On January 14, 2016 Geron Corporation (Nasdaq:GERN) reported the dosing of the first patient in a Phase 2/3 clinical trial to evaluate imetelstat in patients with myelodysplastic syndromes (MDS) (Press release, Geron, JAN 14, 2016, View Source [SID:1234508792]). This clinical trial, also referred to as the IMergeTM study, is being conducted by Janssen Research & Development, LLC, and is the second study to be initiated under the terms of the exclusive worldwide imetelstat license and collaboration agreement between Geron and Janssen Biotech, Inc. (Janssen). Schedule your 30 min Free 1stOncology Demo! Phase 2/3 Clinical Trial Design
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 purpose of the Phase 2/3 clinical trial is to evaluate imetelstat in transfusion dependent patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who have relapsed after or are refractory to prior treatment with an erythropoiesis-stimulating agent (ESA).
As designed, the trial consists of two parts, and a total of approximately 200 patients are expected to be enrolled. Part 1 of the trial is planned as a Phase 2, open-label, single-arm design to assess the efficacy and safety of imetelstat. Up to 30 patients are expected to be enrolled in Part 1, all of whom will receive imetelstat and be followed for safety, hematologic improvement and reduction in transfusion requirement. Before proceeding to Part 2, the data from Part 1 must support a positive assessment of the benefit/risk profile of imetelstat in these patients. Part 2 of the trial is planned as a Phase 3 double-blind, randomized, placebo-controlled design to compare the efficacy of imetelstat against placebo. Approximately 170 patients are expected to be enrolled in Part 2, who will be assigned randomly, in a 2:1 ratio, to receive either imetelstat or placebo. The inclusion criteria for both parts of the trial require that at the time of enrollment each patient must be red blood cell transfusion-dependent. Imetelstat (or placebo in Part 2) will be administered as an intravenous infusion. The starting dose will be 7.5 mg/kg every 4 weeks and may be escalated according to certain protocol-specified conditions. Dose reductions for adverse events may follow protocol-specified algorithms. All patients may receive supportive care, including transfusions or myeloid growth factors, as needed per investigator discretion and according to local standard practices.
The primary efficacy endpoint is designed to be the rate of red blood cell transfusion-independence lasting at least 8 weeks, defined as the proportion of patients without any red blood cell transfusion during any consecutive 8 weeks since entry to the trial. A primary efficacy analysis is planned to occur 12 months after the last patient is enrolled.
Secondary efficacy endpoints in the trial include the proportion of patients achieving red blood cell transfusion-independence lasting at least 24 weeks, the time to and duration of red blood cell transfusion-independence, the proportion of patients achieving hematologic improvement, the proportion of patients achieving complete remission (CR) or partial remission (PR) per 2006 International Working Group (IWG) criteria for MDS, the proportion of patients requiring red blood cell transfusions and the amount, the proportion of patients requiring the use of myeloid growth factors and the dose, as well as assessments of the change in the patients’ quality of life using several different validated instruments. Patients are also planned to be followed for an assessment of overall survival and time to progression to acute myeloid leukemia (AML). These secondary endpoints are expected to be assessed at the time of the primary efficacy analysis.
Safety outcomes will be monitored throughout the trial and will include enhanced data collection and reporting for adverse events of interest, including hepatobiliary-associated laboratory findings and hepatic adverse events.
Multiple medical centers across North and South America, Europe and Asia are planned to participate in the trial. For more information about the IMergeTM study being conducted by Janssen, please visit View Source
Orphan Drug Designation
On December 23, 2015, the United States Food and Drug Administration (FDA), granted orphan drug designation to imetelstat for the treatment of MDS. The FDA has previously granted orphan drug designation to imetelstat for the treatment of myelofibrosis (MF). Orphan drug designation is granted by the FDA’s Office of Orphan Drug Products in order to support development of medicines for underserved or rare diseases and patient populations that affect fewer than 200,000 people in the United States. Orphan drug designation qualifies the sponsor of the drug for various development incentives of the ODA, including, if regulatory approval is received, seven years of market exclusivity with certain limited exceptions, exemption from FDA application fees, and certain tax credits for qualified clinical testing. The granting of orphan drug designation does not alter the standard regulatory requirements and process for obtaining marketing approval. The safety and effectiveness of a drug must be established through adequate and well-controlled studies. Orphan drug exclusivity does not prevent the FDA from approving a different drug for the same disease or condition, or the same drug for a different disease or condition.
About MDS
The myelodysplastic syndromes (MDS) are a group of blood disorders that arise from the proliferation of malignant progenitor cell clones in the bone marrow resulting in disordered and ineffective production of the myeloid lineage, which includes red blood cells, white blood cells and platelets. In MDS, bone marrow and peripheral blood cells may have abnormal, or dysplastic, cell morphology. MDS is frequently characterized clinically by severe anemia (low red cell counts and low hemoglobin). In addition, other peripheral cytopenias, or low numbers of white blood cells and platelets, may cause life-threatening infections and bleeding. Transformation to secondary acute myeloid leukemia (AML) occurs in up to 30% of MDS cases and results in poorer overall survival.
MDS is the most common of the myeloid malignancies. There are approximately 12,000 reported new cases in the US every year and approximately 60,000 people living with the disease. MDS is primarily a disease of the elderly, with median age at diagnosis around 70 years. The majority of patients, approximately 70%, fall into what are considered to be the lower risk groups at diagnosis, according to the IPSS that takes into account the presence of a number of disease factors, such as cytopenias and cytogenetics to assign relative risk of progression to AML and overall survival.
When initially diagnosed with MDS, approximately 80% of patients have anemia, and chronic anemia is the predominant clinical problem in lower risk disease. Many of these patients become dependent on red blood cell transfusions, which can lead to elevated levels of iron in the blood and other tissues that the body has no normal way to eliminate. Iron overload is a potentially dangerous condition. Studies in patients with MDS have shown that iron overload resulting from regular red blood cell transfusions is associated with a poorer overall survival and a higher risk of developing AML.
About Imetelstat
Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat has disease-modifying activity by inhibiting the progenitor cells of the malignant clone associated with hematologic malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies conducted to date include fatigue, gastrointestinal symptoms and cytopenias. Patients in these studies also experienced elevated liver enzymes, which resolved to normal or baseline in the majority of patients followed after imetelstat treatment was withdrawn. Imetelstat has not been approved for marketing by any regulatory authority.
About the Collaboration with Janssen
On November 13, 2014, Geron entered into an exclusive worldwide license and collaboration agreement with Janssen to develop and commercialize imetelstat for oncology, including hematologic myeloid malignancies, and all other human therapeutics uses. Under the terms of the agreement, Geron received an upfront payment of $35 million and is eligible to receive additional payments up to a potential total of $900 million for the achievement of development, regulatory and commercial milestones, as well as royalties on worldwide net sales. Certain regulatory, development, manufacturing and promotional activities are being managed through a joint governance structure, with Janssen responsible for these activities.