On January 13, 2020 Geron Corporation (Nasdaq: GERN), a late-stage clinical development biopharmaceutical company, reported 2019 accomplishments and key development priorities for 2020 (Press release, Geron, JAN 13, 2020, View Source [SID1234553099]). The Company is currently enrolling patients in the Phase 3 IMerge clinical trial of imetelstat in lower risk myelodysplastic syndromes (MDS), and plans to complete enrollment by the end of 2020 with top-line results expected by mid-year 2022.

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"From regaining control of the imetelstat program and building an impressive in-house development team to initiating the Company’s first Phase 3 clinical trial, 2019 was a pivotal year for Geron," said John A. Scarlett, M.D., Chairman and Chief Executive Officer. "We plan to build on the progress achieved in 2019 as we set our 2020 priorities and finalize our development plans."

2019 – A Year of Accomplishments

Advancing the Imetelstat Development Program

In May 2019, Geron assumed the imetelstat investigational new drug (IND) sponsorship from Janssen Biotech, Inc. (Janssen), and executed on its 2019 imetelstat development plans, including advancing into late-stage clinical development with the initiation of the Phase 3 IMerge clinical trial in lower risk MDS.

Geron completed the transition of the imetelstat program, including the transfer of the remaining non-clinical, manufacturing and ex-U.S. clinical and regulatory responsibilities from Janssen at the end of September 2019.

Throughout the year, Geron continued to build a solid foundation of extensive hematology-oncology and drug development expertise in key functional areas by attracting senior leadership with extensive experience, including many new development team members and executives with prior experience with imetelstat. This highly capable in-house team will support current and future imetelstat development plans, including plans to explore additional indications, as well as provide the ability to evaluate other hematology-oncology assets to expand the Company’s pipeline in the future.

Commencing the Phase 3 in Lower Risk MDS

In June 2019, Geron presented updated efficacy and safety data for the Phase 2 IMerge clinical trial. The presentation highlighted meaningful and durable transfusion independence, activity across different MDS subtypes and potential disease-modifying activity in lower risk MDS with imetelstat treatment.

Geron achieved a significant milestone in August 2019 with the opening of the Phase 3 IMerge clinical trial for patient screening and enrollment, and the first patient was dosed in October. Many key aspects from the Phase 2 portion of IMerge remained the same for the Phase 3 portion, including the primary and secondary endpoints, the dose and schedule of imetelstat administration, and the target patient population. This trial is an important step in developing imetelstat as a potential alternative for lower risk MDS patients who have limited treatment options.

Regulatory Interactions Related to Myelofibrosis (MF)

The United States Food and Drug Administration (FDA) granted Fast Track designation to imetelstat for the treatment of adult patients with Intermediate-2 or High-risk MF whose disease has relapsed after or is refractory to janus kinase (JAK) inhibitor treatment, or relapsed/refractory MF, in September 2019. The FDA’s Fast Track Program is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious conditions and supported by data that demonstrate the potential to address an unmet medical need.

Geron announced that it conducted an End of Phase 2 meeting with the FDA to discuss the results of the IMbark Phase 2 clinical trial of imetelstat in patients with relapsed/refractory MF in December 2019.

Development Priorities for 2020

Geron is setting development priorities that are expected to shape the Company’s 2020 milestones, which will be discussed at a conference call to be held in March 2020 in connection with the announcement of the Company’s year-end 2019 financial results.

Building Momentum in Phase 3 IMerge Clinical Trial in Lower Risk MDS

The Company expects to complete enrollment for the Phase 3 IMerge clinical trial in 2020, which is a key step toward achieving top-line results from the trial by mid-year 2022. As of the beginning of 2020, approximately 40% of the planned clinical sites are open for enrollment.

Determining Potential Late-Stage Development in MF

Based on feedback from the End of Phase 2 meeting, Geron plans to submit several Phase 3 trial design proposals in MF, and to have further discussions with the FDA regarding a potential regulatory approval path. Subsequent to these additional discussions, and after considering the timing and resources required, as well as other clinical development opportunities for imetelstat, Geron plans to make a decision regarding potential late-stage development of imetelstat in MF.

Broadening Imetelstat Program with Additional Hematologic Myeloid Malignancy Indication

Geron expects to expand development of imetelstat within hematologic myeloid malignancies by initiating a proof-of-concept study in an additional indication in 2020.

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 consist of IMerge, a Phase 2/3 trial in lower risk myelodysplastic syndromes (MDS), and IMbark, a Phase 2 trial in Intermediate-2 or High-risk myelofibrosis (MF). Imetelstat has been granted Fast Track designation by the United States Food and Drug Administration for both the treatment of patients with non-del(5q) lower risk MDS who are refractory or resistant to an erythropoiesis-stimulating agent and for patients with Intermediate-2 or High-risk MF whose disease has relapsed after or is refractory to janus kinase (JAK) inhibitor treatment.

On January 13, 2020 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC) (TSX: ONC.TO), currently developing pelareorep, an intravenously delivered immuno-oncolytic virus, reported a recap of a Key Opinion Leader call sponsored by ROTH Capital Partners which was held on Thursday, January 9, 2020 (Press release, Oncolytics Biotech, JAN 13, 2020, View Source [SID1234553098]). The KOL call focused on recent data presented at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition and highlighted that carfilzomib promotes reovirus infection, that pelareorep upregulates PD-L1, and that delivery of additional data from ongoing pelareorep studies in multiple myeloma is planned for presentation at ASCO (Free ASCO Whitepaper) in June 2020.

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The KOL call was hosted and conducted by the equity research department at ROTH Capital and featured two of Oncolytics’ multiple myeloma clinical investigators:

Dr. Craig Hofmeister M.D., Winship Cancer Institute/Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA.
Dr. Flavia Pichiorri Ph.D., Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA and Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA.
"I think that carfilzomib promotes pelareorep infection by suppressing the innate antiviral response and our data suggest that it does not get in the way of T-cell activation," said Dr. Hofmeister. "Pelareorep infection, not proteasome inhibition, can upregulate PD-L1 expression on myeloma cells and the adaptive immune system can then assist in clearing infected tumor cells. The combination in fact enhances the body’s immune attack on infected myeloma cells."

Dr. Hofmeister confirmed that adding PD-1 inhibition is appropriate in these patients, as viral infection with replication has been associated with an increase in PD-L1 tumor expression preclinically. "We are seeing some signs of cytokine release with associated clinical responses and we look forward to describing the clinical results in more detail at ASCO (Free ASCO Whitepaper) 2020," Dr. Hofmeister added.

The call also discussed the competitive landscape for refractory multiple myeloma and the paucity of available therapies to treat these patients.

"Reovirus is the only strategy I see in the market that is completely different and may be able to activate the immune system of these patients," said Dr. Pichiorri. "It would be a salvage therapy for now, but so many patients need a salvage therapy after being refractory to other therapies."

Oncolytics would like to thank Doctors Pichiorri and Hofmeister for their time and insightful commentary, as well as ROTH Capital for hosting the call.

About Pelareorep

Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers and has been demonstrated to be able to escape neutralizing antibodies found in patients.

On January 13, 2020 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium"), reported that it has entered into an agreement with the University of California, Davis (UC Davis) to utilize Actinium’s Antibody Radiation-Conjugate or ARC apamistamab-I-131 for targeted conditioning and replace the chemotherapy conditioning being used in an ongoing Phase 1/2 stem cell gene therapy clinical trial (Press release, Actinium Pharmaceuticals, JAN 13, 2020, View Source [SID1234553097]). In the trial, patients with relapsed or refractory HIV-related lymphoma are being treated with autologous stem cell gene therapy. This is the first gene therapy clinical trial that will utilize ARC based conditioning. The clinical trial will be conducted at UC Davis and may be expanded to additional sites in the future.

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Dr. Mehrdad Abedi, Professor, Hematology and Oncology at UC Davis and study lead, said, "This collaboration represents an exciting combination of revolutionary technologies that could further our ability to treat patients with HIV and other life-threatening diseases with gene therapy. Despite the advances made in the field of gene therapy, the reliance on non-targeted chemotherapy and external radiation as conditioning regimens is less than optimal and poses a problem that we hope to reduce or eliminate as part of this collaboration by replacing our conditioning regimen in this study with Actinium’s ARC based targeted conditioning. Advances in HIV therapies have dramatically improved patient survival, but current therapies require life-long daily use to keep the HIV virus at bay, can have severe side effects, may be overcome by HIV resistance and do not address the needs of all patients like those in this study with HIV-related lymphomas. We envision a future where a single treatment of our stem cell gene therapy can cure patients of their lymphoma and HIV leaving the patient with a new immune system that can fight, be resistant to and prevent the mutation of HIV. Apamistamab-I-131’s demonstrated antitumor effect against lymphoma and ability to condition patients in a targeted manner with a demonstrated tolerable safety profile in the bone marrow transplant setting makes it an ideal conditioning agent for this patient population. Based on these factors and extensive supporting clinical data in the Iomab-B program, we selected this ARC as the conditioning agent for the next phase of our trial as we believe antibody radiation-conjugates are more advanced and hold distinct advantages over novel but unproven conditioning technologies such as Antibody Drug Conjugates and naked antibodies that are beginning to be developed albeit at the preclinical stage."

In the current clinical trial, the anti-HIV stem cell gene therapy is produced by taking a patient’s own or autologous, blood forming stem cells and genetically modifying them via gene therapy with a combination of three anti-HIV genes. The intended result is for the gene modified bone marrow stem cells to produce a new immune system and newly arising immune cells that are resistant to HIV via a single treatment. Conditioning is necessary prior to adoptive cell therapies such as gene therapy to eliminate certain cell types such as immune cells and stem cells in the bone marrow so the transplanted cells can engraft. Until now, conditioning in this trial, as is typical, used a multi-drug chemotherapy regimen administered over several days. This approach is non-targeted, associated with toxicities that impairs patients and restricts the use and efficacy of cellular therapy. Apamistamab-I-131, which requires just one therapeutic administration, will displace the non-targeted chemotherapy to condition patients in a targeted manner with the goal of reducing conditioning related toxicities and improving patient outcomes. Actinium and UC David will cross-reference their respective Investigational New Drug applications and will work collaboratively to obtain necessary regulatory and institutional approvals. In this clinical collaboration, Actinium will provide drug product, support for its administration and certain trial costs. UC Davis will be responsible for the production of the anti-HIV stem cell gene therapy and overall conduct of the study and its cost.

Dr. Dale Ludwig, Actinium’s Chief Scientific Officer, said, "We are excited to be working with Dr. Abedi on this clinical study and we appreciate his recognition of the value of our Iomab-ACT targeted conditioning program may provide in support of gene stem cell therapy. This targeted approach using our CD45 ARC, enables both anti-tumor activity and effective conditioning with the potential for reduced toxicity compared to non-targeted chemotherapy and external radiation in the bone marrow transplant setting. Supported by extensive clinical investigation in 12 trials and over 300 patients, a single therapeutic dose of apamistamab-I-131 is sufficient for conditioning and, due to its dual activity, even a patient with active disease could expect to receive therapy within two weeks, which is anticipated to lead to better outcomes compared to chemotherapy, external beam radiation, or exploratory approaches such as naked antibodies or Antibody Drug Conjugates. In addition, CD45, the target of apamistamab-I-131, is ideal for targeted conditioning, as it is not expressed outside of the haemopoietic system and, because it is a poorly internalizing receptor. An ARC approach which does not require internalization of its radionuclide warhead for target cell killing, is anticipated to be more viable and more effective than Antibody Drug Conjugate approaches which need to internalize their payloads. Given the potential of this
ARC targeted conditioning technology for bone marrow transplant, we are grateful to Dr. Abedi for the opportunity to advance the Iomab-ACT program into the promising field of gene stem cell therapy."

Sandesh Seth, Actinium’s Chairman and Chief Executive Officer, said, "Actinium is thrilled to be working with UC Davis and honored to now be part of this important trial. It has become evident that better conditioning regimens are needed for cell and gene therapies to reach their full potential. Our team is proud to be the first company to establish a clinical stage targeted conditioning portfolio for both cell and gene therapy. We are pleased to extend our ARC technology for targeted conditioning into these rapidly advancing fields and we are committed to establishing a strong leadership position in enabling these adoptive cell therapies fully realize their great potential for improving patients’ lives."

Apamistamab-I-131’s demonstrated conditioning and antitumor effect in lymphoma1

Actinium’s apamistamab-I-131 ARC has been studied as a targeted conditioning agent in over 300 patients in the bone marrow transplant setting in the Iomab-B Program and is currently being studied in a pivotal Phase 3 clinical (SIERRA) trial in patients with relapsed or refractory acute myeloid leukemia. Clinical proof of concept has been established with Iomab-B for targeted conditioning in high-risk, relapsed or refractory lymphoma patients prior to an autologous stem cell transplant where a favorable safety profile with no dose limiting toxicities and minimal non-hematologic toxicities observed and promising efficacy with median overall survival not reached (range: 29 months to infinity) and 31% of patients in prolonged remission at a median of 36 months follow up (range: 25 – 41 months)1.

1) Cassaday et al. Phase I Study of a CD45-Targeted Antibody–Radionuclide Conjugate for High-Risk Lymphoma. AACR (Free AACR Whitepaper) Clin Cancer Res Published OnlineFirst September 3, 2019

On January 13, 2020 EUSA Pharma (EUSA) and BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160) reported that they have entered into an exclusive development and commercialization agreement for the orphan biologic products SYLVANT (siltuximab) and QARZIBA▼ (dinutuximab beta) in Greater China (Press release, EUSA Pharma, JAN 13, 2020, View Source [SID1234553096]).

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Under the terms of the agreement, EUSA has granted BeiGene exclusive rights to SYLVANT in Greater China and to QARZIBA▼in mainland China. Under the agreement, BeiGene will fund and undertake all clinical development and regulatory submissions in the territories, and will launch and commercialize both products once approved. EUSA will receive an upfront payment and be eligible to receive payments upon the achievement of regulatory and commercial milestones up to a total of $160 million. EUSA will also be eligible to receive tiered royalties on future product sales.

"Our teams are excited to work with EUSA to commercialize SYLVANT and QARZIBA, two important biologics which are already available to patients with rare diseases outside of China," said Xiaobin Wu, Ph.D., General Manager of China and President of BeiGene. "This collaboration further demonstrates our commitment to bringing high quality therapies to people in China and around the world."

Lee Morley, Chief Executive Officer of EUSA Pharma, said, "This exclusive agreement with BeiGene represents an important milestone for EUSA as we deliver on our promise to bring our innovative cancer and rare disease therapies to patients around the world. BeiGene brings to our collaboration exceptional development and commercialization capabilities in China and a clear focus on delivering innovative, targeted oncology medicines. We look forward to working together over the coming months to ensure these important orphan products are made available to Chinese patients."

SYLVANT is currently approved in more than 40 countries worldwide for the treatment of idiopathic multicentric Castleman’s disease (iMCD), a rare, life-threatening and debilitating orphan condition of the lymph nodes and related tissues. QARZIBA▼ is the only EMA approved targeted immunotherapy for the treatment of high-risk neuroblastoma, an aggressive neoplasm and the most common childhood solid tumor that originates outside of the brain. Both products have been listed for fast-track approval in China by the National Medical Products Administration (NMPA) via its Review and Approval Procedures for Urgently-Needed Pharmaceutical Drugs Developed Overseas.

Jefferies International Limited acted as exclusive advisor to EUSA on the transaction.

About QARZIBA▼ (dinutuximab beta)

QARZIBA▼ is a monoclonal antibody that is specifically directed against the carbohydrate moiety of disialoganglioside 2 (GD2), which is overexpressed on neuroblastoma cells. Dinutuximab beta was approved by the European Commission in 2017 and is indicated for the treatment of high-risk neuroblastoma in patients aged 12 months and above, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and stem cell transplantation, as well as patients with history of relapsed or refractory neuroblastoma, with or without residual disease. Prior to the treatment of relapsed neuroblastoma, any actively progressing disease should be stabilised by other suitable measures. In patients with a history of relapsed/refractory disease and in patients who have not achieved a complete response after first line therapy, dinutuximab beta should be combined with interleukin-2 (IL-2).

About SYLVANT (siltuximab)

SYLVANT is a monoclonal antibody that blocks the action of interleukin-6 (IL-6), a multifunctional cytokine detected at elevated levels in iMCD patients. SYLVANT is approved in a number of jurisdictions and indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. iMCD is a rare, life-threatening and debilitating lymphoproliferative disorder, which causes abnormal overgrowth of immune cells and shares many symptomatic and histological features with lymphoma.

On January 13, 2020 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell-based therapies, reported the successful administration of the next-generation, NKG2D-based candidate CYAD-02 to a relapsed/refractory acute myeloid leukemia (r/r AML) patient enrolled in the Phase 1 CYCLE-1 trial (Press release, Celyad, JAN 13, 2020, View Source [SID1234553095]).

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Dr. Dries Deeren, Head of Clinical Hematology at AZ Delta Hospital Roeselare, said, "We are proud to be participating in the CYCLE-1 trial evaluating the novel CAR-T cell therapy, CYAD-02, for the treatment of patients with advanced acute myeloid leukemia. Initial clinical results from Celyad’s AML and MDS program look encouraging. Based on preclinical data, where CYAD-02 has shown a differentiated and more potent profile to the first-generation approach, we’re excited to clinically evaluate the next-generation NKG2D construct in such an extremely challenging patient population."

Frédéric Lehmann, VP of Clinical Development & Medical Affairs at Celyad, added, "Dosing the first patient with CYAD-02 marks another major milestone to systematically advance our pipeline of proprietary autologous product candidates in our relapsed/refractory acute myeloid leukemia program. We look forward to investigating this next-generation approach which combines our NKG2D receptor, shRNA technology and OptimAb manufacturing process. Enrollment in the CYCLE-1 trial will continue over the coming months and we expect to report preliminary data from the study during the second half of 2020."

Background on CYAD-02
CYAD-02 is an investigational CAR-T therapy that engineers an all-in-one vector approach in patient’s T-cells to express both (i) the NKG2D chimeric antigen receptor (CAR), a receptor expressed on natural killer cells that binds to eight stress-induced ligands expressed on tumor cells, and (ii) short hairpin RNA (shRNA) SMARTvector technology licensed from Horizon Discovery to knockdown the expression of NKG2D ligands MICA and MICB on the CAR-T cells. In preclinical models, shRNA-mediated knockdown of MICA and MICB expression on NKG2D CAR-T cells has shown enhanced in vitro expansion, as well as enhanced in vivo engraftment and persistence, of the CAR-T cells, as compared to first-generation NKG2D-based CAR-T cells.

Background on CYCLE-1 Phase 1 Trial
In November 2019, the Company initiated the Phase 1 CYCLE-1 trial (NCT04167696). The open-label, dose-escalation trial will evaluate the safety and clinical activity of a single infusion of CYAD-02 produced with the OptimAb manufacturing process following preconditioning chemotherapy cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), or CyFlu, in patients with r/r AML and myelodysplastic syndromes (MDS). In addition, patients are also eligible to receive bridging therapy, based on physician’s choice, in advance of treatment with CYAD-02. The trial will evaluate three dose levels of CYAD-02, at 100 million, 300 million and one billion cells per infusion.