On June 11, 2022 Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and CRISPR Therapeutics (Nasdaq: CRSP) reported that presentation of new data on exa-cel, formerly known as CTX001, from CLIMB-111, CLIMB-121 and CLIMB-131 highlighting the potentially transformative profile of this investigational therapy for people with transfusion-dependent beta thalassemia (TDT) or severe sickle cell disease (SCD) and provided additional program updates (Press release, CRISPR Therapeutics, JUN 11, 2022, View Source [SID1234615905]).

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New Data for exa-cel from CLIMB Clinical Studies
The data presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress are from 75 patients (44 with TDT and 31 with SCD) with follow-up ranging from 1.2 to 37.2 months after exa-cel dosing.

Of the 44 patients with TDT, 26 had beta-zero/beta-zero or other beta-zero-like severe genotypes. Forty-two of 44 patients with TDT were transfusion-free with follow-up ranging from 1.2 to 37.2 months after exa-cel infusion. Two patients who were not yet transfusion-free had 75% and 89% reductions in transfusion volume. TDT patients had substantial mean increases in fetal hemoglobin (HbF) and corresponding increases in mean total hemoglobin (Hb) with mean total Hb levels increasing to >11 g/dL by Month 3 and maintained thereafter.

All 31 patients with severe SCD characterized by recurrent vaso-occlusive crises (VOCs) (mean of 3.9 VOCs per year over the prior two years) were free of VOCs after exa-cel infusion through duration of follow-up, with follow-up ranging from 2.0 to 32.3 months. SCD patients had mean HbF (as a proportion of total Hb) of approximately 40% by Month 4 and maintained thereafter.

The safety was generally consistent with myeloablative conditioning with busulfan and autologous stem cell transplant. All patients engrafted neutrophils and platelets after exa-cel infusion. Among the 44 patients with TDT, two patients had serious adverse events (SAEs) considered related to exa-cel. As previously reported, one patient had three SAEs considered related to exa-cel, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and headache, and one SAE of idiopathic pneumonia syndrome that was considered related to both exa-cel and busulfan. All four SAEs occurred in the context of HLH and have resolved. One patient had SAEs of delayed neutrophil engraftment and thrombocytopenia, both of which were considered related to exa-cel and busulfan, and both SAEs have resolved. Among the 31 patients with SCD, there were no SAEs considered related to exa-cel.

Additional details were presented during the EHA (Free EHA Whitepaper) media briefing and can be found in the published abstract and presentation.

Late-breaking abstract #LB2367 entitled "Efficacy and Safety of a Single Dose of CTX001 For Transfusion-Dependent Βeta-Thalassemia and Severe Sickle Cell Disease," will be an oral presentation on Sunday, June 12 at 09:45-11:15 CEST.

"These robust data from 75 patients, of which 33 have one year or more of follow-up after exa-cel infusion, further demonstrate the potential of this investigational therapy as a one-time functional cure for patients with transfusion-dependent beta thalassemia or severe sickle cell disease," said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex.

"By reactivating a naturally occurring developmental process, exa-cel restores fetal hemoglobin production and thereby can ameliorate the course of these diseases," said Haydar Frangoul, M.D., Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute, HCA Healthcare’s The Children’s Hospital at TriStar Centennial Medical Center. "The remarkable results based on this approach give me great optimism and confidence in the potential of this treatment for patients."

"I have seen first-hand the impact that this investigational therapy has had on patients in these clinical trials and continue to be impressed by the totality of the data," said Franco Locatelli, M.D., Ph.D., Professor of Pediatrics at the Sapienza University of Rome, Director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital. "Given the urgency for highly effective and curative therapies for patients with hemoglobinopathies, I am excited to be part of the team working towards the goal of addressing this unmet need."

Exa-cel Study Updates
Following ongoing discussions with regulators, the clinical trial protocols for CLIMB-111 and CLIMB-121 were amended to incorporate feedback on the primary endpoints for regulatory submission. Specifically, the primary endpoint in CLIMB-111 for TDT has been amended from proportion of subjects achieving transfusion reduction after exa-cel infusion to proportion of subjects maintaining weighted average Hb ≥9 g/dL without red blood cell (RBC) transfusions for at least 12 consecutive months after exa-cel infusion.

The primary endpoint in CLIMB-121 for SCD has been updated from proportion of subjects with HbF ≥20% after exa-cel infusion, to proportion of subjects who have not experienced any severe VOCs for at least 12 consecutive months after exa-cel infusion.

Both clinical trials are now in Phase 3 and are fully enrolled. All patients will have the opportunity to join CLIMB-131, a long-term follow-up study, after completing participation in the initial studies.

Additional Pediatric Studies
In line with the company’s strategy of developing therapies for patients of all ages, two additional Phase 3 studies of exa-cel have begun. Earlier this year, the Independent Data Monitoring Committee (DMC) met to review the data in adults and adolescents and endorsed expanding into younger pediatric patients. CLIMB-141 and CLIMB-151 are Phase 3 open-label trials designed to assess the safety and efficacy of a single dose of exa-cel in patients ages 2 to 11 years with TDT or SCD, respectively. The trials are now open for enrollment and currently enrolling patients ages 5 to 11 years and will plan to extend to patients 2 to less than 5 years of age at a later date. Each trial will enroll approximately 12 patients. Patients will be followed for approximately two years after infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial.

Vertex also presented three additional abstracts on the burden of disease in sickle cell disease and beta thalassemia at the EHA (Free EHA Whitepaper) Congress.

Abstract #P1704 entitled "Projected Lifetime Economic Burden of Severe Sickle Cell Disease in the United States," presented via poster on Friday, June 10 at 16:30-17:45 CEST.
Abstract #P1703 entitled "Economic Burden of Transfusion-Dependent Beta-Thalassemia in the United States," presented via poster on Friday, June 10 at 16:30-17:45 CEST.
Abstract #P1482 entitled "Patients With Severe Sickle Cell Disease on Standard-of-Care Treatment Are Very Unlikely to Become VOC-Free for One Year: A Cohort Study of Medicaid Enrollees," presented via poster on Friday, June 10 at 16:30-17:45 CEST.
About exagamglogene autotemcel (exa-cel)
Exa‑cel, formerly known as CTX001, is an investigational, autologous, ex vivo CRISPR/Cas9 gene‑edited therapy that is being evaluated for patients with TDT or SCD characterized by recurrent VOCs, in which a patient’s own hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen‑carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. The elevation of HbF by exa‑cel has the potential to alleviate transfusion requirements for patients with TDT and reduce painful and debilitating sickle crises for patients with SCD. Earlier results from these ongoing trials were published in The New England Journal of Medicine in January of 2021.

Based on progress in this program to date, exa‑cel has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration (FDA) for both TDT and SCD. Exa-cel has also been granted Orphan Drug Designation from the European Commission, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA), for both TDT and SCD.

Among gene‑editing approaches being evaluated for TDT and SCD, exa‑cel is the furthest advanced in clinical development.

About CLIMB‑111 and CLIMB‑121
The ongoing Phase 1/2/3 open‑label trials, CLIMB‑111 and CLIMB‑121, are designed to assess the safety and efficacy of a single dose of exa‑cel in patients ages 12 to 35 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now closed for enrollment. Patients will be followed for approximately two years after exa‑cel infusion. Each patient will be asked to participate in CLIMB‑131, a long‑term follow‑up trial.

About CLIMB-131
This is a long‑term, open‑label trial to evaluate the safety and efficacy of exa‑cel in patients who received exa‑cel in CLIMB‑111, CLIMB‑121, CLIMB‑141 or CLIMB‑151. The trial is designed to follow participants for up to 15 years after exa‑cel infusion.

About CLIMB‑141 and CLIMB‑151
The ongoing Phase 3 open-label trials, CLIMB‑141 and CLIMB‑151, are designed to assess the safety and efficacy of a single dose of exa‑cel in patients ages 2 to 11 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now open for enrollment and currently enrolling patients ages 5 to 11 years of age and will plan to extend to patients 2 to less than 5 years of age at a later date. Each trial will enroll approximately 12 patients. Patients will be followed for approximately two years after infusion. Each patient will be asked to participate in CLIMB-131, a long‑term follow‑up trial.

About the Gene‑Editing Process in These Trials
Patients who enroll in these trials will have their own hematopoietic stem and progenitor cells collected from peripheral blood. The patient’s cells will be edited using the CRISPR/Cas9 technology. The edited cells, exa‑cel, will then be infused back into the patient as part of an autologous hematopoietic stem cell transplant (HSCT), a process which involves a patient being treated with myeloablative busulfan conditioning. Patients undergoing HSCT may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of exa‑cel. Patients will initially be monitored to determine when the edited cells begin to produce mature blood cells, a process known as engraftment. After engraftment, patients will continue to be monitored to track the impact of exa‑cel on multiple measures of disease and for safety.

About the Vertex‑CRISPR Collaboration
Vertex and CRISPR Therapeutics entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. Exa‑cel represents the first potential treatment to emerge from the joint research program. Under an amended collaboration agreement, Vertex now leads global development, manufacturing and commercialization of exa‑cel and splits program costs and profits worldwide 60/40 with CRISPR Therapeutics.

On June 11, 2022 Orphagen Pharmaceuticals, an early-stage biopharmaceutical company focused on developing and commercializing novel therapies for cancer and other serious diseases with significant unmet need, reported that additional data from its preclinical program to develop OR-449 for the treatment of adrenocortical cancer (ACC) was presented at the 104th Annual Meeting of the Endocrine Society (ENDO 2022) being held in Atlanta from June 11 to 14 (Press release, Orphagen, JUN 11, 2022, View Source [SID1234615906]). ACC is a rare endocrine malignancy frequently diagnosed at an advanced stage with very limited treatment options. OR-449 is in preclinical development for treatment of ACC with a first-in-human clinical trial targeted for early 2023.

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OR-449 is a potent, selective, and orally bioavailable small molecule antagonist to steroidogenic factor-1 (SF-1 or NR5A1), a nuclear receptor and a transcription factor essential for the growth and development of the adrenal gland. SF-1 was recently described as a candidate "master transcription factor" in adult ACC.1 ACC tumors often secrete a "malignant" but variable pattern of steroids not normally found in the circulation. The preclinical findings reported show, first, that a malignant steroid profile is also secreted from two separate patient-derived ACC xenografts maintained in immunocompromised mice. Second, the secreted steroids from SW1939, derived from a pediatric ACC, were markedly regulated by treatment with OR-449. Similar steroid regulation in response to OR-449 treatment could occur in the clinic, facilitating selection of a treatment dose for a Phase 2 clinical trial.

Paul Crowe, Ph.D., presenting author and Vice President of Drug Discovery at Orphagen, stated, "We are once again excited to share preclinical data for the efficacy of OR-449 in ACC, this time in a novel preclinical model, the pediatric ACC xenograft, SW1939, developed by Peter Houghton and colleagues at U. T. Health Sciences Center in San Antonio. Not only does OR-449 inhibit the growth of this patient-derived xenograft, but it also regulates the levels of circulating adrenocortical tumor-derived steroids and steroid precursors. Circulating steroid secretion may provide a clinically relevant pharmacodynamic biomarker for OR-449 target engagement in ACC patients."

Orphagen CEO, Scott Thacher, Ph.D., said, "This is a satisfying success story for Orphagen’s corporate strategy to find first-in-class small molecules for unexplored nuclear receptor targets with efficacy in translationally relevant animal models of disease. The biomarker findings are a secondary, but potentially highly valuable outcome of these preclinical studies. We’re grateful for the strong support we’ve received from leading clinical investigators in the ACC field during this preclinical work, and we look forward to working with them on clinical trials for OR-449. Our hope is to bring a new and valuable therapeutic option to ACC patients."

Click to VIEW POSTER

Poster Presentation Information

Title: Downstream Targets of the Steroidogenic Factor-1 (SF-1) Antagonist OR-449 in PDX Models of ACC

Presenter: Paul D Crowe, PhD

Co-Authors: Ray Fox, PhD, Haiyan Tao, PhD, Neil Raheja, PhD, Richard J. Auchus, MD, PhD, Peter Houghton, PhD, Scott Thacher, PhD

Poster Session: PSUN355

1 Corces et al., Science. 2018; 362(6413); Reddy et al., Sci Adv. 2021; 7(48).

On June 11, 2022 Oxford Drug Design reported that it will be attending the 28th tRNA Conference, 12-16 June 2022 in Columbus, Ohio, USA (Press release, Oxford Drug Design, JUN 11, 2022, View Source [SID1234615907]). On 13 June at 4:45pm EST Paul will be participating in a Panel Discussion on "Emerging Opportunities in tRNA Therapeutics", which will showcase the emerging opportunities for translational science and entrepreneurism in tRNA-related therapeutics and biotechnology across multiple therapeutic areas and treatment modalities. This is an exciting area with untapped therapeutic potential in which Oxford Drug Design is taking a leading position.

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On June 11, 2022 Genmab A/S (Nasdaq: GMAB) reported that primary results from the large B-cell lymphoma (LBCL) expansion cohort in the EPCORE NHL-1 phase 2 clinical trial evaluating subcutaneous epcoritamab (DuoBody-CD3xCD20), an investigational bispecific antibody (Press release, Genmab, JUN 11, 2022, View Source [SID1234615908]). In the study, treatment with epcoritamab demonstrated deep and durable responses with an overall response rate (ORR) of 63 percent and a complete response rate (CR) of 39 percent in patients who had previously received at least two prior lines of systemic anti-lymphoma therapy. Additionally, patients naïve to treatment with chimeric antigen receptor (CAR) T-cell therapy achieved 69 percent ORR and 42 percent CR and patients previously treated with CAR T achieved a 54 percent ORR and 34 percent CR. Data were presented in a late-breaking oral presentation as a part of the Presidential Symposium at the 27th Annual Meeting of the European Hematology Association (EHA) (Free EHA Whitepaper) (EHA2022) in Vienna, Austria (Abstract #LB2364).

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"Large B-cell lymphoma is a fast-growing, difficult to treat type of aggressive non-Hodgkin’s lymphoma. Some treatment approaches like chemotherapy and immunotherapy have been in place for decades and newer treatments like CAR T-cell therapies involve multiple steps before a patient can begin treatment, so there is still a need for additional treatment options," said Professor Catherine Thieblemont, Head of the Hemato-Oncology Department at Hôpital Saint-Louis, Paris, France. "The data presented today suggest that epcoritamab has the potential to provide patients living with relapsed/refractory LBCL an accessible, effective treatment with a safety profile that may fulfill an unmet need."

The study cohort, which included 157 relapsed/refractory LBCL patients, previously treated with a median of three lines of prior therapy, demonstrated an overall response rate (ORR) of 63 percent and a complete response rate (CR) of 39 percent. Baseline characteristics included 61 percent of patients who were refractory to primary treatment, 20 percent who had prior autologous stem cell transplantation (ASCT), and 39 percent who were treated with CAR T-cell therapy (75 percent of those refractory to CAR T). Patients enrolled in the study who were naïve to CAR T therapy achieved a 69 percent ORR and a 42 percent CR and patients who received prior CAR T-cell treatment achieved a 54 percent ORR and a 34 percent CR. After a median follow up of 10.7 months, the median duration of response (mDOR) was estimated to be 12 months, while the mDOR among patients achieving a CR was not reached, with 89 percent still in CR at nine months. Topline results from this study were previously announced in April 2022.

"These latest data are promising because they suggest that treatment with epcoritamab may benefit patients with this fast-growing, aggressive and difficult to treat type of non-Hodgkin’s lymphoma who are in need of new therapeutic advances," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. "We are encouraged by the potential of epcoritamab and look forward to continuing to advance our robust clinical development program with our partner, AbbVie."

The safety profile of epcoritamab was manageable and consistent with previous findings. The majority of treatment-emergent AEs (TEAEs) occurred during the first 12 weeks of treatment and resolved. The most common TEAEs of any grade (greater than or equal to 15 percent) included cytokine release syndrome (CRS) (49.7 percent), pyrexia (23.6 percent), fatigue (22.9 percent), neutropenia (21.7 percent), diarrhea (20.4 percent), injection site reaction (19.7%), nausea (19.7%), and anemia (17.8%). The most common Grade 3 or 4 treatment-emergent adverse events (greater than or equal to 5 percent) included neutropenia (14.6 percent), anemia (10.2 percent), neutrophil count decrease (6.4 percent), and thrombocytopenia (5.7 percent). The observed Grade 3 CRS was low (2.5 percent). No Grade 4/5 CRS was observed.

Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ broad oncology collaboration. The companies remain committed to evaluating epcoritamab as a monotherapy, and in combination, across lines of therapy for a variety of hematologic malignancies, including an ongoing phase 3, open-label, randomized trial evaluating epcoritamab as a monotherapy in patients with relapsed/refractory DLBCL (NCT: 04628494).

About Large B-cell Lymphoma (LBCL)
LBCL is a fast-growing type of non-Hodgkin’s lymphoma (NHL) – a cancer that develops in the lymphatic system – that affects B-cell lymphocytes, a type of white blood cell. There are an estimated 150,000 new LBCL cases each year globally. LBCL includes DLBCL, which is the most common type of NHL worldwide and accounts for approximately 31 percent of all NHL cases.1,2,3,4

About the EPCORE NHL-1 Trial
EPCORE NHL-1 an open-label, multi-center safety and preliminary efficacy trial of epcoritamab including a phase 1 first-in-human, dose escalation part; a phase 2 expansion part; and an optimization part. The trial was designed to evaluate subcutaneous epcoritamab in patients with relapsed, progressive or refractory CD20+ mature B-NHL, including LBCL and DLBCL. The dose escalation findings, which determined the recommended phase 2 dose, were published in The Lancet in 2021. In the phase 2 expansion part, additional patients are treated with epcoritamab to further explore the safety and efficacy of epcoritamab in three cohorts of patients with different types of relapsed/refractory B-NHLs who had limited therapeutic options.

The primary endpoint of the phase 2 expansion part was ORR as assessed by an IRC. Secondary efficacy endpoints included duration of response, complete response rate, progression-free survival, and time to response as determined by the Lugano criteria. Overall survival, time to next therapy, and rate of minimal residual disease negativity were evaluated as secondary efficacy endpoints.

About Epcoritamab
Epcoritamab is an investigational IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology. 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.5 Epcoritamab was developed with selective, silencing mutations that may limit systemic, non-specific activity. CD20 is expressed on B-cells and a clinically validated therapeutic target in many B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia.6,7 Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ broad oncology collaboration.

On June 11, 2022 Daiichi Sankyo reported that Positive results from the global pivotal QuANTUM-First phase 3 trial of Daiichi Sankyo’s (TSE:5468) quizartinib combined with standard induction and consolidation chemotherapy and then continued as a single agent demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in adult patients aged 18-75 with newly diagnosed FLT3-ITD positive acute myeloid leukemia (AML) compared to standard chemotherapy alone (Press release, Daiichi Sankyo, JUN 11, 2022, View Source [SID1234615910]). The data were featured as part of the press program and presented during the Presidential Symposium (#S100) at the European Hematology Association (EHA) (Free EHA Whitepaper) (#EHA2022) Congress.

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AML is one of the most common leukemias in adults with an estimated five-year survival rate of approximately 30.5%.1,2 Of all newly diagnosed cases of AML, 25% carry the FLT3-ITD gene mutation, which is associated with particularly unfavorable prognosis including increased risk of relapse and shorter overall survival.3

Quizartinib combined with standard induction and consolidation chemotherapy and then continued as a single agent demonstrated a 22.4% reduction in the risk of death compared to standard chemotherapy alone (HR = 0.776 [95% CI: 0.615-0.979; 2-sided p=.0324]) in patients with newly diagnosed FLT3-ITD positive AML. After a median follow-up of 39.2 months, median OS was more than double at 31.9 months for patients receiving quizartinib (95% CI: 21.0-NE) compared to 15.1 months for patients receiving chemotherapy (95% CI: 13.2-26.2).

The safety of quizartinib combined with intensive chemotherapy and as continuation monotherapy in QuANTUM-First was generally manageable, with no new safety signals observed. Rates of grade 3 or higher treatment emergent adverse events (TEAEs) were similar for both study groups and the most common grade 3 or higher TEAEs occurring in ≥ 10% of patients were febrile neutropenia (43.4% quizartinib; 41.0% placebo), neutropenia (18% quizartinib; 8.6% placebo), hypokalemia (18.9% quizartinib; 16.4% placebo) and pneumonia (11.7% quizartinib; 12.7% placebo). Rates of TEAEs associated with fatal outcomes were 11.3% for quizartinib versus 9.7% for chemotherapy alone and were mainly due to infections.

QTcF > 500 ms occurred in 2.3% of patients receiving quizartinib and 0.8% of patients discontinued quizartinib due to QT prolongation. Ventricular arrhythmia events with quizartinib were uncommon. Two (0.8%) patients experienced cardiac arrest with recorded ventricular fibrillation on ECG (one with fatal outcome) both in the setting of severe hypokalemia.

"The QuANTUM-First results show that adding quizartinib to standard chemotherapy significantly improved overall survival in patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia," said Harry P. Erba, MD, PhD, Instructor, Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke Cancer Institute. "There is great interest in the increased use of targeted therapies to improve outcomes for patients with AML, particularly those with the FLT3-ITD subtype, which is one of the most common, aggressive and difficult-to-treat."

"We are proud that another one of our medicines has demonstrated a significant survival advantage, as our goal is to leverage innovative science to change the way cancer is treated," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "Adding targeted treatment with quizartinib, a potent and selective FLT3 inhibitor, to standard chemotherapy resulted in a doubling of median overall survival in patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia compared to standard chemotherapy alone. Based on these positive QuANTUM-First results, we have initiated global regulatory filings in order to bring quizartinib to patients as quickly as possible."

The OS improvement with quizartinib was also supported by a sensitivity analysis censoring for the effect of allogenic hematopoietic stem cell transplant (HSCT) (HR = 0.752; [95% CI: 0.562-1.008]).

Additional secondary and exploratory analyses provide further understanding and some supporting evidence for improved OS in patients receiving quizartinib combined with chemotherapy in the trial.

The primary event-free survival (EFS) analysis (with induction treatment failure (ITF) defined as not achieving complete remission (CR) by day 42 of the last induction cycle), did not show a statistically significant difference between the two study arms; two pre-specified sensitivity analyses on EFS (the first one defining ITF as not achieving CR by the end of induction; the second one defining ITF as having not achieved composite complete remission (CRc) by the end of induction) showed HR = 0.818 [95% CI: 0.669, 0.999] and HR = 0.729 [95% CI: 0.592-0.897], respectively.

The CRc rate was numerically higher for patients receiving quizartinib compared to chemotherapy alone (71.6% versus 64.9%), and rates of CR were similar for the two study arms (54.9% and 55.4%). The median duration of CR was 38.6 months for quizartinib (95% CI: 21.9-NE) and 12.4 months for chemotherapy (95% CI: 8.8-22.7).

The median relapse-free survival (RFS) for patients who achieved CR was 39.3 months for quizartinib and 13.6 months for placebo, representing a 38.7% relative risk reduction of relapse or death (HR = 0.613 [95% CI: 0.444-0.845]).

*A hierarchical testing procedure was used to test the primary endpoint OS, followed by EFS, CR and CRc. Formal statistical testing was stopped after EFS as its result was not statistically significant.
Data cut-off: August 13, 2021
Abbreviations: HR = Hazard ratio; NE = not estimable; OS = overall survival

About QuANTUM-First

QuANTUM-First is a randomized, double-blind, placebo-controlled global phase 3 study evaluating quizartinib in combination with standard induction and consolidation chemotherapy and then as continued single agent therapy in adult patients (aged 18-75) with newly diagnosed FLT3-ITD positive AML. Patients were randomized 1:1 into two treatment groups to receive quizartinib or placebo combined with anthracycline- and cytarabine-based regimens. Eligible patients, including those who underwent allogeneic HSCT, continued with single agent quizartinib or placebo for up to 36 cycles.

The primary study endpoint was OS. Secondary endpoints include EFS, post-induction rates of CR and CRc, and the percentage of patients who achieve CR or CRc with FLT3-ITD minimal residual disease negativity. Safety and pharmacokinetics, along with exploratory efficacy and biomarker endpoints, also were evaluated. QuANTUM-First enrolled 539 patients at 193 study sites across Asia, Europe, North America, Oceania and South America. For more information, visit ClinicalTrials.gov.

About Acute Myeloid Leukemia (AML)

More than 474,500 new cases of leukemia were reported globally in 2020 with more than 311,500 deaths.4 AML is one of the most common types of leukemia in adults, representing about one-third of all cases, and the average age of diagnosis is 68 years old.1 The five-year survival rate for AML is 30.5%, the lowest by far among the major leukemia subtypes, and is 9.4% for patients aged 65 and older.5,6,7 The conventional treatment for newly diagnosed AML is intensive induction and consolidation chemotherapy with HSCT for eligible patients.8 The introduction of new targeted therapies in recent years has added to the standard of care and improved outcomes for some patients with molecularly defined AML subtypes.9

About FLT3-ITD

FLT3 (FMS-like tyrosine kinase 3) is a tyrosine kinase receptor protein normally expressed by hematopoietic stem cells that plays an important role in cell development, promoting cell survival, growth and differentiation through various signaling pathways.3 Mutations of the FLT3 gene, which occur in approximately 30% of AML patients, can drive oncogenic signaling.3 FLT3-ITD (internal tandem duplication) is the most common type of FLT3 mutation in AML, occurring in about 25% of all newly diagnosed patients, and is associated with increased risk of relapse and shorter overall survival.3

About Quizartinib

Quizartinib is an oral, highly potent and selective type II FLT3 inhibitor currently in clinical development for the treatment of FLT3-ITD positive AML.3 In addition to QuANTUM-First, the quizartinib development program includes a phase 1/2 trial in pediatric and young adult patients with relapsed/refractory FLT3-ITD AML in Europe and North America. Several phase 1/2 combination studies with quizartinib are also underway at The University of Texas MD Anderson Cancer Center as part of a strategic research collaboration focused on accelerating development of Daiichi Sankyo pipeline therapies for AML.

Quizartinib has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of adult patients with newly diagnosed AML that is FLT3-ITD positive, in combination with standard cytarabine and anthracycline induction and cytarabine consolidation. Orphan Drug Designation has been granted to quizartinib for the treatment of AML in Europe, Japan and the U.S.

Quizartinib is currently approved for use in Japan under the brand name VANFLYTA for the treatment of adult patients with relapsed/refractory FLT3-ITD AML, as detected by an approved test. Quizartinib is an investigational medicine in all countries outside of Japan.