Developing Imetelstat to Treat Hematologic Myeloid Malignancies

Many hematologic malignancies are known to arise from malignant progenitor cells in the bone marrow that express high telomerase activity and have shorter telomeres when compared to normal healthy cells. These disease characteristics support telomerase as a rational and potentially specific oncology target for the use of imetelstat.

Proof-of-Concept in Essential Thrombocythemia

In January 2011, we initiated a Phase 2 clinical trial of imetelstat in patients with ET. The Phase 2 ET trial was a multi-center, single arm, and open-label trial that we designed to provide proof-of-concept for the potential use of imetelstat as a treatment for hematologic myeloid malignancies, including MF, MDS and AML. The trial leveraged clinical observations from Phase 1 trials suggesting that imetelstat reduces platelet counts, as well as non-clinical observations that imetelstat distributes well to bone marrow in rodent models and selectively inhibits the proliferation of malignant progenitors ex vivo from patients with ET. Hematologic responses were measured by reductions in platelet counts, and molecular responses were measured by reductions in the JAK2 V617F mutant allele burden in circulating granulocytes as assessed by reduction in the proportion of the abnormal Janus kinase 2, or JAK2, gene compared to the normal, or wild type JAK2 gene. We believe a decrease in the proportion of the JAK2 V617F mutant relative to the wild type JAK2 is consistent with selective inhibition of the malignant progenitor cells responsible for the disease.

We presented top-line data from the Phase 2 ET clinical trial at the American Society of Hematology (ASH) annual meeting in December 2012 and at the Congress of the European Hematology Association (EHA) in June 2013. A total of 18 ET patients were enrolled into the study. Imetelstat induced platelet count reductions in all patients (a 100% hematologic response rate) and normalizations in 16 out of 18 patients (an 89% complete response rate). The JAK2 V617F gene mutation was detected in eight patients at baseline. Seven out of the eight (88%) patients achieved 72% to 96% reductions in JAK2 V617F allele burden that qualified as partial molecular responses within three to 12 months of treatment with imetelstat. Partial molecular responses were maintained in six of the seven (86%) patients, with a median follow-up of 9.5 months (range 0 to 19 months) after first achieving a response. As of the EHA Meeting in June 2013, the median durations of hematologic and molecular response had not yet been reached, and 11 patients remained on study, with the longest duration being three years. These data suggest that imetelstat inhibits the progenitor cells of the malignant clone believed to be responsible for the underlying disease in a relatively selective manner.

Adverse events reported in the Phase 2 ET trial have been similar to the adverse events reported in other imetelstat clinical trials, with fatigue, gastrointestinal symptoms (specifically nausea, diarrhea, constipation, and vomiting) and cytopenias being the most frequently observed adverse events. At least one abnormal LFT was observed in laboratory findings in all patients in this trial, with some patients experiencing persistent low grade LFT abnormalities with longer dosing. With longer dosing, Grade 1 increases in alkaline phosphatase were observed, associated with mostly Grade 1 to some Grade 2 unconjugated hyperbilirubinemia. The clinical significance and long-term consequences of such persistent low grade LFT abnormalities is currently undetermined.

In March 2014, we received written notice from the U.S. Food and Drug Administration (FDA), that our Investigational New Drug application (IND) for imetelstat has been placed on full clinical hold following their review of data related to hepatotoxicity in our then-ongoing clinical studies. A full clinical hold is an order that the FDA issues to a trial sponsor to suspend all ongoing clinical trials and delay all proposed trials. With this clinical hold, any patients in an ongoing Geron-sponsored clinical trial cannot receive any further treatment with imetelstat. Therefore, we have stopped imetelstat treatment in our Phase 2 clinical trial in ET. We have previously announced that our Phase 2 ET trial was a mechanistic proof-of-concept study, and that we did not plan to develop imetelstat for commercial use in ET.

In November 2014, the FDA removed the full clinical hold on Geron's IND for imetelstat.

Myelofibrosis Pilot Study

Based on the data from the Phase 2 ET trial, in November 2012, Dr. Ayalew Tefferi of Mayo Clinic initiated an investigator-sponsored trial at Mayo Clinic evaluating imetelstat in myelofibrosis, which we refer to as the Myelofibrosis Pilot Study. The Myelofibrosis Pilot Study is an open-label trial in patients with primary MF (PMF), post-ET MF, or post-PV MF who have two to three risk factors (intermediate-2) or four or more risk factors (high risk) as defined by DIPSS Plus. In the Myelofibrosis Pilot Study, imetelstat is administered as a single agent through a two-hour intravenous infusion to patients in multiple patient cohorts. In the first cohort, Cohort A, imetelstat is given once every three weeks. In the second cohort, Cohort B, imetelstat is given weekly for four weeks, followed by one dose every three weeks. Under the protocol, patients in Cohorts A and B may receive an intensified dosing regimen, up to once per week after the initial six cycles of treatment. The starting dose of imetelstat in Cohorts A and B is 9.4mg/kg, with dose reductions and dose holds allowed for toxicity. The primary endpoint is overall response rate, which is defined by the proportion of patients who are classified as responders having achieved either a clinical improvement (CI), partial remission (PR), or complete remission (CR) according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Secondary endpoints include reduction of spleen size by palpation, improvement in anemia or inducement of red blood cell transfusion independence, safety and tolerability. Please visit ClinicalTrials.gov for a trial summary. As of January 2014, the Myelofibrosis Pilot Study is closed to new patient enrollment.

At the ASH annual meeting in December 2013, the investigator presented preliminary efficacy data from the Myelofibrosis Pilot Study for the first 22 patients enrolled sequentially in Cohorts A and B, and preliminary safety data from the first 33 patients treated in the same two cohorts in the trial.

Click here to download a presentation summarizing our preliminary efficacy analysis of the first 22 MF patients enrolled in the study as of October 2013 and the investigator’s findings related to safety of the first 33 MF patients enrolled as presented at ASH.

In January 2014, the Myelofibrosis Pilot Study was closed to new patient enrollment. The remaining patients in the Myelofibrosis Pilot Study continue to receive imetelstat treatment and are being followed under the Myelofibrosis Pilot Study protocol.

In August 2014, sponsorship of the IND for imetelstat under which the Myelofibrosis Pilot Study has been conducted was transferred to Geron. In addition, Geron assumed responsibility for the conduct of the study and Dr. Tefferi remains the principal investigator.

Future Clinical Development in Myelofibrosis or Other Hematologic Myeloid Malignancies - Collaboration with Janssen

In November 2014, we entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. to develop and commercialize imetelstat for oncology, including hematologic malignancies, and other human therapeutic uses. Development of imetelstat will proceed under a mutually agreed clinical development plan witch includes multiple potential studies in MF, MDS and AML. Click here for the press release.

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