Date: 2014-11-03
Type of information: Initiation of preclinical development
phase: 2
Announcement: clinical trial authorisation
Company: Geron (USA - CA)
Product: imetelstat
Action
mechanism: enzyme inhibitor/telomerase inhibitor. Imetelstat is a telomerase inhibitor. This lipid-conjugated 13-mer oligonucleotide sequence is complementary to and binds with high affinity to the RNA template of telomerase, thereby directly inhibiting telomerase activity. The compound has a proprietary thio-phosphoramidate backbone, which is designed to provide resistance to the effect of cellular nucleases, thus conferring improved stability in plasma and tissues, as well as significantly improved binding affinity to its target. Imetelstat’s IC50, or half maximal inhibitory concentration, is 0.5-10nM in cell-free assays. The tissue half life of imetelstat, or the time it takes for the concentration or amount of imetelstat to be reduced by half, in bone marrow, spleen, liver and tumor has been estimated to be 41 hours in humans, based on data from animal studies and clinical trials.
Disease: myelofibrosis
Therapeutic area: Rare diseases
Country:
Trial
details: This pilot clinical trial studies how well imetelstat sodium works in treating patients with primary or secondary myelofibrosis and other myeloid malignancies. Imetelstat sodium may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth (NCT01731951).
Latest
news: * On November 3, 2014, Geron announced that the FDA has removed the full clinical hold on Geron's investigational new drug (IND) application for imetelstat. In addition, the FDA stated that Geron's proposed clinical development plan for imetelstat that is focused on high-risk myeloid malignancies, such as myelofibrosis (MF), is acceptable. The FDA acknowledged that the company does not intend to conduct further studies in, or develop imetelstat for, the treatment of essential thrombocythemia (ET) or polycythemia vera, which is consistent with the company's plans as originally disclosed in April 2013. To address the full clinical hold, the FDA required Geron to provide follow-up information from imetelstat-treated patients who experienced liver function test (LFT) abnormalities until such abnormalities resolved to normal or baseline. Geron obtained clinical follow-up information from patients in the previously ongoing company-sponsored Phase 2 trials in ET and multiple myeloma (MM). These data were submitted to the FDA as part of the company's complete response. The company's analysis of these data concluded that in the ET trial LFT abnormalities resolved to normal or baseline in 14 of 18 follow-up patients. For the remaining four ET patients, at the time of the data cut-off, three patients showed improvement in LFT abnormalities and one patient had unresolved LFT abnormalities. Currently, two of the remaining four ET patients continue in follow-up. In the MM trial, LFT abnormalities resolved to normal or baseline in all nine follow-up patients. In addition, no emergent hepatic adverse events were reported during follow-up for either study. The FDA also requested information regarding the reversibility of liver toxicity after chronic imetelstat administration in animals. The company submitted data from its previously conducted non-clinical toxicology studies, which included a six-month study in mice and a nine-month study in cynomolgus monkeys. In these studies, no clinical pathology changes indicative of hepatocellular injury were observed, and no clear signal of LFT abnormalities were identified. With the lift of the full clinical hold, a multi-center Phase 2 clinical trial in MF is projected to begin in the first half of 2015. * On June 12, 2014, Geron Corporation announced that the FDA has removed the partial clinical hold on the investigator-sponsored clinical trial of imetelstat in myelofibrosis (Myelofibrosis IST). The partial clinical hold was placed in March 2014 due to a safety signal of hepatotoxicity that was identified in clinical trials of imetelstat. In order to resolve the partial clinical hold, the investigator, Dr. Ayalew Tefferi of Mayo Clinic, Rochester, Minnesota, was required to provide follow-up information regarding reversibility of hepatotoxicity for all patients who received imetelstat in the Myelofibrosis IST. In its letter dated June 11, 2014, the FDA informed the investigator that it had completed the review of his complete response submission and concluded that the Myelofibrosis IST may proceed. As previously announced, the Myelofibrosis IST ceased enrolling new patients in January 2014, and Mayo Clinic did not cite any safety concerns as the basis for that decision. Previously enrolled patients who are deriving clinical benefit continue to receive treatment with imetelstat. Geron\'s Investigational New Drug (IND) application for imetelstat remains on full clinical hold affecting the company\'s clinical trials in essential thrombocythemia or polycythemia vera and in multiple myeloma. Until the FDA lifts the full clinical hold on Geron\'s IND, the company is unable to submit any new clinical trial protocols to the FDA under the company\'s IND for imetelstat and is unable to initiate any new clinical trials for imetelstat in the United States. The company is working diligently to seek release of the full clinical hold.
