On June 9, 2023 Genmab A/S (Nasdaq: GMAB) reported data from its ongoing phase 1/2 EPCORE NHL-2 trial investigating epcoritamab, a T-cell engaging bispecific antibody administered subcutaneously, in combination with rituximab-lenalidomide (R2) showed an overall response rate (ORR) of 98 percent and complete metabolic response (CMR) of 87 percent in response evaluable patients (n=104) with relapsed or refractory (R/R) follicular lymphoma (FL) (Press release, Genmab, JUN 9, 2023, View Source [SID1234632591]). These preliminary results will be presented today during an oral presentation at the 2023 European Hematology Association (EHA) (Free EHA Whitepaper) Congress, being held in Frankfurt, Germany and virtually, June 8-11, 2023 (Abstract #S222). Epcoritamab is being co-developed by Genmab and AbbVie (NYSE: ABBV) as part of the companies’ oncology collaboration.

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Additional findings from the study observed consistent ORR and CMR across high-risk subgroups, including a 98 percent ORR and a 75 percent CMR in patients whose disease progressed within 24 months (POD24, n=40), a 95 percent ORR and 75.7 percent CMR in patients who were double refractory (refractory to both an anti-CD20 and an alkylating agent, n=37), a 100 percent ORR and 83.8 percent CMR in patients who were primary refractory (no response or relapse within six months after first-line treatment, n=37), and a 96 percent ORR and 80.9 percent CMR in patients refractory to prior anti-CD20 treatment (n=47). Median time to any response and CMR was 1.4 months. Estimated nine-month progression-free survival was 85 percent.

"Follicular lymphoma is a challenging cancer where disease progression within two years of initial treatment with chemoimmunotherapy, known as POD24, occurs in approximately 20 percent of patients and is a strong predictor of poor outcomes. Currently, there is no standard treatment approach for patients with high-risk, relapsed or refractory follicular lymphoma, including POD24," said Anna Sureda, MD, PhD, Head of the Hematology Department and Hematopoietic Stem Cell Transplant Programme, Institut Català d’Oncologia, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain. "The results being presented today are encouraging and warrant further evaluation of epcoritamab in combination with R2 in this patient population to determine if this combination could potentially be offered as a treatment option for patients in need of alternative therapeutic options."

Among the 111 patients in the safety analysis, the most common treatment emergent adverse events (TEAE) were neutropenia (57 percent) and cytokine release syndrome (CRS) (48 percent), injection-site reactions (41 percent), and fatigue (36 percent). CRS events were mostly low grade (G1-2, 46 percent; G3, 2 percent) and mostly occurred following the first full dose (cycle 1, day 15). All events resolved and none led to treatment discontinuation. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in two patients (G1, G2) and resolved. Results from this study were also presented at this year’s American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting on June 6, 2023.

"Together with AbbVie, through our comprehensive clinical development program, we remain committed to evaluating epcoritamab, alone or in combination with other therapies, as a potential treatment option across a variety of people affected by hematologic cancers," said Dr. Judith Klimovsky, Executive Vice President and Chief Development Officer of Genmab. "The data being presented at EHA (Free EHA Whitepaper) demonstrate our shared commitment to develop epcoritamab as a potential core therapy for B-cell malignancies."

Additional Data Evaluating Epcoritamab
A poster presentation (Abstract #1118) at EHA (Free EHA Whitepaper) featured updated results from the EPCORE NHL-1 large B-cell lymphoma (LBCL) expansion cohort, including longer follow-up (median follow up was 20 months) in challenging-to-treat, relapsed or refractory CD20+ LBCL patients. Of the 157 patients with R/R LBCL, including diffuse large B-cell lymphoma (DLBCL) and high grade B-cell lymphoma (HGBCL) (n=148), Primary mediastinal large B-cell lymphoma (PMBCL [n=4]), and FL (n=5), 36 remain on treatment. Results from the trial showed an overall response (OR) of 63.1 percent and complete response (CR) of 39.5 percent in patients with R/R LBCL and a 61.9 percent OR and 39.6 percent CR in patients with R/R DLBCL. The median overall survival (OS) was 18.5 months for LBCL patients and 19.4 months for DLBCL patients. The median duration of CR in both patient populations was 20.8 months. OS was not reached among complete responders in both patient populations.

The most common TEAEs of any grade (G) were CRS (51 percent), neutropenia (24 percent), pyrexia (24 percent), fatigue (23 percent), nausea (22 percent), and diarrhea (21 percent). Nine patients (6 percent) had G1–2 ICANS, and one patient had a G5 ICANS with confounding factors.

Demonstrating the company’s commitment to evaluating the potential of epcoritamab in earlier lines of therapy, the first patients have been dosed in the phase 3 EPCORE DLBCL-2 (NCT: 05578976) and phase 2 EPCORE DLBCL-3 (NCT: 05660967) trials, designed to evaluate the safety and efficacy of epcoritamab as first-line treatment in adult and elderly patients with newly diagnosed DLBCL, respectively. The safety and efficacy of epcoritamab for first-line treatment in DLBCL has not been established.

About the EPCORE NHL-2 Study
EPCORE NHL-2 is a phase 1b/2, open-label, multinational, interventional trial to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics/biomarkers, immunogenicity, and preliminary efficacy of epcoritamab in combination with other standard of care agents in patients with B-cell non-Hodgkin lymphoma, including FL. In arms 2a and 2b of the EPCORE NHL-2 trial, 111 patients with R/R CD20+ FL received subcutaneous epcoritamab 48mg + R2 for 12 cycles (28 days each). Epcoritamab was dosed once weekly in cycles 1–3, once every two weeks in cycles 4–9, and once every four weeks in cycles ≥10 (2a) or once weekly in cycles 1–2 and once every four weeks in cycles ≥3 (2b) for ≤2 years.

Baseline characteristics included 58 percent of patients who had Follicular Lymphoma International Prognostic Index (FLIPI) 3–5, 60 percent who had stage IV disease, and 57 percent who had received only one prior line of treatment. Most had received alkylating agents (92 percent) or anthracyclines (63 percent); two had received prior CAR T therapy. The data being presented at EHA (Free EHA Whitepaper) represent a pooled analyses from arms 2a and 2b of the EPCORE NHL-2 trial evaluating epcoritamab in combination with R2 in patients with R/R FL.

About Follicular Lymphoma (FL)
FL is typically an indolent (or slow growing) form of non-Hodgkin’s lymphoma (NHL) that arises from B-lymphocytes.i FL is the second most common form of NHL overall, accounting for 20-30 percent of all NHL cases, and represents 10-20 percent of all lymphomas in the western world.ii,iii Although FL is an indolent lymphoma, it is considered incurable with conventional therapy.iv,v

About Large B-cell Lymphoma (LBCL)
LBCL is a fast-growing type of NHL, a cancer that develops in the lymphatic system and affects B-cell lymphocytes, a type of white blood cell. There are an estimated 150,000 new LBCL cases each year globally.vi

About Epcoritamab
Epcoritamab is an IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology and administered subcutaneously. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response towards target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T-cells and CD20 on B-cells and induces T-cell mediated killing of CD20+ cells.vii

Epcoritamab-bysp (EPKINLY) was recently approved in the United States and is indicated for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified (NOS), including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma (HGBL) after two or more lines of systemic therapy.

This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In October 2022, a Marketing Authorization Application was submitted for epcoritamab for the treatment of patients with R/R DLBCL after two or more lines of systemic therapy, which was validated by the European Medicines Agency. Additionally, in December 2022, a Japan new drug application was submitted to the Ministry of Health, Labor and Welfare of Japan for epcoritamab for the treatment of patients with R/R LBCL after two or more lines of systemic therapy. Epcoritamab is not approved in the European Union and Japan. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. AbbVie will continue to pursue regulatory submissions for epcoritamab across international markets excluding the U.S. and Japan throughout the year.

Genmab and AbbVie are continuing to evaluate the use of epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes an ongoing phase 3, open-label, randomized trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL (NCT: 04628494), an ongoing phase 3, open-label, randomized trial evaluating epcoritamab in combination in adult participants with newly diagnosed DLBCL (NCT: 05578976), and a phase 3, open-label clinical trial evaluating epcoritamab in combination in patients with R/R follicular lymphoma (FL) (NCT: 05409066). Epcoritamab is not approved to treat newly diagnosed patients with DLBCL or FL. The safety and efficacy of epcoritamab has not been established for these investigational uses. Please visit clinicaltrials.gov for more information.

U.S. IMPORTANT SAFETY INFORMATION
BOXED WARNINGS

Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving EPKINLY (epcoritamab-bysp). Initiate treatment with the EPKINLY step-up dosing schedule to reduce the incidence and severity of CRS. Withhold EPKINLY until CRS resolves or permanently discontinue based on severity.

Immune effector cell–associated neurotoxicity syndrome (ICANS), including life-threatening and fatal reactions, can occur with EPKINLY. Monitor patients for neurological signs or symptoms of ICANS during treatment. Withhold EPKINLY until ICANS resolves or permanently discontinue based on severity.
Cytokine Release Syndrome (CRS)

EPKINLY can cause CRS, including serious or life-threatening reactions. CRS occurred in 51 percent of patients at the recommended dose in the clinical trial (37 percent grade 1, 17 percent grade 2, and 2.5 percent grade 3). Recurrent CRS occurred in 16 percent of patients. Of all the CRS events, most (92 percent) occurred during cycle 1. In cycle 1, 9 percent of CRS events occurred after the 0.16 mg dose (cycle 1, day 1), 16 percent after the 0.8 mg dose (cycle 1, day 8), 61 percent after the 48 mg dose (cycle 1, day 15), and 6 percent after the 48 mg dose (cycle 1, day 22). The median time to onset of CRS from the most recently administered EPKINLY dose across all doses was 24 hours (range, 0-10 days). The median time to onset after the first full 48 mg dose was 21 hours (range, 0-7 days). CRS resolved in 98 percent of patients; the median duration of CRS events was 2 days (range, 1-27 days).
Signs and symptoms of CRS can include pyrexia, hypotension, hypoxia, dyspnea, chills, and tachycardia. Concurrent neurological adverse reactions associated with CRS occurred in 2.5 percent of patients and included headache, confusional state, tremors, dizziness, and ataxia.
Initiate EPKINLY according to the step-up dosing schedule. Administer pretreatment medications to reduce the risk of CRS and monitor patients for potential CRS. Following administration of the first 48 mg dose, patients should be hospitalized for 24 hours. At the first signs or symptoms of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care as appropriate. Withhold or discontinue EPKINLY based on the severity of CRS.
Patients who experience CRS (or other adverse reactions that impair consciousness) should be evaluated and advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.
Immune Effector Cell–Associated Neurotoxicity Syndrome (ICANS)

EPKINLY can cause life-threatening and fatal ICANS. ICANS occurred in 6 percent (10/157) of patients in the clinical trial (4.5 percent grade 1, 1.3 percent grade 2, 0.6 percent fatal: 1 event). Of the 10 ICANS events, 9 occurred in cycle 1 of treatment. The median time to onset was 16.5 days (range, 8-141 days) from the start of treatment. Relative to the most recent administration, the median time to onset was 3 days (range, 1-13 days). The median duration of ICANS was 4 days (range, 0-8 days), with ICANS resolving in 90 percent of patients with supportive care.
Signs and symptoms of ICANS can include confusional state, lethargy, tremors, dysgraphia, aphasia, and nonconvulsive status epilepticus. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.
Monitor for potential ICANS. At the first signs or symptoms of ICANS, immediately evaluate patient and provide supportive therapy based on severity. Withhold or discontinue EPKINLY per recommendations and consider further management per current practice guidelines.
Patients who experience signs or symptoms of ICANS or any other adverse reactions that impair cognition or consciousness should be evaluated, including potential neurology evaluation, and patients at increased risk should be advised not to drive and to refrain from operating heavy or potentially dangerous machinery until resolution.
Infections

EPKINLY can cause serious and fatal infections. In the clinical trial, serious infections, including opportunistic infections, were reported in 15 percent of patients treated with EPKINLY at the recommended dose (14 percent grade 3 or 4, 1.3 percent fatal). The most common grade 3 or greater infections were sepsis, COVID-19, urinary tract infection, pneumonia, and upper respiratory tract infection.
Monitor patients for signs and symptoms of infection prior to and during treatment with EPKINLY and treat appropriately. Avoid administration of EPKINLY in patients with active infections.
Prior to starting EPKINLY, provide Pneumocystis jirovecii pneumonia (PJP) prophylaxis and consider prophylaxis against herpes virus.
Withhold or consider permanent discontinuation of EPKINLY based on severity.
Cytopenias

EPKINLY can cause serious or severe cytopenias, including neutropenia, anemia, and thrombocytopenia. Among patients who received the recommended dose in the clinical trial, grade 3 or 4 events occurred in 32 percent (decreased neutrophils), 12 percent (decreased hemoglobin), and 12 percent (decreased platelets). Febrile neutropenia occurred in 2.5 percent.
Monitor complete blood counts throughout treatment. Based on severity of cytopenias, temporarily withhold or permanently discontinue EPKINLY. Consider prophylactic granulocyte colony-stimulating factor administration as applicable.
Embryo-Fetal Toxicity

EPKINLY may cause fetal harm. Advise pregnant women of the potential risk to the fetus. Verify pregnancy status in females of reproductive potential prior to initiating EPKINLY. Advise females of reproductive potential to use effective contraception during treatment with EPKINLY and for 4 months after the last dose.

Adverse Reactions

The most common (≥20 percent) adverse reactions were CRS, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common grade 3 to 4 laboratory abnormalities (≥10 percent) were decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets.
Lactation

Advise women not to breastfeed during treatment and for 4 months after the last dose of EPKINLY.

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

On June 8, 2023 Elevation Oncology, Inc. (Nasdaq: ELEV), an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, reported a proposed underwritten public offering in which it intends to offer and sell (i) shares of its common stock and, in lieu of common stock to investors that so choose, pre-funded warrants to purchase shares of common stock and (ii) of accompanying warrants to purchase shares of common stock (Press release, Elevation Oncology, JUN 9, 2023, View Source;utm_medium=rss&utm_campaign=elevation-oncology-announces-launch-of-proposed-public-offering [SID1234632589]). All of the shares of common stock, pre-funded warrants and accompanying warrants are being offered by Elevation Oncology. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering.

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SVB Securities and TD Cowen are acting as joint bookrunning managers in the offering.

Elevation Oncology intends to use the net proceeds from the offering primarily to fund clinical development of its lead product candidate EO-3021, an antibody drug conjugate (ADC) that has been designed to selectively deliver a cytotoxic payload directly to cancer cells expressing Claudin 18.2, and other general corporate purposes.

The shares, pre-funded warrants and accompanying warrants are being offered by Elevation Oncology pursuant to a registration statement on Form S-3 previously filed and declared effective by the Securities and Exchange Commission (SEC). A preliminary prospectus supplement and accompanying prospectus relating to this offering will be filed with the SEC. When available, copies of the preliminary prospectus supplement and the accompanying prospectus relating to this offering may be obtained from: SVB Securities LLC, Attention: Syndicate Department, 53 State Street, 40th Floor, Boston, MA 02109, by telephone at (800) 808-7525, ext. 6105, or by email at [email protected]; or Cowen and Company, LLC, 599 Lexington Avenue, New York, NY 10022, by email at [email protected] or by telephone at (833) 297-2926. Electronic copies of the preliminary prospectus supplement and accompanying prospectus will also be available on the website of the SEC at View Source

This press release does not constitute an offer to sell or the solicitation of an offer to buy the securities, nor shall there be any sale of the securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of such state or other jurisdiction.

On June 9, 2023 Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) reported data from the Phase 3 MORPHO clinical trial which demonstrated favorable results in subgroups of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutated acute myeloid leukemia (AML) patients, including a subgroup of patients with detectable measurable residual disease (MRD) (Press release, Astellas, JUN 9, 2023, View Source [SID1234632587]). The data were shared during the 2023 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress Press Briefing, taking place in Frankfurt, Germany, and will also be presented as an oral session on June 11.

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These data from the Phase 3 MORPHO trial, which evaluated gilteritinib as a maintenance therapy following allogeneic hematopoietic stem cell transplantation (HSCT) for patients with FLT3-ITD AML, did not demonstrate statistically significant improvement of relapse-free survival (RFS) in the entire cohort (Hazard Ratio [HR] for gilteritinib versus placebo 0.68; P=0.0518). However, there was clinical improvement of RFS in a subgroup of patients with detectable MRD (gilteritinib [72.4%] vs placebo [57.4%] at 2 years with HR: 0.515; 95% Confidence Interval [CI], 0.316-0.838; nominal P=0.0065) compared to patients without detectable MRD (HR: 1.213; 95% CI, 0.616-2.387; nominal P=0.575). In exploratory analysis, gilteritinib showed favorable RFS for the approximate 50% of patients with detectable MRD pre- or post-HSCT, compared to those without detectable MRD. In addition, RFS in the North American sub-population showed a HR of 0.397 (P=0.0022) for gilteritinib versus placebo. Further analysis is being conducted to understand regional results across the study population.

"While we are continuing to conduct a thorough assessment of the full data set from our Phase 3 MORPHO trial, we are encouraged by these data which explore the potential of gilteritinib in a maintenance setting," said Ahsan Arozullah, M.D., M.P.H., Senior Vice President and Head of Oncology Development, Astellas. "AML patients with a FLT3-ITD mutation often face worse outcomes than those with other mutations and have restricted post-HSCT treatment options with unmet need. With these findings, we remain focused on sharing updates with the scientific community to inform continued innovation for the AML community."

"As the AML treatment landscape continues to evolve, the exploration of prognostic indicators like MRD, which may be used to guide the management of AML, is vital to advance science and patient care," said Mary M. Horowitz, M.D., Principal Investigator of the BMT CTN Data and Coordinating Center. "We look forward to continuing our collaboration with Astellas to explore innovative approaches for those impacted by AML."

The Phase 3 MORPHO trial is a randomized, double-blind, placebo-controlled, multi-center trial that compares gilteritinib to placebo as maintenance therapy over a period of two years following HSCT in 356 patients with FLT3-ITD mutated AML and in remission after induction therapy. The study did not meet its pre-defined primary endpoint of RFS and key secondary endpoint of overall survival or patients treated with gilteritinib compared to placebo. The most frequent treatment-emergent adverse events (TEAEs) were decrease in neutrophil count, diarrhea and nausea, which were generally consistent with previous studies of gilteritinib. In FLT3-ITD AML patients, TEAEs associated with gilteritinib compared to placebo were neutrophil decrease (42.1% versus 15.8%) and increased incidence of chronic graft-versus-host disease (GVHD) (52.2% versus 42.1%). Additional data and sub-analyses will be submitted for publication and for consideration at upcoming medical meetings.

Gilteritinib is a FLT3 inhibitor with demonstrated activity against FLT3-ITD, a common driver mutation that presents with a high disease burden and poor prognosis, and FLT3-tyrosine kinase domain (TKD) mutations. Gilteritinib is available as XOSPATA in the U.S., Japan, China and selected European countries for the treatment of adult patients who have relapsed or refractory FLT3+ AML.

About Gilteritinib
Gilteritinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor with demonstrated activity against FLT3-ITD, a common driver mutation that presents with a high disease burden and poor prognosis, and FLT3-TKD mutations.1 It was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global development, commercialization and manufacturing rights to gilteritinib.2

XOSPATA (gilteritinib) U.S. Indication & Important Safety Information

Indication

XOSPATA is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test.

Important Safety Information

Contraindications
XOSPATA is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials.

WARNING: DIFFERENTIATION SYNDROME
Patients treated with XOSPATA have experienced symptoms of differentiation syndrome, which can be fatal or life-threatening if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, or renal dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

Warnings and Precautions

Differentiation Syndrome (See BOXED WARNING) 3% of 319 patients treated with XOSPATA in the clinical trials experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and other clinical findings of differentiation syndrome in patients treated with XOSPATA included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. Some cases had concomitant acute febrile neutrophilic dermatosis. Differentiation syndrome occurred as early as 1 day and up to 82 days after XOSPATA initiation and has been observed with or without concomitant leukocytosis. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. Taper corticosteroids after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt XOSPATA until signs and symptoms are no longer severe.

Posterior Reversible Encephalopathy Syndrome (PRES) 1% of 319 patients treated with XOSPATA in the clinical trials experienced posterior reversible encephalopathy syndrome (PRES) with symptoms including seizure and altered mental status. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XOSPATA in patients who develop PRES.

Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). 1% of the 317 patients with a post-baseline QTc measurement on treatment with XOSPATA in the clinical trial were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with XOSPATA, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration.

Pancreatitis 4% of 319 patients treated with XOSPATA in the clinical trials experienced pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis.

Embryo-Fetal Toxicity XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

Adverse Reactions
Fatal adverse reactions occurred in 2% of patients receiving XOSPATA. These were cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis. The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%).

7% discontinued XOSPATA treatment permanently due to an adverse reaction. The most common (>1%) adverse reactions leading to discontinuation were aspartate aminotransferase increased (2%) and alanine aminotransferase increased (2%).

The most frequent (≥5%) grade ≥3 nonhematological adverse reactions reported in patients were transaminase increased (21%), dyspnea (12%), hypotension (7%), mucositis (7%), myalgia/arthralgia (7%), and fatigue/malaise (6%).

Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (9%), hypersensitivity (8%), pancreatitis (5%), cardiac failure (4%), pericardial effusion (4%), acute febrile neutrophilic dermatosis (3%), differentiation syndrome (3%), pericarditis/myocarditis (2%), large intestine perforation (1%), and posterior reversible encephalopathy syndrome (1%).

Lab Abnormalities Shifts to grades 3-4 nonhematologic laboratory abnormalities in XOSPATA treated patients included phosphate decreased (14%), alanine aminotransferase increased (13%), sodium decreased (12%), aspartate aminotransferase increased (10%), calcium decreased (6%), creatine kinase increased (6%), triglycerides increased (6%), creatinine increased (3%), and alkaline phosphatase increased (2%).

Drug Interactions
Combined P-gp and Strong CYP3A Inducers Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases XOSPATA exposure which may decrease XOSPATA efficacy. Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers.

Strong CYP3A inhibitors Concomitant use of XOSPATA with a strong CYP3A inhibitor increases XOSPATA exposure. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity.

Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor Concomitant use of XOSPATA may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient.

P-gp, BCRP, and OCT1 Substrates Based on in vitro data, gilteritinib is a P-gp, breast cancer resistant protein (BCRP), and organic cation transporter 1 (OCT1) inhibitor. Coadministration of gilteritinib may increase the exposure of P-gp, BCRP, and OCT1 substrates, which may increase the incidence and severity of adverse reactions of these substrates. For P-gp, BCRP, or OCT1 substrates where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such substrate and monitor for adverse reactions as recommended in the respective prescribing information.

Specific Populations
Lactation Advise women not to breastfeed during treatment with XOSPATA and for 2 months after the last dose.

Please see Full Prescribing Information, including BOXED WARNING for additional safety information.

About MORPHO Phase 3 Clinical Trial The Phase 3 MORPHO Study is a two-arm, randomized, double-blind, placebo-controlled, multi-center trial in 356 patients with a diagnosis of AML harboring a FLT3/ITD mutation. Participants must be in first complete remission prior to transplant, as defined by less than five percent blasts in the bone marrow (BM) with no morphologic characteristics of acute leukemia in the BM with no evidence of extra-medullary leukemia. After undergoing transplantation, participants will be randomized to receive gilteritinib (120 mg) or placebo beginning after the time of engraftment for a two-year period. Participants will be stratified according to: 1) conditioning regimen intensity (myeloablative vs. reduced intensity/non-myeloablative), 2) time from first day of hematopoietic cell infusion to randomization (30-60 days vs. 61-90 days) and 3) presence vs. absence of or unknown minimal residual disease from the most recent pre-registration BM aspirate. The primary endpoint of the trial is RFS. The study is being conducted in countries across North America, Europe and the Asia-Pacific region, including Japan.

For more information about this trial, please visit www.clinicaltrials.gov under trial identifier NCT02997202.

About Acute Myeloid Leukemia (AML) Acute myeloid leukemia (AML) is an aggressive cancer that affects the bone marrow and blood, and its incidence increases with age.3,4 Of patients newly diagnosed with AML and tested for FLT3 mutations, approximately one-third have an alteration to the FLT3 gene. FLT3-ITD mutations have been associated with worsened disease-free survival and overall survival, and a higher risk of getting the disease more than once. FLT3 mutation status can change over the course of AML treatment, even after relapse.

On June 9, 2023 Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") reported the submission of a New Drug Application (NDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for zolbetuximab, a first-in-class investigational Claudin 18.2 (CLDN18.2)-targeted monoclonal antibody, for first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2-positive (Press release, Astellas, JUN 9, 2023, View Source [SID1234632586]). If approved, zolbetuximab would be the first CLDN18.2-targeted therapy available in Japan for these patients.

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"Gastric cancer remains the third deadliest cancer in Japan, leading to approximately 50,000 deaths per year despite significant strides to reduce the impact of this cancer," said Pranob Bhattacharya, DrPH, MS, MBA, Executive Director and Interim Head of Immuno-Oncology Development, Astellas. "Astellas’ submission of a New Drug Application to Japan’s Ministry of Health, Labour and Welfare for zolbetuximab demonstrates critical momentum in addressing the unmet needs of patients with gastric cancer in Japan."

The NDA is based on results from the Phase 3 SPOTLIGHT and GLOW clinical trials. The SPOTLIGHT study evaluated zolbetuximab plus mFOLFOX6 (a combination regimen that includes oxaliplatin, leucovorin and fluorouracil) compared to placebo plus mFOLFOX6. The GLOW study evaluated zolbetuximab plus CAPOX (a combination chemotherapy regimen that includes capecitabine and oxaliplatin) compared to placebo plus CAPOX.

In both SPOTLIGHT and GLOW, approximately 38% of patients screened for the trials had tumors that were CLDN18.2-positive (≥75% of tumor cells with moderate-to-strong membranous CLDN18 staining intensity), as determined by a validated immunohistochemistry assay.1,2

About Locally Advanced Unresectable Metastatic Gastric and Gastroesophageal Junction Cancer
Gastric cancer, also commonly known as stomach cancer, is the fifth most commonly diagnosed cancer worldwide.3 Gastric cancer kills 50,000 people per year in Japan, making it the third deadliest cancer by number of deaths in the country.4 Signs and symptoms can include indigestion or heartburn, pain or discomfort in the abdomen, nausea and vomiting, diarrhea or constipation, bloating of the stomach after meals and loss of appetite and sensation of food getting stuck in the throat while eating.5 Signs of more advanced gastric cancer can include unexplained weight loss, weakness and fatigue and vomiting blood or having blood in the stool.6 Risk factors associated with gastric cancer can include older age, male gender, family history, H. pylori infection, smoking and gastroesophageal reflux disease (GERD).5,7 Because early-stage gastric cancer symptoms frequently overlap with more common stomach-related conditions, gastric cancer is often diagnosed in the advanced or metastatic stage, or once it has spread from the tumor’s origin to other body tissues or organs.5 The five-year relative survival rate for patients at the metastatic stage is 6.6%.8 Gastroesophageal junction (GEJ) adenocarcinoma is a cancer that starts at the area where the esophagus joins the stomach.9

About Zolbetuximab
Zolbetuximab is an investigational, first-in-class chimeric IgG1 monoclonal antibody (mAb) that targets and binds to CLDN18.2, a transmembrane protein. Zolbetuximab acts by binding to CLDN18.2 on the cancer cell surface of gastric epithelial cells. In pre-clinical studies, this binding interaction then induces cancer cell death by activating two distinct immune system pathways — antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).10 Zolbetuximab has not been approved by any regulatory bodies for the treatment of patients with gastric, GEJ and pancreatic cancers and there is no guarantee the agent will receive regulatory approval or become commercially available for the uses being investigated.

INVESTIGATIONAL STUDIES

About SPOTLIGHT Phase 3 Clinical Trial
SPOTLIGHT is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab (IMAB362) plus mFOLFOX6 (a combination regimen that includes oxaliplatin, leucovorin and fluorouracil) compared to placebo plus mFOLFOX6 as a first-line treatment in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. The study enrolled 565 patients at 215 study locations in the U.S., Canada, United Kingdom, Australia, Europe, South America and Asia, including Japan. The primary endpoint is progression-free survival (PFS) of participants treated with the combination of zolbetuximab plus mFOLFOX6 compared to those treated with placebo plus mFOLFOX6. Secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), safety and tolerability and quality-of-life parameters.

Data from the SPOTLIGHT clinical trial were presented during the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal (GI) Cancers Symposium in an oral presentation on January 19 and were subsequently published in The Lancet on April 14.1

For more information, please visit clinicaltrials.gov under Identifier NCT03504397.

About GLOW Phase 3 Clinical Trial
GLOW is a Phase 3, global, multi-center, double-blind, randomized study, assessing the efficacy and safety of zolbetuximab (IMAB362) plus CAPOX (a combination chemotherapy regimen which includes capecitabine and oxaliplatin) compared to placebo plus CAPOX as a first-line treatment in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. The study enrolled 507 patients at 166 study locations in the U.S., Canada, United Kingdom, Europe, South America and Asia, including Japan. The primary endpoint is PFS in participants treated with the combination of zolbetuximab plus CAPOX compared to those treated with placebo plus CAPOX. Secondary endpoints include OS, ORR, DOR, safety and tolerability and quality-of-life parameters.

Data from the GLOW study were initially presented at the March 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series with an encore presentation during an oral presentation at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting on June 3.2

For more information, please visit clinicaltrials.gov under Identifier NCT03653507.

Investigational Pipeline in Claudin 18.2
An expanded Phase 2 trial in metastatic pancreatic adenocarcinoma is in progress. The trial is a randomized, multi-center, open-label study, evaluating the safety and efficacy of investigational zolbetuximab in combination with gemcitabine plus nab-paclitaxel as a first-line treatment in patients with metastatic pancreatic adenocarcinoma with CLDN18.2-positive tumors (defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining based on a validated immunohistochemistry assay). For more information, please visit clinicaltrials.gov under Identifier NCT03816163.

In addition to zolbetuximab, ASP2138 is under development in our Primary Focus Immuno-Oncology. ASP2138 is a bispecific monoclonal antibody that binds to CD3 and Claudin 18.2, and it is currently in a Phase 1 trial for people with gastric, gastroesophageal junction or pancreatic cancer. The safety and efficacy of the agents under investigation have not been established for the uses being considered. For more information, please visit clinicaltrials.gov under Identifier NCT05365581.

There is no guarantee that the agent will receive regulatory approval and become commercially available for the uses being investigated.

On June 9, 2023 Abeona Therapeutics Inc. (Nasdaq: ABEO) reported that it received feedback from the U.S. Food and Drug Administration (FDA) on June 8, 2023, in which the Company gained the Agency’s alignment on the data required to establish retroviral vector (RVV) comparability, a critical Chemistry, Manufacturing and Controls (CMC) component for the EB-101 Biologics License Application (BLA) (Press release, Abeona Therapeutics, JUN 9, 2023, View Source [SID1234632583]).

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"Gaining alignment with the FDA on the RVV comparability package is a very important de-risking milestone for our BLA submission after our recent successful completion of the Process Performance Qualification (PPQ) manufacturing validation runs," said Vish Seshadri, Chief Executive Officer of Abeona.

As part of the package, the FDA requested additional assay data to establish comparability between RVV sourced from Indiana University and RVV manufactured in-house at Abeona, both of which have been used in the EB-101 clinical studies. The Company has the necessary reagents in-house to promptly generate the requested data. To allow the FDA the necessary time to review the requested RVV data, Abeona has requested that its pre-BLA meeting date for EB-101 be rescheduled for August 2023. The Company expects to file its BLA for EB-101 in the third quarter of 2023.