On May 16, 2022 Bristol Myers Squibb (NYSE: BMY) reported the Phase 3 CheckMate -901 trial, comparing Opdivo (nivolumab) plus Yervoy (ipilimumab) to standard-of-care chemotherapy as a first-line treatment for patients with untreated unresectable or metastatic urothelial carcinoma, did not meet the primary endpoint of overall survival (OS) in patients whose tumor cells express PD-L1 ≥1% at final analysis (Press release, Bristol-Myers Squibb, MAY 16, 2022, View Source;901-Trial-Evaluating-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-as-First-Line-Treatment-for-Patients-with-Unresectable-or-Metastatic-Urothelial-Carcinoma/default.aspx [SID1234614650]). The company remains blinded to the data, and an independent Data Monitoring Committee recommended that the trial continue to assess other primary and secondary endpoints. No new safety signals were observed at the time of the analysis.

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"Despite some progress in recent years, metastatic urothelial carcinoma remains a difficult disease to address, with a limited number of treatment options that can extend patients’ lives," said Dana Walker, M.D., M.S.C.E., vice president, development program lead, genitourinary cancers, Bristol Myers Squibb. "Opdivo plus Yervoy has demonstrated durable, long-term survival improvements in several challenging-to-treat advanced cancers, and we are disappointed that the final analysis of CheckMate -901 did not show this same benefit in urothelial carcinoma patients whose tumor cells express PD-L1 ≥1%. We remain committed to advancing research in urothelial carcinoma, we look forward to seeing data from other parts of the CheckMate -901 trial, and we thank all of the patients, investigators and site personnel involved."

The CheckMate -901 trial is also assessing Opdivo plus Yervoy in patients with unresectable or metastatic urothelial carcinoma who are ineligible for cisplatin-based chemotherapy. Additionally, a sub-study of CheckMate -901 with pivotal intent is evaluating Opdivo in combination with chemotherapy versus chemotherapy alone in patients who are eligible for cisplatin-based chemotherapy. The CheckMate -901 primary study and sub-study are ongoing, and the company will report results for these additional components of the study when available.

Opdivo plus Yervoy-based combinations have shown significant improvements in OS in six Phase 3 clinical trials in five tumors to date: non-small cell lung cancer, metastatic melanoma, advanced renal cell carcinoma, malignant pleural mesothelioma and esophageal squamous cell carcinoma. In addition, Opdivo has shown clinical benefit in second-line metastatic urothelial carcinoma and adjuvant muscle-invasive urothelial carcinoma.

About CheckMate -901

CheckMate -901 is a Phase 3, randomized, open-label trial evaluating Opdivo in combination with Yervoy (primary study)or Opdivo in combination with chemotherapy (sub-study) compared to standard-of-care chemotherapy alone, in patients with untreated unresectable or metastatic urothelial cancer.

In the primary study, a total of 707 patients were randomized to receive either Opdivo (1 mg/kg) plus Yervoy (3 mg/kg) every three weeks for four cycles, followed by Opdivo (480 mg) every four weeks for a maximum of two years, or chemotherapy (gemcitabine-cisplatin or gemcitabine-carboplatin) every three weeks for six cycles. The primary endpoints of the primary study are overall survival (OS) in patients who are ineligible for cisplatin-based chemotherapy and OS in patients with tumor cell PD-L1 expression ≥1%. Key secondary endpoints include OS in all randomized patients, progression-free survival (PFS) and safety outcomes.

A sub-study of CheckMate -901 is evaluating Opdivo in combination with chemotherapy versus chemotherapy alone in patients who are eligible for cisplatin-based chemotherapy.

The OS outcomes for patients whose tumor cells express PD-L1 ≥1% are based on the final efficacy analysis for this endpoint of the CheckMate -901 primary study; the other parts of the study are ongoing.

About Urothelial Carcinoma

Bladder cancer is the 10th most common cancer in the world, with more than 573,000 new cases diagnosed annually. Urothelial carcinoma, which most frequently begins in the cells that line the inside of the bladder, accounts for approximately 90% of bladder cancer cases. In addition to the bladder, urothelial carcinoma can occur in other parts of the urinary tract, including the ureters and renal pelvis. The majority of urothelial carcinomas are diagnosed at an early stage, but rates of recurrence and disease progression are high. Approximately 50% of patients who undergo surgery will experience disease recurrence. Additionally, approximately 20% to 25% of patients with urothelial carcinoma develop metastatic disease. For patients with metastatic cancer, the prognosis is poor, with a median overall survival of approximately 12 to 14 months when treated with systemic therapy. The poor durability of responses in the first-line setting presents a major challenge in the treatment of metastatic disease, and there are limited treatment options in the second-line setting for patients with advanced urothelial carcinoma.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In October 2015, the Company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

About Yervoy

Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types.

INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of adult patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (nivolumab), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

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

OPDIVO (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).

OPDIVO (nivolumab), in combination with fluoropyrimidine- and platinum- containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune- mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune- mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non- bullous/exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30- minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI- H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

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

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Checkmate 816, serious adverse reactions occurred in 30% of patients (n=176) who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy. In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in ≥4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in ≥2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). In Checkmate 577, serious adverse reactions occurred in 33% of patients receiving OPDIVO (n=532). A serious adverse reaction reported in ≥2% of patients who received OPDIVO was pneumonitis. A fatal reaction of myocardial infarction occurred in one patient who received OPDIVO. In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO- treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Checkmate 816, the most common (>20%) adverse reactions in the OPDIVO plus chemotherapy arm (n=176) were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). In Checkmate 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (≥20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (≥20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent (n=74), the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Attraction-3, the most common adverse reactions (≥20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%). In Checkmate 577, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=532) were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%). In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

Clinical Trials and Patient Populations

Checkmate 037–previously treated metastatic melanoma; Checkmate 066-previously untreated metastatic melanoma; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 238–adjuvant treatment of melanoma; Checkmate 816–neoadjuvant non-small cell lung cancer, in combination with platinum-doublet chemotherapy; Checkmate 227-previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LA–previously untreated recurrent or metastatic non-small cell lung cancer in combination with YERVOY and 2 cycles of platinum-doublet chemotherapy by histology; Checkmate 017–second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 743–previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 025–previously treated renal cell carcinoma; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275–previously treated advanced or metastatic urothelial carcinoma; Checkmate 274–adjuvant treatment of urothelial carcinoma; Checkmate 142– MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040–hepatocellular carcinoma, in combination with YERVOY; Attraction-3–esophageal squamous cell carcinoma; Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 649– previously untreated advanced or metastatic gastric or gastroesophageal junction or esophageal adenocarcinoma

About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

On May 16, 2022 Synthetic Biologics, Inc. (NYSE American: SYN), a diversified clinical-stage company developing therapeutics designed to treat diseases in areas of high unmet need, reported financial results for the year ended March 31, 2022, and provided a corporate update (Press release, Synthetic Biologics, MAY 16, 2022, View Source [SID1234614666]).

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Recent Developments:

Pipeline updates (OV): The acquisition of VCN Biosciences transformed Synthetic Biologics’ pipeline with the addition of VCN’s lead clinical-stage drug candidate, VCN-01, as well as preclinical stage VCN-11, which incorporates a proprietary albumin binding domain in the virus shell which is intended to improve systemic delivery by enabling the virus to coat itself in albumin and thereby evade neutralizing antibodies (NAbs).
In May 2022, announced an upcoming oral presentation on VCN-11 at the 25th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper). The presentation will include preclinical results showcasing the potential of VCN-11 to balance safety, with no major toxicities observed, and effectively target tumors after intravenous re-administration, even in the presence of high level NAbs.
In March 2022, announced the peer-reviewed publication of a Phase 1, multicenter, open-label, dose-escalation study investigating the therapeutic potential of intravenous VCN-01 oncolytic adenovirus with or without standard-of-care (SoC) chemotherapy (gemcitabine/nab-paclitaxel) in patients with advanced solid tumors. The data, published in the Journal for ImmunoTherapy of Cancer, suggests that treatment with VCN-01 is feasible and has an acceptable safety profile, with encouraging biological and clinical activity. These findings provide valuable dose-finding context and inform the clinical development strategy for VCN-01.
SYN-020: In May 2022, reported positive safety data from the Phase 1a multiple ascending dose study of SYN-020 in healthy volunteers. Analyses of preliminary data demonstrated that SYN-020 maintained a favorable safety profile and was well-tolerated across all dose levels. There were a few treatment-related adverse events, and all were mild (grade 1) and resolved without medical intervention. Both the previously reported Phase 1 single ascending dose (SAD) study and the current MAD study are intended to support the development of SYN-020 in multiple clinical indications.
Corporate Updates
In May 2022, formed a Scientific Advisory Board (SAB) composed of industry leaders in oncolytic viruses and gene therapies. The SAB will work cohesively with the Synthetic Biologics’ leadership team to support the Company’s transformative clinical development strategy and extension into oncology. The founding members of the SAB are:
Chairman: Ramon Alemany, Ph.D., Head of Immunotherapy and Virotherapy Group at Translational Research Laboratory of the Institut Catala d’Oncologia (ICO) and Institut de Investigacio Biomedica de Bellvitage (IDIBELL).
Member: Mark S. Blumenkranz, M.D., MMS, is HJ Smead Professor Emeritus in the Department of Ophthalmology at Stanford University.
Member: Ennio Antonio Chiocca, M.D., Ph.D., is Harvey W. Cushing Professor of Neurosurgery at Harvard Medical School, Neurosurgeon-in-Chief and Chairman, Department of Neurosurgery and Co-Director, Institute for the Neurosciences at Brigham and Women’s Faulkner Hospital.
Member: Daniel DiMaio, M.D., Ph.D., is the Waldemar Von Zedtwitz Professor of Genetics and Professor of Molecular Biophysics and Biochemistry, and of Therapeutic Radiology at Yale School of Medicine, as well as a Senior Advisor to the Director, Yale Cancer Center.
Member: Tom Dubensky, Ph.D., President of Tempest Therapeutics.
Member: Josep Tabernero, M.D., Ph.D., is Head of the Medical Oncology Department at the Vall d’Hebron University Hospital, Director of the Vall d’Hebron Institute of Oncology (VHIO) and Professor of Medicine at UVic.
In March 2022, Frank Tufaro, Ph.D., transitioned from Chief Operating Officer of recently acquired VCN Biosciences (VCN) to Chief Operating Officer of Synthetic Biologics. Dr. Tufaro will be responsible for leading strategic operations and optimizing organizational functions. As part of this acquisition, Manel Cascallό, Ph.D., former CEO of VCN, was appointed as General Director of Synthetic Biologic’s European Subsidiary.
Anticipated Milestones:

VCN-01

Initiation of VCN-01 dosing in an investigator sponsored study of brain tumors at the University of Leeds (H1 2022).
Initiation of VCN-01 dosing in combination with mesothelin-directed CAR-T cells for pancreatic and ovarian cancer in an investigator sponsored study at the University of Pennsylvania (H1 2022).
Initiation of a Phase 2 study of VCN-01 in combination with standard-of-care chemotherapy (gemcitabine/nab-paclitaxel) as a first line therapy in newly diagnosed metastatic PDAC patients (Q4 2022).
Initiation of a Phase 2/3 trial of VCN-01 as either an adjunct to chemotherapy or a potential rescue therapy in pediatric patients with advanced retinoblastoma (early 2023).
SYN-004

Data read out from the first cohort of the SYN-004 study in allo-HCT patients (H2 2022).
SYN-020

Planning for the initiation of a Phase 2a study of SYN-020 (H2 2022).
"We are extremely pleased with the continued momentum following the transformative VCN acquisition, and our significant corporate advancements that mark a new phase of strategic growth," said Steven A. Shallcross, Chief Executive Officer of Synthetic Biologics. "This is an important phase of Synthetic Biologics’ evolution, and to support our extension into oncology, we strengthened our leadership team and recently formed a Scientific Advisory Board of leading experts composed of key opinion leaders. These distinguished leaders have made groundbreaking scientific advances in their respective fields of oncology, immunology and gene therapy, and we look forward to their counsel as we advance our oncolytic adenovirus development program to address devastating cancers with high unmet need. We are well positioned to deliver on our sharpened clinical development strategy and are poised for an exciting year ahead with the anticipation of multiple clinical studies and pivotal milestones that should continue to drive shareholder value."

Quarter Ended March 31, 2022 Financial Results
General and administrative expenses increased to $1.7 million for the for the three months ended March 31, 2022, from $1.4 million for the three months ended March 31, 2021. This increase of 17% primarily composed of increased consulting and legal costs related to the VCN acquisition, higher insurance costs, audit fees, and public relations expenses and VCN administrative expenses not included in prior year. The charge related to stock-based compensation expense was $85,000 for the three months ended March 31, 2022, compared to $82,000 the three months ended March 31, 2021.

Research and development expenses increase to $2.6 million for the three months ended March 31, 2022, from approximately $1.1 million for the three months ended March 31, 2021. This increase of 132% is primarily the result of higher manufacturing expense for SYN-020, costs incurred related to our Phase 1a clinical trial of SYN-020 and the Phase 1b/2a clinical trial of SYN-004 (ribaxamase) in allogeneic HCT recipients and VCN research expenses related to VCN-01 not incurred in the prior year. We anticipate research and development expense to increase as we plan for and initiate enrollment for our phase 2 clinical trial for VCN-01 in PDAC, phase 2/3 clinical trial in retinoblastoma, expand GMP manufacturing activities for VCN-01 and SYN-020, and continue with supporting our VCN-11 and other preclinical and discovery initiatives. The charge related to stock-based compensation expense was $28,000 for the three months ended March 31, 2022, compared to $19,000 related to stock-based compensation expense for the three months ended March 31, 2021.

Other expense was $21,068 for the three months ended March 31, 2022 compared to other income of $347 for the three months ended March 31, 2021. Other expense is primarily composed of exchange loss of $22,607, offset by interest income of $1,539. Other income for the three months ended March 31, 2021 is primarily comprised of interest income.

Cash and cash equivalents totaled $56.7 million as of March 31, 2022, a decrease of $10.5 million from December 31, 2021.

Conference Call

Synthetic Biologics will host a conference call at 8:30 a.m. ET today to review first quarter 2022 operational highlights and financial results. Individuals may participate in the live call via telephone by dialing (877) 451-6152 (domestic) or (201) 389-0879 (international) and using the conference ID: 13729717. Participants are asked to dial in 15 minutes before the start of the call to register. Investors and the public can access the live and archived webcast of this call via the "News & Media" section of the company’s website, View Source, under "Events" or by clicking here, for 90 days after the call.

On May 16, 2022 Dynavax Technologies Corporation (Nasdaq: DVAX), a commercial-stage biopharmaceutical company developing and commercializing innovative vaccines, reported that Ryan Spencer, Chief Executive Officer, reported that it will present at the H.C. Wainwright Global Investment Conference, being held May 23-26, 2022 (Press release, Dynavax Technologies, MAY 16, 2022, https://www.prnewswire.com/news-releases/dynavax-to-present-at-the-hc-wainwright-global-investment-conference-301548166.html [SID1234614682]).

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The on demand presentation will be available, beginning Tuesday, May 24, 2022 at 7:00 a.m. E.T. and may be accessed through the "Events & Presentations" page on the "Investors" section of the Company’s website at View Source

On May 16, 2022, Sanofi reported Q1 2022 sales growth driven by Dupixent and CHC (Press release, Sanofi, MAY 16, 2022, View Source [SID1234614709])

Specialty Care grew driven by Dupixent

Vaccines were up reflecting strong PPH franchise as well as gradual recovery of Travel vaccines

General Medicines core assets up, driven by Rezurock and overall GBU sales broadly stable

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CHC continued strong growth momentum driven by Cough & Cold and Pain care categories

Q1 2022 business EPS(1) up 16.1% at CER driven by higher sales and improving margins

IFRS EPS of €1.61 (up 28.8%)

Business operating income (BOI) margin up reflecting improvement in gross margin while investing in R&D

Business EPS(1) up, also benefitting from an improved effective tax rate

Key milestone and regulatory achievements on R&D transformation

Efanesoctocog alfa met phase 3 primary endpoint in hemophilia A and demonstrated superiority to prior factor prophylaxis

Dupixent approved in EU for severe asthma in children aged 6 to 11 years; Priority Review obtained in atopic dermatitis for children (6 months to 5 years) and eosinophilic esophagitis patients 12 years and older in the U.S.

Nirsevimab EMA regulatory submission accepted under accelerated assessment for RSV protection in all infants

FDA approved Enjaymo, first treatment for use in patients with cold agglutinin disease (CAD)

Xenpozyme approved in Japan, first and only approved therapy indicated to treat acid sphingomyelinase deficiency (ASMD)

Sanofi and GSK applied for conditional regulatory authorization for their first-generation COVID-19 vaccine in Europe with data supporting its use as a universal booster, designed to boost all currently approved COVID-19 vaccine platforms

(1) In order to facilitate an understanding of operational performance, Sanofi comments on the business net income statement. Business net income is a non-GAAP financial measure (definition in Appendix 7). The consolidated income statement for Q1 2022 is provided in Appendix 3 and a reconciliation of reported IFRS net income to business net income is set forth in Appendix 4; (2) 2021 business EPS was €6.56.

2022 first-quarter Sanofi sales

Unless otherwise indicated, all percentage changes in sales in this document are stated at CER1

———————————–

In the first quarter of 2022, Sanofi sales were €9,674 million, up 12.6% on a reported basis. Exchange rate movements had a positive effect of 4.0 percentage points, mainly due to the U.S. dollar.

Global Business Units

First-quarter 2022 net sales by Global Business Unit (variation at CER; € million; % of total sales)

See Appendix 7 for definitions of financial indicators.

First-quarter 2022 net sales by geographic region (variation at CER; € million; % of total sales)

First-quarter 2022 operating income

First-quarter business operating income (BOI) increased.. The ratio of BOI to net sales increased 1.0 percentage point to 31.7%.

Pharmaceuticals

First-quarter 2022 Pharmaceutical sales increased 7.5% to €7,326 million, mainly driven by the Specialty Care portfolio (up 17.8%) with continued strong performance of Dupixent while sales in General Medicines decreased 0.7%.

Specialty Care

Dupixent
In the first quarter, Dupixent (collaboration with Regeneron) sales increased 45.7% to €1,614 million. In the U.S., Dupixent sales of €1,176 million (up 38.1%) were driven by continued strong demand in AD in adults, adolescents, and children aged 6 to 11 years, and continued uptake in asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). Dupixent total prescriptions (TRx) increased 43% (year-over-year) and new-to-brand prescriptions (NBRx) grew 32%. In Europe, first-quarter Dupixent sales

grew 53.3% to €211 million reflecting continued growth in AD and additional launches in younger population in AD, asthma and CRSwNP.

Neurology and Immunology

In the first quarter, Neurology and Immunology sales grew 0.3% to €611 million, reflecting strong Kevzara sales which were partially offset by lower Aubagio sales.

Aubagio sales decreased 6.6% in the first quarter to €491 million due to lower sales in the U.S. as a result of both competitive pressure and price. Sales in Europe were stable.

First-quarter Kevzara (collaboration with Regeneron) sales increased 61.4% to €95 million due to a COVID-19 related increase in global demand for IL-6 receptor blockers and the temporary tocilizumab shortage.

Rare Disease

In the first quarter, Rare Disease sales increased 1.9% to €804 million driven by the Pompe franchise, partially offset by unfavorable purchasing patterns in Rest of the World region primarily for the Gaucher and Fabrazyme franchises. Underlying patients base treated grew around 6% compared to the same quarter of last year.

First-quarter sales of the Pompe franchise (Myozyme/Lumizyme + Nexviazyme) increased 8.9% to €265 million primarily from new patient accruals and the ramp up of Nexviazyme. Myozyme/Lumizyme sales decreased 3.0% to €235 million mainly reflecting the conversion to Nexviazyme in the U.S. Sales of Nexviazyme (which was launched in the US in August 2021 and in Japan in November 2021) were €30 million in the first quarter (of which €26 million in the U.S.).

Sales of the Gaucher franchise (Cerezyme + Cerdelga) decreased 4.2% (to €232 million) in the first quarter. Over the period, Cerezyme sales decreased 6.7% to €165 million, mainly due to unfavorable buying patterns resulting in lower sales in the Rest of the World region. In parallel, Cerdelga sales were up 3.2% driven by switches and new patient accruals in Europe and the U.S.

First-quarter Fabrazyme sales increased 2.4% to €220 million driven mainly by Europe and the U.S. In the Rest of the World region, despite unfavorable purchasing patterns, Fabrazyme sales were stable.

Oncology

First-quarter 2022 sales of Oncology increased 6.8% (to €244 million) driven by the Sarclisa launch which more than offset the impact of Jevtana generic competition in Europe.

First-quarter Jevtana sales decreased 25.4% to €98 million following the entry of generic competition in some European markets (down 75.6%) at the end of March 2021. In the U.S., sales were up 8.6%, where Jevtana is currently covered by four Orange Book listed patents US 7,241,907, US 8,927,592, US 10,583,110 and US 10,716,777. Sanofi filed patent infringement suits under Hatch-Waxman against generic filers asserting the ‘110 patent, the ‘777 patent and the ‘592 patent in the US District Court for the District of Delaware. Sanofi has reached settlement agreements with some of the defendants and the suit against the remaining defendants is ongoing. A 3-day trial against Apotex and Sandoz has been scheduled starting January 2023 and the remaining defendants have agreed not to launch any generic cabazitaxel product until the earlier of a district court decision in favor of the defendants or four months after the completion of the post-trial briefing. Jevtana also received a regulatory data exclusivity related to the CARD clinical study which expires in December 2023.

First-quarter Sarclisa sales were €65 million (versus €34 million in the first quarter of 2021) primarily driven by performance in the U.S. (€25 million), Europe (€22 million) and Japan.

Rare Blood Disorders

In the first quarter, Rare Blood Disorders franchise sales increased 1.8% (€293 million), reflecting Cablivi and Alprolix growth partially offset by lower Eloctate/Alprolix industrial sales to Sobi (recorded in the Rest of the World region).

Eloctate sales were €138 million in the first quarter, down 3.0% reflecting lower sales in the U.S. (down 1.9%) and in the Rest of the World region.

First-quarter Alprolix sales were up 2.0% to €108 million driven by the U.S. sales (up 8.9%), partially offset by lower sales in the Rest of the World region.

Cablivi sales increased by 15.8% to €46 million in the first quarter driven by launches in Europe (up 46.7% to €23 million). In the U.S., sales of the product were down 4.5% to €22 million, due to the COVID-19 environment impacting treatment initiations at the hospital level.

General Medicines

First quarter General Medicines sales decreased 0.7% to €3,760 million and were stable excluding portfolio streamlining.

Core assets

In the first quarter, core assets sales increased 4.7% to €1,594 million, driven by Toujeo, Praluent, Multaq, Thymoglobulin and Rezurock (consolidated from November 9, 2021), partially offset by lower sales of Lovenox. Core assets sales grew across all geographies in the first quarter.

First-quarter Lovenox sales decreased 8.2% to €377 million, mainly reflecting lower sales in the Rest of the World region (down 11.9%) due to high base of comparison in the first quarter of 2021 which benefitted from strong Covid-related demand (WHO guidelines recommending the use of low molecular weight heparins in hospitalized COVID-19 patients). In addition, biosimilar competition and supply limitations affected the performance.

First-quarter Toujeo sales increased 6.3% to €274 million due to growth in Europe and the Rest of the World region, partially offset by lower sales in the U.S.

In China, the Volume Based Procurement (VBP) for insulins is expected to be implemented in May 2022. In November 2021, Sanofi participated in the VBP tender for basal insulin analogues and was among the bidding winners in the group A with Lantus/Toujeo. Sanofi expects its glargine (Toujeo/Lantus) sales to decrease in China in 2022, due to high volumes at significantly lower prices. In China, Toujeo/Lantus sales were €459 million in 2021.

Plavix sales were stable in the first quarter to €261 million, higher sales in the Rest of the World region (up 1.4%) offsetting lower sales in Europe. Plavix sales in China were down 3.4% to €123 million due to a high base of comparison in the first quarter of 2021.

Multaq first quarter sales grew 13.9% to €87 million, reflecting strong U.S. sales growth.

Sales of Rezurock, a recently FDA-approved, first-in-class treatment for chronic graft-versus-host disease (cGVHD) for adult and pediatric patients 12 years and older who have failed at least two prior lines of systemic therapy, were consolidated as of November 9, 2021 (through the Kadmon acquisition) and generated €41 million in the first quarter. Rezurock performance reflects the rapidly expanding pool of prescribing institutions as well as pent-up demand from cGVHD patients who have already failed multiple systemic therapies.

Praluent first-quarter sales were €69 million, up 21.4% driven by Europe performance. In Rest of the World region, sales were up 6.7%. In China, Praluent was included in the NDRL list at the beginning of 2022.

First-quarter Soliqua sales increased 15.9% to €53 million driven by the Rest of World region (up 54.5%) supported by new launches and Solimix results.

In the first quarter, non-core assets sales decreased 4.2% to €1,983 million reflecting portfolio streamlining (-1.4ppt), lower Lantus sales as well as the impact of VBP wave 5 in China on Eloxatin and Taxotere sales.

Lantus sales were €671 million, down 1.5% in the first quarter, due to lower sales in Europe, reflecting biosimilar competition and continuous Toujeo switches.

First-quarter Aprovel/Avapro sales were up 17.8% to €125 million, due to some supply improvement and compared with a low base in the first quarter of 2021.

Pharmaceuticals business operating income

In the first quarter, business operating income (BOI) of Pharmaceuticals increased. The ratio of BOI to net sales increased by 0.3 percentage point to 38.6%, reflecting an improvement of the gross margin ratio.

First-quarter Vaccines sales increased 6.8% to €1,020 million driven by double-digit growth of Polio/Pertussis/Hib vaccines sales and partial recovery of Travel vaccines.

In the first quarter, Polio/Pertussis/Hib (PPH) vaccines sales increased 10.3% to €613 million. In the Rest of the World region, PPH sales grew 23.1% driven by a strong performance of Pentaxim in China compared to a low base last year and favorable timing of polio tender delivery. In the U.S., PPH sales were impacted by inventory fluctuation and progressive ramp up of Vaxelis sales. As a reminder, Vaxelis in-market sales are not consolidated and the profits are shared equally between Sanofi and Merck.

First-quarter Meningitis sales decreased 16.4% to €112 million, due to lower sales in Latin America reflecting price competition in public tenders.

Booster vaccines sales increased 4.0% in the first quarter to €109 million, driven by the Rest of the World region.

First-quarter Travel and endemic vaccines sales increased 61.0% to €98 million, reflecting a partial recovery of Travel vaccines in Europe and the U.S. as well as higher endemic vaccines sales in the Rest of the World region.

Influenza vaccines sales decreased 18.2% in the first quarter, reaching €66 million due to an exceptional high demand in the first quarter of 2021.

Vaccines business operating income

In the first quarter, business operating income (BOI) decreased compared to the same period of last year. This reflects higher R&D expenses related to Translate Bio and the mRNA center of excellence and the payment from Daiichi Sankyo recorded in the first quarter of 2021. BOI to net sales ratio was 29.0% (versus 40.5% in the first quarter of 2021, 27.5% excluding the payment from Daiichi Sankyo).

Consumer Healthcare

In the first quarter, Consumer Healthcare (CHC) sales increased 17.0% to €1,328 million sustained by growth in Europe and the Rest of the World region. This performance was mainly driven by the strong demand for Cough & Cold products, as well as the performance of Pain Care and Digestive Wellness categories. This global performance includes a positive price effect of 3%. The divestments of non-core products had an impact of -0.6 ppt of growth in the first quarter.

In the U.S., first-quarter CHC sales increased 2.1% to €310 million driven by double-digit growth of Allergy category partially offset by lower sales of Personal care and non-core assets mainly due to supply constraints.

In Europe, first-quarter CHC sales increased 21.0% to €406 million mainly reflecting strong growth of the Cough & Cold and Pain Care categories.

In Rest of World, first-quarter CHC sales increased 22.8% to €612 million, supported by growth in all categories.

CHC business operating income

In the first quarter, business operating income (BOI) of CHC increased. The ratio of BOI to net sales increased 9.5 percentage point to 44.9% versus the prior year, reflecting strong top line growth as well as a capital gain related to divestments of non-strategic assets.

Company sales by geographic region

First-quarter sales in the U.S. increased +12.1% to €3,484 million supported by the strong performance of Dupixent.

In Europe sales increased +6.7% in the first quarter to €2,392 million mainly driven by Dupixent performance as well as strong CHC growth.

In Rest of World sales increased +7.0% to €3,798 million in the first quarter, reflecting the performance of Dupixent, CHC and Vaccines which largely offset lower sales of General Medicines. Sales in China increased 13.4% to €901 million mainly as a result of the growth of Dupixent, Vaccines and CHC. In Japan, first-quarter sales increased 1.6% to €433 million driven by Dupixent and Sarclisa which more than offset lower sales of General Medicines. In Russia, due to strong cough, cold and flu related sales, higher vaccines sales and unprecedented stockpiling at pharmacy and patient level sales increased 34.4% in the first quarter. In March, Sanofi decided to stop any new spending not related to the supply of its essential and life-changing medicines and vaccines in Russia. This includes all advertising and promotional spending.

R&D update at the end of the first quarter 2022

Regulatory update

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending to extend the approval of Dupixent (dupilumab) in the European Union to include add-on maintenance treatment for children aged 6 to 11 years with severe asthma with type 2 inflammation characterized by raised blood eosinophils and/or raised fractional exhaled nitric oxide (FeNO) who are inadequately controlled on two maintenance therapies.

The U.S. Food and Drug Administration (FDA) has accepted for Priority Review the supplemental Biologics License Application (sBLA) for Dupixent as an add-on maintenance treatment for children aged 6 months to 5 years with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The target action date for the FDA decision on this investigational use is June 9, 2022. Dupixent remains the only biologic medicine approved for patients 6 years of age and older in this indication.

The FDA has accepted for Priority Review the supplemental Biologics License Application (sBLA) for Dupixent 300 mg weekly to treat adults and adolescents aged 12 years and older with eosinophilic esophagitis (EoE), a chronic and progressive type 2 inflammatory disease that damages the esophagus and the ability to swallow.

The FDA has approved Enjaymo (sutimlimab-jome), the first and only approved treatment to decrease the need for red blood cell transfusion due to hemolysis in adults with cold agglutinin disease (CAD). CAD is a chronic and rare blood disorder that impacts the lives of an estimated 5,000 people in the U.S. Sanofi estimates around 3,200 patients to be drug-treated per year and that Enjaymo could reach a market share of around 25% in the years to come.

The Japanese Ministry of Health, Labor and Welfare (MHLW) has granted marketing authorization for Xenpozyme (olipudase alfa) for the treatment of adult and pediatric patients with non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD). Xenpozyme is currently the only approved treatment for ASMD and represents Sanofi’s first therapy to be approved under the SAKIGAKE or pioneer designation, which is the Japanese government’s regulatory fast-track pathway to promote research and development of innovative new medical products addressing urgent unmet medical needs.

The EMA has accepted the Marketing Authorization Application (MAA) for nirsevimab under an accelerated assessment procedure. Nirsevimab, the first investigational long-acting antibody designed to protect all infants against medically attended lower respiratory tract infections (LRTI) for the respiratory syncytial virus (RSV) season, is being developed by Sanofi and AstraZeneca. The New England Journal of Medicine (NEJM) published detailed Phase 3 results of the MELODY trial. In this study, with healthy infants born at term or late preterm entering their first RSV season, the primary endpoint was met, reducing the incidence of medically attended LRTI, such as bronchiolitis or pneumonia, caused by RSV by 74.5% compared to placebo.

The EMA has started to evaluate the application for the conditional marketing authorization of the Sanofi-GSK first-generation recombinant COVID-19 vaccine as a primary vaccine and a booster designed to boost all currently approved COVID-19 vaccine platforms. Final analysis of the VAT02 COVID-19 booster trial confirms universal ability to boost neutralizing antibodies 18- to 30-fold across vaccine platforms. The VAT08 primary series trial, with two doses of the Sanofi-GSK vaccine in seronegative populations demonstrated 100% efficacy against severe COVID-19 disease and hospitalizations, 75% efficacy against moderate or severe COVID-19 disease, and 57.9% efficacy against any symptomatic COVID-19 disease, in line with expected vaccine effectiveness in today’s environment dominated by variants of concern. When the Sanofi-GSK vaccine was used as a two-dose primary series followed by a booster dose, neutralizing antibodies increased 84- to 153-fold compared to pre-boost levels.

Sanofi and Regeneron announced the voluntary withdrawal of the sBLA for Libtayo (cemiplimab-rwlc) as a second-line treatment for patients with advanced cervical cancer. The decision was made after the companies and the FDA were not able to align on certain post-marketing studies. Discussions with regulatory authorities outside of the U.S. are ongoing.

Portfolio update

Sanofi and Sobi announced positive topline results from the pivotal XTEND-1 study evaluating the safety, efficacy and pharmacokinetics of efanesoctocog alfa (BIVV001), a once-weekly recombinant factor VIII therapy, in previously treated patients ≥12 years of age with severe hemophilia A. The study met both primary and secondary endpoints, showing a clinically meaningful prevention of bleeds in people with severe hemophilia A over a period of 52 weeks, with a median annualized bleeding rate (ABR) of 0 and a mean ABR of 0.71, and a superiority to prior prophylactic factor VIII replacement therapy based on intra-patient comparison. Sanofi plans to submit the data in the U.S. mid-2022. Submission in the EU is expected to follow the availability of data from the ongoing XTEND-Kids pediatric study, expected in 2023.

A second trial (PRIME) evaluating Dupixent in adults with uncontrolled prurigo nodularis (PN), met its primary and key secondary endpoints, showing it significantly reduced itch and skin lesions compared to placebo at 24 weeks in this investigational setting. The data confirm the positive results that were previously reported from the Phase 3 PRIME2 trial.

The LIBERTY-CPUO-CHIC study evaluating the efficacy and safety of subcutaneous Dupixent for the treatment of adult participants with chronic pruritus of unknown origin (CPUO) has initiated, and enrolled its first participant.

The CUPID Study B evaluating Dupixent in patients with chronic spontaneous urticaria (CSU), who were refractory to omalizumab, stopped due to futility based on a pre-specified interim analysis. Although positive numerical trends in reducing itch and hives were observed, the results from the interim analysis did not demonstrate statistical significance for the primary endpoints. The LIBERTY-CUPID pivotal program was initiated in 2020 with an accelerated direct-to-Phase 3 strategy. The previously reported Phase 3 trial (Study A), which evaluated a different group of patients who were biologic-naïve, met its primary and all key secondary endpoints at 24 weeks showing that adding Dupixent to standard-of-care antihistamines significantly reduced itch and hives compared to antihistamines alone. Sanofi and Regeneron remain committed to advancing Dupixent for patients with CSU uncontrolled on antihistamines, next steps are being evaluated including discussions with regulatory authorities.

The clinical trial evaluating the efficacy and safety of amcenestrant compared with tamoxifen in patients with HR+ early breast cancer who have discontinued adjuvant aromatase inhibitor (AI) therapy due to treatment related toxicity (AMEERA-6), enrolled its first participant.

Three studies assessing rilzabrutinib have initiated, and enrolled their first participants: a randomized, double-blind, placebo-controlled study in adults with moderate-to-severe asthma, a randomized, double-blind, placebo-controlled study in CSU, and an open-label study in adults with Warm Autoimmune Hemolytic Anemia (wAIHA).

The non-randomized and open-label study assessing the clinical benefit of SAR444245 combined with other anticancer therapies for the treatment of adults with advanced or metastatic gastrointestinal cancer was initiated, and was administered to the first participant.

The pivotal AMEERA-3 clinical trial evaluating amcenestrant, an investigational optimized oral selective estrogen receptor degrader (SERD), as monotherapy compared to endocrine treatment of physician’s choice in patients with locally advanced or metastatic ER+/HER2- breast cancer who progressed on or after hormonal therapies, did not meet its primary endpoint of improving progression-free survival as assessed by an independent central review.

The study assessing the safety and efficacy of 4 investigational HSV 2 vaccines in adults with recurrent genital herpes caused by HSV 2 (HSV15) has been discontinued.

Given the war in Ukraine and the suffering of the Ukrainian people, Sanofi has adapted its clinical trial implementation in the region. The company decided to halt any new recruitment of patients for ongoing clinical trials in Russia and Belarus, though it will continue to treat patients already enrolled. In Ukraine, Sanofi seeks to continue to support and supply patients currently enrolled in Sanofi-sponsored clinical trials, including transferring them within Ukraine or into neighboring countries. In anticipation of potential loss of data, the company is currently activating new clinical sites and expanding patient enrollment in geographies not impacted by the war. This may lead to the planned primary completion dates of its pivotal trials in MS and COPD to shift, but previously communicated submission timelines remain unchanged.

Acquisitions and major collaborations

Sanofi and Blackstone announced a strategic, risk-sharing collaboration under which funds managed by Blackstone Life Sciences will contribute up to €300 million to accelerate the global pivotal studies and the clinical development program for the subcutaneous formulation and delivery of the anti-CD38 antibody Sarclisa, to treat patients with multiple myeloma (MM), expecting to begin in the second half of 2022.

Sanofi announced the research collaboration and license agreement to develop up to 15 novel small molecule candidates across oncology and immunology with Exscientia, leveraging their end-to-end AI-driven platform utilizing actual patient samples. The companies have been working together since 2016 and in 2019, Sanofi in-licensed Exscientia’s novel bispecific small molecule candidate capable of targeting two distinct targets in inflammation and immunology.

Sanofi announced the completion of the acquisition of Amunix Pharmaceuticals, Inc, adding a promising pipeline of T-cell engagers and cytokine therapies. The acquisition also provides access to their Pro-XTEN, XPAT, and XPAC technology to deliver next generation conditionally activated biologics. The technology platform is highly complementary to Sanofi’s existing R&D platforms and supports Sanofi’s efforts to accelerate and expand its contributions to innovative medicines for oncology patients, with approximately 20 molecules currently in development.

Sanofi and Seagen announced an exclusive collaboration agreement to design, develop, and commercialize antibody-drug conjugates (ADCs) for up to three cancer targets. The collaboration will utilize both Sanofi’s proprietary monoclonal antibody technology and Seagen’s proprietary ADC technology.

Sanofi and IGM Biosciences announced the signing of an exclusive worldwide collaboration agreement to create, develop, manufacture, and commercialize IgM antibody agonists against three oncology targets and three immunology/inflammation targets.

An update of the R&D pipeline at as of March 31, 2022, is available on Sanofi’s website:

View Source

Covid Update

Sanofi and GSK applied for regulatory authorization of their first-generation COVID-19 vaccine in Europe with data supporting its use as a universal booster, designed to boost all currently approved COVID-19 vaccine platforms. In addition, the companies are developing a next-generation booster vaccine designed to provide broad protection against all variants of concern, from the original strain to Omicron BA.2. The data (VAT02 Cohort 2) is expected to be communicated in Q2 2022.

First-quarter 2022 financial results

Business Net Income2

In the first quarter of 2022, Sanofi generated net sales of €9,674 million, an increase of 12.6% (up 8.6% at CER).

First-quarter other revenues increased 28.5% (up 23.7% at CER) to €379 million, including VaxServe sales contribution of non-Sanofi products of €286 million (up 16.7 % at CER).

First-quarter Gross Profit increased 15.7% (up 11.1% at CER) to €7,175 million. The gross margin ratio increased 2.0 percentage points to 74.2% versus the first quarter of 2021, reflecting strong improvement of the Pharmaceuticals gross margin ratio (which increased from 75.2% to 77.9%) driven by favorable impact of growing weight of Specialty Care, efficiency gains in Industrial Affairs and lower royalty expenses. The Vaccines gross margin ratio slightly decreased to 61.6% from 62.0%. CHC gross margin ratio was 67.3%, down 0.7 percentage point.

Research and Development (R&D) expenses increased 17.5% (up 14.0% at CER) to €1,489 million in the first quarter, reflecting increase in priority assets development as well as recent acquisitions.

First-quarter selling general and administrative expenses (SG&A) increased 8.4% to €2,379 million. At CER, SG&A expenses were up 4.3%, reflecting increased commercial investments in Specialty Care growth drivers which were partially offset by continued streamlining initiatives. In the first quarter, the ratio of SG&A to sales decreased 0.9 percentage point to 24.6% compared to the prior year.

First-quarter operating expenses were €3,868 million, an increase of 11.8% and 7.8% at CER.

First-quarter other current operating income net of expenses was -€265 million versus -€101 million in the first quarter of 2021. Other current operating income net of expenses included an expense of €477 million (versus an expense of €279 million in the first quarter of 2021) corresponding to the share of profit to Regeneron of the monoclonal antibodies Alliance, reimbursement of development costs by Regeneron and the reimbursement of commercialization-related expenses incurred by Regeneron. In the first quarter, this line also included €232 million of net capital gains related to General Medicines and CHC portfolio streamlining compared to €56million in the same period of 2021.

The share of profit from associates was €30 million versus €9 million in the first quarter of 2021 and included the share of U.S profit related to Vaxelis.

First-quarter business operating income2 (BOI) increased. . The ratio of BOI to net sales increased 1.0 percentage point to 31.7% mainly reflecting gross margin ratio improvement.

Net financial expenses were €78 million versus €84 million in the same period of 2021.

First-quarter effective tax rate was 19.0% versus 21.0% in the prior year. Sanofi expects its effective tax rate to be around 19% in 2022.

First-quarter business net income2 increased 20.2% to €2,424 million and increased 16.0% at CER. The ratio of business net income to net sales increased 1.6 percentage point to 25.1% versus the first quarter of 2021.

In the first quarter of 2022, business earnings per share2 (EPS) was €1.94, up 20.5% on a reported basis (up 16.1% at CER). The average number of shares outstanding was 1,249.2 million versus 1,249.3 million in first quarter 2021.

Reconciliation of IFRS net income reported to business net income (see Appendix 4)

2 See Appendix 3 for 2021 first-quarter consolidated income statement; see Appendix 7 for definitions of financial indicators, and Appendix 4 for reconciliation of IFRS net income reported to business net income.

In the first quarter of 2022, the IFRS net income was €2,009 million. The main items excluded from the business net income were:

An amortization charge of €449 million related to fair value remeasurement on intangible assets of acquired companies (primarily Genzyme: €145 million, Bioverativ: €88 million, Boehringer Ingelheim CHC business: €48 million, Ablynx: €42 million and Kadmon: €37 million) and to acquired intangible assets (licenses/products: €24 million). These items have no cash impact on the Company.

An impairment of intangible assets of €5 million.

Restructuring costs and similar items of €175 million related to streamlining initiatives.

A €232 million tax effect arising from the items listed above, mainly comprising €96 million of deferred taxes generated by amortization and impairments of intangible assets and €46 million associated with restructuring costs and similar items (see Appendix 4).

Capital Allocation

In the first quarter of 2022, free cash flow before restructuring, acquisitions and disposals4 decreased by 15.5% to €1,998 million, after net changes in working capital (-€468 million) and capital expenditures (-€356 million). After acquisitions (-€277 million), proceeds from disposals3 (+€347 million) and payments related to restructuring and similar items (-€361 million), free cash flow4 decreased by 11.3% to €1,707 million. After the acquisition of Amunix (-€803 million), net debt decreased from €9,983 million at December 31, 2021 to €9,432 million at March 31, 2022 (amount net of €8,728 million cash and cash equivalents).

On May 16, 2022 Compugen Ltd. (Nasdaq: CGEN), a clinical-stage cancer immunotherapy company and a pioneer in computational target discovery, reported financial results for the first quarter ended March 31, 2022 and provided a corporate update on key events since the start of 2022 (Press release, Compugen, MAY 16, 2022, View Source [SID1234614586]).

"I am excited about the outlook of Compugen’s immune checkpoint inhibitors based on their unique characteristics, encouraging preliminary clinical data and our differentiated clinical development strategy," said Anat Cohen-Dayag, Ph.D., President, and Chief Executive Officer of Compugen. We are the first to evaluate the triple blockade of the DNAM-1 axis, targeting PVRIG, TIGIT and PD-1 in the clinic. Based on the totality of the data we have to date on the PVRIG pathway, we believe triple blockade of PVRIG/TIGIT/PD-1 may be required for optimizing clinical responses in both inflamed and less inflamed tumors where other checkpoint inhibitors have so far been unsuccessful. Our Phase 1 clinical data demonstrated durable disease control rates, consistent immune activation, and good tolerability. With COM902, we are the first company to present clinical data with an IgG4 anti-TIGIT antibody, with low Fc-effector function. Having over a decade of expertise in this space, we believe this is the optimal design for an anti-TIGIT antibody. COM902 achieved a disease control rate of 50%. Unlike some other anti-TIGIT antibodies, to date studies have shown that COM902 avoids depletion of the CD8+ T cells, crucial for efficacy and we believe the IgG4 backbone may come with additional safety benefits. We look forward to proving our DNAM-1 axis hypothesis through our robust differentiated clinical strategy with studies designed to maximize the potential of COM701."

Dr. Cohen-Dayag also commented, "Continuing on our excellent track record in execution, our first quarter of 2022 has been focused on execution of our differentiated clinical strategy to further enhance our leadership in DNAM-1 axis evaluation. Enrollment continues in our well designed, comprehensive Phase 1 clinical studies with our pioneering immunotherapy drug candidates COM701, targeting PVRIG, and COM902, targeting TIGIT. In addition, we continue to be data-driven, invest in cutting edge research and innovate as reflected by presentations at the AACR (Free AACR Whitepaper) and Keystone Symposium as well as expansion of COM701 intellectual property portfolio with a new U.S. patent covering triple combination use with anti-PD-1 and anti-TIGIT antibodies. Our $107 million cash balance affirms our financial discipline, with bold execution on our DNAM-1 axis hypothesis."

Dr. Cohen-Dayag continued, "Our clinical program is comprised of three ongoing cohort expansion combination studies, with overlapping indications, in patients with relapsed disease and indications so far insensitive to immunotherapy. The program was designed to focus on patients with limited treatment options and indications with greatest unmet need to efficiently demonstrate proof-of-concept for our novel immune therapies. Our intention is to report data from fully enrolled cohorts of each of these studies, taking into consideration that certain cohorts/indications enroll faster than others. We are on track to provide results from these studies starting with the microsatellite stable colorectal cancer, COM701/nivolumab combination expansion cohort, in the fourth quarter of 2022. We are also planning to report results from the other cohorts throughout 2023. The data from these studies will guide our regulatory strategy on a cohort-by-cohort basis."

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Dr. Cohen-Dayag concluded, "We are committed and we look forward to updating the medical and investment communities with our progress."

Financial Results

As of March 31, 2022, cash, cash equivalents, short-term bank deposits and restricted cash totaled approximately $107 million, compared with approximately $118 million as of December 31, 2021. The Company expects its existing cash and cash related balances to be sufficient to fund its operating plan into 2024, at the current rate of expenses. Compugen does not have any debt.

R&D expenses for the first quarter ended March 31, 2022, were approximately $7.2 million compared with approximately $7.3 million for the comparable period in 2021.

General and administrative expenses for the first quarter ended March 31, 2022, were approximately $2.6 million compared with approximately $2.7 million for the comparable period in 2021.

Net loss for the first quarter ended March 31, 2022, was approximately $9.7 million, or $0.11 per basic and diluted share, compared with a net loss of approximately $9.9 million, or $0.12 per basic and diluted share, in the comparable period of 2021.