On March 20, 2024 Bristol Myers Squibb (NYSE: BMY) reported that the European Commission (EC) has granted approval to Abecma (idecabtagene vicleucel; ide-cel) for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody and have demonstrated disease progression on the last therapy (Press release, Bristol-Myers Squibb, MAR 20, 2024, View Source [SID1234641290]). Abecma is the first chimeric antigen receptor (CAR) T cell immunotherapy approved in the European Union (EU) for use in earlier lines of therapy for relapsed and refractory multiple myeloma. This expanded approval of Abecma covers all EU member states.* In the EU, Abecma has maintained its Orphan Designation for the treatment of multiple myeloma.

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"Today’s approval in the European Union marks an exciting milestone in our efforts to bring the transformative potential of cell therapies into earlier lines of treatment," said Monica Shaw, M.D., senior vice president and head of European Markets, Bristol Myers Squibb. "Abecma is an important treatment option for patients with triple-class exposed relapsed and refractory multiple myeloma who have received at least two prior therapies and is leading the way toward a promising shift in the treatment paradigm."

The current treatment paradigm for multiple myeloma includes IMiDs, PIs, and anti-CD38 monoclonal antibodies; however, many patients go on to relapse and/or become refractory to these classes of therapy. With increased use of the three main classes of therapy as combination regimens, more patients are becoming triple-class exposed earlier in their treatment journey. There have historically been limited options for patients with triple-class exposed relapsed and/or refractory multiple myeloma, and patients tend to have poor outcomes with a median progression-free survival of three to five months.

"As patients with multiple myeloma become exposed to the three main classes of therapy earlier in treatment and still experience relapsed and/or refractory disease, it is critical that we continue to add innovative treatment options to our arsenal that can potentially provide long-term disease control," said Paula Rodriguez-Otero, M.D., Ph.D., Department of Hematology, Clinica Universidad de Navarra, Pamplona, Spain. "This expanded approval of ide-cel represents key progress in bringing a personalized therapy that delivers significantly improved, durable outcomes to patients with triple-class exposed relapsed and refractory multiple myeloma after two prior therapies."

With a significant increase in manufacturing capacity and over 90% manufacturing success rate globally, Bristol Myers Squibb is prepared to meet increased demand for Abecma. The company is focused on making Abecma available in the EU for this indication, including completion of reimbursement procedures.

Based on the KarMMa-3 study, Abecma is also the first cell therapy approved in Switzerland for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapies and the first cell therapy approved in Japan for adult patients with triple-class exposed relapsed or refractory multiple myeloma after two prior lines of therapy.

Abecma is also approved in the U.S. for adult patients with triple-class exposed relapsed or refractory multiple myeloma after four or more prior lines of therapy and approved in Great Britain and Israel for adult patients with triple-class exposed relapsed and refractory multiple myeloma after three or more prior lines of therapy. A supplemental Biologics License Application for Abecma for triple-class exposed relapsed and refractory multiple myeloma is currently under review with the U.S. Food and Drug Administration (FDA). The FDA’s Oncologic Drugs Advisory Committee (ODAC) recently voted positively that Abecma demonstrated a favorable benefit/risk profile for patients with triple-class exposed relapsed or refractory multiple myeloma based on results from the pivotal Phase 3 KarMMa-3 study.

*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland and Wales).

Abecma KarMMa-3 Clinical Trial Results

The EC approval of Abecma is based on results from KarMMa-3, a pivotal Phase 3, open-label, global, randomized controlled study evaluating Abecma compared to standard combination regimens in patients with relapsed and refractory multiple myeloma who received two to four prior lines of treatment, including an IMiD, a PI, and an anti-CD38 monoclonal antibody (triple-class exposed), and who were refractory to the last treatment regimen.

At a pre-specified interim analysis with a median follow-up of 18.6 months, treatment with Abecma (n=254) significantly improved progression-free survival (PFS), the study’s primary endpoint, compared to standard regimens (n=132), with a median PFS of 13.8 months (95% CI: 11.8-16.1) versus 4.4 months (95% CI: 3.4-5.8) (HR: 0.49 [95% CI: 0.38-0.63]; p<0.0001), representing a 51% reduction in the risk of disease progression or death. Results from the primary analysis, with a median follow-up of 30.9 months, were consistent with the interim analysis and represent the longest follow-up for a randomized Phase 3 CAR T cell therapy in this patient population. Treatment with Abecma also showed a significant improvement in overall response rate (ORR) with the majority (71.3% [95% CI: 65.7-76.8]) of patients treated with Abecma achieving a response, and 43.7% achieving a complete or stringent complete response. In comparison, less than half of patients (42.4% [95% CI: 34-50.9]) who received standard regimens achieved a response, with 5.3% experiencing a complete response or stringent complete response.

The KarMMa-3 trial had a patient-centric design that allowed for crossover from standard regimens to Abecma upon confirmed disease progression, with more than half (56%) of patients in the standard regimens arm crossing over to receive Abecma as a subsequent therapy, due to disease progression while receiving standard regimens. Median overall survival (OS), a secondary endpoint of the study, was 41.4 months with Abecma (95% CI: 30.9-NR) and 37.9 months with standard regimens (95% CI: 23.4-NR) (95% CI: 0.73-1.40; HR: 1.01). Based on real-world evidence, median OS for patients with triple-class exposed relapsed and refractory multiple myeloma is approximately 13 months, underscoring the confounding impact that crossover had on the median OS observed with standard regimens in the KarMMa-3 trial.

Based on a pooled analysis of the KarMMa, CRB-401 and KarMMa-3 studies (n=409), Abecma has exhibited a well-established and consistent safety profile with mostly low-grade and transient occurrences of cytokine release syndrome (CRS) and neurotoxicity. In patients treated with Abecma, any grade CRS has occurred in 84.6% of patients, with Grade ≥3 CRS occurring in 5.1% of patients and fatal (Grade 5) CRS reported in 0.7% of patients. The median time to onset of CRS was one day (range: 1 to 17) and the median duration of CRS was four days (range: 1 to 63). In the KarMMa and KarMMa-3 studies (n=353), any-grade neurotoxicity occurred in 16.1% of patients, with Grade 3/4 neurotoxicity occurring in 3.1% of patients, and no Grade 5 events reported. Median time to onset of neurotoxicity was three days (range: 1-317 days) and median duration of neurotoxicity was three days (range: 1-252 days). No cases of Parkinsonism were reported.

About Abecma

Abecma is a CAR T cell therapy that recognizes and binds to the B-cell maturation antigen (BCMA) on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. Abecma is the first-in-class BCMA-directed CAR T cell immunotherapy approved by the U.S. FDA for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Please see the Important Safety Information section below, including Boxed WARNINGS for Abecma regarding CRS, neurologic toxicities, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome and Prolonged Cytopenia.

Abecma is being jointly developed and commercialized in the U.S. as part of a Co-Development, Co-Promotion, and Profit Share Agreement between Bristol Myers Squibb and 2seventy bio. Bristol Myers Squibb assumes sole responsibility for Abecma drug product manufacturing and commercialization outside of the U.S. The companies’ broad clinical development program for Abecma includes ongoing and planned clinical studies (KarMMa-2, KarMMa-9) for patients with multiple myeloma. For more information visit clinicaltrials.gov.

Full European Summary of Product Characteristics for Abecma is available from the EMA website at www.ema.europa.eu.

Abecma U.S. FDA-Approved Indication

ABECMA (idecabtagene vicleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

U.S. Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed.
Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA.
ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS.
WARNINGS AND PRECAUTIONS:

Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA in 85% (108/127) of patients. Grade 3 or higher CRS occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time to onset of CRS, any grade, was 1 day (range: 1 – 23 days) and the median duration of CRS was 7 days (range: 1 – 63 days). The most common manifestations included pyrexia, hypotension, tachycardia, chills, hypoxia, fatigue, and headache. Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome, and HLH/MAS.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Fifty four percent (68/127) of patients received tocilizumab (single dose: 35%; more than 1 dose: 18%). Overall, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of CRS and monitor patients for signs or symptoms of CRS for at least 4 weeks after ABECMA infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic Toxicities: Neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS), which may be severe or life- threatening, occurred concurrently with CRS, after CRS resolution, or in the absence of CRS following treatment with ABECMA. Neurologic toxicities occurred in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 – 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median time to resolution of 5 days (range: 1 – 61 days). The median duration of neurotoxicity was 6 days (range: 1 – 578) in all patients including 3 patients with ongoing neurotoxicity. Thirty-four patients with neurotoxicity had CRS with onset in 3 patients before, 29 patients during, and 2 patients after CRS. The most frequently reported manifestations of CAR T cell-associated neurotoxicity include encephalopathy, tremor, aphasia, and delirium. Grade 4 neurotoxicity and cerebral edema in 1 patient, Grade 3 myelitis, and Grade 3 parkinsonism have been reported with ABECMA in another study in multiple myeloma.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of neurologic toxicities and monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after ABECMA infusion and treat promptly. Rule out other causes of neurologic symptoms. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms occur at any time.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient developed fatal multi-organ HLH/MAS with CRS and another patient developed fatal bronchopulmonary aspergillosis with contributory HLH/MAS. Three cases of Grade 2 HLH/MAS resolved. All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4 – 9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional guidelines.

ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Further information is available at www.AbecmaREMS.com or 1-888-423-5436.

Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.

Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines.

Febrile neutropenia was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care.

Viral Reactivation: CMV infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: In the clinical study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months.

Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support.

Hypogammaglobulinemia: Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA.

Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage appropriately per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

The safety of immunization with live viral vaccines during or after ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.

Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions: The most common nonlaboratory adverse reactions include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.

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

On March 20, 2024 BioNTech SE (Nasdaq: BNTX, "BioNTech" or "the Company") reported financial results for the three months and full year ended December 31, 2023, and provided an update on its corporate progress (Press release, BioNTech, MAR 20, 2024, View Source [SID1234641289]).

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"2023 was another year of good performance for BioNTech. We have maintained our leading position in the COVID-19 vaccine market which lays the foundation for establishing a sustainable respiratory vaccines business. In oncology, we have strengthened our core competencies by entering into several partnerships and have made numerous clinical advances. Today, our oncology pipeline encompasses multiple candidates in mid- and late-stage clinical development, including investigational ADCs, mRNA vaccines and innovative immunotherapies," said Prof. Ugur Sahin, M.D., CEO and Co-Founder of BioNTech. "Our goal is to achieve product approvals in ten oncological indications by 2030 and with this improve the treatment options for patients around the globe."

Financial Review for the Fourth Quarter and Full Year 2023 Financial Results

in millions €, except
per share data

Fourth Quarter 2023

Fourth Quarter 2022

Full Year 2023

Full Year 2022

Total Revenues

1,479.0

4,278.3

3,819.0

17,310.6

Net Profit

457.9

2,278.7

930.3

9,434.4

Diluted Earnings per Share

1.90

9.26

3.83

37.77

Total revenues reported were €1,479.0 million for the three months ended December 31, 2023, compared to €4,278.3 million for the comparative prior year period. For the year ended December 31, 2023, total revenues were €3,819.0 million, compared to €17,310.6 million for the comparative prior year period. Inventory write-downs by BioNTech’s collaboration partner Pfizer, Inc. ("Pfizer") reduced BioNTech’s revenues by €291.3 million and €906.7 million for the three and twelve months ended December 31, 2023, respectively.

Cost of sales were €179.1 million for the three months ended December 31, 2023, compared to €183.5 million for the comparative prior year period. For the year ended December 31, 2023, cost of sales were €599.8 million, compared to €2,995.0 million for the comparative prior year period. The change was mainly caused by the decrease in COVID-19 vaccine sales.

Research and development (R&D) expenses were €577.8 million for the three months ended December 31, 2023, compared to €509.8 million for the comparative prior year period. For the year ended December 31, 2023, research and development expenses were €1,783.1 million, compared to €1,537.0 million for the comparative prior year period. R&D expenses are mainly influenced by progressing clinical studies for pipeline candidates as well as by our newly acquired product candidates and the development of variant-adapted COVID-19 vaccines. The increase was further driven by an increase in wages, benefits and social security expenses resulting from an increase in headcount.

General and administrative (G&A) expenses reached €124.3 million for the three months ended December 31, 2023, compared to €119.9 million for the comparative prior year period. For the year ended December 31, 2023, G&A expenses were €495.0 million, compared to €481.7 million for the comparative prior year period. G&A expenses were mainly influenced by increased expenses for IT services as well as by wages, benefits and social security expenses resulting from an increase in headcount.

Income taxes were accrued in an amount of €205.3 million for the three months ended December 31, 2023, compared to €893.9 million accrued for the comparative prior year period. For the year ended December 31, 2023, income taxes were accrued with an amount of €255.8 million, compared to €3,519.7 million accrued for the comparative prior year period. The derived annual effective income tax rate for the year ended December 31, 2023, was 21.6%.

Net profit was €457.9 million for the three months ended December 31, 2023, compared to €2,278.7 million for the comparative prior year period. For the year ended December 31, 2023, net profit was €930.3 million, compared to €9,434.4 million net profit for the comparative prior year period.

Cash and cash equivalents as well as security investments2as of December 31, 2023, reached €17,653.4 million, comprising €11,663.7 million cash and cash equivalents and €5,989.0 million security investments, respectively.

Diluted earnings per share was €1.90 for the three months ended December 31, 2023, compared to diluted earnings per share of €9.26 for the comparative prior year period. For the year ended December 31, 2023, diluted earnings per share were €3.83, compared to €37.77 diluted earnings per share for the comparative prior year period.

Shares outstanding as of December 31, 2023, were 237,725,735, excluding 10,826,465 shares held in treasury.

In March 2023, the Management Board and Supervisory Board authorized the 2023 share repurchase program, under which BioNTech was permitted to purchase ADSs, each representing one ordinary share, with a value of up to $0.5 billion, which started June 2, 2023, and concluded on September 18, 2023. During the three months ended December 31, 2023, 114,513 ADSs were repurchased under the share repurchase program at an average price of $112.22 (€105.07), for total consideration of $12.9 million (€12.0 million). For the year ended December 31, 2023, a total of 4,646,965 ADSs were repurchased related to the 2023 program at an average price of $107.58 (€98.24), for total consideration of $0.5 billion (€456.5 million).

"In 2023, we strengthened our financial position while concurrently progressing our clinical pipeline of immunotherapies and executing acquisitions and collaborations. Looking ahead to 2024, we will maintain a prudent capital allocation strategy as we invest and execute in our maturing pipeline and prepare for our first potential oncology launches," said Jens Holstein, CFO of BioNTech. "Our COVID-19 vaccine franchise is expected to remain an important cash contributor in 2024. We believe our solid financial position will enable us to push forward with our long-term strategy to develop novel therapies against cancer, infectious and other severe diseases thereby generating added value for patients, society, investors and the Company."

Outlook for the 2024 Financial Year

The Company’s outlook contains the following components:

Total revenues for the 2024 financial year

€2.5 billion – €3.1 billion

BioNTech expects group revenue for the full 2024 financial year to be in the range of €2.5 – €3.1 billion. The range reflects certain assumptions, including, but not limited to, expectations regarding: the timing and grant of regulatory approvals and recommendations, COVID-19 vaccine uptake and price levels, inventory write-downs by BioNTech’s collaboration partner Pfizer that would negatively influence the Company’s revenues, seasonal variations in SARS-CoV-2 circulation and vaccination uptake which are expected to lead to demand peaks in the autumn and winter compared to other seasons, revenues from a pandemic preparedness contract with the German government as well as revenues from BioNTech Group service businesses, namely InstaDeep, JPT Peptide Technologies GmbH and in Idar-Oberstein at BioNTech Innovative Manufacturing Services GmbH. Generally, the Company continues to remain largely dependent on revenues generated in its collaboration partner’s territories in 2024.

Planned 2024 Financial Year Expenses and Capex3:

R&D expenses4

€2.4 billion – €2.6 billion

SG&A expenses5

€700 million – €800 million

Capital expenditures for operating activities

€400 million – €500 million

BioNTech expects to continue to focus investments on R&D and scaling the business for commercial readiness in oncology, while continuing to be cost disciplined. Strategic capital allocation will continue to be an important driver of the Company’s trajectory. As part of BioNTech’s strategy, the Company may continue to evaluate appropriate corporate development opportunities with the aim of driving sustainable long-term growth and create future value.

The full audited consolidated financial statements as of and for the year ended December 31, 2023, can be found in BioNTech’s Annual Report on Form 20-F for the period ended December 31, 2023, filed today with the United States Securities and Exchange Commission ("SEC") and available at View Source (the "Annual Report").

On March 20, 2024 Barinthus Biotherapeutics plc (NASDAQ: BRNS), formerly Vaccitech plc, reported its financial results for the year ended December 31, 2023, and an overview of the Company’s progress (Press release, Barinthus Biotherapeutics, MAR 20, 2024, View Source [SID1234641288]). Barinthus Bio is a clinical-stage biopharmaceutical company developing novel T cell immunotherapeutic candidates designed to guide the immune system to overcome chronic infectious diseases, autoimmunity, and cancer.

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"2023 was a productive year for Barinthus Bio, with data presented in our HBV and HPV programs, the first patient visit in our next generation prostate cancer program and up to $35 million of future funding committed from the Coalition for Epidemic Preparedness Innovations (CEPI) secured for our MERS program," said Bill Enright, Chief Executive Officer of Barinthus Bio. "We expect another data rich year in 2024, with anticipated final results from our Phase 1b/2 HPV APOLLO trial of VTP-200, and additional data from our two ongoing Phase 2 trials of VTP-300 in chronic HBV infection. In addition, our SNAP-TI platform is heading into the clinic for the first time as we expect to initiate a Phase 1 clinical trial of VTP-1000 in celiac disease, our lead program in autoimmunity."
2023 Corporate Milestones
Clinical Developments

HBV (VTP-300):
•In March 2023, we announced positive topline final data from the HBV002 Phase 2 clinical trial for VTP-300 in Chronic Hepatitis B (CHB). The data showed meaningful, durable reductions of Hepatitis B Surface Antigen (HBsAg) in all participants with a >0.5 log10 reduction in HBsAg who received VTP-300 alone or in combination with a single administration of low-dose PD-1 inhibitor, nivolumab. Two of five patients with baseline HBsAg below 100 IU/mL in Group 3, developed a non-detectable HBsAg level, which continued eight months after last dose. We presented the final data in June 2023 at the European Association for the Study of the Liver Congress 2023 – The International Liver CongressTM.
•In November 2023, we presented interim data from the HBV003 Phase 2b clinical trial for VTP-300 in CHB showing that VTP-300 in combination with nivolumab continued to show sustained HBsAg reductions, particularly in patients with HBsAg levels below or equal to 200IU/mL at screening. We presented this data during an oral presentation at the American Association for the Study of Liver Diseases (AASLD) – The Liver Meeting 2023.
•Also in November 2023, interim data from the Phase 2a AB-729-202 clinical trial in collaboration with Arbutus Biopharma Corporation (Arbutus) in CHB patients were presented at AASLD, showing that imdusiran in combination with VTP-300 demonstrated meaningful and sustained declines in HBsAg levels.
HPV (VTP-200):
•In March 2023, we announced favorable topline interim data from the HPV001 Phase 1b/2 clinical trial of VTP-200 in high-risk HPV (hrHPV) infection.
•In April, we presented interim data from the VTP-200 APOLLO (HPV001) Phase 1b/2 clinical trial in hrHPV infection at the 35th Annual International Papillomavirus Conference. Immunological results showed VTP-200 induced high T cell responses to HPV antigens, and was generally well-tolerated with no product-related grade 3 unsolicited events and no product-related SAEs.
Celiac Disease (VTP-1000):
•In December 2023, we submitted an Australian ethics submission and regulatory notification to the Alfred Research Review Committee for the Phase 1 GLU001 study in Celiac disease.
Prostate Cancer (VTP-850):
•In June 2023, we announced the dosing of the first patient in the PCA001 Phase 1/2 clinical trial for VTP-850 in prostate cancer.
MERS (VTP-500):
•In December 2023, we announced an agreement with the Coalition for Epidemic Preparedness Innovations (CEPI) and the University of Oxford, aiming to fast-track the development of our vaccine candidate, VTP-500, for the prevention of Middle East Respiratory Syndrome. This agreement includes CEPI investing funding of up to $35 million to Barinthus Bio in addition to funds previously committed to the University of Oxford to develop and stockpile a ready reserve of VTP-500.

Key Operational Updates

•In January 2023, we announced the appointment of Nadège Pelletier, Ph.D., as Chief Scientific Officer.
•In June 2023, we completed the move of our U.S. facility to Germantown, Maryland, which houses a state-of-the art wet laboratory and office space.
•In November 2023, we announced the company’s renaming as Barinthus Biotherapeutics plc to represent the evolution and expansion of its focus beyond vaccines. As part of the renaming, the Company changed its Nasdaq ticker to "BRNS", which became effective on Nasdaq on November 7, 2023.
Upcoming Milestones
In 2024, the Company expects to:
•Q2 2024:
◦HBV:
▪Announce interim data from HBV003, our Phase 2b trial evaluating additional dosing of VTP-300 and timing of PD-1 inhibition, in people with CHB on NUC therapy.
▪Announce interim data from the Phase 2a AB-729-202 clinical trial evaluating the combination of VTP-300 and Arbutus’ imdusiran, in people with CHB on NUC therapy.
◦HPV:
▪Announce final results from participants receiving VTP-200 in the Phase 1b/2 APOLLO (HPV001) trial evaluating the safety, immunogenicity and efficacy of VTP-200 in persistent HPV infection and low-grade cervical lesions.
◦Celiac disease:
▪Initiate a Phase 1 clinical trial of VTP-1000.
•Q4 2024:
◦HBV:
▪Announce more mature interim data from HBV003, our Phase 2b trial evaluating additional dosing of VTP-300 and timing of PD-1 inhibition, in people with CHB on NUC therapy.
▪Announce more mature interim data from the Phase 2a AB-729-202 clinical trial evaluating the combination of VTP-300 and Arbutus’ imdusiran, in people with CHB on NUC therapy.
2023 Financial Highlights
•Cash position: As of December 31, 2023, cash was $142.1 million, compared to $194.4 million as of December 31, 2022. The cash used in operating activities was $50.9 million, primarily resulting from our net loss of $73.4 million, adjusted by foreign exchange loss on translation of $7.5 million, share-based compensation of $5.1 million, depreciation and amortization of $5.4 million, deferred tax movements of $3.1 million and changes in our operating assets and liabilities, net of $6.2 million primarily related to a $5.8 million decrease in accounts receivable, a $2.2 million decrease in prepaid expenses and other current assets, $3.4 million decrease in accounts payable and $2.0 million increase in accrued expenses.
•Revenue: Revenue was $0.8 million in 2023 compared to $44.7 million in 2022 and was comprised of the Company’s share of royalties received by Oxford University Innovation as a result of commercial sales of Vaxzevria by AstraZeneca, sales of which reduced significantly in 2023 when compared to 2022.

•Research and development expenses: Research and development expenses were $44.9 million in 2023 compared to $42.4 million in 2022, demonstrating the progression of our pipeline through the clinic. Direct research and development expenses reduced $0.6 million, comprising of a $3.3 million increase in expense on the SNAP platform candidates, namely VTP-1000, offset by a reduction in expense of $2.4 million due to the phasing of VTP-300 in two ongoing Phase 2 clinical trials, and a $2.3 million reduction as a result of VTP-850 getting into the clinic in a Phase 1/2 clinical trial in prostate cancer. Indirect research and development expenses increased $3.1 million as a result of an increase in headcount attributing to an increase in personnel costs of $2.3 million and an increase in facility costs due to moving the U.S. office to a 19,700 square foot, state-of-the-art wet laboratory and office facility in Germantown, Maryland, in June 2023. The year-on-year R&D expense per program is outlined in the following table.

Year ended December 31,
2023 December 31,
2022 Change
$000 $000 $000
Direct research and development expenses by program:
VTP-200 HPV $ 4,950 $ 4,050 $ 900
VTP-300 HBV 11,276 13,700 (2,424)
VTP-600 NSCLC1
597 532 65
VTP-850 Prostate cancer 2,726 5,011 (2,285)
VTP-1000/VTP-1100 Celiac/HPV Cancer 8,420 5,118 3,302
Other and earlier stage programs 1,787 1,916 (129)
Total direct research and development expenses $ 29,756 $ 30,327 $ (571)
Indirect research and development expenses:
Personnel-related (including share-based compensation) 12,702 10,424 2,278
Facility-related 1,339 1,308 31
Other internal costs 1,077 291 786
Total indirect research and development expenses 15,118 12,023 3,095
Total research and development expense $ 44,874 $ 42,350 $ 2,524

1The VTP-600 NSCLC Phase 1/2a trial is sponsored by Cancer Research UK.
•General and administrative expenses: General and administrative expenses were $39.8 million in 2023, compared to $6.4 million in 2022. The increase is primarily attributable to a $7.6 million loss on foreign exchange in 2023 compared to a $26.4 million gain on foreign exchange in 2022 as a result of movements in the USD:GBP exchange rate during the respective periods.
•Net loss: For the financial year 2023, the Company generated a net loss attributable to its shareholders of $73.3 million, or $1.91 per fully diluted share and per basic share, compared to a net income attributable to shareholders of $5.3 million, or $0.14 per fully diluted share and per basic share, for 2022.

On March 19, 2024, Intellia Therapeutics, Inc. (the "Company" or "Intellia") notified Regeneron Pharmaceuticals, Inc. ("Regeneron") reported that the Company is opting out of its Factor IX Co-Development and Co-Funding Agreement (the "Co-Co Agreement"), which the Company and Regeneron entered into in May 2020 (Filing, 8-K, Intellia, MAR 19, 2024, View Source [SID1234641383]). The Co-Co Agreement will terminate 180 days after Intellia provided written notice to Regeneron, and the Company will continue to have obligations under the Co-Co Agreement related to the co-development of gene editing products directed to factor IX until the effective date of termination. Upon termination, the Company will no longer be obligated for sharing 35% of the development costs, or be entitled to receive 35% of the profits, for gene editing products directed to factor IX under the Co-Co Agreement. In addition, after termination of the Co-Co Agreement Intellia would continue to support Regeneron with the development of gene editing products directed to factor IX, as applicable, under the License and Collaboration Agreement between the Company and Regeneron, dated April 11, 2016, as amended (the "LCA"), and the LCA will control the parties’ obligations to develop and commercialize gene editing products directed to factor IX, including any milestone payments and royalties that would be owed to the Company if Regeneron develops and commercializes such products and the intellectual property licenses and other rights related to such products. Under the LCA, Intellia may be eligible to receive up to $320.0 million in milestone payments and royalties in the high-single digits to low teens, which royalties are potentially subject to various reductions, offsets and upstream payment obligations. The termination of the Co-Co Agreement does not affect any other target or programs that are the subject of the Company’s collaboration with Regeneron under the LCA or any other co-development and co-funding agreement with Regeneron.

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The foregoing summary is qualified in its entirety by reference to the form of Co-Development and Co-Promotion Agreement which the Company filed as Exhibit 10.16 to its Annual Report on Form 10-K for the year ending December 31, 2023.

On March 19, 2024 Takeda (TSE:4502/NYSE:TAK) reported that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for ICLUSIG (ponatinib) for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy (Press release, Takeda, MAR 19, 2024, View Source [SID1234641282]). This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. This accelerated approval application was granted Priority Review and evaluated under the Real-Time Oncology Review (RTOR) program, an FDA initiative designed to expedite the delivery of cancer medicines by allowing components of an application to be reviewed before submission of the complete application.

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"This label expansion for ICLUSIG is an incredibly exciting milestone, allowing U.S. adult patients with newly diagnosed Ph+ ALL to have an approved, targeted treatment option in the frontline," said Awny Farajallah, MD, chief medical officer, oncology at Takeda. "We are thrilled that the FDA has recognized the potential of ICLUSIG to fill a large gap in care for these patients and look forward to seeing the impact this can have on people with this rare and aggressive form of cancer."

The approval was supported by data from the PhALLCON study – the first, global, Phase 3, registrational, head-to-head clinical trial in adults with newly diagnosed Ph+ ALL. The study, in which patients received either ICLUSIG or imatinib, plus reduced-intensity chemotherapy, met its primary endpoint of MRD-negative CR at the end of induction. MRD-negative CR is a composite endpoint defined in alignment with the FDA that reflects deep molecular and clinical responses and is an important prognostic indicator for long-term outcomes for patients with Ph+ ALL. ICLUSIG demonstrated superiority compared to imatinib, with patients who received ICLUSIG achieving a greater than two-fold improvement in the rate of MRD-negative CR at the end of induction (cycle 3). In the trial, the safety profile of ICLUSIG was comparable to imatinib, and no new safety signals were identified.

"Ph+ ALL is an extremely aggressive cancer and patients with this disease suffer from poor outcomes. There has long been a need for a potent TKI that can suppress mutation development and elicit deep responses in the frontline," said Elias Jabbour, MD, The University of Texas MD Anderson Cancer Center and lead investigator of the PhALLCON trial. "Ponatinib may help address these factors and impact long-term outcomes."

ICLUSIG is a kinase inhibitor indicated in the U.S. for adult patients with newly diagnosed Ph+ ALL in combination with chemotherapy. This indication is approved under accelerated approval based on MRD-negative CR at the end of induction. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). In addition, it is approved as monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL, chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated or T315I-positive CML (chronic phase, accelerated phase, or blast phase). ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

About the PhALLCON Trial
The PhALLCON study is a Phase 3, randomized, international, open-label multicenter trial evaluating the efficacy and safety of ICLUSIG versus imatinib, in combination with reduced-intensity chemotherapy as a frontline therapy for adult patients with newly diagnosed Ph+ ALL.

A total of 245 patients were randomized 2:1 and treated with ICLUSIG or imatinib plus reduced-intensity chemotherapy. The median age of patients was 54 and 52 in the ICLUSIG and imatinib arms, respectively. 164 patients were treated with ICLUSIG receiving a starting dose of 30mg/day and 81 patients were treated with imatinib at a starting dose of 600mg/day. All patients received either ICLUSIG or imatinib with reduced-intensity chemotherapy through induction, consolidation and maintenance phase. After combination therapy, patients continued to receive single-agent ICLUSIG or imatinib until relapse from CR, progressive disease (PD), hematopoietic stem cell transplantation (HSCT), start of alternative therapy or unacceptable toxicity. The primary endpoint of the study was MRD-negative CR rate at the end of induction (3 cycles of treatment). Event-free survival, the key secondary endpoint of the trial, is not yet mature.

About Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
Ph+ ALL is a rare form of ALL that affects approximately 25% of adult ALL patients in the U.S. and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome-positive (Ph+), an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR::ABL1 and is associated with Ph+ ALL.

About ICLUSIG (ponatinib) tablets
ICLUSIG is a kinase inhibitor targeting BCR::ABL1, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR::ABL1 and its mutations. ICLUSIG inhibits native BCR::ABL1, as well as all BCR::ABL1 treatment-resistant mutations, including the most resistant T315I mutation. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is a kinase inhibitor indicated in the U.S. for adult patients with newly diagnosed Ph+ ALL in combination with chemotherapy. This indication is approved under accelerated approval based on MRD-negative CR at the end of induction. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). In addition, it is approved as monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL, chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated, or T315I-positive CML (chronic phase, accelerated phase, or blast phase). ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

IMPORTANT SAFETY INFORMATION

WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning.

Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG based on severity. Consider benefit-risk to guide a decision to restart ICLUSIG.
Venous thromboembolic events (VTEs) have occurred in ICLUSIG-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ICLUSIG based on severity.
Heart failure, including fatalities, occurred in ICLUSIG-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ICLUSIG for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor liver function tests. Interrupt or discontinue ICLUSIG based on severity.

WARNINGS AND PRECAUTIONS
Arterial Occlusive Events (AOEs): AOEs, including fatalities, have occurred in patients who received ICLUSIG in PhALLCON, OPTIC and PACE. These included cardiovascular, cerebrovascular, and peripheral vascular events. In PhALLCON, 6% of 163 patients experienced AOEs; 3.7% experienced Grade 3 or 4. The incidence of AOEs in OPTIC (45 mg-> 15 mg) was 14% of 94 patients; 6% experienced Grade 3 or 4. In PACE, the incidence of AOEs was 26% of 449 patients; 14% experienced Grade 3 or 4. Fatal AOEs occurred in 0.6% of patients in PhALLCON, 2.1% of patients in OPTIC, and in 2% of patients in PACE. Some patients in PACE experienced recurrent or multisite vascular occlusion. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed with these events in PACE were history of hypertension, hypercholesterolemia, and non-ischemic cardiac disease. In PhALLCON, OPTIC and PACE, AOEs were more frequent with increasing age.

In PhALLCON, patients with uncontrolled hypertension, hypertriglyceridemia, or diabetes were excluded. Patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, venous thromboembolism, clinically significant atrial/ventricular tachyarrhythmias, unstable angina, or congestive heart failure within the 6 months prior to the first dose of ICLUSIG, were also excluded.

In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease were excluded.

In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease within the 3 months prior to the first dose of ICLUSIG were excluded.

Consider whether the benefits of ICLUSIG are expected to exceed the risks. Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Consider benefit-risk to guide a decision to restart ICLUSIG.

Venous Thromboembolic Events (VTEs): Serious or severe VTEs have occurred in patients who received ICLUSIG. In PhALLCON, VTEs occurred in 12% of 163 patients, including serious or severe (Grade 3 or 4) in 3.1% of patients. One of 94 patients in OPTIC experienced a VTE (Grade 1 retinal vein occlusion). In PACE, VTEs occurred in 6% of 449 patients including serious or severe (Grade 3 or 4) VTEs in 5.8% of patients. In PhALLCON and PACE VTEs included deep venous thrombosis, embolism, pulmonary embolism, superficial vein thrombosis, thrombosis, jugular vein thrombosis, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss. The incidence of VTEs in PACE was higher in patients with Ph+ ALL (9% of 32 patients) and BP-CML (10% of 62 patients). Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity.

Heart Failure: Fatal, serious or severe heart failure events have occurred in patients who received ICLUSIG. In PhALLCON, heart failure occurred in 6% of 163 patients; 1.2% experienced serious or severe (Grade 3 or 4) heart failure. Heart failure occurred in 13% of 94 patients in OPTIC; 1.1% experienced serious or severe (Grade 3 or 4). In PACE, heart failure occurred in 9% of 449 patients; 7% experienced serious or severe (Grade 3 or higher). In PhALLCON the most frequently reported heart failure event (>1 patient) was increased brain natriuretic peptide (BNP) (2.5%). In OPTIC, the most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (3.2%) and BNP increased (3.2%). In PACE, the most frequently reported heart failure events (≥2%) were congestive cardiac failure (3.1%), decreased ejection fraction (2.9%), and cardiac failure (2%). Monitor patients for signs or symptoms consistent with heart failure and manage heart failure as clinically indicated. Interrupt, then resume at reduced dose or discontinue ICLUSIG for new or worsening heart failure.

Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in 3 patients, with hepatic failure occurring within 1 week of starting ICLUSIG in one of these patients. These fatal cases occurred in patients with BP-CML or Ph+ ALL treated with monotherapy. Hepatotoxicity occurred in 66% of 163 patients in PhALLCON, in 28% of 94 patients in OPTIC and in 32% of 449 patients in PACE. Grade 3 or 4 hepatotoxicity occurred in PhALLCON (30% of 163 patients), in OPTIC (6% of 94 patients), and in PACE (13% of 449 patients). The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at a reduced dose or discontinue ICLUSIG based on recurrence/severity.

Hypertension: Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received ICLUSIG. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. For significant worsening, labile or treatment-resistant hypertension, interrupt ICLUSIG and consider evaluating for renal artery stenosis.

Pancreatitis: Serious or severe pancreatitis has occurred in patients who received ICLUSIG. Elevations of lipase and amylase also occurred. In the majority of cases that led to dose modification or treatment discontinuation, pancreatitis resolved within 2-3 weeks. Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first-line treatment of newly diagnosed patients with CP-CML, single agent ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

Neuropathy: Peripheral and cranial neuropathy occurred in patients in PhALLCON, OPTIC and PACE. Some of these events in PhALLCON and PACE were Grade 3 or 4. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Ocular Toxicity: Serious or severe ocular toxicity leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. The most frequent ocular toxicities occurring in PhALLCON, OPTIC and PACE were dry eye, blurred vision, and eye pain. Retinal toxicities included age-related macular degeneration, macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Fatal and serious hemorrhage events have occurred in patients who received ICLUSIG. Fatal hemorrhages occurred in PACE and serious hemorrhages occurred in PhALLCON, OPTIC and PACE. In PACE, the incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Intracranial hemorrhage, gastrointestinal hemorrhage and subdural hematoma were the most frequently reported serious hemorrhages. Events often occurred in patients with Grade 4 thrombocytopenia. Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Fluid Retention: Fatal and serious fluid retention events have occurred in patients who received ICLUSIG. In PACE, one instance of brain edema was fatal and serious events included pleural effusion, pericardial effusion, and angioedema. In PhALLCON serious fluid retention included pericardial effusion. The most frequent occurrences of fluid retention in patients who received ICLUSIG were peripheral edema and pleural effusion. Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Cardiac Arrhythmias: Cardiac arrhythmias, including ventricular, atrial arrhythmias, tachycardia, syncope, atrial fibrillation and supraventricular tachycardia occurred in patients in PhALLCON, OPTIC, and PACE. For some patients, events were serious or severe (Grade 3 or 4) and led to hospitalization. Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity.

Myelosuppression: Grade 3 or 4 events of neutropenia, thrombocytopenia, and anemia occurred in patients in PhALLCON, OPTIC and PACE. In PACE, the incidence of myelosuppression was greater in patients with AP-CML, BP-CML, and Ph+ ALL treated with monotherapy than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 x 109/L or platelets less than 50 x 109/L, interrupt ICLUSIG until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L, then resume at same or reduced dose.

Tumor Lysis Syndrome (TLS): Serious TLS was reported in ICLUSIG-treated patients in PhALLCON, OPTIC and PACE. Ensure adequate hydration and treat high uric acid levels prior to initiating ICLUSIG.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received ICLUSIG. Patients may present with neurological signs and symptoms, visual disturbances, and hypertension. Diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown.

Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG. Permanently discontinue in patients with gastrointestinal perforation.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose.

ADVERSE REACTIONS
The most common adverse reactions (occurring in >20% of patients) are:

ICLUSIG as a single agent: rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.
ICLUSIG in combination with chemotherapy: hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia and cardiac arrhythmias. The most common Grade 3 or 4 laboratory abnormalities (>20%) are decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase and increased alanine aminotransferase.
To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-817-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Strong CYP3A Inhibitors: Avoid coadministration or reduce ICLUSIG dose if coadministration cannot be avoided.
Strong CYP3A Inducers: Avoid coadministration.

USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 1 week following last dose.

Females and Males of Reproductive Potential: Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG.

Ponatinib may impair fertility in females, and it is not known if these effects are reversible.

Pre-existing Hepatic Impairment: For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL receiving monotherapy, reduce the starting dose of ICLUSIG to 30mg orally once daily for patients with pre-existing hepatic impairment as these patients are more likely to experience adverse reactions compared to patients with normal hepatic function. For patients with newly diagnosed Ph+ ALL, no dosage adjustment is recommended.