solid research collaborations on Leniozid and additional indications with renowned institutes.

Speaker Change: And that is actually something we're looking into as well, to actually see whether we can actually formulate an additional clinical trial program in the not-too-distant future to investigate subsequent indications for leniolysis beyond APDS.

That was actually something we are looking into as well.

So actually see whether we can actually formulate an additional clinical trial program.

Not too distant future.

To investigate a subsequent indications, Florida for linear ownership beyond <unk> and Essex. This is a very exciting prospect as well that will not bring any complications obviously to the manufacturing, but just add synergies I would say.

Speaker Change: And that's a very exciting prospect as well. That will not bring any complications, obviously, to the manufacturing, but just add synergies, I would say. Very helpful.

Okay very helpful. Simon Thanks, a lot.

Thank you Joe.

Speaker Change: Our next question comes from Alex Koga with Kempen. Alex, please go ahead.

Our next question comes from Alex <unk> with Kempen, Alex. Please go ahead.

Hi, good.

Alex Koga: Good morning or afternoon, I just have a couple of questions on the guidance. So within your.

Good day.

Or afternoon.

Got a couple of quick on the guidance.

Within your.

Alex Koga: single-digit top-line growth. How much is that due to volume growth expectations or the 5% increase that you've enacted for this?

Single digit top line growth, how much is that due to volume growth expectations or the 5% increase that you've enacted for this year.

Speaker Change: Yeah, Alex, I saw that. You noted that this morning. We actually, in line with industry practice,

Yeah, Alex I saw that.

You know start.

This morning, we.

We actually.

In line with industry practice, we sort of take it.

Speaker Change: we sort of take a, you know, a typical price increase year on year and have been doing that. But there's an underlying, there's underlying volume growth, as I was hopefully explaining earlier in the presentation. And if you want to sort of, you know, I don't know what precisely the mix will be, because it's a little bit more complex than that, of course, because there's a gross net effect as well, which is always difficult to estimate how large that will be going forward. But I would say 50-50 is probably a reasonable

Typical price increase year on year and have been doing that.

There is an underlying.

Lying volume growth as always hopefully explaining earlier in the presentation.

And if you want to sort of.

I don't know what precisely the mix will be because it's a little bit more complex than that of course, because there is a gross to net effect as well, which is always difficult to estimate how large that will be going forward, but I would say 50 50 is probably a reasonable guess.

Speaker Change: with regards to pricing and volume effects, but it's definitely a positive volume trend underlying these remarks here. I hope you understand that by now.

With regards to print to pricing and volume effects, because it's definitely a positive volume trends underlying these <unk>. These remarks here I hope you understand that by now.

Speaker Change: Yeah, of course. Thank you. And I also noticed a sentence in your guidance or in your outlook on no longer investing in the current business. Does that include other indications?

Yes of course, thank you.

I noticed in your guidance or in your outlook on no longer investing in our current business and does that include other indications.

Farooq on that.

Speaker Change: Yes, it does, but that's a really long-term game, as you rightfully pointed out, and I think, you know, the very best case, of course, is that we will be working for a while with our AKI study, which is a 2B study, which has to be followed by a pivotal study, and this is, of course, a different animal. This is going to be large studies.

Yes, it does but.

That's a really long term game as you rightfully pointed out and I think.

The very best case of course is that we will be working on.

While with our <unk> study.

Which is to be study, which has to be followed by a pivotal study and this is of course, a different animal is going to be launched studies. So definitely that's a long term thats. The long term. This long term perspective, but for the short term I think it's much more important to realize that we are going to significantly invest in linear ownership preparations for long.

Speaker Change: So definitely, that's a long-term perspective. But for the short-term, I think it's much more important to realize that we are going to.

Speaker Change: significantly invest in learning ownership preparations for launch, but also, as I was just saying earlier, in actually.

But also as I was just saying earlier.

And actually I'm trying to formulate.

Speaker Change: I'm trying to formulate these research collaborations that Novartis has done for leniolecip and coming to hopefully filing another IND in the not-too-distant future for leniolecip for a secondary indication.

These research collaborations that Novartis has done for linear ownership and I'm coming to hopefully filing another IND and the not so distant future for lending only support a secondary indication that will of course drive growth much sooner than that.

Speaker Change: and that will of course drive growth much sooner than that these long-term projects as for instance AKI would be. So I would say for the near-term growth, Lanyosip is not only a significantly larger, has a significantly larger commercial potential we believe than Rupines,

These are long term projects for instance, Hai would be so I would say for the near term growth Lenny ownership is not only a significantly larger hasnt significantly larger commercial potential. We believe then refinanced.

Speaker Change: But also, there's a second indication possibility. And of course, we continue our search for additional acquisitions and in-licensing opportunities, which we can afford, of course, because as I was saying earlier, we have access to additional debt capital if necessary. We have a balance sheet of 190 million euros. And as Jeroen was showing, we have very strong cash flows from our operating business.

But also there is a second indication possibility and of course, we continue our search for additional acquisitions and in licensing opportunities, which we can afford of course, because as I was saying earlier, we have access to additional debt capital if necessary.

Our balance sheet of 190 million euros.

As your room was showing very strong cash flows.

From from operating from our operating business. So that those all those elements together I think those things will drive are far more important to drive the growth prospects of the company going forward and to help us.

Speaker Change: So that those all those elements together, I think those things will drive are far more important to drive the growth prospects of the company going forward and to help us, you know, grow significantly over the coming and the coming years.

Grow significantly over the coming in the coming years.

I hope it answer your questions Alex.

Speaker Change: Yeah, so just to be clear, the preeclampsia study will never restart.

So just indicating that theyre paying clumps that study will never pretty stark.

Speaker Change: I think we'll have a critical look at these kind of projects, indeed, what the prospects of those projects would be for the growth prospects of the company. And as you already heard me say, most important ones are not related to the C1 in the short to medium term, but are related to the Lenioli SIP and other opportunities.

I think we will have a critical look at so these kind of projects indeed, what's the what's the prospects of those.

<unk> would be.

The growth prospects of the company and as you've already heard me say.

Most important ones are not related to the Q1.

In the short to medium term, but are related to the linearity Sip and other opportunities.

Speaker Change: Got it. And then on on linearity, as I mentioned, there's a second potential indication. Can you give us a bit more details on that?

Got it and then on linear they notice it as I mentioned Theres, a second potential indications can you give us a bit more details on that.

Speaker Change: No, because there's several research collaborations that Novartis have engaged in, and, you know, we're very happy to have a chief scientific officer since last year, August .

No because there are several our research collaborations that novartis have engaged in and we're very happy to have chief Scientific officer since since last year August these diving into these things.

Speaker Change: He's diving into these things in a very enthusiastic way, and we're trying to, of course, to make a selection which of these research collaborations, research results, are the most promising ones that we can actually develop. But those are additional rare indications where the PI3 kinase delta pathway is involved.

And a very enthusiastic way and we're trying to of course to make a selection which of these research collaborations research results are the most promising ones.

That we could actually develop but those are additional rare rare indications, where the <unk> kinase Delta pathway is involved in as you know the Pi three kinase Delta profit is quite an important one so.

Speaker Change: As you know, the PI3 kinase delta pathway is quite an important one.

Speaker Change: So, you know, we'll of course update the market as and when we have decided on such thing to move forward.

So we'll of course update the market as and when we have decided on such thing to move to move forward, it's not going to be tomorrow of course, obviously, Alex but not too distant future hopefully.

Speaker Change: It's not going to be tomorrow, of course, obviously, Alex, but not too distant future.

Speaker Change: Fair enough. And just the last one on lenoriceb. I've got in the local press that you mentioned that it can be a bigger drug than ruconet. So shall we take that as official guidance that pixels are over 200 million?

Fair enough and just a last one on that and then you always said I've gotten in the local press that.

You mentioned that it can be a bigger driver than require so shall we think that as official guidance.

<unk>.

Speaker Change: No, there's no official guidance because, you know, I leave guidance to, I leave these kind of predictions happily to the professionals, i.e. you guys, the analysts.

No there's no official guidance because I leave guidance to do these kind of predictions heavily to the professionals you guys. The analysts.

Speaker Change: But, you know, if you sort of look at the number of patients, and Anurag was alluding to that, you know, there's already, without any systematic patient search, there's already 60 patients identified in France by a couple of doctors.

If you sort of look at.

The number of patients on <unk> was alluding to that.

Theres already without any systematic systematic.

<unk> search there is already 60 patients identified in France by a couple of the doctors.

Speaker Change: starting a registry. That means that there is already a million, one in a million patients identified.

Charting a registry.

That means that there is already a million one in 1 million patients identified and we haven't even started looking Florida for these patients in earnest. So we will significantly amp up the search.

Speaker Change: And we haven't even started looking for these patients in earnest.

Speaker Change: So we will significantly amp up the search for these patients by means of deploying a significant number of new medical colleagues in the US and the European market.

Search for these patients by means of deploying a significant number of medical call it new medical colleagues in the.

In the U S and the European markets to find those patients and of course as and when these patient numbers come up you can make your own calculations I would say, but we definitely.

Speaker Change: find those patients. And of course, as and when these patient numbers come up, you can make your own calculations, I would say. But we definitely, at this point in time, are confident that the product will have a potential that is significantly larger than the Nuconest.

At this point in time, our confidence that the product will have a potential that is significantly larger than interconnect.

Okay. Thank you very much.

Thank you Alex.

Speaker Change: Our next question comes from Christian Glenny of Stifel. Christian, please go ahead. Yeah, good afternoon. Three questions.

Our next question comes from Christian Glennie of Stifel. Christian. Please go ahead.

Yes, good afternoon.

Three questions and take them in turn.

I'll answer the first one in terms of the U S potential refinance great, but thinking about rest of Europe and rest of world growth.

Christian Glenny: growth but thinking about rest of Europe and rest of world growth or some sort of guidance on on 22 numbers obviously had

So some sort of guidance on 'twenty two numbers, obviously, you had a bit of a step down last year in Q4.

I had a pretty pretty low number there.

Christian Glenny: low number there just for my idea about how revenues reconnect.

My idea about how revenues recognized revenue might recover will grow in 'twenty.

Speaker Change: Yeah, I mean, yeah, Christian, thanks, but you know that that there is little commercial opportunity in Europe for all sorts of reasons, historical reasons, mainly. So that's one thing. Secondly, you heard to say that, yes, we are expanding and of course, we will again, we will sell Ruknest and make some money out of that in the additional territories that we're exploiting, exploring and exploiting.

Yeah, Yeah, Chris.

There is little commercial.

Opportunity in Europe for all sorts of reasons historical reasons, mainly.

So that's one thing.

It could be you heard to say that yes, we are expanding and of course, we will again, we will sell <unk> and make some money.

The additional territories they'd be exploiting exploring and exploiting.

Speaker Change: I think the main thing is, of course, that we are looking to put our network out for the rollout of Flaniosa, because there we are not inside a reference pricing system with historical pricing.

I think the main thing is of course that we are looking to put our network out for the rollout of <unk>. It because there we are not.

In.

Inside our reference pricing system are at historical prices, but there of course, we will introduce the product in a certain price band worldwide. So therefore, the commercial potential and that respectfully in your ownership is significantly larger than very significantly large andrukonis. So this would mean that we can have proper commercialization operations on both sides of the Atlantic in Europe .

Speaker Change: But there, of course, we will introduce the product in a certain price band worldwide. So therefore, the commercial potential in that respect for Lenny Olusep.

Speaker Change: significantly larger than, very significantly larger than Ruknets, which will mean that we can have, you know, proper commercialization operations on both sides of the Atlantic. And you heard already Anurag say in Japan as well.

Alright, <unk> say in Japan, as well and with regards to those fluctuations and look at US you mentioned an interesting one.

Speaker Change: And with regards to those fluctuations in Rukidas, you do mention an interesting one. The fluctuation in Rukidas also, to a great extent, was because there was, before Brexit in the end of 2020, there was a significant order placed.

The fluctuation.

<unk> also to a great extent was because there was before Brexit and the end of 2020, there was a significant order placed to.

Speaker Change: to make sure that the UK had sufficient supplies of rucinacin.

To make sure that the UK had sufficient supplies of loopnet available on that order actually meant that for I think for the most part of 2021. There was no order from this in the United Kingdom that was a big swing in the in the negative results versus 'twenty one.

Speaker Change: available. And that order actually meant that for I think the most part of 2021, there was no order from the from the United Kingdom. That was, you know, a big swing in in the negative results versus 21 versus 20 in Europe . So you had this big swing in the U.S. Q4 21 with regards to the COVID, you know, where patients were with hindsight.

Versus 'twenty in Europe . So you had this big swing in the U S Q4, 'twenty, one with regards to the Colgate.

Patients.

Speaker Change: uh filling more prescriptions that fill their prescriptions quicker just to make sure they had drug we have the same in the brexit so q4 20 uh 2020 was really um you know a super quarter i think one of the best quarters we ever had but now we know why

With hindsight.

Sterling more prescriptions that and filling their prescriptions quicker just to make sure that drug with the same so Brexit. So Q4, 'twenty 2020 was really.

A super quarter, I think on the best quarters, we've ever had but now we know well.

Speaker Change: uh and of course that Brexit thing has been mentioned before so it should be a little bit more balanced out this this year we believe but the guidance overall is not specific for the US it is for the company as a whole right the the single digit growth that we're expecting in in 2022 over 2021. All right Christian. Yeah thank you um and then on a sort of modeling one OPEX uh two things there one was

Alright, otherwise.

And of course that Brexit.

Thing has been mentioned before so it should be a little bit more balanced out. We said this year, we believe but the guidance overall is not specific for the U S. It is for the company as a whole right. The single digit growth that we're expecting in 'twenty two over 2021 alright Christian.

Yes. Thank you.

And then on a sort of modeling one opex.

Two things that one of them is G&A stepped up quite significantly.

Okay.

What was driving that and then the overall.

Of course, the run rate if you exclude some of the one off some impairments and things is that is that a run rate to take forward into 2022.

Speaker Change: Well, I think Christian, on SG&A, a big part of the expenditure in the whole year, but also in Q4, was because of these additional insurance costs.

Well I think I think Krishna.

SG&A big part of the expenditure and the whole year, but also in Q4 was because of this.

Additional insurance costs.

Speaker Change: and yeah going forward the impairments that we had were in split in R&D for PONDA and DSP was the DSP impairment was in SGNA. Those are one-offs and that will not happen obviously again this year and I don't foresee these kind of big impairments anyway in this year with the current information that we have.

And going forward.

The impairments that we that we had were in.

Splits in R&D for upon them and.

DSP was the DCP impairment was in SG&A those are one offs and that will not happen obviously again this year.

Percy.

These kind of big impairments anyway, and this year with the current information that we have.

Speaker Change: I think you know you agree that we will significantly invest right in in preparations for linearity. Yeah yeah of course but yeah you were talking about impairment but but indeed we are we are stepping up our linearity investments. We did so in 2021 and we will do so even further in in 2022. That's that's clear and that will have an impact on the on the profit as we said before. Yeah.

I think you agree that review significantly invest right in them and preparations from any answer but yes of course, but you were talking about impairments, but indeed, we are we are.

Dipping up our linear leadership investments, we did so into 2021 and we will do so even further in 2022.

Clearly that will have an impact on the profit as we said before.

Yeah.

Okay.

These redemptions will continue.

Run rate as the new base.

Speaker Change: uh yes yes but but i think uh lenny ellisip will will even be more than what we did in q4 throughout 2022 christian okay thank you and then um a related point maybe

Yes, yes, but I think Len.

Let me illustrate we'll even be more than what we did in Q4 throughout 2022 question.

Okay. Thank you and then.

Yeah.

A related point maybe.

Just to clarify when you call out additional manufacturing costs $9 million of money.

Hey.

What does that assume.

Relate to that is is it part of it.

Transplants.

Have you ever in CMI from Novartis.

Speaker Change: Correct. The cost, exactly as you say, is the cost of tech transfer and the cost at the CMO that they are, they have been producing the first tablets. So it's basically development cost at the CMO to produce the first products of Laniolus.

Correct correct.

Correct the cost exactly as you say, it's because of the tech transfer and of course at the CMO that they are having.

<unk> been producing the first first tablets, that's just basically development cost up the CMO to produce the first products of linear ownership.

Speaker Change: And then just finally, on earlier, then you talked about Japan as a potential new market and obviously with development there, is that typically people will look to partner?

And then just finally.

An earlier than you talked about Japan is as a potential new market and sell.

Element there.

Is that typically people will look to partner find a local partner.

Okay trait development.

Is that something you need to see you need to have in place for us.

Before or thoughts in our product in Japan.

Speaker Change: Yes and no. We're working together with a one-stop shop, if I may call it that way, that can help us with the, that helps us with the regulators and has helped us already with the regulators.

Yes, I know, we're working together with <unk>.

One stop shop, if I may call it that way.

Can you help us with the that helps us with the regulators and that helps us already with our regulators that will help us with the clinical trial.

Speaker Change: that will help us with the clinical trial. But again, you know, this is not something where you have to put a ton of people in the market to actually go around to the country. In Japan, as in some of the European markets, in opposite to the U.S.

But again.

This is not something where you have to put a ton of people in the market to actually go around the country and in Japan.

As in some of the European markets in opposite to the U S.

Speaker Change: the treatment of these kind of patients is relatively well concentrated and the pool of patients we find are located in one or two or maybe three centers. So initially that's not a necessity we would say and then we take it further from that. So we think that you know our our idea is to to keep as much as the value chain inside farming as we are doing with Rukiness.

The treatment of these kind of patients is relatively well concentrated in the pool of patients we find.

It is located in one or two or maybe three centers. So initially that's not a necessity we would say and then we take it further from that so we think that.

Our idea is to keep as much as the value chain inside farming as.

As we are doing with <unk> and we see the possibility of maintaining nuts in with linear ownership as well for those reasons as I just described.

Speaker Change: And we see the possibility of maintaining that with Laniolisip as well for those reasons as I just described.

Speaker Change: There will be some partnerships where, but it's more that, you know, you're looking for distribution partnerships where, you know, the vast majority of the proceeds will still end up in our part of the value chain.

There will be some partnerships, where but it's more of that youre looking for distribution partnerships.

The vast majority of the proceeds will still end up in our part of the value chain.

Okay. Thank you.

Right some things.

Speaker Change: We have no further questions on the phone line so I'll hand back for any closing remarks.

We have no further questions on the phone line, so I'll hand back for any closing remarks.

Speaker Change: Yeah, thank you very much. Thank you very much for joining this conference.

Yes, thank you very much.

Thank you very much for joining us for this conference as I was explaining in the beginning of the conference. We're very excited to have for the second time in the history of our company to have closed the cervical data in our hands.

Speaker Change: As I was explaining in the beginning of the conference, we're very excited for the second time in the history of our company to have positive service all data in our hands, but this time to be able to launch a product ourselves.

But this time to be able to launch a product ourselves.

Speaker Change: This will mean all that we can actually keep the value of the product in-house going forward, which means that the company can transform from the one product, one market it currently is, depending on, to two products in multiple markets on both or actually both sides of the Atlantic, but also both sides of the Pacific.

This will mean on that so we can actually keep the value of the product in house going forward.

Which means that the company can transform from a one product one market. It's currently is depending on two two products in multiple.

Markets on boats or actually both sides of the Atlantic, but also both sides of the Pacific, which excites us very much. However, as you also noted in the in the confidence that we will continue to invest very heavily obviously.

Speaker Change: which excites us very much. However as you also noted in the in the conference that we will continue to invest very heavily obviously going forward in 2022 in this launch and that will have a significant impact of course on the profitability of the company for the short term to stimulate that growth from the new product linearship that we anticipate to be launching in within the year from now.

Going forward in 2003, two in this launch and that will have a significant impact of course on the profitability of the company for the short term.

To stimulate that growth from.

The new product Lenny ownership that we anticipate to be launching in within a year from now I would like to thank you very much for your attendance. Thanks. My colleagues you don't Rocco moment underwrite relevant as well and we look forward to updating you in the future on the next occasion when we have the results available. Thank you very much and have a good day.

Speaker Change: I would like to thank you very much for your attendance. Thanks to my colleagues, Jeroen Rockeman and Eric Relen as well. And we look forward to updating you in the future on the next occasion when we have results available. Thank you very much and have a good day.