What changed in this filing

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Item 1. Business

2023-03-01 compared with 2022-03-01 · 344 added, 344 removed, 781 unchanged (47% of the section changed)

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In addition, we leverage our efficient, scalable operating model and integrated capabilities across our global infrastructure to effectively reach patients around the world.

At the 40th Annual J.P.

Morgan Healthcare Conference in January 2022, we announced our Vision 2025, which aims to deliver sustainable growth and enhanced value, driving our continued transformation to an innovative, high-growth global pharmaceutical leader.

In January 2022, we announced our Vision 2025, which aims to deliver sustainable growth and enhanced value, driving our continued transformation to an innovative, high-growth global pharmaceutical leader.

The three core components of our Vision 2025 focus on commercial execution, pipeline productivity and operational excellence.

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Food and Drug Administration, or FDA, in July 2020 and launched in the U.S.

in November 2020 for the treatment of cataplexy or excessive daytime sleepiness, or EDS, in patients with narcolepsy aged seven years of age and older, and also approved by FDA in August 2021 for the treatment of idiopathic hypersomnia, or IH, in adults and launched in the U.S.

in November 2020 for the treatment of cataplexy or excessive daytime sleepiness, or EDS, in patients with narcolepsy seven years of age and older, and also approved by FDA in August 2021 for the treatment of idiopathic hypersomnia, or IH, in adults and launched in the U.S.

in November 2021.

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• Xyrem (sodium oxybate) oral solution , a product approved by FDA and distributed in the U.S.

for the treatment of both cataplexy and EDS in patients seven years of age and older with narcolepsy;

for the treatment of cataplexy or EDS in patients with narcolepsy seven years of age and older;

Jazz also markets Xyrem in Canada for the treatment of cataplexy in patients with narcolepsy.

Xyrem is also approved and distributed in Europe, Great Britain and other markets through a licensing agreement;

Xyrem is also approved and distributed in the European Union, or EU (EU market authorizations include Northern Ireland), Great Britain and other markets through a licensing agreement;

• Epidiolex® (cannabidiol) oral solution , a product approved by FDA and launched in the U.S.

in 2018 by GW Pharmaceuticals plc, or GW, and currently indicated for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex, or TSC, in patients one year of age or older;

in Europe (where it is marketed as Epidyolex®) and other markets, it is approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, in conjunction with clobazam (EU and Great Britain only), in patients 2 years of age and older and for adjunctive treatment of seizures associated with TSC in patients 2 years of age and older;

• Sunosi® (solriamfetol) , a product approved by FDA and marketed in the U.S., Canada, Europe and Great Britain to improve wakefulness in adult patients with EDS associated with narcolepsy or obstructive sleep apnea, or OSA;

• Sativex® (nabiximols) oral solution , a product approved and marketed in the U.K., Canada and other markets as treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis, or MS, who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

• Zepzelca® (lurbinectedin) , a product approved by FDA in June 2020 and launched in the U.S.

in 2018 by GW Pharmaceuticals plc, or GW, and currently indicated for the treatment of seizures associated with Lennox-Gastaut syndrome, or LGS, Dravet syndrome, or DS, or tuberous sclerosis complex, or TSC, in patients one year of age or older;

in the EU and Great Britain (where it is marketed as Epidyolex®) and other markets listed in the table below, it is approved for adjunctive treatment of seizures associated with LGS or DS, in conjunction with clobazam (EU and Great Britain only), in patients 2 years of age and older and for adjunctive treatment of seizures associated with TSC in patients 2 years of age and older.

• Zepzelca® (lurbinectedin) , a product approved by FDA in June 2020 under FDA's accelerated approval pathway and launched in the U.S.

in July 2020 for the treatment of adult patients with metastatic small cell lung cancer, or SCLC, with disease progression on or after platinum-based chemotherapy;

i n Canada, Zepzelca was approved in September 2021 for the treatment of adults with Stage III or metastatic SCLC, who have progressed on or after platinum-containing therapy;

• Rylaze™ (recombinant Erwinia asparaginase), a product approved by FDA in June 2021 and launched in the U.S.

in July 2021 for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia, or ALL, or lymphoblastic lymphoma, or LBL, in adults and pediatric patients who have developed hypersensitivity to E.

in Canada, Zepzelca received conditional approval in September 2021 for the treatment of adults with Stage III or metastatic SCLC, who have progressed on or after platinum-containing therapy;

• Rylaze® (asparaginase erwinia chrysanthemi (recombinant)-rywn) , a product approved by FDA in June 2021 and launched in the U.S.

coli -derived asparaginase;

• Vyxeos® (daunorubicin and cytarabine) liposome for injection , a product approved in the U.S., Canada, Europe and Great Britain (marketed as Vyxeos® liposomal in Europe and Great Britain) for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia, or t-AML, or AML with myelodysplasia-related changes (AML-MRC).

• Vyxeos® (daunorubicin and cytarabine) liposome for injection , a product approved in the U.S., Canada, EU, Great Britain and other markets listed in the table below (marketed as Vyxeos® liposomal in the EU, Great Britain and other markets) for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia, or t-AML, or AML with myelodysplasia-related changes, or AML-MRC.

An expanded indication was granted in the U.S.

for the treatment of newly diagnosed t-AML or AML-MRC in pediatric patients aged 1 year and older;

• Defitelio® (defibrotide sodium) , is a product approved in the U.S.

and Brazil for the treatment of hepatic veno-occlusive disease, or VOD, with renal or pulmonary dysfunction following hematopoietic stem cell transplantation, or HSCT, and in Japan for the treatment of hepatic sinusoidal obstruction syndrome (hepatic-veno occlusive disease).

It is currently approved in the EU, Great Britain, Canada, Israel, South Korea, Australia and Switzerland for the treatment of severe hepatic VOD, also known as sinusoidal obstructive syndrome, or SOS, in HSCT therapy.

• Defitelio® (defibrotide sodium) , a product approved in the U.S.

It is currently approved in the EU, Great Britain and other markets listed in the table below for the treatment of severe hepatic VOD, also known as sinusoidal obstructive syndrome, or SOS, in HSCT therapy.

It is indicated in adults and pediatric patients over 1 month of age.

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For a summary of our ongoing research and development activities, see “Business—Research and Development” in this Part I, Item 1.

Acquisition of GW Pharmaceuticals

In May 2021, we acquired GW Pharmaceuticals plc, or GW.

The total consideration paid by us for the entire issued share capital of GW was $7.2 billion.

The acquisition, which we refer to as the GW Acquisition, closed on May 5, 2021.

We acquired GW with the objective of broadening our neuroscience portfolio, further diversifying our revenue and driving sustainable, long-term value creation opportunities.

GW was a global leader in discovering, developing, manufacturing and commercializing novel, regulatory approved therapeutics from its proprietary cannabinoid research platform to address a broad range of diseases.

For further information regarding the GW Acquisition, please see Note 3 Business Combinations, Asset Acquisitions and Collaborations of the Notes to Consolidated Financial Statements, included in Part IV of this Annual Report on Form 10‑K .

Our Commercialized Products

Xywav is a product approved by FDA for the treatment of cataplexy or EDS in both adult and pediatric patients aged seven years of age and older with narcolepsy and for the treatment of adults with IH.

Xywav is an oxybate product that contains 92% less sodium than Xyrem.

Our Oxybate Products .

We are the global leader in the development and commercialization of oxybate therapy for patients with sleep disorders.

Xyrem was approved by FDA in 2002 and has become a standard of care for treating EDS and cataplexy in narcolepsy.

In 2020, we received FDA approval for Xywav for the treatment of cataplexy or EDS, in patients seven years of age and older with narcolepsy.

Xywav is an oxybate therapy that contains 92% less sodium than Xyrem.

In August 2021, Xywav became the first and only therapy approved by FDA for the treatment of IH in adults.

In July 2020, FDA approved Xywav for the treatment of both cataplexy and EDS in patients with narcolepsy.

We commenced the U.S.

launch in November 2020.

We met our goal to obtain broad payor coverage of Xywav within six months of launch.

To date, we have entered into agreements with various entities and have achieved benefit coverage for Xywav for approximately 90% of commercial lives.

Narcolepsy is a chronic, debilitating neurological disorder characterized by EDS and the inability to regulate sleep-wake cycles normally.

It affects an estimated one in 2,000 people in the U.S., with symptoms typically appearing in childhood.

Since there is not currently a cure for narcolepsy and we believe there is unmet need in the patient population for long-term disease management, we believe that Xywav represents an important new therapeutic option for patients with this sleep disorder.

Narcolepsy affects an estimated one in 2,000 people in the U.S., with symptoms typically appearing in childhood.

There are five primary symptoms of narcolepsy, including EDS, cataplexy, disrupted nighttime sleep, sleep-related hallucinations, and sleep paralysis.

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Narcolepsy patients, by virtue of their diagnosis, are at increased risk of cardiovascular events and disease, and the impact of sodium on cardiovascular health is well established.

There is also extensive scientific evidence that reducing sodium

consumption, which is a modifiable risk factor, is associated with clinically meaningful reductions in blood pressure and cardiovascular disease risk.

There is also extensive scientific evidence that reducing sodium consumption, which is a modifiable risk factor, is associated with clinically meaningful reductions in blood pressure and cardiovascular disease risk.

Therefore, we believe that reducing sodium intake compared to the standard of care by 92% each and every day is a significant advancement for these patients.

The 92% reduction of sodium translates into a reduction of approximately 1,000 to 1,500 milligrams per day for a patient prescribed Xyrem, depending on the dose.

Our commercial efforts with respect to Xywav are focused on educating patients and physicians about the lifelong impact of high sodium intake, and how the use of Xywav enables them to address what is a modifiable risk factor.

When patients transition from Xyrem to Xywav, Xywav treatment is initiated at the same dose and regimen (gram for gram) and titrated as needed based on efficacy and tolerability.

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Our internal market research finds that health care providers and patients who understand the increased risk of cardiovascular disease faced by narcolepsy patients and who have been educated on the meaningful reduction in sodium from Xyrem to Xywav cite that meaningful reduction as a key reason for prescribing or starting on Xywav.

In June 2021, FDA recognized seven years of Orphan Drug Exclusivity, or ODE, for Xywav in narcolepsy through July 21, 2027, stating that Xywav is clinically superior to Xyrem by means of greater safety due to reduced chronic sodium burden.

In approving Xywav, FDA approved a REMS to cover both Xywav and Xyrem.

In June 2021, FDA recognized seven years of Orphan Drug Exclusivity, or ODE, for Xywav in narcolepsy through July 21, 2027, stating that

Xywav is clinically superior to Xyrem by means of greater safety because Xywav provides a greatly reduced chronic sodium burden compared to Xyrem.

FDA's summary also stated that “the differences in the sodium content of the two products at the recommended doses will be clinically meaningful in reducing cardiovascular morbidity in a substantial proportion of patients for whom the drug is indicated.” We view the adoption of Xywav in narcolepsy as a positive indication that physicians and patients appreciate the benefits of a lower sodium oxybate option.

In approving Xywav, FDA approved a risk evaluation and mitigation strategy, or REMS, to cover both Xywav and Xyrem.

The Xywav and Xyrem REMS has the same requirements for both products and both products are also distributed by the central pharmacy through exclusive agreements described more fully below.

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commercial launch of Xywav for the treatment of IH in adults on November 1, 2021.

In January 2022, FDA recognized seven years of ODE for Xywav in IH through August 12, 2028.

IH is a debilitating neurologic sleep disorder characterized by chronic EDS (the inability to stay awake and alert during the day resulting in the irrepressible need to sleep or unplanned lapses into sleep or drowsiness), severe sleep inertia, and prolonged and non-restorative nighttime sleep.

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have been diagnosed with IH and are actively seeking healthcare.

In January 2022, FDA recognized seven years of ODE for Xywav in IH through August 12, 2028.

In 2021, net product sales of Xywav were $535.3 million, which represented 17% of our total net product sales.

We commenced the U.S.

launch in November 2020.

To date, we have entered into agreements for Xywav with all three major pharmacy benefit managers, or PBMs, in the U.S.

and various other entities and have achieved benefit coverage for Xywav in both narcolepsy and IH indications for approximately 90% of commercial lives.

We have seen strong adoption of Xywav in narcolepsy since its launch in November 2020 and increasing adoption in IH since its launch in November 2021.

In 2022, net product sales of Xywav were $958.4 million, which represented 26% of our total net product sales for the year.

There were approximately 10,300 active patients on Xywav exiting the fourth quarter of 2022, including approximately 8,550 active patients with narcolepsy and approximately 1,750 active patients with IH.

With respect to Xywav and Xyrem in the aggregate, the average number of active oxybate patients on therapy was approximately 18,000 in the fourth quarter of 2022.

Xyrem is a product approved by FDA and distributed in the U.S.

for the treatment of both cataplexy and EDS in both adult and pediatric patients with narcolepsy.

Sodium oxybate, the active pharmaceutical ingredient, or API, in Xyrem, is a formulation of the sodium salt of gamma-hydroxybutyrate, an endogenous neurotransmitter and metabolite of gamma-aminobutyric acid.

Xyrem was approved in the U.S.

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In its updated 2021 treatment guidelines, the American Academy of Sleep Medicine gives sodium oxybate a strong recommendation for the treatment of narcolepsy in adults.

To support the development and commercialization of Xyrem internationally, we have license and distribution agreement with UCB Pharma Limited, or UCB, across other countries.

To support the development and commercialization of Xyrem internationally, we have a license and distribution agreement with UCB Pharma Limited, or UCB, across other countries.

This agreement provides UCB and its affiliates with the sole right to commercialize Xyrem in exclusive territories for all indications.

In 2021, net product sales of Xyrem were $1.3 billion, which represented 41% of our total net product sales.

In 2022, net product sales of Xyrem were $1.0 billion, which represented 28% of our total net product sales for the year.

Xywav and Xyrem REMS .

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and provide patient support services related to Xyrem since 2002.

In July 2020, upon expiration of the existing exclusive agreements with ESSDS, we entered into new agreements with ESSDS with a two-year term.

Our current agreements with ESSDS, which expire on July 1, 2022, may be terminated by either party at any time without cause on 180 days’ prior written notice to the other party.

We acquired Epidiolex (Epidyolex outside the U.S.) in May 2021 as part of the GW Acquisition, which expands our growing neuroscience business with a global, high-growth childhood-onset epilepsy franchise.

Epidiolex is a pharmaceutical formulation comprising highly purified plant-derived cannabidiol, or CBD, for which we retain global commercial rights.

In December 2022, we entered into new agreements with ESSDS with a two-year term.

Our current agreements with ESSDS, which expire on December 1, 2024, may be terminated by either party at any time without cause on 180 days’ prior written notice to the other party.

On May 5, 2021, we acquired the entire issued share capital of GW.

As a result, GW became an indirect wholly owned subsidiary of the Company.

The aggregate consideration for the GW Acquisition was $7.2 billion.

We acquired Epidiolex (Epidyolex outside the U.S.) in May 2021 as part of our acquisition of GW, which expanded our growing neuroscience business with a global, high-growth childhood-onset epilepsy franchise.

We refer to the acquisition of GW as the GW Acquisition.

Epidiolex was approved in the U.S.

in June 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome, or LGS, and Dravet syndrome, or DS, in patients two years of age and older, and subsequently approved in July 2020 for the treatment of seizures associated with tuberous sclerosis complex, or TSC, in patients one year of age and older.

in June 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, LGS and DS, in patients two years of age and older, and subsequently approved in July 2020 for the

treatment of seizures associated with TSC in patients one year of age and older.

FDA also approved the expansion of the prior approved indications, LGS and DS, to patients one year of age and older.

The rolling European launch of Epidyolex is also underway following European Commission, or EC, approval in September 2019 for use as adjunctive therapy of seizures associated with LGS or DS, in conjunction with clobazam, for patients two years of age and older.

The clobazam restriction is limited to EU and Great Britain.

Epidyolex is now launched in all five key European markets:

United Kingdom, Germany, Italy, Spain and France.

The clobazam restriction is limited to the EU and Great Britain .

Epidyolex was also approved for adjunctive therapy in seizures associated with TSC for patients 2 years of age and older in the EU in April 2021 and Great Britain in August 2021, and is approved for this indication in other markets.

Outside the U.S.

and Europe, Epidiolex/Epidyolex is approved in Israel and Australia.

and Europe, Epidiolex/Epidyolex is approved in Israel, Australia and New Zealand.

See “Research and Development” below for a discussion of clinical development activities for Epidiolex.

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Epidiolex has received ODE to treat seizures associated with LGS and DS through 2025 and TSC through 2027.

Net product sales of Epidiolex/Epidyolex in 2021, beginning from the closing of the GW Acquisition on May 5, 2021 were $463.6 million , w hich represented 15% of our total net product sales.

On a pro forma basis, assuming the GW Acquisition had closed on January 1, 2021, Epidiolex/Epidyolex net product sales in 2021 were $658.3 million.

For a detailed discussion of the GW Acquisition, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in Part II, Item 7 of this Annual Report on Form 10-K.

Sunosi received FDA approval in March 2019 and was launched in the U.S.

in July 2019 to improve wakefulness in adult patients with EDS associated with narcolepsy or OSA.

Sunosi was also approved in January 2020 by the EC to improve wakefulness and reduce EDS in adults with narcolepsy (with or without cataplexy) or OSA.

We launched Sunosi in Germany for the treatment of narcolepsy in May 2020 followed by OSA in July 2021 and for the treatment of both indications in Denmark in October 2020, in France in March 2021, and in Italy in April 2021.

We expect to continue the rolling launch in Europe as we secure pricing and reimbursement approvals in more European countries.

Sunosi was approved in Canada in May 2021 for the treatment of EDS associated with narcolepsy or OSA in adult patients.

OSA, commonly referred to as sleep apnea, is a highly prevalent disease, and EDS, a major symptom of OSA, is characterized by the inability to stay awake and alert during the day resulting in unplanned lapses into sleep or drowsiness.

Although positive airway pressure therapy, with its most common form being continuous positive airway pressure, or CPAP, has been shown to be an effective therapy for sleep apnea that frequently results in improvement in EDS in many patients, not all patients tolerate CPAP therapy and among those who tolerate CPAP, usage is highly variable.

EDS may persist in people with OSA despite using CPAP.

In 2021, net product sales of Sunosi were $57.9 million, which represented 2% of our total net product sales.

We acquired Sativex (nabiximols) in May 2021 as part of the GW Acquisition.

Sativex is approved in the U.K.

and certain other countries outside the U.S.

as treatment for symptom improvement in adult patients with moderate to severe spasticity due to MS, who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

Nabiximols is a complex botanical mixture formulated from extracts of the cannabis sativa plant that contains the principal cannabinoids delta-9-tetrahydrocannabinol, or THC, and CBD as well as specific minor cannabinoids and other non-cannabinoid components.

We developed nabiximols to be administered as an oromucosal spray, whereby the active ingredients are absorbed in part in the lining of the mouth, either under the tongue or inside the cheek.

Nabiximols is already approved in more than 25 countries outside the U.S.

for the treatment of spasticity due to multiple sclerosis under the brand name Sativex.

We market Sativex directly in the U.K.

To support the development and commercialization of Sativex internationally, we have license and development agreements with commercial partners across other countries.

These agreements provide our collaborators with the sole right to commercialize Sativex in exclusive territories for all indications.

See “Research and Development” below for a discussion of clinical development activities for nabiximols.

Net product sales of Sativex in 2021, beginning from the closing of the GW Acquisition on May 5, 2021 were $12.7 million , w hich represented less than 1% of our total net product sales.

On a pro forma basis, assuming the GW Acquisition had closed on January 1, 2021, Sativex net product sales in 2021 were $18.5 million.

In December 2019, we entered into an exclusive license agreement with Pharma Mar, S.A., or PharmaMar, pursuant to which we obtained exclusive U.S.

development and commercialization rights to Zepzelca.

Net product sales of Epidiolex/Epidyolex in 2022 were $736.4 million , w hich represented 20% of our total net product sales for the year.

In addition to our currently-marketed products, we previously marketed Sunosi® (solriamfetol) in the U.S., Europe and Canada.

In March 2022, we entered into an agreement to divest Sunosi to Axsome Therapeutics, Inc., or Axsome.

In May 2022, we completed the U.S.

divestiture of Sunosi to Axsome and in November 2022, we completed the ex-U.S.

The Sunosi divestiture was intended to enable us to sharpen our focus on our highest strategic priorities.

Further, we believed that Axsome is well positioned to deliver access to this important medicine and deliver value to us through anticipated royalties.

For more information, see “ Sunosi Disposition ” in Note 3 of the Notes to Consolidated Financial Statements, included in Part IV of this Annual Report on Form 10‑K.

We acquired U.S.

development and commercialization rights to Zepzelca in early 2020, and launched six months thereafter, with an indication for treatment of patients with SCLC with disease progression on or after platinum-based chemotherapy.

Our education and promotional efforts are focused on SCLC-treating physicians.

We are continuing to raise awareness of Zepzelca across academic and community cancer centers, and believe there are opportunities for further growth in second-line share and overall demand, reflecting the significant unmet need and favorable Zepzelca product profile.

Our exclusive U.S.

development and commercialization rights to Zepzelca were acquired through an exclusive license agreement we entered into with Pharma Mar, S.A., or PharmaMar, in December 2019.

In October 2020, we entered into an amendment to the license agreement with PharmaMar to expand our exclusive license to include rights to develop and commercialize Zepzelca in Canada.

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See “Research and Development” below for a discussion of clinical development activities for Zepzelca.

In 2021, net product sales of Zepzelca were $246.8 million, which represented 8% of our total net product sales.

Rylaze was approved by FDA in June 2021 under the Real-Time Oncology Review (RTOR) program, and was launched in the U.S.

In 2022, net product sales of Zepzelca were $269.9 million, which represented 7% of our total net product sales for the year.

Rylaze was approved by FDA in June 2021 under the Real-Time Oncology Review, or RTOR, program, and was launched in the U.S.

in July 2021, for use as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL or LBL in pediatric and adult patients one month and older who have developed hypersensitivity to E.

coli -derived asparaginase.

Rylaze is the only recombinant erwinia asparaginase manufactured product that maintains a clinically meaningful level of serum asparaginase activity throughout the entire intended duration of treatment.

We developed Rylaze with the goal of addressing the needs of patients and health care providers for an innovative, high-quality erwinia asparaginase with reliable supply.

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See “Research and Development” below for a discussion of clinical development activities for Rylaze.

In 2021, net product sales of Rylaze were $85.6 million, which represented 3% of our total net product sales.

Vyxeos is a liposomal formulation of a fixed ratio combination of daunorubicin and cytarabine for intravenous infusion that is indicated for the treatment of adults with newly-diagnosed t-AML or AML-MRC and has been shown to have synergistic effects at killing leukemia cells in vitro and in animal models.

Vyxeos is the first drug delivery combination product based on our CombiPlex ® technology platform to be approved by FDA and the EC.

The initial approved recommended dosage of Rylaze was for an intramuscular, or IM, administration of 25 mg/m2 every 48 hours.

In November 2022, FDA approved a supplemental Biologics License Application, or sBLA, for a Monday/Wednesday/Friday, or M/W/F IM dosing schedule.

See “Research and Development” below for a discussion of clinical development activities for Rylaze.

In 2022, net product sales of Rylaze were $281.7 million, which represented 8% of our total net product sales for the year.

In 2017, we launched Vyxeos in the U.S.

after FDA approved our NDA for the treatment of adults with newly-diagnosed t-AML or AML-MRC.

In August 2018, the EC granted marketing authorization for Vyxeos and, as part of our rolling launch of Vyxeos in Europe, we are continuing to make pricing and reimbursement submissions in European countries.

In March 2021, FDA approved a revised label to include a new indication to treat newly-diagnosed t-AML, or AML-MRC, in pediatric patients aged one year and older.

AML is a rapidly progressing and life-threatening blood cancer that begins in the bone marrow, which produces most of the body's new blood cells.

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Patients with newly diagnosed t-AML or AML-MRC may have a particularly poor prognosis.

In 2017, we launched Vyxeos in the U.S.

after FDA approved our NDA for the treatment of adults with newly-diagnosed t-AML or AML-MRC.

In March 2021, FDA approved a revised label to include a new indication to treat newly-diagnosed t-AML or AML with myelodysplasia-related changes in pediatric patients aged one year and older.

We have a number of ongoing development activities and continue to expand into new markets internationally.

See “Research and Development” below for a discussion of clinical development activities for Vyxeos.

In 2021, Vyxeos product sales were $134.1 million, which represented 4% of our total net product sales.

Defibrotide, the API in Defitelio, is approved for the treatment of VOD, a potentially life-threatening complication of HSCT, and is in development for other complications following anti-cancer treatment.

Defibrotide is the sodium salt of a complex mixture of single-stranded oligodeoxyribonucleotides derived from porcine DNA.

Defibrotide mediates its effects via interaction with endothelial cells.

Non-clinical data suggest that defibrotide stabilizes endothelial cells by reducing endothelial cell activation and by protecting them from further damage.

In 2022, Vyxeos product sales were $128.0 million, which represented 4% of our total net product sales for the year.

Defitelio is the first and only FDA approved treatment for patients with VOD, a potentially life-threatening complication of HSCT.

In addition, it is currently approved in the EU, Great Britain and other markets.

Stem cell transplantation is a frequently used treatment modality for hematologic cancers and other conditions in both adults and children.

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An analysis of retrospective data, prospective cohort studies and clinical trials published between 1979 and 2007 found that the 100-day mortality rate in severe VOD cases is greater than 80%.

The EC granted marketing authorization under exceptional circumstances for Defitelio for the treatment of severe VOD in adults and children undergoing HSCT in 2013.

We commenced a rolling launch of Defitelio in European countries in 2014.

In 2016, FDA approved our NDA for Defitelio for the treatment of adult and pediatric patients with VOD with renal or pulmonary dysfunction following HSCT.

We launched Defitelio in the U.S.

shortly after FDA approval.

We also launched defibrotide in Canada in 2017.

In June 2019, Nippon Shinyaku Co., Ltd., the partner to whom we have granted exclusive rights to develop and commercialize defibrotide in Japan, received marketing authorization from Japan’s Ministry of Health, Labour and Welfare and launched defibrotide in Japan in September 2019.

Further geographic expansion occurred in July 2020 and September 2020, as Defitelio was approved by the Australian Therapeutic Goods Administration and Swissmedic in Switzerland, respectively, for the treatment of VOD.

In 2021, Defitelio/defibrotide product sales were $197.9 million, which represented 6% of our total net product sales.

In 2022, Defitelio/defibrotide product sales were $194.3 million, which represented 5% of our total net product sales for the year.

Revenue Diversification

As part of our objective to reduce business risk by diversifying our revenue sources, we have been actively seeking to expand our commercial portfolio thorough a combination of launching internally developed therapies and corporate development.

In 2018, 75% of net product sales were generated by one product, Xyrem.

In the fourth quarter of 2021, 59% of net product sales were generated from products that we launched or acquired since 2019, including Xywav, Zepzelca, Epidiolex, Sunosi, Sativex and Rylaze.

For the year ended December 31, 2022, 63% of net product sales were generated from products that we launched or acquired since 2019, including Xywav, Epidiolex, Zepzelca, Rylaze, Sunosi 1 and Sativex 2 .

1 Net product sales of Sunosi U.S.

are included until the date of divestment to Axsome on May 9, 2022.

2 Sativex (nabiximols) is a product approved outside the U.S.

for the treatment of adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication.

We continue to support the availability of Sativex in the 29 markets outside the U.S.

where it is approved.

Our lead marketed products, listed below, are approved in countries around the world to improve patient care.

Product Indication(s) Initial Approval Date Market(s)

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For adjunctive therapy of seizures associated with LGS or DS, in conjunction with clobazam, for patients 2 years of age and older.*

For adjunctive therapy of seizures associated with TSC for patients 2 years of age and older.** June 2018

For adjunctive therapy of seizures associated with TSC for patients 2 years of age and older.

September 2019

April 2021 U.S.

EU, Great Britain, other markets

Sunosi ® (solriamfetol)

Improve wakefulness in adult patients with EDS associated with narcolepsy or OSA.

Improve wakefulness and reduce EDS in adult patients with narcolepsy (with or without cataplexy) or adult patients with OSA whose EDS has not been satisfactorily treated by primary OSA therapy, such as CPAP.

Treatment of EDS in adult patients with narcolepsy or OSA.

May 2021 U.S.

EU, Great Britain

Sativex ® (nabiximols)

Treatment for adult patients with moderate to severe spasticity due to MS, who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy.

June 2010 U.K.

and Canada (other markets through licensing agreements with partners)

EU, Great Britain, Israel, Australia and New Zealand

EU, Great Britain and Israel

Zepzelca ® (lurbinectedin)

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Rylaze ® (asparaginase erwinia chrysanthemi (recombinant)-

rywn) A component of a multi-agent chemotherapeutic regimen for the treatment of ALL, and LBL, in adult and pediatric patients 1 month or older who have developed hypersensitivity to E.

A component of a multi-agent chemotherapeutic regimen for the treatment of ALL, and LBL, in adult and pediatric patients 1 month or older who have developed hypersensitivity to E.

coli -derived asparaginase.

June 2021 U.S.

A component of a multi-agent chemotherapeutic regimen for the treatment of ALL and LBL, in adults and pediatric patients 1 year or older who have developed hypersensitivity to

coli -derived asparaginase.

September 2022 U.S.

Vyxeos ® (daunorubicin and cytarabine) liposome for injection

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Treatment of adults with newly diagnosed therapy-related t-AML or AML with AML-MRC.

EU, Great Britain

EU, Great Britain, Switzerland, Israel, Australia, South Korea

Defitelio ® (defibrotide)

Defitelio ® (defibrotide sodium)

Defitelio ® (defibrotide)

Treatment of severe hepatic VOD, also known as SOS, following HSCT therapy.

Treatment of adult and pediatric patients with hepatic VOD, also known as SOS, with renal or pulmonary dysfunction following HSCT.

Treatment of severe hepatic VOD, also known as SOS, following HSCT therapy.

October 2013 U.S.

EU, Great Britain, other markets

Treatment of hepatic sinusoidal obstruction syndrome (hepatic VOD).

June 2019 EU, Great Britain, Switzerland, Israel, Australia, South Korea, Saudi Arabia

*The Clobazam restriction limited to EU and Great Britain

**TSC approval pending in certain markets

**Accelerated approval received from FDA

***Conditional approval received from Health Canada

Research and Development

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We are focused on research and development activities within our neuroscience and oncology therapeutic areas, such as our expansion into movement disorders and solid tumors, and exploring and potentially investing in adjacent therapeutic areas.

Our development activities encompass all stages of development and currently include clinical testing of new product candidates and activities related to clinical improvements of, or additional indications or new clinical data for, our existing marketed products.

We also have active preclinical programs for novel therapies, including precision medicines in hematology and oncology and the GW cannabinoid platform.

Our research and development activities encompass all stages of development and currently include clinical testing of new product candidates and activities related to clinical improvements of, or additional indications for, our existing marketed products.

We also have active preclinical programs for novel therapies, including precision medicines in hematology and oncology, and our proprietary GW Cannabinoid Platform.

We are increasingly leveraging our growing internal research and development function, and we have also entered into collaborations with third parties for the research and development of innovative early-stage product candidates and have supported additional investigator-sponsored trials, or ISTs, that are anticipated to generate additional data related to our products.

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We have a number of licensing and collaboration agreements with third parties, including biotechnology companies, academic institutions and research-based companies and institutions, related to preclinical and clinical research and development activities in hematology and in precision oncology, as well as in neuroscience.

Our current and planned development activities in our neuroscience therapeutic area are focused on an additional indication for Epidiolex, and advancing novel therapies, including nabiximols, suvecaltamide (JZP385) and JZP150.

We anticipate the initiation of a pivotal Phase 3 clinical trial of Epidiolex for the treatment of Epilepsy with Myoclonic-Atonic Seizures, or EMAS, also known as Doose syndrome, in the first half of 2022.

Our neuroscience R&D efforts include the initiation of a pivotal Phase 3 clinical trial of Epidiolex for the treatment of Epilepsy with Myoclonic-Atonic Seizures, or EMAS, also known as Doose syndrome, in August 2022.

This trial is designed to evaluate Epidiolex in a fourth childhood-onset epileptic encephalopathy with high unmet need.

EMAS is characterized by generalized myoclonic-atonic seizures, and this trial is designed to provide the first randomized, controlled clinical data with Epidiolex in this syndrome type.

characterized by generalized myoclonic-atonic seizures, and this trial is designed to provide the first randomized, controlled clinical data with Epidiolex in this syndrome type.

Seizure types including atonic, tonic, clonic, tonic-clonic, and partial onset seizures are seen in LGS, DS and TSC.

We have three ongoing Phase 3 clinical trials in multiple sclerosis (MS)-related spasticity.

Collectively these trials will expand the body of evidence on the safety and efficacy of nabiximols in addressing spasticity in MS patients, and either individually or jointly may support an NDA submission to FDA.

Spasticity occurs in up to 84% of MS patients, and approximately one-third of those who experience spasticity live with uncontrolled symptoms.

The first trial is a smaller, shorter trial relative to the other two.

The first trial is assessing changes in muscle tone using elements of the Modified Ashworth scale.

If results from this first trial are positive, there is the potential for an NDA submission to FDA by the end of 2022.

The two additional trials have larger sample sizes.

We enrolled the first patient in a Phase 3 trial of Epidyolex for LGS, DS and TSC in Japan in October 2022.

Suvecaltamide .

Suvecaltamide (JZP385) is a highly selective modulator of T-type calcium channels currently in development for the treatment of essential tremor, or ET.

Suvecaltamide (JZP385) is a highly selective modulator of T-type calcium channels currently in development for the potential treatment of essential tremor, or ET.

ET is the most common pathological movement disorder, and there have been no new approved therapies in more than 50 years.

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The primary efficacy outcome measure is the change from baseline to Week 12 on the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) composite outcome score, which represents items from the TETRAS-Activities of Daily Living and TETRAS-Performance Subscale, and measures the functional impact due to tremor.

Additionally, in November 2022, we initiated a Phase 2 trial of suvecaltamide in patients with Parkinson's disease tremor.

JZP150 is a fatty acid amide hydrolase, or FAAH, inhibitor program for the potential treatment of post-traumatic stress disorder, or PTSD, and associated symptoms.

PTSD affects up to 8% of adults during their lifetime, and there are limited treatment options available.

In October 2020, we entered into an asset purchase and exclusive license agreement with SpringWorks, under which we acquired SpringWorks’ FAAH inhibitor program, including an assignment of SpringWorks’ proprietary FAAH inhibitor PF-04457845, or PF-’845, now named JZP150.

In October 2020, we entered into an asset purchase and exclusive license agreement with SpringWorks Therapeutics, Inc., or SpringWorks, under which we acquired SpringWorks’ FAAH inhibitor program, including an assignment of SpringWorks’ proprietary FAAH inhibitor PF-04457845, or PF-’845, now named JZP150.

We initiated a Phase 2 clinical trial of JZP150 for PTSD in December 2021.

In this trial, we are evaluating the safety and efficacy of JZP150 in the treatment of adults with PTSD as measured by improvement in the Clinician Administered Post Traumatic Stress Disorder (PTSD) Scale (CAPS-5) Total Symptom Severity Score, a validated clinical instrument for assessing the severity of PTSD symptoms.

Our current and planned research and development activities in our oncology therapeutic area are focused on Rylaze and Zepzelca, including in combination with other therapeutic agents, exploring additional indications for Vyxeos, and the research and development of new product candidates through our external collaborations.

JZP441 is a potent, highly selective oral orexin-2 receptor agonist with potential application for the treatment of narcolepsy, IH and other sleep disorders.

In May 2022, we announced that we had entered into a licensing agreement with Sumitomo Pharma Co., Ltd, or Sumitomo, to acquire exclusive development and commercialization rights in the U.S., Europe and other territories for DSP-0187, now referred to as JZP441.

In November 2022, we initiated a Phase 1 development program to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of JZP441 in sleep-deprived healthy volunteers.

Our licensor, Sumitomo, initiated a Phase 1 trial in Japan in November 2021 to evaluate safety, tolerability and pharmacokinetics of JZP441 in healthy volunteers.

On June 28, 2022, we announced the nabiximols Phase 3 RELEASE MSS1 trial in multiple sclerosis (MS)-related spasticity did not meet the primary endpoint of change in Lower Limb Muscle Tone-6 between baseline and Day 21, as measured by the Modified Ashworth Scale.

The analysis of the MSS1 trial has been completed.

We have assessed the nabiximols program's potential to support regulatory approval for MS-related spasticity in the U.S., as well as in the context of our broader pipeline opportunities, and have made the decision to discontinue the program.

Sativex (nabiximols) was approved outside the U.S.

for the treatment of MS-related spasticity based on a comprehensive clinical trial program, including multiple late-stage randomized, controlled trials completed in Europe.

We continue to support the availability of Sativex in the 29 markets outside the U.S.

where it is approved.

We remain committed to the GW Cannabinoid Platform and are working to advance multiple early-stage cannabinoid programs with the potential to address critical unmet patient needs.

Our current and planned research and development activities in our oncology therapeutic area are focused on Zepzelca, including in combination with other therapeutic agents, Rylaze, Zanidatamab, Vyxeos, JZP815 and the research and development of new product candidates through our external collaborations.

Within our oncology R&D program, there is a robust development plan being executed for Zepzelca.

In collaboration with F.

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This is a three-arm trial comparing Zepzelca as either monotherapy or in combination with irinotecan to investigator's choice of irinotecan or topotecan.

Data from this trial, if positive, would serve as the confirmatory trial for Zepzelca to secure full approval in the U.S.

Data from either the first-line trial of Zepzelca in combination with Tecentriq or the PharmaMar trial could serve to confirm clinical benefit of Zepzelca and support full approval in the U.S.

We initiated a Phase 2 basket trial in the first quarter of 2022 to explore Zepzelca monotherapy in patients with select advanced or metastatic solid tumors.

Cohorts will include advanced urothelial cancer, large cell neuroendocrine tumor of the lung, and homologous recombinant deficient positive (HRD+) cancers.

Cohorts will include advanced urothelial cancer, poorly differentiated neuroendocrine carcinomas, or PD-NECs, and homologous recombination deficient, or HRD, cancers.

In addition, we have initiated a Phase 4 observational study to collect real world safety and outcome data in adult Zepzelca monotherapy patients with SCLC who progress on or after prior platinum-containing chemotherapy.

The current approved recommended dosage of Rylaze is for an intramuscular, or IM, administration of 25 mg/m 2 every 48 hours.

In February 2022, we announced the submission of a supplemental Biologics License Application, or sBLA, to FDA with data to support a Monday/Wednesday/Friday (M/W/F) IM dosing schedule, which has also been granted review under the RTOR program.

An additional part of the ongoing Rylaze study has evaluated intravenous, or IV, administration and, if the data are supportive, we expect to submit an additional sBLA to FDA in 2022 in support of IV administration.

We also are planning a regulatory submission in Europe for IM and IV administration in mid-2022.

The initial approved recommended dosage of Rylaze was for an IM administration of 25 mg/m 2 every 48 hours.

In November 2022, FDA approved a sBLA with a M/W/F IM dosing schedule.

In April 2022, we submitted an additional sBLA for intravenous, or IV, administration.

In February 2023, we received a complete response letter from FDA requesting additional clinical data on the IV administration of Rylaze.

There is no impact on the approved product labeling for Rylaze IM administration.

We also submitted a Marketing Authorization Application, or MAA, to the European Medicines Agency, or EMA, in May 2022 for M/W/F and every 48-hour dosing schedules and IV and IM administration.

Zanidatamab .

Zanidatamab is an investigational HER2-targeted bispecific antibody.

In October 2022, we entered into an exclusive licensing agreement with a subsidiary of Zymeworks Inc., or Zymeworks, providing us the right to acquire the development and commercialization rights to Zanidatamab across all indications in the U.S., Europe, Japan and all other territories except for those Asia/Pacific territories previously licensed by Zymeworks, and such agreement became effective on November 29, 2022.

In December 2022, we exercised the option to continue with the exclusive development and commercialization rights to zanidatamab.

In collaboration with Zymeworks, zanidatamab is currently being evaluated in Phase 1, Phase 2, and pivotal clinical trials as a treatment for patients with HER2-expressing cancers.

These trials include a Phase 2 trial examining zanidatamab in combination with chemotherapy, in first-line patients with HER2-expressing metastatic gastroesophageal adenocarcinoma, or GEA, a Phase 3 randomized clinical trial, evaluating zanidatamab in combination with chemotherapy plus or minus tislelizumab as a first-line treatment for HER2-expressing GEA and a pivotal Phase 2 clinical trial evaluating zanidatamab monotherapy in patients with previously treated advanced or metastatic HER2-amplified biliary tract cancers, or BTC.

Our Vyxeos clinical development strategy is designed to target potential new patient segments across the AML landscape and to generate clinical data on Vyxeos when used in combination with other therapeutic agents.

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In addition, there are multiple ongoing ISTs studying Vyxeos.

JZP815 is a pan-RAF inhibitor for the treatment of solid tumors and hematologic malignancies that contain mutations in the mitogen-activated protein kinase, or MAPK, pathway.

In October 2022, we enrolled our first patient in a Phase 1 study to investigate the safety, dosing, and initial antitumor activity of JZP815 in participants with advanced or metastatic solid tumors harboring alterations in the MAPK pathway.

CombiPlex Platform.

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Through third parties, we are also pursuing preclinical and clinical research and development activities in hematology and in precision oncology under a number of licensing and collaboration agreements, including with:

• Codiak BioSciences, Inc., or Codiak, for an exclusive, worldwide, royalty-bearing license to develop, manufacture and commercialize potential therapeutic candidates directed at up to four targets to be developed using Codiak's engEx™ precision engineering platform for exosome therapeutics;

• Pfenex, Inc., which was acquired by Ligand Pharmaceuticals Incorporated, or Ligand, for rights to JZP341, an early-stage long-acting Erwinia asparaginase;

• Codiak BioSciences, Inc., or Codiak, for an exclusive, worldwide, royalty-bearing license to develop, manufacture and commercialize potential therapeutic candidates directed at up to three targets to be developed using Codiak's engEx™ precision engineering platform for exosome therapeutics;

• Ligand Pharmaceuticals Incorporated, or Ligand, for rights to JZP341, an early-stage long-acting e rwinia asparaginase;

• XL-protein GmbH, or XLp, for rights to use XLp’s PASylation ® technology to extend the plasma half-life of selected asparaginase product candidates;

• Redx Pharma, or Redx, for preclinical collaboration activities related to the pan-Raf inhibitor program that we purchased from Redx for the potential treatment of Raf and Ras mutant tumors and to discover and develop drug candidates for two cancer targets in the Ras/Raf/MAP kinase pathway.

• Redx Pharma plc, or Redx, for preclinical collaboration activities related to the Ras/Raf/MAP kinase pathway program that we purchased from Redx;

• Werewolf Therapeutics, Inc., or Werewolf, for an exclusive, worldwide, royalty-bearing license to develop, manufacture and commercialize Werewolf's investigational WTX-613, now referred to as JZP898.

JZP898 is a differentiated, conditionally-activated interferon alpha, or IFNα, INDUKINE™ molecule.

Below is a summary of our key ongoing and planned development projects related to our products and pipeline and their corresponding current stages of development:

Product Candidates Description

Epidiolex EMAS, also known as Doose syndrome (planned study)

Nabiximols MS Spasticity (multiple studies ongoing)

Spinal cord injury spasticity (planned study)

Epidiolex EMAS, also known as Doose syndrome (ongoing trial)

LGS, TSC and DS (ongoing trial in Japan)

Suvecaltamide (JZP385)

ET (ongoing study)

PTSD (ongoing study)

Additional cannabinoids Schizophrenia (ongoing study)

Autism spectrum disorders (ongoing study)

JZP324 Oxybate extended-release formulation (planned study)

Additional cannabinoids Neonatal hypoxic-ischemic encephalopathy (ongoing study)

Neuropsychiatry targets (ongoing study)

ET (ongoing trial)

Suvecaltamide (JZP385)

Parkinson's disease tremor (ongoing trial)

PTSD (ongoing trial)

JZP541 Irritability associated with autism spectrum disorders, or ASD (planned trial)

Additional cannabinoids ASD (ongoing trial)

JZP324 Oxybate extended-release formulation (planned trial)

JZP441* Potent, highly selective oral orexin-2 receptor agonist (ongoing trials in Japan and the U.S.)

Additional cannabinoids Neonatal hypoxic-ischemic encephalopathy (completed study)

Neuropsychiatry targets (ongoing trial)

Undisclosed targets Neuroscience

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FDA approval in June 2021;

announced completion of sBLA submission to FDA in January seeking approval for Monday/Wednesday/Friday intramuscular dosing schedule;

regulatory submission planned for Europe in mid-2022

Zepzelca First-line extensive stage SCLC in combination with Tecentriq (collaboration with Roche) (ongoing study)

Confirmatory Study (Pharma Mar study) (ongoing study)

Vyxeos AML or high-risk Myelodysplastic Syndrome, or MDS (AML18) (cooperative group studies) (ongoing study) Newly diagnosed adults with standard- and high-risk AML (AML Study Group cooperative group study) (ongoing study) Newly diagnosed pediatric patients with AML (Children’s Oncology Group cooperative group study) (ongoing study)

Zepzelca Basket trial including urothelial cancer, large cell neuroendocrine tumor of the lung, and HRD+ (homologous recombinant deficient) cancers (ongoing study)

Vyxeos High-risk MDS (European Myelodysplastic Syndromes Cooperative Group cooperative group study) (ongoing study)

Newly diagnosed older adults with high-risk AML (cooperative group study) (planned study)

Vyxeos + venetoclax De novo or relapsed/refractory, or R/R, AML (MD Anderson collaboration study) (ongoing study)

Vyxeos Low intensity dosing for higher risk MDS (MD Anderson collaboration study) (ongoing study)

Vyxeos + other approved therapies R/R AML or hypomethylating agent failure MDS (MD Anderson collaboration study) (ongoing study)

First-line, fit AML (Phase 1b study) (ongoing study)

Low intensity therapy for first-line, unfit AML (Phase 1b study) (ongoing study)

approval for M/W/F IM dosing schedule in November 2022;

received complete response letter from FDA requesting additional data on the IV administration of Rylaze in February 2023;

submitted MAA to EMA in May 2022

Zepzelca First-line extensive stage SCLC in combination with Tecentriq (collaboration with Roche) (ongoing trial)

Confirmatory Study (Pharma Mar study) (ongoing trial)

Zanidatamab HER2-positive gastroesophageal adenocarcinoma, or GEA (ongoing trial)

Vyxeos AML or high-risk Myelodysplastic Syndrome, or MDS (AML18) (cooperative group studies) (ongoing trial) Newly diagnosed adults with standard- and high-risk AML (AML Study Group cooperative group study) (ongoing study) Newly diagnosed pediatric patients with AML (Children’s Oncology Group cooperative group study) (ongoing trial)

Pivotal Phase 2

Zanidatamab Previously treated, advanced HER2-expressing biliary tract cancer, or BTC (ongoing trial)

Zepzelca Basket trial including urothelial cancer, PD-NECs and HRD cancers (ongoing trial)

Vyxeos High-risk MDS (European Myelodysplastic Syndromes) (cooperative group study) (ongoing trial)

Newly diagnosed untreated patients with high-risk AML (cooperative group study) (planned trial)

Vyxeos + venetoclax De novo or relapsed/refractory, or R/R, AML (MD Anderson collaboration study) (ongoing trial)

Zanidatamab HER2-expressing GEA, BTC or colorectal cancer in combination with standard first-line chemotherapy (ongoing trial)

Zanidatamab Previously treated HER2+HR+ breast cancer in combination with palbociclib

Zanidatamab First line breast cancer and GEA (BeiGene trial) (ongoing trial)

Zanidatamab HER2-expressing breast cancer in combination with ALX148 (ongoing trial)

Vyxeos + other approved therapies First-line, fit AML (ongoing trial)

Low intensity therapy for first-line, unfit AML (ongoing trial)

Vyxeos Low intensity dosing for higher risk MDS (MD Anderson collaboration study) (ongoing trial)

Vyxeos + other approved therapies R/R AML or hypomethylating agent failure MDS (MD Anderson collaboration study) (ongoing trial)

JZP815 Raf and Ras mutant tumors (acquired from Redx) (ongoing trial)

Zanidatamab In previously treated metastatic HER2-expressing cancers in combination with select antineoplastic therapies (ongoing trial)

JZP341 (long-acting e rwinia asparaginase)

Solid tumors (licensed from Ligand) (ongoing trial)

Hematology/oncology exploratory activities

JZP341 (long-acting Erwinia asparaginase)

ALL and other hematological malignancies (collaboration with Ligand)

Pan-Raf inhibitor program Raf and Ras mutant tumors (acquired from Redx, which is continuing development)

Undisclosed targets Ras/Raf/MAP kinase pathway (collaboration with Redx)

Exosome targets (up to 4) Hematological malignancies/solid tumors (collaboration with Codiak BioSciences, Inc., or Codiak)

JZP898 Conditionally-activated IFNα INDUKINE™ molecule

Undisclosed target Ras/Raf/MAP kinase pathway (collaboration with Redx)

Exosome targets (up to 3) Hematological malignancies/solid tumors (collaboration with Codiak)

Undisclosed targets Oncology

As a result of the effects of the COVID-19 pandemic, we have taken measures to implement remote and virtual approaches, including remote data monitoring where possible, to maintain patient safety and trial continuity and to preserve study integrity.

For a more detailed discussion of the impact of the COVID-19 pandemic on our clinical trial activities, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Overview—COVID-19 Business Update” in Part II, Item 7 of this Annual Report on Form 10‑K and “Risk Factors” in Part I, Item 1A of this Annual Report on Form 10‑K.

*Also known as DSP-0187

Commercialization Activities

We have commercial operations primarily in the U.S., Europe and Canada.

In the U.S., our products are commercialized through a number of teams, including a team of experienced, trained sales professionals who provide education and promote Xywav, Xyrem, Epidiolex, Sunosi, Zepzelca, Rylaze, Vyxeos and Defitelio to healthcare providers in the appropriate specialties for each product, a team that interacts with payors and institutions to ensure access and coverage for the products, and a team that distributes the products throughout the U.S.

We have direct Jazz commercial operations in the U.S., Europe, Australia and Canada and a network of commercial distributors that represent our commercial interests in other key markets across the globe.

In the U.S., our products are commercialized through a number of teams, including a team of experienced, trained sales professionals who provide education and promote Xywav, Xyrem, Epidiolex, Zepzelca, Rylaze, Vyxeos and Defitelio to healthcare providers in the appropriate specialties for each product, a team that interacts with payors and institutions to ensure access and coverage for the products, and a team that distributes the products throughout the U.S.

healthcare system (wholesalers, pharmacies, hospitals, and community and academic institutions) and provides patient services.

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In markets where these products either are not approved or are unable to be promoted under local regulation, we have medical affairs personnel responsible for responding to medical information requests and for providing information consistent with local treatment protocols with respect to such products.

In certain European markets, we have a sales team and a team of medical science liaisons supporting our rolling launches of Epidyolex and Sunosi.

Outside the U.S., we directly market Xyrem, Sunosi and Zepzelca in Canada.

We also utilize distributors in certain markets outside the U.S.

where we do not market our products directly.

Other commercial activities include marketing related services, industry analytics and insights, distribution services and commercial support services.

In certain European markets, we have a sales team and a team of medical science liaisons supporting our rolling launch of Epidyolex.

In addition, we directly market Xyrem and Zepzelca in Canada.

Other commercial activities include marketing related services, pricing and access, industry analytics and insights, distribution services and commercial support services.

We employ third party vendors, such as advertising agencies, market research firms and suppliers of marketing and other sales support-related services, to assist with our commercial activities.

We also provide reimbursement support for our U.S.

We also provide reimbursement and patient assistance support for our U.S.

We intend to scale the size of our sales force as appropriate to effectively reach our target audience in the specialty markets in which we currently operate.

We promote Zepzelca, Rylaze, Vyxeos and Defitelio to many hematology and oncology specialists who operate in the same hospitals and outpatient clinical sites, and we believe that we benefit from operational synergies from this overlap.

We expect that a potential launch of Rylaze in Europe would require minimal additional support.

Continued growth of our current marketed products and the launch of any future products may require a

reevaluation of our field force and support organization in and outside the U.S.

In addition, beginning in March 2020, we transitioned our field-based sales, market access, reimbursement and medical employees out of the field and suspended work-related travel and in-person customer interactions as a result of the COVID-19 pandemic.

We utilized technology to continue to engage healthcare professionals and other customers virtually to support patient care.

In late June 2020, as clinics and institutions began to allow in-person interactions pursuant to local health authority and government guidelines, our field teams resumed in-person interactions with healthcare professionals and clinics combined with virtual engagement.

The level of renewed engagement varies by account, region and country.

There continues to be some negative impact on demand, new patient starts and treatments for our products arising from the pandemic, primarily due to the inherent limitations of telemedicine and a reprioritization of healthcare resources toward COVID-19.

As healthcare systems have adapted to cope with the ongoing situation, we have seen improvements.

The lack of access to health care providers has caused, and may continue to cause, delays in appropriate diagnosis, treatment and ongoing care for some patients, which could subsequently impact prescribing and use of our products.

For a more detailed discussion of the impact of the COVID-19 pandemic on our commercialization activities, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Overview—COVID-19 Business Update” in Part II, Item 7 of this Annual Report on Form 10‑K.

We expect that a potential launch of Rylaze in Europe, if approved, would be executed primarily through our existing team.

Continued growth of our current marketed products and the launch of any future products may require a reevaluation of our field force and support organization in and outside the U.S.

Human Capital Management and Environment, Health and Safety

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As of February 17, 2023, Jazz employed approximately 2,800 people worldwide, of which approximately 48% were employed in the U.S.

and approximately 50% were outside the U.S.

and approximately 52% were employed outside the U.S.

primarily in the U.K., Ireland and across the European Union, or EU.

As an innovative biopharmaceutical company, we have over 700 full-time employees — greater than 22% of our global workforce — supporting our research and development activities.

As an innovative biopharmaceutical company, we have over 700 full-time employees — representing approximately 25% of our global workforce — supporting our research and development activities.

We consider our employee relations to be very good.

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We seek to surround underrepresented groups with allies to enable all employees to thrive equitably.

Our Board and management team are committed to fostering DEIB in all parts of our business.

Our board of directors and management team are committed to fostering DEIB in all parts of our business.

Our DEIB strategy includes:

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In this regard, we have made some meaningful progress, as demonstrated by the following, as of February 17, 2023:

• 50% of each of our board of directors and Executive Committee is diverse in terms of gender, ethnicity and sexual orientation.

• 50% of our board of directors and 55% of our executive committee is diverse in terms of gender, ethnicity and sexual orientation.

• Females represent 54% of our global workforce and 46% at the leadership level (employees at executive director and above).

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workforce and 19% at the leadership level.

While we are proud of what we have accomplished to date, we recognize there is still much to do.

We remain committed to furthering our goals of providing a diverse, equitable and inclusive workplace that is supportive of all backgrounds, including among our broader leadership.

While we are proud of what we have accomplished to date, we remain committed to furthering our goals of providing a diverse, equitable and inclusive workplace that is supportive of all backgrounds, including among our broader leadership.

Employee Engagement.

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We believe employee engagement and the power of our employee voices is foundational to strong performance.

We have transparent and regular communication channels with our employees consisting of many forms – including all employee meetings, regular communication messages from executive leadership, top leadership forums, pulse check feedback mechanisms and engagement surveys.

Our employee feedback surveys are designed to help us measure overall employee engagement and we consistently achieve participation rates between 80 to 90% in our annual engagement survey.

We consistently have high levels of engagement measured by feelings of connection to our mission, Jazz as a great place to work where their well-being is supported and they feel valued and included.

It also provides important insight into the areas where we need to focus in the year ahead for several key components of our company objectives, such as decision-making, opportunities for development, and diversity, equity and inclusion.

We have transparent and regular communication channels with our employees consisting of many forms – including all employee meetings, regular communication messages from executive leadership, town halls, top leadership forums, pulse check feedback mechanisms and engagement surveys.

Our employee feedback surveys are designed to help us measure overall employee engagement as well as gather insights on other important areas of our employee experience, and we consistently achieve participation rates above 75%.

We consistently have high levels of engagement as measured by feelings of connection to our purpose, as well as Jazz being considered a good place to work by our employees.

Our surveys also provide important insight into the areas where we have opportunities to focus, such as decision-making, planning and prioritizing work, and creating a greater sense of belonging.

Our survey informs programs and activities aligned with achieving our corporate objectives and achieving our goal of evolving our operating culture for agility and scalability.

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We believe there is ample opportunity for growth and development at Jazz and there is not a one size fits all approach to growing our talent.

We strive to create the best career experience for all of our employees.

We work with each employee to chart their own course that matches their career ambitions and strengths with customized development.

We strive to create the best career experience for all of our employees, and encourage them to have regular dialogue with their leadership to create meaningful career development plans.

Our performance management process supports our culture of continual feedback and coaching, and ongoing growth and development through new experiences and learning.

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We deliver our “Harmonize” program to all managers to ensure they are grounded in our core Leadership Behaviors we expect all leaders to demonstrate (Instills Trust, Values Differences, Executes through Teams, Develops Talent, Drives Accountability and Provides and Receives Feedback).

In 2021, we targeted a development effort towards our Global Leadership Team (top 70 leaders) and created a 9-month learning journey to build leadership excellence, strengthen relationships, and encourage cross functional collaboration in pursuit of our enterprise strategic goals.

Additionally, we focused on diverse early career talent by piloting an executive coaching program to support their development.

We offer tuition reimbursement in our major markets aimed at growth and career development.

In 2022, we continued to develop our top leadership, or Global Leadership Team (top 70 leaders), to build leadership excellence, strengthen relationships, and encourage cross functional collaboration in pursuit of our enterprise strategic goals.

Additionally, we continue to focus on diverse early career talent by piloting an executive coaching program to support their development.

We continue to offer tuition reimbursement in our major markets aimed at growth and career development.

Our management and leadership teams place significant focus and attention to diversity, capability development, and succession planning for critical roles.

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In addition to traditional employee benefits, Jazz supports employees and their families through access to a suite of innovative programs that are designed to enhance their physical, financial, emotional and social well-being.

For 2022, we are introducing an enhanced suite of differentiated global leave and time-off polices to address the needs of our diverse employee population through varying stages of life, including minimum standards for new parent leave (irrespective of gender or how a family is created), family caregiver leave, and bereavement leave.

Additionally, in 2022, we are launching a new global volunteer day, which will provide employees time off with full pay to give back to their communities.

Workplace Safety & Employee Care During COVID-19 .

In 2022, we introduced an enhanced suite of differentiated global leave and time-off polices to address the needs of our diverse employee population through varying stages of life, including minimum standards for new parent leave (irrespective of gender or how a family is created), family caregiver leave, and bereavement leave.

Additionally, in 2022, we launched a new global volunteer day, to provide employees time off with full pay to give back to their communities.

Workplace Safety & Employee Care .

Workplace safety is always a top priority for Jazz.

To create and sustain a safe and healthy workplace, we have implemented initiatives designed to address risk evaluation, education and training of employees, use of appropriate personal protective equipment, and compliance with relevant national and international health and safety standards.

In response to COVID-19, we launched an employee support framework focused on Care, Connection, Continuity and Consciousness (our “4Cs”) to enable our employees to live into our values and support one another while doing everything we can to deliver on our patient mission.

Important to this framework were new leader expectations and tools given the rise and complexity of emerging employee demands and needs – including more flexibility to address personal needs, a greater connection to understand the whole person and their lives, and more active support surrounding social injustice.

For example, we provided productivity and collaboration tools and resources for employees working remotely, including training and toolkits to help leaders effectively lead and manage remote teams;

We leverage an employee support framework focused on Care, Connection, Continuity and Consciousness (our “4Cs”) to enable our employees to live into our values and support one another while doing everything we can to deliver on our patient mission.

Important to this framework are new leader expectations and tools given the rise and complexity of emerging employee demands and needs – including more flexibility to address personal needs, a greater connection to understand the whole person and their lives, and more active support surrounding social injustice.

We provide productivity and collaboration tools and resources for employees working remotely, including training and toolkits to help leaders effectively lead and manage remote teams;

increased flexibility within work schedules and leave programs to support employees caring for children and others;

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and increased investment in resources focused on inclusion and belonging.

Through direct input from employees, external insights and best practices, we developed our flexible working model and expanded the power of intentional collaboration and our ability to more effectively manage our global and highly distributed team workforce.

This approach to work, called “Jazz Remix,” aims to provide eligible employees with the greatest flexibility and agility to globally connect, collaborate, innovate and perform.

Environment, Health and Safety .

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Generic competition often results in decreases in the prices at which branded products can be sold.

We are aware of:

exploratory research into the effects of THC and CBD drug formulations;

discovery research within the pharmaceutical industry into synthetic agonists and antagonists of CB1 and CB2 receptors;

companies that supply synthetic cannabinoids and cannabis extracts to researchers for pre-clinical and clinical investigation;

and various companies that cultivate cannabis plants with a view to supplying herbal cannabis or nonpharmaceutical cannabis-based formulations to patients.

These activities have not been approved by the FDA but may in the future compete with our products.

In particular, our products and most advanced product candidates face or may face competition as described below:

• Xywav and Xyrem .

While Xywav and Xyrem are currently the only products approved by FDA and marketed in the U.S.

for the treatment of both cataplexy and EDS in both adult and pediatric patients with narcolepsy, we and others have launched products to treat EDS in narcolepsy and may in the future launch products to treat cataplexy in narcolepsy that are competitive with or disrupt the market.

We expect to face competition from authorized generic and generic versions of sodium oxybate.

For a description of generic versions of sodium oxybate and/or new products for the treatment of cataplexy and/or EDS that could compete with, or otherwise disrupt the market for, Xywav and Xyrem, as well as a description of our settlement agreements with abbreviated new drug application, or ANDA, filers, see the risk factor under the heading “ The introduction of new products in the U.S.

Xywav and Xyrem are approved by FDA and marketed in the U.S.

for the treatment of both cataplexy and EDS in both adult and pediatric patients with narcolepsy.

We and others have launched products to treat EDS in narcolepsy and may in the future launch products to treat cataplexy in narcolepsy that are competitive with or disrupt the market.

An authorized generic version of sodium oxybate launched in January 2023 and in the future we expect competition from other authorized generic and generic versions of sodium oxybate.

For a description of generic versions of sodium oxybate and/or new products for the treatment of cataplexy and/or EDS that currently compete or could in the future compete with, or otherwise disrupt the market for, Xywav and Xyrem, as well as a description of our settlement agreements with abbreviated new drug application, or ANDA, filers, see the risk factor under the heading “ The introduction of new products in the U.S.

market that compete with, or otherwise disrupt the market for, our oxybate products and product candidates would adversely affect sales of our oxybate products and product candidates” in Part I, Item 1A of this Annual Report on Form 10‑K.

In addition to generic competition, Xywav and Xyrem may face competition in the future from other new sodium oxybate formulations for treatment of narcolepsy.

In February 2021, FDA accepted for filing an NDA submitted by Avadel Pharmaceuticals plc, or Avadel, for an extended-release formulation of sodium oxybate which uses its proprietary technology for the treatment of EDS and cataplexy in patients with narcolepsy with a Prescription Drug User Fee Act, or PDUFA, target action date of October 15, 2021.

On October 15, 2021, Avadel announced that FDA review is ongoing and FDA will likely not take action in October 2021 and will provide a new target action date.

To obtain approval with ODE, Avadel will have to show clinical superiority to Xywav and Xyrem.

We cannot predict the timing or approvability of Avadel’s sodium oxybate product candidate or how FDA will evaluate any clinical superiority arguments that either we or Avadel may make, but in any event, we expect to face competition from Avadel, if its product candidate is approved.

Xywav and Xyrem may also face increased competition from new branded entrants to treat EDS or cataplexy in narcolepsy such as pitolisant, which has been approved by FDA for the treatment of both cataplexy and EDS in adult patients with narcolepsy.

Other companies have announced that they have product candidates in various phases of development to treat the symptoms of narcolepsy, such as Axsome Therapeutics, Inc.’s reboxetine, and various companies are performing research on orexin agonists for the treatment of sleep disorders.

In addition, we are also aware that prescribers often prescribe branded or generic medications for cataplexy before prescribing or instead of prescribing oxybate therapy in Xywav or Xyrem, and that payors often require patients to try such medications before they will cover Xywav or Xyrem, even if they are not approved for this use.

In July 2022, Avadel Pharmaceuticals plc, or Avadel, announced that it had received tentative FDA approval of FT218, an extended-release formulation of sodium oxybate which uses its proprietary technology for the treatment of EDS and cataplexy in patients with narcolepsy, and pending disposition of our REMS patent, Avadel stated that it is seeking to accelerate full approval.

For additional information on litigation involving this matter, see “ Avadel Patent Litigation ” in Note 14, Commitments and Contingencies-Legal Proceedings of the Notes to Consolidated Financial Statements, included in Part IV of this Annual Report on Form 10‑K.

Moreover, Avadel has announced that it has obtained an orphan drug designation from FDA related to its extended-release sodium oxybate formulation.

To obtain approval in light of the prior

approval of our oxybate products and to obtain its own Orphan Drug Exclusivity for FT218 if approved, we believe Avadel will have to show clinical superiority to Xywav, which requires establishing that FT218 has greater effectiveness, greater safety, or otherwise makes a major contribution to patient care when compared to our products.

We cannot predict the timing of full approval of Avadel’s sodium oxybate product or how FDA will evaluate any clinical superiority arguments that either we or Avadel may make, but in any event, we expect to face competition from Avadel.

Non-oxybate products intended for the treatment of EDS or cataplexy in narcolepsy or IH (Xywav is the first and only FDA-approved therapy to treat IH), including new market entrants, even if not directly competitive with Xywav or Xyrem, could have the effect of changing treatment regimens and payor or formulary coverage of Xywav or Xyrem in favor of other products, and indirectly materially and adversely affect sales of Xywav and Xyrem.

Xywav and Xyrem may face increased competition from new branded entrants to treat EDS or cataplexy in narcolepsy such as pitolisant, which has been approved by FDA for the treatment of both cataplexy and EDS in adult patients with narcolepsy.

Pitolisant is also in late-stage development for the treatment of IH.

Other companies have announced that they have product candidates in various phases of development to treat the symptoms of narcolepsy, such as Axsome’s reboxetine, and various companies are performing research on orexin agonists for the treatment of sleep disorders, including Takeda Pharmaceutical Company Limited and Alkermes plc.

In addition, we are also aware that prescribers often prescribe branded or generic medications for cataplexy before prescribing or instead of prescribing oxybate therapy, and that payors often require patients to try such medications before they will cover Xywav or Xyrem, even if they are not approved for this use.

For example, prescribers often treat mild cataplexy with drugs that have not been approved by FDA for this indication, including tricyclic antidepressants and selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitors.

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Patients in the U.S.

suffering from seizures associated with Dravet or LGS are treated with a variety of FDA-approved products, including clobazam, clonazepam, valproate, lamotrigine, levetiracetam, rufinamide, topiramate, ethosuximide, and zonisamide.

FDA approved Zogenix, Inc.'s low-dose fenfluramine, or Fintepla, in DS in June 2020, and Zogenix submitted its supplemental NDA for LGS in 2021.

In January 2022, Zogenix announced that it entered into a definitive agreement with UCB S.A.

for the acquisition of Zogenix by UCB.

Ovid Therapeutics Inc./Takeda Pharmaceutical Company Limited and Marinus Pharmaceuticals, Inc.

are developing therapies for treating Developmental and Epileptic Encephalopathies (includes Dravet and LGS).

suffering from seizures associated with DS or LGS are treated with a variety of FDA-approved products, including clobazam, clonazepam, valproate, lamotrigine, levetiracetam, rufinamide, topiramate, ethosuximide, and zonisamide.

FDA approved Zogenix, Inc.'s low-dose fenfluramine, or Fintepla, in DS in June 2020, and for LGS in March 2022.

In March 2022, UCB S.A.

announced that it had completed its acquisition of Zogenix.

FDA approved Marinus Pharmaceuticals, Inc.’s ganaxolone for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in March 2022.

Ovid Therapeutics Inc./Takeda Pharmaceutical Company Limited and Eisai Company Limited are developing therapies for treating Developmental and Epileptic Encephalopathies (includes DS and LGS).

Stiripentol has been approved in Europe for several years to treat DS and was approved in 2018 by the FDA.

Zynerba Pharmaceuticals, Inc.

is developing a topical formulation of CBD, for which it is working with FDA on a path forward on CONNECT-FX data for Zygel in Fragile X syndrome.

is developing a topical formulation of cannabidiol, or CBD, for which it is working with FDA on a path forward on CONNECT-FX data for Zygel in Fragile X syndrome.

There are a number of public and private companies in the early stages of developing genetic therapies for DS, including Stoke Therapeutics, Inc., which has an antisense oligonucleotide, STK-001, in early clinical trials.

Sunosi faces competition from existing branded and generic products that treat EDS or improve wakefulness in adult patients with narcolepsy or OSA in a competitive retail pharmacy market.

To successfully commercialize Sunosi, we need to differentiate Sunosi from other branded and generic products that treat EDS in patients with narcolepsy, including stimulants, wake-promoting agents, such as modafinil and armodafinil, and generic versions of stimulants and wake-promoting agents.

We are also aware that stimulants are prescribed off-label for patients to treat excessive sleepiness in OSA.

Sunosi faces competition from new branded entrants such as pitolisant, a drug that was approved by FDA in August 2019 for the treatment of EDS in adult patients with narcolepsy and in October 2020 for the treatment of cataplexy in adult patients with narcolepsy.

Pitolisant became commercially available in the U.S.

in the fourth quarter of 2019, and has also been approved and marketed in Europe to treat adult patients with narcolepsy,

with or without cataplexy, and OSA.

Sunosi may also face competition from other products in development as potential treatments for EDS in patients with narcolepsy or OSA.

• Nabiximols.

Nabiximols aims to treat adult patients with MS-related spasticity.

Patients in the U.S.

suffering from MS-related spasticity are currently treated with a variety of FDA-approved therapies such as baclofen, tizanidine, gabapentin, dantrolene and various botulinum toxin products.

Bionorica SE is in late stage development of an oral solution containing dronabinol for spasticity due to MS.

Ipsen and Echo pharmaceuticals are in the early stages of development with various oral products aimed to treat MS-related spasticity.

Zepzelca faces competition from topotecan, which is also an approved treatment in second line SCLC in the U.S., as well as other regimens for relapsed SCLC currently recommended in compendia guidelines.

In addition, there are non-FDA approved CBD preparations being made available from companies in the medical marijuana industry, which might attempt to compete with Epidiolex.

While federal law prohibits the sale and distribution of most marijuana products not approved or authorized by FDA, the vast majority of states and the District of Columbia have legalized either CBD or marijuana for either recreational or medical use, or both.

Under the U.S.

Farm Bill, enacted in late 2018, certain extracts and other material derived from cannabis are no longer controlled under the Federal Controlled Substances Act, or CSA.

However, the marketing of such products as a food, dietary supplement, or for medical purposes remains subject to FDA requirements.

With respect to the marketing of CBD as a food or dietary supplement, in January 2023 FDA concluded that the existing regulatory frameworks for foods and supplements were not appropriate for CBD products and denied three citizen petitions that had asked the agency to conduct rulemaking to allow the marketing of CBD products as dietary supplements.

In addition, Congressional efforts related to legalization of marijuana continue.

Although our business is distinct from that of entities marketing FDA-unapproved marijuana and CBD-containing dietary supplement, future legislation or federal government action authorizing the sale, distribution, use, and insurance reimbursement of non-FDA approved marijuana or CBD products could increase competition for and adversely affect our ability to generate sales of Epidiolex and our cannabinoid product candidates.

We are aware of:

exploratory research into the effects of tetrahydrocannabinol, often referred to as THC, and CBD drug formulations;

discovery research within the pharmaceutical industry into synthetic agonists and antagonists of CB1 and CB2 receptors;

companies that supply synthetic cannabinoids and cannabis extracts to researchers for pre-clinical and clinical investigation;

and various companies that cultivate cannabis plants with a view to supplying

herbal cannabis or nonpharmaceutical cannabis-based formulations to patients.

These activities have not been approved by the FDA but may in the future compete with our products.

Moreover, we expect that Epidiolex will face competition from generic products in the future.

In November and December 2022, we received notices from various ANDA filers that they have each filed with FDA an ANDA for a generic version of Epidiolex (cannabidiol) oral solution.

In January 2023, we filed patent infringement suits against these ANDA filers.

For a description of this litigation, see “ Epidiolex Patent Litigation ” in Note 14, Commitments and Contingencies-Legal Proceedings of the Notes to Consolidated Financial Statements, included in Part IV of this Annual Report on Form 10‑K.

As a result of these lawsuits, we expect that a stay of approval of up to 30 months will be imposed by FDA on these ANDA filers.

There are also a number of products and immunotherapies for the treatment of second line SCLC in various phases of development.

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In April 2020, Porton Biopharma Limited, or PBL, granted Clinigen Group plc, or Clinigen, a global license for Erwinase.

However, in December 2021, Clinigen announced that FDA has issued a Complete Response Letter to PBL’s BLA for Erwinaze, indicating that the BLA cannot be approved in its current form.

Rylaze may also face competition from other companies who have developed or are developing new treatments for ALL, including an L-asparaginase product candidate that is in development for the treatment of ALL patients.

However, in December 2021, Clinigen announced that FDA issued a complete response letter to PBL’s BLA for Erwinaze, indicating that the BLA cannot be approved in its current form.

Rylaze may also face competition from other companies who have developed or are developing new treatments for ALL.

In addition, some new asparaginase treatments could reduce the rate of hypersensitivity in patients with ALL, and new treatment protocols are being developed and approved for ALL that may not include asparaginase-containing regimens, including some for the treatment of relapsed or refractory ALL patients.

As a biologic product, Rylaze also faces potential competition from biosimilar products.

With respect to Vyxeos, there are a number of alternative established therapies in AML.

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Also in the U.S., Epidiolex is sold to specialty pharmacies, wholesalers and specialty distributors.

Sunosi is distributed through a retail channel consisting of numerous distributors who sell Sunosi to retail pharmacies.

Defitelio is sold to hospital customers through subsidiary specialty distributors of McKesson Corporation, or McKesson.

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Purchases are made on a purchase order basis.

In certain countries in Europe, Sunosi, Defitelio and Vyxeos are sold pursuant to marketing authorizations.

We distribute these products through Durbin PLC, a U.K.-based wholesaler and distributor, and O&M Movianto Nederland BV, our centralized European logistics services provider, to hospitals and local wholesalers in Europe where we market these products

directly and, in other markets in Europe and elsewhere where we do not market these products directly, to local distributors and wholesalers.

In certain countries in Europe, Defitelio and Vyxeos are sold pursuant to marketing authorizations.

in other markets in Europe and elsewhere where we do not market these products directly, to local distributors and wholesalers.

In certain countries in Europe, Epidyolex is sold pursuant to marketing authorizations.

We distribute Epidyolex through a variety of wholesalers and distributors.

Sativex is sold outside of the United States for the treatment of spasticity due to MS, pursuant to license agreements with commercial partners and directly to customers in the U.K.

In countries where there is no marketing authorization, Defitelio, Vyxeos, Epidyolex and Sativex are sold pursuant to named patient programs, temporary use authorizations or similar authorizations.

In countries where there is no marketing authorization, Defitelio, Vyxeos and Epidyolex are available pursuant to named patient programs, temporary use authorizations or similar authorizations in accordance with local regulations controlling the medical use of unapproved products.

We directly market Xyrem in Canada for the treatment of cataplexy in patients with narcolepsy.

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Manufacturing

We have a manufacturing and development facility in Athlone, Ireland where we manufacture Xywav and Xyrem, a manufacturing and development facility in the U.K.

in Kent Science Park, where we produce Epidiolex/Epidyolex and Sativex, and a manufacturing plant in Villa Guardia, Italy where we produce the defibrotide drug substance.

We currently do not have our own commercial manufacturing or packaging capability for our other products, product candidates or their APIs.

As a result, our ability to develop and supply products in a timely and competitive manner depends primarily on third party suppliers being able to meet our ongoing commercial and clinical trial needs for API, other raw materials, packaging materials and finished products.

We have a manufacturing and development facility in Athlone, Ireland where we manufacture Xywav and Xyrem, a manufacturing and development facility in Kent Science Park, U.K.

where we produce Epidiolex/Epidyolex, and a manufacturing plant in Villa Guardia, Italy where we produce defibrotide drug substance.

We currently do not have our own commercial manufacturing or packaging capability for our other products, product candidates or their active pharmaceutical ingredients, or APIs.

As a result, our ability to develop and supply products in a timely and competitive manner depends on third party suppliers being able to meet our ongoing commercial and clinical trial needs for API, other raw materials, packaging materials and finished products.

Our manufacturing facilities currently continue to be operational with essential staff onsite and office-based staff working onsite and remotely as business needs require.

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As a result, Xywav and Xyrem are subject to regulation by the U.S.

Drug Enforcement Administration, or DEA, under the Federal Controlled Substances Act, or CSA, and its manufacturing and distribution are highly restricted.

Quotas from the DEA are required in order to manufacture and package calcium, magnesium, potassium and sodium oxybate, Xywav and Xyrem in the U.S.

Drug Enforcement Administration, or DEA, under the CSA, and its manufacturing and distribution are highly restricted.

Quotas from the DEA are required in order to manufacture or procure calcium, magnesium, potassium and sodium salts of gamma-hydroxybutyric acid in the U.S.

For information related to DEA quota requirements, see “Business—Government Regulation—Other Post-Approval Pharmaceutical Product Regulation—Controlled Substance Regulations” in this Part I, Item 1.

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under highly controlled and standardized conditions.

Siegfried AG is our sole supplier of both the API and finished product for Sunosi for both commercial sale as well as development activities.

Although Siegfried AG is currently our only manufacturer and supplier of Sunosi, we have the right to purchase a portion of our worldwide requirements of API and drug product from other suppliers.

Under our agreement, we provide periodic rolling forecasts to Siegfried AG, and a portion of each rolling forecast is binding.

The initial term of the agreement with Siegfried AG will expire in December 2024 and will then be subject to automatic one-year extensions until either party provides advance notice of its intent to terminate the agreement.

Solriamfetol, the API of Sunosi, and Sunosi were designated Schedule IV controlled substances by the DEA under the CSA.

Sativex is manufactured by us in our Kent Science Park facility in the U.K.

Sativex (nabiximols) is a complex botanical mixture formulated from extracts of the cannabis sativa plant that contains the principal cannabinoids THC and CBD as well as specific minor cannabinoids and other non-cannabinoid components.

We cultivate our cannabinoid plants in the U.K.

under highly controlled and standardized conditions.

Zepzelca is manufactured by Baxter.

The initial term of the agreement with Baxter will expire in December 2023 and will then be subject to automatic two-year extensions, unless either party provides advance notice of its intent to terminate the agreement.

Zepzelca is manufactured by Baxter Oncology GmbH, or Baxter.

The current term of the agreement with Baxter will expire in December 2025 and will then be subject to automatic two-year extensions, unless either party provides advance notice of its intent to terminate the agreement.

PharmaMar retains manufacturing rights for the API for U.S.

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The initial term of the agreement with AGC Biologics A/S will expire in October 2026 and will then be subject to automatic three-year extensions, unless either party provides advance notice of its intent to terminate the agreement.

Vyxeos is manufactured by Baxter Oncology GmbH, or Baxter, which is a sole source supplier from a single site location, using our CombiPlex technology platform.

CombiPlex products represent formulations with increased manufacturing complexities associated with producing drug delivery vehicles encapsulating two or more drugs that are maintained at a fixed ratio and, in the case of Vyxeos, two drugs that are co-encapsulated in a freeze-dried liposomal format.

Vyxeos is manufactured by Baxter, which is a sole source supplier from a single site location, using our CombiPlex technology platform.

CombiPlex products represent formulations with increased manufacturing complexities

associated with producing drug delivery vehicles encapsulating two or more drugs that are maintained at a fixed ratio and, in the case of Vyxeos, two drugs that are co-encapsulated in a freeze-dried liposomal format.

Our manufacturing agreement with Baxter expires in August 2025, subject to automatic three-year renewal terms, unless either party provides advance notice of its intent to terminate the agreement.

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The marketing authorization in the EU for Vyxeos also requires us to comply with certain manufacturing-related post-approval commitments.

We are our own sole supplier of, and we believe that we are currently the sole worldwide producer of, the defibrotide API.

We manufacture the defibrotide API from porcine DNA in a single facility located in Villa Guardia, Italy.

Patheon currently processes the defibrotide API into its finished vial form under a specific product agreement entered into under a separate agreement with Patheon.

We are our own sole supplier of, and we believe that we are currently the sole worldwide producer of, defibrotide API.

We manufacture defibrotide API from porcine DNA in a single facility located in Villa Guardia, Italy.

Patheon currently processes defibrotide API into its finished vial form under a specific product agreement entered into under a separate agreement with Patheon.

Patheon is the sole provider of our commercial and clinical supply of Defitelio;

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Xywav has been granted ODE by FDA to treat narcolepsy through 2027 and to treat IH through 2028.

We currently have six issued, unexpired patents in the U.S.

relating to Xyrem.

These patents are listed in FDA’s publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” or the Orange Book.

We currently have six issued patents in the U.S.

relating to Xyrem listed in FDA’s publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” or the Orange Book.

Our patents relate to Xyrem’s restricted distribution system and a drug-drug interaction, or DDI, between Xyrem and divalproex sodium.

In October 2018, as a result of FDA’s grant of pediatric exclusivity, an additional six months was added to the original expiration dates of all of our Orange Book-listed patents that existed at that time.

our Orange Book-listed patents have periods of exclusivity between December 2022 and September 2033.

As a result, our Orange Book-listed patents have periods of exclusivity between December 2022 (with an additional six months for pediatric exclusivity) and September 2033.

Some of our Xyrem patents have been subject to patent litigation with the companies who filed ANDAs seeking to market a generic version of Xyrem, including challenge through the inter partes review, or IPR, procedures of the Patent Trial and Appeal Board, or PTAB, of the U.S.

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For additional information on litigation involving or Orange Book-listed patents, see

“ Avadel Patent Litigation ” in Note 14, Commitments and Contingencies-Legal Proceedings of the Notes to Consolidated Financial Statements, included in Part IV of this Annual Report on Form 10‑K

A Xyrem formulation patent that had issued in multiple non-U.S.

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These issued patents are directly aligned with the Epidiolex label, and we have listed them in the Orange Book.

These patents have expiry between 2022 and 2041.

The patents currently listed in the Orange Book have expiry between 2035 and 2041.

We have filed corresponding patent applications in many jurisdictions worldwide, including Europe, UK, Canada, Japan, Mexico, Australia and New Zealand.

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Epidiolex has received ODE to treat seizures associated with LGS and DS through 2025 and TSC through 2027.

We acquired worldwide development, manufacturing and commercial rights to solriamfetol from Aerial BioPharma LLC, or Aerial, in 2014, including Aerial’s patent rights relating to solriamfetol, other than in certain jurisdictions in Asia where SK Biopharmaceuticals Co., Ltd.

retains rights.

We have a portfolio of U.S.

patents and patent applications for solriamfetol relating to various compositions, formulations and methods of use.

Four of our U.S.

patents are method of use patents covering treatment of sleep-related conditions expiring between 2026 and 2027 and another U.S.

patent is directed to dose escalation regimens expiring in 2038.

Two other U.S.

patents cover, respectively, the formulation of solriamfetol and the method of treating select conditions with formulations of solriamfetol (both expiring in 2037).

A request for a patent term extension for one of the above method of use patents has been filed.

Requests for Supplementary Protection Certificate in certain European validation countries for a related European patent have been granted in Austria, Denmark, France, Ireland, Italy, Netherlands, Spain and Sweden (expiring in 2031) and remain pending in the others.

Sunosi has also been granted ODE for narcolepsy and new chemical entity exclusivity in the U.S.

In the U.S., our patents (and our pending applications if they issue) relating to nabiximols would expire on various dates between 2022 and 2029, excluding possible patent term extensions.

We have at least seven different patent families containing one or more pending and/or issued patents directed to the nabiximols formulation, the medical use of nabiximols, the extracts from which nabiximols is composed, the extraction technique used to produce the extracts and the therapeutic use of nabiximols.

Due to the product’s significant complexity, we believe that nabiximols will benefit from strong long-term market regulatory protection.

In December 2019, we entered into an exclusive license agreement with PharmaMar pursuant to which we obtained exclusive U.S.

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A request for extension (CSP) has also been filed in Canada.

Zepzelca has also been granted orphan drug exclusivity for the treatment of adults with metastatic

SCLC with disease progression on or after platinum-based chemotherapy until 2027 and new chemical entity exclusivity until 2025 in the U.S.

Zepzelca has also been granted ODE for the treatment of adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy until 2027 and new chemical entity exclusivity until 2025 in the U.S.

In 2016, we obtained worldwide rights from Pfenex, Inc., including Pfenex’s patent rights relating to Rylaze, to develop and commercialize multiple early-stage hematology product candidates, including a license to two U.S.

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Pfenex has been acquired by Ligand Pharmaceuticals Incorporated.

Rylaze has been granted ODE for the treatment of patients with ALL or LBL until 2028.

Rylaze has been granted orphan drug designation for the treatment of patients with ALL or LBL.

We have two patent application families relating to dosing regimens.

One covers the current dosing regimen (25mg/m2 intramuscularly every 48 hours), while the other covers various dosing regimens of interest.

One covers the dosing regimen (25mg/m2 intramuscularly every 48 hours), while the other covers various dosing regimens of interest.

If issued, these would expire in 2040 and 2042, respectively.

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Defibrotide has been granted ODE by FDA to treat and prevent VOD until March 2023.

Defibrotide has also been granted orphan drug designation by the EC and the Korean Ministry of Food and Drug Safety to treat and prevent VOD, by the Commonwealth of Australia-Department of Health for the treatment of VOD and by the EC for the prevention of acute Graft-versus-Host Disease, or aGvHD, and have also received approvals in Canada, Brazil and Switzerland.

and have also received approvals in Canada, Brazil and Switzerland.

We acquired the rights to defibrotide for the treatment and prevention of VOD in North America, Central America and South America from Sigma-Tau Pharmaceuticals, Inc.

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composition of matter patent relating to JZP150, which expires in 2029.

Through a license agreement with Sumitomo Pharma Co., Ltd.

in 2022, we obtained a license to a portfolio of U.S.

patents and patent applications, including rights relating to compositions and methods of using JZP441.

The portfolio contains a U.S.

composition of matter patent relating to JZP441, which expires in 2040 (excluding any adjustments or extensions).

Through a collaboration agreement and an asset purchase agreement with Redx in 2019, we acquired a portfolio of U.S.

patents and patent applications, including rights relating to compositions and methods of using JZP815.

The portfolio contains a U.S.

composition of matter patent relating to JZP815, which expires in 2035 (excluding any adjustments or extensions).

• Zanidatamab .

Through a license agreement with Zymeworks BC Inc.

in 2022, we obtained a license to a portfolio of U.S.

patents and patent applications, including rights relating to compositions and methods of using zanidatamab.

The portfolio contains a U.S.

composition of matter patent relating to zanidatamab, which expires in 2034 (excluding any adjustments or extensions).

In addition, we have rights to a number of trademarks and service marks, and pending trademark and service mark applications, in the U.S.

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• conducting adequate and well-controlled human clinical trials to establish the safety and efficacy of the product candidate in the desired indication;

• submitting an NDA, sNDA, or BLA, as appropriate, to FDA seeking approval for a specific indication;

• submitting an NDA, supplemental New Drug Application, or sNDA, or Biologics License Application, or BLA, as appropriate, to FDA seeking approval for a specific indication;

• completing inspections by FDA of the facilities where the product candidate is manufactured, analyzed and stored to demonstrate compliance with current Good Manufacturing Practices, or cGMP, and any requested FDA audits of the clinical trial sites that generated the data supporting the application.

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Once accepted for filing, FDA begins an in-depth review of the application.

Under the current goals and policies agreed to by FDA under the PDUFA for a new molecular entity, FDA has ten months from the filing decision in which to complete its initial review of a standard application and respond to the applicant, and six months from the filing decision for a priority application.

Under the current goals and policies agreed to by FDA under the Prescription Drug User Fee Act, or PDUFA, for a new molecular entity, FDA has ten months from the filing decision in which to complete its initial review of a standard application and respond to the applicant, and six months from the filing decision for a priority application.

FDA does not always meet its PDUFA goal dates, and in certain circumstances, the PDUFA goal date may be extended.

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Xywav and Xyrem are required to have a REMS.

For more discussion regarding the Xywav and Xyrem REMS, see the risk factors under the headings “ The distribution and sale of our oxybate products are subject to significant regulatory restrictions, including the requirements of a REMS, and these regulatory requirements subject us to risks and uncertainties, any of which could negatively impact sales of Xywav and Xyrem ” and “Risks Related to Our Intellectual Property” in Part I, Item 1A of this Annual Report on Form 10‑K.

For more discussion regarding the Xywav and Xyrem REMS, see the risk factors under the headings “ The distribution and sale of our oxybate products are subject to significant

regulatory restrictions, including the requirements of a REMS, and these regulatory requirements subject us to risks and uncertainties, any of which could negatively impact sales of Xywav and Xyrem ” and “Risks Related to Our Intellectual Property” in Part I, Item 1A of this Annual Report on Form 10‑K.

The EU and many individual countries have regulatory structures similar to the U.S.

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Among the areas of absence of mutual recognition are batch testing and batch release.

has unilaterally agreed to accept EU batch testing and batch release for a period of at least 2 years until January 1, 2023.

has unilaterally agreed to accept EU batch testing and batch release until January 2023.

In December 2022, the U.K.

announced its decision to make permanent the approach of maintaining a list of approved countries for import into Great Britain which require no import testing or U.K.

“qualified person” release certification.

However, the EU continues to apply EU laws that require batch testing and batch release to take place in the EU territory.

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In the EU, if an applicant can demonstrate that comprehensive data on the efficacy and safety of the product under normal conditions of use cannot be provided due to certain specified objective and verifiable reasons, products may be granted marketing authorization “under exceptional circumstances.” A marketing authorization granted under exceptional circumstances is valid for five years, subject to an annual reassessment of conditions imposed by the EC.

The marketing authorization in the EU for Defitelio was granted under exceptional circumstances because it was not possible to obtain

complete information about the product due to the rarity of the disease and because ethical considerations prevented conducting a study directly comparing Defitelio with best supportive care or a placebo.

The marketing authorization in the EU for Defitelio was granted under exceptional circumstances because it was not possible to obtain complete information about the product due to the rarity of the disease and because ethical considerations prevented conducting a study directly comparing Defitelio with best supportive care or a placebo.

As a result, the marketing authorization requires us to comply with a number of post-marketing obligations, including obligations relating to the manufacture of the drug substance and finished product, the submission of data concerning patients treated with the product collected through a third-party patient registry and the establishment of a multi-center, multinational and prospective observational patient registry to investigate the long-term safety, health outcomes and patterns of utilization of Defitelio during normal use.

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Promotional activity that does not comply with the SmPC is considered off-label and is prohibited in the EU.

further limit or restrict the advertising and promotion of our products to the general public and to health care professionals.

Other applicable laws at the EU level and in the individual EU member states also apply to the advertising and promotion of medicinal products, including laws that prohibit the direct-to-consumer advertising of prescription-only medicinal products and further limit or restrict the advertising and promotion of our products to the general public and to health care professionals.

Violations of the rules governing the promotion of medicinal products in the EU could be penalized by administrative measures, fines and imprisonment.

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The statute has been interpreted to apply to arrangements between pharmaceutical companies on one hand and patients, prescribers, purchasers and formulary managers on the other.

Although there are a number of statutory exemptions and regulatory safe harbors protecting certain common manufacturer business arrangements and activities from prosecution and administrative sanction, the exemptions and safe harbors are drawn narrowly and are subject to regulatory revision or changes in interpretation by the U.S Department of Justice, or DOJ, and the Office of Inspector General of the U.S.

and are subject to regulatory revision or changes in interpretation by the U.S.

Department of Justice, or DOJ, and the Office of Inspector General of the U.S.

Department of Health and Human Services, or OIG.

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If, upon review, an authority determines that any events and/or reports indicate a trend or signal, they can require a change in a product label, restrict sales and marketing, require post-approval safety studies, require a labor intensive collection of data regarding the risks and benefits of marketed products and ongoing assessments of those risks and benefits and/or require or conduct other actions, potentially including withdrawal or suspension of the product from the market.

For example, if the EMA has concerns that the risk-benefit profile of a product has changed, it can, following an investigation

procedure, adopt an opinion advising that the existing marketing authorization for the product be varied or suspended and requiring the marketing authorization holder to conduct post-authorization safety studies.

For example, if the EMA has concerns that the risk-benefit profile of a product has changed, it can, following an investigation procedure, adopt an opinion advising that the existing marketing authorization for the product be varied or suspended and requiring the marketing authorization holder to conduct post-authorization safety studies.

The opinion is then submitted for approval by the EC.

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The Physician Payment Sunshine Act requires tracking of payments and transfers of value to physicians and teaching hospitals and ownership interests held by physicians and their families, and reporting to the federal government and public disclosure of these data.

Beginning in 2022, reporting will also be required of information regarding payments and transfers of value provided to physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, and certified nurse-midwives.

Beginning in 2022, reporting is required of information regarding payments and transfers of value provided to physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, and certified nurse-midwives.

A number of states now require pharmaceutical companies to report expenses relating to the marketing and promotion of pharmaceutical products and to report gifts and payments to healthcare providers in the states.

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Pharmaceutical products approved for use in the U.S.

may be listed as Schedule II, III, IV or V, with Schedule II substances considered to present the highest potential for abuse or dependence and Schedule V substances the lowest relative risk of abuse.

may be classified as Schedule II, III, IV or V, with Schedule II substances considered to present the highest potential for abuse or dependence and Schedule V substances the lowest relative risk of abuse.

The API of Xywav and Xyrem, oxybate salts, are regulated by the DEA as Schedule I controlled substances, and Xywav and Xyrem are regulated as Schedule III controlled substances.

The API of Sunosi, solriamfetol, and Sunosi are regulated as Schedule IV controlled substances.

Individual countries also impose similar requirements for controlled substances.

Nabiximols and certain other product candidates we are developing contain controlled substances as defined in the CSA.

Certain product candidates we are developing contain controlled substances as defined in the CSA.

Drug products approved by FDA that contain cannabis or cannabis extracts may be controlled substances and will be rescheduled to Schedules II-V after approval, or, like Epidiolex, removed completely from the schedules by operation of other laws.

The DEA limits the quantity of certain Schedule I controlled substances that may be manufactured and procured in the U.S.

The DEA limits the quantity of certain Schedule I and II controlled substances that may be manufactured and procured in the U.S.

in any given calendar year through a quota system and, as a result, quotas from the DEA are required in order to manufacture and package sodium oxybate and Xyrem in the U.S.

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As Schedule III drugs, Xywav and Xyrem are also subject to DEA import volume limits and state regulations relating to manufacturing, storage, distribution and physician prescription procedures, including limitations on prescription refills.

In addition, the third parties who perform our clinical and commercial manufacturing, distribution, dispensing and clinical studies

for Xywav and Xyrem are required to maintain necessary DEA registrations and state licenses.

In addition, the third parties who perform our clinical and commercial manufacturing, distribution, dispensing and clinical studies for Xywav and Xyrem are required to maintain necessary DEA registrations and state licenses.

The DEA periodically inspects facilities for compliance with its rules and regulations.

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are subject to the U.S.

Foreign Corrupt Practices Act, or FCPA, and similar anti-bribery or anti-corruption laws, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct or rules of other countries in which we operate, including the U.K.

Foreign Corrupt Practices Act, or FCPA, and similar anti-bribery or anti-corruption laws, regulations, industry self-regulation codes of conduct and physicians’ codes of professional

conduct or rules of other countries in which we operate, including the U.K.

Bribery Act of 2010, or the U.K.

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This data and information are provided instead of data and information independently demonstrating the proposed generic product’s safety and effectiveness.

The Hatch-Waxman Act requires an ANDA or a Section 505(b)(2) NDA applicant to certify that there are no patents listed for that product in the Orange Book, or that for each Orange Book-listed patent either the listed patent has expired, the listed patent will expire on a particular date and approval is sought after patent expiration, or the listed patent is invalid or will not be infringed by the manufacture, use or sale of the new product.

not be infringed by the manufacture, use or sale of the new product.

A certification that approval is sought after patent expiration is called a “Paragraph III Certification.” A certification that the new product will not infringe the RLD’s Orange Book-listed patents, or that such patents are invalid, is called a “Paragraph IV Certification.” If a relevant patent covers an approved method of use, an ANDA or Section 505(b)(2) NDA applicant can also file a statement, called, in the case of an ANDA, a “section viii statement,” that the application does not seek approval of the method of use covered by the listed patent.

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Data exclusivity prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic application or biosimilar application for eight years from the date of authorization of the innovative product, after which a generic or biosimilar marketing authorization application can be submitted, and the innovator’s data may be referenced.

However, the generic

product or biosimilar products cannot be marketed in the EU for a further two years thereafter.

However, the generic product or biosimilar products cannot be marketed in the EU for a further two years thereafter.

The overall ten-year period may be extended for a further year to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

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If a product is approved for its orphan designated use, it may be entitled to ODE, which blocks FDA from approving for seven years any other application for a product that is the same drug for the same indication.

If there is a previously-approved product that is the same drug for the same indication, orphan drug designation requires the sponsor to provide a plausible hypothesis of clinical superiority over the approved product, whereas ODE requires the sponsor to actually demonstrate clinical superiority.

If there is a previously-approved product that is the

same drug for the same indication, orphan drug designation requires the sponsor to provide a plausible hypothesis of clinical superiority over the approved product, whereas ODE requires the sponsor to actually demonstrate clinical superiority.

Clinical superiority can be established by way of greater efficacy, greater safety, or making a major contribution to patient care.

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Third party payors may also limit coverage to specific products on an approved list, or formulary, which might not include all of the approved products for a particular indication.

For certain categories of products, third party payors, principally through contracted pharmacy benefit managers, or PBMs, negotiate rebates with drug manufacturers for inclusion of products on their formularies in specific positions or coverage criteria.

Beginning in the third quarter of 2019, we have been entering into agreements with certain PBMs to provide rebates for our products where coverage was provided and products were listed in certain formulary positions, among other conditions.

certain categories of products, third party payors, principally through contracted pharmacy benefit managers, or PBMs, negotiate rebates with drug manufacturers for inclusion of products on their formularies in specific positions or coverage criteria.

Beginning in the third quarter of 2019, we have been entering into agreements with certain PBMs or similar organizations to provide rebates for our products where coverage was provided and products were listed in certain formulary positions, among other conditions.

Medicaid is a joint federal and state program that is administered by the states for low‑income and disabled beneficiaries.

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Since 2010, the total Medicaid rebate amount a drug manufacturer is required to pay under the Medicaid Drug Rebate Program has been capped at 100 percent of the Average Manufacturer Price.

The elimination of the cap on rebates means that manufacturer discounts to Medicaid may rise beginning in 2024 and, in certain circumstances, rebates could exceed the amount that state Medicaid programs pay for the

This policy change will have the greatest impact on drugs whose prices have reached the 100 percent Average Manufacturer Price rebate cap.

Further, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022, or IRA, into law, which, among other things, requires the U.S.

Department of Health and Human Services Secretary to negotiate, with respect to Medicare units and subject to a specified cap, the price of a set number of certain high Medicare spend drugs and biologicals per year starting in 2026, penalizes manufacturers of certain Medicare Parts B and D drugs for price increases above inflation, and makes several changes to the Medicare Part D benefit, including a limit on annual out-of-pocket costs, and a change in manufacturer liability under the program, which could negatively affect our business and financial condition.

Effective January 2023, a provision of the Infrastructure Investment and Jobs Act requires a manufacturer of single source drugs or biologicals in single-use packages or single dose containers to pay a refund on discarded amounts of drug under Medicare Part B where the discarded amount exceeds an applicable threshold.

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Department of Veterans Affairs, or VA, Federal Supply Schedule, or FSS, pricing program.

Under this program, we are obligated to make our products available for procurement on an FSS contract under which we must comply with standard government terms and conditions and charge a price to certain federal agencies that is no higher than the statutory Federal Ceiling Price, or FCP.

Under this program, we are obligated to make our products available for procurement on an FSS contract under which we must comply with standard government terms and conditions and charge a

price to certain federal agencies that is no higher than the statutory Federal Ceiling Price, or FCP.

The FCP is based on the non-federal average manufacturer price, or Non-FAMP, which we calculate and report to the VA on a quarterly and annual basis.

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There are numerous ongoing efforts at the federal and state level seeking to indirectly or directly regulate drug prices to reduce overall healthcare costs using tools such as price ceilings, value-based pricing and increased transparency and disclosure obligations.

Several states have passed or are considering legislation that requires or purports to require companies to report pricing information, including proprietary pricing information.

Numerous states have passed or are considering legislation that requires or purports to require companies to report pricing information, including proprietary pricing information.

For example, in 2017, California adopted a prescription drug price transparency state bill requiring advance notice of and an explanation for price increases of certain drugs that exceed a specified threshold.

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Pressure by governments and other stakeholders on prices and reimbursement levels continue to exist.

In various EU member states we expect to be subject to continuous cost-cutting measures, such as lower maximum prices, lower or lack of reimbursement coverage and incentives to use cheaper, usually generic, products as an alternative.

In various EU member states we expect to be subject to continuous cost-cutting measures, such as voluntary and temporary sales rebates, lower maximum prices, lower or lack of reimbursement coverage and incentives to use cheaper, usually generic, products as an alternative.

Health technology assessment, or HTA, of medicinal products is becoming an increasingly common part of the pricing and reimbursement procedures in some EU member states, including countries representing major markets.

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In the EU, prices can be reduced further by parallel distribution and parallel trade, or arbitrage between low-priced and high-priced EU member states.

third party payors may not be available for our products and we may be unable to successfully contract for coverage from pharmacy benefit managers and group purchasing organizations, which could diminish our sales or affect our ability to sell our products profitably;

For more information, including with respect to recent legal developments regarding the Medicaid Drug Rebate Program, Medicare Part B, and the 340B program, see the risk factors under the headings “ Adequate coverage and reimbursement from third party payors may not be available for our products and we may be unable to successfully contract for coverage from pharmacy benefit managers and group purchasing organizations, which could diminish our sales or affect our ability to sell our products profitably;

conversely, to secure coverage from these organizations, we may be required to pay rebates or other discounts or other restrictions to reimbursement that could diminish our sales,” “ The pricing of pharmaceutical products has come under increasing scrutiny as part of a global trend toward healthcare cost containment and resulting changes in healthcare law and policy may impact our business in ways that we cannot currently predict, which could have a material adverse effect on our business and financial condition” and “If we fail to comply with our reporting and payment obligations under the Medicaid Drug Rebate Program or other governmental pricing programs, we could be subject to additional reimbursement requirements, penalties, sanctions and fines, which could have a material adverse effect on our business, financial condition, results of operations and growth prospects” in Part I, Item 1A of this Annual Report on Form 10‑K.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business