Q4 2021 Jazz Pharmaceuticals PLC Earnings Call

Operator: David Amsellem, David Amsellem, David Amsellem, David Amsellem Good day, and welcome to the fourth quarter 2021 Jazz Pharmaceuticals Earnings Conference Call. At this time, all participants are in listen-only mode.

Good day and welcome to the fourth quarter 2021 Jazz Pharmaceuticals earnings Conference call. At this time, all participants are in listen only mode.

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After the speaker's presentation, there will be a question and answer session to ask a question during this session.

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Operator: As a reminder, this call may be recorded. I would like to turn the call over to Andrea Flynn, Head of Investor Relations. You may begin. Thank you, and good afternoon, everyone.

As a reminder, this call may be recorded I.

I would like to turn the call over to Andrea Flynn head of Investor Relations you may begin.

Andrea Flynn: Today Jazz Pharmaceuticals reported its fourth quarter and full year 2021 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, Rene Gala, Executive Vice President and Chief Financial Officer, Dan Swisher, President, and Rob Iannone, Executive Vice President, Global Head of R&D. Kim Sablich, Executive Vice President and General Manager, North America will join the team for Q&A.

Thank you and good afternoon, everyone today jazz Pharmaceuticals reported its fourth quarter and full year 2021 financial results. The slide presentation accompanying this webcast.

Billable on the investors section of our website.

<unk> may also refer to the press release, we issued earlier today, which is also posted to our website on the call today are Bruce <unk>, Chairman and Chief Executive Officer, Renee Gala Executive Vice President and Chief Financial Officer, Dan Swisher, President and Rob <unk> Executive Vice President Global head of R&D, Kim Stabler Executive Vice.

President and general manager of North America will join the team for Q&A.

Andrea Flynn: On slide two, I'll remind you that today's webcast includes forward-looking statements, such as those related to our future financial and operating results, including expectations related to Vision 2025 and our guidance for 2022, 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.

On slide two I'll remind you that today's webcast includes forward looking statements such as those related to our future financial and operating results, including expectations related to vision 2025, and our guidance for 2022 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, and our slide deck and in our latest SEC disclosure documents, 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.

Andrea Flynn: Turning to slide three on this webcast, we'll discuss non-GAAP financial measures. Reconciliations of GAAP to non-GAAP financial measures are included in today's press release and in the slide presentation available on the investor section of our website. I'll now turn the call over to Bruce. Thanks, Andrea. Good afternoon, everyone, and thank you for joining us today.

Turning to slide three on this webcast, we'll discuss non-GAAP financial measures reconciliations of GAAP to non-GAAP financial measures are included in today's press release and in the slide presentation available on the industrial section of our website.

I'll now turn the call over to Bruce.

Thanks, Andrea good afternoon, everyone and thank you for joining us today I'll start on slide five.

Bruce Cozadd: I'll start on slide five. 2021 was a transformative year for jazz, with strong performance and consistent execution. In the fourth quarter and throughout 2021, we made substantial progress across commercial, R&D, and corporate development. Continuing our evolution to a diversified, innovative, global biopharmaceutical company. Beginning with our overall 2021 financial performance, for the first time, we exceeded $3 billion in annual revenue, delivering top line performance at the upper end of our guidance range, and recorded nearly $1 billion of adjusted net income on a non-gap basis. Rene will discuss our financial results in more detail later in the call.

2021 was a transformative year for jazz with strong performance and consistent execution in.

In the fourth quarter and throughout 2021, we made substantial progress across commercial R&D and corporate development, continuing our evolution to a diversified innovative global biopharmaceutical company.

Beginning with our overall 2021, the financial performance for the first time, we exceeded $3 billion in annual revenue delivering topline performance at the upper end of our guidance range and recorded nearly $1 billion of adjusted net income on a non-GAAP basis, Renee will discuss our financial results.

In more detail later in the call.

Bruce Cozadd: Our exceptional top-line results were driven by strong commercial execution across our portfolio. We met our ambitious target of five key launches in 2020 and 2021. Two of those launches, Rylase and Xywave Enidiopathic Hypersomnia, or IH, are therapies that Jazz advanced from concept to commercialization. Coupled with the addition of Epidiolex to our commercial portfolio through the GW Pharmaceuticals acquisition, we have significantly diversified our revenue and are on track to meet our goal of at least 65% of net product sales in 2022 coming from newly approved or acquired products.

Our exceptional top line results were driven by strong commercial execution across our portfolio. We met our ambitious target of five key launches in 2020 and 2021 two of those launches reillys and sideways in idiopathic hypersomnia or IH, our therapies the Jasmine.

From concept to commercialization.

Coupled with the addition of up of dialects to our commercial portfolio through the GW Pharmaceuticals acquisition, we have significantly diversified our revenue and are on track to meet our goal of at least 65% of net product sales in 2022 coming from newly approved or acquired products.

Bruce Cozadd: On the regulatory side, we secured FDA approval for Riley's for the treatment of ALL and PsiWave NIH in June and August 2021 respectively. We also received orphan drug exclusivity from FDA for ZyWave for narcolepsy in June, with FDA citing the clinical benefits of ZyWave as a lower sodium oxidate therapy compared to ZyWave. Subsequently, we received orphan drug exclusivity for Zywave NIH. In addition, in January of this year, we submitted the SBLA for Riles to support an updated dosing regimen in the U.S.

On the regulatory side, we secured FDA approval for Riley's for the treatment of ALLL and highway of NIH.

June and August 2021, respectively. We also received orphan drug exclusivity from FDA for XI wafer narcolepsy in June with FDA, citing the clinical benefits of sideways as a lower sodium <unk> therapy compared to xyrem.

Subsequently, we received orphan drug exclusivity for XI wave NIH.

In addition in January of this year, we submitted the BLA for Riley's to support an updated dosing regimen in the U S.

Bruce Cozadd: In concert with delivering strong commercial results and achieving important regulatory milestones, we continue to advance our R&D pipeline, which now comprises 18 novel candidates being studied in 36 active clinical trials. On the neuroscience side, we initiated two important clinical programs in 2021, beginning phase two trials for subacalpamide, or JZP-385, in essential tremor and for JZP-150 in post-traumatic stress disorder. We also initiated the third phase three nebiximals clinical trial in multiple sclerosis-related spastic. We also initiated the third phase three nebiximals clinical trial in multiple sclerosis-related spastic.

In concert with delivering strong commercial results and achieving important regulatory milestones. We continue to advance our R&D pipeline, which now comprises 18 novel candidates being studied in 36 active clinical trials.

On the neuroscience side, we initiated two important clinical programs in 2021, beginning phase III trials for <unk> or <unk> hundred $85 in essential tremor and for <unk> 150, and post traumatic stress disorder.

We also initiated the third phase III <unk> clinical trial in multiple sclerosis related specificity.

Bruce Cozadd: And as part of our ongoing growth in oncology, we have a robust development effort for Zep Zelka, headlined by the initiation of a phase three trial in collaboration with our partner Roche, evaluating Zapsalka in combination with Tithentrick as maintenance therapy in first-line extensive stage, small cell lung cancer. A noteworthy milestone in 2021 that contributed to our growth was the acquisition of GW Pharmaceuticals. The integration of GW has proceeded exceptionally well, and as I've noted in the past, there is a superb cultural fit between the Jazz and GW teams.

And as part of our ongoing growth in oncology, we have a robust development effort for <unk> zilkha headlined by the initiation of the phase III trial in collaboration with our partner Roche evaluating <unk> in combination with centric as maintenance therapy in first line extensive stage small cell lung cancer.

Sure.

A noteworthy milestone in 2021 that contributed to our growth was the acquisition of GW pharmaceuticals.

The integration of GW has proceeded exceptionally well.

And as I have noted in the past there was a superb cultural fit between the jazz and GW teams. The acquisition is proving to be highly complementary to our existing commercial portfolio and has added the industry, leading GW cannabinoid platform to our R&D pipeline.

Bruce Cozadd: The acquisition is proving to be highly complementary to our existing commercial portfolio and has added the industry-leading GW cannabinoid platform, to our R&D pipeline. Just as important, we're thrilled that many talented and experienced members of the GW team are in leadership positions across our combined enterprise. [inaudible] These accomplished... All of which were underpinned by strategic allocation of capital and strong cash flow have set the stage for an exciting year ahead. We continue to be laser focused on executing our strategy to build a high value portfolio of differentiated commercial and clinical stage therapies that deliver sustainable growth and enhanced value. At the J.P. Morgan Healthcare Conference this January, we introduced Vision 2025, which included commercial, pipeline, and operational components. On slide six.

Just as important we're thrilled that many talented and experienced members of the GW team are in leadership positions across our combined enterprise.

These accomplishments all of which were underpinned by strategic allocation of capital and strong cash flow have set the stage for an exciting year ahead.

We continue to be laser focused on executing our strategy to build a high value portfolio of differentiated commercial and clinical stage therapies that deliver sustainable growth and enhanced value.

At the Jpmorgan Health Care Conference. This January we introduced vision 2025, which included commercial pipeline and operational components.

On slide six we've called out several upcoming value drivers that we believe will enable us to deliver on this vision.

Bruce Cozadd: We've called out several upcoming value drivers that we believe will enable us to deliver on this vision. For commercial, we are focused on execution across our neuroscience and oncology portfolios, including maintaining the strong momentum of our ZyWave, ZepZelka, and Rylai's launch, as well as continuing the growth of Epidiolex in the U.S. and global markets. With respect to our pipeline, we are advancing multiple mid and late stage programs and anticipate the first clinical data from our Demyximals program in the first half of this year, and we will continue to focus on operational, including advancing our goal of achieving less than three and a half times net leverage by the end of 2022. Turning to slide 7.

For commercial we are focused on execution across our neuroscience and oncology portfolios, including maintaining the strong momentum of our sideways zapped zilkha and reilly's launches as well as continuing the growth of <unk> in the U S and global markets.

With respect to our pipeline, we are advancing multiple mid and late stage programs and anticipate the first clinical data from our <unk> program in the first half of this year.

And we will continue to focus on operational excellence, including advancing our goal of achieving less than three five times net leverage by the end of 2022.

Turning to slide seven.

Bruce Cozadd: Vision 2025 will frame our business for the next several years as we strive to bring new and innovative therapies to patients. Critical Needs As I noted, there are three core components to our vision: commercial, pipeline, and operational expertise.

Vision 2025, we will frame our business for the next several years as we strive to bring new and innovative therapies to patients in critical need.

As I noted there are three core components to our vision commercial pipeline and operational excellence.

First commercial.

Bruce Cozadd: After achieving over $3 billion in revenue in 2021, we're positioned to grow revenue to $5 billion in 2025. We expect to generate revenue from current products, as well as realize contributions from pipeline candidates that we expect to advance to market and products that we may acquire through strategic corporate development transactions. The $5 billion also includes the anticipated organics-fails growth of existing products in our commercial portfolio, as well as indication and geographic expansion. Second, our pipe.

After achieving over $3 billion in revenue in 2021, we're positioned to grow revenue to $5 billion in 2025.

We expect to generate revenue from current products as well as realized contributions from pipeline candidates that we expect to advance to market and products that we may acquire through strategic corporate development transactions.

The $5 billion also includes anticipated organic sales growth of existing products in our commercial portfolio as well as indications and geographic expansion.

Second our pipeline.

Bruce Cozadd: In 2021, our R&D organization advanced key programs addressing significant patient needs in neuroscience and oncology. With a solid foundation in place, we believe we will deliver at least five novel product approvals in areas of critical unmet need and significant market opportunity by the end of the decade. In addition to legacy compounds in our pipeline, we're excited about promising assets emerging from the GW cannabinoid platform. And we are continuing to evaluate and pursue novel neuroscience and oncology programs through potential corporate development opportunities. Finally, operational, Our 2021 Adjusted Operating Margin was 43% and we plan to improve our adjusted operating margin by 5 percentage points.

In 2021, our R&D organization and advanced key programs addressing significant patient needs in neuroscience and oncology.

With a solid foundation in place we believe we will deliver at least five novel product approvals in areas of critical unmet need and significant market opportunity by the end of the decade.

In addition to legacy compounds in our pipeline, we're excited about promising assets emerging from the GW cannabinoid platform and we are continuing to evaluate and pursue novel neuroscience and oncology programs through potential corporate development opportunities.

Finally operational excellence, our 2021 adjusted operating margin was 43% and we plan to improve our adjusted operating margin by five percentage points from 2021% to 2025, delivering more of our topline through to the bottom line.

Bruce Cozadd: 2021 to 2025, delivering more of our top line through to the bottom line. Our Track Record of Strong Execution and Accomplished, gives us confidence in our ability to achieve Vision 2025. And our 2022 guidance, which Rene will cover shortly, is in line with, I'll now turn the call over to Dan for an overview of our commercial performance, after which Rob will share an update on progress of our R&D program. Rene will provide a financial over, And then we'll open the call to Q&A. Dan?

Our track record of strong execution and accomplishments gives us confidence in our ability to achieve vision 2025.

And our 2022 guidance, which Renee will cover shortly is in line with this vision.

I'll now turn the call over to Dan for an overview of our commercial performance after which Rob will share an update on progress of our R&D programs Renee will provide a financial overview and then we'll open the call to Q&A.

Dan.

Dan Swisher: Thanks, Bruce. Well, I'm excited to share the continued progress across our commercial portfolio. So starting with neuroscience, we continue to build momentum in our OxyBait franchise, as highlighted on slide 9. This includes market leading adoption of Zaiwave and Narcolepsy and the commercial launch of Zaiwave and IH in November 2021, enabling us to deliver this important therapy to another patient population with significant needs. Average active oxidative patients increased to approximately 16,200 in the fourth quarter, an approximate 6% increase compared to the same period last year.

Thanks, Bruce, but I am excited to share the continued progress across our commercial portfolio.

With neuroscience, we continue to build momentum in our Oxidate franchise as highlighted on slide nine.

This includes market, leading the adoption of <unk>, the narcolepsy and the commercial launches highways NIH in November 2021, enabling us to deliver this important therapy to another patient population with significant need.

Average active oxidate patients increased to approximately 16200 in the fourth quarter, an approximate 6% increase compared to the same period last year.

Dan Swisher: With the introduction of Zywave and narcolepsy in late 2020, we meaningfully advanced patient care with a lower sodium oxybate product and are pleased with its exceptional adoption. We remain focused on educating physicians and narcolepsy patients about the lifelong burden of high sodium intake in this patient population who live with an increased risk of cardiovascular comorbidities.

With the introduction of <unk> in narcolepsy in late 2020, we meaningfully advance patient care with a lower sodium oxidate product and are pleased with its exceptional adoption. We remain focused on educating physicians in narcolepsy patients.

Ross a lifelong burden of high sodium intake in this patient population, who live with an increased risk of cardiovascular comorbidities.

Dan Swisher: The benefits of lowering sodium intake are resonating strongly with patients and prescribers, and we exited the year with approximately 6,650 active Zywave patients with narcolepsy. Our commercial launch is iWave for adults with IH began in November 1, 2021, and we're excited to bring the first and only FIA approved IH treatment to patients. We've been encouraged by the positive early launch momentum and feedback we've received from prescribers and the IH community. Based on the reports from the field, prescribers have been impressed with the profile of this medicine.

The benefits of lowering sodium intake are resonating strongly with patients and prescribers and we exited the year with approximately 6650 active <unk> patients with narcolepsy.

Our commercial launches of <unk> for adults with IH began in November one 2021, and we're excited.

To bring the first and only FDA approved <unk> treatment to patients we have.

Been encouraged by the positive early launch momentum and feedback we've received from prescribers and the IH community.

Based on the reports from the field prescribers had been impressed with the profile of this medicine.

Dan Swisher: Healthcare providers are excited to have a treatment option that addresses IH and not just its symptoms. Importantly, prescribers have also been pleased with the initial coverage and access of Zyways for their IH patients. Xywave and Narcolepsy currently has approximately 90% of commercial lives covered.

Healthcare providers are excited to have a treatment option that addresses IH and not just its symptoms.

Importantly, prescribers have also been pleased with the initial coverage and access is evaluated for their IH patients.

The highways in narcolepsy currently has approximately 90% of commercial lives covered we anticipate that <unk>. The NIH will have similar coverage to narcolepsy and expect this to occur in a similar or faster timeframe.

Dan Swisher: We anticipate that Xywave and IH will have similar coverage to Narcolepsy and expect this to occur in a similar or faster time frame. While payers continue to update their policies to include IH, we're encouraged to see a higher percentage of commercial claims approved than originally anticipated during this phase of launch. Exiting the quarter, there were approximately 250 active Zyway patients with IH.

While payers continue to update their policies to include IH were encouraged to see a higher percentage of commercial claims.

<unk> than originally anticipated during this phase of launch.

Exiting the quarter there were approximately 250 active <unk> patients with IH, while still early in the IH launch we're pleased with the positive feedback from both healthcare professionals and patients.

Dan Swisher: While still early in the IH launch, we're pleased with the positive feedback from both health care professionals and patients. Unlike the recent launch in narcolepsy, where there was a significant number of oxybate-experienced patients transitioning over to Zywave, we expect that the cadence of new patient starts in IH to be more in line with a rare disease launch where there has been previously no approved therapy. IH represents a significant growth driver for Zywave.

Like the recent launch of narcolepsy, where there was a significant number of oxidative experienced patients.

Transitioning over desire with we expect that the cadence of new patient starts NIH to be more in line with a rare disease launch where there had been previously no approved therapies.

Iaa's represents a significant growth driver for XI with our initial focus is on driving awareness and adoption among existing oxidate prescribers and the approximately 37000 people diagnosed with IH that are actively seeking health care <unk>.

Dan Swisher: Our initial focus is on driving awareness and adoption among existing Oxybate prescribers and the approximately 37,000 people diagnosed with IH that are actively seeking health care. Expanding the market beyond diagnosed IH patients who are actively seeking treatment provides us with a longer-term growth opportunity as we estimate that the total diagnosed IH patient population is likely close to the diagnosed narcolepsy market, which is approximately 70,000 to 80,000 patients. Turning to slide 10, in Epidiolex, we saw 35% revenue growth in the fourth quarter compared to the same period in 2020 on a pro forma basis. In the fourth quarter, Epidiolex Net Product Sales benefited from a temporary increase, Specialty Pharmacy Inventory Levels.

Spanning the market beyond diagnosed <unk> patients who are actively seeking treatment provides us with a longer term growth opportunity as we estimate that the total diagnosed <unk> patient population is likely close to the diagnosed narcolepsy market, which is approximately 70% to 80000 patients.

<unk>.

Turning to slide 10, and Thats. The dialogues, we saw 35% revenue growth in the fourth quarter compared to the same period in 2020 on a pro forma basis.

Fourth quarter <unk> net product sales benefited from a temporary increase in specialty pharmacy inventory levels. Excluding this inventory effect. We were pleased that revenue increased 10% on a sequential basis in fourth quarter versus third quarter 2021 with growth in.

Dan Swisher: Excluding this inventory effect, we were pleased that revenue increased 10% on a sequential basis in fourth quarter versus third quarter 2021, with growth in both the U.S. and international markets. 2021 was the first full year of the COVID-19 pandemic, which has changed how our industry engages with customers and how HCPs engage with their patients. Despite the challenges of this new environment, we were able to achieve robust year full year revenue growth of 29% compared to 2020 on a pro forma basis. In the US, where we have seen access to customers impacted by surges of COVID-19, our non-personal promotion continues to have a high level of engagement.

Both the U S and international markets.

2021 was the first full year of the COVID-19, pandemic, which has changed our industry engages with customers and how hcp's engaged with their patients. Despite.

The challenges of this new environment, we were able to achieve robust year.

Full year revenue growth of 29% compared to 2020 on a pro forma basis.

In the U S, where we have seen access to customers impacted by surges of COVID-19.

Our non personal promotion continues to have a high level of engagement.

Dan Swisher: We've adjusted our commercial initiatives to adapt to a new normal that includes more hybrid and virtual engagement with healthcare providers. In addition to strong revenue growth, we continue to add new prescribers and grow Epidiolex's active prescriber base. We expect that as new prescribers gain experience and understanding of the therapeutic benefits of Epidiolex and broaden its use within their practices, this will contribute to continued adoption. As underlying growth drivers continue to build momentum, we remain confident in this medicine's blockbuster potential.

We've adjusted our commercial initiatives to adapt to a new normal that includes more hybrid and virtual engagement with health care providers.

In addition to strong revenue growth, we continue to add new prescribers and grow at the dialogue is active prescriber base, we expect that as new prescribers gain experience and understanding of the therapeutic benefits of that the dialogues and broaden its use within their practices. This will contribute to continued adoption.

As underlying growth drivers continue to build momentum we remain confident in this medicine blockbuster potential.

Dan Swisher: I also want to highlight that we continue to strengthen the IP durability of Epidiolex, In December, a new patent was issued covering the composition of the botanically-derived CBD preparation used in epidiolex and the treatment of indicated disorders using that CBD preparation. This patent, now listed in the U.S. FDA Orange Book, extends through 2039. We are also continuing to make significant progress in Europe. During the third quarter, we successfully launched Epidiolex in Italy, Spain, and Switzerland, with our most recent launch in Ireland in January of this year.

I also want to highlight that we continue to strengthen the IP durability at.

The dialogues.

In December a new patent was issued covering the composition of the botanically derived CBD preparation used in that the dialogues and the treatment of indicated disorders using that CBD preparation.

This patent now listed in the U S. FDA Orange book extends through 2039.

Dan Swisher: In addition, we expect to launch in France later this year, pending final pricing, reimbursement, and access discussions, at which point Epidilex would be launched and reimbursed in all five major European markets. Overall, we continue to be excited about the future growth potential of Epidiolex as a significant contributor to both our top line in 2022 and Vision 2025. Even as we navigate the challenges of the pandemic, we're encouraged by the steady growth and positive customer feedback for the brand.

We are also continuing to make significant progress in Europe . During the third quarter, we successfully launched Epidiorite in Italy, Spain, and Switzerland with our most recent launch in Ireland in January of this year. In addition, we expect to launch in France. Later this year pending final pricing reimbursement in <unk>.

Access discussions.

Each point Epidiorite will.

Would be launched and reimbursed in all five major European markets.

Overall, we continue to be excited about the future growth potential of <unk> as a significant contributor to both our top line in 2022 and vision 2025.

Even as we navigate the challenges of the pandemic, we are encouraged by the steady growth.

Dan Swisher: We remain confident we can achieve Blockbuster status as the standard of care in treatment-resistant epilepsy. The increasing use of Epidiolex earlier in the treatment algorithm and positive experiences in real-world settings are based on its unique mechanism of action, efficacy and safety profile, and ability to be combined with other therapies. So now moving to oncology and starting with ZepDelco on slide 11, we are continuing to see strong demand for ZepDelco with net revenue for the fourth quarter of $64.8 million, 21% growth compared to the same period in 2020.

And positive customer feedback for the brand we remain confident we can achieve blockbuster standard status as the standard of care and treatment resistant epilepsy.

The increasing use of <unk> earlier in the treatment algorithm and positive experiences in real world settings are based on its unique mechanism of action efficacy and safety profile and ability to be combined with other therapies.

So now moving to oncology and starting with <unk> on Slide 11, we are continuing to see strong demand for <unk> with net revenue for the fourth quarter of $64 8 million, 21% growth compared to the same period in 2020.

Dan Swisher: We have established DEPZOCA as the treatment of choice in second-line small cell lung cancer and have a robust development plan in place to evaluate additional patients who can benefit from this therapy, which Rob will cover in more depth. Within our current indication of second-line small cell lung cancer, we see opportunities for growth with DefDelca continuing to displace TopoTecam and immuno-oncology products being used as monotherapies.

We have established <unk> as the treatment of choice in second line small cell lung cancer and have a robust development plan in place to evaluate additional patients who can benefit from this therapy, which Rob will cover in more depth.

Within our current indication of second line small cell lung cancer, we see opportunities for growth with <unk>, continuing to displace <unk> and immuno oncology products being used as monotherapy.

Dan Swisher: We also see potential among patients being re-challenged with platinum-based chemotherapies or receiving other chemotherapy regimens. Findings from the pivotal Zepzelka trial support use in the setting and our ongoing Phase 4 trial will provide additional clinical data on Zepzelka in this patient population. Turning to slide 12, we launched Rylase, our recombinant Erwinia asparaginase therapy in July 2021. Fourth quarter net product sales, which was the first full quarter on the market, were $65 million.

We also see potential among patients being re challenged with platinum based chemotherapies or receiving other chemotherapy regimens.

<unk> from the pivotal <unk> trial support used in this setting.

And our ongoing phase four trial will provide additional clinical data on <unk> in this patient population.

Turning to slide 12, we launched <unk>, our recombinant erwinia asparaginase therapy in July 2021.

Fourth quarter net product sales, which was the first full quarter on the market were $65 million.

Dan Swisher: We continue to receive encouraging feedback from customers with commentary on the ease of both ordering and dose preparation, as well as our suite of support services. As we discussed previously, there was a notable uptick in Rylase orders beginning in September as remaining supply of Erwin Ace was depleted. Fourth quarter 21 revenues showed strong performance for Rylase, reflecting increased brand awareness among customers and its position in the market as the only therapy available to patients in the U.S. who have a hypersensitivity reaction to E. coli-derived asparagin.

We continue to receive encouraging feedback from customers with commentary on the ease of both ordering and dose preparation as well as our suite of support services.

As we discussed previously there was a notable uptick in relates to orders.

Beginning in September as remaining supply of Irwin a Swiss depleted.

Fourth quarter 'twenty, one revenues showed strong performance for <unk>, reflecting increased brand awareness among customers and its position in the market as the only therapy available to patients in the U S. We have a hypersensitivity reactions E coli derived asparaginase.

Dan Swisher: We also saw an initial buildup of inventory, which is typical for new products. We're very pleased with the launch to date, expect a strong performance in 2022, and we're excited to evolve our launch messaging based on the potential label update to Monday, Wednesday, Friday dosing, which Rob will cover in more detail. So in summary, our team delivered strong results in 2021, driven by successful launches and execution across our commercial portfolio. Now I'll turn the call over to Rob to discuss our R&D successes in 2021, near-term pipeline opportunities, and anticipated milestones for 2022. Rob?

We also saw an initial buildup of inventory, which is typical for a new products. We're very pleased with the launch to date and expect a strong performance in 2022, and we're excited to evolve our launch messaging based on the potential label update to Monday, Wednesday, Friday, dosing, which Rob will cover in more.

Dale.

So in summary, our team delivered strong results in 2021, driven by successful launches in execution.

Across our commercial portfolio now I will turn the call over to Rob to discuss our R&D successes in 2021 near term pipeline opportunities.

And anticipated milestones for 2022, Rob.

Thanks, Dan.

On slide 14, we detailed the mid and late stage clinical programs in our pipeline on today's call.

Rob Iannone: Thanks, Dan. On slide 14, we've detailed the mid and late stage clinical programs in our pipeline. On today's call, I'm going to recap a few key accomplishments in 2021 and then focus on 2022 milestones. It was a very productive year for our R&D organization. We received two FDA approvals, for Ryleson ALL, and Zai Wei's and Iann, both of which we brought from concepts to approval. We initiated multiple clinical trials, including phase two trials for subacaltamide, or JZP385, an essential tremor, and for JCP 150 for Post Traumatic Stress Disorder.

To recap a few key accomplishments in 2021, and then focus on 2022 milestones.

A very productive year for our R&D organization.

We received two FDA approvals for <unk>, <unk>, and <unk> and high eights.

Of which we brought some concepts to approval.

We initiated multiple clinical trials.

Including phase III trials for Super Kalsomine, or GBP, three eight side and essential tremor.

And for <unk> for post traumatic stress disorder.

Rob Iannone: Both of these compounds were acquired through corporate development efforts, and our team is excited to build upon the existing clinical data for these promising therapies. In addition, the acquisition of GW Pharmaceuticals has added a number of clinical and preclinical programs to our pipeline. The industry-leading GW cannabinoid class, and talented professionals with deep expertise in drug development in the cannabinoid space. The integration between Jazz and GW R&D organizations has progressed even better than we could have predicted, and our combined group has many exciting program milestones ahead of us in 2022 and beyond.

Both of these compounds were acquired through corporate development efforts and our team is excited to build upon the existing clinical data for these promising therapies.

In addition, the acquisition of GW Pharmaceuticals.

Added a number of clinical and preclinical programs to our pipeline.

The industry, leading GW cannabinoid platform and.

And talented professionals with deep expertise in drug development in the cannabinoid space.

The integration between jazz and GW R&D organizations has progressed, even better than we could have predicted.

And our combined group has many exciting program milestones ahead of us in 2022 and beyond.

Rob Iannone: We are also advancing a robust development after Prasad Stalka. Three separate trials were initiated in 2021. Phase 3 trial supported by Jazz and our partner Roche to evaluate Zipzelka in combination with Decentric in first-line extensive stage small cell lung cancer.

We are also advancing a robust development asset for us it's Duncan.

Three separate trials were initiated in 2021.

<unk> III trial supported by jazz and our partner Roche to evaluate <unk> in combination with the century.

First line extensive stage small cell lung cancer.

Rob Iannone: A confirmatory Phase III trial in second-line small cell lung cancer being run by our partner PharmaMod, and our own post-marketing observational trial in second-line small cell lung cancer that Dan noted earlier. In addition, earlier this year, we have initiated our Phase 2 BASCCA trial, evaluating Fibs-Elka as monotherapy in several solid tumor. One area of particular focus for our team is the treatment of movement, where there is a significant unmet need and potential to deliver new therapies, are Navixom All Programs now, has three active trials focused on multiple sclerosis-related spasticity.

Our confirmatory phase III trial in second line small cell lung cancer being run by our partner final remark.

And our own post marketing observational trial and second line small cell lung cancer as Dan noted earlier.

In addition earlier this year, we have initiated our phase II basket trial evaluating <unk> as monotherapy in several solid tumor types.

One area of particular focus for our team is the treatment of movement disorders.

There is a significant unmet need and potential to deliver new therapies.

Mimic similar programs now.

Has three active trials focused on multiple sclerosis related spasticity.

Rob Iannone: Specificity, which occurs in up to 84% of MS patients, is a major issue with limited treatment options. Despite the critical need, no new oral antispasticity medicines have been approved in the U.S. in the last 20 years. We expect data from our first trial in the first half of 2022. This trial, which is smaller and shorter relative to two others, is assessing change in muscle tone using elements of the modified Ashworth scale.

Specificity, which occurs in up to 84% of MF patients as.

As a major issue with limited treatment options.

Despite the critical need no new oral anti spasticity medicines had been approved in the U S. In the last 20 years.

We expect data from our first trial in the first half of 2022.

This trial, which is smaller and shorter relative to others.

Is assessing change in muscle tone using elements of the modified ashworth scale.

Rob Iannone: If results from this trial are positive... There is the potential for a regulatory submission in the U.S. later this year. We expect data from two additional trials, which have larger sample size, to read out in late 2022 and early 2023. As Dan mentioned earlier... We also have submitted an SPLA for Riley's to update our label to an intramuscular Monday, Wednesday, Friday dosing schedule, with patients receiving 25 milligrams per meter squared on Monday and Wednesday and 50 milligrams per meter squared on Friday.

If results from this trial are positive.

The potential for a regulatory submission in the U S. Later this year.

We expect data from two additional trials, which have larger sample sizes to readout in late 2022 in early 2023.

As Dan mentioned earlier.

We also have submitted an S. BLA for Riley's update our label to an intramuscular Monday Wednesday Friday dosing schedule.

With patients receiving 25 milligrams per meter squared on Monday and Wednesday.

50 milligrams per meter squared on Friday.

Rob Iannone: This schedule, which is more in line with current clinical practice to avoid weekend dosing, allows patients to maintain a clinically meaningful level of serum asparaginase activity through the entire duration of treatment. Currently the label dosing schedule is every 48 hours. 25 milligrams per meter squared.

This schedule, which is more in line with current clinical practice to avoid weekend dosing.

Allows patients to maintain a clinically meaningful level of serum asparaginase activity through the entire duration of treatment.

Currently the label dosing schedule is every 48 hours.

25 milligrams per meter squared.

Rob Iannone: Similar to the review of our original BLA, the FBLA will be reviewed under the real time on call to review process. We're also planning another regulatory application to FDA to support intravenous administration later this year, as well as an application in Europe for both IV and IM administration in mid-2022. Now I will pass the call off to Renee for a financial update. Renee?

Similar to the review of our original BLA BLA.

BLA will be reviewed under the real time oncology review process.

We're also planning another regulatory application to FDA to support intravenous administration later this year as.

As well as an application in Europe for both IV and Im administration.

Mid 2022.

Now ill pass the call off to Rene for a financial update.

Yes.

Renee Gala: Thanks, Rob. I'll begin on slide 16. We have made significant strides in transforming our business throughout 2021, and we finished the year with positive momentum entering 2022. As Bruce noted, we achieved the top end of our 2021 total revenue guidance, as well as our neuroscience and oncology guidance. Our total 2021 revenues of $3.1 billion represented growth of 31% compared to 2020. This included neuroscience and oncology revenues of $2.3 billion and $734 million, respectively, with both franchises delivering more than 30% growth compared to 2020. Turning to operating expense, our 2021 adjusted SG&A expense was 36% of total revenues, which reflects a three percentage point increase from 2020, driven by strategic investments across multiple product launches.

Thanks, Rob I'll begin on slide 16.

Renee Gala: 2021 adjusted R&D expense increased to 15% of revenues, reflecting the initiation of multiple mid and late stage clinical trials and the addition of the GW pipeline and cannabinoid platform. Through our strategic investments in commercial launches, pipeline expansion, and transformative M&A, we are demonstrating our ability to generate significant revenue while remaining disciplined in our approach to capital allocation. This focus on both the top and bottom line drove nearly a billion dollars in full year adjusted net income with ANI and adjusted EPS growth of 41 and 30 percent respectively compared to 2020.

We have made significant strides in transforming our business throughout 2021, and we finished the year with positive momentum entering 2022.

As Bruce noted we achieved the top end of our 2021 total revenue guidance as well as our neuroscience and oncology guidance.

Our total 2021 revenues of $3 1 billion represented growth of 31% compared to 2020. This included neuroscience and oncology revenues of $2 3 billion and $734 million, respectively with both franchises delivered.

More than 30% growth compared to 2020.

Turning to operating expense our 2021 adjusted SG&A expense was 36% of total revenues, which reflects a three percentage point increase from 2020, driven by strategic investments across multiple product launches.

2021, adjusted R&D expense increased to 15% of revenues.

<unk> the initiation of multiple mid and late stage clinical trials and the addition of the GW pipeline and cannabinoid platform.

Through our strategic investments in commercial launches pipeline expansion and transformative M&A, we are demonstrating our ability to generate significant revenue while remaining disciplined in our approach to capital allocation. This focus on both the top and bottom line drove nearly 1 billion.

Full year, adjusted net income with ASI, and adjusted EPS growth of 41, and 30% respectively compared to 2020.

Renee Gala: Turning to slide 17, our strong performance in 2021 positions us for continued growth in 2022. On the top line, our total revenue guidance range for 2022 is $3.46 to $3.66 billion. This represents approximately 15% year over year growth at the midpoint, driven by both our neuroscience and oncology franchises. For neuroscience, our net sales guidance is $2.56 to $2.76 billion, representing growth of 14% at the midpoint compared to 2021. Our guidance reflects conviction in the opportunity for further Epidiolex growth and confidence in the durability of our Oxivate franchise.

Turning to slide 17, our strong performance in 2021 positions us for continued growth in 2022 on.

On the topline our total revenue guidance range for 2022 is three <unk> to $3 six 6 billion.

This represents approximately 15% year over year growth at the midpoint driven by both our neuroscience and oncology franchises.

For neuroscience, our net sales guidance is $2 five six to $2 76 billion representing growth of 14% at the midpoint compared to 2021 our.

Our guidance reflects conviction and the opportunity for further <unk> growth and confidence in the durability of our Oxidate franchise.

Renee Gala: Our Oncology Net Guidance is $840 to $920 million representing growth of 20% at the midpoint compared to 2021. Our oncology franchise continues to grow towards being a billion-dollar-plus business, aligned to our vision 2025, and we're excited to have rapidly established SEPSELCA as the second-line small-cell lung cancer treatment of choice, and by the significant demand for Rilase, both of which demonstrate our commercial execution capability. Turning to OPEX, on a non-GAAP basis, our SG&A guidance is $1.12 to $1.19 billion, or approximately 32% of revenue at our midpoint.

Our oncology and that guidance is $840 to $920 million representing growth of 20% at the midpoint compared to 2021.

Our oncology franchise continues to grow towards being a $1 billion plus business aligned to our vision 2025, and we're excited to have rapidly establish that silica as the second line small cell lung cancer treatment of choice and by the significant demand for <unk>, both of which demonstrate our commercial.

Execution capabilities.

Turning to Opex on a non-GAAP basis, our SG&A guidance is 112 to $1 $109 billion or approximately 32% of revenue at our mid point.

Renee Gala: And our R&D guidance is $560 to $600 million, approximately 16% of revenue at our midpoint. Our expense guidance reflects continued focus on driving sustainable revenue growth, advancing our pipeline, and optimizing our operations. I would note our guidance does not include any new corporate or business development transactions.

And our R&D guidance is $560 million to $600 million apiece.

Approximately 16% of revenue at our midpoint.

Our expense guidance reflects continued focus on driving sustainable revenue growth advancing our pipeline and optimizing our operations.

I would note our guidance does not include any new corporate or business development transactions. However, we do expect to be active in this area across 2022.

Renee Gala: However, we do expect to be active in this area across 2022. We are projecting 2022 non-gap adjusted net income of $1.13 to $1.2 billion, which represents a 17% increase at the midpoint compared to 2021, reflecting our continued focus on delivering improved bottom line growth and our commitment to operational excellence. With multiple important product launches underway and gaining momentum, we feel confident in our ability to effectively scale our operations and improve our adjusted operating margin, driving towards our Vision 2025 target of achieving a five percentage point improvement from 2021 to 2025. I'd like to note several important assumptions underlying our guidance. First, with respect to our neuroscience guidance and XIRM-authorized generics. The first AG launch is slated for January 1st, 2023 or earlier under certain circumstances.

We are projecting 2022 non-GAAP adjusted net income of 113 to $1 2 billion, which represents a 17% increase at the midpoint compared to 2021, reflecting our continued focus on delivering improved bottom line growth.

And our commitment to operational excellence.

With multiple important product launches underway and gaining momentum we feel confident in our ability to effectively scale, our operations and improve our adjusted operating margin driving towards our vision 2025 target of achieving a five percentage point improvement from 2021 to <unk>.

2025.

I'd like to note several important assumptions underlying our guidance.

First with respect to our neuroscience guidance and Xyrem authorized generic.

The first AG launch is slated for January one 2023 or earlier under certain circumstances. Given the continued strong launch of <unk>, which has a direct effect of reducing ziram sales our guidance assumes the potential for AG entry in the second half of 2000.

Renee Gala: Given the continued strong launch of ZyWave, which has the direct effect of reducing ZyREM sales, our guidance assumes the potential for AG entry in the second half of 2022. We do not anticipate AG entry before the second half of 2022. Even accounting for AG entry and other future potential Oxivate competition, we continue to expect PsiWave to be the Oxivate therapy of choice in 2023. As a reminder, HCMA is the first AG allowed onto the market and they are volume unlimited.

'twenty two.

We do not anticipate AG entry before the second half of 2022.

Even accounting for AG entry and other future potential Oxidate competition, we continue to expect <unk> to be the oxalate therapy of choice in 2023.

As a reminder, hikma is the first AG allowed onto the market and they are volume unlimited.

Renee Gala: The following HCMA royalty components are relevant to our neuroscience guidance. During the first six months of the AG term, the AG royalty rate paid to Jazz is tiered and wide-ranging, starting at 10% and going to 90% based on the total volume of AG units sold as a percentage of total Oxivate units, with that total volume referring to ZyWave, ZyRAM, and ZyRAM AG.

Following hikma royalty components are relevant to our neuroscience guidance.

During the first six months of the AG term the AG royalty rate paid to jazz is tiered and wide ranging starting at 10% and going to 90%.

Just on the total volume of <unk> unit sold as a percentage of total Oxidate unit with that total volume, referring to Valuate XI and.

And sigh around AG.

Renee Gala: During the second six-month period, the royalty rate to Jazz would become fixed at a rate where we and HICMA each have substantial economics, regardless of the AG volume. Should the AG term be extended beyond one year, the HCMA royalty rate paid to Jazz will then increase considerably to a higher fixed rate in the high double digits for the remaining four years of the AG period. With respect to our EPS guidance, it is important to note that beginning in 2022, under the new Accounting Standard for Convertible Debt, we will include the full approximately 9 million shares underlying our convertible debt instruments as part of our share count for calculating EPS.

During the second six months period, the royalty rate to jazz would become fixed at a rate, where we and hikma each have substantial economics, regardless of the AG volume.

Should the AG term be extended beyond one year, the hikma royalty rate paid to jazz will then increase considerably to a higher fixed rate in the high double digits for the remaining four years of the AG period.

With respect to our EPS guidance. It is important to note that beginning in 2022 under the new accounting standard for our convertible debt.

We will include the full approximately 9 million shares underlying our convertible debt instruments as part of our share count for calculating EPS.

Renee Gala: This accounting change results in dilution of approximately $2.00 per share in our 2022 adjusted EPS guidance. Adjusting our 2021 results for this accounting change implies 2022 growth of 14% in our non-GAAP adjusted EPS at the midpoint. Turning to slide 18, our strong cash flow and disciplined capital allocation are enabling us to strategically invest in our business to drive sustainable growth and enhanced value, as well as deliver on our near-term financial objectives.

This accounting change results and dilution of approximately $2 per share in our 2022 adjusted EPS guidance.

Adjusting our 2021 results for this accounting change implies 2022 growth up 14% and our non-GAAP adjusted EPS at the midpoint.

Turning to slide 18, our strong cash flow and disciplined capital allocation are enabling us to strategically invest in our business to drive sustainable growth and enhanced value as well as deliver on our near term financial objectives.

Renee Gala: We have significantly advanced our revenue diversification with 59% of net product sales in the fourth quarter generated from products launched or acquired since 2019. And we are on track to meet our diversification target of 65% in 2022. In just eight months following the close of the GW acquisition, we reduced our non-GAAP net leverage ratio by nearly a full turn to approximately 4.1 times at the end of 2021, keeping us on track to achieve our stated target of being below 3.5 times by the end of this year.

We have significantly advanced our revenue diversification with 59% of net product sales in the fourth quarter generated from products launched or acquired since 2019, and we are on track to meet our diversification target of 65% in 2000.

'twenty two.

In just eight months following the close of the GW acquisition, we reduced our non-GAAP net leverage ratio by nearly a full turn to approximately four one times at the end of 2021, keeping us on track to achieve our stated target of beer.

Going below three five times by the end of this year.

Renee Gala: In summary, we delivered strong financial results in 2021 and expect significant growth on the top and bottom line in 2022, positioning us well to deliver our Vision 2025 targets. I'd now like to turn the call back to Bruce.

In summary, we delivered strong financial results in 2021, and expect significant growth on the top and bottom line in 2022 positioning us well to deliver our vision 2025 targets I would now like to turn the call back to Bruce.

Bruce Cozadd: Thanks, Renee. I'll conclude our prepared remarks on slide 20. 2021 was a year of transformation and execution. We achieved double-digit revenue growth. We have expanded our pipeline and expertise and executed key transactions to grow our business and capabilities, most notably the acquisition of GW Pharmaceuticals, and with FDA approval of Rylase and Zywave for i8. We achieved our ambitious goal of five key launches in two years.

Thanks, Renee I'll conclude our prepared remarks on slide 20.

2021 was a year of transformation and execution, we achieved double digit revenue growth expanded our pipeline and expertise and executed key transactions to grow our business and capabilities, most notably the acquisition of GW pharmaceuticals, and with FDA approval of Reilly's.

Sideway for IH, we achieved our ambitious goal of five key launches in two years or.

Bruce Cozadd: Our commercial teams demonstrated strong performance on the launches of ZyWave for Narcolepsy and Zebzelka, and we expect that successful execution will continue with the launches of Rylase and ZyWave for IH. The addition of Epidiolex to our commercial portfolio provides us with the opportunity to deliver an important therapy to patients with refractory epilepsy. Our R&D organization continues to deliver and is expanding its capabilities.

Our commercial team has demonstrated strong performance on the launches of <unk> for narcolepsy and <unk> and.

And we expect that successful execution will continue with the launches of <unk> and highway for IH <unk>.

The addition of <unk> to our commercial portfolio provides us with the opportunity to deliver an important therapy to patients with refractory epilepsies.

Our R&D organization continues to deliver and is expanding its capabilities.

Bruce Cozadd: Trials for multiple important products are underway and we are planning to initiate additional mid and late stage clinical trials over the next 12 months. Looking forward, we have a clear roadmap with Vision 2025, we are optimistic about the year ahead, and we're focused on delivering across the business. We're excited about our.., and I look forward to updating you on our progress as we advance. That concludes our prepared remarks. I'd now like to turn the call over to the operator to open the line for Q&A. If you'd like to ask a question, please press star then 1. If your question hasn't been answered and you'd like to remove yourself from the queue, press the pound key.

Trials for multiple important products are underway and we are planning to initiate additional mid and late stage clinical trials over the next 12 months.

Looking forward, we have a clear roadmap with vision 2025, we are optimistic about the year ahead, and we're focused on delivering across the business. We're excited about our future and I look forward to updating you on our progress as we advance.

That concludes our prepared remarks, I'd now like to turn the call over to the operator to open the line for Q&A.

If you'd like to ask a question. Please press Star then one if your question has been answered and you'd like to move yourself from the queue press the pound key.

Operator: Our first question comes from Ken Cacciatore with Cohen & Company. Your line is open. Hey, Bruce and Kim, congratulations on all the progress. I just want to ask about ZyWave and IEH. Our recent clinical and survey work indicates that they believe ZyWave and IEH could be as big as Zyrum and narcolepsy. So wondering if you could share even a little bit more of your internal data and your expectations. I know you categorize the markets as the same size, but wondering, you know, kind of your hopes for the eventual potential for ZyWave.

First question comes from Ken Cacciatore with Cowen <unk> Company. Your line is open.

Operator: And then Dan, you mentioned that ZyWave NIH could look like an orphan launch. Can you put a little bit more granularity in that, if you could, as we try to frame out the next few years? Thanks so much.

Hey, Bruce and team congratulations on all the progress. So I just wanted to ask about XI wave NIH, our recent clinical and survey work indicates.

They believe XI wave NIH to be as big as Xyrem in narcolepsy. So wondering if you could share even a little bit more of your internal data.

And your expectations I know you categorized the markets at the same size, but wondering kind of your hopes for the eventual potential for XI wave and then Dan you mentioned that sideways Nia.

And IH could look like an orphan launch can you put a little bit more granularity on that if you could as we try to frame out. The next few years. Thanks, so much.

Bruce Cozadd: Yeah, Ken, thanks for the questions. And maybe I'll just start and remind people that, you know, there are a couple similarities as we think about Xiwave for narcolepsy, and XiWave for idiopathic hypersomnia. The first is to remember that both of these are really debilitating.

Yes, Ken Thanks for the question, so maybe I'll, just start and remind people that.

There are a couple of similarities as we think about XI wave for narcolepsy and XI wave for idiopathic Hypersomnia is the first is to remember that both of these are really debilitating.

Bruce Cozadd: Sleep disorders, right? These are very life-altering conditions, high level of disability. And patients are really motivated to find effective treatments, right, that reduce their symptoms and improve their, you know, their ability to function. So need is high in both cases. The second thing I'd remind you in terms of a similarity is we've seen excellent efficacy of the agent in both these conditions. Our phase three data were very strong in terms of the benefit provided to patients. So, you know, we start with those as similarities.

Sleep disorders right. These are very life altering conditions high level of disability.

And patients are really motivated to find effective treatments that reduce their symptoms and improve there.

Their ability to function.

So need is high in both cases, the second thing I'd remind you in terms of a similarity is we've seen excellent efficacy of the agent in both these conditions our phase III data were very strong in terms of the benefit provided to patients. So we start with those similarities as for the specific size of the opportune.

In front of us and where we get that data and maybe I'll ask Kim.

To comment on that Jim.

Bruce Cozadd: As for the specific size of the opportunity in front of us and where we get that data, maybe I'll ask Kim, to comment on that, Kim. Sure, yeah, so I'll start by saying that, you know, since the launch that began back in November, we're very encouraged by the positive feedback from our prescribers and the IH community at large, and we really are seeing momentum continuing to build, you know, based on reports from the field.

Sure, Yes, so I'll start by saying that since.

The launch that began back in November we're very encouraged by the positive feedback from our prescribers and the IH community at large and we really are seeing the momentum continuing to build.

Based on reports from the field prescribers I've been very impressed with the profile of the medicine.

Bruce Cozadd: Prescribers have been very impressed with the profile of the medicine, especially excited to have a treatment option with a positive and compelling clinical trial results that address, as Dan said, the full IH condition and not just one or two of its symptoms. In terms of the opportunity, we've, you know, been communicating that we are, at the outset, focusing our launch on our existing sleep call universe of approximately 30,007 adult patients, you know, who have been diagnosed with IH and are actively seeking healthcare.

Especially excited to have a treatment option with a positive and compelling clinical trial results that address as Dan said, the full IH condition and not just one or two.

That symptom.

In terms of the opportunity we have been communicating that we are at the outset, focusing our launch on.

Our existing fleet call universe of approximately 37.

Bruce Cozadd: But longer term, we do estimate that based on data, claims data, that the total diagnosed IH patient population is likely to be closer to the size of the diagnosed narcolepsy market, which is about 70,000 to 80,000 patients. So, you know, this approval for us is, you know, a significant milestone for Jazz, you know, as our OxyBate franchise continues to be a pillar of Jazz's value, we are feeling already that we're starting to see successful execution of a market-leading launch in evaluating narcolepsy and that we're going to continue to build on it here with brand recognition as we launch IH in the marketplace throughout the rest of this year. And Ken, this is, yes, sorry, Bruce.

Adult patients who have been diagnosed with IH and are actively seeking health care and but longer term. We do estimate that based on data claims data that the total diagnosed <unk> patient population is likely to be closer to the size of the diagnosed narcolepsy market, which is about 70% to 80.

<unk> thousand patient. So this approval for us is a significant milestone for gas.

As our acetate franchise continues to be a pillar <unk> value.

We are feeling already that we're starting to see successful execution of our market leading launch.

Xylene Narcolepsy and then we're going to continue to build on it here.

With brand recognition as we launched IH.

In the marketplace throughout the rest of this year.

Bruce Cozadd: Yeah, Ken, just to go on the Orkland side. You know, it's kind of similar to Xyrem coming into narcolepsy. We're building a new market. It's the first and only approved therapy in NIH. And so while the patients are diagnosed, the cadence is to, you know, get them, you know, familiar with Xy waves, get them into the REM system, dose them up to an efficacious dose. So there's not this pool of existing oxybate-experienced patients that we can immediately convert over.

Dan and Ken This is yes, sorry, Bruce Ken just to go on the orphan side.

It's kind of similar to Xyrem coming into narcolepsy, we're building a new market. It's the first and only approved therapy NIH.

And so the patients are diagnosed the cadences to get them.

Familiar with highways get them into the into the <unk> system does them up to an efficacious dose so theres not this pool of existing.

Oxidate experienced patients that we can immediately convert over so.

Bruce Cozadd: So, you know, we're encouraged by the high level of awareness, as Kim is saying, and the experiences we're seeing to date. And, you know, look forward to build on that cadence in coming quarters. Thanks so much.

We are encouraged by the high level of awareness as Kim is saying and the experiences we're seeing to date and look forward to build on that cadence in coming quarters.

Thanks, so much.

Dan Swisher: Our next question comes from Jessica Fye with J.P. Morgan. Your line is open. Hey guys, good afternoon. Thanks for taking my question. Looks like Riley's came in well above our expectation this quarter.

Our next question comes from Jessica Fye with Jpmorgan. Your line is open.

Hey, guys. Good afternoon. Thanks for taking my question it looks like related came in well above our expectation this quarter, how should we think about the trajectory of that product off of the four key run rate.

Bruce Cozadd: How do we think about the trajectory of that product off of the 4Q run rate? Yeah, Jeff, thanks for the question. You know, we were really pleased with how Riley's performed in its first full calendar year, a full calendar quarter on the market and you know sort of made good on our thesis that the docs who treat these pediatric ALL patients were, you know, desperate to have a reliable treatment option that would always be there when they ordered it. So maybe I can let Kim comment a little bit on the early launch trajectory and and our thoughts on the fourth quarter results. Sure.

Yes, just thanks for the question we were really pleased with how <unk> performed in its first full calendar year.

Full calendar quarter on the market.

Sort of.

Made good on our thesis that the docs, who treat these pediatric allo patients were.

So desperate to have a reliable treatment option that would always be there when they ordered it.

So maybe I can let Tim comment a little bit on the early launch trajectory and our thoughts on the fourth quarter results.

Kim Sablich: So 2021 revenues, I'll say reflect both the strong demand that we saw for Rylai's in the marketplace, and as well as some initial inventory build as part of the launch, which is typical for new products. But we believe our strong performance really reflects increased brand awareness among our customers and appreciation for the strong product profile, and really recognition that Rylai's is the only therapy available following the depletion of Erwin A's supply.

Sure.

2021 revenues.

I'll say reflect both the strong demand that we saw for Rai lays in the marketplace.

And as well as some initial inventory build as part of the launch which is typical for new products.

We believe our strong performance really reflects.

Increased brand awareness, among our customers and appreciation for the strong product profile and really recognition that <unk> is the only therapy available following the completion of <unk> supply.

Kim Sablich: Feedback from clinicians has been quite positive and revolves around both the high quality and reliable supply of Rylai's, and we've received positive reports on the ease of ordering and dose preparation for Rylai's. So overall, we're very pleased with the launch to date, and I'll say that our commercial strategy does account for and is prepared for a competitive market, but overall, we believe Rylai's represents a clinically significant advance as the only recombinant Erwinia asparaginase manufactured product that maintains a clinically meaningful level of asparaginase activity through the entire duration of treatment, and we think customers are really starting to recognize and appreciate that. Yeah, Rob, you just might want to comment on where we're going to because we're not done with our strategy on Riley's.

Feedback from clinicians has been quite positive and revolves around both the high quality and reliable supply of Riley.

And we've received positive reports on the ease of ordering and dose preparation for.

O'reilly. So overall, we're very pleased with the launch to date and update our commercial strategy does account for and is prepared for a competitive market, but overall, we believe <unk> represents a clinically significant advance is the only recombinant erwinia asparaginase manufactured product that maintains a clinically meaningful level.

<unk> activity through the entire duration of treatment and we think customers are really starting to recognize and appreciate that.

Yes, Rob you just might want to comment on where we're going to because we're not done with our strategy on railways.

Rob Iannone: Yeah, happy to Bruce. So as you know, our indication now which was based on an ongoing trial is for every 48 hours, of Rylase. And so we also evaluated a regimen that allows for Monday, Wednesday, Friday IM dosing, where we give twice as much on Friday to ensure, Optimal coverage through that three-day weekend, with the 50 milligrams per meter squared on a Friday. We've submitted that as an SPLA to the FDA and we were granted real-time oncology review, which is underway. We'll follow that with IV data as a supplement in the U.S. but also in Europe and with IM and IVs. Our next question comes from Akash Tewari with Jeffries. Your line is open. Hey, guys.

Yes happy to Bruce So as you know our indication now which was based on an ongoing trial.

For every 48 hours.

Brian Lace and so we also evaluated regimen that allows for Monday, Wednesday, Friday dosing, where we give twice as much on Friday to ensure.

Optimal coverage through that three day weekend.

With the 50 milligrams per meter squared on Friday, we submitted that hasn't S BLA to the FDA.

And we were granted real time oncology review, which is underway, we will follow that with.

Data as a supplement in the U S. But also in Europe , and with an IV as well.

Our next question comes from a cost line with Jefferies. Your line is open.

Hey, guys, if we assume that epic diode contributes the same percent of sales for your neuro franchise as it did in 2022 as it did in 2021.

Operator: If we assume that Epidiolex contributes the same percent of sales for your Neuro franchise as it did in 2022 as it did in 2021, we get implied sales of about $700 million, or only about 5% growth year over year from a pro forma perspective. That said, for you to hit your 2025 guidance, it looks like Neuro needs to grow at an 11% CAGR. So can you comment on what Epidiolex growth looks like post-2022, and what would drive an inflection in Epidiolex growth long-term?

We get implied sales of about $700 million only about 5% growth year over year from a pro forma perspective.

For you to hit your 2025 guidance it looks like neuro needs to grow at an 11% CAGR. So can you comment on what <unk> growth looks like post 2022, and what would drive an inflection in <unk> growth long term. Additionally, can you comment if GW ended up being accretive in 2022 as previously guided thank you.

Sure.

Operator: Additionally, can you comment if GW ended up being accretive in 2022 as previously guided? Thank you. Yeah, so let me start with the first piece of that. And then Renee, maybe you can jump in on EPS accretion.

Yes, So let me start with the first piece of that and then Renee maybe you can jump in on EPS accretion.

Bruce Cozadd: I, you know, we were really pleased with how Epidiolex performed in the fourth quarter, you know, up even factoring out the higher inventories at the pharmacy level, up 10%, sequentially fourth quarter over third quarter and, you know, looking at annual growth on a proform basis as if we had reported a full year of Epidiolex sales, still up 29%. So, we're excited about Epidiolex's continued growth both in the U.S. market, but remember, we're also continuing to roll it out in more markets ex-U.S. and even where we have rolled it out, we're still early in that launch process with excellent pricing and reimbursement. So, you know, we haven't given a specific breakdown. Further breakdown of what we expect in each of the upcoming years, but we see a substantial continued growth opportunity with Epidiolex. Yeah, thanks, Bruce.

We were really pleased with how <unk> performed in the fourth quarter up even factoring out the higher inventories at the pharmacy level up 10% sequentially fourth quarter over third quarter and looking at annual growth on a pro forma basis as if we had reported a full year of <unk> sales still up.

29%. So we're excited about Epidiorite is continued growth both in the U S market, but remember we're also continuing to roll it out.

More markets ex U S and even where we have rolled it out we're still early in that launch process with excellent pricing and reimbursement. So we haven't given a specific breakdown.

Further breakdown of what we expect in each of the upcoming years, but we see a substantial continued growth opportunity with epic dialects Rene.

Renee Gala: So yes, we did state that we expected the GW transaction to be accretive in the first full calendar year, so 2022, and substantially accretive thereafter. We do, with our 2022 guidance, continue to expect the GW transaction to be accretive in 2022. I'll also note, however, as I stated in the prepared remarks, that we do have an accounting change that has the impact of increasing our underlying shares used in EPS in 2022 by approximately 9 million shares, and that's the number of shares that are underpinning our convertibles, as I explained in the call. Our next question comes from Mark Goodman with SVB Lyric. Your line is open.

Yeah. Thanks, Bruce So yes, we did state that we expected the TWU transaction to be accretive in the first full calendar year, So 2022 and substantially accretive thereafter, we do with our 2022 guidance continue to expect the GW.

Transaction to be accretive in 2022.

Also note however, as I stated in the prepared remarks that we do have an accounting change that increases our has the impact of increasing our underlying shares used in EPS in 2022 by approximately 9 million shares and Thats the shares.

That are underpinning our convertibles as I explained on the call.

Our next question comes from Marc Goodman with SBB Leerink. Your line is open.

Operator: Yeah, Bruce, can you talk about this new Epidiolex patent, how you think we should view this patent and, And then just a follow-up on the Riley's question. Should we be thinking that this is the new run rate? You said that there was some inventory build in the quarter. Can you help us understand how much inventory was in there so we can understand what a real kind of underlying demand quarter was and how we should think about the run rate there? Thanks.

Yeah.

Can you talk about this new effort dialogues patent how you think we should view this patent.

And.

And then just a follow up on the <unk> question should we be thinking that this is the new run rate you said that there was some inventory build in the quarter can you help us understand how much inventory was in there. So we can understand what a real kind of underlying demand quarter was and how we should think about the run rate there.

Okay.

Bruce Cozadd: Yeah, Mark, thanks for the question. On the patent, this is a patent on composition of botanically derived CBD and its use in treating certain disorders, meaning those that are in our label and has a different expiration date. Prior Patents listed in the orange book, this one going out to 2039. I'll remind you this is part of a significant IP estate, that is also established over time that we believe is relevant to thinking about the durability of Epidelex.

Yes, Mark Thanks for the question.

On the patent this is a pattern on composition of botanically derived CBD and its use in treating certain disorders meeting those that are in our label and how is it different exploration date from prior patents listed in the Orange book just from going out to 2039 I'll remind you. This is part of a significant IP.

State.

Established over time.

That we believe is relevant to thinking about the durability.

The dialect, so very pleased that that patent issued at.

Bruce Cozadd: So very pleased that that patent issued at the tail end of 2021 and was included in the Orange Book earlier this year. So, you know, one more piece of the puzzle around why we're confident that Epidelex.., is a durable asset.

At the tail end of 2021 and was included in the Orange book earlier. This year. So one more piece of the puzzle around why we are confident that up or dialects.

As a durable asset.

Bruce Cozadd: And then on Riley's, you know, I'll just I'll just say, that we don't really know what the true run rate for this Erwinia-derived asparaginase can be because we've always than supply constrained in the past, right? Before the launch of Ryleys, we did not have access to stable supply of the agent, and clinicians in some cases adjusted their practice, try to minimize use or save available product for patients most in need. Ideal use of the product would be at a higher level, and you know people are just adjusting to the fact that Rileys is now available that it's a more modern manufactured product with high quality with you know substantial supply available i'm not surprised to see that there's uh... you know up some build up as people want to stock a Rileys and have it immediately available that's a luxury they've not had in the past couple of years But we're also excited to expand use over time now as people get used to the fact that they can use it in all appropriate patients rather than trying to delay use by pre-medication, or other means.

And then on relays.

I'll just I'll just say.

That we don't really know what the true run rate.

For this or Wynia derived asparaginase can be because we've always been supply constrained in the past right before the launch of <unk>. We did not have access to stable supply of the age and clinicians in some cases adjusted their practice to try to.

Minimize use or save.

Available product for patients most in need.

You'll use of the product would be at a higher level.

And people are just adjusting to the fact that <unk> is now available that it's a more modern manufactured product with high quality with.

Substantial supply available.

Not surprised to see that there is.

Some buildup as people want to stock a reillys and have it immediately available.

<unk> they have not had in the past couple of years.

But we're also excited to expand use over time now as people get used to the fact that they can use it at all.

All.

Appropriate patients rather than trying to delay us by pre medication.

Or other means.

Bruce Cozadd: And then, you know, Rob talked about obviously trying to get some more ideal dosing with Monday, Wednesday, Friday, giving an IV option as well, and then also submitting in Europe. So we go back to having more of a worldwide product, which is just today a U.S. opportunity for us. So, you know, lots of progress ahead of us. I could not be more pleased with the initial response, but we just don't have a basis mark for a more accurate view of what that run rate will be. Our next question comes from Jeff Hung with Morgan Stanley. Your line is open. If your telephone is muted, please unmute.

And then Rob talked about obviously trying to get some more ideal dosing with Monday Wednesday Friday.

Giving an IV option as well and then also submitting in Europe .

So we go back to having more of a worldwide product, which is just today a U S opportunity for us so.

Lots of progress.

Ahead of us.

Could not be more pleased with the initial response, but we just don't have a basis mark for a more accurate view of what that run rate will be.

Our next question comes from Jeff Hung with Morgan Stanley . Your line is open.

Our next question comes from Jeff Hung with Morgan Stanley . Your line is open.

If your telephones immediate please on mute.

Operator: Our next question comes from Jason Gerberry with Bank of America. Your line is open. Hey guys, thanks for taking my questions. Bruce, just a request, if you could put that HICMA settlement structure in a slide in future earnings calls, that'd be great, just so we have the schematic updated. But, so my questions are, is Oxidate growing in 2022?

Our next question comes from Jason <unk> with Bank of America. Your line is open.

Hey, guys. Thanks for taking my questions. Bruce just a request if you could put that hikma settlement structure in a slide in future earnings calls that'd be great. So we have the schematic updated but so my questions are.

Operator: And then, you know, on Epidiolex, this IP update, I guess your thoughts on whether we'll get a patent challenge this year, just in terms of ear to the ground, whether someone has the capability of filing. And my understanding, is this the patent that includes compositions with trace amounts of THC, which showed in monkeys, I think, a benefit versus synthetic or synthetic cannabidiol? I believe that that might have some synergism with the FDA guidance requirements for generic scent.

Octavate growing in 2022, and then got.

Canepa dielectrics IP update.

Just your thoughts on whether it will get a patent challenge. This year just in terms of ear to the ground whether someone has the capability of of filing and my understanding is this the patent that includes compositions with trace amounts of THC, which showed in monkeys, I think a benefit versus synthetic or synthetic cannabinoid <unk>.

I believe that that might have some synergism with the FDA guidance requirements for generics.

Operator: Yeah, so Jason, thanks for the suggestion on the on the royalty structure. On Oxivate, you know, we're continuing to grow Oxivate use, we see it in narcolepsy, obviously, IH is brand new just weeks into that launch. In terms of our fourth quarter.

Yes, so Jason thanks for the suggestion on the on the royalty structure on ox abate, we're continuing to grow oxalate use we see it in narcolepsy, obviously IH is brand new just weeks into that launch.

In terms of our fourth quarter.

Bruce Cozadd: Results. So we do expect substantial growth during the year. You know, as we said in our guidance, we've made room in our guidance for an assumed second half launch of an authorized generic. And while we do have economics in that, we don't have 100% economics in that as we do the current Xyrom products.

Our results so we do expect substantial growth.

Growth during the year.

As we said in our guidance, we've made room in our guidance for.

Assumed second half launch of an authorized generic and while we do have economics in that we don't have a 100% economics in that as we do the current xyrem product. So.

Bruce Cozadd: So, you know, it's growth in the whole market, but not with complete revenue pull through to jazz. And so that's what you're seeing in how we think about that going forward. In terms of Epidiolex, I think we gave it a patent number. If we didn't, we can give it, so you can look up that patent and see everything that's included there, but we do believe... There's relevance to the entire composition, of that product which is largely but not completely cannabidiol.

It's growth in the in the whole market.

But not with complete.

Revenue pull through to jazz and so thats, what youre seeing and how we think about that going forward.

In terms of <unk> I think we gave the patent number.

If we didn't we can give it so you can look.

A cup that patent and see everything Thats included there, but we do believe.

There is relevance to the entire composition.

Of that product, which is largely but not completely can have a dial.

Bruce Cozadd: And in terms of potential challenge, you know, there's the opportunity for people to step in and, and submit as early as later this year. Whether that will happen, we don't know. It could, but of course, again, we feel confident that we've got good protection of that product.

And in terms of potential challenge there is the opportunity for people to step in and.

And submit.

As early as later this year, whether that will happen, we don't know it could.

But of course again, we feel confident that we've got good protection.

Of that product.

Okay. Thank you.

Okay.

Operator: Okay, thank you. Our next question comes from Ami Fadia with Needham. Your line is open. Hi, good afternoon.

Our next question comes from Amy <unk> with Needham Your line is open.

Okay.

Operator: Thanks for taking my question. I had one main and one follow up. Just with regards to diabetes, type of hypothermia, we saw about 150 patients, on that indication in the fourth quarter. Is that a precedent for the type of cadence you expect in terms of new patient ads in the upcoming quarters, how should we think about that? And then secondly, just with regard to Riley's.

Hi, good afternoon, Thanks for taking my question.

I had one and one follow up.

With regard to depart the type of Tommy I'll be Saba clients titration patients.

Patients.

On that indication in the fourth quarter.

Is that a precedent for that type of cadence you expect in terms of new patient adds in the upcoming quarters.

Should we think about that.

And then secondly, just with regard to <unk>.

Bruce Cozadd: Can you give us some color on whether you saw, Utilization Beyond Pediatrics, Thank you. Yeah, so on, on Zywave IH, I'll just remind you, we're super early in that launch, right? This launch happened just in November, uh... there's never been a drug marketed in idiopathic hypersomnia so for us to predict exactly what the cadence of new patient ads quarter by quarter will be uh... after only a couple months is probably a little bit premature again we're super excited about the size of the opportunity the effectiveness of the drug the early reaction we're hearing, You know, the ability to get the drug paid for, which has been excellent, um... the fact that we're calling on the same largely the same prescribers uh... for narcolepsy and adiopathic hypersomnia so you know we've got our work to do to continue to educate physicians and patients about the availability of this new and effective treatment but uh... too early to be predicting you know a particular ramp, In terms of RILAs and utilization, you know, beyond pediatrics.

Can you give us some color on whether you felt.

Utilization beyond pediatric.

Into teenagers or young adult thank you.

Yes.

Yes, so on.

<unk> XI wave IH I'll, just remind you we're super early in that launch right. This launch happened just in November .

There's never been a drug marketed in idiopathic hypersomnia, so for us to predict exactly what the cadence of new patient adds quarter by quarter will be.

After only a couple of months is probably a little bit premature again, we're super excited about the size of the opportunity the effectiveness of the drug the early reaction we're hearing.

The the ability to get the drug paid for which has been excellent.

The fact that we're calling on the same largely the same prescribers.

For narcolepsy and Eddie idiopathic hypersomnia. So we've got our work to do to continue to educate physicians and patients about the availability of this new and effective treatment, but too early to be predicting.

Particular ramp.

In terms of Reillys and utilization beyond pediatric.

Bruce Cozadd: Let me ask Kim if she has any information she'd like to share there. Now, we don't have any data specifically, you know, by age or patient type, you know, just really the overall positive feedback in the marketplace. And, you know, the notion that we are seeing some customers start to utilize second line asparaginase and go to Rylase faster than they had when the market was supply constrained. Unknown Speaker Yeah, and I'll just remind people that one of the great things about, The approval of Rylase is we can get back to promoting the appropriate use of this product, which in our mind certainly includes, you know, all the pediatric patients who are experiencing a hypersensitivity response to E. coli derived asparaginase but also include. Adolescent and Young Adult Patients as well. We turned off our promotional efforts for several years. Because we didn't believe it would be ethical to try to create demand that we couldn't supply.

Let me ask Kim if she has any information she'd like to share there.

Now we don't have any data specifically by age or patient type you know just really the overall positive feedback in the marketplace and the notion that we are seeing from customers.

Start to utilize.

Second line of Feraheme, Nathan Reilly faster than they had when the market was supply constrained.

Yes.

I'll just I'll, just remind people that one of the great things about.

The approval of <unk>, we can get back to promoting the appropriate use of this product.

And our minds certainly includes all the pediatric patients who are experiencing a hypersensitivity response to E. Coli derived asparaginase, but also include.

Adolescent and young adult patients as well, we turned off our promotional efforts for several years.

Because we didn't believe it will be ethical to try to create demand that we couldnt supply.

Bruce Cozadd: So we have that opportunity now to go out and remind people of the data that you see when you do use an asparaginates-containing regimen, uh... kind of a pediatric inspired regiment for the AYA patients, We can also, you know, make sure people understand silent inactivation where you're creating an antibody response that may be inactivating the very enzyme you're counting on for efficacy. I and then over time. You know, as we pursue an ex-U.S. registration strategy, again, to broaden into markets where Irwin-Ace was never commercialized because of lack of adequate supplies.

We have that opportunity now to go out and remind people of the data.

Or that you see when you do use an asparaginase containing regimen.

Kind of a pediatric inspired regimen for the Hawaii patients.

We can also.

Sure people understand.

Islands in activation, where Youre Cree.

Creating an antibody response that maybe inactivating very enzyme you're counting on for efficacy.

And then over time.

As we pursue an ex U S registration strategy again to broadened into markets where.

<unk> was never commercialized because of lack of adequate supplies. So we really do believe there is an opportunity.

Bruce Cozadd: So we really do believe there's an opportunity going forward to increase that utilization, but as Kim says, we don't have specific data on what we saw in the fourth quarter. Our next question comes from Ronnie Gao with Bernstein. Your line is open. Good morning, good afternoon. Thank you for taking my question. To be fair, I don't mind.

Going forward to increase that utilization, but as Tim says, we don't have specific data.

What we saw in the fourth quarter.

And our next question comes from Ronny Gal with Bernstein. Your line is open.

Hi, Good morning, good afternoon, and thank you for taking my question two if I don't mind first sticking up will that 250 initial patients on idiopathic hypersomnia I Wonder if you can share with us kind of like a couple of.

Operator: First, picking up with that 250 initial patient on idiopathic hypersomnia, I wonder if you could share with us kind of like a couple of numbers around that. First, how many of those 250 were actually in the clinical trial program? And on the other hand, given how long it takes for patients to get on the drug, roughly how many patients have you had at the end of the year in the pipeline of trying to get those patients on the drug just so we could... Get a Better Feel for the Early Adoption.

Numbers around that first.

Any of those 250, we're actually in the clinical trial program and on the other hand, given how long it takes for patients to get on the drug.

Roughly how many patients have you had at the end of the year in the pipeline with trying to get those patients on the drug just trying to get.

Get a better feel for the early adoption and separately Occidental pay dialects relative price increases in the end of the year.

Operator: And separately, off the bid and the pay dial explosive price increases in the end of the year, what percentage of that price increase do you expect to realize as a net given the rebate structures? Thank you. Ronnie, I was co-processing.

Kind of what percentage of that price increase do you expect to realize that Matt given the rebate structure. Thank you.

Ronny I was co processing remind me, which products you were talking about at the end of that question with price increase.

Operator: Remind me which product you were talking about at the end of that question with price increase? Oxabat of Epidiolex? Yeah.

Oxidative epidiorite, yes, okay.

Operator: Um, so on on the first, you know, somebody from the team jumped in if we know how many patients came out of clinical trial. I'm not, I'm not sure I've heard that that was a significant contributor to our early, Adoption. I, we're not going to give, you know, more data, Ronnie, than we've already given in terms of patients on drug at the end of the year. You know, we sometimes have patients starting the process of enrolling in the REMS.

So on the first.

From the team jumped in if we know how many patients came out of clinical trial.

I'm not sure I've heard that that was a significant contributor to our early.

Adoption.

We're not going to give.

More data Ronny than we've already given in terms of patients on drug at the end of the year.

We sometimes have patients starting the process of enrolling in the Rems.

Operator: You know, we don't sort of count those as patients until we know they actually get a shipment of drug. Not everyone that starts the process for the REMS ends up getting a shipment of drug, so not sure that would be accurate information. And on realized price increase, you know, our gross price increase does not flow all the way down in the net sales given that we've contracted particularly.

Don't sort of count those as patients until we know they actually get ship.

Shipment of drug not everyone that starts the process for the Rems ends up getting a shipment of drugs. So not sure that would be accurate information.

On realized price increase.

Our gross price increase does not flow all the way down.

Net sales given that we've contracted particularly.

Bruce Cozadd: In recent years around Oxybate, but we do receive some bottom line benefit. I think historically we've said it's a meaningful percentage, but, you know, certainly don't assume that we realize all of the gross price. Our next question comes from Balaji Prasad with Barclays. Your line is open. Thank you and congratulations. A couple of questions for me.

In recent years around ox abate, but we do receive some.

Bottom line benefit I think historically, we've said, it's a it's a meaningful percentage but.

Certainly don't assume that we realize all of the gross price increase.

Our next question comes from <unk> Prasad with Barclays. Your line is open.

Operator: Firstly, on Epidiolex, you had called out the challenges with the patient visits in the previous quarter. Can you give an update on current clinic dynamics as to what you're seeing with respect to visits in Q1, Q2D till now? And secondly, on Epidiolex itself, there seems to be a decision from the Texas court with the Canopy versus GW litigation and the court has tossed Canopy's litigation. So does this settle all existing legal challenges or is there anything else we're not aware of? Dan, you want to talk about what we're seeing in terms of visits on the pediatric epilepsy side? Yeah, I don't have the exact numbers.

Alright, Thank you and congratulations.

Couple of questions from me firstly on <unk>.

Could you you had called out the challenges with the patients.

In the previous quarter can you give an update on kind clinic that it makes sense to own what are you seeing with respect to.

Visits in Q1 <unk>.

Now.

And secondly on EBITDAR less itself there seems to be a decision from the banks of course with the kind of be worsening GW litigation on the <unk> litigation. So does this.

Settle all existing legal challenges.

And again anything else been hardly at all thanks.

Dan you want to talk about what we're seeing in terms of visits.

On the pediatric epilepsy Sun.

Dan Swisher: And there's definitely been some continued impact on, well, definitely our customer engagement side of things, but also certain offices, as any of us saw with Omicron, you know, folks were getting infected and were out of service and offices were temporarily closed, even in locations where they typically have been open. I think the good news is, it does seem to be, it peaks early and comes down rapidly. And so, you know, our expectation for the rest of the year is fairly optimistic in that patients will be flowing back into the offices at a more normal cadence. I think the one exception is, you know, again, the vaccination rates, for children under five.

Yes, I don't have the exact numbers and theres definitely been some continued impact.

Well definitely our customer engagement side of things, but also certain offices as any of us saw with micron.

Folks are getting infected and were out of service and offices were temporarily closed even in locations where they typically have been open I think the good news is it does seem to be it peaks early and comes down rapidly and so our expectation for the rest of the year.

Fairly optimistic and that patients will be flowing back into into the offices at a more normal cadence I think the one exception is again the vaccination rates.

For children under five.

Dan Swisher: And, you know, with our therapy, we have a number of patients who are under five, you know, currently the vaccines are not available. And for those that are between five and 11, they're getting vaccinated, but it's still at a slower percentage than, or at a lower percentage than the regular population. But again, the trends are going in the right direction. And then on the litigation, and then on the litigation side, you know, we were pleased with where, uh... the court came out on the final judgment in the litigation uh... with canopy they do have the right uh... to appeal that but you know we're we're certainly pleased with where we stand uh... and i'm not sure if there's some other litigation you're particularly interested in but uh... you know we have had other litigation it's not been something we've been significantly concerned about and that remains the case, Our next question comes from Annabel Samimy with Stiefel. Your line is open.

With our therapy, we have a number of patients who are under five currently the vaccines are not available and for those that are between five and 11 theyre getting vaccinated, but it's still at a slower percentage then or at a lower percentage than the.

The regular population, but again the trends are going in the right direction.

And then on that litigation.

And then on the litigation side, we were pleased with where.

The court came out on the final judgment in the litigation with.

With canopy, they do have the right to appeal that but we're certainly pleased with where we stand.

And I'm not sure if theres. Some other litigation you are particularly interested in but.

We have had other litigation, it's not been something we've been significantly concerned about and that remains the case.

Our next question comes from Annabel <unk> with Stifel. Your line is open.

Operator: Hi, thanks for taking my question. Just going back to Epidiolex and I'm hoping to get a little bit more more color there. So obviously custom win this quarter, 10%, I guess, excluding the inventory.

Hi, Thanks for taking my question just going back to the dialogue.

I'm going to add a little bit more more color. There is obviously a customer win this quarter, 10% I guess.

Excluding the inventory.

Operator: And I know that you mentioned that there's still some COVID headwind, but can you maybe talk about where you're seeing the most penetration? Is it in primarily the new indications, is it new patients, or is it persistence of treatment? We have heard from KOLs that the persistence is not as high. So can you tell us what work you're doing there in terms of that persistence as well as where the new patients are coming from? Thanks.

And I know you mentioned that there are still some headwinds, but can you maybe talk about where youre seeing the most penetration is it primarily the new indications and new patients or is it persistence of treatment, we have heard from kols that.

Persistence is not as high so can you talk about what youre doing there.

In terms of that persistence as well as.

Where are the new patients are coming from thanks.

Bruce Cozadd: Yeah, Annabel, that's the new information to me, we continue to be exceptionally pleased with what we're seeing in terms of persistence, and we think it's one of the hallmarks, of this drug when we when we talk to KOLs, about how they use it, remembering that most of these patients are going to be treated with you know multiple agents in combination and one of the things we've noted before and we believe still remains the case is that you'll often see Epidiolex added into a treatment regimen and that if they want to sub anything out later as they add new agents they tend to hang on to the Epidiolex. At the AES meeting in Chicago in early December there was you know data presented that really went out to multiple years of you know continued and in some cases increasing efficacy over time of the agent so you know I'd be surprised to hear data that goes in the other direction.

Yes, Annabel Thats the new information to me, we continue to be exceptionally pleased with what we're seeing in terms of Ah persist.

Persistence and we think it's one of the hallmarks.

Of this drug when we when we talk to Kols.

About how they use it remembering that most of these patients are going to be treated with <unk>.

Multiple agents in combination.

And one of the things we've noted before and we believe still remains the case is that you often see upper dialects added into a treatment regimen and that if they want to solve anything out later as they add new agents they tend to hang on to.

<unk> at the <unk>.

S meeting in Chicago in early December there was.

Data presented that really went out to multiple years of kantar.

Continued and in some cases, increasing efficacy over time.

The agents so.

I'd be surprised to hear data that goes in the other direction.

Bruce Cozadd: Kim or Dan, does one of you want to jump in on where we're seeing growth in terms of indications? Yeah, sure. I'll basically say, you know, this is the growth we believe is coming from everywhere. We're not sharing specific, you know, penetration numbers.

Okay or Dan does one of you want to jump in on where we're seeing growth in terms of <unk>.

Indications.

Dan Swisher: But we do continue to see room for growth across all of our indications, particularly see the greatest growth opportunity and the two largest indications, LGS, and TFC, which is still early, you know, in the launch phase. And, you know, this is a well tolerated treatment with high persistency, as Bruce said, it can be added in a polypharmacy setting. It's important to remember that on average, you know, treatment resistant patients are on three anti-seizure medications.

Yeah, sure I'll basically saying that the growth we believe is coming from everywhere, we're not sharing that.

Penetration numbers, but we do continue to see room for growth across all of our indications, particularly see the greatest growth opportunity in the two largest indications lgs.

TLC, which is still early.

The launch phase.

And this is a well tolerated treatment with high persistence as Bruce said it can be added.

Dan Swisher: So, you know, overall, we are seeing that our customer base is getting more and more comfortable with Epidiolex. And as they're doing so and getting experience with it, they're moving it up earlier in the treatment regimen.

A polypharmacy setting it's important to remember that on average in a treatment resistant patients are on three anti seizure medications. So.

Overall, we are seeing that our customer base is getting more and more comfortable with at the dielectric theyre doing doing sale and getting experience with it they are moving it up earlier in the treatment regimen and we're pleased to see that that prescriber base continues to grow in those new prescribers again will start to gain more.

Dan Swisher: And we're pleased to see that that prescriber base continues to grow and those new prescribers, again, will start to gain more comfort with the product and use it more broadly and earlier. So, you know, overall, we remain very confident that we can achieve blockbuster status and really become a standard of care in treatment resistant epilepsy. And just as a reminder outside the U.S., we're earlier in sort of the launch cycle, but importantly in the second half, we had additional launches going on in Spain, Italy, Switzerland, Ireland this quarter, and continued penetration now in four of the five major countries with France anticipated in 2022.

With the product.

And use it more broadly.

Earlier, so overall, we remain very confident that we can achieve blockbuster status and really become a standard of care and treatment resistant epilepsy.

As a reminder, yes, yes, thanks, Kevin just as a reminder, outside the U S were earlier.

Sure the launch cycle, but.

Importantly in the second half we had.

Additional launches going on in Spain, Italy, Switzerland.

Ireland this quarter.

And continued penetration now in four of the five major countries with France anticipated in 2000 to 2022 and.

Dan Swisher: And with the value proposition that is in front of Epidiolex in those markets, we've achieved greater than 70% of the U.S. WAC in those reimbursed markets. So that's also, you know, adding growth and tailwind as we go into 22.

The value proposition.

Is in front of the dialects in those markets, we've achieved greater than 70% of the U S whack and those reimbursed markets. So thats also.

Adding growth in tailwind as we go into 'twenty two.

Rob Iannone: Rob, anything you'd like to add in terms of how how treaters are looking at this drug based on based on what you're hearing? You referred to AES, Bruce, and certainly, yeah, I mean, we spent a lot of time with docs who are very familiar with this drug, have been using it, and my impression was yours, that not only do they see it as highly effective, but as you say, well-tolerated, and, you know, very sticky, patients are staying with it. So that's certainly what we continue to hear from the medical affairs. Our next question comes from Gary Nachman with BMO Capital Markets. Your line is open.

Rob anything you'd like to add in terms of how how treaters are looking at this drug based on based on what Youre hearing.

You referred to Aes, Bruce and certainly correct yes.

Yes.

We spent a lot of time.

With docs, who are very familiar with this drug using it.

And my impression was yours that not only do they see it as highly effective but as you say.

Well tolerated.

Very sticky patients are staying with it so.

Certainly what we continue to hear from the medical Medical Affairs perspective.

Our next question comes from Gary Nachman with BMO capital markets. Your line is open.

Okay.

Operator: Thanks. So, Zywave was at about 43% conversion of the Oxybate franchise in the fourth quarter. How much do you see that conversion accelerating over this year and how much are you trying to manage that conversion? if at all, you know, when considering the trigger for the A.G. sometime in the second half of this year.

Thanks.

So as I wave was at about 43% conversion of the OXXO based franchise in the fourth quarter, how much do you see that conversion accelerating over this year and how much are you trying to manage that conversion.

If if at all.

When considering the trigger for the AG sometime in the second half of this year.

Operator: And then specifically for I.H., what initiatives are you taking to increase diagnosis and improve awareness? And, you know, will you be doing that as aggressive as you've been with narcolepsy? Thank you. Yeah, maybe I'll take the first part of that, Gary, and then ask Kim to talk about, you know, efforts around increasing diagnosis and IH and when it might be appropriate for us to invest significantly in that. You know, on the first part of your question, you refer to conversion.

Specifically for IH, what initiatives are you taking to increase diagnosis and improve awareness and.

You'd be doing that as aggressive as you've been with narcolepsy. Thank you.

Bruce Cozadd: And I'll just remind you that, you know, our growth in this eye wave comes from multiple sources, it certainly does come largely, from existing Xyrem or Oxybate-experienced patients. Moving over to this newer agent with the 92% reduction in sodium with, you know, the safety benefit that FDA highlighted in, in the Orphan Drug Exclusivity Decision. But we're also seeing brand new patients, you know, narcolepsy patients who may never have been on Oxybate.

Yes, maybe I'll take the first part of that Gary and then ask him to talk about.

Efforts around increasing diagnosis, NIH and when it might be appropriate for us to invest significantly.

And that on the first part of your question you refer to conversion and I'll, just remind you that our.

Our growth in the XI wave comes from multiple sources. It certainly does come largely.

From existing Xyrem or ox debate experienced patients.

Moving over to this newer agent with a 92% reduction in sodium.

With the safety benefit that FDA highlighted in the.

In the orphan drug exclusivity decision.

But we're also seeing brand new patients narcolepsy patients, who may never have been on oxo abate, we're seeing narcolepsy patients who may have not been on ox abate historically, even though they had a diagnosis.

Bruce Cozadd: We're seeing narcolepsy patients who may have not been on Oxybate historically, even though they had a diagnosis, because they were concerned about that high sodium load. And now on top of that, we're seeing IH patients as well. So, you know, I'd hesitate to just call it conversion because it's really multi-component.

Because they were concerned about the high sodium load and now on top of that we're seeing IH patients as well so.

I'd hesitate to just call it conversion because it's really multi component.

Bruce Cozadd: To the second part of your question around that, You know, we are not managing that at all. We would like as many patients to be benefiting from what we believe is a better, safer product in Zywave as possible, uh... so you know we know that takes time uh... we've been very pleased with how the rollout of narcolepsy has progressed in just just over a year on the market now uh... to see how far we've uh... how far we've come but you know we we want as many patients to get that benefit as soon as possible and in no way are holding back on that, Kim, you want to talk about how we're thinking about our effort tonight?

The second part of your question around that.

We are not managing that at all we would like as many patients to be benefiting from what we believe is a better safer product <unk> XI wave as possible.

So we know that takes time.

We've been very pleased with how the rollout of narcolepsy has progressed and just just over a year on the market now.

See how far we've how far we've come but we want as many patients to get that benefit as soon as possible and in no way are holding back on that.

Tim you want to talk about how we're thinking about our efforts and IH.

Bruce Cozadd: Yeah, sure. So to your question about whether we're focusing on increased diagnosis, the answer is right now no, because as we talked about earlier, there's a substantial population of already diagnosed patients out there, specifically 37,000 patients that have a formal diagnosis of idiopathic hypersomnia. And not only that, but we can see through claims data that in the last year, they've been actively engaging with the healthcare system. So the market is there, you know, many of the patients currently taken or have tried products, traditional, you know, stimulants and weight promoting agents or antidepressants off label. And we hear back from the patients and the healthcare providers that just not meeting their needs. And there's still a tremendous unmet need for, you know, greater relief for these patients. So the market is there.

Yes sure.

So to your question about was whether we're focusing on increased diagnosis. The answers right now no because as we talked about earlier, there's a substantial population of already diagnosed patients out there specifically 37000 patients that have a formal diagnosis of idiopathic hypersomnia and not only that we can.

See through claims data that in the last year, they've been actively engaging with the healthcare system.

The market is there.

Kim Sablich: So we're out there really educating more about the product profile. And if anything, just trying to help HCPs come become more confident in their diagnosis, and to, you know, identify those patients that are diagnosed and that would benefit from, you know, a try with Ziway for idiopathic hypersomnia. Our next question comes from David Amsellem with Piper Sandler. Your line is open. Thanks, so just a couple. On epidiolex, can you talk about... Asks Starsky Brand if they see patients exposed to modafinil and stimulants. ??do you know how to get to the other high school if I have to go there? pals I wish I never knew that.

Patients.

Currently taken already tried prada.

Product traditional stimulants and wake promoting agents are antidepressants off label and we hear back from the patients and health care providers that just not meeting their need and there's still a tremendous unmet need.

For greater relief for these patients. So the market is there. So we're out there really educating more about the product profile and if anything just trying to help HCP can become more confident in their diagnosis and too.

Identify those patients that are diagnosed and that would benefit from.

I'll try with the highway for idiopathic hypersomnia.

Operator: Yeah, maybe, David, I'll have Rob take both of these. On the on the Epidiolex side, again, just talking about how the drug is being used based on our understanding. And then on the idiopathic hypersomnia side, you know, super early in the launch, and I'm not sure we've got that, that granular data, but we can certainly refer back to what we saw in clinical trials in terms of, you know, what patients have tried other agents, and how often we think they've already tried metaphenol or other stimulants. So Rob.

Our next question comes from David <unk> with Piper Sandler Your line is open.

Thanks, So just a couple on <unk>.

Can you talk about the.

The <unk>.

The extent of off label usage.

In our K well conversation, it's clearly happening how much of that is.

And factor in the overall growth trajectory of the product in the United States.

That's number one and then number two is on IH.

I apologize if I missed this but can you talk to the kinds of patients who are getting on therapy. I know. It's early days are these patients mainly have been exposed to modafinil stimulants.

Or are the newly diagnosed treatment nave patients as their mix.

If you could talk to that that would be helpful. Thank you.

Yes, maybe David I'll have Rob take both of these on the on the upper dialect side again, just talking about how the drug is being used based on our understanding and then.

On the idiopathic hypersomnia side Super early in the launch and I'm not sure we've got that.

That granular data, but we can certainly refer back to what we saw in clinical trials in terms of what patients have tried other agents and how often we think.

They've already tried modafinil or other stimulant so rob.

Rob Iannone: Yes, so starting with epidiolex, you know, the indications is across syndromes, but practitioners, neurologists treat seizure types. And what is, I think, notable about epidiolex is the activity across different seizure types. Unknown Speaker, within those, within those syndromes.

Yeah, so starting with <unk>.

The indications as across syndromes.

Practitioners neurologist treat.

Seizure types and what is I think notable about <unk> as the activity across different seizure types.

Within those.

Within our syndromes and so it's viewed as being broadly active across a number of different major types of seizures that occur.

So certainly.

While we wouldn't promote off label.

That information is available for prescribers.

Rob Iannone: And so it's viewed as being broadly active across a number of different major types of seizures that occur. And so certainly, while we wouldn't promote off-label, that information is available for prescribing. With regards to IH in the clinical trial, The majority of patients came in on daytime wake promoting agents, and despite that, had severity scores sufficient for trial enrollment, and and whether or not they were on daytime alerting agents derived benefit from Zion.

With regards to IHS in the clinical trial.

The majority of patients came in on daytime wake promoting agents and despite that.

Had severity scores sufficient for trial enrollment.

And whether or not they were on duty time alerting agents derive benefit from.

<unk> XI ways.

Rob Iannone: And I'll say even for patients who are not today on some of the stimulants or daytime weight promoting agents, many of them have tried them in the past with limited success and so sometimes have stopped. Stop trying those, Our next question comes from Nivan Tai with Citi.

And I'll say, even for patients who are not today on some of the stimulants or daytime wake promoting agents. Many of them have tried them in the past with limited success and so sometimes hubs have stopped.

Stop trying those agents.

Operator: Your line is open. Hi, good afternoon. Just a clarification on epidiolex outside of the US.

Our next question comes from Nevada tie with Citi. Your line is open.

Operator: Do you expect a launch in France in the second half? And do you expect to launch in other key European markets? And then a second one on BD from your comments, can we expect both on this year and potentially more substantial BD once you reach the three and a half leverage target? Thank you. Yeah, Dan, maybe you could start with Epidiolex XUS and then Renee, if you could jump in on the second question.

Hi, good afternoon.

Just a clarification on <unk>.

The U S. Do you expect the launch in France in the second half and do you expect to launch in other key European markets and then a second one on from your comments can we expect bolt on.

And potentially more substantial long uhm.

Todd It thank you.

Yes, Dan maybe you could start with <unk> and then Renee if you could jump in on the second question.

Operator: Yeah on the launch in France we're just saying in 2022 and we're in active dialogue with the French authorities but it really depends on the cadence of how that goes through and it's much more important for us to land the right price because you only have one chance to have a launch price there in France so but we're confident that we will get to a price and get to a launch in 2022. Importantly there's 34 countries where we have approval only 13 launches to date you know France would be the last major of the European countries but there's plenty of you know smaller countries that can add up and provide meaningful growth and we've got active development plans and thoughts toward Asia-Pac like Japan that could provide meaningful growth in the future. Yeah, this is Renee.

Yeah on the.

Sort of launch in France, we're just saying in 2022.

We are in active dialogue with the French authorities, but it really depends on the cadence of how that goes through and it's much more important for us to land the right price.

We only have one chance to have a launch price there in France. So.

But we're confident that we will get to a price and get to a launch in 2022.

Accordingly, there is 34 countries, where we have approval only 13 launches to date.

France would be the last major of the European countries, but there's plenty of.

Smaller countries that can add up and provide meaningful growth and we've got active development plans and thoughts towards Asia Pac like Japan that could provide meaningful growth in the future.

Renee Gala: I'll chime in. And just adding here to the second part of your question on corporate development. So as I had mentioned in our prepared remarks, we do expect to be active on the corporate and business development side across 2022. We're actively looking to augment the pipeline to continue to expand our opportunities there within neuroscience across sleep. Also now with essential tremor studies and PTSD, and of course, a market leading position in epilepsy, this is all of interest to us.

Yes. This is Renee I'll chime in.

And just adding here to the second part of your question on corporate development. So as I had mentioned in our prepared remarks, we do expect to be active on the corporate and business development side across 2022.

We're actively looking to augment the pipeline to continue to expand our opportunities there within neuroscience across sleep also now with essential tremor studies in PTSD and of course a.

Renee Gala: And then also on the oncology side, looking at thoracic oncology, additional opportunities in solid tumors, and areas that would align with future commercial activities and our R&D expertise are all areas of interest. So I would expect us to be active probably on the smaller side throughout 2022. You could think about size being anything along the lines of a SpringWorks or Red X type of transaction on the smaller side, or even something slightly larger, like what we executed for Zipselka with PharmaMar, which was a couple hundred million dollars up front and a great way for us to convert cash into a revenue generating asset, and clearly an important product.

Market, leading position in epilepsy.

This all of interest to US and then also on the oncology side looking at thoracic oncology additional opportunities in solid tumors and areas that would align with that.

Future commercial activities and R&D expertise are all areas of interest so I would expect us to be active probably on the smaller side. Throughout 2022, you can think about size being anything.

Along the lines of a spring works or Red X type of transaction on the smaller side or even some things slightly larger like what we executed four as themselves with pharma La <unk>, which was a couple of hundred million dollars upfront and a great way for us to convert cash into a revenue generating asset and clear.

Renee Gala: We are focused from a capital allocation standpoint on deleveraging this year, in addition to supporting our ongoing launches, expanding the pipeline. So we do expect and we're well positioned to meet our state and net leverage targeted getting below three and a half times, but we would expect to also be active in CorpDev. And then beyond that, I think we have great optionality as we enter 2023 and beyond.

An important product we are focused from a capital allocation standpoint on deleveraging. This year. In addition to supporting our ongoing launch of expanding the pipeline. So we do expect and we are well positioned to meet our stated net leverage target of getting below three five times, but we would expect to also be active in court.

Operator: Our business generates a significant amount of cash flow, and we demonstrated our ability to both lever up to be able to execute the GW transaction, but we also demonstrated the ability to quickly delever following that transaction, as well as integrate their operations rapidly and effectively.

Doug and then beyond that I think we have great optionality as we enter 2023 and beyond our business generates a significant amount of cash flow and we've demonstrated our ability to both lever up to be able to execute the GW transaction, but also we've demonstrated the ability to quickly delever.

Following that transaction as well as integrate their operations rapidly and effectively.

And our last question comes from Greg Fraser.

Securities Your line is open.

Operator: Good afternoon, folks. Thanks for taking the question. On Zywave for IH, what have been the early trends in terms of the mix between once-nightly and twice-nightly dosing, if you have data on that? And where would you expect the average dose per patient to normalize over time?

Good afternoon folks thanks for taking the question.

<unk> four is what it's been the early trends.

In terms of the mix between once and twice daily dosing. If you have data on that and where would you expect the average dose per patient to normalized at overtime. Thank you.

Okay.

Operator: Yeah, I would say, Greg, in answer to that, we haven't seen anything since launch that would tell us anything different from what we saw in our clinical trials in terms of once nightly and twice nightly dosing or on what those people end up with. So maybe I could ask Rob to jump in and just remind people what we did see on that.

Yes, I would say Greg in answer to that we haven't seen anything since launch.

That would tell us.

Anything different from what we saw in our clinical trials in terms of once nightly and twice nightly dosing.

Or on what dose people end up with so maybe I could ask Rob.

To jump in and just remind people what we did see.

Bruce Cozadd: I'll steal the thunder on the second half, which is to say, we saw essentially the same nightly dosing, very slightly lower in idiopathic hypersomnia than we see in narcolepsy. Yeah, that's right, Bruce. So by and large, it's very similar overall total dosing to narcolepsy. And the great majority of patients on the clinical trial ended up on twice nightly, you know, with idiopathic hypersomnia, which might be a little different than narcolepsy.

On that I'll I'll steal the Thunder on the second half, which is to say we saw essentially the same nightly dosing very slightly lower in idiopathic hypersomnia than we see in narcolepsy.

Rob Iannone: Some of the patients on the clinical trial were started once nightly, Title Microsoft Office Word Document MSWordDoc Word. Document.8, At this time, I'd like to turn the call back over to Bruce Cozadd for any closing remarks. All right. Thanks, operator. And thanks, everyone, for joining us. You know, I couldn't be happier with our strong fourth quarter and year revenue up 31%. ANI up 41% year-over-year with guidance for this year that contemplates 15% midpoint revenue growth, ANI about 17%, and I think really puts us right on track to achieve Vision 2025.

Yes.

So by and large is very similar overall total dosing to narcolepsy.

And the great majority of patients in the clinical trial ended up on twice nightly.

Oh, Pathics, hypersomnia, which might be a little different in narcolepsy.

Some of the patients on the clinical trial were started once nightly tighter.

Titrated up and as they derive benefit from the drug for them.

We're positioned to take that benefit from that second dose and so.

Even though is that we're starting up once nightly tended to transition over to <unk>.

Twice nightly.

At this time I would like to turn the call back over to Bruce does that for any closing remarks.

Alright, thanks, operator, and thanks, everyone for joining us I couldnt be happier with our strong fourth quarter and year revenue up 31%.

Ni up 41% year over year.

With guidance for this year that contemplates, 15% mid point revenue growth.

About 17% and I think really puts us right on track to achieve vision 2025.

Bruce Cozadd: So let me close today's call by recognizing all of our Jazz colleagues for their tenacity, dedication, and creativity in successfully delivering these new therapeutic options to patients. And I also want to thank our partners and shareholders for their continued confidence and support. We look forward to updating you on our progress this year as we drive toward our 2022 guidance and Vision 2025. Thank you all for joining us, and stay well. This concludes the program. You may now disconnect. The End, [music] [inaudible] David Amsellem, David Amsellem, David Amsellem, David Amsellem Dr. Prasad Prasad Prasad Prasad Prasad Prasad, [music] music playing music playing music playing music playing music playing [inaudible] [music]

So let me close today's call by recognizing all of our <unk> colleagues for their tenacity dedication and creativity.

Successfully delivering these new therapeutic options to patients and I also want to thank our partners and shareholders for their continued confidence and support we look forward to updating you on our progress this year as we drive toward our 2022 guidance and vision 2025. Thank you all for joining us and stay well.

This concludes the program and you may now disconnect.

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