On March 1, 2021 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported the company is voluntarily withdrawing the U.S. indication for KEYTRUDA (pembrolizumab) for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy (Press release, Merck & Co, MAR 1, 2021, View Source [SID1234575841]). The withdrawal of this indication was done in consultation with the U.S. Food and Drug Administration (FDA), and Merck is working to complete this process over the coming weeks. This decision does not affect other indications for KEYTRUDA, Merck’s anti-PD-1 therapy.

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This accelerated approval for KEYTRUDA was granted in June 2019 based on tumor response rate and durability of response data from KEYNOTE-158 (cohort G) and KEYNOTE-028 (cohort C1). Continued approval for this indication was contingent upon completion of the post-marketing requirement establishing superiority of KEYTRUDA as determined by overall survival (OS). As announced in Jan. 2020, KEYNOTE-604, the confirmatory Phase 3 trial for this indication, met one of its dual primary endpoints of progression-free survival but did not reach statistical significance for the other primary endpoint of OS.

Merck’s consultation with the FDA on this withdrawal is part of an industry-wide evaluation of indications based on accelerated approvals that have not yet met their post-marketing requirements. Merck is notifying health care professionals about this withdrawal. Patients being treated with KEYTRUDA for their metastatic SCLC should discuss their care with their health care provider.

"The accelerated pathways created by the FDA have been integral to the remarkable progress in oncology care over the past five years and have helped many cancer patients with advanced disease, including small cell lung cancer, access new treatments," said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. "KEYTRUDA remains a foundational treatment for certain patients with metastatic non-small cell lung cancer. We will continue to rigorously evaluate the benefits of KEYTRUDA in small cell lung cancer and other types of cancer, in pursuit of Merck’s mission to save and improve lives."

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,300 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

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

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

Non-Small Cell Lung Cancer

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

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

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

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

Small Cell Lung Cancer

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

Head and Neck Squamous Cell Cancer

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

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

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

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

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

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

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

Gastric Cancer

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

Esophageal Cancer

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

Cervical Cancer

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

Hepatocellular Carcinoma

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

Merkel Cell Carcinoma

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

Renal Cell Carcinoma

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

Tumor Mutational Burden-High

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

Cutaneous Squamous Cell Carcinoma

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

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. 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 KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, 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 adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus 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. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. 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 indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

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 KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. 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. Some 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, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; 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 (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

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

Embryofetal Toxicity

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

Adverse Reactions

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

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

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

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

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

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

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

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

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

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

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC (n=596) who had not been previously treated with chemotherapy in the metastatic setting, fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy, the most common were: pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common adverse reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were: fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).

Lactation

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

Pediatric Use

In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months).

Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).

Merck’s Focus on Cancer

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

On March 1, 2021 Avid Bioservices, Inc. (NASDAQ:CDMO) (NASDAQ:CDMOP), a dedicated biologics contract development and manufacturing organization (CDMO) working to improve patient lives by providing high quality development and manufacturing services to biotechnology and pharmaceutical companies, reported that it will report financial results for the third quarter of fiscal year 2021 on March 8, 2021 after market close and will host a conference call and webcast at 1:30 PM Pacific Time (4:30 PM Eastern Time) (Press release, Avid Bioservices, MAR 1, 2021, View Source [SID1234575840]). Members of Avid’s senior management will discuss financial results for the third quarter and review recent corporate developments.

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On March 1, 2021 Biohaven Pharmaceutical Holding Company Ltd. ("Biohaven" or the "Company") (NYSE: BHVN), a commercial-stage biopharmaceutical company with a portfolio of innovative, late-stage product candidates targeting neurological diseases, including rare disorders, reported financial results for the fourth quarter and full year 2020 and provided a review of recent accomplishments and anticipated upcoming milestones (Press release, Biohaven Pharmaceutical, MAR 1, 2021, View Source [SID1234575839]).

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Vlad Coric, M.D., Chief Executive Officer of Biohaven commented, "The impressive market growth of NURTEC ODT, despite continued headwinds from the pandemic, reflects the significant unmet need that exists for patients suffering from the debilitating effects of migraine and our differentiated product label compared to competitors. We’re proud of our commercial and R&D team members who have been dedicated to delivering this important medication to patients despite the challenges of the past year. Fourth quarter net product revenues of $35.1 million increased 98% from the previous quarter and was particularly strong, reflecting patient demand and improved gross-to-net from broad insurance coverage." Dr. Coric added, "With the launch of NURTEC ODT exceeding expectations, we are focused on disciplined life-cycle management to maximize the value of our CGRP-antagonist program and look to expand our portfolio of approved products through advancement of our late-stage clinical assets, including intranasal zavegepant for migraine, troriluzole in SCA and OCD, and verdiperstat in MSA and ALS. The formation of Biohaven Labs provides the potential for internally developed next-generation innovative compounds to expand our pipeline for continued future growth."

Full Year and Recent Business Highlights

Continued strong uptake of NURTEC ODT and Updates Regarding Calcitonin Gene-Related Peptide (CGRP) Antagonist Platform

Full-year 2020 net product revenues from sales of NURTEC ODT totaled $63.6 million – The Company began recording product revenues in the first quarter of 2020 following the approval of NURTEC ODT by the U.S. Food and Drug Administration (FDA) in February 2020 and its subsequent commercial launch in the U.S. the second week of March 2020. During the year ended December 31, 2020, the Company recognized $63.6 million of net product revenues related to sales of NURTEC ODT. Net product revenues related to sales of NURTEC ODT for the fourth quarter of 2020 were $35.1 million, representing a 98% increase compared to the third quarter of 2020. There were no material changes in channel inventory between the third and fourth quarter.

EU MAA submission of first ever dual acting filing for the treatment of migraine, inclusive of both acute and preventive treatment – In the first quarter of 2021 the Company submitted the marketing authorization application (MAA) for rimegepant dual activity, inclusive of acute and prevention of migraine. The submission has been validated by the European Medicines Agency and the EU procedure has been initiated. If approved, Vydura will be the commercial name for Rimegepant in the EU. In Japan, Biohaven has met with the Pharmaceuticals and Medical Devices Agency (PMDA) and plans a filing for acute and preventive treatment of migraine. BioShin’s program supporting a filing in China and Korea is underway with a Phase 3 supplementary local trial that commenced in October 2020. The Company has filed for the acute treatment of migraine in Israel, the United Arab Emirates, Kuwait, and Bahrain. Approvals expected for some of these countries starting in 2021 and other global filings are also expected later in the year.

U.S. FDA approved NURTEC ODT for the acute treatment of migraine in adults – On February 27, 2020, the U.S. FDA approved NURTEC ODT for the acute treatment of migraine in adults. On March 12, 2020, NURTEC ODT became commercially available in U.S. pharmacies. NURTEC ODT offers fast pain relief and can return patients to normal function within one hour while delivering sustained efficacy that lasts up to 48 hours for many patients. For more information about NURTEC ODT, see "About NURTEC ODT" below in this release.

U.S. FDA accepted Biohaven’s NURTEC ODT sNDA filing for the preventative treatment of migraine – In October 2020, the Company announced that the U.S. FDA filed and accepted for review the Company’s recently submitted supplemental New Drug Application (sNDA) for NURTEC ODT (rimegepant) for the preventive treatment of migraine. In addition to the proven acute treatment of migraine, NURTEC ODT has been shown to reduce monthly migraine days at the same 75 mg dose administered every other day for preventive treatment. NURTEC ODT is the first CGRP-targeting agent to file for regulatory approval as a single medication to both treat acute episodes and prevent future migraine attacks. The Prescription Drug User Fee Act (PDUFA) goal date for completion of the FDA review is set for the second quarter of 2021. The Company had announced the achievement of positive results in the pivotal trial of NURTEC ODT for the preventative treatment of migraine in March of 2020.

Biohaven advanced its intranasal formulation of zavegepant for its ultra-rapid onset of action in migraine and also developed oral formulations of zavegepant that received U.S. FDA authorization to proceed with human dosing – In September 2020, Biohaven achieved first-in-human dosing in a Phase 1 trial designed to assess the safety and pharmacokinetic profile of oral zavegepant (formerly BHV-3500). Zavegepant is a third generation, high affinity, selective and structurally unique, small molecule CGRP receptor antagonist in development for both migraine and non-migraine indications. Intranasal zavegepant previously demonstrated superior efficacy as compared to placebo in a Phase 2/3 study for the acute treatment of migraine. A second Phase 3 trial of intranasal zavegepant for the acute treatment of migraine was initiated in October 2020. Intranasal zavegepant is also being studied in an ongoing double blind, randomized, placebo-controlled trial in COVID-19 infected hospitalized patients requiring supplemental oxygen.

BioShin enrolled first patients in Phase 3 clinical trial of rimegepant for the acute treatment of migraine – In November 2020, BioShin Limited (BioShin) announced that the first patients were enrolled in a multi-center Phase 3 clinical trial to evaluate safety and efficacy of rimegepant in the acute treatment of migraine. BioShin is advancing the Biohaven clinical portfolio in the Asia-Pacific region. The study obtained a Clinical Trial Application from China’s National Medical Products Association in March 2020 and filed an Investigational New Drug Application with the Korean Ministry of Food and Drug Safety in June 2020.

Expanded portfolio of CGRP-antagonists by entering into a Global Collaboration and License Agreement with Sosei Heptares to explore non-migraine indications – In November 2020, the Company entered into a global collaboration and license agreement with Sosei Heptares. The Company received exclusive global rights to develop, manufacture and commercialize a portfolio of novel, small-molecule CGRP receptor antagonists discovered by Sosei Heptares for the treatment of CGRP-mediated disorders.
Glutamate Modulation Platform – Milestones and Next Steps

Completed enrollment in pivotal Phase 3 trial of troriluzole in SCA –The Company completed enrollment in the Phase 3 clinical trial of troriluzole in SCA. We have received both orphan drug designation and fast track designation from the FDA for troriluzole for the treatment of SCA.

Initiated pivotal Phase 3 trial of troriluzole in OCD – In January 2021, the Company announced that it had commenced enrollment in a Phase 3 clinical trial assessing the efficacy and safety of troriluzole in patients with OCD. Biohaven is advancing the 280 mg once daily dose of troriluzole into two double-blind, placebo-controlled Phase 3 clinical trials with identical study designs and plans to enroll approximately 600 patients in each of these adjunctive treatment trials across study sites in both the United States and Europe. Phase 3 trial enhancements include increased sample size to adequately power for previously observed treatment effects, a higher dose of troriluzole and optimized clinical trial design to minimize the placebo effect.

Phase 2/3 clinical trial of troriluzole in Alzheimer’s patients did not statistically differentiate from placebo on the study’s prespecified co-primary endpoints – In January 2021, the Company announced that troriluzole did not statistically differentiate from placebo at 48 weeks on the study’s pre-specified co-primary endpoints on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-cog) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) in study participants with mild-to-moderate Alzheimer’s Disease (AD). Troriluzole also did not differentiate from placebo on the key secondary measure of hippocampal volume assessed by magnetic resonance imaging (MRI) in the overall population. The Company is awaiting additional biomarker data and other secondary analyses that will help inform whether troriluzole may provide benefit in early AD as a disease modifying agent.
MPO Platform – Milestones and Next Steps

Completed enrollment in pivotal Phase 3 trial of Verdiperstat in MSA – In July 2020, the Company announced it completed enrollment in the M-STAR study, an international Phase 3 clinical trial evaluating the safety and efficacy of verdiperstat in multiple system atrophy (MSA), a rare, rapidly progressive and fatal neuroinflammatory disease with no cure or effective treatments, ahead of schedule. Verdiperstat is a first-in-class, potent, selective, brain-permeable, irreversible myeloperoxidase ("MPO") enzyme inhibitor. MPO generates an array of cytotoxic oxidants and is a key driver of oxidative and inflammatory processes that underlie a broad range of disorders. MPO plays a key role in neurodegenerative, inflammatory, and immune-mediated diseases, including MSA, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic and hemorrhagic forms of stroke, epilepsy, depression and other neuropsychiatric disorders. Verdiperstat has received Orphan Drug and Fast Track designations for MSA from the U.S. FDA, as well as Orphan Drug designation from the European Medicines Agency.

Enrollment of first patients in pivotal Healey ALS trial, including Verdiperstat – In August 2020, Verdiperstat was selected as one of the first three drug candidates to be studied in the innovative HEALEY Amyotrophic Lateral Sclerosis (ALS) Platform Trial at Massachusetts General Hospital. The HEALEY ALS Platform Trial is being conducted across over 50 sites by leading ALS experts from the Healey Center in collaboration with the Northeast ALS Consortium clinical trial network.
Biohaven Labs and Collaborations

Acquired novel immune modulating platforms and target degrader platform – In January 2021, the Company acquired Kleo Pharmaceuticals, Inc. (Kleo), including its MATE and ARM platforms, and exclusively licensed a target degrader platform from Yale University based on intellectual property derived from ground-breaking research in the laboratory of Professor David Spiegel. The Company assumed Kleo’s laboratory facilities located in Science Park in New Haven, Connecticut and formed Biohaven Labs to serve as the integrated chemistry and discovery research arm of Biohaven. Biohaven Labs will continue several existing Kleo discovery partnerships, including with the Bill and Melinda Gates Foundation for the development of a Hyperimmune Globulin Mimic for COVID-19 and PeptiDream for the development of immuno-oncology therapeutics.

Announced BHV-1200 Demonstrates Effective Neutralization of Multiple Strains of COVID-19 – In February 2021, the Company announced that a hyperimmune globulin mimic developed with Biohaven’s proprietary MATE platform has demonstrated functional binding and neutralization of the SARS-CoV-2 virus, including the strains known as the "English" and "South African" variants (also known as B.1.1.7 and B.1.351, respectively). The preliminary experiments conducted by Biohaven Labs and an academic collaborator demonstrated that BHV-1200 substantially reduced viral entry into cells. The Company intends to advance BHV-1200 into a full clinical development program. Accelerated development of the COVID-19 MATE program has been supported by the Bill and Melinda Gates Foundation. In addition, the in vitro data indicate that BHV-1200 may activate important immune system components including antibody-dependent cellular phagocytosis and antibody dependent cellular cytotoxicity. Biohaven’s proprietary MATE-conjugation technology could also be used against other infectious diseases by changing the targeting moiety of its antibody binders.

Investment in and Option and License Agreement with Artizan Biosciences – In December 2020, Biohaven invested in and entered into an Option and License Agreement with Artizan Biosciences, Inc. (Artizan). Artizan is a New Haven-based biotechnology company founded by renowned immunologists Richard Flavell, PhD, Noah Palm, PhD, and Marcel R. de Zoete, PhD, to address inflammatory diseases that stem from the human intestinal microbiota. In addition to rights to develop Artizan’s novel treatments for inflammatory conditions, the option and license agreement provides an opportunity for a collaboration combining Artizan’s proprietary IgA-SEQ platform with Biohaven to discover and develop novel treatments for neurological diseases.

Partnered with National Ataxia Foundation in Inaugural Drug Development Collaborative – In November 2020, Biohaven became the first industry sponsor of the National Ataxia Foundation’s Drug Development Collaborative. The partnership aims to accelerate development of new treatments for Ataxia.

Established International Partnerships to Accelerate the Accessibility of NURTEC ODT – In April 2020, Biohaven entered into agreements with Genpharm Services and Medison Pharma to distribute NURTEC ODT in the Middle East & Gulf Countries and Israel, respectively. Earlier in April 2020, Biohaven established a collaboration with Cove, a leading migraine telemedicine company, to enhance accessibility to NURTEC ODT during an unprecedented time of decreased access to routine office visits.
Recent Financing Activities and Corporate Updates:

Environmental, Social and Governance ("ESG") Highlights Update – In February 2020, the Company announced the advancement of several important steps that underscore its commitment to sound ESG practices. The Company’s Board of Directors designated its Nominating & Governance Committee to oversee a management ESG Working Group, responsible for evaluating, recommending and implementing policies, procedures and projects focused on the ESG impacts of the Company’s operations, strategy, policies and procedures. The Company announced in January 2021 that Maryellen McQuade joined as Chief Talent and Sustainability Officer. Ms. McQuade joins Biohaven from Novo Nordisk where she was Corporate Vice President of Human Resources, and she has previously held leadership and other roles in human resources with GlaxoSmithKline, Novartis Pharmaceuticals, and Bristol-Myers Squibb.

Entered into Funding Agreement with Royalty Pharma – In August 2020, the Company secured up to $250.0 million in funding to advance the company’s CGRP receptor antagonist program through the development of zavegepant. The zavegepant program encompasses intranasal zavegepant as well as oral zavegepant for migraine prevention and non-migraine indications. In exchange for these funds, Royalty Pharma will obtain a 0.4% royalty on annual worldwide net sales of NURTEC ODT and if certain zavegepant regulatory approvals are achieved, a royalty of up to 3% on annual worldwide net sales of zavegepant and success-based milestone payments. The success-based milestone payments range from 0.6x to 2.95x of the zavegepant funded amount depending on the number of regulatory approvals achieved for zavegepant (including 1.9x for the first zavegepant migraine regulatory approval) and would be paid over a ten-year period. Royalty Pharma will also provide further support for the ongoing launch of NURTEC ODT through the committed, non-contingent purchase of Commercial Launch Preferred Equity from Biohaven for a total of $200 million payable between 2021 and 2024. In return, Biohaven will pay to Royalty Pharma a series of equal fixed payments between 2025 and 2030 with an internal rate of return of approximately 12%.

Amended $500.0 Million Non-Dilutive Term Loan with Sixth Street – In February 2021, Biohaven and Sixth Street Specialty Lending, Inc. (Sixth Street) amended its August 2020 $500.0 million non-dilutive term loan to remove the sales contingency provision relating to NURTEC ODT given the strong product net revenues in the fourth quarter of 2020. Under the original agreement, the first $375.0 million was immediately available on closing, and an additional $125.0 million was committed and would be available when net sales of NURTEC ODT reached $45.0 million in the first or second quarter of 2021.
Upcoming Late-stage Milestones:

Biohaven is continuing to support the launch of NURTEC ODT and develop its portfolio of product candidates through clinical and preclinical programs in a number of common and rare disorders. The Company expects to reach significant late-stage pipeline milestones with its CGRP receptor antagonists, glutamate modulators, and MPO inhibitors over the next two years.

Biohaven expects to:

Continue to advance the commercialization of NURTEC ODT (rimegepant) for the acute treatment of migraine.
Prepare rimegepant toward potential commercialization for the preventive treatment of migraine in the second quarter of 2021, if U.S. FDA approval is received.
Report topline of intranasal zavegepant in the acute treatment of migraine in the second half of 2021.
Initiate a Phase 3 clinical trial of oral zavegepant for the preventive treatment of migraine later in the first quarter of 2021.
Report topline of troriluzole in Spinocerebellar Ataxia in the fourth quarter of 2021 or early 2022.
Report topline of troriluzole in OCD in 2022.
Report topline of verdiperstat for the treatment of MSA in the fourth quarter of 2021.
Report topline of verdiperstat for the treatment of ALS in the fourth quarter of 2021.
Capital Position

Cash, cash equivalents, and marketable securities as of December 31, 2020, were $355.3 million, excluding $2.1 million of restricted cash, compared to $316.7 million as of December 31, 2019. As of March 1, 2021, we have $425.0 million in committed capital funding from our August 2020 Sixth Street financing and Royalty Pharma (RPI) agreements, and we expect to have an additional $100.0 million from the August 2020 RPI funding agreement on the start of the oral zavegepant Phase 3 trial, which is anticipated to begin at the end of the first quarter of 2021.

Fourth Quarter 2020 Financial Highlights

Product Revenues, Net: We recorded NURTEC ODT net product revenues of $35.1 million in the fourth quarter of 2020, net of sales allowances and rebates.

Research and Development (R&D) Expenses: R&D expenses, including one-time regulatory and license fees and non-cash share-based compensation costs, were $73.5 million for the fourth quarter of 2020, compared to $66.0 million for the fourth quarter of 2019. The increase of $7.5 million was primarily due to a one-time upfront payment of $9.9 million, consisting of cash and Biohaven common shares, for the Sosei Heptares collaboration in the fourth quarter of 2020, partially offset by reduction in spending for rimegepant development programs in the fourth quarter of 2020 as compared to the same period in 2019. Non-cash share-based compensation expense included in R&D expense was $5.8 million for the fourth quarter of 2020, an increase of $3.5 million as compared to the same period in 2019.

Selling, General and Administrative (SG&A) Expenses: SG&A expenses, including non-cash share-based compensation costs, were $122.4 million for the fourth quarter of 2020, compared to $69.0 million for the fourth quarter of 2019. The increase of $53.4 million was primarily due to an increase in spending to support commercial sales of NURTEC ODT. Less than half of the SG&A expense was for commercial organization personnel costs, excluding non-cash share-based compensation expense. Non-cash share-based compensation expense included in SG&A expense was $8.4 million for the fourth quarter of 2020, an increase of $6.3 million as compared to the same period in 2019.

Net Loss: The Company reported a net loss attributable to common shareholders of $217.7 million for the fourth quarter of 2020, or $3.62 per share, compared to $149.3 million, or $2.85 per share, for the same period in 2019. Non-GAAP adjusted net loss for the fourth quarter of 2020 was $161.7 million, or $2.69 per share, compared to $124.4 million, or $2.38 per share, for the same period in 2019.

These non-GAAP adjusted net loss and non-GAAP adjusted net loss per share measures, including those presented for full year 2020 below, are more fully described below under "Non-GAAP Financial Measures" and exclude non-cash share-based compensation charges, non-cash interest expense related to the accounting for our mandatorily redeemable preferred shares and liability related to sale of future royalties, changes in the fair value of our derivatives, losses from our equity method investment, collaboration and license upfront expenses, accrued development milestone payments, and the expense related to priority review voucher acquisition. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the tables below.

Full Year 2020 Financial Highlights

Product Revenues, Net: Beginning late in the first quarter of 2020, following approval by the U.S. FDA, we recorded NURTEC ODT net product revenues of $63.6 million for the full year of 2020, net of sales allowances and rebates.

R&D Expenses: R&D expenses, including one-time regulatory and license fees, were $229.0 million for the full year of 2020, compared to $344.7 million for 2019. The decrease of $115.7 million was primarily due to a one-time payment of $105.0 million for a priority review voucher to expedite the regulatory review of the rimegepant ODT formulation in the second quarter of 2019 and other one-time filing fees and milestones payable related to the rimegepant NDA submission in 2019. Non-cash share-based compensation expense included in R&D expense was $23.7 million for the full year of 2020, a decrease of $2.6 million as compared to 2019.

SG&A Expenses: SG&A expenses were $462.3 million for the full year of 2020, compared to $134.4 million for 2019. The increase of $327.9 million was primarily due to an increase in spending to support the commercial launch of NURTEC ODT. Less than half of the SG&A expense was for commercial organization personnel costs, excluding non-cash share-based compensation expense. Non-cash share-based compensation expense included in SG&A expense was $33.7 million for the full year of 2020, an increase of $5.0 million as compared to 2019.

Net Loss: The Company reported a net loss attributable to common shareholders of $766.8 million for the full year of 2020, or $13.06 per share, compared to $528.8 million, or $10.91 per share, for the same period in 2019. Non-GAAP adjusted net loss for the full year of 2020 was $605.4 million, or $10.31 per share, compared to $296.5 million, or $6.11 per share, for 2019.

Conference Call Information
As previously announced, the Company will hold a conference call to discuss its fourth quarter and full year 2020 results today, March 1, 2021 at 8:30 a.m. EST. To access the call, please dial 877-407-9120 (domestic) or 412-902-1009 (international). The conference call webcast, and accompanying slide presentation, can be accessed through the "Investors" section of Biohaven’s website at www.biohavenpharma.com. To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast. A replay of the call will be made available for two weeks following the conference call. To hear a replay of the call, dial 877-660-6853 (domestic) or 201-612-7415 (international) with conference ID 13715754. An archived webcast will be available on Biohaven’s website.

Non-GAAP Financial Measures
This press release includes financial results prepared in accordance with accounting principles generally accepted in the United States (GAAP) as well as certain non-GAAP financial measures. In particular, Biohaven has provided non-GAAP adjusted net loss and adjusted net loss per share, adjusted to exclude the items below. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. However, Biohaven believes the presentation of non-GAAP adjusted net loss and adjusted net loss per share, when viewed in conjunction with our GAAP results, provides investors with a more meaningful understanding of our ongoing operating performance. These measures exclude (i) non-cash share-based compensation that are substantially dependent on changes in the market price of our common shares, (ii) non-cash interest expense related to the accounting for our mandatorily redeemable preferred shares and liability related to sale of future royalties, which are in excess of the actual interest owed, (iii) changes in the fair value of our derivative liabilities, which does not correlate to our actual cash payment obligations in the relevant periods, (iv) losses from our equity method investment, because it generates non-cash losses, which are based on the financial results of another company that we did not manage or control, (v) collaboration and license upfront expenses, which we do not believe are normal, recurring operating expenses due to their nature, variability of amounts, and lack of predictability as to occurrence and/or timing, (vi) non-routine accrued development milestone expenses, and (vii) expense related to non-routine priority review voucher acquisition.

Biohaven believes the presentation of these non-GAAP financial measures provides useful information to management and investors regarding Biohaven’s financial condition and results of operations. When GAAP financial measures are viewed in conjunction with these non-GAAP financial measures, Biohaven believes investors are provided with a more meaningful understanding of Biohaven’s ongoing operating performance and are better able to compare Biohaven’s performance between periods. In addition, these non-GAAP financial measures are among those indicators Biohaven uses as a basis for evaluating performance and planning and forecasting future periods. These non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between these non-GAAP measures and the most directly comparable GAAP measures is provided later in this press release.

On March 1, 2021 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biopharmaceutical company creating a new class of drugs based on targeted protein degradation, reported financial results for the fourth quarter and full year ended December 31, 2020 and provided a corporate update (Press release, Arvinas, MAR 1, 2021, View Source [SID1234575838]).

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"2020 was a breakthrough year for Arvinas and for the patients we aim to serve, as we reported clear signals of efficacy in both of our clinical-stage programs. These data provided further validation that our approach to protein degradation could potentially change the lives of patients with few or no therapeutic options," said John Houston, Ph.D., Chief Executive Officer at Arvinas. "Despite the unprecedented circumstances of a pandemic, our clinical trials and preclinical research continued to deliver, and we enter 2021 well positioned to extend our success and progress our programs in oncology and neurodegeneration."

Business Highlights and Recent Developments

Presented interim Phase 1 data for ARV-471 showing potential for best-in-class safety and tolerability, estrogen receptor (ER) degradation greater than that previously reported for the current standard of care agent (fulvestrant), and a robust efficacy signal in heavily pretreated patients with locally advanced or metastatic ER positive / HER2 negative (ER+/HER2-) breast cancer
Presented data from the ongoing dose escalation portion of the Phase 1/2 trial of ARV-110 in men with metastatic castration-resistant prostate cancer (mCRPC), providing additional evidence of anti-tumor activity and patient benefit, including a prostate specific antigen reduction ≥50% (PSA50) in 2 of 5 (40%) in a molecularly defined patient population
Closed an underwritten public offering of 6,571,428 shares of common stock at a public offering price of $70.00 per share, including the exercise in full by the underwriters of their option to purchase additional shares of common stock. Arvinas received net proceeds of $431.9 million, after deducting underwriting discounts and commissions and offering expenses
Initiated the ARDENT Phase 2 dose expansion study of ARV-110 (Dose: 420 mg daily)
Initiated the VERITAC Phase 2 dose expansion study of ARV-471 (Dose: 200 mg daily)
Initiated a Phase 1b trial of ARV-471 in combination with Ibrance (palbociclib)
Anticipated Milestones and Expectations

ARV-471

Completion of the Phase 1 dose escalation (1H21)
Presentation of completed Phase 1 dose escalation data (2H21)
Announcement of safety data from the Phase 1b trial in combination with Ibrance (palbociclib) (2H21)
Initiation of a window of opportunity study in adjuvant breast cancer (2H21)
Initiation of a combination trial of ARV-471 and another targeted therapy in 2L/3L metastatic breast cancer (2H21)
ARV-110

Completion of the Phase 1 dose escalation (1H21)
Presentation of completed Phase 1 dose escalation data (2H21)
Announcement of interim data from the ARDENT Phase 2 dose expansion at 420 mg (2H21)
Initiation of combination trial(s) with standards-of-care (2021)
Other Clinical Milestones

Initiation of first-in-human study of ARV-766, an androgen receptor (AR) degrader with a differentiated profile from ARV-110, in patients with metastatic castration-resistant prostate cancer (1H21)
Financial Guidance

Based on its current operating plan, Arvinas expects its cash, cash equivalents, and marketable securities will be sufficient to fund its planned operating expenses and capital expenditures into 2024.

Full Year and Fourth Quarter Financial Results

Cash, Cash Equivalents and Marketable Securities Position: As of December 31, 2020, cash, cash equivalents and marketable securities were $688.5 million as compared with $280.9 million as of December 31, 2019. The increase primarily related to net proceeds from the issuance of common stock and proceeds from the exercise of stock options of $504.7 million, proceeds from two collaborators of $7.4 million, partially offset by cash used to fund operations of approximately $98.1 million and cash used to purchase fixed assets and leasehold improvements of $6.4 million.

Research and Development Expenses: Research and development expenses were $108.4 million and $33.2 million for the year and quarter ended December 31, 2020, respectively, as compared with $67.2 million and $20.4 million for the year and quarter ended December 31, 2019, respectively. The increase in research and development expenses for the year of $41.2 million primarily related to Arvinas’ continued investment in its wholly owned platform, exploratory and lead optimization programs of $17.6 million, its androgen receptor (AR) program of $12.3 million and estrogen receptor program (ER) of $11.3 million. The increase in research and development expense for the quarter of $12.8 million primarily related to Arvinas’ continued investment in its wholly owned platform, exploratory and lead optimization programs of $5.1 million, its AR program of $4.8 million and ER program of $2.9 million.

General and Administrative Expenses: General and administrative expenses were $38.3 million and $12.2 million for the year and quarter ended December 31, 2020, respectively, as compared with $27.3 million and $7.3 million for the year and quarter ended December 31, 2019, respectively. The increase in general and administrative expenses for the year of $11.0 million related to an increase of $9.6 million in personnel and facility related costs, including $4.8 million related to stock compensation expense, and insurance, taxes and professional fees of $1.4 million. The increase in general and administrative expenses for the quarter of $5.0 million primarily related to an increase of $2.9 in personnel and facility cost, including $1.4 million related to stock compensation expense and $1.7 million of legal and other professional services.

Revenues: Revenues were $21.8 million and $2.2 million for the year and quarter ended December 31, 2020, respectively, as compared with $43.0 million and $4.9 million for the year and quarter ended December 31, 2019, respectively. Revenue for the year ended December 31, 2019 included $24.7 million of revenue recognized from the Arvinas contribution of the license to the joint venture between Bayer and Arvinas to pursue the PROTAC technology in agricultural applications (the Joint Venture). The remaining collaboration revenue of $18.3 million and revenue of $4.9 million for the year and quarter ended December 31, 2019, respectively, was generated from the license and rights to technology fees and research and development activities related to the collaboration and license agreement with Bayer that was initiated in July 2019, the collaboration and license agreement with Pfizer that was initiated in January 2018, and the amended and restated option, license and collaboration agreement with Genentech that was initiated in November 2017. The increase in collaboration revenue of $3.5 million for the year was primarily related to the Bayer agreement having only a partial year of revenue recognized in 2019 and an increase in activities related to the Pfizer agreement. The decrease in collaboration revenue of $2.7 million in the quarter primarily related to a collaborator adding new targets that extended the period of revenue recognition for the collaboration agreement.

Loss from Equity Method Investment: Loss from equity method investment for the year ended December 31, 2019 was $24.7 million, which related to the loss from the equity method investment in the Joint Venture. The loss was generated from the Joint Venture’s expensing the values associated with the contributed intellectual property from the Joint Venture partners.

Net Loss: Net loss was $119.3 million and $41.5 million for the year and quarter ended December 31, 2020, respectively, as compared with $70.3 million and $21.0 million for the year and quarter ended December 31, 2019, respectively. The increase in net loss for the year and quarter ended December 31, 2020 of $49.0 million and $20.5 million, respectively, primarily related to Arvinas’ continued investment in its platform, exploratory and lead optimization programs, its AR program, its ER program, and an increase in general and administrative infrastructure costs.

About ARV-110
ARV-110 is an investigational orally bioavailable PROTAC protein degrader designed to selectively target and degrade the androgen receptor (AR). ARV-110 is being developed as a potential treatment for men with metastatic castration-resistant prostate cancer.

ARV-110 has demonstrated activity in preclinical models of AR mutation or overexpression, both common mechanisms of resistance to currently available AR-targeted therapies.

About ARV-471
ARV-471 is an investigational orally bioavailable PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with locally advanced or metastatic ER+/HER2- breast cancer.

In preclinical studies, ARV-471 demonstrated near-complete ER degradation in tumor cells, induced robust tumor shrinkage when dosed as a single agent in multiple ER-driven xenograft models, and showed superior anti-tumor activity when compared to a standard of care agent, fulvestrant, both as a single agent and in combination with a CDK4/6 inhibitor.

On March 1, 2021 The board of directors of Targovax ASA (OSE:TRVX) ("Targovax" or the "Company") reported that it has resolved to increase the share capital of the Company following the completion of an exercise period for vested share options under the Company’s long-term incentive program for employees (Press release, Targovax, MAR 1, 2021, View Source [SID1234575837]). The exercise period for the LTI program commenced on 19 February 2021 at 10:00 hours (CET) and ended on 1 March 2021 at 10:00 hours (CET).

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1. Exercise of options

In total, 29,788 options were exercised, giving the option holders the right to subscribe for 29,788 shares, each with a par value of NOK 0.10, of which:

– 13,000 options were exercised at a subscription price of NOK 5.77 per share;

– 6,250 options were exercised at a subscription price of NOK 6.58 per share; and

– 10,538 options were exercised at a subscription price of NOK 7.74 per share.

2. Resolutions to increase the share capital in Targovax ASA

The Company’s board of directors has on 1 March 2021, in accordance with the authorisation granted by the general meeting on 29 April 2020, resolved to increase the share capital with NOK 2,978.80 by the issuance of 29,788 new shares, each with a par value of NOK 0.10 in order to facilitate the exercise of options.

Accordingly, the new share capital of the Company is NOK 8,656,110.60, divided into 86,561,106 shares, each with a par value of NOK 0.10. The share capital increase will be registered with the Norwegian Register of Business Enterprises (Nw. Foretaksregisteret) as soon as practically possible after the share contribution has been fully paid.