On January 31, 2023 Guardant Health, Inc. (Nasdaq: GH), a leading precision oncology company, reported the introduction of Guardant GalaxyTM, a suite of advanced analytical technologies developed internally and through outside partnerships to enhance the performance and clinical utility of Guardant Health’s portfolio of cancer tests and to power the next generation of biomarker and drug discovery (Press release, Guardant Health, JAN 31, 2023, View Source [SID1234626663]).

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"Precision medicine has clearly demonstrated its potential to improve outcomes for patients with cancer, and our genomic profiling tests play a key role by identifying cancer biomarkers and other factors that can inform diagnosis and therapy selection," said Helmy Eltoukhy, co-CEO of Guardant Health. "With Guardant Galaxy, we are now accessing the most advanced AI analytics and complementary technologies from leading companies in cancer diagnostics. This will enable us to enhance the capabilities of our tests to provide oncologists and researchers with precise and actionable information and accelerate the development of new biomarker and drug discovery technologies."

The first application in the Guardant Galaxy suite is an AI-backed digital pathology platform developed by Lunit, a Seoul, South Korea-based company that develops AI solutions for precision diagnostics and therapeutics. The AI-powered scoring algorithm for the enhanced Guardant360 TissueNext PD-L1 test, which is now commercially available,* improved detection of the cancer biomarker by more than 20 percent compared to manual pathologist interpretation in the most challenging non-small cell lung cancer (NSCLC) cases. Findings from a recently published study indicate that the algorithm can assist pathologists by minimizing interpretation discrepancy and allowing for much better prediction of treatment outcomes.1

"We are excited to partner with Guardant Health in leveraging the power of AI and digital pathology to enhance the capabilities of Guardant’s portfolio for cancer patients," said Brandon Suh, CEO at Lunit. "The development of the AI-supported scoring algorithm for the Guardant360 TissueNext PD-L1 test is a great example of using advanced medical image analytics to enhance precision diagnostics in lung cancer and help oncologists find the right treatment for the right patients."

In addition to enhancing current standard-of-care biomarker interpretation, early Guardant Galaxy applications will also include novel native AI analysis applications, including the prediction of patient response to immunotherapy based on the spatial distribution of immune, stromal and tumor cells in standard H&E-stained slides.

Additional planned applications include enhanced oncology drug and biomarker discovery and development capabilities based on mining the extensive genomic and epigenomic data produced by Guardant Health’s diagnostic tests, cross-referenced to real-world outcomes data available through the GuardantINFORM data platform. Guardant Health also plans to expand the Guardant Galaxy technology suite over time to include other technology partnerships that will support additional segments of its cancer diagnostics portfolio.

On January 31, 2023 Fennec Pharmaceuticals Inc. (NASDAQ: FENC; TSX: FRX), a commercial stage specialty pharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Exclusivity to PEDMARK (sodium thiosulfate injection), which is indicated to reduce the risk of ototoxicity, or hearing loss, associated with cisplatin use in pediatric patients one month of age and older with localized, non-metastatic solid tumors (Press release, Fennec Pharmaceuticals, JAN 31, 2023, View Source [SID1234626662]).

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The FDA’s Orphan Drug Designation program is designed to advance the development of drugs that treat a condition affecting 200,000 or fewer U.S. patients annually. The seven-year market exclusivity for PEDMARK began on September 20, 2022, the date of its FDA approval, and continues until September 20, 2029. Additionally, in the approved prescribing label, the FDA has explicitly directed that PEDMARK is not substitutable with other sodium thiosulfate products.i

"We are pleased that the FDA has granted Orphan Drug Exclusivity to PEDMARK, which represents an important breakthrough treatment option for the pediatric cancer community," said Rosty Raykov, chief executive officer of Fennec Pharmaceuticals. "Further, as the first and only FDA approved drug for the treatment of pediatric cancer patients with localized, non-metastatic solid tumors at risk for cisplatin-induced hearing loss, we will continue to focus on strengthening our patent portfolio to extend intellectual property protection for PEDMARK beyond the seven years provided with Orphan Drug Exclusivity."

In addition to Orphan Drug Exclusivity, PEDMARK currently has three Orange Book listings for U.S. Patent No. 11,291,728 (‘728) and U.S. Patent No. 11,510,984 (‘984) that covers PEDMARK pharmaceutical formulation and U.S. Patent No. 10,156,190 (‘190), which relates to a method of use for our PEDMARK product. The ‘728 and ‘984 patents expire in 2039 and the ‘190 patent expires in 2038.

About Cisplatin-Induced Ototoxicity

Cisplatin and other platinum compounds are essential chemotherapeutic agents for the treatment of many pediatric malignancies. Unfortunately, platinum-based therapies can cause ototoxicity, or hearing loss, which is permanent, irreversible, and particularly harmful to the survivors of pediatric cancer.ii

The incidence of ototoxicity depends upon the dose and duration of chemotherapy, and many of these children require lifelong hearing aids or cochlear implants, which can be helpful for some, but do not reverse the hearing loss and can be costly over time.iii Infants and young children that are affected by ototoxicity at critical stages of development lack speech and language development and literacy, and older children and adolescents often lack social-emotional development and educational achievement.iv

PEDMARK (sodium thiosulfate injection)

PEDMARK is the first and only U.S. Food and Drug Administration (FDA) approved therapy indicated to reduce the risk of ototoxicity associated with cisplatin treatment in pediatric patients with localized, non-metastatic, solid tumors. It is a unique formulation of sodium thiosulfate in single-dose, ready-to-use vials for intravenous use in pediatric patients.7 PEDMARK is also the only therapeutic agent with proven efficacy and safety data with an established dosing paradigm, across two open-label, randomized Phase 3 clinical studies, the Clinical Oncology Group (COG) Protocol ACCL0431 and SIOPEL 6.

In the U.S. and Europe, it is estimated that, annually, more than 10,000 children may receive platinum-based chemotherapy. The incidence of ototoxicity depends upon the dose and duration of chemotherapy, and many of these children require lifelong hearing aids. There is currently no established preventive agent for this hearing loss and only expensive, technically difficult, and sub-optimal cochlear (inner ear) implants have been shown to provide some benefit. Infants and young children that suffer ototoxicity at critical stages of development lack speech language development and literacy, and older children and adolescents lack social-emotional development and educational achievement.

PEDMARK has been studied by co-operative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity, COG ACCL0431 and SIOPEL 6. Both studies have been completed. The COG ACCL0431 protocol enrolled childhood cancers typically treated with intensive cisplatin therapy for localized and disseminated disease, including newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, medulloblastoma, and other solid tumors. SIOPEL 6 enrolled only hepatoblastoma patients with localized tumors.

Indications and Usage

PEDMARK (sodium thiosulfate injection) is indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumors.

Limitations of Use

The safety and efficacy of PEDMARK have not been established when administered following cisplatin infusions longer than 6 hours. PEDMARK may not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred.

Important Safety Information

PEDMARK is contraindicated in patients with history of a severe hypersensitivity to sodium thiosulfate or any of its components.

Hypersensitivity reactions occurred in 8% to 13% of patients in clinical trials. Monitor patients for hypersensitivity reactions. Immediately discontinue PEDMARK and institute appropriate care if a hypersensitivity reaction occurs. Administer antihistamines or glucocorticoids (if appropriate) before each subsequent administration of PEDMARK. PEDMARK may contain sodium sulfite; patients with sulfite sensitivity may have hypersensitivity reactions, including anaphylactic symptoms and life-threatening or severe asthma episodes. Sulfite sensitivity is seen more frequently in people with asthma.

PEDMARK is not indicated for use in pediatric patients less than 1 month of age due to the increased risk of hypernatremia or in pediatric patients with metastatic cancers.

Hypernatremia occurred in 12% to 26% of patients in clinical trials, including a single Grade 3 case. Hypokalemia occurred in 15% to 27% of patients in clinical trials, with Grade 3 or 4 occurring in 9% to 27% of patients. Monitor serum sodium and potassium levels at baseline and as clinically indicated. Withhold PEDMARK in patients with baseline serum sodium greater than 145 mmol/L.

Monitor for signs and symptoms of hypernatremia and hypokalemia more closely if the glomerular filtration rate (GFR) falls below 60 mL/min/1.73m2.

Administer antiemetics prior to each PEDMARK administration. Provide additional antiemetics and supportive care as appropriate.

The most common adverse reactions (≥25% with difference between arms of >5% compared to cisplatin alone) in SIOPEL 6 were vomiting, nausea, decreased hemoglobin, and hypernatremia. The most common adverse reaction (≥25% with difference between arms of >5% compared to cisplatin alone) in COG ACCL0431 was hypokalemia.

On January 31, 2023 EpicentRx, reported this direct quote came courtesy of an executive at a major pharmaceutical company after he reviewed the mechanism of action of RRx-001 and learned about the results of a Phase 2 randomized trial called ROCKET of RRx-001 vs. regorafenib in 3rd/4th line colorectal cancer at the January 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium in San Francisco (Press release, EpicentRx, JAN 31, 2023, View Source [SID1234626661]).

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By way of context, the anti-angiogenic agent, bevacizumab (Avastin), is one of the most ubiquitously administered medications for the treatment of cancer, particularly colorectal cancer. Avastin decreases pressure in the tumor through improved vessel function, leading to better delivery and efficacy of systemic chemotherapy agents. Similarly, the NLRP3 inhibitor, RRx-001, also potentially decreases the leakiness of vessels in the tumor, which may lead to increased delivery, penetration, and anticancer activity of chemotherapy drugs.

However, unlike Avastin, which is associated with several severe side effects among them high blood pressure and perforation of the intestine, to date, in over 300 patients treated, no dose limiting toxicities or DLTs have been observed with RRx-001. Also, unlike Avastin, which directly binds to vascular endothelial growth factor (VEGF) to block the formation of new blood vessels or angiogenesis, RRx-001 not only inhibits VEGF in cancer and normalizes tumor vessels or makes them deliver blood more efficiently but also releases nitric oxide, inhibits epigenetic enzymes, blocks the inflammatory protein complex, NLRP3, and reprograms tumor associated macrophages or TAMs to attack tumor cells.

Presumably, this was the reason for the pharmaceutical exec to describe RRx-001 as "Avastin on steroids", the implication being that it does what Avastin does only much better. RRx-001 is still experimental and, therefore, not approved by the FDA, which makes it impossible for us to officially confirm or deny but, in animals, at least, RRx-001 is more active than Avastin. Experiments described in a peer-reviewed, published article titled vascular priming with RRx-001 to increase the uptake and accumulation of temozolomide and irinotecan in orthotopically implanted gliomas demonstrate that administration of RRx-001 prior to the chemotherapy agents, temozolomide or irinotecan, results in significantly increased uptake of irinotecan and temozolomide in tumors consistent with ‘remodeling’ of the dysfunctional tumor vessels.

In the Phase 2 ROCKET trial, (study schema shown below), RRx-001, given for 2 months, is hypothesized to have primed or prepared the tumor to respond better to the chemotherapy agent, irinotecan, than it normally would have in 3rd/4th line colorectal cancer after patients had already received irinotecan in first or second line. It is not standard in colorectal cancer to re-administer or rechallenge patients with chemotherapy on which they previously progressed. However, if RRx-001 is successful in this regard, as a chemotherapy "resensitizer", it may lead to a treatment loop in which patients are repeatedly shuttled between RRx-001 and chemotherapy, since each time RRx-001 is administered it potentially makes the tumor more susceptible to conventional treatments like irinotecan.

To read more about the activity of RRx-001 in colorectal cancer, view the newly published, open access manuscript in the journal, Clinical Colorectal Cancer: ROCKET, a Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer,

Anyway, with the Big Pharma exec having inadvertently touched off an unofficial competition between Avastin and RRx-001 what immediately comes to mind is the show tune from the Broadway musical, Annie Get Your Gun. The most memorable line from this tune, sung by the sharpshooter, Annie Oakley, and her love interest, a man named Frank Butler, is "Anything you can do; I can do better; I can do anything better than you." Annie and Frank each sing over each other, loudly insisting that they are better than the other at any given activity, whatever that activity is, shooting and singing included. By their own admission, however, neither can bake a pie. Here we can state with confidence that, however versatile they are, this is also true for RRx-001 and Avastin.

On January 31, 2023 Amgen (NASDAQ: AMGN) reported financial results for the fourth quarter and full year 2022 versus comparable periods in 2021 (Press release, Amgen, JAN 31, 2023, View Source [SID1234626660]).

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"We executed effectively in 2022, delivering strong volume growth, advancing numerous first-in-class medicines in our pipeline, and staying on track to achieve our long-term growth objectives," said Robert A. Bradway, chairman and chief executive officer. "The announced acquisition of Horizon Therapeutics, which we expect to complete in the first half of this year, represents a compelling opportunity to serve more patients and strengthen our growth profile."

Key results include:

For the fourth quarter, total revenues were $6.8 billion, largely unchanged from Q4 2021. Q4 revenues benefited from a 4% increase in product sales, offset by lower Other Revenue from our COVID-19 manufacturing collaboration. Product sales growth was driven by 10% volume growth, partially offset by 3% lower net selling price and 2% negative impact from foreign exchange. Excluding the 2% negative impact of foreign exchange on product sales, total revenues increased 2%.

Volume growth of 10% included double-digit volume growth for a number of products including LUMAKRAS/LUMYKRAS (sotorasib), Nplate (romiplostim), EVENITY (romosozumab-aqqg), Repatha (evolocumab), Parsabiv (etelcalcetide), AMGEVITA (adalimumab), KYPROLIS (carfilzomib), and Prolia (denosumab).

For the full year, total revenues increased 1% to $26.3 billion, resulting from a 2% increase in product sales driven by a 9% increase in volume, partially offset by 5% lower net selling price and 2% negative impact from foreign exchange. Excluding the 2% negative impact of foreign exchange on product sales, total revenues increased 3% for the full year.

GAAP earnings per share (EPS) decreased 11% from $3.36 to $3.00 in the fourth quarter driven by increased other expense, partially offset by lower weighted-average shares outstanding in Q4 2022. For the full year, GAAP EPS increased 18% from $10.28 to $12.11, primarily driven by the write-off of $1.5 billion in Acquired In-Process Research & Development (Acquired IPR&D) associated with our acquisition of Five Prime Therapeutics in 2021.

For the fourth quarter, GAAP operating income decreased from $2.3 billion to $2.2 billion, and GAAP operating margin decreased 2.7 percentage points to 34.0%. For the full year, GAAP operating income increased from $7.6 billion to $9.6 billion, and GAAP operating margin increased 7.2 percentage points to 38.6%.

Non-GAAP EPS decreased 7% from $4.40 to $4.09 in the fourth quarter, driven by increased other expense, partially offset by lower weighted-average shares outstanding in Q4 2022. For the full year, non-GAAP EPS increased 27% from $13.92 to $17.69 driven by the write-off of $1.5 billion in Acquired IPR&D associated with our acquisition of Five Prime Therapeutics in 2021 and lower weighted-average shares outstanding in 2022.

For the fourth quarter, non-GAAP operating income remained unchanged at $3.0 billion, and non-GAAP operating margin decreased 1.9 percentage points to 45.9%. For the full year, non-GAAP operating income increased from $10.5 billion to $12.8 billion, and non-GAAP operating margin increased 8.2 percentage points to 51.5%.

The Company generated $8.8 billion of free cash flow for the full year versus $8.4 billion in 2021.

Non-GAAP EPS has been recast due to an update to our non-GAAP policy effective January 1, 2022, resulting in a $0.04 increase for the fourth quarter of 2021 and a $3.18 decrease for the full year 2021 of previously-reported non-GAAP EPS. Refer to Non-GAAP Financial Measures below for further discussion.

$Millions, except EPS, dividends paid per share and percentages

Q4 ’22

Q4 ’21

YOY Δ

FY ’22

FY ’21

YOY Δ

Total Revenues

$ 6,839

$ 6,846

— %

$ 26,323

$ 25,979

1 %

GAAP Operating Income

$ 2,230

$ 2,304

(3 %)

$ 9,566

$ 7,639

25 %

GAAP Net Income

$ 1,616

$ 1,899

(15 %)

$ 6,552

$ 5,893

11 %

GAAP EPS

$ 3.00

$ 3.36

(11 %)

$ 12.11

$ 10.28

18 %

Non-GAAP Operating Income

$ 3,009

$ 2,997

— %

$ 12,761

$ 10,519

21 %

Non-GAAP Net Income

$ 2,202

$ 2,487

(11 %)

$ 9,570

$ 7,978

20 %

Non-GAAP EPS

$ 4.09

$ 4.40

(7 %)

$ 17.69

$ 13.92

27 %

Dividends Paid Per Share

$ 1.94

$ 1.76

10 %

$ 7.76

$ 7.04

10 %

References in this release to "non-GAAP" measures, measures presented "on a non-GAAP basis," "free cash flow" (computed by subtracting capital expenditures from operating cash flow), "total revenues and product sales adjusted for foreign currency exchange rate impact" (computed by converting our current period local currency product sales using the prior period foreign currency exchange rates and comparing that to our current period product sales), "EBITDA, or earnings before interest, taxes, depreciation and amortization" (computed by adding interest expense, provision for income taxes, and depreciation and amortization expense to GAAP net income) and "debt leverage ratio" (calculated as the ratio of GAAP total debt to EBITDA) refer to non-GAAP financial measures. Beginning January 1, 2022, the Company’s non-GAAP financial measures no longer exclude adjustments for upfront license fees, development milestones and IPR&D expenses of pre-approval programs related to licensing, collaboration and asset acquisition transactions. For purposes of comparability, the non-GAAP financial results for the fourth quarter and full year of 2021 have been updated to reflect this change. Adjustments to the most directly comparable GAAP financial measures and other items are presented on the attached reconciliations. Refer to Non-GAAP Financial Measures below for further discussion.

Product Sales Performance

Total product sales increased 4% for the fourth quarter of 2022 versus the fourth quarter of 2021. Unit volumes grew 10%, partially offset by 3% lower net selling price and 2% negative impact from foreign exchange. Product sales for the full year increased 2% versus 2021, driven by 9% volume growth, partially offset by 5% lower net selling price and 2% negative impact from foreign exchange.

General Medicine

Prolia sales increased 14% year-over-year to a record $992 million for the fourth quarter and 12% for the full year, primarily driven by volume growth. Volumes grew 11% for the quarter and 10% for the full year.

EVENITY sales increased 57% year-over-year to a record $225 million for the fourth quarter and 48% for the full year, driven by strong volume growth across our markets. Volumes grew 62% for the quarter and 52% for the full year.

Repatha sales increased 22% year-over-year to a record $333 million for the fourth quarter and 16% for the full year. Volume growth of 31% for the quarter and 47% for the full year was partially offset by lower net selling price. In the U.S., sales grew 9% for the full year, driven by 36% volume growth, partially offset by lower net selling price resulting from higher rebates to support and improve access for patients. Outside the U.S., sales grew 23% for the full year, driven by 58% volume growth, partially offset by lower net selling price. This volume growth and lower net selling price were both impacted by the inclusion of Repatha on China’s National Reimbursement Drug List as of January 1, 2022. Repatha remains the global proprotein convertase subtilisin/kexin type 9 (PCSK9) segment leader, with over 1.5 million patients treated since launch.

Aimovig (erenumab-aooe) sales increased 27% year-over-year to a record $114 million for the fourth quarter and 31% for the full year, driven by higher net selling price, partially offset by lower volume. Going forward, we expect net selling price to decline to maintain broad formulary access for patients due to competitive dynamics.

EPOGEN (epoetin alfa) sales decreased 11% year-over-year for the fourth quarter, primarily driven by lower net selling price. For the full year, sales decreased 3%, driven by lower net selling price and lower inventory levels, partially offset by a 4% increase in volume. Going forward, we expect further declines in net selling price and volume erosion as we transition through the expiration of our contract with DaVita.

Aranesp (darbepoetin alfa) sales decreased 4% year-over-year for the fourth quarter, driven by unfavorable foreign exchange and lower net selling price, partially offset by increased volume. Sales decreased 4% for the full year, driven by lower net selling price and unfavorable foreign exchange impact, partially offset by favorable changes to estimated sales deductions and increased volume.

Parsabiv sales increased 35% year-over-year for the fourth quarter and 36% for the full year, primarily driven by volume growth resulting from 2022 purchases from a large dialysis organization following decreased usage in 2021.
Sensipar/Mimpara (cinacalcet) sales decreased 61% year-over-year for the fourth quarter, primarily driven by unfavorable changes in estimated sales deductions and unfavorable foreign exchange impact. Full year sales decreased 24%, primarily driven by volume declines in response to generic competition.
Inflammation

TEZSPIRE (tezepelumab-ekko) generated $79 million of sales in the fourth quarter and $170 million in its first year of launch, driven by strong adoption in the U.S. by both allergists and pulmonologists across patients with all types of severe asthma. Healthcare providers acknowledge TEZSPIRE’s unique, differentiated profile and its broad potential to treat the 2.5 million patients worldwide with severe asthma who are uncontrolled, without any phenotypic or biomarker limitation.
TAVNEOS (avacopan) was acquired on October 20, 2022 and generated $21 million of sales in the fourth quarter. TAVNEOS is a recently launched, first-in-class treatment for severe active ANCA-associated vasculitis (AAV), an autoimmune disease that leads to inflammation and eventual destruction of small blood vessels.
Otezla (apremilast) sales decreased 2% year-over-year for the fourth quarter, driven by lower net selling price and unfavorable changes to estimated sales deductions, partially offset by 7% volume growth. Full year sales increased 2%, primarily driven by 7% volume growth, partially offset by lower net selling price largely because of enhancements to our co-pay and patient assistance programs to support new patients starting treatment as well as additional rebates to improve the quality of coverage.
Enbrel (etanercept) sales decreased 1% year-over-year for the fourth quarter, driven by declines in volume and net selling price, partially offset by higher year-end inventory levels. Full year sales decreased 8%, driven by a 5% unfavorable impact of changes to estimated sales deductions related to prior periods, 3% decline in volume and lower net selling price. Going forward, we expect further declines in net selling price year-over-year, driven by increased competition.

We expect Otezla and Enbrel to follow the historical pattern of lower sales in the first quarter relative to subsequent quarters due to the impact of benefit plan changes, insurance reverification and increased co-pay expenses as U.S. patients work through deductibles.
AMGEVITA sales increased 3% year-over-year to a record $119 million for the fourth quarter and 5% for the full year, driven by 25% volume growth for both periods, partially offset by unfavorable foreign exchange impact and lower net selling price resulting from increased competition. AMGEVITA continued to be the most prescribed adalimumab biosimilar in Europe.

Hematology-Oncology

LUMAKRAS/LUMYKRAS generated $71 million of sales for the fourth quarter and $285 million for the full year. Quarter-over-quarter sales declined 5%, driven by lower net selling price and unfavorable changes to estimated sales deductions, partially offset by 12% volume growth. Outside the U.S., LUMYKRAS has been approved in over 45 countries around the world. We are actively launching in 30 markets and pursuing reimbursement in the remaining countries.
KYPROLIS sales increased 14% year-over-year to a record $325 million for the fourth quarter and 13% for the full year, driven by 13% and 14% volume growth, respectively.
XGEVA (denosumab) sales decreased 11% year-over-year for the fourth quarter, primarily driven by 4% decline in volume and unfavorable changes to estimated sales deductions, partially offset by higher net selling price. Full year sales were relatively unchanged year-over-year as higher net selling price was offset by a 2% decline in volume and unfavorable foreign exchange impact. Going forward, we expect volume will continue to be impacted by competitive dynamics.
Vectibix (panitumumab) sales decreased 2% year-over-year for the fourth quarter, driven by unfavorable foreign exchange impact, partially offset by higher net selling price. Full year sales increased 2% year-over-year, driven by higher net selling price and volume growth, partially offset by unfavorable foreign exchange impact.
Nplate sales increased 66% year-over-year to a record $469 million for the fourth quarter and 27% for the full year, driven by volume growth. Nplate sales in the fourth quarter included $207 million related to a one-time order from the U.S. government.
BLINCYTO (blinatumomab) sales increased 24% year-over-year to a record $164 million for the fourth quarter, primarily driven by favorable changes to estimated sales deductions and higher net selling price. Sales increased 24% for the full year, driven by volume growth and higher net selling price.
MVASI (bevacizumab-awwb) sales decreased 33% year-over-year for the fourth quarter, primarily driven by lower net selling price. Sales decreased 23% for the full year, driven by lower net selling price, partially offset by volume growth. The most recently published Average Selling Price (ASP) for MVASI in the U.S. declined 38% year-over-year and 12% quarter-over-quarter. Looking forward, we expect continued net selling price erosion and declining volume driven by increased competition.
KANJINTI (trastuzumab-anns) sales decreased 55% year-over-year for the fourth quarter, driven by lower net selling price and unfavorable changes to estimated sales deductions. Sales decreased 45% for the full year, driven by lower net selling price and decline in volume. The most recently published ASP for KANJINTI in the U.S. declined 51% year-over-year and 22% quarter-over-quarter. Going forward, we expect continued net selling price deterioration and volume declines driven by increased competition.
Neulasta (pegfilgrastim) sales decreased 37% year-over-year for the fourth quarter and 35% for the full year, driven by declines in both net selling price and volume. The most recent published Average Selling Price for Neulasta in the U.S. declined 29% year-over-year and 16% quarter-over-quarter. Going forward, we expect increased competition to result in further declines in net selling price and volume.
NEUPOGEN (filgrastim) sales increased 10% year-over-year for the fourth quarter, primarily driven by favorable changes in estimated sales deductions, partially offset by volume declines. Full year sales decreased 14% year-over-year, driven by volume declines.
Product Sales Detail by Product and Geographic Region

$Millions, except percentages

Q4 ’22

Q4 ’21

YOY Δ

US

ROW

TOTAL

TOTAL

TOTAL

Prolia

682

310

992

873

14 %

EVENITY

157

68

225

143

57 %

Repatha

147

186

333

273

22 %

Aimovig

109

5

114

90

27 %

EPOGEN

114

—

114

128

(11 %)

Aranesp

124

224

348

362

(4 %)

Parsabiv

64

29

93

69

35 %

Sensipar/Mimpara

(3)

10

7

18

(61 %)

TEZSPIRE

79

—

79

—

NM

TAVNEOS

16

5

21

—

NM

Otezla

520

96

616

630

(2 %)

Enbrel

1,079

19

1,098

1,108

(1 %)

AMGEVITA

—

119

119

115

3 %

LUMAKRAS/LUMYKRAS

62

9

71

45

58 %

KYPROLIS

224

101

325

284

14 %

XGEVA

358

126

484

545

(11 %)

Vectibix

109

129

238

243

(2 %)

Nplate

374

95

469

282

66 %

BLINCYTO

96

68

164

132

24 %

MVASI

134

71

205

304

(33 %)

KANJINTI

50

13

63

139

(55 %)

Neulasta

187

34

221

351

(37 %)

NEUPOGEN

22

12

34

31

10 %

Other products*

90

29

119

106

12 %

Total product sales

$ 4,794

$ 1,758

$ 6,552

$ 6,271

4 %

* Other products include Corlanor, AVSOLA, IMLYGIC and RIABNI, as well as sales by GENSENTA and Bergamo subsidiaries

NM = not meaning

$Millions, except percentages

FY ’22

FY ’21

YOY Δ

US

ROW

TOTAL

TOTAL

TOTAL

Prolia

2,465

1,163

3,628

$ 3,248

12 %

EVENITY

533

254

787

530

48 %

Repatha

608

688

1,296

1,117

16 %

Aimovig

398

16

414

317

31 %

EPOGEN

506

—

506

521

(3 %)

Aranesp

521

900

1,421

1,480

(4 %)

Parsabiv

253

129

382

280

36 %

Sensipar/Mimpara

10

54

64

84

(24 %)

TEZSPIRE

170

—

170

—

NM

TAVNEOS

16

5

21

—

NM

Otezla

1,886

402

2,288

2,249

2 %

Enbrel

4,044

73

4,117

4,465

(8 %)

AMGEVITA

—

460

460

439

5 %

LUMAKRAS/LUMYKRAS

222

63

285

90

*

KYPROLIS

850

397

1,247

1,108

13 %

XGEVA

1,480

534

2,014

2,018

— %

Vectibix

396

497

893

873

2 %

Nplate

848

459

1,307

1,027

27 %

BLINCYTO

336

247

583

472

24 %

MVASI

602

299

901

1,166

(23 %)

KANJINTI

257

59

316

572

(45 %)

Neulasta

959

167

1,126

1,734

(35 %)

NEUPOGEN

87

57

144

168

(14 %)

Other products**

296

135

431

339

27 %

Total product sales

$ 17,743

$ 7,058

$ 24,801

$ 24,297

2 %

* Change in excess of 100%

** Other products include Corlanor, AVSOLA, IMLYGIC and RIABNI, as well as sales by GENSENTA and Bergamo subsidiaries

NM = not meaningful

Operating Expense, Operating Margin and Tax Rate Analysis

On a GAAP basis:

Total Operating Expenses increased 1% year-over-year for the fourth quarter. For the full year, Total Operating Expenses decreased 9%. Cost of Sales margin decreased 0.7 percentage points in the fourth quarter and decreased 0.8 percentage points for the full year, primarily driven by lower COVID-19 antibody shipments and lower manufacturing cost, partially offset by acquisition-related charges and changes in our product mix. Research & Development (R&D) expenses decreased 2% in the fourth quarter and decreased 8% for the full year, primarily due to higher business development activity in 2021 and lower marketed product support, partially offset by higher late stage program support and research and early pipeline spend. Selling, General & Administrative (SG&A) expenses increased 10% in the fourth quarter and increased 1% for the full year primarily driven by expenses related to the ChemoCentryx acquisition.
Operating Margin as a percentage of product sales decreased 2.7 percentage points to 34.0% in the fourth quarter and increased 7.2 percentage points for the full year to 38.6%.
Tax Rate decreased 3.3 percentage points in the fourth quarter and decreased 1.3 percentage points for the full year. The fourth quarter tax rate decrease was primarily due to the Five Prime Therapeutics non-deductible Acquired IPR&D expense in the prior year and net favorable items, partially offset by a nondeductible loss from a nonstrategic divestiture. The full year tax rate decrease was primarily due to the Five Prime Therapeutics non-deductible Acquired IPR&D expense in the prior year, partially offset by a nondeductible loss from a nonstrategic divestiture and net unfavorable items.
On a non-GAAP basis:

Total Operating Expenses were unchanged for the fourth quarter and decreased 12% for the full year. Cost of Sales margin decreased 1.2 percentage points in the fourth quarter and decreased 0.5 percentage points for the full year, driven by lower COVID-19 antibody shipments and lower manufacturing cost, partially offset by changes in our product mix. R&D expenses decreased 2% in the fourth quarter and decreased 8% for the full year, primarily due to higher business development activity in 2021 and lower marketed product support, partially offset by higher late-stage program support and research and early pipeline spend. SG&A expenses increased 2% in the fourth quarter driven by higher marketed product support. For the full year, SG&A expenses were unchanged.
Operating Margin as a percentage of product sales decreased 1.9 percentage points in the fourth quarter to 45.9%, and increased 8.2 percentage points to 51.5% for the full year.
Tax Rate increased 2.8 percentage points in the fourth quarter and decreased 0.7 percentage points for the full year. The fourth quarter tax rate increase was primarily due to earnings mix and net favorable items in the prior year as compared to the current quarter. The full year tax rate decrease is primarily due to the Five Prime Therapeutics non-deductible Acquired IPR&D expense in the prior year, partially offset by net unfavorable items in the current year as compared to the prior year.

$Millions, except percentages

GAAP

Non-GAAP

Q4 ’22

Q4 ’21

YOY Δ

Q4 ’22

Q4 ’21

YOY Δ

Cost of Sales

$ 1,747

$ 1,718

2 %

$ 1,071

$ 1,096

(2 %)

% of product sales

26.7 %

27.4 %

(0.7) pts

16.3 %

17.5 %

(1.2) pts

Research & Development

$ 1,324

$ 1,348

(2 %)

$ 1,291

$ 1,319

(2 %)

% of product sales

20.2 %

21.5 %

(1.3) pts

19.7 %

21.0 %

(1.3) pts

Selling, General & Administrative

$ 1,572

$ 1,425

10 %

$ 1,468

$ 1,434

2 %

% of product sales

24.0 %

22.7 %

1.3 pts

22.4 %

22.9 %

(0.5) pts

Other

$ (34)

$ 51

*

$ —

$ —

NM

Total Operating Expenses

$ 4,609

$ 4,542

1 %

$ 3,830

$ 3,849

— %

Operating Margin

operating income as % of product sales

34.0 %

36.7 %

(2.7) pts

45.9 %

47.8 %

(1.9) pts

Tax Rate

7.6 %

10.9 %

(3.3) pts

13.4 %

10.6 %

2.8 pts

pts: percentage points

* change in excess of 100%

NM = not meaningful

$Millions, except percentages

GAAP

Non-GAAP

FY ’22

FY ’21

YOY Δ

FY ’22

FY ’21

YOY Δ

Cost of Sales

$ 6,406

$ 6,454

(1 %)

$ 3,951

$ 3,994

(1 %)

% of product sales

25.8 %

26.6 %

(0.8) pts

15.9 %

16.4 %

(0.5) pts

Research & Development

$ 4,434

$ 4,819

(8 %)

$ 4,341

$ 4,696

(8 %)

% of product sales

17.9 %

19.8 %

(1.9) pts

17.5 %

19.3 %

(1.8) pts

Acquired IPR&D

$ —

$ 1,505

NM

$ —

$ 1,505

NM

% of product sales

— %

6.2 %

NM

— %

6.2 %

NM

Selling, General & Administrative

$ 5,414

$ 5,368

1 %

$ 5,270

$ 5,265

— %

% of product sales

21.8 %

22.1 %

(0.3) pts

21.2 %

21.7 %

(0.5) pts

Other

$ 503

$ 194

*

$ —

$ —

NM

Total Operating Expenses

$ 16,757

$ 18,340

(9 %)

$ 13,562

$ 15,460

(12 %)

Operating Margin

operating income as % of product sales

38.6 %

31.4 %

7.2 pts

51.5 %

43.3 %

8.2 pts

Tax Rate

10.8 %

12.1 %

(1.3) pts

13.8 %

14.5 %

(0.7) pts

pts: percentage points

* change in excess of 100%

NM = not meaningful

Cash Flow and Balance Sheet

The Company generated $2.3 billion of free cash flow in the fourth quarter of 2022 versus $2.5 billion in the fourth quarter of 2021. The Company generated $8.8 billion of free cash flow for the full year 2022 versus $8.4 billion in 2021.
The Company’s fourth quarter 2022 dividend of $1.94 per share was declared on October 28, 2022, and was paid on December 8, 2022, to all stockholders of record as of November 17, 2022, representing a 10% increase from 2021.
During the fourth quarter, there were no repurchases of common stock. 26.1 million shares of common stock were repurchased in 2022.
Cash and investments totaled $9.3 billion and debt outstanding totaled $38.9 billion as of December 31, 2022. Debt leverage was approximately 3.2 times EBITDA as of December 31, 2022.

$Billions, except shares

Q4 ’22

Q4 ’21

YOY Δ

FY ’22

FY ’21

YOY Δ

Operating Cash Flow

$ 2.6

$ 2.8

$ (0.2)

$ 9.7

$ 9.3

$ 0.5

Capital Expenditures

$ 0.3

$ 0.3

$ 0.1

$ 0.9

$ 0.9

$ 0.1

Free Cash Flow

$ 2.3

$ 2.5

$ (0.2)

$ 8.8

$ 8.4

$ 0.4

Dividends Paid

$ 1.0

$ 1.0

$ 0.1

$ 4.2

$ 4.0

$ 0.2

Share Repurchases

$ —

$ 1.5

$ (1.5)

$ 6.3

$ 5.0

$ 1.3

Average Diluted Shares (millions)

539

565

(26)

541

573

(32)

Note: Numbers may not add due to rounding

$Billions

12/31/22

12/31/21

YTD Δ

Cash and Investments

$ 9.3

$ 8.0

$ 1.3

Debt Outstanding

$ 38.9

$ 33.3

$ 5.6

Note: Numbers may not add due to rounding

2023 Guidance (Excludes any contribution from the announced acquisition of Horizon Therapeutics)

For the full year 2023, excluding any contribution from the announced acquisition of Horizon Therapeutics, the Company expects:

Total revenues in the range of $26.0 billion to $27.2 billion.
On a GAAP basis, EPS in the range of $13.16 to $14.41, and a tax rate in the range of 17.0% to 18.5%.
On a non-GAAP basis, EPS in the range of $17.40 to $18.60, and a tax rate in the range of 18.0% to 19.0%.
Capital expenditures to be approximately $925 million.
Share repurchases not to exceed $500 million.
Fourth Quarter Product and Pipeline Update

The Company provided the following updates on selected product and pipeline programs:

General Medicine

Repatha

In November, results were presented from the Repatha FOURIER and FOURIER-open label extension studies demonstrating a direct relationship between lower achieved low-density lipoprotein cholesterol (LDL-C) levels, down to very low LDL-C levels <20 mg/dL, with a lower risk of cardiovascular outcomes in the long term. There was no increase in adverse safety events during the extended follow-up period of up to 8.6 years.
The 2022 American College of Cardiology Expert Consensus Decision Pathway on the Role of Non-statin Therapies for LDL-Cholesterol Lowering indicated that "there appears to be no LDL-C level below which benefit ceases" for atherosclerotic cardiovascular disease patients at very high risk. Additionally, LDL-C recommendations were updated to reflect a reduction in target LDL-C levels in highest risk patients from 70 mg/dl to 55 mg/dl; a level that is not attainable for a large number of patients without PCSK9 inhibitor therapy.
Olpasiran (AMG 890)

In November, results were presented from a Phase 2 study of olpasiran, a small interfering RNA molecule that reduces Lipoprotein(a) (Lp(a)) synthesis in the liver, demonstrating that patients with very high Lp(a) levels who received olpasiran dosed at 75 mg or above every 12 weeks had a 95% or greater reduction in Lp(a) compared to placebo at week 36. Overall, the rates of adverse events were similar in the olpasiran and placebo arms. The most common treatment-related adverse events were injection site reactions, primarily pain. These data were presented at the American Heart Association Scientific Sessions and simultaneously published in The New England Journal of Medicine.
The Company has begun enrolling the double-blind, randomized, placebo-controlled, multicenter Phase 3 cardiovascular outcomes study that assesses the impact of olpasiran treatment on major cardiovascular events in participants with atherosclerotic cardiovascular disease and elevated Lp(a).
AMG 133

In December, results were presented from a Phase 1 study of AMG 133 a multispecific that inhibits the gastric inhibitory polypeptide receptor (GIPR) and activates the glucagon-like peptide 1 (GLP-1) receptor, demonstrating that following three monthly doses of AMG 133, participants experienced a mean percentage reduction in body weight of 14.5% at the highest dose (420 mg Q4W) by day 85. Weight loss was durable at the higher doses tested, with reductions observed for up to 150 days after the final (third) AMG 133 administration. Most treatment-emergent adverse events were mild and transient, with the majority being GI-related and resolving within 48 hours.
The Company has begun enrolling patients in a randomized, placebo-controlled, double-blind, dose-ranging Phase 2 study to evaluate the efficacy, safety, and tolerability of AMG 133 in overweight or obese adult patients, with or without type 2 diabetes mellitus.
AMG 786

A small molecule, continues to enroll patients in a Phase 1 study. This molecule has a different target than AMG 133 and other incretin based therapies.
Inflammation

TEZSPIRE

In January 2023, TEZSPIRE received a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) for a variation adding a new prefilled, single-use pen presentation for self-administration by patients aged 12 years and older with severe asthma. The CHMP opinion can be implemented without the need for a European Commission decision, due to the nature of the Type-II label variation.
In severe asthma, the PASSAGE Phase 4 real-world effectiveness study, the WAYFINDER Phase 3b study and the SUNRISE Phase 3 study continue to enroll patients.
A Phase 3 study of TEZSPIRE in chronic rhinosinusitis with nasal polyps continues to enroll patients.
A Phase 3 study of TEZSPIRE in patients with eosinophilic esophagitis has started.
A Phase 2b study of TEZSPIRE in chronic spontaneous urticaria is fully enrolled. Data readout is anticipated in H1 2023.
A Phase 2 study of TEZSPIRE in chronic obstructive pulmonary disease is fully enrolled.
Rocatinlimab (AMG 451 / KHK4083)

The ROCKET Phase 3 program evaluating rocatinlimab, a first-in-class anti-OX40 monoclonal antibody, is enrolling adult and adolescent patients with moderate to severe atopic dermatitis.
In December, the results from the rocatinlimab Phase 2b multicenter, double-blind, placebo-controlled study of adults with moderate to severe atopic dermatitis were published in The Lancet.
Rozibafusp alfa (AMG 570)

A Phase 2b study of rozibafusp alfa, an antibody-peptide conjugate that simultaneously blocks inducible T-cell costimulatory ligand (ICOSL) and B-cell activating factor (BAFF) activity, in systemic lupus erythematosus (SLE), continues to enroll patients.
Efavaleukin alfa (AMG 592)

A Phase 2b study of efavaleukin alfa, an interleukin-2 (IL-2) mutein Fc fusion protein, in SLE continues to enroll patients.
A Phase 2b study of efavaleukin alfa in ulcerative colitis, continues to enroll patients.
Ordesekimab (AMG 714 / PRV-015)

A Phase 2b study of AMG 714, a monoclonal antibody that binds interleukin-15, in nonresponsive celiac disease, continues to enroll patients.
Oncology

BLINCYTO

In December, results were presented from the registration-enabling E1910 study conducted by the National Cancer Institute, the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group that demonstrated superior overall survival with BLINCYTO treatment added to consolidation chemotherapy over standard-of-care consolidation chemotherapy in newly diagnosed adult patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia who were measurable residual disease (MRD)-negative following induction and intensification chemotherapy.
In December, results were presented from a Phase 1b dose-escalation study of subcutaneously administered BLINCYTO that demonstrated an acceptable safety profile and anti-leukemia activity in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Pharmacokinetic exposures and pharmacodynamic profiles were consistent with those reported for the continuous intravenous infusion regimen of BLINCYTO. The Company will continue to investigate BLINCYTO in earlier lines of treatment and in the subcutaneous route of administration.
LUMAKRAS/LUMYKRAS

A Phase 3 study of LUMAKRAS in combination with Vectibix in third-line colorectal cancer continues to enroll patients. Data readout is anticipated in H2 2023.
The Company continues to explore novel combinations and is advancing a comprehensive global clinical development program in non-small cell lung cancer, colorectal cancer, and other solid tumors to further explore the potential of LUMAKRAS.
Bemarituzumab

FORTITUDE-101, a Phase 3 study of bemarituzumab, a fibroblast growth factor receptor 2b (FGFR2b) targeting monoclonal antibody, plus chemotherapy in first-line gastric cancer, continues to enroll patients.
FORTITUDE-102, a Phase 1b/3 study of bemarituzumab plus chemotherapy and nivolumab in first-line gastric cancer, continues to enroll patients in the Phase 3 portion of the study.
FORTITUDE-103, a Phase 1b study of bemarituzumab plus oral chemotherapy regimens with or without nivolumab in first-line gastric cancer, continues to enroll patients.
FORTITUDE-201, a Phase 1b study of bemarituzumab monotherapy and in combination with standard-of-care therapy, in squamous NSCLC with FGFR2b overexpression, continues to enroll patients.
FORTITUDE-301, a Phase 1b/2 basket study of bemarituzumab monotherapy in solid tumors with FGFR2b overexpression, continues to enroll patients.
Tarlatamab (AMG 757)

DeLLphi-301, a potentially registrational Phase 2 study of tarlatamab, a half-life extended BiTE molecule being studied in heavily pretreated patients with small-cell lung cancer (SCLC), continues to enroll patients. In November, a recommended Phase 2 dose was agreed to with the U.S. Food and Drug Administration. Data readout is anticipated in H2 2023.
DeLLphi-300, a Phase 1 study of tarlatamab in relapsed/refractory SCLC, continues to enroll patients.
DeLLphi-302, a Phase 1b study of tarlatamab in combination with AMG 404, an anti-programmed cell death-1 monoclonal antibody, in second-line or later SCLC is ongoing, with data readout anticipated in H2 2023.
DeLLphi-303, a Phase 1b study of tarlatamab in combination with standard-of-care in first-line SCLC, continues to enroll patients.
DeLLpro-300, a Phase 1b study of tarlatamab, in de novo or treatment-emergent neuroendocrine prostate cancer, continues to enroll patients.
The Company plans to initiate a Phase 3 study of tarlatamab in second-line SCLC in H1 2023.
AMG 509

A Phase 1 dose-escalation/expansion study of AMG 509, a bispecific molecule targeting six-transmembrane epithelial antigen of prostate 1 (STEAP1) in metastatic castrate-resistant prostate cancer (mCRPC) continues to enroll patients. Preliminary data readout is anticipated in H2 2023.
AMG 340

A Phase 1 dose-escalation study of AMG 340, a lower T-cell affinity BiTE molecule targeting prostate-specific membrane antigen (PSMA), in mCRPC, continues to enroll patients.
AMG 193

A Phase 1/1b/2 study of AMG 193, a small-molecule methylthioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) molecular glue continues to enroll patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors.
Biosimilars

A Phase 3 study to support an interchangeability designation in the U.S. for ABP 654, an investigational biosimilar to STELARA (ustekinumab) is ongoing, with data readout anticipated in H1 2023.
A Phase 3 study to support an interchangeability designation in the U.S. for AMJEVITA (adalimumab-atto) is ongoing, with data readout anticipated in H1 2023.
The final analysis from a Phase 3 study evaluating the efficacy and safety of ABP 938, an investigational biosimilar to EYLEA (aflibercept) compared with EYLEA in patients with neovascular age-related macular degeneration, is expected in H1 2023.
TEZSPIRE is being developed in collaboration with AstraZeneca.
Rocatinlimab, formerly AMG 451 / KHK4083 is being developed in collaboration with KKC.
Ordesekimab formerly AMG 714 and also known as PRV-015 is being developed in collaboration with Provention Bio.
AMG 509 is being developed in collaboration with Xencor.
STELARA is a registered trademark of Janssen Pharmaceutica NV.
EYLEA is a registered trademark of Regeneron Pharmaceuticals, Inc.
SOLIRIS is a registered trademark of Alexion Pharmaceuticals, Inc.

Non-GAAP Financial Measures

In this news release, management has presented its operating results for the fourth quarters and full years of 2022 and 2021, in accordance with U.S. Generally Accepted Accounting Principles (GAAP) and on a non-GAAP basis. In addition, management has presented its full year 2023 EPS and tax guidance in accordance with GAAP and on a non-GAAP basis. These non-GAAP financial measures are computed by excluding certain items related to acquisitions, divestitures, restructuring and certain other items from the related GAAP financial measures. Beginning January 1, 2022, following industry guidance from the U.S. Securities and Exchange Commission, the Company no longer excludes adjustments for upfront license fees, development milestones and IPR&D expenses of pre-approval programs related to licensing, collaboration and asset acquisition transactions from its non-GAAP financial measures. For purposes of comparability, the non-GAAP financial results for the fourth quarter and full year of 2021 have been updated to reflect this change. Reconciliations for these non-GAAP financial measures to the most directly comparable GAAP financial measures are included in the news release. Management has presented Free Cash Flow (FCF), which is a non-GAAP financial measure, for the fourth quarters and full years of 2022 and 2021. FCF is computed by subtracting capital expenditures from operating cash flow, each as determined in accordance with GAAP. Management has presented Total Revenues and Product Sales Adjusted for Foreign Currency Exchange Rate Impact, which is a non-GAAP financial measure, for the fourth quarter and full year of 2022. Total Revenues and Product Sales Adjusted for Foreign Currency Exchange Rate Impact is computed by converting our current period local currency product sales using the prior period foreign currency exchange rates and comparing that to our current period product sales. Management has also presented Earnings Before Interest, Taxes, Depreciation and Amortization (EBITDA) and debt leverage ratio for 2022, both of which are non-GAAP financial measures. EBITDA is computed by adding interest expense, provision for income taxes, and depreciation and amortization expense to GAAP net income. Debt leverage ratio is calculated as the ratio of GAAP total debt to EBITDA.

The Company believes that its presentation of non-GAAP financial measures provides useful supplementary information to and facilitates additional analysis by investors. The Company uses certain non-GAAP financial measures to enhance an investor’s overall understanding of the financial performance and prospects for the future of the Company’s ongoing business activities by facilitating comparisons of results of ongoing business operations among current, past and future periods. The Company believes that FCF provides a further measure of the Company’s liquidity. The Company believes Total Revenues and Product Sales Adjusted for Foreign Currency Exchange Rate Impact provides supplementary information on the Company’s product sales performance by excluding changes in foreign currency exchange rates between comparative periods. The Company believes its debt leverage ratio provides an important ongoing operating metric as it compares the amount of cash generated by our operations during a given period relative to our debt obligations outstanding for the same period.

The Company uses the non-GAAP financial measures set forth in the news release in connection with its own budgeting and financial planning internally to evaluate the performance of the business, including to allocate resources and to evaluate results relative to incentive compensation targets. The non-GAAP financial measures are in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP.

On January 31, 2023 Acorda Therapeutics, Inc. (NASDAQ: ACOR) reported that Ron Cohen, M.D., Acorda’s President and Chief Executive Officer, will make a virtual presentation at the Sequire Biotechnology Conference on Thursday, February 2 at 3:00 p.m. ET (Press release, Acorda Therapeutics, JAN 31, 2023, View Source [SID1234626659]).

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Event: Acorda Therapeutics Presentation at the Sequire Biotechnology Conference
Date: Thursday, February 2, 2023
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A webcast of the presentation can also be accessed under "Investor Events" in the Investor section of the Acorda website at www.acorda.com, beginning Friday, February 3 by clicking the following link: View Source