Horizon Therapeutics PLC (HZNP) 2022 Q2 法說會逐字稿

Good morning, and thank you for standing by. Welcome to the Horizon Therapeutics plc Second Quarter 2022 Earnings Conference Call. As a reminder, today's conference is being recorded.

I would now like to introduce Ms. Tina Ventura, Senior Vice President and Chief Investor Relations Officer. Ms. Ventura, please go ahead.

Thank you, Chris. Good morning, everyone, and thank you for joining us. On the call with me today are Tim Walbert, Chairman, President and Chief Executive Officer; Liz Thompson, Executive Vice President, Research and Development; Aaron Cox, Executive Vice President, Chief Financial Officer; and Andy Pasternak, Executive Vice President, Chief Strategy Officer.

Tim will provide a review of the business, including our second quarter performance and our revised full year guidance. Liz will then review our R&D programs, followed by Aaron, who will discuss our financial performance and guidance in more detail. After closing remarks from Tim, we'll take your questions. We posted our investor slide deck this morning as well.

During today's call, we'll be making certain forward-looking statements, including statements about financial projections, development activities, our business strategy and the expected timing and impact of future events. Our actual results could differ materially from these forward-looking statements due to a number of factors, including the risk factors and other information outlined in our latest Forms 10-K, 10-Q and any 8-Ks filed with the Securities and Exchange Commission and our earnings press release, which we issued this morning.

You're cautioned not to place undue reliance on these forward-looking statements, and Horizon disclaims any obligation to update such statements. In addition, on today's conference call, non-GAAP financial measures will be used. These non-GAAP financial measures are reconciled to the comparable GAAP financial measures in our earnings press release, our slide presentation and other filings from today that are available on our investor website at www.horizontherapeutics.com.

With that, I will turn the call over to Tim.

Thank you, Tina, and good morning, everyone. Before we move into the details of the quarter, I want to summarize a few key points today. Our Orphan segment generated net sales growth of 13%, driven by our strong commercial execution. We delivered another quarter of outstanding KRYSTEXXA performance of nearly 30%, driven by increased uptake of our immunomodulation strategy and strong momentum in nephrology.

Our relaunch of UPLIZNA is also tracking well, and our Rare Disease Medicines business delivered another solid quarter. And as expected, TEPEZZA net sales were impacted by Omicron-related effects in the second quarter. Of course, we're disappointed that TEPEZZA didn't rebound from Omicron as fast as we anticipated. We expected TEPEZZA trends to continue to show the positive progress we saw in the post-Omicron recovery and that didn't happen.

We have spent a considerable amount of time to understand the reasons for this and identify what we need to do to accelerate growth. We are now executing on these plans to drive near-term results and realize the full potential of TEPEZZA, which is significant given our estimates of more than 100,000 addressable U.S. patients with thyroid eye disease. Our revised full year TEPEZZA net sales guidance this morning is for growth in the high teens, still significant growth of our 2021 net sales of $1.66 billion.

While our pace of growth to reach peak sales is different, given the slower start to this year, we remain highly confident in our global peak annual net sales expectation of more than $3.5 billion. We expect to drive at least mid-teens growth next year. We also see upside opportunity to our peak annual net sales expectations from a potential launch in Europe, which I'll touch on later.

With that, let me provide additional perspective on TEPEZZA and then move on to the rest of the business. We launched TEPEZZA into an undeveloped and complex market and what turned out to be an unprecedented external environment of both COVID and the ensuing government mandated TEPEZZA supply disruption. The journey since launch has been anything but typical, driven by the fact that TEPEZZA, with its impressive profile, has dramatically changed the TED treatment paradigm for both physicians and patients. And we've learned a great deal. In fact, the first year of our launch, we initially expected net sales of approximately $35 million, and we ended the year at $820 million.

We achieved this rapid success because we executed extremely well to prepare the market and drive adoption of TEPEZZA among our core prescriber base, ocular specialists such as oculoplastic surgeons, who are TED specialists and know the disease well. We generated particularly fast uptake with early adopters and their highly motivated patients who had symptoms aligned to our clinical trial data.

We have a clear commercial strategy, which as we shared on our last earnings call, has not changed. With ocular specialists, we are focused on increasing the breadth as well as the depth of our prescriber base so that they identify more patients appropriate for TEPEZZA. With ophthalmologists, we are working to increase the breadth of prescribers while encouraging those who are not yet comfortable prescribing to diagnose and refer to a TED specialist. And with endocrinologists, our focus is on driving an urgency for them to diagnose and refer their patients to a TED specialist as well.

So what changes we provided to our previous full year guidance? First, based on prior trends, we expected a faster pace of growth from ocular specialists as we move from the early adopters and the most motivated patients to a broader set of physicians and patients. We realize that we underappreciated some of the challenges in further penetrating this segment and that it will take more time and effort to accomplish this.

Second, we also expect that a faster pace of referrals from ophthalmologists and endocrinologists to our core TEPEZZA prescribers. We now realize that our sales force does not have adequate bandwidth to properly dedicate the time required, not only to engage with ocular specialists but also educate physicians about TED to drive key referrals. This underscores the need to expand our sales force, which I'll touch on shortly.

The timing and broad impact of Omicron complicated our ability to understand these dynamics more quickly to make these necessary adjustments. As we discussed on our first quarter call, TEPEZZA growth trends dipped with Omicron earlier this year. We expected that to persist into the second quarter, with growth accelerating in the second half of the year as the Omicron impact waned. However, the recovery didn't progress as fast as we expected, indicating to us that Omicron wasn't the only dynamic impacting the business.

After digging deeper, we better understood those dynamics. We made several adjustments and are deploying more resources in a targeted manner to drive short- and long-term growth of TEPEZZA. First, we are adapting our commercial focus to these new learnings. This includes focusing our targeting, simplifying our messaging and increasing the accountability of our field organization. Accordingly, we have recently made several changes to the leadership of the TEPEZZA commercial and sales force organizations.

Second, we're spending more time and focus on the reimbursement process, which, as we've mentioned previously, is burdensome on physicians, especially with surgeons who are not accustomed to it. We have changed how the patient services team operates, combining our patient and reimbursement access teams to streamline the process to more effectively support physicians and patients in the patient access journey. These changes free up time for our sales force to focus on driving TEPEZZA prescriptions.

Third, we are spending more time educating physicians as part of the medical management process for their patients. Unlike most diseases, which are managed by one physician, TEPEZZA patients are typically co-managed by their surgeon and either their ophthalmologist or their endocrinologist. We're educating physicians on monitoring requirements and best practice protocols through peer-to-peer education.

And finally, based on recent learnings and findings from our market segmentation work, we realized the importance of expanding our sales force more significantly than we had initially planned. We're in the process of doing just that. We are adding about 60 field-based employees. This gives our sales representatives more time for engagement with ocular specialists and now ophthalmologists and endocrinologists. We'll now cover a universe of approximately 12,000 total physicians. This broader effort will enable them to further educate ophthalmologists and endocrinologists about thyroid eye disease, driving urgency to diagnose and refer their patients to a TEPEZZA prescriber.

These physician specialties see tens of thousands of potential TEPEZZA patients, but are much less familiar with TED, the pathology of the disease and the relevance of the TEPEZZA mechanism of action as acute treatment approach. So currently, we believe many patients never make it out of their ophthalmologist or endocrinologist's office to find the care they need. And this is why our sales force expansion and our TTC investments are so critical.

Over time, we expect more and more ophthalmologists to prescribe TEPEZZA. We recently completed a survey of ophthalmologists whose awareness of TED and TEPEZZA is very high. The survey issued over 60% intent to increase their TEPEZZA prescribing, underscoring the benefits of a larger sales force expansion. We'll conclude my comments on TEPEZZA with a brief review of the market. It is one of the key reasons we're so confident in the continued growth of TEPEZZA.

We recently completed an exhaustive market analysis to better identify the types of TED patients and where they're being treated. It confirmed that patient symptoms, regardless of the time since diagnosis, are what motivates them to seek treatment and drive physicians to prescribe TEPEZZA. This research also confirmed our estimate that there are more than 100,000 patients in the U.S. appropriate for treatment with TEPEZZA.

We have segmented these patients based on disease severity and clinical activity score, or CAS. We estimate that more than 20,000 have high CAS with key severity symptoms, such as high proptosis, diplopia or both. It is also where we have currently the highest penetration at less than 20%. These patients are more likely to be seen by an ocular specialist. We believe we have the highest penetration in this segment because it's where we conducted our prelaunch work where we primarily focused our sales force and where we have shown impressive efficacy in our randomized placebo-controlled trials.

We estimate that more than 80,000 patients in the next segment are also appropriate for TEPEZZA. They have low clinical activity scores with high proptosis, diplopia or both. And we have low single-digit penetration of this segment today. These patients are primarily treated by ophthalmologists or endocrinologists where, as I mentioned before, there is relatively low awareness of the disease. It's also where we're focusing our sales force expansion.

In addition to our sales and marketing efforts, we are generating additional clinical evidence intended to drive adoption in low CAS patients. Today, most TEPEZZA use is in high CAS patients. So our chronic trial, the trial in low CAS patients, will be important because it will round out the picture of the efficacy of TEPEZZA in all CAS types. We have already seen good efficacy from TEPEZZA in this patient population through various physician-driven case reports. We expect to release top line data from this randomized placebo-controlled trial in the first half of next year. We also anticipate presenting the data at key medical conferences and publishing it in peer-reviewed medical journals beginning in the second half of next year. As a result, we have the potential for more meaningful uptick in the market from this data beginning in 2024.

Our continued significant investment in DTC will amplify all of our actions discussed today, and our campaigns continue to generate above-average returns. Beyond the significant opportunity in the U.S., we expect our global expansion to contribute meaningfully outside of the U.S. beginning in 2025. While our current TEPEZZA peak annual net sales estimate does not assume a launch in Europe, we are finalizing our assessment of that opportunity and expect to be in a position to provide an update later this year. We expect this will provide upside to our peak annual net sales expectations for TEPEZZA.

We have learned a great deal over the last 2.5 years, first, in creating the market for TEPEZZA, then as the market has evolved. Our track record of commercial execution gives us confidence in building towards a long-term growth expectation to help thousands more TED patients with this life-changing medicine.

Moving on to KRYSTEXXA. Second quarter net sales were $168 million, representing strong year-over-year growth of nearly 30%. This continued strong performance was driven by growing adoption of both rheumatology and nephrology market segments as well as uptake of KRYSTEXXA with immunomodulation, which is now running at more than 50% of new patients.

Following the recent FDA approval of our sBLA for the co-administration of KRYSTEXXA with methotrexate, the team was well prepared to execute the launch. In less than 24 hours, we launched our new promotional campaign, trained the field force, and launched new websites for both physicians and patients. We also hosted a live national launch broadcast, which include physician and patient speakers to educate more than 700 physicians across the country.

Since acquiring KRYSTEXXA, we have dramatically transformed the growth trajectory of this life-changing treatment for patients with uncontrolled gout. So our efforts to educate the physician community on the benefits of KRYSTEXXA as well as investing in clinical data show its efficacy and safety. This sBLA approval is a combination of our efforts.

With the expanded label, our commercial team is now promoting the benefits of KRYSTEXXA with methotrexate for the first time. We expect this to drive higher clinical conviction, rounding our reach to more physicians and increasing patient penetration among current treating physicians. In fact, we are already seeing this happen. Physicians who have never prescribed KRYSTEXXA before, who have not prescribed in a long time, are changing their opinion. One physician who had not prescribed KRYSTEXXA in over a decade said the new data shifted the way he viewed KRYSTEXXA, and he already had a patient in mind who would be a good candidate for treatment.

Building on the momentum we are seeing in this launch and to leverage the current nephrology progress, we're expanding the KRYSTEXXA sales force by approximately 20% over the coming months. We're driving a significant momentum with this medicine, giving us continued confidence in our peak annual net sales expectation of more than $1 billion.

With UPLIZNA, we delivered another strong quarter, generating net sales of $39 million, where we doubled our U.S. sales compared to last year. We continue to make progress on our relaunch in the United States and are encouraged by the steady and consistent growth in new prescribers and new patient starts. As part of our global expansion strategy, our commercial launch is now underway in Germany. We're increasingly confident in the prospects for UPLIZNA in NMOSD, and we are progressing towards our global peak annual net sales expectation of more than $1 billion across all potential indications.

I will now turn the call over to Liz.

Thank you, Tim, and good morning, everyone. We continue to make progress on our R&D strategy in the second quarter and advanced our pipeline programs.

Starting with KRYSTEXXA. As Tim just mentioned, the FDA label expansion was a result of a successful priority review by FDA and was based on the data from our MIRROR trial. As you know, the 6-month primary endpoint showed a 30 percentage point improvement in the response rate using KRYSTEXXA with methotrexate compared with KRYSTEXXA alone. New 12-month data from the trial are also now included in the expanded label and also show a nearly 30 percentage point improvement in the KRYSTEXXA with methotrexate arm.

From a safety perspective, infusion reactions were meaningfully reduced in the KRYSTEXXA with methotrexate arm. Only 4% of patients randomized to receive KRYSTEXXA with methotrexate experienced an infusion reaction compared to 31% in the KRYSTEXXA monotherapy group. Taken together, the data around coadministration with methotrexate are a significant change to the original label that was used to launch this medicine, the only one for uncontrolled gout 12 years ago.

Moving to daxdilimab, which is the first and only plasmacytoid dendritic cell depleter in clinical development. We're studying daxdilimab in several indications and made notable progress this quarter. First, we completed enrollment in our Phase II trial evaluating daxdilimab in patients with systemic lupus erythematosus, or SLE, in the second quarter. We expect to announce top line results in the second half of 2023.

We also initiated a Phase II clinical trial in the second quarter in alopecia areata, an autoimmune disorder characterized by nonscarring hair loss. This open-label trial is expected to enroll approximately 30 patients with moderate-to-severe disease and we expect to announce top line data in 2023.

Looking forward, we expect to initiate 3 additional clinical trials with daxdilimab. First, our Phase II randomized controlled trial in patients with discoid lupus erythematosus or DLE. DLE is a chronic inflammatory skin condition characterized by lesions. Second, our Phase II randomized controlled trial in lupus nephritis or LN. LN is an autoimmune inflammatory condition of the kidney, and is the most common major organ manifestation of SLE. Current treatment regimens include intensive immunosuppressive therapy that can be associated with adverse events, supporting the need for a more specific medicine to address the unmet need in those with proliferative LN. And third, our Phase II trial in dermatomyositis, an autoimmune inflammatory disorder characterized by rashes that often burn as well as by debilitating muscle weakness.

Moving on to dazodalibep, our CD40 ligand antagonist designed to block a central pathway involved in many autoimmune and inflammatory diseases. We completed enrollment in the Phase II trial evaluating dazodalibep for Sjögren's syndrome in the second quarter, and we expect results in 2023. We also announced top line results from our Phase II double-blind placebo-controlled trial of dazodalibep in rheumatoid arthritis patients, demonstrating that the primary endpoint was met in all 4 dazodalibep dosing arms and showing that it was well tolerated. We expect to present the full results at an upcoming medical meeting. We're also working with regulatory agencies to finalize the details of our trial design for FSGS, a rare kidney disorder.

As for TEPEZZA, we're continuing to enroll patients in our Phase IV randomized controlled trial in TED patients with a low clinical activity score, otherwise referred to as our chronic TED trial, with top line data expected in the first half of 2023. We continue to advance our TEPEZZA subcutaneous administration program, recently initiating enrollment in a Phase Ib trial in TED patients, and we continue to progress our work on our high concentration formulation as well. We also continue to enroll patients in the OPTIC-J trial in Japan.

UPLIZNA is our anti-CD19 humanized monoclonal antibody, currently indicated for NMOSD, a rare and devastating neuroinflammatory autoimmune disease that attacks the optic nerve, spinal cord and brainstem. We continue to enroll patients in our myasthenia gravis trial. However, the complex geopolitical situation in the Russian and Ukrainian regions along with the COVID lockdowns in China have impacted enrollment and site availability. As a result, we now expect the top line data readout for this trial in 2024. We continue to work diligently with patients and sites across the impacted regions and are putting the appropriate measures in place to meet enrollment targets. Enrollment is also advancing in our IgG4-related disease Phase III clinical trial.

And with that, I will now turn the call over to Aaron.

Thanks, Liz. My comments this morning will primarily focus on our non-GAAP results, unless otherwise noted. I will review our second quarter results followed by our revised 2022 financial guidance.

Our Orphan segment generated second quarter net sales of $841 million, representing year-over-year growth of 13%. Our Orphan segment operating income was $315 million. Net sales for the Inflammation segment were $35 million and segment operating loss was $7 million, primarily due to the impact of the at-risk launch of a generic PENNSAID 2% entrant on May 6. As a result of the subsequent market erosion, we are in the process of winding down the Inflammation segment, which we expect to conclude by the end of the year.

Our second quarter gross profit ratio was 86% of net sales, somewhat below our expectations, driven by the Inflammation segment. Second quarter operating expenses were $448 million. This included R&D expense of $95 million, or 11% of net sales, and SG&A expense of $352 million. Second quarter adjusted EBITDA was $307 million. The tax rate for the second quarter was 11.7%. As we have seen in prior years, there can be variability in our tax rate across quarters. Net income in the quarter was $254 million, and diluted earnings per share were $1.07. The weighted average shares outstanding used to calculate second quarter 2022 diluted EPS were 236 million shares.

Second quarter operating cash flow was $251 million. As of June 30, cash and cash equivalents were $1.89 billion. Backed by this strong cash position and expected future cash flows, we expect business development to continue to play a critical role in expanding our pipeline and diversifying our business. The total principal amount of our outstanding debt is $2.6 billion, with the earliest maturity in 2026. Our gross debt to last 12 months adjusted EBITDA leverage ratio was 1.6x as of June 30, and our net leverage ratio was well under 1x.

I will now turn to our revised outlook for 2022 and how we see the rest of the year playing out. We are revising our full year 2022 net sales guidance to $3.53 billion to $3.60 billion, representing year-over-year growth of 10% at the midpoint. We now expect TEPEZZA full year 2022 net sales growth in the high teens with quarter-over-quarter sequential growth expected over the third and fourth quarters.

For KRYSTEXXA, we continue to expect full year 2022 net sales growth of more than 20%. For the Inflammation segment, we expect net sales of less than $30 million in the second half of the year due to the market erosion caused by the generic PENNSAID 2% entrant. As we wind down the business, we expect our net sales for this segment to be immaterial beginning next year. We continue to expect full year 2022 gross margin of approximately 87%. We expect full year adjusted EBITDA to be between $1.3 billion and $1.35 billion.

As it relates to operating expenses, we expect third and fourth quarter expenses to be in a similar range as the second quarter. We expect a modest benefit in the fourth quarter from the wind down of the Inflammation business unit, which will be mostly offset by the expansions of the TEPEZZA and KRYSTEXXA field forces. We continue to expect our full year net interest expense to be approximately $85 million to $90 million.

We continue to expect our full year 2022 tax rate to approach 12%. As with every year, we anticipate variability in our tax rate on a quarterly basis. We continue to estimate that our 2022 cash tax rate will be in the mid- to high single digits. As always, our tax rates could change significantly as a result of acquisitions or divestitures we may make or any changes in tax laws. We continue to expect our full year 2022 weighted average diluted share count to be approximately 238 million shares.

With that, I will turn it over to Tim for his concluding remarks.

Thank you, Aaron. A few thoughts this morning. We delivered strong growth this quarter with KRYSTEXXA, UPLIZNA and our Rare Disease Medicines, as well as the continued advances we're making with our pipeline. With TEPEZZA, we are expanding our presence and putting in place the actions we believe are needed to accelerate growth.

We are revising our growth this year to high teens and expect at least mid-teens growth next year. While the expected pace of growth is different than our original expectations, we remain highly confident in our TEPEZZA global peak annual net sales expectations of more than $3.5 billion, which does not include our potential entry into Europe.

We've also updated our full year guidance of the recent and unexpected at-risk launch of a generic PENNSAID 2%. We'll be winding down the inflammation business by the end of the year. It is our legacy business that launched Horizon 12 years ago and which provided the investment to allow our rapid and successful diversification into rare diseases. Five years ago, the Inflammation segment represented roughly 60% of our net sales, and is a reminder of how quickly we have executed to transform Horizon to the rare disease-focused biotech company we are today.

Part of executing our business is recognizing the changes that need to be made in the short term to drive long-term growth. We have demonstrated this strategic agility throughout our history. We have leveraged our commercial and R&D expertise to breathe new life into underutilized medicines. We've built new markets, and we've made some of the highest returning acquisitions in the health care sector, and we've completely transformed our company in an incredibly short period of time.

As we look ahead, the medicines that are driving our future growth are truly remarkable medicines with impressive efficacy, significant opportunity for increased penetration and they address important patient needs. We continue to expand our pipeline to support our future growth and look forward to several key readouts beginning in the first half of next year.

With nearly $2 billion in cash at the end of the quarter, we are strongly positioned to continue to build and diversify our company through our business development activity and pipeline programs. We remain committed as ever to continue to make a difference in the lives of patients and build long-term value for shareholders.

I'll pass that on to Tina, and we'll now open the call up for questions.

Thanks, Tim. Chris, if you'd like to do that?

(Operator Instructions) Our first question will come from Chris Schott of JPMorgan.

Great. Just two on TEPEZZA. I guess the first one is just how different, I guess, is the profile of the patient sitting today at the ophthalmologist or endocrinologist versus those who are at the ocular specialists? I guess, are these all these low CAS patients you referred to in the opening remarks?

And I guess I'm sure to get my hands around, what is the risk that, I guess, these patients' symptoms just aren't severe enough to motivate the patient to get therapy even if the physicians are better educated and better aware with some of the promotion efforts that you're planning?

And then just my second question is again both upfront is, if I look at the guidance on TEPEZZA, it seems like pretty limited sales growth in the second half of the year versus the first half, if I take the midpoint of the guide. And I'm just trying to understand why we aren't expecting a bit more growth in the second half? I guess, given the COVID impact you talked about in the first half and then some of these promotion efforts that you're investing behind. Is it just not enough time to see traction with those? Or just a little bit more color there would be appreciated.

Sure, Chris, and thanks for the question. So first, when we look at the approximately 2/3 percent of patients of that 100,000 plus that are in ophthalmologists and endocrinologists, right now, we're doing a very effective job through our PTC of activating patients and getting them into those offices. When you look at those patients relative to the two segments we're talking about, high versus low CAS, they are not all low CAS patients. Many of them are also high CAS patients. It's just that they have been sitting in ophthalmologists' and endocrinologists' offices without us being able to effectively pull through because we haven't had sales reps focus on that broader audience.

So the real focus of our sales force expansion is to get into that broader 12,000 target where 65% of patients fit. It's a mix of high and low CAS patients. And based on our research and market research and talking to ophthalmologists, who we expect to continue to increase their prescribing, 60% of them said they indicate they'll significantly increase their prescribing. So we feel confident that these efforts will begin to generate the growth we need.

To your second question, Chris, it's a good one. We expect to complete the expansion here in the third quarter. We have moved a number of our original IBU, or inflammation business, representatives who have had great long-term success into the TEPEZZA team and they will begin training shortly. So we expect to have training done and the amount in the territories, beginning to make an impact as we end the year and expect that growth to really accelerate as we move into 2023, which is really what guides us to talking about at least mid-teen growth in 2023.

And then as we get to the end of the year, in '23, we expect to get the data from the chronic low CAS study, which will allow that to really start accelerating in '24 and lead into '25 when we expect to start also seeing the global launches come into market. So that's how we view things moving forward.

Thanks, Chris. Chris, next question, please.

Our next question will come from Ken Cacciatore of Cowen & Company.

Tim, it seems we've moved from TEPEZZA the question of are the patients out there, which is always key when you're launching it to a new market to now just more logistical on 3 levels. And I don't want to be repetitive. I just want to make sure I have this right and then make sure I understand the focus. So the first level here is helping to support the current practices. I mean, in our conversations, it does sound as it's very labor-intensive on reimbursement and scheduling. So just wanted to understand, as we think about investments, how much are we upping to kind of support the current high-volume practices?

It sounds like the second is bringing on new ocular surgeons. Wonder if you could just flush that out a little bit more, maybe those high-volume practices that have been adopted and to what degree this sales force expansion supports them? And then you've talked in great detail about digging out from the community ophthalmologists and endocrinologists, and that sounds like the biggest point of investment. But could you hit on all 3? And do we have it right? Is this more now just logistical kind of investment focus as opposed to patient focus?

Thanks, Ken. I think you hit on a number of the key points. When we look at our sales force expansion, there are a couple of key aspects to it, in addition to the changes we made in our patient and reimbursement access team. So with the reps, they're going to have smaller territories. What -- as you heard in my prepared remarks, we've talked a lot about that combination of trying to sell and also manage the reimbursement process and not having enough time to focus on selling.

So with our expanded sales force, we will have more time to focus on selling not only in that initial core oculoplastic specialist group, but also being able to get into those broader ophthalmologist and endocrinologist offices and allow our combined patient access and reimbursement access group to have a single point of contact with key offices to really help pulling those patients through to get their infusions. So that's the real focus of our broader effort there.

Thanks, Ken. Next question, please.

Our next question will come from David Amsellem of Piper Sandler.

So just taking a step back here, it's a question for Tim. As you look at what has become a fairly heavy lift in terms of marketing and promotion of TEPEZZA and how that is -- and how the trajectory is playing out, does that mean that you are more likely to get more aggressive on M&A, not just to sort of add to the pipeline, but to bring in another commercial stage asset or assets? So how do you think about that, given where TEPEZZA is?

And then secondly, just sort of a backward-looking question. In hindsight, do you think there may have been just a bolus of patients or low-hanging fruit, if you will, in the thyroid eye disease setting that you work through and now you're in, what I guess I would call, an air pocket in terms of demand? How should we think about that?

So relative to the bolus, I think that there were -- when you look at any launch, they're early adopters. And based on our premarketing work, we have prepared a number of those key ocular specialists to get patients onto treatment and through COVID, our DTC efforts, we're able to activate those patients to take action. And we outperformed extremely well there when we look at it, David. So when you look at the next phase, our DTC continues to outperform. The bottom line is that these patients are being sent to broader ophthalmologists' and endocrinologists' offices. We're not actively there. So we need to expand, get into those offices.

With the existing ocular specialists, we're now moving into the moderate to late adopters, and we need to continue to increase our efforts there, continue to drive them into looking at broader sets of symptomology and taking action. When we talk about ophthalmologists and endocrinologists, it's twofold. Endocrinologists, it's all about driving awareness and getting them to refer to a TEPEZZA writer. With ophthalmologists, it's really bifurcated from ophthalmologists willing to prescribe and also ophthalmologists that we need to focus on referring to TEPEZZA writers.

So we really look at it as the next phase of launch. I think a lot of it, as I discussed, was masked by what was going on with COVID and supply shortage and then Omicron. But I think we feel really good about the plans we have in place, the focus of our new sales force, the focus of our patient services organization and it's now the blocking and tackling and really driving day-to-day conversion of those patients.

To read through to your second comment, first of all, we have 3 key growth drivers in TEPEZZA, KRYSTEXXA and UPLIZNA, and we see over $5.5 billion in potential peak sales with further upside from TEPEZZA in Europe as we'll get into further detail throughout the rest of this year. So we feel great about those growth drivers. As I mentioned, KRYSTEXXA and UPLIZNA are tracking extremely well. But whenever you have a launch that has the blockbuster uptake, as we talked about, getting into billions of dollars, that changes the slope of your curve and the focus of your business development efforts. And maybe, Andy, you want to speak to that?

Sure. Thanks, Tim, and thanks, David. So I think it goes without saying that the Horizon has had a very successful track record of business development. And as Aaron said, BD is going to continue to play a pretty critical role in expanding our pipeline and further diversifying our business. So we remain focused on individual asset licensing and collaboration deals, but we are certainly also looking at larger transactions. And we have the financial flexibility and capacity for such transactions.

I think in a larger transaction, we'd be seeking a combination of approved medicines and development-stage assets to manage risks. So we wouldn't want to take binary best at that kind of scale. And I think Viela is a good example of that. There are some larger opportunities we see right now that make sense strategically for us. However, we remain financially disciplined and aligning -- frankly, aligning on deal terms that work for both us and the seller. That remains the biggest barrier to getting deals done right now. And there are some management teams and Boards who haven't adjusted their expectations relative to where the equity market is currently setting their valuations. So we're just going to have to see how that plays out.

But, I think the bottom line is we see a lot of opportunities, and we expect to be aggressive.

Chris, next questions, please.

Next question shall come from Annabel Samimy of Stifel.

So just for TEPEZZA, I want to clarify that the bottleneck is not necessarily reimbursement per se, but the support needed to usher the patient through the system. Obviously, this is a product that's grown very rapidly. So have there been any new roadblocks that the payers have put up given the high demand?

And then my second question is more of a long-term margin impact. Obviously, you're putting a lot of support behind TEPEZZA. I just want to verify that the mid-40s margin and possibly 50s operating margin is still a goal that you can obtain. And I guess, along those lines, obviously, your DTC was very effective, maybe too effective because they brought more patients than they support. So is there any thought to pulling some of that back for a bit, so you can absorb some of the demand and get these patients through?

I'll start with the last question. We do not plan on pulling our DTC back at all. It's been highly effective. It's driving both uptick in the core oculoplastic specialists, but also in continuing to put patients into those ophthalmologists' and endocrinologists' offices where our sales force will be focusing. From a margin standpoint, the mid-40s to 50 you mentioned, that certainly continues to be an achievable goal for us. And as Aaron mentioned in his remarks, we are offsetting that reduced spend in the inflammation business with moving those resources over to TEPEZZA and to a smaller extent to KRYSTEXXA.

When we look at the roadblocks, reimbursement or really access to policies and efforts by payers have not changed materially over the last -- I would say, really through the last year plus. The roadblocks are not greater. This is a function of ocular specialists who have been the key early adopters that have driven the great uptick we've had, not being generally comfortable or even experienced in managing reimbursement. So it's really moving patients as fast as possible through that process. And that is part of why we restructured our patient access and reimbursement groups into one, so we can put one point of contact and continue to find efforts to reduce the effort there.

And as we move into ophthalmologists and endocrinologists, they do have more experience in both managing reimbursement, managing medical monitoring of patients as well as just the broader process of treating patients. So we feel confident in our ability to continue to drive the business there.

Our next question will come from Michael Ulz of Morgan Stanley.

Maybe I could just ask one on KRYSTEXXA here. It seems like you're still seeing nice growth in 2Q. So maybe you can give a little bit more color on what the key drivers there have been through the past quarter here?

And then also now that you have expanded label, and you touched on this in your prepared remarks, but maybe you can give a little bit more color on the impact you've seen so far over the past month and then maybe how that could evolve moving forward in the second half?

Thanks a lot for the question. We've seen great progress. I think we've been really impressed by the fact that our growth -- our sequential growth and growth metrics in nephrology have caught up to our growth metrics in rheumatology. So that team is really performing and that's part of where we're going to be expanding to leverage that uptake. Additionally, we're seeing our KRYSTEXXA with methotrexate and other immunomodulators penetration now exceed 50%. So we continue to see entrenchment there, and also the vial per patient continues to increase as we move forward. So that has all contributed to the success and the 30% year-over-year growth that we saw in the quarter.

With the expanded label, and some of this I mentioned in my remarks, we've had physicians who have been out of the market for a decade who were either fearful of 40% efficacy, and that meant 60% that weren't going to respond, and then that brought them to questioning whether there were infusion reactions or other things that they needed to worry about or they had a bad first experience. And those are the kind of dialogues that have really changed. We can go in a lot of folks that I need to see it in the label, I need to see the data to get the confidence to get back in, given my early experience. And those are the dialogues that are occurring, and they've been really promising so far.

So I think we're seeing new prescribers come into the market that haven't been there. So as we look at existing and new prescribers, those are really -- both groups are growing extremely well, along with the real progress we've made in nephrology.

Our next question shall come from Madhu Kumar of Goldman Sachs.

This is Rob, on for Madhu. Two quick questions here. One, just how are you thinking about business development versus deleveraging? I know you made some comments about the M&A outlook so far. And then on TEPEZZA, what do you think the potential for the chronic TED readout is to drive further uptake in 2023?

Sure. So we are deleveraged, and I think on a net basis, under 1, and feel we're in a great position with approximately $2 billion on the balance sheet to be aggressive in M&A, both for on-market assets and to fill in the pipeline. So we feel we're in a great place to be aggressive there and really leverage, as Andy discussed, continuing to see movement in willingness to -- for management teams and Boards to recognize the environment that we're in.

With the chronic market, that is something that I talked about in a few of the prior questions, but as we look at the key growth drivers and when we look at '23 in the mid-teens, that's really going to be driven by expansion into those broader ophthalmologists' and endocrinologists' office, expanding our call on targets to 12,000. Getting that data in the first half of '23 on our chronic low CAS study, we expect to be published in the second half. And as we head into 2024, we do expect that to be the next leg of growth that will then drive us into our global launches coming from the broader international markets.

Chris, next question, please?

Our next question will come from Jason Gerberry of Bank of America.

So I just wanted to confirm, for the 2023 TEPEZZA growth outlook, that does not assume like a positive Phase IV chronic TED trial outcome. And then my second question is just appetite for repurchasing your own stock. The stock right now, I think, is trading in the low $60 and the premarket on the quarter update. So just curious, I mean, if your confidence remains strong in your peak sales outlook, why not buy back some of your own stock?

Thanks for the question. What was the first one? I think, around...

Chronic data for TED.

The chronic -- we do not expect that to be the key driver in '23. At least mid-teens growth that we expect is going to be driven by our expansion, our focus on the broader targets, we're 65% or 2/3 of those patients now sit, continued execution of our DTC to really funnel patients in there and begin to enter us -- pull them through. And then the chronic low CAS study would then feed into '24 and beyond.

Relative to buying back shares and those actions, with our balance sheet, our history of successfully buying assets like TEPEZZA, like KRYSTEXXA, where we can drive them differentially, we think it's -- our cash is best used to significantly bring on assets that are going to drive our long-term value.

Our next question shall come from Akash Tewari of Jefferies.

This is Amy, on for Akash. With the insurance reauthorization benefit you historically have seen between Q1 to Q2 suggest that TEPEZZA new start this quarter are even lower than expected? Additionally, recently, you talked about seeing an inflection in PES post Q1. What's happened since then? And then finally, what gives you confidence to reiterate a $3.5 billion plus long-term TEPEZZA guidance? And does that now account for the chronic study reading out positively and a potentially higher penetration in chronic patients?

So from the $3.5 billion or greater than $3.5 billion in peak sales, we are extremely confident. Again, that does not include our expected entry into Europe, so certainly upside there. As we look at -- it's a 3-phase approach that we think are going to drive our approach to those peak sales. It's really driving our expansion, putting additional 60 field force folks out there getting to that broader targets where 65% of the patients are now sitting the chronic trial and penetrating into that audience.

We don't look at the market as acute and chronic anymore based on our understanding of how physicians treat these patients. It's really based on high and low-CAS patients who have high proptosis or high diplopia or double vision. So we see our ability to drive there sufficient to meet or exceed our peak sales expectations and that would carry us into our global launches in 2025. When we look at the first quarter and insurance reauthorizations, we don't feel that, that had any impact on the second quarter.

Chris, next question, please?

Our next question will come from Derek Archila of Wells Fargo.

Maybe just first, can you talk to the level of TEPEZZA awareness among the endos and the ophthalmologists that are not referring patients right now to ocular specialists? Is it that they just don't know about it or is it that they don't want to refer patients for treatment? And then one pipeline question. I guess when could we see the Phase II data from the subcu TEPEZZA presentation?

As far as TEPEZZA awareness among endocrinologists and ophthalmologists, it is extremely high. I think the biggest challenge has been that we're not in those offices. We're not helping them understand the seriousness of thyroid eye disease and the seriousness in getting them treated in the short term with medicine like TEPEZZA and then where to refer them to get treated. This is not an issue of lack of willingness to refer, it's lack of us being in there to drive that action.

Liz, do you want to speak to the second question?

Yes. So we're making good progress on our subcu program with TEPEZZA. We've gotten through our first -- very first phase, which was a single dosing. We've just initiated, as we announced on today's call, our dosing in patients with thyroid eye disease. We will continue to update as we proceed along with these trials and anticipate more information on upcoming calls.

And Chris, we have time for one more question, please.

And our last question shall come from Mr. Gary Nachman of BMO Capital Markets.

Okay. Great. So Tim, with all your market research, just talk about your confidence in the number of these TED patients that are out there, the 20,000 acute and 100,000 total. And with the increased sales force, how many of those patients will you be covering if you hit the broader 12,000 physicians that you're talking about?

Then on the chronic TED study, just talk about your confidence with enrollment in that study and how it's designed for success? And then lastly, just how should we think about operating margins trending over the next few years with revenue run rates coming down and now increased spending that you're talking about?

Sure. So from a spend standpoint, we think a lot of that increased spend will be offset by reduced spend in our Inflammation segment. I'll let Aaron in a second here take the question on operating margins over time. From an enrollment standpoint, we feel that we're well on track to achieve our goal to release data in the first half.

Liz, do you want to speak to how you feel about the trial?

Absolutely. We've taken into account a number of learnings that we've had about chronic thyroid eye disease or specifically patients with low clinical activity scores who nevertheless have high rates of proptosis when we were designing our trial. We feel confident that we've designed this appropriately to show a clinically meaningful outcome. And we do have a lot of data that supports in that direction with all the case reports and case series out there. And to reiterate, as Tim said, we had a little bit of a slowdown in enrollment during Omicron, that's picked back up. We're very confident in completing enrollment this year and having data in the first half of next year.

So relative to the market size question that you asked, we see 100,000 patients being covered by those 12,000 targets, with 1/3 of them being in the oculoplastic specialists and 2/3 being in the ophthalmology/endocrinology group. Aaron?

From a margin standpoint, as Tim mentioned, over the long term, targeting 50% is -- remains our longer-term goal. From a near-term perspective, we expect third quarter and fourth quarter to be similar to the second quarter from an OpEx standpoint, with modestly higher R&D offset by modestly lower SG&A. And then as we look forward to 2023, which we'll provide guidance on our fourth quarter call, we'd anticipate 2023 SG&A to increase modestly versus 2022 with a more meaningful step-up in R&D spend, given the trial initiations that we've discussed.

Thanks, Aaron. And Chris, that concludes our call this morning. The webcast will be available in about 2 hours. Thank you, everyone, for joining us.

This concludes today's conference call. Thank you all for participating. You may now disconnect, and have a pleasant day.