On March 30, 2021 Moleculin Biotech, Inc., (Nasdaq: MBRX) (Moleculin or the Company), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting highly resistant tumors and viruses, reported that the U.S. Food and Drug Administration ("FDA") has approved its request for Fast Track Designation for its drug, Annamycin, for the treatment of soft tissue sarcoma (STS) lung metastases (Press release, Moleculin, MAR 30, 2021, View Source [SID1234577330]).

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"We are pleased to receive our second Fast Track Designation from the FDA for Annamycin. We now have potential pathways for accelerated approval in two indications, STS lung metastases, and the treatment of relapsed or refractory acute myeloid leukemia," commented Walter Klemp, Moleculin’s Chairman and CEO. "Not only does this make us eligible for accelerated approval and priority review for our NDA submission, but it serves as an important reminder of the unmet need in STS lung metastases. We are now focused on initiating our internally funded clinical trial in the US, possibly prior to mid-year. In addition, we recently announced a $1.5 million grant awarded in Poland for an investigator initiated clinical trial there for this indication which should start later this year."

A drug that receives Fast Track designation is eligible for some or all of the following:

More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval

More frequent written communication from FDA about such things as the design of the proposed clinical trials and use of biomarkers

Eligibility for Accelerated Approval and Priority Review, if relevant criteria are met

Rolling Review, which means that a drug company can submit completed sections of its Biologic License Application (BLA) or New Drug Application (NDA) for review by FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed. BLA or NDA review usually does not begin until the drug company has submitted the entire application to the FDA

Soft tissue sarcomas are the most common form of sarcoma, accounting for an estimated 130,000 incident cases per year worldwide. While many sarcomas can be addressed through surgical removal, it is estimated that as many 20% to 50% of STS sarcomas will eventually metastasize to the lungs, where treatment can become more challenging.

Once metastasized to the lungs, if tumors cannot be surgically removed, the primary chemotherapy regimen is the anthracycline doxorubicin (also known as Adriamycin). While 10% to 30% of patients with sarcoma lung metastases may initially respond to doxorubicin, most will relapse leaving the majority of these patients without an alternative chemotherapy. Treatment options are further limited because of the inherent cardiotoxicity of currently approved anthracyclines, including doxorubicin, which limits the amount of anthracycline that can be given to patients.

Annamycin is a "next generation" anthracycline that has recently been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin. Importantly, Annamycin has also demonstrated a lack of cardiotoxicity in recently conducted human clinical trials for the treatment of acute myeloid leukemia, so we believe that the use of Annamycin may not face the same usage limitations imposed on doxorubicin.

On March 30, 2021 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending that the European label for KEYTRUDA, Merck’s anti-PD-1 therapy, be updated to include data from KEYNOTE-361, a Phase 3, open-label trial that evaluated KEYTRUDA as a monotherapy and in combination with chemotherapy for the first-line treatment of certain patients with advanced or metastatic urothelial carcinoma (Press release, Merck & Co, MAR 30, 2021, View Source [SID1234577329]). In Europe, KEYTRUDA is approved for the treatment of adult patients with advanced or metastatic urothelial carcinoma (bladder cancer) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 with a Combined Positive Score (CPS) ≥10. This approval was based on a single-arm study, KEYNOTE-052; KEYNOTE-361 was conducted as part of a post-marketing commitment following the initial approval of KEYTRUDA for these patients.

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As previously announced, KEYNOTE-361 did not meet its primary endpoints of progression-free survival (PFS) and overall survival (OS) for the combination of KEYTRUDA plus chemotherapy. However, the CHMP concluded that the benefit-risk profile remains positive and that including data from KEYNOTE-361 in the label allows physicians to evaluate the potential benefit-risk of KEYTRUDA on an individual basis.

"KEYTRUDA has become an important treatment option for certain patients with locally advanced or metastatic bladder cancer in the European Union and other countries around the world," said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. "We are pleased with today’s positive opinion by the CHMP, which fulfills our post-marketing requirement for KEYTRUDA in these patients in the European Union and will enable continued access for patients in need of another treatment option."

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 1,400 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.

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 locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

in combination with platinum- and fluoropyrimidine-based chemotherapy, or
as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD L1 (CPS ≥10) as determined by an FDA approved test
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%).

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.

In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).

Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy 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 30, 2021 Cullinan Oncology, Inc. (Nasdaq: CGEM) ("Cullinan"), an oncology company seeking to drive shareholder returns by focusing on the patient, reported its financial results for the full year ended December 31, 2020 and reported on recent business highlights (Press release, Cullinan Oncology, MAR 30, 2021, View Source [SID1234577328]).

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"We are proud of the significant progress across many facets of our business in 2020 and intend to maintain that momentum in 2021," stated Owen Hughes, Chief Executive Officer of Cullinan. "We remain laser focused on delivering results for our various stakeholders through disciplined capital allocation, decisive action, prudent risk taking and creative business development. We look forward to sharing additional clinical and pre-clinical updates as the year unfolds."

2020 and Recent Portfolio Highlights:

Cullinan Pearl: Demonstrated encouraging clinical proof of concept for CLN-081 in NSCLC patients with EGFRex20ins mutations and initiated Phase 2a dose expansion in the 100 mg BID cohort.

CLN-081 is an orally available, irreversible EGFR inhibitor that is designed to selectively target cells expressing mutant EGFR variants while sparing cells expressing wild type EGFR. Cullinan is evaluating various doses of CLN-081 in a Phase 1/2a trial in patients with NSCLC harboring EGFRex20ins mutations that have progressed post chemotherapy. As of the November 10, 2020 data cut-off, among 25 evaluable patients across all dose cohorts, we observed a best overall response of partial response in 10 patients (confirmed and unconfirmed), stable disease in 14 patients and disease progression in one patient. Cullinan recently initiated Phase 2a dose expansion at the 100 mg BID dosing level, which will enable enrollment of up to 36 patients at this dose level, inclusive of 13 previously enrolled patients. Cullinan is contemplating additional expansion cohorts and intends to provide updated safety and efficacy data in mid-2021.
Cullinan MICA: Advanced CLN-619 through IND-enabling activities, including drug product manufacturing, to support an IND submission planned for the second quarter of 2021.

CLN-619 is a MICA/B-targeted, humanized IgG1 monoclonal antibody that Cullinan intends to develop in patients with advanced solid tumors. MICA/B are stress-induced ligands expressed on tumor cells and recognized by the activating NKG2D receptor present on innate and adaptive immune cells. To evade potential cytotoxic destruction by NK cells and T cells, tumors shed MICA/B from the cell surface. CLN-619 is designed to promote an antitumor response through multiple mechanisms of action, including preventing the proteolytic cleavage of MICA/B from cancer cells.
Cullinan Florentine: Acquired an exclusive license from the German Cancer Research Center (DKFZ) and the University of Tübingen to develop CLN-049, a novel FLT3 x CD3 bispecific antibody for the treatment of patients with acute myeloid leukemia (AML).

CLN-049 is a humanized bispecific antibody targeting FLT3 on target leukemic cells and CD3 on T cells, triggering cancer cell lysis via T cell cytolytic mechanisms. FLT3 is expressed frequently on AML cells and leukemic blasts but minimally on healthy blood cells, unlike other tumor surface antigens such as CD33 and CD123. Cullinan submitted an IND to the U.S. Food and Drug Administration ("FDA") for its first-in-human clinical trial evaluating CLN-049 in relapsed or refractory AML patients in January 2021. After receiving FDA feedback, Cullinan is updating the clinical protocol and intends to resubmit its IND in mid-2021.
Cullinan Amber: Launched Cullinan Amber, a company focused on developing a next generation immuno-oncology platform to deliver immune-stimulatory cytokine combinations with an enhanced therapeutic window for the treatment of cancer.

Cullinan Amber’s lead program, CLN-617, is a fusion protein uniquely combining in a single agent two potent antitumor cytokines, IL-2 and IL-12, with a collagen-binding domain for the treatment of solid tumors. The collagen-binding domain engineered into CLN-617 is designed to retain cytokines in the tumor microenvironment following intratumoral administration, thereby minimizing systemic dissemination and associated toxicities while prolonging immunostimulatory antitumor activity. In preclinical studies, murine surrogates of CLN-617 demonstrated robust single agent antitumor activity in both injected and non-injected contralateral tumors without inducing systemic toxicity. Cullinan expects to submit an IND for CLN-617 in 2022.
Cullinan NexGem: Initiated IND-enabling studies for CLN-978, an internally derived asset that seeks to address the limitations of existing CD19 bispecific antibodies.

CLN-978 is a half-life extended, humanized, single-chain T cell engager designed to simultaneously engage CD19 on target cancer cells and CD3 on T cells, triggering redirected T cells to lyse the target cancer cells. In addition to CD19 and CD3 binding domains, CLN-978 has a human serum albumin binding domain, which is designed to prolong half-life. Several design components of CLN-978, including its high affinity binder to CD19, its serum half-life extension component and its overall stability, are intended to address limitations related to blinatumomab, the only CD19-targeting bispecific T cell engager approved for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia, or ALL. Cullinan expects to submit an IND for CLN-978 in 2022.
2020 and Recent Corporate Highlights:

Executed a strategic collaboration and licensing agreement in December 2020 with Zai Lab (Shanghai) Co., Ltd. ("Zai Lab") to develop and commercialize CLN-081 in Greater China.
Raised $131.2 million in gross proceeds from an oversubscribed Series C financing in December 2020, which broadened Cullinan’s shareholder base to include additional leading life sciences focused institutions.
Completed an oversubscribed initial public offering (IPO). In January 2021, Cullinan announced the closing of its IPO of 13,685,000 shares of common stock, including the exercise in full by the underwriters of their over-allotment option, at a public offering price of $21.00 per share for gross proceeds of $287.4 million before deducting underwriting discounts and commissions and other offering expenses.
Strengthened and expanded Cullinan’s management team and Board of Directors in 2020 by promoting Jennifer Michaelson, PhD, to Chief Development Officer, Biologics, and by adding Jon Wigginton, M.D. as Chief Medical Officer, Jeff Trigilio as Chief Financial Officer, and Raymond T. Keane, Esq. as Chief Legal Officer, along with Stephen Webster to its Board of Directors.
Financial Results for Full Year 2020

Cash Position: Cash, cash equivalents and short-term investments were $210.2 million as of December 31, 2020, compared to $98.6 million as of December 31, 2019. This does not include $264.7 million in net proceeds from the company’s IPO completed in January 2021 nor does it include upfront proceeds from the Zai Lab transaction, which were received in Q1 2021. Net cash used in operating activities was $29.8 million while net cash provided from financing activities was $140.1 million for the year ended December 31, 2020.
R&D Expenses: Research and development expenses were $43.2 million for the year ended December 31, 2020, including $5.9 million of non-cash equity-based compensation expense and $6.4 million of non-cash IPR&D expense related to the Cullinan MICA transaction, which was treated as an asset acquisition.
G&A Expenses: General and administrative expenses were $17.1 million, including $9.0 million of non-cash equity-based compensation expense.
Net loss: The Company’s net loss was $59.5 million for the year ended December 31, 2020, which included $22.8 million of non-cash charges.

On March 30, 2021 BioNTech SE (Nasdaq: BNTX, "BioNTech" or "the Company"), a next generation immunotherapy company pioneering novel therapies for cancer and infectious diseases, reported financial results for the quarter and full year ended December 31, 2020 (Press release, BioNTech, MAR 30, 2021, View Source [SID1234577327]).

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"2020 was a transformational year for BioNTech with the development and approval of the first mRNA drug in history. As of March 2021, we had delivered more than 200 million doses of our vaccine to more than 65 countries and regions together with our partners, and we are already seeing the first signs of vaccine associated reduction of COVID-19 cases and mortality in multiple countries" said Ugur Sahin, Co-founder and CEO of BioNTech. "We will continue to focus on innovating in the COVID-19 field by advancing new formulations and addressing vaccine variants, as well as initiating new trials in additional sub-populations. At the same time, we are accelerating the development of our cancer immunotherapies. We see a tremendous opportunity to reinvest the proceeds from our COVID-19 vaccine into extending and accelerating the research and development of new vaccines and therapeutics to improve the health of people worldwide by harnessing the full potential of the immune system."

Fourth Quarter 2020 and Subsequent Updates

Infectious disease

COVID-19 vaccine program – BNT162b2
In December 2020, BNT162b2 became the first mRNA vaccine to be approved or authorized for emergency or conditional use. BNT162b2 now has authorization or approval for emergency use or temporary use in more than 65 countries worldwide, including the United States, United Kingdom and European Union.

On November 18, 2020, BioNTech and Pfizer announced that BNT162b2 met the Phase 3 study’s primary efficacy endpoints in the final efficacy analysis. Analysis of the data indicated a vaccine efficacy rate of 95% for the prevention of a COVID-19 disease, measured seven days after the second dose. No serious safety concerns related to the vaccine were observed in the trial, with most solicited adverse events resolving shortly after vaccination. On December 10, 2020, results from the trial were published in the New England Journal of Medicine.
On March 11, 2021, BioNTech and Pfizer announced additional real-world evidence data from the Israel Ministry of Health (MoH) that demonstrated dramatically lower incidence rates of COVID-19 disease in individuals fully vaccinated with our COVID-19 vaccine. The latest data from the MoH show that two weeks after the second vaccine dose, protection is even stronger with a vaccine effectiveness of at about 97% in preventing symptomatic disease, severe/critical disease and death. The analysis also showed a vaccine effectiveness of 94% against asymptomatic SARS-CoV-2 infections. Since this observational analysis was conducted when the variant B.1.1.7 (UK variant) was the dominant strain in Israel, it also provides real-world evidence of the effectiveness of BNT162b2 for prevention of COVID-19 infections, hospitalizations and deaths due to variant B.1.1.7. The data from this observational analysis were published on March 24, 2021, on Lancet’s preprint server.
Clinical development updates

On October 21, 2020, BioNTech and Pfizer announced the start of a Phase 1/2 clinical trial in Japan to evaluate safety, tolerability and immunogenicity of BNT162b2 in healthy adults 20 to 85 years of age.
On November 25, 2020, BioNTech and Fosun Pharma announced the start of a Phase 2 clinical trial of BNT162b2 in China to evaluate the safety and immunogenicity of BNT162b2 in healthy adults.
On February 18, 2021, BioNTech and Pfizer announced that the first participants were dosed in a global Phase 2/3 trial to evaluate the safety, tolerability and immunogenicity of BNT162b2 in preventing COVID-19 in approximately 4,000 healthy pregnant women 18 years of age and older. The study will also assess safety in infants of vaccinated pregnant women and the transfer of potentially protective antibodies to their infants.
On February 18, 2021, BioNTech and Pfizer announced that safety and efficacy data from the global Phase 3 study with subjects 12 to 15 years of age are expected to be submitted to the regulatory authorities in the second quarter of 2021.
On February 25, 2021, BioNTech and Pfizer announced a trial to evaluate the safety and immunogenicity of a third dose of our COVID-19 vaccine on prolonging immunity against COVID-19 and to address potential newly emerging SARS-CoV-2 variants.
In March, 2021, the U.S Food and Drug Administration (FDA) approved an additional amendment to the study protocol of the global Phase 1/2/3 trial for an additional dose of BNT162b2 or its modified version carrying the spike protein sequence of the South African variant (BNT162b2SA) in order to further describe duration of protection, and protection against the emerging variants of concern. An additional dose of either BNT162b2 or BNT162b2SA will be given to approximately 600 Phase 3 participants about five to seven months after their second dose of BNT162b2. A further dose of BNT162b2SA will be given to approximately 30 of those participants who receive BNT162b2SA. Approximately 300 BNT162b2-naïve participants will be enrolled and receive two doses of BNT162b2SA to describe protection against the emerging variants of concern and reference strains. The part of the trial with BNT162b2SA is expected to start in the second quarter of 2021.
In March 2021, first participants were dosed in a Phase 1/2/3 study in healthy children 6 months to under 12 years of age. The Phase 1 dose-finding portion will evaluate the safety, tolerability and immunogenicity of two doses of BNT162b2 separated by 21 days in up to three age groups. Once the preferred dose level of BNT162b2 is identified for each age group, a Phase 2/3 trial to evaluate the safety, tolerability and immunogenicity in each age group will start. In addition, efficacy against confirmed COVID-19 and against asymptomatic infection will be assessed. Approximately 450 participants (300 in the BNT162b2 group and 150 in the placebo group) in each age group are expected to contribute to the immunobridging and persistence of immune response at 6 months after second dose analyses. Participants will be unblinded at the 6-month follow-up visit and participants that received placebo will be offered the opportunity to receive BNT162b2. All of the expected 4,500 participants will contribute to the vaccine effectiveness (VE) analysis for conditional VE and asymptomatic infection.
BioNTech and Pfizer are also planning studies to further evaluate the vaccine in people with compromised immune systems.
BioNTech and Pfizer will start a Phase 3 trial to evaluate the safety, tolerability and immunogenicity of lyophilized BNT162b2 presented in single-dose vials and of frozen liquid BNT162b2 in multidose vials. This trial will also assess the non-inferiority of the lyophilized formulation. The trial will be conducted in healthy adults 18 through 55 years of age and will start in the United States in April. We expect data from this trial in the third quarter of 2021.
Data on SARS-CoV-2 variants

On March 8, 2021, BioNTech and Pfizer published data in the New England Journal of Medicine from an in vitro study of the neutralizing activity of BNT162b2-elicited serum against the variants first detected in the United Kingdom (B.1.1.7 lineage), Brazil (P.1 lineage) and South Africa (B.1.351 lineage). The findings provide strong support that BNT162b2 will continue to protect against the B.1.1.7 lineage and the P.1 lineage. Sera neutralized all the viruses tested and showed no significant reduction in activity against both B.1.1.7-spike and P.1-spike viruses. While neutralization of the B.1.351-spike virus was lower, it was still robust.
Regulatory updates

On December 2, 2020, BioNTech and Pfizer announced that the Medicines & Healthcare Products Regulatory Agency (MHRA) in the United Kingdom granted a temporary authorization for emergency use for BNT162b2 against COVID-19.
On December 11, 2020, BioNTech and Pfizer announced that the U.S. FDA authorized the emergency use of BNT162b2 in individuals 16 years of age or older. BNT162b2 is authorized in the United States under an Emergency Use Authorization (EUA) while BioNTech and Pfizer gather additional data and prepare to file a planned Biologics License Application (BLA) with the U.S. FDA for full regulatory approval in 2021.
On December 21, 2020, BioNTech and Pfizer announced the European Commission (EC) granted a conditional marketing authorization (CMA) for BNT162b2 in individuals 16 years of age and older. The CMA is valid in all 27 member states of the European Union.
On February 14, 2021, Japan’s Health Ministry approved BNT162b under the exceptional approval scheme in Japan.
On February 25, 2021, the U.S. FDA and on March 26, 2021, the EMA, approved that undiluted frozen vials of BNT162b2 may be transported and stored at conventional temperatures commonly found in pharmaceutical freezers (-25°C to -15°C or -13°F to 5°F) for a period of up to two weeks. Further formulation optimization activities are ongoing.
Commercial Updates
We and our collaboration partners have supplied more than 200 million doses of our COVID-19 vaccine worldwide, as of March 23, 2021.
BioNTech and Pfizer have signed orders of 1.4 billion doses for delivery in 2021. Discussions for additional dose commitments are ongoing.

On February 12, 2021, BioNTech and Pfizer announced that the U.S. government exercised its option for an additional 100 million doses of our COVID-19 vaccine. This agreement brings the total number of doses to be delivered to the United States to 300 million. Consistent with the agreements for the prior 200 million doses, the U.S. government will pay $1.95 billion for the additional 100 million doses.
On February 17, 2021, BioNTech and Pfizer announced an agreement with the EC to supply an additional 200 million doses of our COVID-19 vaccine. The EC has an option for an additional 100 million doses. The total number of doses to be delivered to the European Union by the end of 2021 is now 500 million, with an option for an additional 100 million doses.
Manufacturing
BioNTech and Pfizer expect to increase BNT162b2 manufacturing capacity to up to 2.5 billion doses by the end of 2021. The increase is driven by the optimization of production processes, the recent initiation of production at BioNTech’s Marburg, Germany facility, regulatory approval for six dose vials, and the expansion of our manufacturing and supplier network. Additional measures and discussions with potential partners to further expand the manufacturing capacity and network are ongoing.

In October 2020, BioNTech acquired a GMP manufacturing facility in Marburg, Germany, to accelerate BNT162b2 manufacturing scale-up for commercial supply in 2021.
On March 26, 2021, BioNTech announced that the European Medicines Agency (EMA) approved the manufacturing of our COVID-19 vaccine drug product at the facility in Marburg. The approvals make BioNTech’s Marburg manufacturing site one of the largest mRNA vaccine manufacturing sites worldwide with an annual production capacity of up to one billion doses of our COVID-19 vaccine, once fully operational. Due to optimized operational efficiencies which were initiated last year, BioNTech was able to increase the expected annual manufacturing capacity by 250 million doses. The first batches of vaccines manufactured at the Marburg site are expected to be delivered in the second half of April. BioNTech plans to produce up to 250 million doses of BNT162b2 in the first half of 2021.
Oncology
BioNTech is accelerating the development of its broad oncology pipeline with 13 product candidates in 14 ongoing trials. In 2021, we expect at least four data updates from our oncology pipeline with up to three programs expected to move into randomized Phase 2 trials and six preclinical programs moving into Phase 1 trials. This includes the first-in-human trials started for the lead candidates for both the CARVac (BNT211) and RiboCytokines (BNT151) product candidates.

mRNA programs
FixVac

BNT111 – We expect to start a randomized Phase 2 trial for the treatment of patients with advanced melanoma progressing during or after prior therapy with a PD-1 inhibitor, utilizing a combination of BNT111 and Regeneron and Sanofi’s Libtayo (Cemiplimab) in the first half of 2021 in the United States and the European Union. Our IND for this trial in the United States is active as is a CTA approval in the European Union.
BNT113 – We expect to start a Phase 2 trial evaluating BNT113 in combination with pembrolizumab versus pembrolizumab monotherapy as a first-line treatment in patients with unresectable recurrent or metastatic HPV16+ head and neck squamous cell carcinoma (HNSCC) expressing PD-L1 in the first half of 2021 in the United States and the European Union. BNT113 has not been combined with anti-PD1 before and the Phase 2 trial will start with a run in portion designed to demonstrate the safety of the combination of BNT113 and pembrolizumab. These data are required to address the partial clinical hold on the subsequent randomized part of the Phase 2 trial.
Individualized neoantigen specific immunotherapy (iNeST)

Our iNeST product candidate BNT122 is partnered with Genentech.

BNT122 has been given the international non-proprietary name (INN) "autogene cevumeran".
An open-label Phase 1a/1b trial evaluating the safety, tolerability, immune response and pharmacokinetics of autogene cevumeran as a single agent and in combination with atezolizumab in patients with locally advanced or metastatic solid tumors (basket trial) is ongoing.
A Phase 2 open-label trial evaluating the efficacy and safety of autogene cevumeran in combination with pembrolizumab versus pembrolizumab alone in patients with previously untreated advanced melanoma is ongoing.
Given challenging accrual timelines in the context of the SARS-CoV-2 pandemic and the evolving landscape of treatment options in non-small cell lung cancer (NSCLC), BioNTech and Genentech decided to discontinue the previously planned Phase 2 trial in patients with high-risk resected early stage NSCLC. Genentech and BioNTech are evaluating further options for treating early disease cancer patients with autogene cevumeran.
One of these early disease development options is adjuvant treatment of colorectal cancer. First patient dosing in a randomized Phase 2 trial in circulating tumor DNA positive, surgically resected Stage 2 (high risk)/Stage 3 colorectal cancer is expected in the first half of 2021.
RiboCytokines

BNT151 is a nucleoside-modified mRNA encoding for an IL-2 variant, a key cytokine in T cell immunity supporting the differentiation, proliferation, survival and effector functions of T cells. BNT151 is designed to stimulate anti-tumoral T cells without extensively triggering immunosuppressive regulatory T cells. In February 2021, the first patient was dosed in a first-in-human, open-label, multicenter Phase 1/2a trial. The trial evaluates dose escalation, safety, pharmacokinetics and pharmacodynamics of BNT151 with expansion cohorts in multiple solid tumor indications, including HNSCC, hepatocellular carcinoma (HCC), renal cell cancer (RCC), NSCLC, and triple-negative breast cancer (TNBC). The monotherapy dose escalation will enroll patients with tumors that are metastatic or unresectable with no available standard therapy likely to confer clinical benefit. In the combined treatment dose escalation, patients with different solid tumors will be enrolled and treated with BNT151 and the respective standard of care.
BNT152+153 – In February, the U.S. FDA approved the IND for a Phase 1 trial for BNT152+153. We plan to start a Phase 1 trial for BNT152 (encoding IL-7) plus BNT153 (encoding IL-2) in multiple solid tumors in the first half of 2021.
RiboMabs

BNT141 – In February, the U.S. FDA approved the IND for a Phase 1 first-in-human clinical trial for BNT141. We expect to start the trial in the second half of 2021.
BNT142 – We expect to start a Phase 1 clinical trial for BNT142 in the second half of 2021.
Antibodies
Next-generation checkpoint immunomodulators

BNT311 and BNT312 are partnered with Genmab.

BNT311/GEN1046 – Data from a first-in-human Phase 1/2a trial of BNT311 (PD-L1x4-1BB) in 61 heavily pretreated patients with advanced solid tumors was presented at the SITC (Free SITC Whitepaper) conference in November 2020. We expect a data update from this trial in the second half of 2021.
BNT312/GEN1042 – We expect first data disclosure from the Phase 1/2a trial of BNT312 in solid tumors in the second half of 2021.
Cell therapies
CAR-T cell immunotherapy

BNT211, BioNTech’s most advanced CAR-T product candidate, targets the tumor-specific antigen CLDN6 and was developed in combination with a CAR-T cell Amplifying RNA Vaccine (CARVac) that encodes the CAR target for in vivo expansion upon CAR-T administration. CARVac is based on RNA-LPX technology known from FixVac and selectively delivers the RNA-encoded CAR target to antigen presenting cells, leading to CAR target expression on the cell surface.

BNT211 – In February 2021, the first patient was dosed in a first-in-human Phase 1/2a open-label, multi-center dose escalation and dose expansion basket trial of BNT211 with or without a CLDN6 CARVac in patients with CLDN6-positive relapsed or refractory advanced solid tumors including but not limited to ovarian and testicular cancers. The combination with CLDN6 CARVac is expected to improve expansion and persistence of CLDN6 CAR-T. The primary outcome measure of the trial will be safety, with secondary efficacy outcome measures to include objective response rate, disease control rate and duration of response. We expect a data update for this trial in the second half of 2021.
Neoantigen-targeting T cell therapy

BNT221 (NEO-PTC-01) – Dosing of the first patient in a Phase 1 dose escalation trial for the treatment of metastatic melanoma in patients who are refractory or unresponsive to checkpoint inhibitors is expected in the first half of 2021. The primary objectives of the trial will be to evaluate the safety and feasibility of administering BNT221, in addition to an evaluation of immunogenicity and clinical efficacy.
Small molecule immunomodulators
Toll-like receptor binding agonist

BNT411 – A Phase 1/2a dose-escalation trial of BNT411 as a monotherapy in patients with solid tumors, and in combination with atezolizumab, carboplatin and etoposide in patients with chemotherapy-naïve extensive-stage small cell lung cancer (ES-SCLC) remains ongoing. We expect a data update from this trial in the second half of 2021.
Full Year 2020 Financial Results
Revenues: Total revenues were estimated to be €345.4 million for the three months ended December 31, 2020, compared to €28.0 million for the three months ended December 31, 2019. For the year ended December 31, 2020, total revenues were estimated to be €482.3 million, compared to €108.6 million for the comparative prior year period. Total revenues increased due to recognizing revenues for the first time under our two new collaboration agreements to develop a COVID-19 vaccine and ultimately led to the recognition of COVID-19 vaccine commercial revenues. Under the Pfizer collaboration, territories have been allocated to BioNTech and Pfizer based on marketing and distribution rights. Our commercial revenues comprise an estimated amount of €188.5 million1 share of gross profit from COVID-19 vaccine sales in the collaboration partner’s territory, which represents a net figure. In addition, €61.4 million sales to our collaboration partner of products manufactured by us and €20.6 million direct COVID-19 vaccine sales to customers in our territory Germany have been recognized.

Cost of Sales: Cost of sales were estimated to be €41.0 million for the three months ended December 31, 2020, compared to €4.4 million for the three months ended December 31, 2019. For the year ended December 31, 2020, cost of sales were estimated to be €59.3 million, compared to €17.4 million for the comparative prior year period. €35.6 million estimated cost of sales were recognized for the first time with respect to our COVID-19 vaccine sales and include Pfizer’s share of gross profits earned by BioNTech. Cost of sales do not include costs relating to production of pre-launch products since those are expensed as research and development expenses in the period incurred.

Research and Development Expenses: Research and development expenses were €257.0 million for the three months ended December 31, 2020, compared to €65.4 million for the three months ended December 31, 2019. For the year ended December 31, 2020, research and development expenses were €645.0 million, compared to €226.5 million for the comparative prior year period. The increase was mainly due to an increase in research and development expenses for our BNT162 program. Research and development expenses include our share of expenses under the terms of the Pfizer collaboration agreement. Development costs are shared equally between Pfizer and us. The increase was further driven by an increase in expenses for purchased laboratory supplies as well as an increase in headcount leading to higher wages, benefits and social security expenses. In addition, from May 6, 2020, the date of acquisition of our new U.S.-based subsidiary, BioNTech US Inc., contributed to our research and development expenses.

General and Administrative Expenses: General and administrative expenses were €36.1 million for the three months ended December 31, 2020, compared to €11.1 million for the three months ended December 31, 2019. For the year ended December 31, 2020, general and administrative expenses were €94.0 million, compared to €45.5 million for the comparative prior year period. The increase was mainly due to higher expenses for professional services, an increase in headcount leading to higher wages, benefits and social security expenses and higher insurance premiums. In addition, from May 6, 2020, the date of acquisition of our new U.S.-based subsidiary, BioNTech US Inc., contributed to our general and administrative expenses.

Income Taxes: Following the authorization and approval of our COVID-19 vaccine for emergency or temporary use or having been granted conditional marketing authorization, the recognition of deferred tax assets was reevaluated. As of December 31, 2020, net deferred tax assets with respect to the accumulated tax losses and temporary differences of the German tax group were recognized with €161.0 million income tax effect.

Net Profit / Loss: Net profit was €366.9 million for the three months ended December 31, 2020, compared to €58.2 million net loss for the three months ended December 31, 2019. For the year ended December 31, 2020, net profit was €15.2 million, compared to €179.2 million net loss for the comparative prior year period.
Cash Position: Cash and cash equivalents as of December 31, 2020 were €1.2 billion.

Shares Outstanding: Shares outstanding as of December 31, 2020 were 241,521,065.

COVID-19 vaccine order book update:

Estimated COVID-19 vaccine revenues to BioNTech upon delivery of currently signed supply contracts (~1.4 billion doses): ~€9.8 billion.

Estimate reflects:

Expected revenues from direct COVID-19 vaccine sales to customers in our territories
Expected revenues from sales to our collaboration partners
Expected sales milestone payments from our collaboration partners
Expected revenues related to our share of gross profit from COVID-19 vaccine sales in the collaboration partners’ territories
Additional revenues related to further supply contracts for deliveries in 2021 expected.

Full year 2021 manufacturing capacity target raised from 2.0 to 2.5 billion doses to be able to address increased demand.
2021 financial outlook: BioNTech is providing the following outlook for the full year 2021 of selected financial metrics based on the current base case projections:

Planned Full Year 2021 Expenses and Capex2
R&D expenses €750 million – €850 million

Ramp-up of R&D investment in 2H 2021 and beyond planned to broaden and accelerate pipeline development.
SG&A expenses Up to €200 million
Capital expenditures €175 million – €225 million
Estimated Full Year 2021 Tax Assumptions
German tax group corporate tax rate ~31%
German tax group accumulated tax loss carryforwards as of December 31, 2020 ~€450million3
Full financial statements can be found in the 20F filing as published on the SEC website under View Source

1 Estimated figures based on preliminary data shared between Pfizer and BioNTech as fully described in our Annual Report on Form 20-F. Changes in our share of the collaboration partner’s gross profit will be recognized prospectively.
2 Ranges reflect current base case projections.

3 €457.9 million corporate income tax losses and €450.9 million trade tax losses related to the German tax group.

On March 30, 2021 Ikena Oncology, Inc. (IKNA), a targeted oncology company currently developing an EP4 antagonist (AAT-007) in the clinic originally licensed from AskAt Inc., reported that debuted on the NASDAQ market on March 26, 2021 (Press release, AskAt, MAR 30, 2021, View Source [SID1234577324]). The company sold 7,812,500 shares at $16 each, then doubled in value over the first day of trading, closing at $32. According to Ikena Oncology’s prospectus, it will allocate approximately $10-15 million from the offering proceeds to the development of AAT-007.

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