Jazz Pharmaceuticals - Q2 2023

Transcript

Operator (participant)

Good afternoon, thank you for attending the Jazz Pharmaceuticals second quarter 2023 financial results call. My name is Alyssa, I will be your moderator for today's call. All lines will be muted during the presentation portion of the call, with an opportunity for questions and answers at the end. I would now like to pass the call over to the Jazz Pharmaceuticals team. You may proceed.

Andrea Flynn (VP and Head of Investor Relations)

Thank you, operator. Good afternoon, everyone. Today, Jazz Pharmaceuticals reported its second quarter 2023 financial results. The slide presentation accompanying this webcast is available on the investors section of our website. Investors may also refer to the press release we issued earlier today, which is also posted to our website. On the call today are Bruce Cozadd, Chairman and Chief Executive Officer, Renee Gala, Executive Vice President and Chief Financial Officer, Dan Swisher, President and Chief Operating Officer, and Rob Iannone, Executive Vice President, Global Head of R&D. Kim Sablich, Executive Vice President and General Manager, United States, will join the team for Q&A.

On slide two, I'd like to remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results, growth potential, and anticipated development and commercialization milestones and goals, which involve risks and uncertainties that could cause actual events, performance, and results to differ materially from those contained in these forward-looking statements. We encourage you to review the statements contained in today's press release, in our slide deck, and in our latest SEC disclosure document, which identify certain factors that may cause the company's actual events, performance, and results to differ materially from those contained in the forward-looking statements made on today's webcast. We undertake no duty or obligation to update our forward-looking statements. Turning to slide three on this webcast, we'll discuss non-GAAP financial measures.

Descriptions of these non-GAAP financial measures and reconciliations of GAAP to non-GAAP financial measures are included in today's press release and the slide presentation available on the investors section of our website. I'll now turn the call over to Bruce.

Bruce Cozadd (Chairman and CEO)

Thanks, Andrea. Good afternoon, everyone, thank you for joining us today. I'll start on slide 5. In the second quarter of 2023, we once again delivered strong commercial results, advanced our efforts to unlock the tremendous potential of our pipeline, and built on our record of driving operational excellence. In particular, our results in the second quarter highlight the durability and growth potential of our commercial portfolio, the capabilities and productivity of our R&D efforts, and our focus on operational excellence. We are pleased to report strong execution across our commercial portfolio with all three key growth drivers of our commercial business, Xywav, Epidiolex, and Rylaze, achieving year-over-year double-digit growth. Xywav grew by 39% in the second quarter compared to the same period last year and is annualizing it well over $1 billion in revenue.

Xywav continues to be the oxybate of choice and the only approved therapy for idiopathic hypersomnia. We expect our oxybate franchise to contribute $2 billion of the $5 billion in total revenue component of Vision 2025 and are well positioned to reach this target. As a reminder, our 2023 neuroscience revenue guidance, which we are raising at the midpoint today, and Vision 2025, both account for the availability of high sodium oxybate authorized generics, or AGs, and branded fixed-dose high sodium oxybate. Epidiolex growth remains strong, and we are confident in its potential to reach blockbuster status. We achieved double-digit net sales growth in 2Q 2023 compared to the same period last year, as we continued to drive prescriber growth across our global markets. Our launch in Europe is gaining momentum, with additional international launches and indication expansions expected this year.

In oncology, Rylaze has continued to grow in the U.S., underpinned by strong demand and our increasing emphasis on the adolescent and young adult market. Moving to our pipeline, given the level of productivity in our R&D organization, I'm going to call out just a few items. Rob will cover our R&D progress in more detail later in the call. Our pipeline continues to advance towards meaningful catalysts, with the potential for as many as 4 late-stage data readouts through 2024. The first being JZP150 late this year, followed by suvecaltamide and zanidatamab and GEA next year, and top-line PFS for Zepzelca in combination with Tecentriq in first-line extensive-stage small cell lung cancer at the end of 2024 or early 2025.

In addition to its strong commercial performance in the U.S., we are extremely pleased that we recently received a positive CHMP opinion on our marketing authorization application for JZP458, marketed as Rylaze in the U.S., and expect European Commission approval later this year. Since we added zanidatamab to our pipeline last year, it has continued to impress, and we're excited by its broad applicability, which we believe represents $2 billion plus in peak sales potential. Positive pivotal data from our phase II-B trial in biliary tract cancers, or BTC, were featured in an oral session at this year's ASCO conference and concurrently published in The Lancet Oncology. These data were also selected for the best of ASCO meeting. Top-line data readout from the ongoing phase III gastroesophageal adenocarcinoma, or GEA trial, is expected in 2024.

I'm also pleased to report that we recently received IND clearance for JZP898, an engineered interferon alpha cytokine prodrug that is activated specifically within the tumor microenvironment, where it can stimulate interferon alpha receptors on cancer-fighting immune effector cells. With this milestone achieved, we remain on track to initiate a phase I trial of JZP898 later this year. On the operational side, we generated continued top and bottom-line growth in the second quarter. Our commercial execution, coupled with our focus on operational excellence, has put us in a strong financial position, enabling us to execute a focused capital allocation strategy to invest in the products, pipeline programs, and corporate development opportunities with the highest potential to deliver sustainable growth and enhanced value. Given our financial strength and our current stock price, we have resumed share repurchases under our existing program, which Renee will expand upon shortly.

Based on our performance in the first half of 2023 and expectations for the remainder of the year, we are raising our full-year financial guidance for 2023. Longer term, we believe we are well positioned to achieve Vision 2025. Renee will provide additional commentary on our financials and guidance later in the call. Turning to slide 6, we are excited about the progress we've achieved in the second quarter and believe it has substantially advanced us in all 3 areas of Vision 2025, and we are well positioned to achieve these important milestones in our transformation to a high-growth global biopharma leader. I'll now turn the call over to Dan to review our commercial performance, after which Rob will share an update on our R&D progress, Renee will provide a financial overview, and then we'll open the call to Q&A. Dan?

Dan Swisher (President and COO)

Thanks, Bruce. I'm excited to provide an update on our commercial progress. Starting on slide 8, with neuroscience and oxybate, we remain confident in the strength and durability of our oxybate franchise, as Xywav continues to be the oxybate of choice and the only approved therapy for IH. Xywav revenues were $327 million for the second quarter of 2023, representing growth of 39% compared to the same period in 2022. I'll note this growth was against the backdrop of high-sodium oxybate competition entering the market in January of this year. In narcolepsy, our focus remains on educating patients and prescribers on the benefits of reducing sodium intake, this message continues to resonate. In addition to health benefits of lower sodium, based on our discussions with Health Care Professionals and experienced oxybate patients, dosing flexibility is a valued attribute of Xywav.

Exiting the second quarter, approximately 9,300 narcolepsy patients were taking Xywav, and Xywav continues to be the oxybate of choice in the marketplace. In IH, we see continued growth of new prescribers, with approximately 2,200 active patients taking Xywav for treatment of IH exiting the second quarter. IH is a 24-hour sleep disorder. Despite sleeping a normal or longer than normal amount of time each night, people with IH may still experience debilitating symptoms during the day. Xywav is the first and only treatment approved by FDA to treat the full condition of IH. We are focused on educating prescribers on the importance of proper diagnosis and identifying appropriate patients who can benefit from Xywav therapy. A survey of sleep specialists indicated that 70% anticipate increasing their prescribing in the next six months.

With regard to the average number of patients on Xywav exiting the quarter, there was an operational change at our specialty pharmacy, which caused delays in getting refills on time for some Xywav patients. This is being addressed, and importantly, overall second quarter Xywav HCP and patient demand were in line with our expectations in prior quarters. As Renee will review in more detail, we have raised our neuroscience revenue guidance at the midpoint, reflecting our continued confidence in the growth opportunity for Xywav and the durability of oxybate. Total revenues for the combined oxybate business, including royalties from a high-sodium oxybate AG, decreased 2% to $492 million in the second quarter compared to the same period in 2022.

There were approximately 16,200 total average active Jazz oxybate patients in the second quarter, a decrease compared to the end of the first quarter, primarily reflecting the expected impact of Xyrem as a result of the availability of a high-sodium oxybate AG. Our focus is on continuing to grow low-sodium Xywav across both narcolepsy and IH, and we are pleased with Xywav's growth across both indications, even as additional high-sodium oxybate competition is available for patients with narcolepsy. The continued growth of Xywav is one of the factors that contributed to our increased 2023 neuroscience revenue guidance, and as Bruce mentioned, we are well positioned to achieve our Vision 2025 target of $2 billion in revenue from our oxybate franchise. Slide 9 highlights the compelling low-sodium health benefits we are sharing with healthcare professionals and patients.

As narcolepsy is a debilitating chronic condition, we have focused on educational efforts around the lifelong burden of high-sodium intake for narcolepsy patients, who live with a 2 to 3 times higher risk than the general population of cardiovascular comorbidities such as stroke and heart failure. Xywav, the only approved low sodium oxybate and the only oxybate without a labeled warning about high sodium intake, has 92% less sodium than high sodium oxybates. The American Heart Association recommends a maximum of 1,500 milligrams of sodium per day. While high sodium AGs and branded oxybates of 1,100 to 1,640 milligrams of sodium, Xywav has only 100 to 140 milligrams, a reduction of 1,000 to 1,500 milligrams of sodium per day.

To put this in perspective, it would take 12 years of treatment with Xywav to equal the sodium intake of one year of high sodium oxybate treatment. This has significant potential health benefits, including lower blood pressure and improved cardiovascular health. To add to the literature on sodium impact, we presented data at this year's American Academy of Neurology Meeting that showed narcolepsy patients treated with high sodium oxybate had a higher risk of new-onset hypertension, diagnosis, or antihypertensive medication initiation within 180 days of starting therapy when compared to a matched control group of narcolepsy patients not being treated with high sodium oxybate. In fact, the risk of those taking high sodium oxybate was approximately twice that of the control group. We believe these data highlight that sodium intake is a health concern for all narcolepsy patients and one that can have near-term consequences.

FDA has recognized that the difference in sodium content between Xywav and high sodium oxybate, including Xyrem, AG Xyrem, and Lumryz, is likely to be clinically meaningful in all patients with narcolepsy, and that Xywav is safer in all such patients. Lumryz is the recently launched branded 6-dose high sodium oxybate that has the same sodium content as Xyrem. We believe that the majority of patients and healthcare providers will continue to prioritize long-term health when evaluating oxybate therapy. With respect to competition from high sodium oxybate, authorized generics or AGs, Amneal announced the launch of their AG in early July. Two additional companies, Lupin and Par, also have rights to launch an AG product. At this time, Par and Lupin have elected not to launch. These three AG suppliers are each restricted to a low single-digit percent of Xyrem sales volume.

As a reminder, earlier this year, Hikma launched a volume unlimited AG. Jazz receives meaningful royalties on all high sodium oxybate AGs. Moving to slide 10, we remain confident in the blockbuster potential of Epidiolex. With yet another quarter of double-digit year-over-year revenue growth, net product sales increased 15% to $202 million in the second quarter compared to the same period in 2022, driven by underlying demand. We have seen increased penetration in the long-term care setting, driven by additional in-person engagement with physicians, we have additional opportunities for growth. Turning to slide 11, we are focused on multiple opportunities to drive Epidiolex to blockbuster status. We continue to see a positive impact from our educational efforts focused on optimal dosing and caregiver-reported outcomes beyond seizure control from the BECOME Survey, which further differentiates Epidiolex from other anti-seizure medicines.

In particular, reports from the field indicate that the BECOME data has been very impactful with both HCPs and caregivers. The compelling clinical data regarding the use of Epidiolex in combination with clobazam versus using the agents individually continues to resonate. Our commercial team also has an enhanced focus on further penetration into the adult setting. We are also pleased our commercialization efforts outside the U.S. continue to gain momentum. Slide 12 illustrates our progress in expanding Epidiolex outside of the U.S.. Epidiolex is now launched and reimbursed in 23 countries around the world, including all five key European markets. While it's early, we are very encouraged by initial uptake in these markets with favorable pricing and access. We anticipate additional reimbursement decisions and submissions through this year and next.

Moving to our oncology franchise, beginning on slide 13, net product sales for Rylaze were $102 million for the second quarter, a 39% increase year-over-year, our fourth consecutive quarter of growth. We continue to see strong demand for Rylaze, reflecting the significant unmet patient need for a high-quality, reliable supply of Erwinia asparaginase for patients with acute lymphoblastic leukemia. Based on the availability of Rylaze, healthcare professionals have indicated they are returning to best clinical practice in switching therapy at the first signs of hypersensitivity. We continue to receive positive feedback from healthcare providers about the adoption of the Monday, Wednesday, Friday dosing regimen, which allows a dosing schedule that is more in line with preferred clinical practice.

Rylaze has been almost universally adopted in pediatric oncology protocols. We are encouraged to see that there is increasing use of Rylaze in the treatment of adolescents and young adults for the AYA market, which is an area of increased emphasis for us in 2023. Outside of the U.S., we recently received a positive CHMP opinion. With the positive opinion granted, we anticipate E.C. approval of our MAA submission later this year. Regarding the market opportunity, I'll note that there is competition in many European markets. Jazz has consistently delivered a reliable, high-quality supply of this important therapy in the U.S., and we are excited for patients and healthcare providers in Europe to have the opportunity to complete their full course of asparaginase therapy. Turning to slide 14, we rapidly established Zepzelca as a treatment of choice in second-line small cell lung cancer.

Net product sales increased 3% to $70 million in the second quarter compared to the same period in 2022. There remains significant unmet need for patients diagnosed with small cell lung cancer, with 5-year overall survival rates of less than 10% and median overall survival of 6-24 months, depending on the stage at diagnosis. Given this prognosis, there is a further opportunity to both improve patient lives and drive growth through our pivotal phase III trial in first-line small cell lung cancer in combination with Tecentriq. We expect top-line PFS data readout at the end of 2024 or early 2025. In the U.S., there are approximately 27,000 first-line small cell lung cancer patients treated annually. Zepzelca has the potential to increase the duration of response with these earlier-stage patients.

With that, I'll turn it over to Rob for an update on our pipeline and upcoming milestones. Rob?

Rob Iannone (EVP and Global Head of Research and Development)

Thanks, Dan. Starting on slide 16, we provided an overview of the key clinical programs in our diversified pipeline. We are excited about the advances we've made so far this year, with the potential for as many as four late-stage data readouts through 2023 and 2024, which include JZP150 in PTSD, suvecaltamide in essential tremor, zanidatamab in GEA, and Zepzelca in combination with Tecentriq in first-line small cell lung cancer. I'll discuss a few of our programs in more detail shortly, but I wanted to broadly highlight our progress across the pipeline before moving on. Starting with neuroscience, we expect top-line data from our phase II trial of JZP150 in PTSD by the end of the year. For JZP441, our orexin-2 receptor agonist that has the potential to treat narcolepsy, IH, and other sleep disorders, we anticipate initial proof of concept in healthy volunteers later this year.

In addition, we have ongoing trials for suvecaltamide in both essential tremor or ET and Parkinson's disease tremor, with top-line data from the ET trial expected in the first half of 2024. Moving to oncology, zanidatamab is a priority program for us. We aim to advance zanidatamab to the market as rapidly as possible, with second-line BTC representing our first potential commercial indication. We are planning for a potentially accelerated approval of zanidatamab in second-line BTC and have alignment with the FDA on a confirmatory trial in first-line metastatic BTC, where there remains unmet patient needs. We are also evaluating zani in GEA, breast cancer, and other HER2-positive solid tumors. For Zepzelca, we expect top-line PFS data readout at the end of 2024 or early 2025. Small cell lung cancer patients have particularly poor outcomes, with a five-year overall survival rate of less than 10%.

Currently, Zepzelca is indicated to treat patients in the second-line setting. We see a clear mechanistic rationale for Zepzelca to potentially benefit more patients and increase the duration of response in the first-line setting as maintenance therapy in combination with the standard of care. Beyond small cell lung cancer, we have elected to close our phase II Basket trial based on limited responses in 3 solid tumor cohorts. We're analyzing the findings from that trial and continue to explore additional tumor types that may benefit from treatment with Zepzelca. As Dan and Bruce mentioned earlier, we are very pleased to have received a positive CHMP opinion on JZP458, which is marketed as Rylaze in the U.S., with Monday, Wednesday, Friday, and every 48-hour dosing regimens, as well as IV and IM administration. We anticipate EC approval later this year.

Moving to slide 17, I'll expand on my earlier comments regarding zanidatamab. Zanidatamab is a novel bispecific antibody that can simultaneously bind two non-overlapping epitopes of HER2, known as bi-paratope binding. This unique design results in multiple mechanisms of action, including dual HER2 signal blockade, receptor clustering on the cell surface, leading to internalization by bi-paratope binding, and potent immune effector functions, including antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity, leading to encouraging antitumor activity in patients. Zanidatamab has shown compelling activity across a broad range of HER2-positive tumors, and we've presented promising efficacy and early survival data at both ASCO and ASCO GI this year. Additional data presentations are planned for later this year, including quality of life outcomes from the HERIZON-BTC-01 pivotal study at the European Society for Medical Oncology Annual Congress.

This slide speaks to our development strategy for zani, which is focused on four key areas. First, target areas with no approved HER2 agents, such as the significant unmet need second-line HER2-positive BTC, as well as other solid tumors. Second, maximize the opportunity in GEA and other HER2-positive tumors, where we believe zanidatamab has the potential to be the HER2-targeted treatment of choice, supplanting current HER2-targeted agents. Compelling data has demonstrated that zanidatamab has the potential to be a foundational treatment for patients with HER2-positive GEA. Third, we see substantial opportunity in settings where zanidatamab could be used in combination with standard of care for other novel therapies, particularly in breast cancer and in earlier lines of treatment. Fourth, we plan to build upon the compelling activity we've seen across a broad range of HER2-positive tumors to address the patient needs in additional tumor types.

We believe this approach will allow us to deliver an important new therapeutic option to patients and maximize the value of zanidatamab. On slide 18, I want to provide more insight into our excitement about the long-term potential of zanidatamab, which we believe could go beyond addressing significant unmet need in BTC and GEA to include breast cancer, as well as multiple additional cancers that overexpress HER2. With the potential to transform the current standard of care in multiple HER2 positive cancers, we are committed to rapidly advancing and expanding our development program. We believe that zanidatamab has the opportunity to be a differentiated bispecific treatment of choice for HER2 positive cancers. We expect to enter the market first in second-line BTC, where physicians will gain important experience with zanidatamab. The approach is supported by recent compelling data presented at ASCO in previously treated HER2 positive BTC.

We are pleased to share that we are planning for a potential accelerated approval of zanidatamab in second-line BTC based on the HERIZON-BTC-01 data and are working to rapidly bring this therapy to patients in critical need. We've shared the impressive second-line data with the FDA and have alignment on a confirmatory trial in first-line metastatic BTC, where there remains an important unmet patient need. We are continuing to work with FDA regarding timelines, and as our conversations progress, we will expect to be able to provide further updates. Following market entry in BTC, we expect to have a path to approval in first-line GEA with a supplemental BLA submission, which provides a more streamlined approval process compared to a full BLA.

With the treatment landscape evolving following recent data readouts, we continue to strongly believe that substantial opportunity remains to address the unmet patient need in first-line GEA, including the HER2 positive, PD-L1 negative patient population, where the standard of care remains trastuzumab plus chemotherapy. For patients who are PD-L1 positive, we continue to believe that zanidatamab has the potential to be the HER2-targeted treatment of choice, while also combining with BeiGene's tislelizumab in order to treat those who are eligible to receive anti-PD-1 therapy in GEA. Further, there remains an opportunity to move into earlier stages of GEA, where we see the potential to help those patients prior to the metastatic setting in the neoadjuvant and adjuvant settings. GEA represents a significantly larger patient opportunity compared to BTC, and a prior approval in BTC may also accelerate adoption into GEA treatment guidelines and protocols.

We look forward to additional data from the ongoing pivotal phase III GEA trial, HERIZON-GEA-01, expected to read out in 2024, which may support U.S. and global regulatory submissions. Breast cancer also represents a considerable opportunity, supported by promising early data as monotherapy in multiple combinations and across lines of therapy. Based on the efficacy and safety seen in studies to date, we believe zanidatamab is well suited for early-stage disease, including potential use as neoadjuvant and adjuvant therapy. Further, we believe there is potential to help patients previously treated with trastuzumab deruxtecan, or T-DXd, or for those patients who are ineligible to receive treatment with T-DXd. Zanidatamab has also shown promise in HER2 positive and hormone receptor-positive breast cancer as part of a novel combination.

Supporting this, we have ongoing trials in neoadjuvant breast cancer and the opportunity to expand into both combination regimens and later lines of therapy in HER2 positive and HER2-HR positive breast cancer. We are also evaluating zanidatamab through multiple earlier-stage trials in other tumor types where few HER2-targeted treatment options are available. Zanidatamab has shown clinical activity across a diverse set of HER2-positive indications, such as colorectal cancer, non-small cell lung cancer, and multiple other cancers where there remain few targeted treatment options available to the patients. Turning to slide 19, I would like to highlight JZP150, our novel, highly selective fatty acid amide hydrolase or FAAH inhibitor. It is currently in clinical development for the potential treatment of PTSD, with phase II top-line data expected later this year.

PTSD is a psychiatric disorder that affects millions of people, and patients frequently have uncontrolled symptoms that impact their ability to perform activities of daily living and function socially. Only 2 antidepressants have received approval from FDA for the treatment of PTSD symptoms in the past 20 years. Current first-line pharmacological treatments for PTSD, such as selective serotonin reuptake inhibitors, mitigate some symptoms of PTSD but are not designed to address the core underlying problem, fear extinction learning, and its consolidation. Response rates to existing pharmacological treatments rarely exceed 60%, and even fewer patients achieve clinical remission. We have been granted FDA Fast Track designation for JZP150, underscoring the significant unmet needs of PTSD patients. JZP150 is a once-daily oral medication that has the potential to impact the pathophysiology and symptoms of PTSD. Data to date have demonstrated benefits with fear extinction and stress response in healthy volunteers.

Slide 20 shows the PTSD pathophysiology and JZP150's mechanism of action and treatment rationale. PTSD can result from direct or indirect exposure to traumatic experiences and events. Individuals with PTSD have intense and disturbing thoughts and feelings related to their experience that persist long after the traumatic event, and they may relive the event through flashbacks or nightmares and feel sadness, fear, anger, and detachment from other people. In PTSD, fear extinction deficits contribute to the persistence of traumatic memories. Interventions to promote fear extinction learning are a foundation of PTSD treatment. Preclinical and clinical data indicates that exposure to stress and anxiety is associated with activation of fatty acid amide hydrolase or FAAH. Inhibition of FAAH has the potential to directly target pathophysiological processes of PTSD. FAAH is the enzyme responsible for the degradation of anandamide.

Anandamide is reduced in PTSD, and failure of anandamide to return to normal levels can result in a number of behavioral conditions underlying PTSD, including increased anxiety and impaired extinction processing of emotional memory. Inhibition of FAAH results in an increase in anandamide. This has been shown to reduce anxiety, improve fear extinction and recall, and improve sleep architecture and self-reported sleep quality. JZP150 is a potent, highly selective, and irreversible inhibitor of FAAH, designed to address the underlying cause of PTSD. Moving to slide 21, we have outlined the design of the phase II PTSD trial. The primary endpoint of the trial is change in total symptom severity score using the clinician-administered PTSD scale, or CAPS-5, from baseline to the end of treatment. CAPS-5 is a structured 30-item clinical interview.

It is a validated instrument considered the standard for diagnosing and assessing patients with PTSD and is an endpoint that has been determined to be appropriate for regulatory purposes. Beyond PTSD diagnosis, it also allows physicians to evaluate the severity of symptoms and impact on social and occupational function. The trial has several secondary endpoints, including changes in scores on clinical global impressions of severity and the patient global impression of severity scales from baseline to the end of treatment. The ongoing trial is enrolling approximately 270 patients and assessing two doses of JZP150 compared to placebo, which we believe adequately powers the trial to assess whether JZP150 is clinically meaningful in this patient population. We expect top-line data by the end of this year. We are excited about the potential of JZP150 and look forward to updating you on our progress.

Turning to slide 22, we are pleased to recently receive IND clearance for JZP898 and expect to initiate a phase I trial later this year. JZP898 is an engineered interferon alpha cytokine prodrug that is activated specifically within the tumor microenvironment, where it can stimulate interferon alpha receptors on cancer-fighting immune effector cells. High-dose interferon alpha therapy is approved in multiple tumor types, but is used sparingly based on its toxicity profile. Systemic delivery of cytokines can cause serious toxicities in peripheral tissues. This leads to poor clinical outcomes given ineffective antitumor immune activation and unmanageable toxicity in patients. JZP898 is a conditionally activated interferon alpha, which is selectively activated in the tumor microenvironment. Through this approach, biologically relevant exposures are coupled with optimal cytokine potency while limiting toxicity in other tissues. We are excited to bring this novel molecule into the clinic later this year.

Overall, our R&D team continues to advance multiple programs from our neurosciences and oncology pipelines, we're looking forward to multiple near-term data readouts. Now I will turn over the call to Renee for a financial update. Renee?

Renee Gala (EVP and CFO)

Thanks, Rob. I'll start with our top and bottom line results on slide 24. As a reminder, our full financial results are available in our press release in 10-Q. In the second quarter of 2023, we achieved $957 million in total revenues. This was driven by growth of our key products in both neuroscience and oncology, including another quarter of double-digit growth of Xywav, Epidiolex, and Rylaze compared to 2Q 2022. We're particularly pleased with the continued trajectory of Xywav, even with competition since the beginning of the year. Coupled with the continued Epidiolex momentum and strong growth for Rylaze, we saw total revenue increase 3% compared to 2Q 2022.

Our disciplined capital allocation and focus on operational excellence drove adjusted net income of $325 million, growth of 6% compared to the same quarter in 2022. We continued to generate significant cash from our business, recording approximately $617 million of cash from operations in the first half of 2023, an increase of more than $100 million compared to the same period in 2022. Our strong overall financial position means we have significant flexibility to invest in priority commercial and R&D programs, as well as corporate development opportunities. Corporate development is a core component of Vision 2025, and we remain active in exploring opportunities to expand our commercial portfolio and pipeline.

Turning to slide 25, we are updating our total 2023 revenue guidance to a range of $3.725 billion-$3.875 billion, reflecting a $25 million increase at the midpoint. This update is underpinned by an increase of $20 million at the midpoint of our neuroscience revenue guidance. Our increased 2023 neuroscience revenue guidance incorporates our continued confidence in the durability of our oxybate franchise, in part based on the performance and growth of Xywav during the first half of the year, a time period in which we saw the introduction of high-sodium oxybate competition. With regard to high-sodium authorized generics, we expect our royalties from Hikma, which is the only volume unlimited authorized generic, to be significantly higher in the second half of 2023 relative to the first half.

During the second half of 2023, the royalty rate from Hikma to Jazz becomes fixed at a rate where we and Hikma both have substantial economics. We also receive royalties on other high-sodium oxybate AGs, all of which are restricted to a low single-digit percentage of Xyrem sales volume. As Dan noted earlier, currently, only one additional AG has been launched. Our 2023 oncology guidance remains unchanged and reflects expectations of continued double-digit growth for this franchise, led by RYLEZ, with a revenue range of $950 million-$1.05 billion, and a midpoint of $1 billion.

Continuing to slide 26, our capital allocation strategy includes investment in commercial brands to drive top-line growth, in our pipeline to drive long-term growth, and in corporate development, where we remain actively engaged in assessing opportunities and which remains an important pillar of our growth strategy. We are maintaining our prior non-GAAP SG&A and R&D guidance for 2023. Consistent with our capital allocation strategy, our enhanced investment in R&D is a direct result of our success in diversifying and advancing our pipeline, as well as prioritizing those programs that we believe will have the biggest impact for patients while delivering value and contributing to our growth. Therefore, supported by our strong cash flows and aligned to our strategic and disciplined approach to capital allocation, we have resumed share repurchases under our existing repurchase program.

In the second quarter, we completed approximately $100 million of share repurchases. As of the end of the second quarter, approximately $336 million remained available for share repurchases under our current plan. Importantly, given our strong overall financial position, we are able to repurchase shares without compromising our ability to execute business development opportunities and invest in our innovative R&D program. On the bottom line, we expect to continue to deliver strong adjusted net income, or ANI, and have increased our non-GAAP ANI guidance to $1.29 billion-$1.34 billion, which implies a 41% year-over-year ANI growth at the midpoint.

I would also like to highlight, we raised our non-GAAP adjusted EPS guidance to a range of $18.15-$19.00, an increase of $1.20 at the midpoint, primarily driven by our increased revenue and ANI outlook, as well as reductions in our fully diluted shares outstanding. The decrease to our weighted average ordinary share guidance relates to both our share repurchase and to our recent irrevocable election to settle in cash the principal of our $575 million exchangeable senior new- notes due in 2024, thereby limiting potential dilution from these instruments. With our strategic investments, expanding product portfolio, R&D progress, and focus on operational excellence, we believe we are well positioned to achieve Vision 2025 and deliver further diversification, sustainable growth, and enhanced value to patients and shareholders. I'd now like to turn the call back to Bruce.

Bruce Cozadd (Chairman and CEO)

Thanks, Renee. I'll conclude our prepared remarks on slide 28. The first half of 2023 has been driven by focused execution and strong commercial results, evidenced by the durability of our oxybate franchise, continued growth of Epidiolex, and strength in Rylaze sales. We continue to advance our pipeline and invest in long-term growth, and we have as many as four late-stage data readouts through 2024 that have the potential to further diversify and transform our business. Our latest pipeline addition, zanidatamab, is approaching several near-term clinical and regulatory milestones. Given its applicability across multiple tumor types and lines of therapy, we believe zanidatamab has $2 billion+ in peak sales potential. We also remain focused on strategic capital allocation.

With our strong cash flow, balance sheet, and margins, we have the financial flexibility to make significant investments across commercial, pipeline, and corporate development to drive sustainable growth and enhance value. That concludes our prepared remarks. I'd now like to turn the call over to the operator to open the line for Q&A.

Operator (participant)

We will now begin the Q&A session. If you would like to queue for a question, press star one on your telephone keypad. To withdraw a question, press star two. Once again, to ask a question, please dial star one. If you are using a speakerphone, please pick up your handset before asking your question. We do ask that you please limit yourself to one question. We will pause here briefly as questions register. The first question comes from the line of Jason Gerberry with Bank of America. Your line is now open.

Jason Gerberry (Managing Director and Equity Research Analyst)

Oh, hey, guys. Thanks for taking my questions. Mine is on the phase III Zani GEA study that's gonna read out first half next year. Can you help frame what sort of data we can expect on the primary efficacy measures, the PFS, the OS? Is this a first interim? I'm just wondering if PFS and OS will be mature, or if the focus really is on ORR in this data cut? Thanks.

Bruce Cozadd (Chairman and CEO)

Yeah, thanks, Jason. Rob, maybe I'll throw that one to you.

Rob Iannone (EVP and Global Head of Research and Development)

Just to clarify, what we said previously was in 2024, we didn't specify exactly when. In that, we are referring to PFS as the initial readout.

Jason Gerberry (Managing Director and Equity Research Analyst)

Thank you.

Rob Iannone (EVP and Global Head of Research and Development)

Does that clarify your question?

Bruce Cozadd (Chairman and CEO)

Yeah.

Operator (participant)

The next question comes from the line of Joseph Thome with TD Cowen. Your line is now open.

Joseph Thome (Managing Director and Senior Research Analyst)

Hi there, good afternoon, and thank you for taking my question. Maybe one on the upcoming PTSD readout. Maybe what's a clinical- clinically meaningful benefit on that CAPS-5 scale? When you talk about the type of patient enrolled, are these on a concomitant SSRI, or are they SSRI treatment failures? Can you just put that into context a little bit for us? That would be great. Thank you.

Bruce Cozadd (Chairman and CEO)

Yeah, go ahead, Rob.

Rob Iannone (EVP and Global Head of Research and Development)

Sure. We haven't said specifically, you know, what treatment effect that we've powered to, but you could draw some of your own inferences by looking at the sample size, et cetera, that's listed on ClinicalTrials.gov.

Bruce Cozadd (Chairman and CEO)

You'll note that it's a placebo-controlled trial, with 2 dose levels, yielding the total sample size. Patients are allowed other concomitant medications.

Operator (participant)

Thank you. The next question comes from the line of Marc Goodman with Leerink Partners. Your line is now open.

Marc Goodman (Senior Research Analyst)

Yes, hi. Could you please give us a little more color on the comment that you made regarding the operational issues with the specialty pharmacy, and the oxybate franchise? Just give us a sense of how much you think it may have impacted, patients in the quarter or, or whatever you think it may have impacted, or is it impacting anything in the third quarter? Thank you.

Bruce Cozadd (Chairman and CEO)

Yeah, thanks for the question, Marc. Kim, you want to take that?

Kim Sablich (EVP and General Manager of United States)

Sure. I'd, I'd be happy to. Let me start out by saying that, you know, we continue to be very confident in the strength and durability of our oxybate franchise, as low-sodium Xywav continues to be the oxybate of choice and the only approved therapy for IH. You know, the decrease in total average active Jazz oxybate patients this quarter primarily, you know, reflects the expected impact to Xyrem as a result of Xywav adoption and the availability of AG Xyrem. In terms of Xywav and the average number of patients on Xywav exiting the quarter, there was what we're calling an operational change at our specialty pharmacy, which unfortunately caused delays in some Xywav patients getting their refills on time.

This has been addressed, and importantly, I think to understand, is that the overall 2Q Xywav HCP and patient demand, the overall market demand for Xywav, was in line with our expectations and with what we saw in prior quarters. This really was an issue at the pharmacy that affected, you know, patients-- some patients getting refills, not the overall demand for Xywav. The benefits of reducing sodium intake, you know, in the market continue to resonate with our customers, and we're very confident in the growth opportunity for Xywav and the durability of the franchise. You know, while we expect Xyrem to continue to decline in line with the Xywav and AG adoption, as you heard, we've raised our full year 2023 financial guidance and increased our neuroscience revenue guidance at the midpoint.

You know, overall, our increased neuroscience revenue guidance, you know, accounts for the performance and growth of Xywav during the first half of the year, in a time period in which we saw the introduction of high-sodium oxybate competition. You know, our focus remains on continuing to grow the low-sodium Xywav, which is already, as you saw, annualizing at well over $1 billion, and we remain very confident in the durability of the business.

Operator (participant)

Thank you. The next question comes from the line of Akash Tewari with Jefferies. Your line is now open.

Akash Tewari (Global Head of Biopharmaceutical Research)

Hey, thanks so much. Can you walk me through your confidence on the $2 billion sodium oxybate number for your long-term guidance? Let's say you continue to add about 250 IH patients a quarter until 2025. That kind of implies IH will contribute about $600 million in sales by 2025. That means that your narcolepsy franchise, which is about $1.7 billion today, only declines to about $1.4 billion for you to hit that $2 billion watermark. How do you achieve that with generics and Evito launching? Like, what are we missing here? Also, I think you've previously mentioned the majority of the erosion impact for the sodium oxybate franchise will occur in 2023. Is that still the case today, given your revised near guide? Thanks so much.

Bruce Cozadd (Chairman and CEO)

Yeah, Akash, thanks for the question. You know, we outlined our confidence that oxybate business at Jazz would contribute about $2 billion toward Vision 2025 at the beginning of last year, at the beginning of 2022. Obviously, we reiterated that coming into 2023, and we've now actually increased our short-term guidance in 2023. As a reminder, what we meant by that $2 billion was the combined revenues from Xywav, both in narcolepsy and in idiopathic hypersomnia, continued brand Xyrem sales, and our royalties on any AGs that come to market through our system. We continue to feel confident in that. You didn't specifically mention the royalties in your analysis.

I'll remind you that the contribution from those royalties expected to be significantly higher in the second half of 2023 relative to the first half, and that the royalty structure, we've disclosed from the Hikma relationship, will actually reset up again in 2024. It's the combination of all those things that get us to the durability. Our big focus, as Kim explained, is on growing Xywav. This is the longer, healthier choice for patients, given the benefits of low sodium in this chronic treatment, and we'd like to see more and more patients get the benefit of Xywav moving forward.

Operator (participant)

Thank you. The next question comes from the line of David Amsellem with Piper Sandler. Your line is now open.

David Amsellem (Managing Director and Senior Research Analyst)

Hey, thanks. I wanted to come back to the Vision 2025.targets, particularly the $5 billion top line. It, it, it seems like the, the Street and the broader investor community is not quite there regarding the $5 billion target. Just can you, can you articulate what you think we're all missing? Is it something surrounding Epidiolex? Is it, is it zanidatamab, for instance, is GEA, or biliary tract cancer, or both, in that 2025 number? Just help us understand why there seems to be daylight between that target and what folks are modeling for 2025. Thanks.

Bruce Cozadd (Chairman and CEO)

Yeah. Well, let's review where we are toward Vision 2025. We rolled this out at the beginning of 2022. We're six quarters in to a four-year period. We're feeling very good about the performance of our business overall, both relative to our guidance for 2023, which has now been raised on both the top and the bottom line, and our Vision 2025. I just spoke about oxybate and the durability of that franchise and the positive progress we're seeing with Xywav. Let me remind you that half of our business today is already coming from Epidiolex and oncology. We're seeing double-digit growth in our three lead assets, Xywav, Epidiolex, and Rylaze, which together are accounting for about 66% of our revenues.

When you look at the oxybate piece, you know, Xyrem is now less than half of that piece of our business. We've got growth coming in all of our key franchises, which we estimated would contribute in 2025, approximately $4.5 billion in aggregate. We left a placeholder in Vision 2025 intentionally, for our ongoing corporate development activities, and said that products that were not part of our portfolio when we started Vision 2025 could contribute that last $500 million. Zanidatamab may well contribute to that. We're not saying it's gonna contribute all of the $500 million, to be clear, but that was something added to the portfolio after we began this process.

We remain very interested in continuing to access new commercial products and pipeline products through our corporate development efforts moving forward. Our financial position is strong. If you look at our cash investments, about $1.4 billion. You look at our cash flow in the first half of the year, approaching $620 million. Our leverage is down, we feel like we're well positioned to continue to bring in new assets, as we have over the company's history. If you go back any two to three-year period in our history, you'll generally see us do a significant transaction. We thought it was unfair to assume that we would suddenly stop doing transactions, particularly given our successful launches of a number of products in a row here and our strong financial position.

Operator (participant)

Thank you. The next question comes from the line of Ami Fadia with Needham. Your line is now open.

Ami Fadia (Managing Director and Senior Analyst)

Hi, good evening. Thanks for taking my question. Perhaps continuing on the vein of the placeholder for corporate development, can you talk about your level of confidence in being able to hit a majority of that $500 million through, you know, some sort of business development? Where, where are you, you know, where are your thoughts at currently in terms of alternative options, in terms of use of capital? Would you consider buying back more shares should you not be in a position to execute on such a deal? Thank you.

Bruce Cozadd (Chairman and CEO)

Yeah, thanks, Ami. Renee, can you jump in on this one?

Renee Gala (EVP and CFO)

Sure, I'm happy to. You know, Ami, we've talked quite a bit about our strategic and disciplined approach to capital allocation, and our priority, first and foremost, is investing in growth. We're investing behind our commercial launches and growth programs. We're investing behind the pipeline, and we expect to continue to invest in corporate development. As Bruce mentioned previously, it has been an important pillar of growth for us, and we expect that to continue to be the case. You know, in addition, we, we also look at opportunities in terms of managing the balance sheet strategically. Bruce also mentioned we delevered pretty quickly, so we're in a great position today to be opportunistic in terms of additional investments for the balance sheet. We did take the opportunity, just given what we view as immense, untapped value right now within the stock.

We did take the opportunity to recommence share repurchases in the second quarter, and we think that was the right thing to do. In terms of future repurchases, we'll continue to look carefully at the opportunity set in front of us, prioritizing growth. Specific to the $500 million placeholder, as you've heard on the call today, we're really excited about the opportunity for zanidatamab. We think that's going to be an important program and eventually product for us and for patients. We don't expect that to cover a large majority of the $500 million, but it's certainly, we certainly expect that to contribute. Beyond that, we're quite active from a corporate development perspective. As you've heard me say previously, we're not going to overpay just to be able to meet this growth objective.

We also don't think that we'll need to. We do think there are opportunities out there, both within neuroscience and oncology, but also within the rare and orphan segment, more broadly. As you know, the vast majority of our commercial products currently do fall within that category, and we think there are applicable learnings in terms of, you know, working directly with patient groups and serving the needs of patients, our underlying infrastructure, that those learnings can be shared both from our existing experience to other rare and orphan conditions. Today, we feel quite confident in our ability to transact. We're well-capitalized to be able to do so, as Bruce mentioned previously, and we think we've established a great track record as a partner of choice to be able to do so as well.

Operator (participant)

Thank you. Our next question comes from the line of Gregory Renza with RBC Capital Markets. Your line is now open.

Gregory Renza (Director and Senior Biotechnology Research Analyst)

Great. Good, good afternoon, Bruce and team. Congrats on, on the quarter, and thanks for taking my question. Bruce, may- maybe just a little bit on, on Epidiolex and just with respect to, to Dan's comments on the drivers for, for potential, continued growth. Just curious if you can comment a bit on, you know, any particular areas or drivers that, that kind of outsized and helped to, to propel the growth that, that you're expecting? Certainly last quarter, first quarter, a little seasonality and, and, and seeing, the, the momentum that you're speaking about now. Just curious how you see that playing out, in, in the near term. Thank you very much.

Bruce Cozadd (Chairman and CEO)

Yeah, Greg, thanks for the question. Dan, you want to take Epidiolex?

Dan Swisher (President and COO)

Yeah. Thanks, Bruce. With Epidiolex, you know, it was another quarter of double-digit growth with 15%, Greg, so really pleased to see, yeah, the continued initiatives that we outlined on the call. Continued face-to-face interactions, very important in the treatment centers, getting to more offices, more prescribers. You know, we've been enhancing our focus on the adult setting. In particular, in the U.S., we've gone after long-term care settings and seen increasing penetration there. You know, we've also been educating HCPs, about the benefits of Epidiolex beyond seizure control, and that was, you know, highlighted in the BECOME data, which was presented at the end of last year, which talks about, you know, cognitive and behavioral benefits.

Yeah, we look forward to continuing to lean into that area, both with caregiver surveys and even interventional studies. So we've got a real commitment to, you know, continuing to generate data both within the indications and kind of outside those indications. You know, outside the U.S., the launches continue to go well. We're at 23 countries globally. We've had six positive pricing reimbursement decisions to date in the U.S.-- sorry, outside the U.S. Importantly, we've got a phase III study on what we think could be a very significant market for us with Epidiolex in Japan. So that's enrolling nicely, and we look forward to providing updates in the coming quarters.

Operator (participant)

Thank you. The next question comes from the line of Annabel Samimy with Stifel. Your line is now open.

Annabel Samimy (Managing Director)

Hi, just two more on Epidiolex. You mentioned two times now, expanded indications. The only indication we know of that you're working on is the EMAS indication. Are there others that we don't know about, that you plan on expanding into? Also with the EU launch, we now have 23 countries approved, I guess, 5 in the major EU countries. Are all those countries all on board? Should we now see a significant expansion in Epidiolex ex U.S.? Thanks.

Bruce Cozadd (Chairman and CEO)

Rob, would you like to talk a little bit about some of the additional data we're generating with Epidiolex, and then maybe, Kim, you could talk a little bit about the potential for broader use of the product over time?

Rob Iannone (EVP and Global Head of Research and Development)

Yeah, you're right that we're evaluating EMAS, and the objective there is to generate data in yet another seizure type, adding to the three indications we have, really trying to demonstrate that Epidiolex is broadly active across different seizure types, regardless of the underlying etiology. We also continue to provide evidence around the indications we have, both in terms of anti-seizure effectiveness, but also in terms of other potential benefits of Epidiolex. You heard Dan refer to the caretaker survey, and we continue to support and do studies along those lines as well.

Kim Sablich (EVP and General Manager of United States)

Yeah, sure, Rob. I'll, I'll say that we've had, you know, very nice growth in the three indicated populations, as well as growth over time in the base of prescribers that are utilizing Epidiolex. You know, what we see traditionally as our customers get more and more experienced with the product, usually starting in the three indications, they see what it can do for their patients in terms of seizure control and now, you know, beyond seizure control, that frankly, they've been hearing about from caregivers since day one of the launch. This really gives them the confidence to start using it more broadly across the spectrum of various seizure types and so forth. We're clearly not, you know, promoting it outside that, but this is what we hear from the providers.

Once they get the experience, they see the efficacy, they do start to utilize it earlier and more broadly, across their patient population. Really, the, you know, the data, as we've talked about, that we've been sharing to really increase the efficacy perception of the product, the clobazam combination data, in and of itself, gets them to stop and think about why, why am I reserving this for certain patient types? Most of my patients are on clobazam. Most of them could still benefit from additional seizure control or beyond seizure benefits. It really gets them to start thinking about, I should be using this more, in, in more and more of, you know, of, of these patients that are taking clobazam.

Operator (participant)

Thank you. Our next question comes from the line of Jeff Hung with Morgan Stanley. Your line is now open.

Jeff Hung (Equity Research Analyst)

Thanks for taking my question. For Rylaze, you've talked about focusing on adolescents and young adults. Can you talk a little bit more about how that's going and how much of that opportunity remains to be addressed? Thanks.

Kim Sablich (EVP and General Manager of United States)

Yeah, Kim? Sure. Love to. Love talking about Rylaze. You know, what we've really seen with Rylaze and is just lots of excitement in general. I think as we told you early on, it didn't take very long for healthcare providers to have confidence in the supply and to return to, you know, best clinical practice in terms of switching patients at the first signs of hypersensitivity. At this point in the pediatric market, it's been, you know, added almost universally to the protocols in that setting. At the beginning of this year, we did tell you that we were looking to start trying to expand the adolescent and young adult market.

There was quite a bit of usage and a fair amount of usage of the product in adolescents and young adults that were being treated in a pediatric center, you know, per pediatric protocol. The, you know, adult centers were less educated, familiar, and experienced with using, you know, using Rylaze in this setting. We've gone out there this year. We have now spent two quarters educating them on the product, about the importance of switching as quickly as possible when they see a hypersensitivity reaction, and we see nice orders coming through and a nice growth rate happening in this setting. We don't think we're done. We haven't gotten all of these centers set to start using it.

Some of them are still dabbling, so there, there definitely is, you know, some more growth to be had there. And I think it's important to remember that in the adult setting, you know, the, because this is a weight-based product, the average dose, you know, is, is higher than in the pediatric center, so each adult patient, is, is, is worth more. You know, we're really pleased with Rylaze at this state, but we think there's a little bit more room to grow here in the U.S., and then, of course, you know, ex-U.S..

Operator (participant)

Thank you. Our next question comes from the line of Balaji Prasad with Barclays. Your line is now open.

Xiao Guo (VP of Equity Research)

Good afternoon. This is Xiao on for Balaji. Thanks for taking our question. Just a quick one on your OX2R program. On the data for TAK-994, that was recently published on New England Journal of Medicine, and the factor for liver toxicity for TAK-994 was the impact of reactive metabolics. Takeda also mentioned that TAK-861 and TAK-994 do have the overlapping metabolic pathways. Do you think JZP441 is well differentiated with TAK-994 to avoid this issue? Thanks.

Bruce Cozadd (Chairman and CEO)

Rob?

Rob Iannone (EVP and Global Head of Research and Development)

Yeah, thank you for the question. The liver toxicity associated with 994 was known at the time, that we entered into the partnership with Sumitomo, and we focused on chemical series that we thought were distinct enough, such that that risk of liver toxicity wouldn't be carried over. We do think that our molecule is substantially differentiated from the chemical series that you referred to.

Operator (participant)

Thank you. The next question comes from the line of Mohit Bansal with Wells Fargo. Your line is now open.

Mohit Bansal (Managing Director and Co-Head of Therapeutics Research)

Great, thank you for taking my question, congrats on all the progress. Maybe, like, one question regarding the authorized generics of Xyrem. Do you think they will have any impact on IH market as well? Because in our talks with doctors, they, they think that they can prescribe, prescribe it, as long as payers cover it, payers will probably cover it. Do you see this as a threat? Because doctors could use it off-label. Thank you.

Bruce Cozadd (Chairman and CEO)

Yeah, well, I'll remind you that Xyrem did not do a comprehensive clinical program in the way that Xywav has in IH. There's slightly different dosing information in the label. While you're right, that physicians can prescribe the product, that does not always mean that that product will be successfully reimbursed. Kim, any comments you want to make on the marketplace?

Kim Sablich (EVP and General Manager of United States)

Yeah, sure. Yeah, I, we've seen traditionally that payer, that HCPs have had trouble getting coverage, you know, for oxybate for idiopathic hypersomnia, because payers restricted it. With the introduction of Xywav for idiopathic hypersomnia, we have achieved nice coverage, as we do with narcolepsy, of 90% of commercial lives, having coverage. There usually is utilization management criteria, you know, in place there, and certainly heavier utilization management criteria around non-indicated products. You know, we feel confident that while a more small portion of healthcare plans may cover high sodium oxybate, you know, in particular the AG for idiopathic hypersomnia, most of them are following the FDA-approved label. You know, Xywav is the only FDA-approved treatment for idiopathic hypersomnia.

Bruce Cozadd (Chairman and CEO)

Rob-

Rob Iannone (EVP and Global Head of Research and Development)

Thank you.

Bruce Cozadd (Chairman and CEO)

Maybe you could just, maybe you could just expand a little bit on that, slightly different dosing information.

Rob Iannone (EVP and Global Head of Research and Development)

Yeah, Bruce, just specifically, with regard to narcolepsy or IH, or?

Bruce Cozadd (Chairman and CEO)

I, I meant IH, but you can talk about dosing flexibility generally.

Rob Iannone (EVP and Global Head of Research and Development)

Sure. Starting with IH then, the clinical trial allowed for an initial dose of up to 6 grams, and at the time, it was designed that way because there was some uncertainty around whether IH patients would wake up to take that second dose. What we found in the clinical trial is that with initiation of Xywav, patients with IH improved substantially, and in fact, were able to go ahead and take the second dose. Overall, that was the more common dosing regimen, even though in the trial, and we find that to be the case in clinical practice as well. Along those lines, for narcolepsy, as you know, Xywav also has dosing flexibility to allow for uneven doses, and we find that patients really do prefer this.

Oftentimes, schedules are different from one patient to another, but even within a patient, schedules may different day to day, different day to day, weekdays, weekends, depending on family obligations. And they like the flexibility of, of uneven doses, potentially.

Operator (participant)

Thank you. The next question comes from the line of Joon Lee with Truist Securities. Your line is now open.

Joon Lee (Managing Director and Senior Biotech Analyst)

Hi, congrats on the quarter, and thanks for taking our questions. How do, how do you quantify the trade-off between having a once-a-night drug with high sodium versus twice-a-night drug with no sodium? Isn't, isn't having to wake up in the middle of the night also unhealthy? And as a quick follow-up, do you have any views on reboxetine currently in phase III/IV for narcolepsy with data expected in the fourth quarter? Thank you.

Bruce Cozadd (Chairman and CEO)

Yeah, Rob, maybe I could have you jump in a little bit on the nighttime impact of oxybate therapy.

Rob Iannone (EVP and Global Head of Research and Development)

Yes, happy to, Bruce. We know that narcolepsy patients have significantly disrupted nighttime sleep. We also know that oxybates have a, a very big impact in improving the architecture of nighttime sleep, and we think that's why for a short-acting drug, patients then have substantial improvement in daytime symptoms like cataplexy or excessive daytime sleepiness. When you look across studies of oxybates, whether that be a fixed-dose, high-sodium version, or immediate release oxybate, there is improvement. It's very comparable. There's no evidence that a fixed-dose regimen improves disruption in nighttime sleep to a greater extent. Patients typically do not normalize their sleep, and there's really no evidence that waking to take a second administration impacts one way or another.

Bruce Cozadd (Chairman and CEO)

Then, Rob, I think there was a question on reboxetine at the, at the end of the question as well.

Rob Iannone (EVP and Global Head of Research and Development)

Sorry, Bruce, could you just repeat that for me then?

Bruce Cozadd (Chairman and CEO)

I think the question was, any thoughts on data on reboxetine? I mean, I'll just jump in-

Rob Iannone (EVP and Global Head of Research and Development)

Anything?

Bruce Cozadd (Chairman and CEO)

Say historically, we, in our conversations with KOLs, we've not found that there's as much interest in that as other drugs available or in development. You know, this has been available in certain markets for a long time, in treatment of other diseases, but we haven't heard of a huge success in this patient population in the U.S.?

Rob Iannone (EVP and Global Head of Research and Development)

Sure. Okay, thanks for clarifying that, Bruce. I, and I would just say that, our focus with Xywav is, is a nighttime administration, to address the underlying cause of, of disrupted nighttime sleep, which has profound effects on daytime symptoms. Reboxetine is, you know, one of, of, several drugs that's used as a daytime alerting agent, and, and is sometimes complementary to oxybate, but we don't think, a substitute for many patients.

Operator (participant)

Thank you. The next question comes from the line of Charles Duncan with Cantor Fitzgerald. Your line is now open.

Charles Duncan (Managing Director)

Hey, good e- good evening, Bruce and team. Congrats on good commercial performance in the quarter, thanks for taking our questions. Sorry to ask about a nuance in the pipeline, but it actually relates to the next readout that could come, and that's on JZP150 and PTSD. Tough disorder. I guess I'm wondering if, you know, given that this is an early phase II, would you focus more on stat sig and effect size or the overall results of the study to enable the drug to move forward? Then in terms of the statistical analysis plan, it, it looks like a wide range of, of doses. I guess I'm wondering, is it each dose relative to placebo, or would you combine doses, the do—the analysis of the two dose groups versus placebo? Thanks.

Bruce Cozadd (Chairman and CEO)

Rob, you want to take the 150 question?

Rob Iannone (EVP and Global Head of Research and Development)

Yeah. Thanks, Bruce. We do think the CAPS-5 is a comprehensive composite endpoint. It has regulatory endorsement as an endpoint that could be used for approval, and it does capture quite a bit the broad range of symptomatology in PTSD patients. We do think that that's a good way to measure the effect of the drug. We are measuring other things in exploratory ways as well, which we certainly will take into account. You're right that the trial is 3 arms. There's 2 active dose levels and placebo, and given the sample size that we have, we feel we're well-powered to make comparisons with both of those different dose levels against placebo. We don't have to collapse across those arms.

Bruce Cozadd (Chairman and CEO)

Well, I think that was our last question, so I just want to jump in and thank all of our questioners for moving us through, I think, most of our commercial business, a lot of our pipeline, and our strategy. You know, hopefully, people feel great about the quarter on the top line, on the bottom line, the new guidance, increased diversification, and the momentum we have in our business, particularly our 3 key growth drivers in, in Xywav, Epidiolex, and Rylaze. I'd just like to close today's call by recognizing all of our Jazz colleagues for their efforts in delivering new therapeutic options to patients, and thank our partners and shareholders for their continued confidence and support. Thank you all for joining us today.

Operator (participant)

This concludes today's call. Thank you for your participation. You may now disconnect your line.