On December 9, 2021 ADC Therapeutics SA, a clinical-stage oncology-focused biotechnology company pioneering the development of highly potent antibody drug conjugates (ADCs) for patients suffering from hematological malignancies and solid tumors, reported interim efficacy and safety data on 52 patients in the ongoing pivotal 145-patient Phase 2 clinical trial of ADCT-402 (loncastuximab tesirine), demonstrating its potential as a single agent for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (Press release, ADC Therapeutics, DEC 9, 2019, View Source [SID1234596051]). Carmelo Carlo-Stella, MD, Section Chief, Lymphoid Malignancies and Cancer Therapeutics, Humanitas Cancer Center, Humanitas University, and an investigator for the trial, presented the data today during an oral session at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, FL.

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"The data continue to reinforce the significant single-agent, anti-tumor activity and manageable toxicity profile of ADCT-402 in patients with relapsed or refractory DLBCL, even in difficult-to-treat patients. Based on the encouraging data seen with this agent today, I believe ADCT-402 has the potential to be an integral part of the treatment paradigm for patients with DLBCL," said Dr. Carlo-Stella. "DLBCL is a common and aggressive cancer that can be challenging to treat due to its frequent resistance to available treatments. Patients who have failed established therapies are limited in their treatment options, creating a critical need for a new therapy."

"We are pleased that the data from our oral presentation at ASH (Free ASH Whitepaper) support the potential of ADCT-402 to be an important treatment option for heavily pretreated patients with DLBCL," said Jay Feingold, MD, PhD, Senior Vice President, Chief Medical Officer and Head of Oncology Clinical Development at ADC Therapeutics. "We look forward to completing the pivotal Phase 2 clinical trial and submitting a Biologics License Application to the U.S. Food and Drug Administration for accelerated approval of ADCT-402 for the treatment of relapsed or refractory DLBCL patients who have failed two or more treatment regimens in the second half of 2020."

The oral presentation included data, as of October 4, 2019, on 52 patients from the pivotal Phase 2 clinical trial of ADCT-402 (loncastuximab tesirine) who were a median age of 63 years (range 24-84) and had received a median of three previous therapies. Key data include:

The overall response rate (ORR) was 46.2% (24/52 patients), comprising 19.2% complete responses and 26.9% partial responses. Comparably, the ORR in the Phase 1 trial of ADCT-402 (loncastuximab tesirine) at the initial dose used in Phase 2 was 41.4% (29/70 patients), comprising 21.4% complete responses and 20% partial responses. The primary endpoint in the pivotal Phase 2 clinical trial is ORR.
For complete responders, the median duration of response has not yet been reached. For complete and partial responders, the preliminary median duration of response is 5.7 months.
Stable disease was attained in 19.2% of patients.
ADCT-402 (loncastuximab tesirine) demonstrated manageable toxicity in patients with relapsed or refractory DLBCL. The most common grade ≥3 treatment-emergent adverse events in at least 5% of patients were: gamma-glutamyltransferase increased (25%), hypokalemia (5.8%), platelet count decreased (21.2%), neutrophil count decreased (32.7%) and anemia (11.5%).
The ongoing single-arm, multi-center, open-label Phase 2 clinical trial is evaluating the safety, efficacy and pharmacokinetics of ADCT-402 (loncastuximab tesirine) as a monotherapy in patients with relapsed or refractory DLBCL. Patients received 30-minute intravenous infusions of ADCT-402 (loncastuximab tesirine) once every three weeks at a dose of 150 μg/kg for the first two cycles, followed by 75 μg/kg for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurred first.

The presentation will be available on the Posters and Presentations page and a video of the investor event ADC Therapeutics hosted on Sunday, December 8 will be available on the Videos page of the Company’s website: View Source

About ADCT-402 (loncastuximab tesirine)
ADCT-402 (loncastuximab tesirine) is an antibody drug conjugate (ADC) composed of a humanized monoclonal antibody directed against human CD19 and conjugated through a linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Once bound to a CD19-expressing cell, ADCT-402 (loncastuximab tesirine) is designed to be internalized by the cell, following which the warhead is released. The warhead is designed to bind irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thus disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death. CD19 is a clinically validated target for the treatment of B-cell malignancies. ADCT-402 (loncastuximab tesirine) is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (NCT03589469), a Phase 1b trial in combination with ibrutinib in patients with R/R DLBCL or mantle cell lymphoma (MCL) (NCT03684694) and a Phase 1b trial in combination with durvalumab in patients with R/R DLBCL, MCL or follicular lymphoma (NCT03685344). The U.S. Food and Drug Administration granted orphan drug designation to ADCT-402 (loncastuximab tesirine) for the treatment of R/R DLBCL and MCL.

On December 9, 2019 Qilu Pharmaceutical reported that The National Medical Products Administration approved it’s Ankeda as a biosimilar to Avastin (bevacizumab) for the treatment of multiple types of cancer (Press release, Qilu Pharmaceutical, DEC 9, 2019, View Source [SID1234595070]). Ankeda is the first Avastin biosimilar approved in China for the treatment of cancer.

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The NMPA’s approval of Ankeda is based on review of evidence that includes extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Ankeda is biosimilar to Avastin.

Qilu made big investment on Ankeda development. It took less than 1.5 years for the NMPA to greenlight Qilu’s Ankeda. Qilu is committed to bringing more biosimilars to patients to help lower healthcare costs and increase access to important therapies.

On December 9, 2019 STORM Therapeutics, the biotechnology company focused on the discovery of small molecule therapies modulating RNA epigenetics reported, that its collaborator Dr. Konstantinos Tzelepis, Sir Henry Wellcome Fellow and Visiting Scientist at the Wellcome Sanger Institute, received the ASH (Free ASH Whitepaper)-BSH Abstract Achievement Award for his work on STORM Therapeutics’ lead programme, METTL3, at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) held on 7th-10th December 2019 in Orlando, Florida (Press release, STORM Therapeutics, DEC 9, 2019, View Source [SID1234561038]).

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Dr. Tzelepis received the meritorious award for his abstract entitled ‘Pharmacological Inhibition of the RNA m6a Writer METTL3 As a Novel Therapeutics Strategy for Acute Myeloid Leukemia’ at the Abstract Achievement Award Ceremony which was held on Saturday, 7th December 2019 at 3:30pm (EST) at the Orange County Convention Center in Exhibit Hall B2-B4.

Dr. Tzelepis’s work, which was carried out in collaboration with the Wellcome Sanger Institute and the University of Cambridge, was presented in an oral presentation during the "802. Chemical Biology and Experimental Therapeutics: Novel Compounds and Mechanisms of Action" session on Sunday, 8th December 2019 at 9:30am-11:30am (EST) at the Orange County Convention Centre. The abstract and talk encapsulated the ground-breaking work made on targeting RNA modifying enzymes for cancer treatment and described the recent progress made with the METTL3 inhibitor.

STORM has identified small molecule inhibitors of METTL3 that are orally bioavailable and show pronounced anti-tumour efficacy in physiologically relevant, proof of concept animal models of Acute Myeloid Leukaemia (AML). The talk demonstrated that small molecule inhibition of METTL3 produces the same phenotype and effects previously described in one of STORM’s founder scientists’ publications using genetic models and validates METTL3 as a druggable target for cancer.

Keith Blundy, CEO of STORM Therapeutics, said: "STORM is progressing fast in its preclinical work with our multiple programmes to showcase the capabilities of our novel platform. STORM is a pioneer in RNA epigenetics and we are very pleased to hear that our collaborator is being recognized for the partnership research of METTL3. As the first company in the world to demonstrate in vivo activity of an RNA methyltransferase inhibitor, we are excited to be leading the field as we look to develop these highly innovative new treatment options for cancer patients."

On December 9, 2019 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported updated results from a Phase 1/2 dose expansion study of flotetuzumab, an investigational, bispecific CD123 x CD3 DART molecule in patients with primary induction failure and early relapsed acute myeloid leukemia (AML) (Press release, MacroGenics, DEC 9, 2019, View Source [SID1234553172]). The data were presented in an oral session at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando, FL, taking place December 7-10, 2019.

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"Patients with AML who have failed primary induction therapy or relapsed early after an initial response represent a significant unmet medical need. A remission rate of 32% observed in the ongoing study of flotetuzumab in this extremely challenging patient population is noteworthy," said Geoffrey Uy, M.D., Associate Professor, Department of Medicine, Division of Oncology at the Washington University School of Medicine in St. Louis. "Importantly, by implementing a lead-in dosing schedule for flotetuzumab, as well as early intervention with tocilizumab in this study, we were able to mitigate cytokine release syndrome, known to be associated with T-cell engagers."

In the Phase 1/2 (NCT02152956) open-label, dose expansion study, 30 patients classified as primary induction failure or early relapsed AML who had received a median of four prior therapies were treated with flotetuzumab at the recommended phase 2 dose (RP2D) of 500 ng/kg/day by continuous infusion. Data were reported as of the cut-off date of November 1, 2019. The study is currently ongoing, with additional patients being enrolled.

Responses, including complete remission (CR), CRh (CR with partial hematological recovery) and CRi (CR with incomplete hematological improvement) per a modified International Working Group (IWG) Response Criteria for AML, are summarized in the table below. Four responders received allogeneic hematopoietic stem cell transplantation as consolidation therapy and remain in remission after 6 to 21 months.

The most common treatment-related adverse event (TRAE) was infusion-related reaction/cytokine release syndrome (IRR/CRS) that occurred in all (30/30) patients. However, most CRS events observed were of short duration and mild to moderate (grade 1 or 2) in severity, with only one grade 3 event reported in one patient.

"Based on the encouraging data from this study, and pending anticipated discussions with the FDA in the first half of 2020, we are planning for a potential registration-enabling study of flotetuzumab in this high unmet need population of patients with refractory AML, who have limited treatment options," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics.

A separate oral presentation described translational research that showed an inflammatory (IFN-γ-related) gene expression signature in a subset of patients with AML that correlated with a lack of response to induction chemotherapy. Furthermore, the same gene signature was associated with patients more likely to respond to flotetuzumab, supporting the mechanism being exploited by this molecule. In addition, AML patients with an immune-infiltrated tumor micro-environment show high expression of immune checkpoint molecules, including PD-L1, which provides a scientific rationale for combining flotetuzumab with checkpoint blockade as a potential mechanism for enhanced anti-leukemic activity. MacroGenics has initiated a study combining flotetuzumab with MGA012, an anti-PD-1 antibody, given the strong preclinical and translational data that indicate the combination may enhance CD123-directed T cell killing.

Flotetuzumab Presentations at ASH (Free ASH Whitepaper)

Oral Presentations

Abstract #733: Uy, et al. "Flotetuzumab, an Investigational CD123 x CD3 Bispecific DART Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients"
Abstract #460: Vadakekolathu, et al. "Immune Landscapes Predict Chemotherapy Resistance and Anti-Leukemic Activity of Flotetuzumab, an Investigational CD123 × CD3 Bispecific DART Molecule, in Patients with Relapsed/Refractory Acute Myeloid Leukemia"
Poster Presentations

Abstract #1410: Goodwin, et al. "Flotetuzumab (FLZ), an Investigational CD123 x CD3 Bispecific DART Protein-Induced Clustering of CD3+ T Cells and CD123+ AML Cells in Bone Marrow Biopsies Is Associated with Response to Treatment in Primary Refractory AML Patients"
Abstract #1387: Gopalakrishnapillai, et al. "Effect of Ara-C on T-Cell Function and Flotetuzumab Activity in Pediatric Acute Myeloid Leukemia"
Abstract #2662: Wei, et al: "A Phase 1 Study of Flotetuzumab, a CD123 x CD3 DART Protein, Combined with MGA012, an Anti-PD-1 Antibody, in Patients with Relapsed or Refractory Acute Myeloid Leukemia"
These slide and poster presentations are available on the Events & Presentations page on MacroGenics’ website at View Source

Conference Call & Webcast

MacroGenics management and external guest speakers will host a conference call and audio webcast today at 8:00 p.m. ET to review the flotetuzumab data presented at the ASH (Free ASH Whitepaper) Annual Meeting and discuss ongoing clinical development plans.

To participate in the MacroGenics ASH (Free ASH Whitepaper) 2019 Conference Call, please dial (877) 303-6253 (domestic) or (973) 409-9610 (international) five minutes prior to the start of the call and provide the Conference ID: 3625435. A listen-only slide and audio webcast of the conference call can be accessed under "Events & Presentations" in the Investor Relations section of the Company’s website at View Source A replay of the webcast will be available shortly after the conclusion of the call and archived on the Company’s website for 30 days.

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a hematopoietic stem cell malignancy characterized by differentiation arrest and uncontrolled clonal proliferation of neoplastic precursors that prevent normal bone marrow hematopoiesis. Nearly 20,000 new cases of AML are diagnosed in the U.S. each year, with a median age of 69 years at diagnosis. Approximately 40-50% of newly diagnosed patients fail to achieve a complete remission with intensive induction therapy (primary induction failure) or experience disease recurrence after a short remission duration (<6 months; early relapsed). A very small number of these patients are expected to respond to salvage therapy. In addition, although new targeted agents have been approved for the treatment of frontline or relapsed/refractory AML in recent years, approximately 50% of patients have no known targetable mutations.

About Flotetuzumab

Flotetuzumab (also known as MGD006) is a clinical-stage molecule that recognizes both CD123 and CD3. CD123, the interleukin-3 receptor alpha chain, has been reported to be over-expressed on cancer cells in AML and other hematologic malignancies. The primary mechanism of action of flotetuzumab is believed to be its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cancer cells.

Flotetuzumab is currently being evaluated in the U.S. and Europe in a Phase 1/2 dose expansion study designed to assess the safety, tolerability, and initial anti-leukemic activity of the molecule in patients with relapsed/refractory AML. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the treatment of AML. A Phase 1/2 study in combination with MGA012, a proprietary anti-PD-1 monoclonal antibody, in patients with relapsed/refractory AML is being conducted ex-U.S. MGA012 (also known as INCMGA00012) was exclusively licensed to Incyte Corporation in 2017 under a global collaboration and license agreement; MacroGenics retains the right to develop its pipeline molecules with MGA012. MacroGenics retains global development and commercialization rights to flotetuzumab.

On December 9, 2019 Seven and Eight BioPharmaceuticals Inc. reported that it has signed a clinical research collaboration agreement with Merck (known as MSD outside the US and Canada), through a subsidiary, to explore the combination of Seven and Eight’s BDB001, an immune modulator targeting toll-like receptors (TLR) 7 and 8, and Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab) in treating patients with advanced solid tumors (Press release, Seven and Eight Biopharmaceuticals, DEC 9, 2019, View Source [SID1234552201]).

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"Seven and Eight is developing a clinical pipeline that aims to address unmet medical needs. This clinical collaboration with Merck represents yet another step in our efforts to help cancer patients who fail to derive desirable clinical benefits from existing therapies."

"We are pleased to enter into a clinical collaboration with Merck," says Dr. Walter Lau, CEO of Seven and Eight. "There has been increasing evidence to show toll-like receptor agonists as a class of immune modulators to stimulate innate immune responses and enhance adaptive anti-tumor immunity. We hope through our joint efforts with Merck, we can explore how to use our lead compound BDB001 together with KEYTRUDA, especially in treating those patients with advanced and difficult-to-treat tumor types."

Dr. Lau adds, "Seven and Eight is developing a clinical pipeline that aims to address unmet medical needs. This clinical collaboration with Merck represents yet another step in our efforts to help cancer patients who fail to derive desirable clinical benefits from existing therapies."

Under the terms of the agreement, Seven and Eight will sponsor and be responsible for the conduct of the clinical study.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.