Pharming Group N.V. (PHAR) Q3 2021 Earnings Report, Transcript and Summary

Thank you very much. Good morning, good afternoon. Welcome to our nine months 2021 results call. I will be happy taking you through the call with a couple of my colleagues, who I’ll introduce later. But before I do that, I would like to point out to the forward-looking statement slide that you see here because we will be making some forward-looking statements that are based upon our current beliefs, expectations and assumptions regarding the future of our business and things can always change, as you know. So, let me go to the next slide, please. And my colleagues who would -- who will be speaking to you as well will be our Chief Medical Officer, Dr. Anurag Relan; and our Chief Financial Officer, Mr. Jeroen Wakkerman, who will speak to you as well. So -- but I will be kicking it off and give you an introduction and talk about the operational growth. Next slide, please. Yes. Thank you. So if we’re looking at our business today, we see a well-funded business supported by commercial sales and a growing pipeline for the treatment of rare diseases and unmet medical needs. And our lead product, RUCONEST, or recombinant human C1 esterase, inhibitor is launched in over more than 40 countries with a sales of more than $146 million in the first 9 months of 2021. And very important, we have a potential near inflection point, a significant inflection point with the anticipated end of 2022 launch of leniolisib, in-licensed from Novartis, for the treatment of orphan disease APDS, activated phosphoinositide 3-kinase delta syndrome, we will now call it APDS going forward. We’re also targeting new large indications to C1 inhibitor within Phase II studies, and we have an early stage pipeline assets, including recently in-licensed potentially curative gene therapy treatment for hereditary angioedema and our own transgenic platform candidate for Pompe disease, alpha-glucosidase protein replacement therapy. Now we are able to leverage our established commercial infrastructure across U.S. and Europe now for in-licensed products and expanding our manufacturing capacity to support continued RUCONEST demand and the C1 pipeline supplies. Last but not least, we have an experienced leadership team and new Board of Directors and a strong balance sheet to support ambitious growth strategy, including potential M&A. And our growth strategy is on the next slide here. It’s built out to 3 pillars. You see on the left-hand side, the first one is to grow and extend our HAE franchise. And therefore, we are fully commercializing RUCONEST in all major markets and expanding the geography still. And of course, we have delivered on this by the recent in-licensing of that early stage asset OTL-105, the ex vivo hematopoietic stem cell gene therapy for hereditary angioedema from Orchard Therapeutics. And then in the middle, of course, you see the extension of the C1 franchise to larger indications and develop new enzyme replacement therapy by means of our own platform. We are engaged in C1 inhibitor for additional large indications and large additional unmet needs, and Dr. Relan will speak to that later. And we are leveraging our transgenic manufacturing platform to develop new next-generation protein replacement therapies. And then on the right-hand side, a recent addition, only last couple of years, we are, of course, able to go seriously into expand -- looking to expand our portfolio and leverage our commercial infrastructure to grow our business. And there, we were already successful, a good 2 years ago when we were successfully in-licensing late-stage asset, leniolisib, for the treatment of APDS. That product that we are aiming to bring to the market by the end of next year, and we will have more in-depth information from that also from Dr. Anurag Relan. And then, of course -- and we’ve said this, we are very active at the moment to in-license or acquire additional late-stage assets in rare ultrarare diseases. We have a very active business development group because we can obviously, through our commercialization infrastructure, leverage that more by additional assets that can be launched within a period between now and 3 years from now. Okay. Let me see what the strategy in action was delivering during the first 9 months on the next slide. Commitment to HAE was, of course, we were successful of in-licensing OTL-105. Then we expanded the reach of RUCONEST with commercialization agreements with NewBridge Pharmaceuticals in North Africa, Middle East, and we got reimbursement in Spain and are bringing RUCONEST also into the Spanish market now. And with regards to the expanding indications, we were successful in restarting the acute kidney injury trial for C1 inhibitor and -- following COVID-19 delays. And recently, we published top line results from recombinant C1 esterase inhibitor clinical trial in severe pneumonia as a result of COVID-19 infection. And then on the right-hand side, we successfully -- of Novartis, actually, because Novartis is still doing this trial, completed enrollment in the Phase II/III registration-enabling study with leniolisib for activated PI3 kinase delta syndrome. And we started to invest seriously into prelaunch activities for the anticipated 4th quarter ‘22 regulatory approval of leniolisib. So it was a busy 9 months, and we look forward to, of course, the following periods. Next slide, please. Now this, of course, shows you the HAE market. This, of course, is our bread and butter and drives, of course, the ability to deliver on all these growth opportunities and to make all these investments. That is RUCONEST’s position, a stable position in the hereditary angioedema treatment market. Hereditary angioedema, as you know, is caused by a deficiency of C1 inhibitor, resulting in those unpredictable attacks of severe swelling in various parts of the bodies. And patients now, especially here, we’re talking about the U.S. market, are using medication for treatment and prevention of these attacks. RUCONEST is approved only for the treatment of acute attacks in adults and adolescents. And in 2020, it was about $2 billion total sales in the hereditary angioedema market. And the good news for the patients is that the increasing use of prophylaxis is taking place because of the fact that newer treatments for prophylaxis offer better attack reduction rates than the previous IV plasma-derived C1 inhibitor prophylaxis treatments. And although these new compounds that are mainly based on the blocking the kallikrein and bradykinin inhibitors, block the main pathway for symptomatology, C1-INH inhibitors levels remain very low. And therefore, it means that approximately half of these patients, despite it being much better than previously, still have breakthrough attacks, some frequently and some regularly and are in need of breakthrough medication. And that is where RUCONEST, apart from the fact that RUCONEST on the right-hand side here has a core segment of severely affected patients, which were unable to get proper results with other therapies, is -- that basically still represents our core of our business. RUCONEST now also finds itself to be treating more patients that are suffering from breakthrough attacks under the new prophylactic treatments that only suppress the bradykinin and kallikrein axis. So therefore, we are optimistic and we remain optimistic, and you have seen it in the results of this year that we have a gradual recovery from the impact of COVID-19. We remain optimistic about continued growth of RUCONEST in the hereditary angioedema markets. We also remain optimistic because of this picture here, what you see, it is indeed that, of course, a busy entry of new better prophylactic therapies, the shift in the U.S. market, as predicted, was moving towards prophylaxis. But we see that trend now as being sort of saturated. And therefore, those who were predicting that there was no place for acute therapies anymore with prophylaxis are actually proven to be not quite right because as you can see and as I was saying too earlier, every -- there needs to be acute treatments available even when you use prophylaxis because prophylactic therapies have breakthrough attacks, and they can be very unpredictable. So good clinical practice actually says that patients need to have always at hand, the acute therapies as well. And that is the opportunity for RUCONEST, certainly because the paradigm has changed from C1 inhibitor prophylaxis towards bradykinin and kallikrein suppression, that’s why RUCONEST has an opportunity now here for even supporting further growth for RUCONEST. So let me then look at what the next key near-term value inflection points will be as we build our sustainable business. You see here that we are looking, of course, to deliver the pivotal study results from the study done by Novartis on leniolisib in the beginning of next year. We anticipate also in H1 to file the regulatory filings for leniolisib, and we do that ourselves to FDA and EMA. Then we expect to initiate pediatric studies for leniolisib in the second half of next year, and we anticipate the regulatory approval, hopefully for leniolisib towards the end of next year. And on top of that, you see here that we anticipate the complete enrollment in the AKI study in the second half of next year and the initiation of a Japanese clinical trial for leniolisib as well in the second half of next year because we have the objective to also spread out to Japan with leniolisib into the future. And that brings me to the last slide of the introduction. It’s an overview of our pipeline here where you clearly see that we have, of course, RUCONEST in the market quickly followed by leniolisib, which, again, we hope to be able to bring into the market by the end of 2022. And with that said, I would like to hand over now to my colleague, Dr. Anurag Relan, to take you through a medical and clinical update. Anurag, over to you, please.

Thank you, Sijmen. I’d like to begin by talking about hereditary angioedema and our new collaboration with Orchard Therapeutics with our product, OTL-105. And with this collaboration, the goal is to develop and commercialize an ex vivo autologous stem cell therapy product, gene therapy product for hereditary angioedema. The product will insert one or more functional copies of the SERPING1 gene into patients, and this will use their own hematopoietic stem cells. And this is done ex vivo, which are then transplanted back into the patient. And the goal is to be able to provide a potential durable C1 expression. In preclinical studies to date, we have seen that OTL-105 demonstrates high expression levels of the C1 inhibitor protein using lentiviral-mediated transduction in multiple cell lines, including stem cells. And we’ve also been able to see that the C1 inhibitor that’s produced is functional in a clinically validated assay. Together with Orchard Therapeutics, we’re able to leverage each of our expertises. And with Orchard, we have a partner that has expertise in gene therapy, in developing these vectors. They have an established network to manufacture the product. They’ve done many animal studies, and they have discovery capabilities. And on our side, we have significant clinical and commercial expertise in HAE, of course. We have an ability to assist with the preclinical disease models for HAE. And we have, as you’ve heard from Sijmen, capital to fund ongoing development and future commercialization. Together, this combined expertise goal is to bring a best-in-class HAE gene therapy to provide a potential cure for these patients with a single administration of OTL-105. The way this works is that it begins with harvesting cells from the patient. These stem cells are then purified. And then outside the body, again, ex vivo, a working copy of the gene is inserted using a viral vector. The patients is then conditioned or spaces made in their bone marrow to receive the treatment. And then essentially, the gene-corrected cells are infused back into the patient where the goal is to be able to spread high levels of C1 inhibitor. This type of approach using HSC in gene therapy has advantages over other potential approaches. The first point is that it’s proven. There are multiple products approved using this approach. The other approaches do not yet have products approved, and this includes AAV-mediated gene therapy as well as gene editing approaches. Secondly, there is proven efficacy based on other clinical programs, and we’ve seen in animal data with OTL-105 that we can achieve significant expression levels. This has proven to be an issue using AAV gene therapy, especially when we think about sustainability of effect. The same goes for gene editing, where preclinical data appears promising, but this -- in a clinical setting, this remains to be seen. And thirdly, on the durability of effect, we’ve seen with other programs from Orchard as well as others that the HSC gene therapy approach can provide sustainable levels over many years. Data that has been published in hemophilia A using AAV-mediated gene therapy suggest that this can be a challenge. And on the gene editing side, this should actually be possible, although, again, the clinical data are not available. And then lastly, on safety, using autologous cells, which the patient does not recognize as foreign, appears to be safe. And again, this has been approved in other disease states. With AAV gene therapies, there have been significant questions that have been raised, especially recently. This may be related to immune-mediated responses to the AAV vector. And then with gene editing, it’s promising, but no conclusion still can be drawn. And I think with the approach in HAE, one of the potential concerns is that this is causing permanent kallikrein inhibition without an on-off switch, if you will. So we’re quite excited about the possibility of using HSC gene therapy in HAE, and you’ll be hearing more about this program in the coming quarters. I want to turn now to talk about APDS and leniolisib and leveraging our commercial infrastructure, our expertise in immunology to grow our business further. Let’s start by talking about APDS. So APDS, activated PI3K delta syndrome, there’s estimated to be more than 1,350 patients across the U.S., EU and Japan that have APDS. This is based on an estimated prevalence of 1.5 per 1 million. Those are estimates, of course. But during just the past few months through our own efforts, we have identified more than 350 patients in these areas that have APDS. And as there’s been a growing understanding of primary immune deficiency among which APDS is one, there is the potential to find even larger patient populations. But APDS is a serious disease. And like many rare diseases, these patients spend a long time undiagnosed or misdiagnosed. They see numerous specialists. The symptoms begin in childhood, but again, there’s a significant delay in diagnosis. This disrupts their quality of life, school and, of course, social development. They haven’t -- oftentimes have had multiple biopsies, numerous specialists are actually -- even after the diagnosis, numerous specialists are required to manage these patients. And because of the burden of the disease, these patients have significant depression as well as fatigue that impacts their quality of life. You see on the bottom the type of manifestations that APDS has. Because it’s primary immune deficiency, it causes severe infections, including a problem eventually called bronchiectasis due to these severe infections. It can also cause issues related to the GI tract and cause problems with absorption and autoimmune phenomena. But the heart of it is, is that it causes swollen lymph nodes because there is this unchecked lymphoproliferation that occurs, and this can be manifested by large lymph nodes and then large spleen as well as liver. And although it’s a primary immune deficiency, it also has this other side of it where it causes autoimmune complications, including severe anemias. And then lastly, because these blood cells have imbalanced signaling in the critical pathway of development, these patients often develop lymphoma. On the top right, we see the treatment options, which really are supportive and nonspecific therapies. So using antibiotics when they get infections, trying to use steroids to try to control the disease. Many of these patients are also on immunoglobulin replacement therapy. There are off-label uses of other types of immunosuppressive drugs to control the lymphadenopathy or swollen lymph nodes that these patients have. And in severe cases, these patients go on to stem cell transplantation. But the bottom line is that there is no approved therapy for these treatments -- for these patients. And despite the availability of these current treatment options, the disease is really poorly managed. In leniolisib, we have something that is in development now for the treatment of APDS. And as you heard from Sijmen, our goal is to have a PDUFA date by the end of next year. Leniolisib is an oral selective PI3K delta inhibitor. The biomarker data shows that it has a direct impact on the root cause, namely PI3K delta over activation. And by doing so, it has the potential to mitigate the progression of the disease and reduce treatment burden. We’ll talk a little bit more about this in the next slide, but the diagnosis is made by a commercially available genetic test, and you’ve heard from us during earlier this year that we’ve launched a program to make that more widely immovable. On the regulatory side, we do have orphan drug designation both in the U.S. as well as in Europe. And again, the nice thing about this program is that it fits on top of our existing core expertise in immunology with HAE. We’ve talked a little bit about what APDS is already on the right, but it’s caused by mutations in 1 of 2 genes, leading to these 2 different forms of APDS, which really have very similar clinical manifestations. And the bottom line here is that there is overactivation of this pathway which causes this dysfunction and dysregulation of the immune system and, of course, balance signaling is needed for immune -- normal immune function. On trying to find patients, we’re doing quite a bit of work. And as I mentioned earlier, just through our initial efforts, we found several hundred patients, both in the U.S. as well as in Europe. We are creating, first of all, a network of specialists and a referral pathway of prescribers that we’ve identified through our field medical activities. On top of that, we’re using an analytical-based approach using artificial intelligence to look at patients who have the clinical manifestations of APDS but may not have yet been diagnosed. And doing this, we can get out there in the field and promote and let doctors and eventually, patients know that we have a free genetic testing program that’s sponsored by Pharming that we have put out there together with Invitae to help diagnose these patients. We’re promoting this both in the community of immunologists and hematologists who see these patients, but also with a variety of organizations that are active in the primary immune deficiency fields, including Immune Deficiency Foundation, Global Genes and the Jeffrey Foundation. Next, I want to talk to you a little bit about the pivotal trial that’s wrapping up as we speak. The study had 2 parts. Part 1 was a dose-finding part. And in this part of the study, 3 doses were evaluated in a dose escalation form. This was looking at patients with APDS with this mutation and typical APDS manifestations and symptoms. Outcomes, of course, were safety and tolerability, looking at pharmacokinetics and looking at the degree at which we could block this hyperactive pathway. Based on that work, the dose of 70 milligrams twice daily was selected and these results have been published, which is the second reference on the bottom of the slide here. And this dose of 70 milligrams twice daily was selected for the double-blind placebo-controlled part of the study. In this part of the study, patients were randomized 2:1 to receive leniolisib or placebo for 12 weeks. And the primary endpoints were the degree of lymph node swelling or lymphadenopathy and the immunophenotype normalization, so looking at specifically in B cells to see which proportion of cells we can return to a functional status so that they can fight infection in these patients. After the randomized controlled phase of the study, the patients were allowed to enroll into an extension phase, which is still ongoing. As Sijmen mentioned earlier, Novartis has completed enrollment in the study, and we expect results to be available early next year. And with that, I will hand it over to Jeroen to review the finances.

Yes. Thank you very much, Anurag. The financial highlights for the first 9 months of 2021, and there’s a subtitle called building a sustainable business, and that’s obviously reflecting the efforts we’re taking on having RUCONEST as the cash generator at the moment, but also building more and more for the future. So that is leniolisib for the, let’s say, medium term and OTL-105 for the longer term, next to our other in-house product development efforts. So we are creating a more balanced portfolio for the future. And that’s also what you will see when I go through the numbers, amongst others in the operational cost. Q3 showed a 6% increase in sales from Q2 this year. And looking for the year-to-date numbers, we have a 4% decrease. So what we basically see in the sales is an ongoing recovery quarter-on-quarter in sales following the impact from COVID-19, especially in Q1, on the U.S. health care economy. And that was previously noted in our earlier financial reports as well. Then if I look at the sales and especially the regional split. The recovery in the U.S. was sharp with an increase of 6%, and the drivers being basically new patient enrollment. Every quarter, we increased the number of new patients being enrolled. But also ongoing product demand despite the prophylactic products that Sijmen also talked about, which seems that the growth seems to be stabilized against acute products. For the first 9 months in the U.S., we had a decrease of 3%. And in Q3, in the rest of the world and Europe, sales were $1.9 million, which is a big increase compared to Q2. But that is mainly because of phasing and which we have seen quarter-on-quarter in Europe and the rest of the world. But also, we entered a new country in Q3 where we sold product for the first time. The 9-month sales in Europe and the rest of the world were $5 million against last year, $6.1 million in Q3 2020. Going to profitability, gross profit increased by 4%, in line with increased quarter-on-quarter revenues and also for Q3. Year-to-date, you see a development in line with the sales development, a 3% decrease in comparison to the first 9 months of last year. And this also means that we have a stable gross margin of around 89%. Moving on towards the operating profit and the operating cost. The operating profit was $15.3 million Q3 year-to-date, and that is a decrease of 72% on last year. So that needs a bit of an explanation. The -- it was mainly because of the increased operating costs, and that includes significant investments in the pipeline. The OTL-105 investment and collaboration was already mentioned. We paid in total $17.7 million for it, $13.1 million has gone through the P&L in Q3 and another $4.6 million you will see later in investments because we bought shares of this company as part of this overall transaction. So again, $17.7 million in total, $13.1 million going through OpEx and $4.6 million is in shares. And also, we had increased cost of corporate development. So operating costs increased from -- sorry, $116 million compared to $78 million last year. Increased R&D expenditure, I will show you the numbers later. The cost of the OTL-105 license, leniolisib prelaunch marketing preparations, but also manufacturing costs for leniolisib. So we have the first manufactured product. An increase in employee numbers to support the future growth of the business and share-based compensation. And in addition, also mentioned before, we had an increase in liability insurance, but also in compliance and control costs and that is related to the recent NASDAQ listing, and that was also previously noted. The net profit for the first 3 quarters of the year was $13.9 million, and that is a 49% decrease from last year. And again, it’s a result of initial in-licensing cost from OTL-105, leading to the lower operating profit. And that is offset by currency exchange rate results and lower funding costs. And that’s what you see on the next slide, a bird’s eye view on what happened to the profit before tax last year of $38.1 million and $21.3 million this year, Q3 year-to-date. So the underlying business gross profit went down by $3.7 million. So that’s both gross profit and other income. As I’ve just mentioned, the OTL-105 investment, $13.1 million cost. Increase in research and development expenditures, and that -- more than half of it is from leniolisib. So that’s an important part of the R&D expenditure. But also an increased SG&A cost, we see leniolisib. For example, the patient-finding cost that Anurag just mentioned, is an increase in cost. So you see that across the board, we are increasing our investments in the launch of -- and manufacturing of leniolisib. Also part of this SG&A increase is the liability insurance increase. The dark blue effects are positive, and they are in the net financing cost, if you go through the P&L. A big foreign exchange effect on the cash that we have. Last year, we had a negative effect of $10 million. This year, we have a positive effect of $10 million. Hence, the comparison is $20 million positive. Last year, we had the settlement expenses from the Orbimed loan. We settled that loan, $4.3 million, and that has a few other things as well. So again, to explain these, the drop in the profit before taxes, it’s important to understand the aim of what we’re doing. We’re build in the business, including the investment in OTL-105 and including investments in the launch of leniolisib. Moving to the cash flow. At the beginning of the year, we had $205 million cash and cash equivalents on the balance sheet. At the end of Q3 was $183 million. And that was driven by operating cash flow increase of $28.2 million, very much in line with the profit before tax. Changes in working capital, cash outflow of $6 million, mainly because we paid more payables so we used the cash for that. Investing activities, it’s a mix. The $15 million that went out, investment in the production facilities for RUCONEST, investment in ERP system that we’re going to bring live next year. OTL-105, as I said. $4.6 million of shares that we invested in, and also included here is license cost for leniolisib. The financing activities is in total $27.7 million, and the big chunk of $25 million, important to note, that is the milestone payment -- the final milestone payment that we paid to Bausch, and that is related to the acquisition -- reacquisition of the commercial rights of RUCONEST. So those cash outflows are over. So overall, a reduction in cash of almost $22 million. But keep in mind, $25 million of that is because of the Bausch one-off payment, $17.7 million in total was related to the OTL-105 payment. So that’s, in total, almost $43 million of one-off payments that are supporting future growth of the business. Yes, we can go to the next slide because this is basically a repetition. So the financial outlook for the remainder of 2021. We continue to expect quarter-on-quarter increase in revenues from RUCONEST sales due to normalizing of the pharmaceutical markets following the impact of COVID-19, especially in Q1 in the U.S. However, with COVID developments, we will continue to monitor the situation in all markets. And given the developments, we could expect some periodic disruptions again. We continue to expect maintenance of positive net earnings during the remainder of the year. We keep on investing in launch-critical medical affairs and premarketing activities for leniolisib as well as continued investments in ongoing clinical trials for RUCONEST and other indications are -- the current indications for RUCONEST and other development activities, including OTL-105. And we are constantly looking, as Sijmen said, at acquisitions and in-licensing of new development opportunities and assets. And that’s the only the financial guidance for 2021 that we will, at this stage, give. With that, that’s the end of the presentation part of this call. And I’d like to hand over to Sijmen for the -- to lead the Q&A.

Thanks, and before I do that -- thanks, Jeroen. Before I do that, I would like to summarize that you’ve seen our well-funded business, supported by commercial sales and a growing pipeline for the treatment of these rare and ultra-rare diseases and unmet medical needs. The lead product from our platform, RUCONEST, as you’ve seen, stable, growing, picking up growth again, and we are optimistic towards the future that growth continues. And we realized $146 million in the first 9 months. I’d point out again that we have a significant potential near inflection point with the anticipated launch of leniolisib towards the end of next year that we in-licensed from Novartis and you heard Anurag talk about it and about our patient finding efforts that have just started and already have yielded more than 350 APDS patients that were identified, and we continue -- in fact, we will increase the activities of this next year for this, of course. We’re targeting the new launch indications for C1 inhibitor. We have early-stage pipelines. Again, you heard Anurag explain our in-licensing of OTL-105. And of course, we are able to leverage further our commercialization infrastructure in the U.S. and Europe for in-licensed products and expanding manufacturing capacity. And we’re on the hunt for additional late-stage assets to add to our portfolio and further leverage the commercialization infrastructure of the company with products that can be launched between now and 3 years’ time. And last but not least, the experienced leadership team and strong balance sheet that continues and can support our ambitious growth strategy, including those potential M&A transactions. With that, I would like to hand over back to the operator now and open the floor for any questions that you may have. And we also have here present our Chief Commercial Officer, Stephen Toor, to answer any questions that you may have on commercialization. So operator, please open the floor for questions. Thank you.

[Operator Instructions] We have one question from Hartaj Singh from Oppenheimer & Co.

Great. I just got a couple of questions and then 1 housekeeping question after that. So, on the OTL-105, can you just kind of walk us through, Anurag, where you are or where Orchard is in terms of just the manufacturing of that product? Are you in that sort of clinical stage? When will we get to commercial state sort of manufacturing? And then, what are some of the investments that will be sort of needed around that? For leniolisib, I just have a question in terms of -- if you recruit that close to 40 patients that it seems on ClinicalTrials.gov that you’re going to recruit, you’re going to have more than 10% of the patient population you identified in the United States. But how certain are you that, that 1 trial is going to be enough, Anurag? That the -- what is your level of conviction and certainty that the regulators are going to be comfortable with 1 trial in this indication? Again, like I said, you’ve got a big patient population there as a percentage of the total in terms of approval next year, hopefully, assuming the trial is positive. And then I’ll just follow up with a quick housekeeping matter question on manufacturing.

Anurag, can you -- want to take these, please?

Sure, thanks for the questions. On OTL-105 in the collaboration with Orchard, this is still -- the work that’s going on right now is still in the preclinical stage. So the manufacturing is really centered around that. I think over the course of the coming quarters, we’ll be able to provide you a little more information on how that’s progressing and the investments that we’ll be making there. Now to take your question on leniolisib, the pivotal study is 30 patients, as I mentioned, and this is a randomized double blind placebo-controlled study. This was designed really with feedback from the regulators. And as you’re probably aware, this is a typical design that’s required -- in a single study, that’s required in this type of rare and ultrarare diseases. So we’re fairly confident that -- and I think not only is the study hitting the endpoints, but really looking at the totality of the data so that we see the endpoints that I’ve mentioned on the immunophenotype, but also on the lymphadenopathy as well as other measures that are likely to be observed, secondary endpoints, and really the overall picture that we observed from the study will be supportive and potential for regulatory approval, both here as well as in Europe. And you said you had a follow-up question, Hartaj.

Yes, Anurag. And just the follow-up question was that as you build up the manufacturing for leniolisib, I assume you’re going to sort of expense that through the R&D line, but then it becomes inventory assuming approval next year, which has certain implications on your cost of goods sold in your gross margin, assuming leniolisib is going to get approved next year.

Jeroen, you want to answer that?

Yes. So the products that will be commercially used will indeed just go to inventory next year and the rest will go -- some for development purposes, will go through the P&L. That’s the way we will treat it going forward.

We have another question from Joe Pantginis from H.C. Wainright.

Just a couple of logistical questions, I guess. First, Sijmen, do you think you can give us any more color on the additional indications you might be looking at? Obviously, we’ve talked about things like pre-eclampsia in the past. With regard to the AKI study as well as combining with the other studies, are you seeing any impact yet with regard to opening up sites or current sites about how it might be loosening up due to -- from COVID restrictions? And then, lastly, on your regulatory efforts for RUCONEST, what -- how should we sort of define your efforts to get it approved in additional countries?

Yes. Okay. First, with regards to clinical trial progress. In general, we see still, of course, that clinical trials are not on top of the priority list of many centers. That means that we are working on expanding the number of sites that are participating, for instance, the AKI study, to expedite the recruitment of that study. You’ve seen the sort of forward-looking statement that we were making on when we expect that study to be fully enrolled. But again, as you rightfully point out, COVID is not over yet. In fact, it’s coming back in a lot of areas in hospitals. And as many of our other colleagues in the industry, we’re not yet out of the woodworks at all with regards to the normal speed of clinical development. That’s one thing. Would you like to add something to that, Anurag? Or is that sort of reasonably summarized?

Yes, that’s a reasonable summary, I think. Joe, there’s still a lot of COVID-related fatigue also out there. A lot of these centers were involved in COVID studies, and it’s just -- they’re still trying to climb out of all of that mess. So I think things are improving, and we’re going in the right direction. But it’s still -- it’s been a slow, sputtering start coming out of COVID.

And with regards to pre-eclampsia, we haven’t started at all coming out of COVID at all. So I think that was your question, right, Joe?

Correct.

Yes. Then with regards to getting RUCONEST approved in more territories. Yes, we’re taking a selective look at this, obviously. But you’ve seen that we recently got the reimbursement sorted out in Spain. We’re also obviously looking for another country that is typical -- that’s one of the big 5 Europeans, that’s Italy, and we’re working towards getting reimbursement there as well. Obviously, the product was approved a long time ago, but reimbursement is a different game in these kind of territories. And you saw, of course, the collaboration with NewBridge where we expand as well into the North African and Middle Eastern territories. So, step by step, we’re taking it further forward. As you know, RUCONEST is hampered by the fact that in the rest of the world outside of the U.S. or everything is referenced to European prices, which are coupled to 1980s [blocked] product prices. And therefore, hereditary angioedema, for none of the companies involved, is commercially very interesting indication in this respect. So therefore, it’s difficult. But on the other hand, our strategy is to get a bigger geographical footprint, obviously, because rolling out leniolisib will be a very different story in this respect. And therefore, we will continue to add additional territories for RUCONEST. And of course, when leniolisib comes on, it may actually drag RUCONEST with it into new markets where we might enter. Does that answer your question, Joe?

It certainly does.

Any more questions, Joe? Thanks.

We have another question from Simon Scholes from First Berlin.

I’ve got 2 or 3. I mean, first of all, I was wondering if you could give us a timing on submission of the IND application in Pompe? Secondly, I was wondering -- I mean, I’ve noticed over that a number of gene therapy-based approaches are now in trials on Pompe. And I was just wondering if you could comment on how your own approach stacks up against those? And thirdly, just on the marketing costs. I think year-on-year, you’ve had a $7.7 million increase. I was just wondering if you could split out how much of that increase relates to leniolisib and other items and how much relates to RUCONEST?

Yes. Shall I answer -- the first one first then, Simon, about Pompe. Pompe’s disease, we’ve taken -- of course, our product -- our development is hampered significantly at this point in time by unavailability of materials necessary for manufacturing. That is a problem that we have in the pharmaceutical supply chains widely, and we are no exception for that, unfortunately. Secondly, so I can’t give you a proper date for the IND. With regards to the uncontinued medical -- unmet medical need. We’ve just done a deep dive into this indication. And we concluded that the unmet medical need is there -- is still there, and we expect it also to continue to be there. Also, because gene therapy might have some additional hurdles in such a lysosomal storage disease as Pompe compared to many of the other diseases. So the answer is we continue to be interested in Pompe. We’re significantly delayed because of the COVID issues with manufacturing, and we have no data at the moment for an IND, therefore, as these supply chain disruptions are widely spread and COVID is not going back and not retreating, in fact. So it’s difficult to say at the moment. That’s my first question. Second one -- the second one, Jeroen, could you answer that?

Yes, that was on the marketing cost. So the increase of $7.7 million, how much of that is leniolisib. Out-of-pocket expenses for leniolisib was $2 million out of the increase of $7.7 million. And the rest is, I would call it, kind of infrastructure cost. So higher spend in general in Europe and the rest of the world. Some of that is for RUCONEST, but we are building our commercial infrastructure in Europe and the rest of the world. And that is not only for RUCONEST. That’s also looking forward to leniolisib. So part of that will -- is RUCONEST, part of it is leniolisib. Difficult to say now what exactly the split is, but the out-of-pocket expenses increase for leniolisib was $2 million.

This is clearly a strategic investment, right? So we want to launch leniolisib far more -- far faster than we did RUCONEST. And of course, the opportunity for leniolisib is significantly bigger -- very significantly bigger in Europe than, of course, this for RUCONEST.

Yes.

Okay. And is the $2.2 million, when you’re saying -- when you’re talking about the $2.2 million, are you talking there about the patient finding costs mainly?

Yes. Yes, that’s a big part of it. Yes, exactly.

And you had more questions, Simon, you said?

No, that’s it.

[Operator Instructions] It appears we have no further questions at this time.

Okay. Thank you. Maybe some closing remarks then. Thank you very much for attending our conference. And we clearly look forward to, as I said in my quote, to the next milestones. We clearly look forward to seeing the results of the leniolisib trial results in the beginning of next year because we believe that this product especially is important for the execution of our strategy because we think it’s a transformational -- not only transformational potential product for APDS patients’ lives, but it’s also a transformational commercial potential for our company. And that’s why we’re looking very much forward to that. So, thank you for attending here, and we look forward to seeing you again at our next conference with our next results sometime in March. Thank you. Goodbye.