On April 27, 2022 AstraZeneca and Daiichi Sankyo reported it’s ENHERTU (fam-trastuzumab deruxtecan-nxki) has been granted Breakthrough Therapy Designation (BTD) in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy (Press release, AstraZeneca, APR 27, 2022, View Source [SID1234613065]). Patients with hormone receptor (HR) positive breast cancer should additionally have received or be ineligible for endocrine therapy.

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ENHERTU is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo.

The Food and Drug Administration’s (FDA) BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat a serious condition and address a significant unmet medical need. The new medicine needs to have shown encouraging preliminary clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.

Up to half of all patients with breast cancer have tumors with a HER2 immunohistochemistry (IHC) score of 1+, or 2+ in combination with a negative in-situ hybridization (ISH) test, a level of HER2 expression not currently eligible for HER2-targeted therapy.1-4 Low HER2 expression occurs in both HR-positive and HR-negative disease.5

HER2 testing is routinely used to determine appropriate treatment options for patients with metastatic breast cancer. Targeting the lower range of expression in the HER2 spectrum may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.6 Currently, chemotherapy remains the only treatment option for patients with HR-positive tumors following progression on endocrine (hormone) therapy.7 Few targeted options are available for those who are HR-negative.8

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: "Today’s news is a significant validation of the potential we see for the historic DESTINY-Breast04 trial to enable a paradigm shift in how breast cancer is classified by targeting the full spectrum of HER2 expression. ENHERTU continues to show transformative potential, and this milestone represents an important advance for patients with HER2-low metastatic breast cancer who are in urgent need of new treatment options and better outcomes."

Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: "Historically, only patients with HER2-positive metastatic breast cancer were shown to benefit from HER2-directed therapy. DESTINY-Breast04, in which ENHERTU showed a clinically meaningful survival benefit in patients with HER2-low metastatic breast cancer, is the first trial to demonstrate that selecting patients for treatment based on low expression of HER2 has the potential to change the diagnostic and treatment paradigms for these patients. This Breakthrough Therapy Designation acknowledges the potential of ENHERTU to fulfill an unmet medical need and we look forward to working closely with the FDA to bring the first HER2-directed therapy to patients with metastatic breast cancer whose tumors have lower levels of HER2 expression."

The FDA granted the BTD based on data from the pivotal DESTINY-Breast04 Phase III trial which reported positive high-level results in February 2022. In the trial, ENHERTU demonstrated a statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) in patients with HER2-low unresectable and/or metastatic breast cancer in all randomized patients with HR-positive and HR-negative disease versus physician’s choice of chemotherapy, which is the current standard of care. The safety profile of ENHERTU was consistent with previous clinical trials with no new safety concerns identified. The data will be presented at an upcoming medical meeting.

This is the third BTD for ENHERTU in breast cancer. ENHERTU previously received BTD’s for the treatment of second-line HER2-positive metastatic breast cancer in 2021 and later-line HER2-positive metastatic breast cancer in 2017. Two additional BTD’s for ENHERTU were granted in 2020 for HER2-mutant metastatic non-small cell lung cancer (NSCLC) and HER2-positive metastatic gastric cancer.

Important Safety Information

Indications

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.

Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications

None.

Warnings and Precautions

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer

In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Locally Advanced or Metastatic Gastric Cancer

In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Metastatic Breast Cancer

In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4mg/kg, a decrease in neutrophil count was reported in 62% of patients. Sixteen percent had Grade 3 or 4 decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 23 days (range: 6 to 547). Febrile neutropenia was reported in 1.7% of patients.

Locally Advanced or Metastatic Gastric Cancer

In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Additional Dose Modifications

Thrombocytopenia

For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less. Reduce dose by one level.

Adverse Reactions

Metastatic Breast Cancer

The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (79%), white blood cell count decreased (70%), hemoglobin decreased (70%), neutrophil count decreased (62%), fatigue (59%), vomiting (47%), alopecia (46%), aspartate aminotransferase increased (41%), alanine aminotransferase increased (38%), platelet count decreased (37%), constipation (35%), decreased appetite (32%), anemia (31%), diarrhea (29%), hypokalemia (26%), and cough (20%).

Locally Advanced or Metastatic Gastric Cancer

The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma in DESTINY‑Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (75%), white blood cell count decreased (74%), neutrophil count decreased (72%), lymphocyte count decreased (70%), platelet count decreased (68%), nausea (63%), decreased appetite (60%), anemia (58%), aspartate aminotransferase increased (58%), fatigue (55%), blood alkaline phosphatase increased (54%), alanine aminotransferase increased (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), blood bilirubin increased (24%), pyrexia (24%), and alopecia (22%).

Use in Specific Populations

Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.
Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were ≥65 years and 5% were ≥75 years. No overall differences in efficacy were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (53%) as compared to younger patients (42%). Of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

Notes

Breast cancer and HER2 expression

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide and in the US.9,10 More than two million cases of breast cancer were diagnosed in 2020 resulting in nearly 685,000 deaths globally.9 In the US, more than 290,000 new cases are expected to be diagnosed in 2022, resulting in more than 43,000 deaths.11

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumors.12 HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which measures the amount of HER2 protein on a cancer cell, and/or an ISH test which counts the copies of the HER2 gene in cancer cells.12,13 HER2-positive cancers are defined as IHC 3+ or IHC 2+/ISH+, and HER2-negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.12

DESTINY-Breast04

DESTINY-Breast04 is a global, randomized, open-label, registrational Phase III trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive (n=480) or HR-negative (n=60) HER2-low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either ENHERTU or chemotherapy.

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive disease based on blinded independent central review (BICR). Key secondary endpoints include PFS based on BICR in all randomized patients (HR-positive and HR-negative disease), OS in patients with HR-positive disease and OS in all randomized patients (HR-positive and HR-negative disease). Other secondary endpoints include PFS based on BICR and investigator assessment, duration of response based on BICR and safety.

DESTINY-Breast04 enrolled approximately 540 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

ENHERTU

ENHERTU is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU development program

A comprehensive development program is underway globally, evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for ENHERTU are currently under review in Europe, Japan, the US and several other countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03 trial.

ENHERTU is also currently under review in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 (ERBB2) mutation and who have received a prior systemic therapy, and in Europe for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2 based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

Daiichi Sankyo collaboration

Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of ENHERTU and datopotamab deruxtecan.

AstraZeneca in breast cancer

Driven by a growing understanding of breast cancer biology, AstraZeneca is starting to challenge, and redefine, the current clinical paradigm for how breast cancer is classified and treated to deliver even more effective treatments to patients in need – with the bold ambition to one day eliminate breast cancer as a cause of death.

AstraZeneca has a comprehensive portfolio of approved and promising compounds in development that leverage different mechanisms of action to address the biologically diverse breast cancer tumor environment.

AstraZeneca aims to continue to transform outcomes for HR-positive breast cancer with foundational medicines fulvestrant and goserelin and the next-generation oral selective estrogen receptor degrader (SERD) and potential new medicine camizestrant.

PARP inhibitor olaparib is a targeted treatment option that has been studied in HER2-negative early and metastatic breast cancer patients with an inherited BRCA mutation. AstraZeneca with MSD (Merck & Co., Inc. in the US and Canada) continue to research olaparib in metastatic breast cancer patients with an inherited BRCA mutation and are exploring new opportunities to treat these patients earlier in their disease.

Building on the first approval of ENHERTU, a HER2-directed ADC, in previously treated HER2-positive metastatic breast cancer, AstraZeneca and Daiichi Sankyo are exploring its potential in earlier lines of treatment and in new breast cancer settings.

To bring much-needed treatment options to patients with triple-negative breast cancer, an aggressive form of breast cancer, AstraZeneca is testing immunotherapy durvalumab in combination with other oncology medicines, including olaparib and ENHERTU, evaluating the potential of AKT kinase inhibitor, capivasertib, in combination with chemotherapy, and collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan.

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

On April 27, 2022 BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) (BioMarin or the Company) reported financial results for the first quarter ended March 31, 2022 (Press release, BioMarin, APR 27, 2022, View Source [SID1234613082]).

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BioMarin Announces Record Revenues in First Quarter 2022
"We begin 2022 from a position of financial strength including significant contributions from our newest product, Voxzogo, the only approved therapy for children with achondroplasia. We continue to be encouraged by the high level of interest in Voxzogo from families and physicians worldwide seeking treatment that addresses the underlying cause of achondroplasia," said Jean-Jacques Bienaimé, Chairman and Chief Executive Officer of BioMarin. "As we stated last quarter, in 2022 we expect to return to double-digit revenue growth and profitability. We begin the journey with record first quarter revenues, and foresee continued momentum based on the essential nature of our innovative medicines for our patients around the world."

Mr. Bienaimé continued, "The regulatory team has been working collaboratively with the European Medicines Agency as we near the completion of the application review procedure for potential approval of valoctocogene roxaparvovec gene therapy for the treatment of severe hemophilia A. We remain encouraged by the potential benefit of valoctocogene roxaparvovec for people with severe hemophilia A based on the clinically meaningful study results to date. These demonstrate an 85% reduction in annualized bleeding rates compared to baseline using standard of care. With potential approvals of valoctocogene roxaparvovec in Europe and United States, the continued strong launch of Voxzogo and our anticipated transition to sustainable profitability, we believe 2022 will be a transformational year for all BioMarin stakeholders."

Financial Highlights:

Total Revenues for the first quarter of 2022 were $519.4 million, an increase of 7% compared to the same period in 2021 despite continued erosion of the U.S. Kuvan market. The increase in Total Revenues was primarily attributed to the following:

Higher Vimizim and Naglazyme product revenues primarily driven by new patients initiating therapy and timing of orders in the Middle East and Europe.

Voxzogo commercial sales due to new patients initiating therapy in Europe and the U.S. following regulatory approvals by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) in the third and fourth quarters of 2021, respectively.

Higher Brineura product revenues primarily attributed to new patients initiating therapy in Europe.
These factors were offset by the following:

Lower Aldurazyme product revenues due to timing of bulk lot product fulfillment to Sanofi. BioMarin Aldurazyme revenues are driven by the timing of when the product is released and control is transferred to Sanofi.

Lower Kuvan product revenues primarily due to generic competition as a result of the loss of exclusivity in the U.S. that occurred in October 2020, consistent with expectations.
GAAP Net Income increased to $120.8 million for the first quarter of 2022 compared to GAAP Net Income of $17.4 million for the same period in 2021. The increase was primarily related to the $89.0 million gain, net of tax, on the sale to a third party of the Rare Pediatric Disease Priority Review Voucher (PRV) we received from the FDA in connection with the U.S. approval of Voxzogo and an increase in gross profit.
Non-GAAP Income for the first quarter of 2022 was $105.3 million, essentially flat compared to the same period in 2021. The increase in gross profit was offset by higher sales and marketing expenses to support the commercial launch of Voxzogo and pre-commercialization activities for valoctocogene roxaparvovec and higher research and development expenses driven by the ramp up of activities for early research programs.
Late-stage Regulatory Portfolio (Voxzogo and valoctocogene roxaparvovec)

The global launch of Voxzogo is actively underway, with market access and reimbursement progressing as anticipated. As of March 31, 2022, an estimated 284 children were being treated with commercial Voxzogo globally, 201 from countries outside the United States and 83 within the United States. As of March 31, 2022, there were 15 active markets contributing to Voxzogo sales, including the addition of Saudi Arabia, Slovenia, the Czech Republic, United Arab Emirates and Italy, since the February 2022 update.
Marketing authorization reviews of Voxzogo are in process in Japan and Australia, with potential approvals in those countries in 2022.
During the quarter, the Company provided a top-line update on the Phase 2 randomized, double-blind, placebo-controlled Voxzogo study in infants and young children up to five years of age with achondroplasia. 52-week results trended in favor of Voxzogo compared to placebo on height Z-score, annualized growth velocity, and with no worsening in proportionality in the overall study population. BioMarin intends to initiate discussions with regulatory health authorities to discuss next steps regarding efforts to expand access to Voxzogo treatment for this younger age group. Results from this study are expected to be shared at a scientific meeting mid-year 2022.
The EMA continues the review of BioMarin’s Marketing Authorization Application (MAA) for valoctocogene roxaparvovec and we anticipate a CHMP opinion mid-year 2022. BioMarin has provided the EMA with two-year follow-up safety and efficacy data from the GENEr8-1 study.
Based on the favorable results from the two-year follow-up safety and efficacy data from the GENEr8-1 study, BioMarin is targeting a BLA resubmission for valoctocogene roxaparvovec in June 2022 followed by an expected 6-month review procedure by the FDA. A pre-submission interaction is scheduled with the FDA later this quarter to discuss BioMarin’s BLA resubmission efforts.
During the first quarter of 2022, the Company announced that a subject treated with valoctocogene roxaparvovec in the Phase 2 study over 5 years ago reported a salivary gland mass in late 2021. The event was reported as unrelated to valoctocogene roxaparvovec by the investigator. The subject was successfully treated, and the Company conducted a genomic analysis from a tissue sample containing the mass. Today, BioMarin announced that the findings from the completed analysis showed a comparable pattern of integration between healthy and tumor containing tissues, with no evidence emerging that vector integration contributed to the salivary gland mass. These data will be presented both in a workshop of the annual American Society of Gene & Cell Therapy meeting and the World Federation of Hemophilia 2022 World Congress in May, supplied to the EMA as part of the ongoing review of the MAA and included in the BLA resubmission.
Earlier-stage Development Portfolio (BMN 255, BMN 331, BMN 351, BMN 349, BMN 293 (DiNA-001))

BMN 255 for primary hyperoxaluria type 1, a subset of chronic renal disease: The Company has completed the single ascending dose arm of the First-in-Human study and is analyzing the results. BioMarin believes the availability of a potent, orally bioavailable, small molecule like BMN 255 may be able to significantly reduce disease and treatment burden in certain people with chronic renal disease.
BMN 331 gene therapy product candidate for Hereditary Angioedema (HAE): The Company announced that it has begun dosing patients in the Phase 1/2 HAERMONY study to evaluate BMN 331, an investigational AAV5-mediated gene therapy for people living with hereditary angioedema (HAE). The FDA granted Orphan Disease Designation status to BMN 331 in 2021.
BMN 351 for Duchenne Muscular Dystrophy (DMD): IND-enabling studies continue with BMN 351, an antisense oligonucleotide therapy for individuals with exon 51-skip-amenable DMD. BMN 351 was developed using familiar chemistry and superior biology, by targeting a novel, upstream, splice enhancer site demonstrating improved binding affinity and tolerability in preclinical models. Preclinical data suggest that restored expression of near-full-length dystrophin protein at levels of up to 40% will convert phenotypes from rapid loss to durable preservation of strength and ambulation. BioMarin expects to file an IND for BMN 351 in the first half of 2022, and anticipates treating clinical trial participants with Duchenne muscular dystrophy in the fourth quarter of 2022.
BMN 349 for alpha-1 antitrypsin deficiency: Preclinical studies have demonstrated that BMN 349 is an orally bioavailable, small molecule that is titratable with rapid onset and high potency and efficacy. Preclinical results have strong implications for potential improvement of current management, particularly for severe liver disease requiring rapid action. BioMarin’s goal is to file the IND in the second half of 2023.
BMN 293 (formerly DiNA-001) for MYBPC3 hypertrophic cardiomyopathy (HCM): Preclinical studies are underway with BMN 293 following a collaboration announced in 2020 with DiNAQOR, a gene therapy platform company, to develop novel gene therapies to treat rare genetic cardiomyopathies. Mutations in MYBPC3 are the most common cause of inherited HCM. Early investigations suggest that gene therapy-mediated gene transfer can lead to widespread expression of the gene product, cardiac myosin-binding protein C (MyBP-C), in cardiac tissue, which can normalize relaxation kinetics and potentially ameliorate the disease phenotype in individuals suffering from cardiomyopathy. BioMarin’s goal is to file the IND in 2023.

(1) All Financial Guidance items are calculated based on U.S. GAAP with the exception of Non-GAAP Income. Refer to Non-GAAP Information beginning on page 9 of this press release for a complete discussion of the Company’s Non-GAAP financial information and reconciliations to the corresponding GAAP reported information.

BioMarin will host a conference call and webcast to discuss first quarter and year to date 2022 financial results today, Wednesday, April 27, 2022 at 4:30 p.m. ET. This event can be accessed on the investor section of the BioMarin website at www.biomarin.com.

On April 27, 2022 Candel Therapeutics, Inc. (Nasdaq: CADL), a late clinical stage biopharmaceutical company developing novel oncolytic viral immunotherapies, reported that an abstract has been accepted for presentation at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2022, which will be held in person from June 3 – 7, 2022, at the McCormick Place Convention Center in Chicago, Illinois (Press release, Candel Therapeutics, APR 27, 2022, View Source [SID1234613156]). The presented data will detail clinical outcomes from Candel’s phase 2 clinical trial evaluating CAN-2409 and valacyclovir in combination with anti-PD-1 or PD-L1 agents in patients with stage III/IV NSCLC.

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Presentation details:

Abstract Title: First report of safety/tolerability and preliminary antitumor activity of CAN-2409 in inadequate responders to immune checkpoint inhibitors for stage III/IV NSCLC
Presenter: Charu Aggarwal, MD, MPH, Associate Professor of Lung Cancer Excellence, Perelman School of Medicine, University of Pennsylvania
Session Date and Time: Monday, June 6, 2022, from 8:00 AM – 11:00 AM CDT
Abstract Link: View Source
Session Title: Lung Cancer – Non-Small Cell Metastatic
Abstract Number: 9037

On April 27, 2022 GlaxoSmithKline reported that strong Q1 2022 sales of £9.8 billion, +32% AER, +32% CER; Total EPS 35.9p +67% AER, +66% CER and Adjusted EPS 32.8p +43% AER, +43% CER (Press release, GlaxoSmithKline, APR 27, 2022, View Source [SID1234613015])

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Highlights
Strong sales growth across Biopharma and Consumer Healthcare
Biopharma: £7.1 billion +40% AER, +40% CER;+14% AER, +15% CER excluding COVID-19 solutions
Specialty Medicines £3.1 billion +98% AER, +97% CER; HIV +15% AER, +14% CER; Oncology +15% AER, +15% CER; Immuno-inflammation, respiratory and other +18% AER, +18% CER; COVID-19 solutions (Xevudy) sales £1.3 billion
Vaccines £1.7 billion +36% AER, +36% CER; Shingrix £698 million >100% AER, >100% CER
General Medicines £2.3 billion +2% AER, +3% CER
Consumer Healthcare £2.6 billion +14% AER, +14% CER
Sales growth also benefited from favourable comparison to Q1 2021
Continued R&D delivery and strengthening of pipeline
US FDA regulatory approvals: Cabenuva treatment of virologically supressed adolescents living with HIV; Triumeq dispersible single tablet regimen for treatment of children with HIV
US FDA regulatory submission acceptance of daprodustat for anaemia of chronic kidney disease (PDUFA action date 1 February 2023)
Benlysta approved in China for adults with active lupus nephritis
EU regulatory submission acceptance for Sanofi-GSK COVID-19 vaccine (Vidprevtyn) and Canadian regulatory approval for Medicago-GSK COVID-19 vaccine (Covifenz)
Proposed acquisition of Sierra Oncology Inc. strengthens late-stage specialty pipeline. Momelotinib has potential to address significant unmet medical need of myelofibrosis patients with anaemia
Multiple pipeline catalysts in next nine months, including phase III data read outs for the RSV Older Adults and meningitis (MenABCWY) vaccine candidates, Blenrep, Jemperli and otilimab, and phase IIb data for bepirovirsen
Cost discipline supports delivery of improved operating margin and Adjusted EPS of 32.8p
Total Group operating margin 28.6%. Total EPS 35.9p +67% AER, +66% CER
Adjusted Group operating margin 26.7%. Adjusted EPS 32.8p +43% AER, +43% CER. This included a contribution to growth from COVID-19 solutions of approximately +15% AER, +15% CER for Q1 2022
Q1 2022 cash generated from operations £2.8 billion. Q1 2022 free cash flow £1.7 billion
On track to demerge and list Haleon, a new global leader in consumer healthcare, in July 2022
New growth outlooks set out in Q1 2022, for annual organic revenue growth of 4-6% and sustainable moderate expansion of adjusted operating margin over medium term at CER
Reconfirming 2022 guidance
GSK expected to deliver growth in 2022 sales of between 5% to 7% at CER and growth in 2022 Adjusted operating profit of between 12% to 14% at CER
2022 guidance excludes any contribution from COVID-19 solutions
Dividend of 14p declared for Q1 2022

Emma Walmsley, Chief Executive Officer, GSK said:
"We have delivered strong first quarter results in this landmark year for GSK, as we separate Consumer Healthcare and start a new period of sustained growth. Our results reflect further good momentum across specialty medicines and vaccines, including the return to strong sales growth for Shingrix and continuing pipeline progress. We also continue to see very good momentum in Consumer Healthcare, demonstrating strong potential of this business ahead of its proposed demerger in July, to become Haleon."

On April 27, 2022 Amgen (NASDAQ: AMGN) reported financial results for the first quarter of 2022 (Press release, Amgen, APR 27, 2022, View Source [SID1234613033]). Key results include:

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Total revenues increased 6% to $6.2 billion in comparison to the first quarter of 2021, resulting from 2% growth in global product sales and increased Other Revenue from our COVID-19 manufacturing collaboration.
Volumes grew double-digits for a number of products including Repatha (evolocumab), Prolia (denosumab) and EVENITY (romosozumab-aqqg).
GAAP earnings per share (EPS) decreased 5% to $2.68 driven by a decrease in other (expense) income, net, partially offset by increased revenues and lower weighted-average shares outstanding. The decrease in other (expense) income, net, was primarily driven by net losses recognized on our strategic equity investments in the current year compared with net gains recognized in the prior year.
GAAP operating income increased 17% to $2.5 billion, and GAAP operating margin increased 5.5 percentage points to 43.6%.
Non-GAAP EPS increased 15% to $4.25, driven by increased revenues and lower weighted-average shares outstanding.
Non-GAAP operating income increased 10% to $3.1 billion, and non-GAAP operating margin increased 3.6 percentage points to 54.8%.
The Company generated $2.0 billion of free cash flow for the first quarter versus $1.9 billion in the first quarter of 2021.
2022 total revenues guidance reaffirmed at $25.4-$26.5 billion; EPS guidance revised to $12.53-$13.58 on a GAAP basis, and reaffirmed at $17.00-$18.00 on a non-GAAP basis.
Amgen will vigorously contest the adjustments and penalties proposed by the Internal Revenue Service (IRS) for the 2010-15 period as discussed in more detail on pages 7-8 of this release. Amgen is confident in its position in the dispute, and in the level of reserves the Company has established.
"We achieved strong, volume-driven growth in the quarter, while launching two very promising first-in-class medicines," said Robert A. Bradway, chairman and chief executive officer. "We are also advancing a robust pipeline with data for several mid-to-late stage candidates expected during the year."

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

References in this release to "non-GAAP" measures, measures presented "on a non-GAAP basis" and "free cash flow" (computed by subtracting capital expenditures from operating cash flow) refer to non-GAAP financial measures. 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 2% for the first quarter of 2022 versus the first quarter of 2021. Unit volumes grew 9%, offset by 7% lower net selling price and 2% negative impact from foreign exchange, and sales in the first quarter benefited 2% ($110 million) from year-over-year favorable changes to estimated sales deductions. Consistent with prior years, Enbrel (etanercept) and Otezla (apremilast) followed the pattern of lower Q1 sales relative to the remainder of the year due to the impact of benefit plan changes, insurance reverifications and increased co-pay expenses as U.S. patients work through deductibles.

COVID-19 continued to affect our business around the world in the first quarter. In March and April, we have seen the impact of the pandemic recede in the U.S., which has led to improved demand patterns and allowed us to engage in increased field-facing activities.

General Medicine

Prolia sales increased 12% year-over-year for the first quarter, driven by 10% volume growth and higher net selling price.

EVENITY sales increased 59% year-over-year to a record $170 million for the first quarter, driven by strong volume growth across our markets. U.S. sales grew 93% year-over-year, driven by 79% volume growth.

Repatha sales increased 15% year-over-year for the first quarter, driven by 49% volume growth partially offset by lower net selling price. Sales grew 19% in the U.S., driven by 41% volume growth partially offset by lower net selling prices resulting from higher rebates to support and expand access for patients. Sales grew 12% outside the U.S., with 57% volume growth partially offset by lower net selling price primarily driven 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 million patients treated since launch.

Aimovig (erenumab-aooe) sales increased 53% year-over-year for the first quarter, driven by favorable changes to estimated sales deductions and higher net selling price, partially offset by a 4% decline in volume.

Inflammation

TEZSPIRE (tezepelumab-ekko) generated sales of $7 million for the first quarter. TEZSPIRE has been well received by prescribers, with initial adoption by both allergists and pulmonologists. Healthcare providers have welcomed the product’s novel approach to treating the approximately 2.5 million worldwide patients with severe asthma who are uncontrolled or biologic eligible, without any phenotypic and biomarker limitation.

Otezla (apremilast) sales decreased 5% year-over-year for the first quarter, primarily driven by lower net selling price and lower inventory levels, partially offset by 7% volume growth. In the U.S., we saw strengthening of the market, with Otezla remaining the market share leader among patients who are new to systemic agents for psoriasis. U.S. sales were impacted in the first quarter as both wholesalers and specialty pharmacies reduced inventory levels. Otezla sales in the U.S. were also impacted by price declines in the first quarter, driven primarily by 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. Going forward, we expect continued strong volume growth and lower year-over-year price erosion for the remaining quarters of 2022.

Enbrel (etanercept) sales decreased 7% year-over-year for the first quarter, driven by declines in net selling price and inventory levels. Year-over-year volume remained flat in the first quarter, supported by Enbrel’s long track record of efficacy and safety.

AMGEVITA (adalimumab) sales increased 2% year-over-year for the first quarter, driven by 16% volume growth, partially offset by foreign exchange impact and lower net selling price resulting from increased competition. AMGEVITA continues to be the most prescribed adalimumab biosimilar in Europe.
Hematology-Oncology

LUMAKRAS/LUMYKRAS (sotorasib) generated $62 million of sales for the first quarter, representing 38% quarter-over-quarter growth. In the U.S., LUMAKRAS has been prescribed to approximately 2,500 patients by over 1,500 physicians in both academic and community settings. Outside the U.S., LUMYKRAS has now been approved in nearly 40 countries around the world, with recent reimbursement approvals in the United Kingdom and Japan.

KYPROLIS (carfilzomib) sales increased 14% year-over-year for the first quarter, driven by 13% volume growth.

XGEVA (denosumab) sales increased 7% year-over-year for the first quarter, driven by favorable changes to estimated sales deductions and higher net selling price, partially offset by a 2% decline in volume growth.

Vectibix (panitumumab) sales increased 5% year-over-year for the first quarter, driven by volume growth in ex-US markets. Vectibix remains the EGFR (epidermal growth factor receptor) inhibitor of choice across all lines of therapy.

Nplate (romiplostim) sales increased 17% year-over-year for the first quarter, driven by 7% volume growth and favorable changes to estimated sales deductions.

BLINCYTO (blinatumomab) sales increased 29% year-over-year for the first quarter, driven by volume growth.

MVASI sales decreased 17% year-over-year for the first quarter, primarily driven by lower net selling price that was partially offset by 13% volume growth. In the U.S., MVASI continues to hold leading volume share with 49% of the bevacizumab segment in the quarter. For the full-year, we expect continued net selling price erosion and volume declines driven by increased competition and Average Selling Price (ASP) erosion.

KANJINTI (trastuzumab-anns) sales decreased 40% year-over-year for the first quarter, primarily driven by declines in net selling price and volume. In the U.S., KANJINTI continues to hold leading volume share with 39% of the trastuzumab segment in the quarter. Going forward, we expect continued net selling price deterioration and volume declines driven by increased competition and ASP erosion.
Established Products

Total sales of our established products, which include Neulasta (pegfilgrastim), NEUPOGEN (filgrastim), EPOGEN (epoetin alfa), Aranesp (darbepotein alfa), Parsabiv (etelcalcetide), and Sensipar/Mimpara (cinacalcet), decreased 12% year-over-year for the first quarter, primarily driven by lower net selling price and volume declines. In the aggregate, we expect the year-over-year net price and volume erosion for this portfolio of products to continue.
Product Sales Detail by Product and Geographic Region

* Change in excess of 100%

** Other products includes Corlanor, GENSENTA, IMLYGIC, AVSOLA, Bergamo, and RIABNI

Operating Expense, Operating Margin and Tax Rate Analysis

On a GAAP basis:

Total Operating Expenses decreased 1%. Cost of Sales margin increased 0.6 percentage points primarily driven by manufacturing cost, including COVID-19 antibody manufacturing, and increased royalties and profit share, partially offset by lower amortization expenses from acquisition-related assets. Research & Development (R&D) expenses decreased 1%. The first quarter of 2021 included $53 million related to the Rodeo Therapeutics acquisition. Selling, General & Administrative (SG&A) expenses decreased 2%.
Operating Margin as a percentage of product sales increased 5.5 percentage points to 43.6%.
Tax Rate increased 0.5 percentage points primarily driven by current year net unfavorable items compared to last year partially offset by changes in earnings mix.
On a non-GAAP basis:

Total Operating Expenses increased 2%. Cost of Sales margin increased 1.1 percentage points primarily driven by manufacturing cost, including COVID-19 antibody manufacturing, and increased royalties and profit share. R&D expenses decreased 1%. The first quarter of 2021 included $53 million related to the Rodeo Therapeutics acquisition. SG&A expenses decreased 1%.
Operating Margin as a percentage of product sales increased 3.6 percentage points to 54.8%.
Tax Rate increased 0.5 percentage points primarily driven by current year net unfavorable items compared to last year partially offset by changes in earnings mix.
$Millions, except percentages

Cash Flow and Balance Sheet

The Company generated $2.0 billion of free cash flow in the first quarter of 2022 versus $1.9 billion in the first quarter of 2021.
The Company’s first quarter 2022 dividend of $1.94 per share was declared on December 3, 2021, and was paid on March 8, 2022, to all stockholders of record as of February 15, 2022, representing a 10% increase from 2021.
On February 24, 2022, the Company entered into Accelerated Stock Repurchase (ASR) agreements to repurchase an aggregate of up to $6 billion of the Company’s common stock with an initial 23.3 million shares received and retired. The final number of shares to be repurchased by the Company under the ASR will be based on the daily volume-weighted average stock price of the Company’s common stock, subject to the terms of the ASR agreements. In total, the Company repurchased 24.6 million shares of common stock at a total cost of $6.3 billion during the first quarter of 2022, including shares received under the ASR agreements.
Cash and investments totaled $6.5 billion and debt outstanding totaled $36.9 billion as of March 31, 2022.
$Billions, except shares

2022 Guidance

For the full year 2022, the Company now expects:

Total revenues in the range of $25.4 billion to $26.5 billion.
On a GAAP basis, EPS in the range of $12.53 to $13.58 and a tax rate in the range of 10.5% to 12.0%.
On a non-GAAP basis, EPS in the range of $17.00 to $18.00 and a tax rate in the range of 13.5% to 14.5%.
Capital expenditures to be approximately $950 million.
Share repurchases in the range of $6.0 billion to $7.0 billion.
U.S. Tax Petition

On April 18, 2022, Amgen received a notice of deficiency from the IRS for the 2013-2015 period proposing adjustments primarily related to the allocation of profits between certain of the Company’s entities in the United States and the U.S. territory of Puerto Rico similar to those previously proposed by the IRS for the 2010-2012 period. This notice seeks to increase Amgen’s U.S. taxable income for the 2013-2015 period by an amount that would result in additional federal tax of approximately $5.1 billion, plus interest. In addition, the notice proposes penalties of approximately $2 billion.

Amgen firmly believes that the adjustments proposed by the IRS for the 2010-2015 period and the penalties proposed by the IRS for the 2013-2015 period are without merit:

Puerto Rico is the site of the Company’s flagship manufacturing complex responsible for the majority of Amgen’s global manufacturing. Amgen has had a substantial manufacturing presence in Puerto Rico for 30 years, and the Company’s Puerto Rico subsidiary produces sophisticated biologic medicines for millions of patients around the world. The many valuable contributions of the Company’s Puerto Rico subsidiary include the effort and expertise of its 2,400 highly skilled staff members, the nearly $4 billion in capital investments it has made on the Island, the valuable assets it possesses, and the significant risks it has assumed in connection with its business. It is through these investments that Amgen has been able to meet the needs of every patient, every time.
Amgen’s allocation of profit between its U.S. and Puerto Rico entities appropriately recognizes the key contributions made by the Company’s Puerto Rico subsidiary. The IRS position fails to adequately account for the importance of these value drivers. The proposed adjustments would result in Amgen’s Puerto Rico subsidiary earning little or no profit from its operations despite the value of and risk associated with its contributions.
The IRS audited Amgen at length for many years on the allocation of profit between the U.S. and Puerto Rico. These audits were resolved through agreements with the IRS, resulting in no financial statement detriment to the Company. Refer to Footnote 5, Income Taxes, in Amgen’s 2007 and 2008 Form 10-K filings, and Footnote 4, Income Taxes, in Amgen’s 2012 and 2013 Form 10-K filings.
Further, the amount of the adjustments proposed by the IRS for the 2010-2015 period overstates by billions of dollars the magnitude of the dispute:

Amgen believes, based upon the positions advanced by the IRS, that the IRS adjustments for the 2010-2015 period are overstated by approximately $2 billion due to the IRS failure to account for certain income and expenses. Amgen has reported its income and expenses in a consistent manner for many years and the IRS has appropriately accounted for the Company’s income and expenses in all prior audits.
Any additional tax that could be imposed for the 2010-2015 period would be reduced by up to approximately $3.1 billion of repatriation tax previously accrued with respect to the Company’s Puerto Rico earnings.
Amgen previously made advance tax deposits to the IRS totaling $1.1 billion for the 2010-2015 period. These deposits would further reduce any additional cash tax that could be imposed.
In addition, Amgen believes the IRS assertion of approximately $2 billion in penalties for the 2013-2015 period is wholly unwarranted. Amgen has applied a consistent transfer pricing methodology since 2002, has documented that transfer pricing methodology as required under relevant tax regulations, and has extensively discussed that methodology with the IRS across multiple tax audits over multiple years. The IRS has never previously proposed transfer pricing penalties.

Amgen believes that the Company has appropriate tax reserves. The Company filed a petition in the U.S. Tax Court in July 2021 to contest the adjustments previously proposed for the 2010-2012 period and plans to file another petition in the U.S. Tax Court to contest the adjustments proposed in the notice for the 2013-2015 period. Amgen will seek consolidation of the two periods into one case in Tax Court. The dispute is expected to take several years to resolve.

The IRS is currently auditing the 2016-2018 period. Amgen expects the audit to continue for several years, and it is possible the 2010-2015 dispute will be resolved before the conclusion of the 2016-2018 audit and administrative appeals process. Any transfer pricing adjustments the IRS may propose for this period will be lessened by the change in tax rates resulting from the 2017 tax reform law, which reduced the difference between the tax rates applicable in the U.S. and Puerto Rico by approximately two thirds beginning in 2018.

First Quarter Product and Pipeline Update

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

Inflammation

TEZSPIRE

In February, data were presented at the American Academy of Allergy, Asthma, and Immunology Annual meeting that demonstrated reductions in the annualized asthma exacerbation rate across biomarker subgroups of patients with severe asthma and consistent efficacy throughout the year, regardless of season.
The WAYFINDER Phase 3b study, designed to demonstrate a reduction in oral corticosteroid use in adult participants with severe asthma on long-term oral corticosteroid therapy, was initiated.
The PASSAGE Phase 4 real-world effectiveness study was initiated in adult and adolescent participants with severe asthma, including underrepresented populations such as Black Americans, smokers and patients with asthma-chronic obstructive pulmonary disease overlap.
A Phase 3 study continues to enroll patients with chronic rhinosinusitis with nasal polyps.
Planning is underway for a Phase 3 study in patients with eosinophilic esophagitis.
A Phase 2b study continues to enroll patients with chronic spontaneous urticaria.
A Phase 2 study continues to enroll patients with chronic obstructive pulmonary disease.
Otezla

In March, data were presented at the American Academy of Dermatology Association meeting. Among others, the Company presented new results from both the ADVANCE and PROMINENT Phase 3 studies reinforcing the efficacy of Otezla in patients with mild to moderate plaque psoriasis, and results from the Phase 2 Japanese trial (PPP-001) in palmoplantar pustulosis (PPP). Results from PPP-001 indicated that Otezla was associated with statistically significant improvements in the primary endpoint and all secondary endpoints vs. placebo.
In March, a Phase 3 study for the treatment of Japanese patients with PPP was initiated.
Rocatinlimab (AMG 451 / KHK4083)

Phase 3 planning continues for rocatinlimab, an anti-OX40 monoclonal antibody being investigated in patients with heterogeneous moderate to severe atopic dermatitis.
Rocatinlimab binds activated pathogenic T-cells expressing OX40. Through its unique mechanism of action, rocatinlimab inhibits and prevents the expansion of activated pathogenic T-cells, and reduces their number.
Initiation of the comprehensive ROCKET Phase 3 program is anticipated in mid-2022.
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, continues to enroll patients with systemic lupus erythematosus (SLE).
Efavaleukin alfa (AMG 592)

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

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

LUMAKRAS/LUMYKRAS

LUMAKRAS/LUMYKRAS is now approved in nearly 40 countries for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with KRAS G12C mutation and who have progressed after at least one prior line of systemic therapy. Regulatory reviews continue in other jurisdictions.
In April, data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting on the long-term outcomes from a two-year analysis of the CodeBreak 100 trial in patients with KRAS G12C-mutated advanced NSCLC. These data showed that 32.5% of patients were still alive at two years and that prolonged tumor response was also observed with a 40.7% objective response rate by central review. There were no new safety signals reported over the course of this 2-year follow-up analysis.
In February, data were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) plenary series demonstrating a centrally confirmed objective response rate of 21% and disease control rate of 84% in 38 patients with heavily pre-treated advanced pancreatic cancer. The Company continues to explore the benefit of LUMAKRAS in this setting.
Initial data from cohorts exploring LUMAKRAS in combination with the anti-programmed cell death 1 protein (PD-1) antibody pembrolizumab in patients with KRAS G12C-mutated NSCLC were submitted to a medical congress taking place in the late summer.
Initial data from cohorts exploring LUMAKRAS in combination with the Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) inhibitor RMC-4630 from Revolution Medicines in patients with KRAS G12C-mutated NSCLC were submitted to a medical congress taking place in the late summer.
Top-line results from the event-driven, confirmatory Phase 3 study comparing LUMAKRAS to docetaxel in patients with KRAS G12C-mutated advanced NSCLC are expected in Q3-2022.
Top-line results from a study comparing the 960 mg/day dose of LUMAKRAS with a lower dose of 240 mg/day in patients with KRAS G12C-mutated advanced NSCLC are expected in Q4-2022.
A Phase 2 study in first-line patients with KRAS G12C-mutated NSCLC whose tumors express serine/threonine kinase 11 (STK11) mutations and/or less than 1% programmed death-ligand 1 continues to enroll.
A Phase 3 study of LUMAKRAS in combination with Vectibix in third-line KRAS G12C-mutated colorectal cancer is enrolling patients.
Bemarituzumab

A Phase 3 study (FORTITUDE-101) of bemarituzumab, a fibroblast growth factor receptor 2b (FGFR2b) targeting monoclonal antibody plus chemotherapy, versus placebo plus chemotherapy in first-line gastric cancer with FGFR2b overexpression continues to enroll patients.
A Phase 1b/3 study (FORTITUDE-102) of bemarituzumab plus chemotherapy and nivolumab versus chemotherapy and nivolumab in first-line gastric cancer with FGFR2b overexpression continues to enroll patients.
A Phase 1b study (FORTITUDE-103) of bemarituzumab plus oral chemotherapy regimens in first-line gastric cancer with FGFR2b overexpression was initiated.
A Phase 1b study (FORTITUDE-201) of bemarituzumab monotherapy and in combination with docetaxel is enrolling patients with squamous NSCLC with FGFR2b overexpression.
Planning is underway for a signal-seeking basket study in other solid tumors.
Tarlatamab (AMG 757)

DeLLphi-301, a potentially registrational Phase 2 study of tarlatamab, an HLE BiTE molecule targeting delta-like ligand 3 (DLL3), for the treatment of relapsed/refractory small cell lung cancer (SCLC) after two or more prior lines of treatment continues to enroll patients.
A Phase 1b study of tarlatamab in combination with AMG 404 continues to enroll patients with second-line or later SCLC.
DeLLphi-303, a Phase 1b study, testing tarlatamab in combination with standard of care in first-line SCLC, is on track to start enrolling patients this quarter.
Updated exploration and first expansion Phase 1 data of tarlatamab in patients with relapsed/refractory SCLC were submitted to a medical congress taking place in late summer.
A Phase 1b study of tarlatamab continues to enroll patients with de novo or treatment emergent neuroendocrine prostate cancer.
Acapatamab (AMG 160)

Data continue to mature in a dose-expansion cohort of acapatamab, a half-life extended (HLE) BiTE molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of patients with metastatic castrate-resistant prostate cancer (mCRPC). Decision-enabling data are expected in H1 2022.
A master protocol evaluating combinations with acapatamab continues to enroll patients with earlier-line mCRPC.
AMG 340

A Phase 1 dose-escalation study of AMG 340, a lower T-cell affinity BiTE molecule targeting PSMA, is enrolling patients with mCRPC.
AMG 509

A Phase 1 dose-escalation study of AMG 509, a bi-specific molecule targeting six-transmembrane epithelial antigen of prostate 1 (STEAP1) continues to enroll patients with mCRPC.
AMG 193

A Phase 1/1b/2 study of AMG 193, a novel small-molecule methylthioadenosine (MTA) cooperative protein arginine methyltransferase 5 (PRMT5) molecular glue, continues to enroll patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors.
AMG 330

Development of AMG 330, a BiTE molecule targeting CD33, being investigated for the treatment of acute myeloid leukemia (AML) has been discontinued based on the overall benefit:risk profile observed and the Company’s on-going efforts to prioritize programs with the greatest potential benefit to AML patients. These on-going programs include AMG 176, a small-molecule inhibitor of myeloid cell leukemia 1 (MCL-1) and AMG 427, an HLE BiTE molecule targeting anti-fms-like tyrosine kinase 3 (FLT3).
General Medicine

Repatha

In April, the Company announced results from two Repatha open label extension (OLE) studies (FOURIER-OLE) designed to assess the long-term safety and tolerability of Repatha in more than 6,600 high-risk adults with clinically evident atherosclerotic cardiovascular disease.
In the OLE studies, patients received Repatha for approximately 5 years, with some patients receiving Repatha for up to 8.5 years in aggregate across the FOURIER and OLE studies.
No new long-term safety findings were observed.
Medically significant and sustained reduction in low-density lipoprotein cholesterol (LDL-C) levels were observed, with more than 85 percent of patients achieving an LDL-C level of <40 mg/dL during the OLE period.
The results of these studies will be presented at an upcoming medical congress later this year.
Olpasiran (AMG 890)

Top-line results from a Phase 2 study of olpasiran, a lipoprotein(a) (Lp(a)) small interfering RNA molecule, in subjects with elevated Lp(a), are expected in H1 2022. Presentation of results is expected at a medical congress in H2 2022.
AMG 133

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, continues to enroll patients in the multidose portion of the study.
Biosimilars

In April, the Company announced preliminary results from a Phase 3 study evaluating the efficacy and safety of ABP 654 compared to STELARA (ustekinumab) in adult patients with moderate to severe plaque psoriasis. The study met the primary efficacy endpoint, demonstrating no clinically meaningful differences between ABP 654 and STELARA.
A Phase 3 study to support an interchangeability designation in the U.S. for ABP 654 is ongoing.
Phase 3 studies of ABP 938, an investigational biosimilar to EYLEA (aflibercept), and ABP 959, an investigational biosimilar to SOLIRIS (eculizumab), are on track, with data expected in 2022.
A Phase 3 study to support an interchangeability designation in the U.S. for AMJEVITA (adalimumab-atto) is enrolling patients.
Environmental, Social & Governance Report Released Today

Amgen today released its latest Environmental, Social & Governance (ESG) report at amgen.com/responsibility, providing a comprehensive overview of the many ways the Company is building a better, healthier world. The report tracks the Company’s progress across four categories:

Healthy People: Focusing on removing barriers that limit equitable access to healthcare so that people can live their healthiest lives. In 2021, for example, the Amgen Safety Net Foundation1 provided $2.2 billion2 of the Company’s medicines, at no cost, to uninsured or underinsured patients in the U.S.
Healthy Society: Working toward a more just society for our employees and the people we serve. In 2021, no-cost science education programs funded by the Amgen Foundation1 reached more than 27 million students and educators globally, helping to level the scientific playing field.
Healthy Planet: Prioritizing sustainability and aiming to minimize our environmental impact. Amgen continued its progress in 2021 toward the goal of achieving carbon neutrality in our operations by 20273.
Healthy Amgen: Holding ourselves to high standards in the Company’s operations – working to ensure that our actions and culture reflect Amgen values. In 2021, and again in 2022, Amgen added an ESG goal to our annual incentive plans to focus our entire Company on activities supporting achievement of our 2027 environment sustainability targets and to strengthen and improve the Company’s diversity, inclusion, and belonging efforts.
1 Amgen Safety Net Foundation and The Amgen Foundation, Inc. are separate legal entities entirely funded by Amgen.
2 Valued at Wholesale Acquisition Cost.
3 Carbon neutrality goal refers to Scope 1 and 2 emissions.

TEZSPIRE is being developed in collaboration with AstraZeneca.
Rocatinlimab, formerly AMG 451 / KHK4083 is being developed in collaboration with Kyowa Kirin.
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 first quarters 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 2022 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, restructuring and certain other items from the related GAAP financial measures. Reconciliations for these non-GAAP financial measures to the most directly comparable GAAP financial measures are included in the news release. Management has also presented Free Cash Flow (FCF), which is a non-GAAP financial measure, for the first quarters of 2022 and 2021. FCF is computed by subtracting capital expenditures from operating cash flow, each as determined in accordance with GAAP.

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 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.