On June 17, 2019 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell therapies, reported that updated clinical data for the CYAD-01 program in r/r AML and MDS was presented in a poster presentation session on Saturday, June 15 at the 24th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Amsterdam, Netherlands (Press release, Celyad, JUN 17, 2019, View Source [SID1234537116]).

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Dr. Frédéric Lehmann, VP of Clinical Development & Medical Affairs at Celyad, commented,"Our observations from the Phase 1 THINK clinical trial evaluating CYAD-01 without prior lymphodepletion in relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome patients show the cell therapy is generally well tolerated. Encouragingly, this safety and tolerability profile was also demonstrated during the early stages of CYAD-01 treatment intensification where an increased systemic persistence of CAR-T cells is obtained after reduced interval dosing or in combination with preconditioning chemotherapy. As such, we continue to focus our efforts on increasing the aggressiveness of CYAD-01 to potentially deepen the breadth, frequency and duration of clinical responses in this refractory patient population."

THINK Phase 1 Trial in Hematological Malignancies Update

As of May 23 2019, preliminary anti-leukemic activity has been observed in six out of thirteen patients (46%) evaluable per protocol in the THINK Phase 1 trial with four out of thirteen patients (31%) exhibiting objective responses, including one out of the four patients experiencing a duration of response of over 90 days
Overall, multiple infusions of CYAD-01 without any prior preconditioning chemotherapy continues to show an encouraging tolerability profile with eight patients from over twenty treated experiencing grade 3/4 treatment-related adverse events (AEs). No neurotoxicity AEs have been observed in any patient receiving CYAD-01.
The denser schedule of infusions in the absence of any bridging or preconditioning chemotherapy without preconditioning chemotherapy evaluated in Cohort 10 showed that of three r/r AML or MDS patients evaluable, one patient experienced disease stabilization and two patients had disease progression following treatment with up to six doses of 1 billion cells of CYAD-01.
The denser dosing schedule was generally reported to be well-tolerated. Three patients of four patients evaluable for safety in Cohort 10 experienced grade 1/2 cytokine release syndrome (CRS), which showed rapid resolution following the appropriate treatment, including tocilizumab. One patient experienced a grade 4 infusion reaction, which was not considered to be a dose-limiting toxicity of the therapy
Overall, better time-averaged engraftment (area under the curve) was observed with a reduced interval dosing (Cohort 10) as compared to the equivalent dose of the THINK trial evaluating a cycle of three injections of CYAD-01 administered every two weeks.
Recruitment in Cohort 11 of the THINK trial evaluating the denser schedule of up to six infusions of three billion cells of CYAD-01 without preconditioning chemotherapy is ongoing and results are expected by the end of 2019.

DEPLETHINK Phase 1 Trial Update

The initial cohorts of the DEPLETHINK trial enrolled six r/r AML or MDS patients who received a single administration of a safety-precaution low-dose CYAD-01 (100 million cells per infusion) following preconditioning chemotherapy consisting of cyclophosphamide and fludarabine, or CyFlu, at two different time-intervals (three or seven days) between the preconditioning regimen and administration of CYAD-01.
As of May 23, 2019, three patients experienced grade 1/2 CRS, which showed rapid resolution following the appropriate treatment, including tocilizumab. One patient experienced a grade 4 infusion reaction, which was not considered to be a dose-limiting toxicity of the therapy, during the consolidation cycle without preconditioning.
Of the five patients evaluable per protocol, two patients experienced disease stabilization following treatment with CYAD-01.
Better time-averaged engraftment was observed after a single infusion of low-dose CYAD-01 with prior preconditioning compared to the dose-escalation segment of the THINK trial evaluating a cycle of three injections of CYAD-01.
Evaluation of higher dose-levels comparable to the Phase 1 THINK trial, including 300 million and 1 billion cells, are ongoing in the dose-escalation trial and preliminary results from these cohorts are expected by year-end 2019.
Background on THINK Phase 1 Trial

The THINK trial (NCT03018405) is an open-label, dose-escalation Phase 1 trial assessing the safety and clinical activity of multiple CYAD-01 administrations without prior preconditioning. The dose escalation segment of the trial evaluated three dose levels (300 million, 1 billion and 3 billion cells per infusion) of one cycle of three CYAD-01 administrations with two-week intervals.

In 2018, the THINK trial was amended to add two cohorts to assess a more frequent dosing schedule of CYAD-01 for the treatment of r/r AML. The cohorts will evaluate six injections of CYAD-01 without preconditioning over two months of administration. The first cycle includes three infusions of CYAD-01 separated by one-week intervals. The second cycle includes three infusions of CYAD-01 separated by two-week intervals. Patients will either receive 1 billion cells per infusion (Cohort 10) or 3 billion cells per infusion (Cohort 11). The primary endpoint of the trial is safety and secondary endpoints include clinical activity and pharmacokinetics.

Background on DEPLETHINK Phase 1 Trial

In October 2018, Celyad initiated the DEPLETHINK Phase 1 trial (NCT03466320). The open-label, dose-escalation trial will evaluate a single infusion of CYAD-01 following treatment with the standard preconditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), or CyFlu. The trial includes two different intervals between lymphodepletion and administration of CYAD-01. In addition, the trial will evaluate three dose levels of CYAD-01 including 100 million, 300 million and 1 billion cells per infusion, respectively. The primary endpoint of the trial is safety and secondary endpoints include clinical activity and pharmacokinetics.

On June 17, 2019 OncoSec Medical Incorporated (OncoSec) (NASDAQ: ONCS), a company developing intratumoral cancer immunotherapies, reported that it has initiated a research collaboration with Roswell Park Comprehensive Cancer Center to evaluate the use of Roswell Park’s intravital microscopy (IVM) and OncoSec’s proprietary plasmid, TAVOPLUS, in combination with the Company’s recently announced APOLLO electroporation generator in preclinical studies (Press release, OncoSec Medical, JUN 17, 2019, View Source [SID1234537115]). The collaboration will be led by Joseph Skitzki, MD, FACS, Associate Professor of Immunology, Associate Professor of Surgery and Chair of the Melanoma/Sarcoma Disease Site Research Group at Roswell Park.

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Intravital microscopy is a powerful tool that has provided unprecedented real time access to visualize and record molecular, cellular, anatomical function, providing insights into the immune activity within the tumor microenvironment. Data uncovered with the technique used in this collaboration will reveal a deeper understanding and possible new approaches to treatment with TAVOPLUS and APOLLO.

Dr. Skitzki’s laboratory plans to focus on IVM studies which provide an in vivo window to visualize and record movements of immune subsets in the periphery or, critically, in established tumors. This collaboration will investigate essential elements of lymphocyte trafficking driven by OncoSec’s enhanced therapeutic platform, including the new low-voltage APOLLO generator and TAVOPLUS plasmids. In addition to investigating the effects of chemokine gradients on rolling/adhesion of specific immune subsets, the laboratory will conduct time-course experiments to determine the associated kinetics of this therapy. The Skitzki laboratory will also perform translational studies to address whether neo-vascularization or changes to vascularization can be used to predict response.

"This research collaboration offers a significant opportunity to leverage cutting edge experimental techniques to gain a deeper mechanistic understanding of how OncoSec’s newest therapy drives lymphocyte trafficking into the tumor. We are particularly pleased to be working with Dr. Skitzki and with Roswell Park, a renowned research organization, and look forward to the critical data and related intellectual property that will emerge from this work," said Christopher G. Twitty, PhD, Chief Scientific Officer of OncoSec.

Dr. Skitzki specializes in the areas of melanoma and sarcoma, with a focus on intratumoral and regional therapies. His independent lab focuses on immunotherapies for melanoma and preclinical modeling of TAVOPLUS and APOLLO with the goal of clinical translation. Dr. Skitzki has authored or co-authored more than 50 journal publications, book chapters and abstracts.

"Based upon a significant body of clinical data, our lead oncology product candidate, TAVO, has distinguished itself by clearly showing an ability to induce T cell activation both within local (treated) and distant (untreated) tumor microenvironments, leading to the positive response data observed across several solid tumor types. The Roswell Park collaboration will enable OncoSec to further characterize the TAVOPLUS immune response and its impact on local and distant tumors, thereby imparting a fuller understanding of its clinical utility in the treatment of cancer," said Daniel J. O’Connor, President and Chief Executive Officer of OncoSec.

On June 17, 2019 Geron Corporation (Nasdaq: GERN) reported that an oral and a poster presentation of clinical data and analyses related to imetelstat, the Company’s first-in-class telomerase inhibitor, were made at the 24th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) held in Amsterdam, the Netherlands on June 15, 2019 (Press release, Geron, JUN 17, 2019, View Source [SID1234537114]).

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Updated Efficacy and Safety Data from the Phase 2 Portion of IMerge

"The EHA (Free EHA Whitepaper) presentation for the Phase 2 portion of IMerge reported higher efficacy responses from prior reported data for both 8-week and 24-week RBC-TI rates, which highlight the meaningful and durable transfusion independence achievable with imetelstat treatment in heavily transfusion dependent lower risk MDS patients," said Aleksandra Rizo, M.D., Ph.D., Geron’s Chief Medical Officer. "These data provide further support for the initiation of the Phase 3 portion of the trial and Phase 3 start-up activities for IMerge are continuing with the goal of opening for screening and enrollment in August 2019."

Title: Treatment with Imetelstat Provides Durable Transfusion Independence (TI) in Heavily Transfused Non-del(5q) Lower Risk MDS (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs) (Abstract #S837)

This oral presentation described updated efficacy and safety data as of April 2019 from 38 imetelstat-treated patients in the Phase 2 portion of the IMerge clinical trial with a median follow-up of 15.7 months. All 38 patients represent a target patient population of transfusion dependent, non-del(5q) lower risk myelodysplastic syndromes (MDS) patients who are relapsed or refractory to ESAs and naïve to hypomethylating agent (HMA) and lenalidomide treatment.

The primary efficacy endpoint is the rate of red blood cell transfusion independence (RBC-TI) lasting at least eight weeks, or 8-week RBC-TI rate, which is defined as the proportion of patients achieving RBC-TI during any consecutive eight weeks since entry into the trial. Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks, or 24-week RBC-TI rate, and the rate of hematologic improvement-erythroid (HI-E), defined as a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden or a rise in hemoglobin of at least 1.5 g/dL above pretreatment level for at least eight weeks.

Efficacy Summary (n=38):

42% (16/38) of patients achieved ≥8-week RBC-TI
29% (11/38) of patients achieved ≥24-week RBC-TI
Median duration of TI was 85.9 weeks (range: 8.0-140.9)
68% (26/38) of patients achieved HI-E, or improvement in red blood cell count, as measured by either transfusion reduction or a rise in hemoglobin:
° All 26 patients had a reduction of at least four RBC units over eight weeks compared with prior transfusion burden
° 12 of 26 patients had a hemoglobin increase of at least 1.5 g/dL lasting at least eight weeks
Mean relative reduction in transfusion burden from baseline was 68%
Additional data were presented showing that transfusion independence was observed across different clinical subgroups, as well as in patients with intermediate or poor cytogenetic risk.

Safety Summary:

No new safety signals were identified. Reversible cytopenias were the most frequent adverse events.
The slide presentation is available on Geron’s website at www.geron.com/r-d/publications.

Statistical Analyses of Median Overall Survival in IMbark Compared to Real World Data

"The EHA (Free EHA Whitepaper) poster presentation reported the results of statistical analyses in which the months of median overall survival for imetelstat-treated relapsed/refractory MF patients in IMbark was calculated to be more than double that for closely matched patients treated with best available therapy using real-world data," said John A. Scarlett, M.D., Geron’s Chairman and Chief Executive Officer. "The outcomes of these analyses were consistent across two different approaches for propensity score analysis and additional sensitivity analyses, underscoring the robustness of the statistical methodologies applied."

Abstract Title: Favorable Overall Survival of Imetelstat-Treated Relapsed/Refractory Myelofibrosis Patients Compared with Closely Matched Real World Data (Abstract #PS1456)

This poster presentation provided a new analysis of overall survival (OS) in relapsed/refractory MF patients treated with imetelstat 9.4 mg/kg in the IMbark Phase 2 clinical trial, compared to OS calculated from real world data (RWD) collected at the Moffitt Cancer Center for patients who had discontinued treatment from ruxolitinib, a JAK inhibitor, and who were subsequently treated with best available therapy (BAT). To make a comparison between the IMbark data and RWD, a cohort from the real-world dataset was identified that closely matched the IMbark patients, using guidelines for inclusion and exclusion criteria as defined in the IMbark clinical protocol, such as platelet count and spleen size.

To mimic the effect of randomization and improve comparability between the IMerge and RWD populations, two different propensity score approaches were used to balance these two populations with respect to baseline covariates and prognostic factors that could have impacted OS outcomes. The calculations from both propensity score approaches resulted in a median OS of 30.7 months for the imetelstat-treated patients from IMbark, which is more than double the median OS of 12.0 months using RWD for patients treated with BAT. The analysis also indicated a 65-67% lower risk of death for the imetelstat-treated patients vs. BAT-treated patients. A sensitivity analysis assessing the impact on OS of subsequent hematopoietic stem cell transplantation showed no substantial differences in median OS calculated for either the imetelstat-treated or BAT-treated patients. The poster presentation concluded that although there are limitations of such comparative analyses between RWD and clinical trial data, favorable OS of imetelstat treatment in this very poor-prognosis patient population warrants further evaluation.

The poster is available at www.geron.com/r-d/publications.

Post-EHA Event with Key Opinion Leaders

On June 25, 2019, Geron will be hosting a webcasted event with authors from each respective data presentation from the EHA (Free EHA Whitepaper) Annual Congress who will reprise the presentations from EHA (Free EHA Whitepaper). Information regarding access to the webcast is available at www.geron.com/investors/events.

Current Ongoing Clinical Trials of Imetelstat

Patients currently enrolled in ongoing imetelstat clinical trials continue to be supported through the respective trial protocols, including treatment and follow-up.

Phase 2 Portion of IMerge

IMerge is a two-part Phase 2/3 clinical trial of imetelstat in lower risk MDS. The first part of IMerge was designed as a Phase 2, open label, single arm study to assess the efficacy and safety of imetelstat. The primary efficacy endpoint is 8-week RBC-TI rate, which is defined as the proportion of patients achieving red blood cell transfusion independence during any consecutive eight weeks since entry into the trial.

Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks, or 24-week RBC-TI rate, and the rate of hematologic improvement-erythroid (HI-E), defined as a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden or a rise in hemoglobin of at least 1.5 g/dL above pretreatment level for at least eight weeks. To be eligible for the Phase 2 or Phase 3 portion of IMerge, patients are required to be transfusion dependent, defined as requiring at least four units of packed RBCs over an eight-week period during the 16 weeks before entry into the trial. The Phase 2 portion of IMerge is closed to new patient enrollment.

IMbark

IMbark was designed as a Phase 2 clinical trial to evaluate two starting dose levels of imetelstat (either 4.7 mg/kg or 9.4 mg/kg administered by intravenous infusion every three weeks) in patients with Intermediate-2 or High-risk MF who have relapsed after or are refractory to prior treatment with a janus kinase (JAK) inhibitor. The co-primary efficacy endpoints for the trial are spleen response rate and symptom response rate. Key secondary endpoints are safety and overall survival (OS). IMbark is closed to new patient enrollment.

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 consists of a Phase 2/3 trial, called IMerge, in lower risk myelodysplastic syndromes (MDS) and a Phase 2 trial, called IMbark, in Intermediate-2 or 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 June 17, 2019 Compass Therapeutics, a clinical-stage biotechnology company targeting the human immune synapse with a new generation of monoclonal and multispecific antibody therapeutics, reported that the U.S. Patent and Trademark Office issued three U.S. patents covering certain anti-CD137 antibodies, including its lead therapeutic candidate, CTX-471 (Press release, Compass Therapeutics, JUN 17, 2019, View Source [SID1234537113]).

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CTX-471 is a fully human antibody that binds and activates a unique epitope of the co-stimulatory receptor CD137 (4-1BB) expressed on T- and NK-cells. In preclinical studies, CTX-471 demonstrates potent monotherapy activity in multiple syngeneic tumor models, including curative efficacy against very large, established tumors where other validated IO antibodies, such as antibodies targeting PD-1, PD-L1, CTLA-4 and OX40 have no or minimal effect. CTX-471 efficacy is associated with a comprehensive reprogramming of the tumor microenvironment, increasing CD8+ T-cell infiltration and penetration while reducing T-cell exhaustion. Unlike other clinical and preclinical CD137 antibodies, CTX-471 shows no evidence of hepatic toxicity in both mice and non-human primates, supporting the potential for a wide therapeutic window in patients.

The CTX-471 Phase 1 study is now open. For more information: View Source

"We’re truly excited about the promise CTX-471 holds for patients with cancer and we’re delighted to secure these patents, which affirm the novelty of our approach," said Thomas Schuetz, MD, PhD, the scientific founder and chief executive officer of Compass. "The intellectual property portfolio we have generated at Compass provides an excellent foundation for us to build on as we continue to advance our pipeline of innovative therapeutic candidates in oncology and autoimmunity."

The newly issued patents are: U.S. Patent No. 10,279,038, which covers the composition of CTX-471; and U.S. Patent Nos. 10,279,039 and 10,279,040, which cover the use of CTX-471 in methods for treating cancer and inducing or enhancing an anti-tumor immune response, respectively. The base term for each patent extends until July of 2038. Additional patent filings by Compass related to CTX-471 are under review.

On June 17, 2019 Molecular Templates, Inc., (Nasdaq: MTEM, "Molecular," "Molecular Templates" or "MTEM") a clinical stage biopharmaceutical company focused on the discovery and development of Engineered Toxin Bodies (ETBs), a new class of targeted biologic therapies that possess unique mechanisms of action in oncology, reported that the U.S. Food and Drug Administration (FDA) has accepted the Investigational New Drug (IND) application for TAK-169, an ETB targeting CD38 (Press release, Molecular Templates, JUN 17, 2019, View Source [SID1234537112]).

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MTEM and partner Takeda Pharmaceutical Company Limited (Takeda) are co-developing TAK-169 and plan to conduct an open label Phase I dose escalation and expansion study in relapsed/refractory multiple myeloma patients.

"We are excited to continue our collaboration with Takeda advancing the development of TAK-169 for the treatment of multiple myeloma patients," said Eric Poma, Ph.D., CEO and CSO of Molecular Templates. "It represents a novel CD38 targeted therapy which could provide benefit in patients with multiple myeloma and overcome mechanisms of resistance to existing CD38 targeted therapies."

About TAK-169
TAK-169 is an ETB consisting of a single chain variable fragment (scFv) with affinity for CD38, fused to the enzymatically active de-immunized Shiga-like toxin-A subunit (SLTA). TAK-169 specifically binds and kills CD38 expressing cells in a manner consistent with SLTA mediated cellular cytotoxicity. TAK-169 has been specifically designed to avoid competition with and to overcome the primary mechanisms of tumor resistance to daratumumab and other monoclonal antibodies targeting CD38. TAK-169 has been shown to be active in the presence of daratumumab. As such, TAK-169 may have the potential to be combined with approved CD38 targeted therapies. TAK-169 mediated ribosomal inhibition and cell death take place intracellularly so changes in the tumor microenvironment, such as CD55/59 upregulation, which inhibit immune-mediated mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) are not expected to inhibit TAK-169 activity.

About the CD38 Co-Development Partnership with Takeda
On September 19, 2018, MTEM announced an agreement with Takeda for the joint development of CD38-targeted ETBs for the treatment of multiple myeloma. TAK-169, the lead development candidate, is a CD38-targeted ETB that resulted from a previous discovery collaboration between the two companies. Under the terms of the agreement, Takeda has made an upfront payment of $30 million and Molecular Templates is eligible to receive development, regulatory and commercial milestone payments of up to $632.5 million if Molecular Templates exercises its co-development option or $337.5 million if Molecular Templates does not exercise or opts out of its co-development option. Takeda has also agreed to pay royalties on sales of the commercial product developed through the collaboration. Molecular Templates and Takeda will share equally in the development costs. MTEM has been awarded a $15.2 million grant from the Cancer Prevention and Research Institute of Texas (CPRIT) to fund development and manufacturing of CD38-targeted ETBs including TAK-169.