On July 30, 2020 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has accepted two new supplemental Biologics License Applications (sBLAs) for KEYTRUDA, Merck’s anti-PD-1 therapy (Press release, Merck & Co, JUL 30, 2020, View Source [SID1234562552]). The FDA has accepted and granted priority review for a new sBLA seeking accelerated approval for KEYTRUDA in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), based on the Phase 3 KEYNOTE-355 trial. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of Nov. 28, 2020. The FDA also accepted for standard review a new sBLA for KEYTRUDA for the treatment of patients with high-risk early-stage TNBC, in combination with chemotherapy as neoadjuvant treatment, and then as a single agent as adjuvant treatment after surgery, based on the Phase 3 KEYNOTE-522 trial. The PDUFA date for this application is March 29, 2021.

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"There is a real need to advance new treatment options for triple-negative breast cancer, an aggressive form of the disease. The FDA’s acceptance of these KEYTRUDA applications for review is an important step toward helping patients with both early-stage and metastatic disease," said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. "These acceptances mark the first U.S. applications for KEYTRUDA in breast cancer, and we look forward to working closely with the FDA to bring these new options to patients as quickly as possible."

The applications are based on data from the KEYNOTE-355 and KEYNOTE-522 trials, respectively. In KEYNOTE-355, KEYTRUDA plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemotherapy alone in patients whose tumors expressed PD-L1 at CPS ≥10. Approximately 38% of patients enrolled in KEYNOTE-355 had tumors expressing PD-L1 at CPS ≥10. These data were presented at the virtual scientific program of the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. As previously announced, the trial will continue without changes to evaluate the other dual primary endpoint of overall survival (OS).

In KEYNOTE-522 – the first randomized trial of an anti-PD-1 therapy in the neoadjuvant/adjuvant setting for TNBC – neoadjuvant KEYTRUDA plus chemotherapy resulted in a statistically significant increase in pathologic complete response (pCR) in patients with early-stage TNBC, regardless of PD-L1 expression. The KEYTRUDA regimen also demonstrated a favorable trend for the other dual primary endpoint of event-free survival (EFS). Data from the KEYNOTE-522 trial were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress and the 2019 San Antonio Breast Cancer Symposium (SABCS). As previously announced, KEYTRUDA plus chemotherapy was granted Breakthrough Therapy designation by the FDA for the neoadjuvant treatment of patients with high-risk early-stage TNBC.

About KEYNOTE-355

KEYNOTE-355 is a randomized, double-blinded, Phase 3 trial (ClinicalTrials.gov, NCT02819518) evaluating KEYTRUDA in combination with one of three different chemotherapies (investigator’s choice of nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) compared with placebo plus one of the three chemotherapy regimens for the treatment of locally recurrent inoperable or metastatic TNBC. Patients were eligible to be enrolled in the trial if they had a disease-free interval of at least 6 months or were de novo metastatic. The dual primary endpoints are PFS and OS in patients whose tumors expressed PD-L1 (CPS ≥1 and CPS ≥10) and in all participants (intention-to-treat population). The secondary endpoints include objective response rate, duration of response, disease control rate and safety. The study enrolled 847 patients who were randomized 2:1 to receive KEYTRUDA (200 mg every three weeks) plus chemotherapy (investigator’s choice of nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) or placebo plus nab-paclitaxel, paclitaxel or gemcitabine/carboplatin.

About KEYNOTE-522

KEYNOTE-522 is a randomized, double-blind, Phase 3 trial (ClinicalTrials.gov, NCT03036488) evaluating KEYTRUDA in combination with chemotherapy compared with placebo plus chemotherapy as neoadjuvant therapy, followed by KEYTRUDA monotherapy compared with placebo as adjuvant therapy in patients with TNBC. The dual primary endpoints are pCR and EFS. The secondary endpoints include pCR rate using alternative definitions (i.e., no invasive or noninvasive residual cancer in breast or nodes) at the time of definitive surgery, OS, EFS in patients whose tumors express PD-L1 (CPS ≥1), safety and patient-reported outcomes. The study enrolled 1,174 patients who were randomized 2:1 to receive either:

KEYTRUDA (every three weeks) plus paclitaxel (weekly) and carboplatin (weekly or every three weeks) for four cycles, followed by KEYTRUDA plus cyclophosphamide and either doxorubicin or epirubicin (every three weeks) for four cycles as neoadjuvant therapy prior to surgery, followed by nine cycles of KEYTRUDA (every three weeks) as adjuvant therapy post-surgery or;
Placebo (every three weeks) plus paclitaxel (weekly) and carboplatin (weekly or every three weeks) for four cycles, followed by placebo plus cyclophosphamide and either doxorubicin or epirubicin (every three weeks) for four cycles, followed by nine cycles of placebo (every three weeks) as adjuvant therapy post-surgery.
About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) ≥10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. 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 confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

Adverse reactions occurring in patients with cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

Pediatric Use

There is limited experience in pediatric patients. In a trial, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with various cancers, including unapproved usages, were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%), and hyponatremia (18%).

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On July 30, 2020 Eli Lilly and Company (NYSE: LLY) reported financial results for the second quarter of 2020 (Press release, Eli Lilly, JUL 30, 2020, View Source [SID1234562551]).

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Certain financial information for 2020 and 2019 is presented on both a reported and a non-GAAP basis. Some numbers in this press release may not add due to rounding. Reported results were prepared in accordance with U.S. generally accepted accounting principles (GAAP), include all revenue and expenses recognized during the periods, and reflect Elanco Animal Health (Elanco) as discontinued operations during 2019. Non-GAAP measures reflect adjustments for the items described in the reconciliation tables later in the release, and assume that the disposition of Elanco occurred at the beginning of 2019 (including the benefit from the reduction in shares of common stock outstanding). The company’s 2020 financial guidance is being provided on both a reported and a non-GAAP basis. The non-GAAP measures are presented to provide additional insights into the underlying trends in the company’s business.

"In the second quarter, Lilly achieved several important R&D milestones, including three FDA approvals for new medicines, positive phase 3 results for several important clinical programs and continued progress in our quest to develop medicines for patients with COVID-19," said David A. Ricks, Lilly’s chairman and CEO. "At the same time, the COVID-19 pandemic continues to strain healthcare systems around the world and has decreased new patient starts for some of Lilly’s medicines. As anticipated, our second quarter financial results reflect the variability caused by the pandemic, but our year-to-date revenue performance, which includes 13 percent volume growth, demonstrates that our underlying business fundamentals remain strong. We expect growth in new prescription volume for our key growth products in the second half of 2020, and we remain confident in our outlook for the year."

Key Events Over the Last Three Months

COVID-19

The company completed dosing of a phase 1 study and initiated a phase 2 study of LY-CoV555, a potential antibody treatment designed to target COVID-19. LY-CoV555 is the first investigational medicine to emerge from the collaboration between Lilly and AbCellera Biologics to create antibody therapies for the potential prevention and treatment of COVID-19.
The company entered into an agreement with Junshi Biosciences to co-develop therapeutic antibodies for the potential prevention and treatment of COVID-19, including LY-CoV016, the lead antibody from the collaboration. Dosing of a phase 1 study of LY-CoV016 in healthy volunteers has been completed and the antibody has demonstrated the safety and tolerability to proceed into further stages of clinical development.
Regulatory

The U.S. Food and Drug Administration (FDA) approved Retevmo, the first therapy specifically indicated for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer, and the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, or advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
The FDA approved Lyumjev, a new rapid-acting insulin indicated to improve glycemic control in adults with type 1 and type 2 diabetes.
The FDA approved a supplemental Biologics License Application (sBLA) for Taltz for the treatment of active non-radiographic axial spondyloarthritis (nr-axSpA) in patients with objective signs of inflammation.
The FDA approved Tauvid, a radioactive diagnostic agent, for positron emission tomography imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease.
The FDA approved Cyramza in combination with erlotinib for the first-line treatment of people with metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 mutations.
Clinical

The company and Boehringer Ingelheim announced positive top-line results from a phase 3 study of Jardiance in adults with heart failure with reduced ejection fraction, with and without diabetes. The study met its primary endpoint, demonstrating superiority with empagliflozin compared to placebo in reducing the risk for the composite of cardiovascular death or hospitalization due to heart failure, when added to standard of care.
The company announced results from a pre-planned interim analysis of a phase 3 study of Verzenio in combination with standard adjuvant endocrine therapy (ET). The study met the primary endpoint of invasive disease-free survival, significantly decreasing the risk of breast cancer recurrence or death compared to standard adjuvant ET alone.
The company announced that mirikizumab met the primary and all key secondary endpoints in a phase 3 study comparing the efficacy and safety of mirikizumab to placebo and Cosentyx in patients with moderate to severe plaque psoriasis.
The company announced that higher investigational doses of Trulicity meaningfully reduced A1C and body weight in people with type 2 diabetes. Data from a phase 3 study showed higher investigational doses of Trulicity (3 mg and 4.5 mg) were well-tolerated and led to A1C reductions up to 1.9 percent and weight reductions up to 10.4 pounds in people with type 2 diabetes.
Business Development/Other Developments

The company announced its participation in, and $100 million commitment to, the AMR Action Fund, a $1 billion initiative from more than 20 biopharmaceutical companies to address the urgent need for new antibiotics to combat antimicrobial resistance (AMR).
Second-Quarter Reported Results

In the second quarter of 2020, worldwide revenue was $5.499 billion, a decrease of 2 percent compared with the second quarter of 2019, comprised of a 6 percent increase in volume, a 7 percent decrease due to lower realized prices, and a 1 percent decrease due to the unfavorable impact of foreign exchange rates. Key growth products launched since 2014, consisting of Trulicity, Tyvyt, Taltz, Verzenio, Emgality, Olumiant, Jardiance, Cyramza, Baqsimi, Basaglar, and Retevmo, contributed nearly 9 percentage points of revenue growth and represented approximately 54 percent of total revenue. The company estimates that the COVID-19 pandemic negatively impacted worldwide revenue in the second quarter of 2020, including approximately $250 million of decreased customer buying that largely offset product stocking that occurred in the first quarter of 2020 and approximately $250 million resulting from delayed new patient prescription trends.

Revenue in the U.S. decreased 3 percent, to $3.145 billion, comprised of a 4 percent increase in volume and an 8 percent decrease due to lower realized prices. The decrease in realized prices in the U.S. was driven primarily by changes to estimates for rebates and discounts, mainly for diabetes products, reflecting both a favorable adjustment in the Medicaid segment in the second quarter of 2019 and an unfavorable adjustment in the commercial segment in the second quarter of 2020. The decrease in realized prices in the U.S. also reflects higher growth in lower net price segments across numerous products and increased rebates to gain and maintain broad commercial access across the portfolio. Increased U.S. volume for key growth products, including Trulicity, Taltz, Emgality, Verzenio, Baqsimi, Retevmo, Jardiance, Olumiant, Cyramza, and Basaglar was partially offset by lower volume for certain other products, including Tradjenta, Forteo and Alimta. The company estimates that the COVID-19 pandemic negatively impacted U.S. revenue in the second quarter of 2020, including approximately $200 million of decreased customer buying that largely offset product stocking that occurred in the first quarter of 2020 and approximately $150 million resulting from delayed new patient prescription trends.

Revenue outside the U.S. decreased 1 percent, to $2.355 billion, comprised of a 7 percent increase in volume, a 7 percent decrease due to lower realized prices, and a 2 percent decrease due to the unfavorable impact of foreign exchange rates. The decrease in realized prices outside the U.S. was driven primarily by the inclusion of Tyvyt and Alimta in government reimbursement programs in China and bi-annual government mandated price decreases in Japan. The increase in volume outside the U.S. was driven primarily by the inclusion of Tyvyt and Alimta in government reimbursement programs in China, as well as volume gains for other key growth products, including Trulicity, Olumiant, Verzenio, Jardiance, Taltz, Cyramza, Emgality, Basaglar, and Baqsimi, partially offset by decreased volume for Cialis, Forteo, and Trajenta. The company estimates that the COVID-19 pandemic negatively impacted revenue outside the U.S. in the second quarter of 2020, including approximately $100 million resulting from delayed new patient prescription trends and approximately $50 million of decreased customer buying that largely offset product stocking that occurred in the first quarter of 2020.

Gross margin decreased 5 percent, to $4.277 billion, in the second quarter of 2020 compared with the second quarter of 2019 and was unfavorably impacted by decreased customer buying patterns and patient prescription trends resulting from the COVID-19 pandemic. Gross margin as a percent of revenue was 77.8 percent, a decrease of 2.2 percentage points compared with the second quarter of 2019. The decrease in gross margin percent was primarily due to the impact of lower realized prices on revenue and higher intangibles amortization expense associated with the launch of Retevmo.

Total operating expenses in the second quarter of 2020, defined as the sum of research and development and marketing, selling, and administrative expenses, decreased 5 percent to $2.839 billion compared with the second quarter of 2019. Research and development expenses decreased 1 percent to $1.390 billion, or 25.3 percent of revenue, driven primarily by lower development expenses for late-stage assets and the pause in new clinical trial initiations and patient enrollment as a result of the COVID-19 pandemic. Marketing, selling, and administrative expenses decreased 9 percent to $1.449 billion, primarily due to lower marketing expenses.

In the second quarter of 2020, the company recognized acquired in-process research and development charges of $241.8 million related to the acquisition of a pre-clinical stage company as well as the previously announced business development transactions with AbCellera Biologics, Evox Therapeutics, and Junshi Biosciences. In the second quarter of 2019, the company recognized an acquired in-process research and development charge of $25.0 million related to the business development transaction with Avidity Biosciences.

Operating income in the second quarter of 2020 was $1.197 billion, compared to $1.498 billion in the second quarter of 2019. The decrease in operating income was primarily driven by lower gross margin and higher acquired in-process research and development charges, partially offset by lower marketing, selling, and administrative expenses.

Other income was $446.9 million in the second quarter of 2020, compared with other expense of $32.4 million in the second quarter of 2019. The increase in other income was driven primarily by favorable mark-to-market adjustments on investment securities, including equity positions the company holds in Asian biopharmaceutical companies as well as two U.S.-based companies that had successful initial public offerings in the second quarter of 2020.

The effective tax rate was 14.1 percent in the second quarter of 2020, compared with 9.5 percent in the second quarter of 2019. The higher effective tax rate in the second quarter of 2020 was driven by a mix of earnings in higher tax jurisdictions, a lower net discrete tax benefit compared to the same period in 2019, and nondeductible acquired in-process research and development charges.

In the second quarter of 2020, net income and earnings per share were $1.412 billion and $1.55, respectively, compared with net income of $1.327 billion and earnings per share of $1.44 in the second quarter of 2019. The increase in net income and earnings per share in the second quarter of 2020 was primarily driven by higher other income, partially offset by lower operating income and, to a lesser extent, higher income tax expense.

Second-Quarter Non-GAAP Measures

On a non-GAAP basis, second-quarter 2020 gross margin decreased 4 percent, to $4.380 billion compared with the second quarter of 2019 and was unfavorably impacted by decreased customer buying patterns and patient prescription trends resulting from the COVID-19 pandemic. Gross margin as a percent of revenue was 79.6 percent, a decrease of 1.4 percentage points. The decrease in gross margin percent was primarily due to the impact of lower realized prices on revenue.

Operating income on a non-GAAP basis decreased $33.5 million, or 2 percent, to $1.541 billion in the second quarter of 2020 compared with the second quarter of 2019, due to lower gross margin, partially offset by lower marketing, selling, and administrative expenses.

The effective tax rate on a non-GAAP basis was 13.4 percent in the second quarter of 2020, compared with 10.0 percent in the second quarter of 2019. The higher effective tax rate for the second quarter of 2020 was driven by a mix of earnings in higher tax jurisdictions and a lower net discrete tax benefit compared to the same period in 2019.

On a non-GAAP basis, in the second quarter of 2020 net income increased 24 percent, to $1.721 billion, while earnings per share increased 26 percent, to $1.89, compared with $1.388 billion and $1.50, respectively, in the second quarter of 2019. The increase in net income and earnings per share was driven primarily by higher other income, partially offset by higher income tax expense.

For further detail on non-GAAP measures, see the reconciliation below as well as the "Reconciliation of GAAP Reported to Selected Non-GAAP Adjusted Information" table later in this press release.

Year-to-Date Reported Results

For the first six months of 2020, worldwide revenue increased 6 percent to $11.359 billion, compared with $10.729 billion in the same period in 2019. The increase in revenue was driven by a 13 percent increase in volume, partially offset by a 7 percent decrease due to lower realized prices. The company estimates that the COVID-19 pandemic negatively impacted revenue in the first six months of 2020 by approximately $250 million due to lower patient prescription trends, while increased customer buying in the first quarter of 2020 was essentially offset by decreased customer buying in the second quarter of 2020. For the first six months of 2020, operating income was $2.788 billion, an increase of 30 percent compared to the same period of 2019. Reported net income and earnings per share for the first six months of 2020 were $2.869 billion and $3.15, respectively, compared with $5.569 billion and $5.84 in the same period of 2019. The decreases in net income and earnings per share in the first six months of 2020 were driven primarily by the approximate $3.7 billion gain recognized on the disposition of Elanco in 2019, partially offset by higher operating income and higher other income for the first six months of 2020.

Year-to-Date Non-GAAP Measures

For the first six months of 2020, operating income was $3.303 billion on a non-GAAP basis, an increase of 14 percent compared to the same period of 2019. Net income and earnings per share, on a non-GAAP basis, were $3.320 billion and $3.64, respectively, compared with $2.625 billion and $2.83 in the same period of 2019.

For further detail on non-GAAP measures, see the reconciliation below as well as the "Reconciliation of GAAP Reported to Selected Non-GAAP Adjusted Information" table later in this press release.

Trulicity

Second-quarter 2020 worldwide Trulicity revenue was $1.230 billion, an increase of 20 percent compared with the second quarter of 2019. U.S. revenue increased 20 percent, to $952.5 million, driven by increased demand, partially offset by lower realized prices. Trulicity’s lower realized prices in the U.S. were primarily due to higher contracted rebates and changes in segment mix, partially offset by higher list prices. Revenue outside the U.S. was $277.2 million, an increase of 17 percent, driven by increased volume, partially offset by the unfavorable impact of foreign exchange rates and lower realized prices.

Humalog

For the second quarter of 2020, worldwide Humalog revenue decreased 18 percent compared with the second quarter of 2019, to $555.1 million. Revenue in the U.S. decreased 29 percent, to $281.7 million, driven primarily by lower realized prices due to changes in estimates for rebates and discounts, reflecting both a favorable Medicaid adjustment in the second quarter of 2019 and an unfavorable Managed Care adjustment in the second quarter of 2020. Revenue outside the U.S. decreased 3 percent, to $273.3 million, driven primarily by the unfavorable impact of foreign exchange rates.

Alimta

For the second quarter of 2020, worldwide Alimta revenue decreased 7 percent compared with the second quarter of 2019, to $539.1 million. U.S. revenue decreased 7 percent, to $317.2 million, primarily driven by decreased demand, partially offset by higher realized prices. Revenue outside the U.S. decreased 6 percent to $221.9 million, primarily driven by lower realized prices, partially offset by increased volume.

Taltz

For the second quarter of 2020, worldwide Taltz revenue increased 12 percent compared with the second quarter of 2019, to $395.2 million. U.S. revenue increased 8 percent, to $289.2 million, driven by increased demand, partially offset by lower realized prices. Revenue outside the U.S. increased 24 percent, to $106.0 million, driven by increased volume, partially offset by lower realized prices.

Humulin

For the second quarter of 2020, worldwide Humulin revenue decreased 3 percent compared with the second quarter of 2019, to $313.6 million. U.S. revenue decreased 3 percent, to $214.3 million, driven by lower realized prices due to changes in segment mix and, to a lesser extent, lower demand. Revenue outside the U.S. decreased 3 percent, to $99.3 million, due to the unfavorable impact of foreign exchange rates, partially offset by higher realized prices.

Basaglar

For the second quarter of 2020, worldwide Basaglar revenue was $290.4 million and was flat compared with the second quarter of 2019. U.S. revenue decreased 1 percent, to $229.7 million, driven by lower realized prices, partially offset by increased demand. Revenue outside the U.S. increased 4 percent, to $60.7 million, driven by increased volume, partially offset by lower realized prices and the unfavorable impact of foreign exchange rates. Basaglar is part of the company’s alliance with Boehringer Ingelheim. Lilly reports as cost of sales payments made to Boehringer Ingelheim for royalties and for its portion of the gross margin in 2020 and 2019, respectively.

Jardiance

The company’s worldwide Jardiance revenue during the second quarter of 2020 was $262.0 million, an increase of 13 percent compared with the second quarter of 2019. U.S. revenue increased 2 percent, to $145.1 million, driven by increased demand. Revenue outside the U.S. was $116.9 million, an increase of 31 percent, driven by increased volume. Jardiance is part of the company’s alliance with Boehringer Ingelheim. Lilly reports as revenue royalties received on net sales of Jardiance and its portion of Jardiance’s gross margin in 2020 and 2019, respectively.

Forteo

For the second quarter of 2020, worldwide Forteo revenue decreased 30 percent compared with the second quarter of 2019, to $252.7 million. U.S. revenue decreased 31 percent, to $119.6 million, driven by lower demand and lower realized prices primarily due to the unfavorable impact of higher contracted rates. Revenue outside the U.S. decreased 29 percent to $133.0 million, primarily driven by decreased volume and lower realized prices.

The company expects further volume declines for Forteo as a result of competitive dynamics in the U.S. and the entry of generic and biosimilar competition following the loss of patent exclusivity in the third quarter of 2019 in the U.S., Japan and major European markets.

Cyramza

For the second quarter of 2020, worldwide Cyramza revenue was $256.7 million, an increase of 6 percent compared with the second quarter of 2019. U.S. revenue was $94.1 million, an increase of 5 percent, primarily driven by higher realized prices and increased demand. Revenue outside the U.S. was $162.7 million, an increase of 7 percent, driven by increased volume, partially offset by lower realized prices.

Verzenio

For the second quarter of 2020, worldwide Verzenio revenue increased 56 percent compared with the second quarter of 2019, to $208.6 million. U.S. revenue was $141.7 million, an increase of 35 percent, primarily driven by increased demand and, to a lesser extent, higher realized prices. Revenue outside the U.S. was $66.9 million, an increase of $38.3 million compared with the second quarter of 2019.

Olumiant

For the second quarter of 2020, Olumiant generated worldwide revenue of $145.0 million. U.S. revenue was $13.2 million. Revenue outside the U.S. was $131.8 million, an increase of 44 percent compared with the second quarter of 2019, driven by increased volume.

Emgality

For the second quarter of 2020, Emgality generated worldwide revenue of $87.4 million, an increase of $13.4 million compared with the first quarter of 2020. U.S. revenue was $80.6 million, an increase of $13.2 million compared with the first quarter of 2020, primarily driven by increased demand and, to a lesser extent, higher realized prices due to changes to estimates in rebates and discounts. Revenue outside of the U.S. was $6.8 million in the second quarter of 2020.

Tyvyt

The company’s Tyvyt revenue during the second quarter of 2020 was $64.1 million, an increase of $6.7 million compared with the first quarter of 2020. Tyvyt is part of the company’s alliance with Innovent Biologics, Inc. in China. Lilly reports total sales of Tyvyt made by Lilly as revenue, with payments made to Innovent for its portion of the gross margin reported as cost of sales. Lilly also reports as revenue a portion of the gross margin for Tyvyt sales made by Innovent.

Baqsimi

For the second quarter of 2020, Baqsimi generated worldwide revenue of $13.6 million, a decrease of 4.2 million compared with the first quarter of 2020. U.S revenue was $11.1 million, while revenue outside the U.S. was $2.6 million.

Retevmo

For the second quarter of 2020, Retevmo generated U.S. revenue of $6.3 million. Retevmo was approved by the FDA and launched in the U.S. during the second quarter of 2020.

2020 Financial Guidance

The company has updated certain elements of its 2020 financial guidance to reflect management’s current expectations for underlying business performance.

There is uncertainty in the company’s 2020 financial guidance surrounding the extent and duration of the impact of the COVID-19 pandemic. Key management assumptions related to the COVID-19 pandemic that support the company’s 2020 guidance include:

Healthcare activity, including non-COVID-19 related patient visits with their physicians, will align more closely with historical levels in the second half of 2020;
New-to-brand prescription trends will improve in the U.S. in the second half of 2020, exceeding pre-pandemic levels by the fourth quarter of 2020 for most brands;
Increased utilization of patient affordability programs and changes in segment mix due to higher U.S. unemployment will have a modestly negative impact U.S. pricing;
Promotional spend will constitute a mix of in-person customer interactions, direct-to-consumer advertising and investments in digital promotion;
Clinical trial enrollment in existing studies, as well as initiation of new clinical trials, will resume in the second half of 2020; and
Investment in COVID-19 related research, testing and support will continue throughout 2020.
The company now expects earnings per share for 2020 to be in the range of $6.48 to $6.68 on a reported basis and $7.20 to $7.40 on a non-GAAP basis, reflecting expectations of lower marketing, selling and administrative expenses, higher other income and a lower effective tax rate.

The company still anticipates 2020 revenue between $23.7 billion and $24.2 billion. Revenue growth is still expected to be driven by volume from key growth products including Trulicity, Taltz, Basaglar, Jardiance, Verzenio, Cyramza, Olumiant, Emgality, Baqsimi, Tyvyt, and Retevmo. Revenue growth is expected to be partially offset by lower revenue for products that have lost patent exclusivity. Revenue growth is also expected to be partially offset by a mid-single digit net price decline in the U.S. (driven primarily by rebates and legislated increases to Medicare Part D cost sharing, and patient affordability programs), as well as net price declines in China, Japan and Europe.

Gross margin as a percent of revenue is now expected to be approximately 78 percent on a reported basis and approximately 80 percent on a non-GAAP basis, reflecting changes in the geographic mix of product sales and lower realized prices on revenue.

Marketing, selling and administrative expenses are now expected to be in the range of $6.0 billion to $6.2 billion, reflecting savings from reduced travel, meetings, and promotional activities. Research and development expenses are still expected to be in the range of $5.6 billion to $5.9 billion.

Operating margin percentage, defined as operating income as a percent of revenue, is still expected to be 28 percent on a reported basis and 31 percent on a non-GAAP basis.

Other income (expense) is now expected to be in the range of $350 to $500 million of income, reflecting mark-to-market gains on investment securities in the second quarter of 2020.

The 2020 effective tax rate is now expected to be approximately 14 percent on both a reported basis and a non-GAAP basis, reflecting net discrete tax benefits recognized in the first six months of 2020.

Webcast of Conference Call

As previously announced, investors and the general public can access a live webcast of the second-quarter 2020 financial results conference call through a link on Lilly’s website at www.lilly.com. The conference call will begin at 9:00 a.m. Eastern time (ET) today and will be available for replay via the website.

Lilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. F-LLY.

On July 30, 2020 Ipsen (Euronext: IPN; ADR: IPSEY), a global specialty-driven biopharmaceutical group, reported financial results for the first half of 2020 (Press release, Ipsen, JUL 30, 2020, View Source [SID1234562540]).

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Resilient H1 financial performance:
Group sales growth of 3.1% as reported and at constant currency, driven by Specialty Care sales growth of 5.9%[1], led by Somatuline (lanreotide) (up 16.4%1). Consumer Healthcare sales were down 21.1%1. Q2 2020 Group sales decreased by 2.2%1, adversely impacted by COVID-19.
Core Operating margin at 32.3% of net sales, up 0.8 points, driven by Specialty Care sales growth and postponed or cancelled expenditures mainly due to COVID-19. IFRS Operating margin at 19.7% of net sales, down 6.1 points.
Core consolidated net profit of €297 million and fully diluted Core EPS of €3.55 (up 5.0%). IFRS Consolidated net profit of €223 million and fully diluted IFRS EPS of €2.66 (up 1.0%).
Robust balance sheet, with closing Net Debt of €923 million and strong Free Cash Flow at €233 million, up €132 million versus 2019, mainly driven by higher Operating Cash Flow.

Negative COVID-19 impact: As anticipated, the Specialty Care portfolio showed overall resilience in Q2 2020, although Oncology sales were impacted by destocking in some European countries and Neuroscience sales were affected by treatment center closures. Consumer Healthcare sales, notably Smecta (diosmectite), continued to be impacted across geographies despite a slow recovery in China in Q2 2020.

2020 guidance: Ipsen has reinstated full year guidance and now expects Group sales growth greater than +2.0% at constant currency and Core Operating margin greater than 30.0% of net sales. Guidance takes into account the high level of uncertainty regarding COVID-19 and assumes only a gradual recovery from the pandemic as well as no impact of any new somatostatin analog (SSA) generic entry.

Significant R&D pipeline progress including (1) Cabometyx (cabozantinib) positive top-line results from Phase 3 CheckMate -9ER trial in combination with nivolumab for 1L RCC2[2], (2) Cabometyx participation in the ongoing Phase 3 trials in combination with atezolizumab for 2L NSCLC3 and 2L CRPC4, (3) Onivyde (irinotecan liposome injection) received Fast Track designation from the FDA for 1L PDAC5, (4) Dysport (botulinum toxin type A) approval in China for glabellar lines and updated indication in the U.S. for the treatment of spasticity in children, (5) IRICoR option agreement in collaboration with the University of Montreal for a discovery-stage oncology program.

David Loew, Chief Executive Officer of Ipsen, stated: "I’m honored since July 1st to lead Ipsen, an exciting global biopharma business with solid business fundamentals, a strong purpose to serve patients and attractive growth opportunities. I am encouraged by the exceptional levels of talent and engagement I have encountered across the organization, as well as the exciting recent clinical data on Cabometyx, and I look forward to helping the Group build on these strong foundations. In my first half-year update, I am pleased to report that, despite the unprecedented backdrop of COVID-19, Ipsen delivered top-line growth and margin improvement. As a result, we are reinstating guidance for 2020 and planning for the future with confidence."

Review of half year 2020 results

Review of the first half 2020 results

Group sales reached €1,268.3 million, up 3.1% year-on-year.

Specialty Care sales reached €1,167.1 million, up 5.9%, driven by growth in Oncology sales of 9.5%, including the continued momentum of Somatuline in major geographies.

Consumer Healthcare sales were €101.2 million, down 21.1%. Smecta was negatively impacted by COVID-19, implementation of hospital central procurement in China and lower sales in France.

Core Operating Income was €410.2 million, up 5.9%, driven by the growth of Specialty Care sales. Significant cost savings were realized in selling expenses, resulting from digital sales detailing, lower travel throughout the Group and the conversion to virtual conference and medical meetings.

Core Operating margin reached 32.3% of sales, up 0.8 points versus the first half of 2019.

Core consolidated net profit was €297.0 million, compared to €283.0 million in 2019, up 5.0%, reflecting increased Other financial expenses and lower core effective tax rate (22.5% versus 23.6% in H1 2019).

Core earnings per share fully diluted grew by 5.0% to reach €3.55, compared to €3.38 in 2019.

IFRS Operating Income was €249.8 million after amortization of intangible assets, impairment losses and other operating expenses. Operating Income margin of 19.7% was down 6.1 points compared to 2019, after amortization of intangible assets for Cabometyx and an impairment loss on the intangible assets of palovarotene following termination of the MO-Ped program.

IFRS Consolidated net profit was €222.7 million versus €220.6 million in 2019, up 1.0%

IFRS Fully diluted EPS (Earnings per share) was €2.66 versus €2.64 in 2019, up 1.0%.

Free Cash Flow of €233.3 million was up 131% versus €101.0 million in 2019, mainly driven by higher Operating Cash Flow.

Closing net debt came to €923.3 million, a €576.2m improvement compared with net debt at June 30 2019 of €1,499.5 million, due mainly to strong Free Cash Flow over the period.

The company’s auditors performed a limited review of the accounts.

The interim financial report, with regard to regulated information, is available on the Group’s website, under the Regulated Information tab in the Investor Relations section.

COVID-19 Impact

In the second quarter of 2020, the business was negatively impacted by COVID-19. While the Specialty Care portfolio of differentiated products for critical conditions remained relatively resilient, Oncology sales were negatively impacted by destocking after a higher level of orders at the end of the first quarter in some European countries. Neuroscience sales were more impacted due to the closure of treatment centers in both the therapeutics and aesthetics markets. Consumer Healthcare sales, notably Smecta, continued to be negatively impacted across geographies despite a slow recovery in China in the second quarter of 2020.

Significant cost savings in selling expenses were realized in the first half of 2020, resulting from digital sales detailing, lower travel throughout the Group and the conversion to virtual conference and medical meetings.

Ipsen continues to operate all of its manufacturing sites. There are adequate inventory levels, with no supply chain issues, for the provision of medicines to patients. There is also limited impact to date on clinical trials, with minimal disruption to investigational drug supply for ongoing patients, despite a general slowdown in the recruitment of new patients as well as new site activations in ongoing trials across Europe and the U.S.

Ipsen remains focused on ensuring that patients continue to have access to their treatments and on addressing the impact of this pandemic in their communities. Ipsen employees around the world, including those at central functions and manufacturing and distribution sites, are gradually returning to the office, and the commercial organization is beginning to resume more normal operations.

2020 Financial guidance reinstated

The Group has reinstated the following financial targets for the current year

Group sales growth greater than +2.0% at constant currency, with an expected negative impact of 0.5% from currencies based on the current level of exchange rates.
Core Operating margin greater than 30.0% of net sales, excluding incremental investments in pipeline expansion initiatives.
Guidance takes into account the high level of uncertainty regarding COVID-19 and assumes only a gradual recovery from the pandemic as well as no impact of any new somatostatin analog (SSA) generic entry.

Palovarotene:

In the last few months, Ipsen has made progress on advancing the palovarotene program. There is an ongoing dialogue with the FDA on the appropriate patient population eligible for treatment and a potential regulatory path forward for palovarotene for the treatment of fibrodysplasia ossificans progressiva (FOP).

Ipsen has taken the decision to terminate the multiple osteochondromas (MO) indication due to the lack of efficacy signals in the analysis of the Phase 2 MO-Ped trial. As a consequence, the Group recognized an impairment loss of €57.8 million before tax on the palovarotene intangible asset and a financial income of €45.0 million related to the Contingent Value Rights (CVR) and milestones reevaluation.

R&D update:

Cabometyx: On April 20, Ipsen announced that CheckMate -9ER, a pivotal Phase 3 trial evaluating Cabometyx in combination with Opdivo (nivolumab) compared to sunitinib in previously untreated advanced or metastatic renal cell carcinoma (RCC), met its primary endpoint of progression-free survival (PFS) at final analysis, as well as the secondary endpoints of overall survival (OS) at a pre-specified interim analysis, and objective response rate (ORR).

The detailed results of CheckMate -9ER were accepted for presentation at the upcoming European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020, during the Presidential Symposium II on September 20, 2020.

In addition, on July 2, Ipsen announced it will join the Exelixis and Roche clinical collaboration of the recently initiated CONTACT-01 and CONTACT-02 global Phase 3 pivotal trials. CONTACT-01 is evaluating the safety and efficacy of Cabometyx in combination with atezolizumab in patients with metastatic non-small cell lung cancer (NSCLC) who have been previously treated with an immune checkpoint inhibitor and platinum-containing chemotherapy. CONTACT-02 is evaluating the safety and efficacy of Cabometyx in combination with atezolizumab versus a second novel hormonal therapy (NHT) in men with metastatic castration-resistant prostate cancer (CRPC) who have previously been treated with one NHT.

Onivyde: On June 17, Ipsen announced that the FDA had granted Fast Track designation for the investigational use of Onivyde in combination with 5- fluorouracil/leucovorin (5-FU/LV) and oxaliplatin (OX) for patients with previously untreated, unresectable, locally advanced and metastatic pancreatic ductal adenocarcinoma (PDAC).

Dysport: On June 5, Dysport received approval in China for the treatment of glabellar lines.

On July 9, Dysport received FDA approval to treat both upper and lower limb spasticity in pediatric patients two years of age and older, including spasticity caused by cerebral palsy.

Portfolio prioritization: As a result of prioritization decisions, in the second quarter, the Group is discontinuing development of the fast-acting neurotoxin rBoNT/E (IPN 10360) and the oncology asset IPN 60090 licensed from MD Anderson Cancer Center. Separately, development of Dysport in Hallux Valgus has been discontinued on efficacy grounds.

Early-stage pipeline: On May 4, Ipsen entered into an option agreement with IRICoR, a pan-Canadian research commercialization center focused on drug discovery, and the University of Montreal for a discovery-stage oncology program under which Ipsen would acquire a licence for worldwide rights.

Conference call

Ipsen will hold a conference call Thursday, 30 July 2020 at 2:30 p.m. (Paris time, GMT+1). Participants should dial in to the call approximately 15 minutes prior to its start. No reservation is required to participate in the conference call.

Participants can register for the call on the link below:

View Source

Conference ID: 3653767

On July 30, 2020 Fresenius Medical Care reported very strong second quarter results (Press release, Fresenius, JUL 30, 2020, View Source [SID1234562539])

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Rice Powell, Chief Executive Officer of Fresenius Medical Care, said: "As anticipated, we saw the COVID-19 pandemic spread globally in the second quarter and continue to rise in Latin America and the U.S. In this challenging environment, the wide-ranging measures we took at a very early stage to ensure the continuity and quality of care for our patients are continuing to pay off. Together with the tireless efforts of our employees, these steps have given Fresenius Medical Care a strong performance in the first half of the year. This validates our core value proposition and the resiliency of our business model, which is grounded in our vertical integration strategy. Against this background and the anticipated financial net effect from COVID-19, we confirm our outlook for the financial year 2020. We continue to monitor further impacts of the pandemic and potential restrictions in the different markets."

2020 targets confirmed: mid to high single digit growth rates
On the basis of the neutral net impact of COVID-19 in the first six months, Fresenius Medical Care continues to expect both revenue and net income1 to grow at a mid to high single digit rate in 2020. These targets are inclusive of anticipated COVID-19 effects in constant currency, exclude special items3 and are based on the adjusted results 2019 including the effects of the operations of the NxStage acquisition and the IFRS 16 implementation.

1 Net income attributable to shareholders of Fresenius Medical Care AG & Co. KGaA
2 For a reconciliation of adjusted figures, please refer to the table at the end of the press release
3 Special items are effects that are unusual in nature and have not been foreseeable or not foreseeable in size or impact at the time of giving guidance.

Measures to contain COVID-19 continued
Fresenius Medical Care continued its wide-ranging measures to fight COVID-19 in the second quarter. Thanks to the comprehensive protective measures taken at an early stage, Fresenius Medical Care was also able to maintain operations in its more than 4,000 dialysis centers worldwide without significant interruptions and minimizing the impact on patients. This was also made possible thanks to the use of telehealth solutions, which were applied – where necessary – to replace in-person with virtual patient interactions.

The COVID-19 pandemic affected people with advanced kidney disease and the resulting severity of illness generated an increase in hospitalization and mortality rates. In addition, the pandemic caused an interruption in routine medical visits and necessary hospitalization for many patients with advanced Chronic Kidney Disease (CKD) needing to consider renal replacement therapy. These two factors impacted the year-on-year growth for the second quarter.

Expansion in home dialysis
The expansion of home dialysis is a major growth area for Fresenius Medical Care. In the second quarter, the home dialysis offering in the Europe, Middle East and Africa (EMEA) region was expanded. The now-completed integration of the NxStage home dialysis products portfolio in the EMEA region enables Fresenius Medical Care to offer even more patients at-home treatment and a wider choice of treatment methods.

In North America, the number of home dialysis treatments increased by 15% compared to Q2 2019, with home hemodialysis treatments growing by 41%. June 2020 was the strongest month on record with regard to the number of patients being trained for home dialysis. This development will be supported by the rollout of additional 100 transitional care units to assist patients transitioning between modalities or returning to dialysis from transplants.

Patients, Clinics and Employees
As of June 30, 2020, Fresenius Medical Care treated 347,683 patients in 4,036 dialysis clinics worldwide. At the end of the second quarter, the Company had 124,736 employees (full-time equivalents) worldwide, compared to 119,631 employees as of June 30, 2019.

Solid revenue and strong income growth
Revenue increased by 5% to EUR 4,557 million (+5% at constant currency), with organic growth of 4%. Health Care Services revenue rose by 5% to EUR 3,614 million (+4% at constant currency), mainly driven by growth in same market treatments and contributions from acquisitions. Health Care Products revenue grew by 6% and amounted to EUR 943 million (+7% at constant currency). This increase was mainly due to higher sales of products for acute care treatments and disposables for in-center dialysis.

In the first half of 2020 revenue rose by 7% to EUR 9,045 million (+6% at constant currency). Organic growth amounted to 4%. Health Care Services revenue grew by 6% to EUR 7,209 million (5% at constant currency). Health Care Products revenue rose by 8% to EUR 1,836 million (+8% at constant currency).

Operating income increased by 26% to EUR 656 million (+24% at constant currency), resulting in an operating income margin of 14.4% (Q2 2019: 12.0%). Based on a strong, underlying business performance, the increase in margin was largely due to the recovery of COVID-19 related negative effects experienced in the first quarter as well as ongoing cost saving measures.

Operating income for the first half increased by 14% to EUR 1,211 million (+12% at constant currency), resulting in a margin of 13.4% (H1 2019: 12.5%).

Net income1 grew by 38% to EUR 351 million (+36% at constant currency). Adjusted net income increased by 40% (+38% at constant currency). Basic earnings per share (EPS) increased by 43% to EUR 1.20 (+41% at constant currency), driven by the earnings effects described above coupled with a decrease in the average weighted shares outstanding.

In the first half of 2020, net income increased by 21% to EUR 634 million (+18% at constant currency). EPS rose by 25% to EUR 2.15 (+22% at constant currency).

Exceptional cash-flow development
Fresenius Medical Care generated EUR 2,319 million of operating cash flow (Q2 2019: EUR 852 million) resulting in a margin of 50.9% (Q2 2019: 19.6%). The increase was largely driven by the U.S. federal government advanced payments under the CARES Act. In the first half of 2020, operating cash flow increased to EUR 2,903 million (H1 2019: EUR 928 million).

Free cash flow (net cash used in operating activities, after capital expenditures, before acquisitions and investments) amounted to EUR 2,103 million (Q2 2019: EUR 559 million), resulting in a margin of 46.1% (Q2 2019: 12.9%). In the first half of 2020, the company generated a free cash flow of EUR 2,407 million (H1 2019: EUR 435 million).

Regional developments
In North America, revenue increased by 6% to EUR 3,240 million (+4% at constant currency, +4% organic). The increase was supported in particular by organic growth in the Dialysis and Care Coordination business and contributions from acquisitions. For the first half, North America revenue rose by 8% to EUR 6,426 million (+5% constant currency, +4% organic).

Operating income grew by 42% to EUR 609 million (39% at constant currency), resulting in a margin of 18.8 % (Q2 2019: 14.0%). Operating income margin increased mainly due to the recovery of COVID-19 related negative effects experienced in the first quarter, ongoing cost saving measures as well as lower costs for renal pharmaceuticals.

For the first half, operating income rose by 34% to EUR 1,073 million (31% at constant currency), resulting in a margin of 16.7% (H1 2019: 13.5%).

EMEA revenue increased by 6% to EUR 687 million (+8% at constant currency, +7% organic), supported by strong organic growth in the Health Care Products business, including higher sales of products for acute care treatment. For the first half, EMEA revenue rose by 5% to EUR 1,366 million (+6% at constant currency, +5% organic).

Operating income for the EMEA region decreased by 19% to EUR 78 million (-19% at constant currency), resulting in a margin of 11.3% (Q2 2019: 14.9%). The decrease in operating margin was mainly due to an unfavorable impact from an impairment of a license held by the joint venture with Vifor Pharma, based on an unfavorable clinical trial for the drug CCX-140. For the first half, operating income decreased by 24% to EUR 179 million (-23% at constant currency), resulting in a margin of 13.1% (H1 2019: 18.0%).

In Asia-Pacific, revenue decreased by 2% to EUR 450 million (-2% at constant currency, -1% organic). The growth was impacted by the effect of closed or sold clinics and a decrease in organic revenue in the Care Coordination business, driven by COVID-19. For the first half, revenue rose by 1% to EUR 893 million (stable at constant currency, +0% organic).

Operating income decreased by 9% to EUR 63 million (-10% at constant currency), resulting in a margin of 14.1% (Q2 2019: 15.1%). The decrease in margin was mainly due to impacts from the COVID-19 pandemic. For the first half, operating income decreased by 15% to EUR 140 million (-15% at constant currency) resulting in a margin of 15.7% (H1 2019: 18.5%).

Latin America revenue decreased by 2% to EUR 170 million (+24% at constant currency, +18% organic). For the first half, revenue rose by 1% to EUR 338 million (+24% constant currency, +17% organic).
Operating income increased by 85% to EUR 11 million (+110% at constant currency), resulting in a margin of 6.4% (Q2 2019: 3.4%). For the first half, operating income increased by 3% to EUR 18 million (+11% at constant currency), resulting in a margin of 5.3% (H1 2019: 5.2%).

Virtual Annual General Meeting
Fresenius Medical Care has postponed its Annual General Meeting to August 27, 2020. With that, the resolutions regarding the allocation of the distributable profit and the payout of the dividend has also been postponed. The proposed dividend remains unchanged at €1.20 per entitled share.

Conference call
Fresenius Medical Care will host a conference call to discuss the results of the second quarter and first half of 2020 on July 30, 2020 at 3:30 p.m. CEDT (UTC +2) / 09:30 a.m. EDT (UTC -4). Details will be available on the company’s website www.freseniusmedicalcare.com in the "Investors" section. A replay will be available shortly after the call.

On July 30, 2020 Aurinia Pharmaceuticals Inc. (NASDAQ: AUPH / TSX: AUP) (the "Company") reported that it will release its second quarter 2020 financial results on Tuesday, August 11, 2020, after the markets close (Press release, Aurinia Pharmaceuticals, JUL 30, 2020, View Source [SID1234562537]). Aurinia’s executive team will host a conference call to discuss the Company’s financial results and to provide a general business update.

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The conference call and webcast is scheduled for 4:30 pm EDT on August 11, 2020. In order to participate in the conference call, please dial +1-877-407-9170 (Toll-free U.S. & Canada). An audio webcast can be accessed under "News/Events" through the "Investors" section of the Aurinia corporate website at www.auriniapharma.com. A replay of the webcast will be available on Aurinia’s website.