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FDA Removes Full Clinical Hold on Imetelstat
The FDA has removed its full clinical hold on the investigational new drug (IND) application for imetelstat. In addition, the agency stated that the proposed clinical development plan for the drug, which is focused on high-risk myeloid malignancies, such as myelofibrosis (MF), is acceptable.
The FDA acknowledged that the product’s developer (Geron Corporation) does not intend to conduct further studies in, or to 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. The company obtained clinical follow-up information from patients in previously ongoing company-sponsored phase II 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 the 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 in 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 nonclinical toxicology studies, which included a 6-month study in mice and a 9-month study in cynomolgus monkeys. In these studies, no clinical pathology changes indicating hepatocellular injury were observed, and no clear signal of LFT abnormalities were identified.
With the lift of the full clinical hold on imetelstat, a phase II clinical trial in MF is projected to begin in the first half of 2015.
Imetelstat is a lipid-conjugated 13-mer oligonucleotide sequence that is complementary to and binds with high affinity to the RNA template of telomerase, thereby directly inhibiting telomerase activity. The compound has a thio-phosphoramidate backbone, which is designed to provide resistance to the effect of cellular nucleases, thereby conferring improved stability in plasma and tissues, as well as improved binding affinity to its target. To improve the ability of imetelstat to permeate through cellular membranes, the oligonucleotide sequence was conjugated to a lipid group.
The drug’s tissue half-life 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.
Sources: Geron Corporation; November 3, 2014; and Imetelstat; 2014.