On December 3, 2018 Geron Corporation (Nasdaq: GERN) reported that updated results from Part 1 of IMerge, the Phase 2 portion of a Phase 2/3 clinical trial of imetelstat in lower risk myelodysplastic syndromes (MDS), were presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California on December 2, 2018 (Press release, Geron, DEC 3, 2018, View Source [SID1234531827]). The oral presentation was made by David Steensma, M.D., Institute Physician at the Dana-Farber Cancer Institute and Associate Professor at Harvard Medical School, and an IMerge clinical investigator. Geron believes these results support initiating the Phase 3 portion of IMerge to address an unmet medical need for patients for whom erythropoiesis stimulating agents (ESAs) are not effective and for whom currently available therapies show only modest efficacy.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The results from the Phase 2 portion of IMerge presented at ASH (Free ASH Whitepaper) highlight imetelstat’s broad clinical activity, especially in difficult-to-treat patients, as indicated by the high baseline transfusion burden of the patients enrolled in IMerge. As such, we believe imetelstat could offer a much-needed alternative treatment in lower risk MDS," said John A. Scarlett, M.D., Geron’s President and Chief Executive Officer. "We remain committed to developing imetelstat and continue to plan the initiation of the Phase 3 portion of IMerge by mid-year 2019."

IMerge Phase 2/3 Clinical Trial Design

IMerge is a two-part clinical trial evaluating imetelstat in transfusion dependent patients with Low or Intermediate-1 risk MDS who have relapsed after or are refractory to prior treatment with an ESA. The first part of the trial was originally designed as a Phase 2, open-label, single-arm trial to assess the efficacy and safety of imetelstat. The second part of the trial is planned as a Phase 3 double-blind, randomized, placebo-controlled trial in approximately 170 patients. To be considered for enrollment into IMerge, patients had to be transfusion dependent, requiring ≥4 units of red blood cells (RBC) over 8 weeks prior to entry into the trial. The primary efficacy endpoint of the trial is the rate of RBC transfusion-independence (RBC TI) lasting at least 8 weeks, defined as the proportion of patients without any RBC transfusion during any consecutive 8 weeks since entry into the trial. Key secondary endpoints are the rate of ≥24-week RBC TI and the rate of hematologic improvement-erythroid (HI-E), defined as a rise in hemoglobin of at least 1.5 g/dL above the pretreatment level for at least 8 weeks or a reduction of at least 4 units of RBC transfusions over 8 weeks compared with the prior RBC transfusion burden.

Among the first 32 patients enrolled in the Phase 2 portion of IMerge, an initial cohort of 13 patients, who were non-del(5q) and naïve to HMA and lenalidomide treatment, showed an increased RBC TI rate and durability compared to the overall trial population. Thus, earlier this year, an additional expansion cohort of 25 patients were enrolled who were non-del(5q) and naïve to HMA and lenalidomide treatment in order to increase the experience and confirm the benefit-risk profile of this target patient population.

Clinical Data Presentation

Title: Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide and HMA Naïve (Abstract #463)

The oral presentation described combined data with a data cut-off date of October 26, 2018 for the target patient population (n=38) in the Phase 2 portion of IMerge, which includes 13 patients from the initial cohort and 25 patients from the expansion cohort. The initial cohort had a median follow up time of 29 months, and the expansion cohort had a median follow up of almost nine months. As of the data cut-off date, median duration of RBC TI had not been reached for the target patient population. Geron expects further data from the Phase 2 portion of IMerge for the target patient population reflecting longer follow up to be available in 2019 and anticipates submitting such data for presentation at a future medical conference.

Efficacy Highlights for Target Patient Population (n=38):

37% (14/38) of patients achieved ≥8-week RBC TI
26% (10/38) of patients achieved ≥24-week RBC TI
Rate of transfusion reduction (HI-E) was 71% (27/38)
Mean relative reduction of RBC transfusion burden from baseline was 68%
Broad clinical activity observed
• Similar 8-week RBC TI was observed in patients with baseline serum erythropoietin (sEPO) levels less than or greater than 500mU/mL
• 8-week RBC TI consistent across ring-sideroblast (RS) patient subtypes, RS+ and RS-
Reductions in mutation burden and presence of RS noted among responding patients, suggesting potential disease modifying activity
Safety Summary for Target Patient Population (n=38):

Cytopenias, particularly neutropenia and thrombocytopenia, were the most frequently reported adverse events which were predictable, manageable and reversible
The slides from the oral presentation at ASH (Free ASH Whitepaper) are available on Geron’s website at www.geron.com/r-d/publications.

Phase 3 Development Plan for Lower Risk MDS

Based on the combined data from the initial and expansion cohorts for the target patient population in the Phase 2 portion of IMerge, Geron plans to initiate the Phase 3 portion of IMerge after the sponsorship of the ongoing imetelstat clinical trials has been transferred back to Geron. Geron anticipates patient screening and enrollment for the Phase 3 portion of IMerge to begin by mid-year of 2019.

Analyst and Investor Event

On December 10, 2018, Geron will host a webcasted event for analysts and investors. At the event, Dr. Azra Raza, a clinical investigator for IMerge, will reprise the oral presentation made at the ASH (Free ASH Whitepaper) Annual Meeting, as well as describe the unmet medical need in lower risk MDS. A live audio webcast of the event will be available on Geron’s website, www.geron.com/investors/events. If you are unable to listen to the live presentation, an archived webcast of the event will be available on the Company’s website for 30 days.

About Imetelstat

Imetelstat is a novel, first-in-class telomerase inhibitor exclusively owned by Geron and being developed in hematologic myeloid malignancies. Early clinical data suggest imetelstat may have disease-modifying activity through the suppression of malignant progenitor cell clone proliferation, which allows potential recovery of normal hematopoiesis. Ongoing clinical studies of imetelstat include a Phase 2/3 trial called IMerge in lower risk myelodysplastic syndromes (MDS) and a Phase 2 trial called IMbark in Intermediate-2 to High-risk myelofibrosis. Imetelstat received Fast Track designation from the United States Food and Drug Administration for the treatment of patients with transfusion-dependent anemia due to lower risk MDS who are non-del(5q) and refractory or resistant to an erythroid stimulating agent

On December 3, 2018 TRIGR Therapeutics, Inc. ("TRIGR"), and ABL Bio, Inc. ("ABL"), reported that they have entered into a collaboration and license agreement for TR009 (formerly known as ABL001 or NOV1501), an ABL developed bispecific antibody candidate targeting two important angiogenic factors, VEGF and DLL4 (Press release, TRIGR Therapeutics, DEC 3, 2018, View Source [SID1234531844]). The license agreement is exclusive and global, excluding the Republic of Korea for all oncology indications and excluding the Republic of Korea and Japan for all ophthalmology indications. This agreement is in addition to the recently announced agreement whereby TRIGR licensed pre-clinical immune engaging bispecific antibodies from ABL.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

TR009 is currently in a dose escalation Phase 1a study being conducted at the Samsung Medical Center in South Korea. The phase 1a study is sponsored by ABL and National OncoVenture (NOV), a South Korean government funded oncology drug development program. A phase 1b study looking to combine TR009 with chemotherapy and a checkpoint inhibitor is expected to commence in the latter part of 2019.

To date, 12 patients have been dosed with TR009 and no dose-limiting toxicities (DLTs) have been reported. Based on preliminary patient data, TR009 single agent clinical activity has been demonstrated across all dose levels among heavily pre-treated (5+ lines of prior therapy) cancer patients with solid tumors including gastric, colon, GIST, and ovarian cancers. At the mid-dose level cohort, more than half of the patients have experienced durable clinical benefit in terms of tumor stabilization (stable disease).

Under the terms of the agreement, TRIGR is responsible for global Phase 2 and subsequent clinical development and commercialization activities for TR009 for all oncology indications. ABL will receive an upfront payment of $5 million and is eligible to receive up to $405 million in regulatory and sales milestones and royalties on oncology sales of TR009 outside of the Republic of Korea. For ophthalmology indications, TRIGR is responsible for all development and commercialization within its territories. ABL is eligible to receive up to $185 million in milestone payments and royalties on TR009 ophthalmology sales outside of the Republic of Korea and Japan.

"We are delighted to expand our relationship with ABL," said George Uy, CEO of TRIGR. "Combining both companies’ core competencies and resources will optimize our chances of success in developing this novel cancer therapy. ABL has an outstanding track record of bispecific antibody research and development with extensive capabilities in antibody engineering and validation. We are excited by the promising clinical activity that TR009 has shown thus far, especially in heavily pre-treated patients with gastric and colon cancers, which is a key differentiator of this program. Based on our pre-clinical validation and additional biomarker work, our short-term strategy for TR009 is to pursue an accelerated approval pathway in Asia and we intend to approach both Chinese (NMPA) and Japanese regulators upon completion of our Phase 1a study in mid-2019. We also plan to simultaneously seek regulatory guidance from the FDA and EMEA for the registration of TR009 in solid tumor patients in the US and Europe."

"We are very pleased to enter into this agreement with our partners at TRIGR, a premier team that is highly experienced in taking anti-cancer drugs through clinical development and commercialization," said Sang Hoon Lee, CEO of ABL. "The dual VEGF/DLL4 bispecific antibodies currently in clinical development have all shown meaningful clinical activity even in patients who have failed or progressed on multiple lines of prior chemotherapy and VEGF-directed therapies such as Avastin and Cyramza. Across all trials, over 140 patients have been treated in monotherapy or in combination settings and we are seeing clinical benefit rates of between 50-85%. This is clearly exciting news for cancer patients worldwide."

Anti-angiogenic therapy is a cornerstone in cancer care, with sales of Avastin (an anti-VEGF antibody, Roche) and Cymraza (an anti-VEGF-R2 antibody, Eli Lilly) comprising approximately $7.5 billion in 2017. Although this class of drugs has proven survival benefits, resistance is creating the need for alternative regimens. Dual blockade of both VEFG and DLL4 is emerging as the next frontier of angiogenic therapy as the combination of these 2 mechanisms has been shown to overcome VEGF inhibitor resistance. There are 3 programs currently in clinical development targeting anti-VEGF/DLL4: AbbVie’s ABT-165 (Nasdaq: ABBV) which has recently entered Phase 2 in colorectal cancer, Oncomed’s OMP305B83 (Nasdaq: OMED) in Phase 1b in platinum-resistant ovarian cancer, and TRIGR’s TR009 in Phase 1a.

On December 3, 2018 Amgen (NASDAQ:AMGN) reported that it will present at the Citi Global Healthcare Conference at 12:35 p.m. ET on Thursday, Dec. 6, 2018, in New York City (Press release, Amgen, DEC 3, 2018, View Source;p=RssLanding&cat=news&id=2379134 [SID1234531860]). Elliott M. Levy, M.D., senior vice president of Global Development at Amgen, will present at the conference. Live audio of the presentation can be accessed from the Events Calendar on Amgen’s website, www.amgen.com, under Investors. A replay of the webcast will also be available on Amgen’s website for at least 90 days following the event

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

On December 3, 2018 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing monoclonal antibodies for the treatment of autoimmune disease, asthma and allergic diseases, and cancer, reported initial data from its ongoing Phase 1 dose-escalation study of XmAb14045, a CD123 x CD3 bispecific antibody, in patients with relapsed/refractory acute myeloid leukemia (AML) (Press release, Xencor, DEC 3, 2018, View Source [SID1234531893]). The data were presented in an oral session at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting by Farhad Ravandi, M.D., Professor of Medicine and Chief of the Section of Developmental Therapeutics in the Department of Leukemia at the University of Texas – MD Anderson Cancer Center.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Key Highlights

66 patients with relapsed/refractory AML received XmAb14045. Patients were a median of 61 years old and were heavily pretreated, having had a median of three prior therapies and 30% (n=20) with a history of allogeneic stem cell transplantation. 86% of patients (n=57) were refractory to their last therapy, and 53% (n=35) were categorized as adverse risk at diagnosis by the European LeukemiaNet (ELN 2017) system.
A maximum tolerated dose (MTD) has not been reached. Cytokine release syndrome (CRS) was the most common toxicity occurring in 55% of patients (n=36). 6% of patients (n=4) experienced Grade 3 or 4 CRS. CRS was more severe on the initial dose and was generally manageable with premedication. Additional adverse events consistent with CRS but not reported as such, including chills, fever, tachycardia, hypotension and hypertension within 24 hours of infusion, were reported in an additional 29% of patients (n=19).
28% of evaluable patients with AML achieved either complete remission (CR) or CR with incomplete hematologic recovery (CRi) at the two highest initial dose levels studied (1.3 and 2.3 mcg/kg weekly; n=5/18).
Two patients with responses were bridged to stem cell transplantation, and a third transplant-ineligible patient has remained in remission for 16+ weeks after discontinuation of therapy.
"We have observed multiple complete remissions in heavily pretreated, relapsed/refractory AML patients from XmAb14045 dosed weekly, and we continue to optimize dosing regimen," said Bassil Dahiyat, Ph.D., president and chief executive officer at Xencor. "Xencor’s XmAb technology enables bispecific antibodies to retain natural antibody properties, simplifying their use and production. Our platform enables the rapid development of new bispecific antibody drug candidates addressing a breadth of targets, and throughout 2019 we anticipate several new clinical trial initiations and additional data readouts."

The data presentation is available under Archived Scientific Presentations on the Events & Presentations page in the Investors section of www.xencor.com.

Analyst & Investor Event and Webcast Information
Xencor will host an analyst and investor event tonight from 8:00 to 10:00 p.m. PST with formal remarks at 8:30 p.m. PST. The formal remarks will feature a discussion of the data presented at ASH (Free ASH Whitepaper) and Xencor’s bispecific oncology pipeline. It will be webcast live and can be accessed under Events & Presentations in the Investors section of www.xencor.com, where it will be archived for 30 days.

About XmAb14045
XmAb14045 is a tumor-targeted antibody that contains both a CD123 binding domain and a cytotoxic T-cell binding domain (CD3) in a Phase 1 clinical trial for the treatment of acute myeloid leukemia (AML) and other CD123-expressing hematologic malignancies. An XmAb Bispecific Fc domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on XmAb14045. CD123 is highly expressed on AML cells and leukemic stem cells, and it is associated with poorer prognosis in AML patients. Engagement of CD3 by XmAb14045 activates T cells for highly potent and targeted killing of CD123-expressing tumor cells.

On December 3, 2018 GlycoMimetics, Inc. (NASDAQ:GLYC) reported that new data on uproleselan-treated high risk patients with both relapsed/refractory and newly diagnosed AML were presented at an oral session during the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, GlycoMimetics, DEC 3, 2018, View Source [SID1234531812]). An analysis of clinical outcomes from the Phase 1/2 clinical study showed that uproleselan (GMI-1271) resulted in the majority of evaluable patients achieving a stringent level of measurable residual disease (MRD) negativity, an effect which translated into extended overall survival relative to matched, historical controls.1-4

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Additionally, an analysis of E-selectin ligand expression on leukemic cells demonstrated that detectable levels are present in every patient tested, providing strong clinical evidence of biological relevance in this disease setting. In bone marrow blasts, leukemic stem cell expression of E-selectin ligand correlated with leukemic blast E-selectin ligand expression (p<0.0001), consistent with the hypothesis that E-selectin-mediated interactions are a mechanism of chemoresistance. Additionally, investigators assessed the association between baseline E-selectin ligand expression and clinical outcomes using a log-rank test. In the R/R cohort of patients (n=22), this analysis demonstrated that ≥10% E-selectin ligand expression at baseline is correlated with prolonged survival (p<0.01) for patients treated with uproleselan. This observation is important since separately Chien et al. (Abstract 1513) report that high levels of E-selectin ligand in patients not treated with uproleselan correlate with worse clinical prognosis.

"The new MRD and correlative efficacy data in difficult-to-treat patients, when combined with the already encouraging response rate and survival results from this trial, further demonstrate the potential of uproleselan to be an important new treatment option in AML," said Daniel J. DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and the trial’s lead investigator. "The fact that more than half of the evaluable patients achieved a stringent level of MRD negativity is particularly noteworthy as uproleselan’s mechanism of action is to selectively disrupt the relationship between leukemic cells and the bone marrow microenvironment."

"It is now clearly established that patients with AML who express E-selectin ligands on their leukemic cells have more infiltrative, aggressive disease and significantly worse clinical outcomes when not treated with uproleselan," said Helen Thackray, M.D., FAAP, GlycoMimetics Senior Vice President, Clinical Development and Chief Medical Officer. "While we would expect patients with R/R AML and >10% E-selectin ligand expression on their leukemic blasts to do very poorly, it is extremely exciting to see that the addition of uproleselan is resulting in statistically significant improvements in clinical outcomes in these high-risk patients. This is completely counterintuitive to what you would expect and provides robust scientific evidence suggesting that uproleselan is exerting biologic activity."

The ASH (Free ASH Whitepaper) presentations referenced above include:

Publication Number: 331
TITLE: Uproleselan (GMI-1271), an E-Selectin Antagonist, Improves the Efficacy and Safety of Chemotherapy in Relapsed/Refractory (R/R) and Newly Diagnosed Older Patients with Acute Myeloid Leukemia: Final, Correlative and Subgroup Analyses

Publication Number: 1513
TITLE: E-Selectin Ligand Expression by Leukemic Blasts Is Associated with Prognosis in Patients with AML

References
1 Feldman et al, J Clin Oncol. 2005 Jun 20;23(18):4110-6.
2 Greenberg et al, J Clin Oncol. 2004 Mar 15;22(6):1078-86.
3 Lowenberg et al, N Engl J Med. 2009 Sep 24;361(13).
4 Lancet et al, Blood. 2014 May 22;123(21):3239-46.

About Uproleselan (GMI-1271)

Uproleselan (yoo’ pro le’sel an) is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with blood cancer cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. In a Phase 1/2 clinical trial, uproleselan was evaluated in both newly diagnosed elderly and relapsed/refractory patients with AML. In both populations, patients treated with uproleselan together with standard chemotherapy achieved better than expected remission rates and overall survival compared to historical controls, which have been derived from results from third party clinical trials evaluating standard chemotherapy, as well as lower than expected induction-related mortality rates. Treatment in these patient populations was generally well tolerated, with fewer than expected adverse effects. The U.S. Food and Drug Administration (FDA) has granted uproleselan Breakthrough Therapy Designation for the treatment of adult AML patients with relapsed/refractory (R/R) disease. GlycoMimetics is currently implementing a comprehensive development program across the clinical spectrum of AML. This includes a company sponsored Phase 3 trial in R/R AML and two consortia-sponsored trials in newly diagnosed patients. One consortium trial is being sponsored by the NCI and will enroll newly diagnosed patients fit for intensive chemotherapy. The other trial is sponsored by the HOVON group in Europe and will enroll newly diagnosed patients unfit for intensive chemotherapy.