FDA Halts Testing of Cancer Drug Imetelstat
Agency cites risk of liver toxicity
Geron Corporation, located in Menlo Park, California, has received verbal notice from the FDA that its investigational new drug (IND) application for imetelstat has been placed on full clinical hold, affecting all ongoing company-sponsored clinical trials. A full clinical hold is an order that the FDA issues to a trial sponsor to suspend an ongoing clinical trial or to delay a proposed trial.
The clinical hold affects the remaining eight patients in the company’s phase II study in essential thrombocythemia (ET) or polycythemia vera (PV) and the remaining two patients in the company’s phase II study in multiple myeloma.
In addition, the company’s planned phase II clinical trial in myelofibrosis will likely be delayed because of the clinical hold. It is possible that other studies using imetelstat, such as ongoing investigator-sponsored trials, may also be placed on clinical hold by the FDA.
Geron has not yet received written notice of its clinical hold from the FDA, but based on the verbal communication, the FDA indicated that the clinical hold is due to the occurrence of persistent low-grade liver function test (LFT) abnormalities observed in the phase II study of imetelstat in ET/PV patients and to the potential risk of chronic liver injury following long-term exposure to imetelstat. The FDA expressed concern about whether these LFT abnormalities are reversible.
Most cancers have a high level of telomerase activity and relatively short telomeres compared with normal cells. 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 half maximal inhibitory concentration (IC50) of imetelstat is 0.5 to 10.0 nM in cell-free assays. The tissue half-life of imetelstat 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.
Imetelstat is the first telomerase inhibitor to advance to clinical development. In phase 1 trials, adverse events were generally manageable and reversible. The dose-limiting toxicities were thrombocytopenia and neutropenia.
A phase II study of imetelstat in patients with ET was initiated in January 2011. A total of 18 patients were enrolled into this ongoing, open-label study. Imetelstat induced platelet-count reductions in all patients (a 100% hematologic response rate) and normalizations in 16 patients (an 89% complete response rate). The JAK2 V617F gene mutation was detected in eight patients at baseline. Seven of these patients (88%) achieved 72% to 96% reductions in the JAK2 V617F allele burden that qualified as partial molecular responses within 3 to 12 months of treatment.
At least one abnormal LFT was observed in laboratory findings in all patients. Most of these abnormalities were grade 1 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST); two grade 3 increases in ALT/AST were reversible on dose reduction. With longer dosing, grade 1 increases in alkaline phosphatase were observed, associated with mostly grade 1 to some grade 2 unconjugated hyperbilirubinemia.
Based on the data from the phase II ET study, an open-label trial evaluating imetelstat in patients with myelofibrosis (MF) was initiated in November 2012. This ongoing study includes patients with primary MF, post-ET MF, or post-PV MF who had two to three intermediate-risk factors or four or more high-risk factors. Imetelstat was administered as a single agent through a 2-hour intravenous infusion. The study’s primary endpoint is the overall response rate.
A preliminary efficacy analysis of the first 22 MF patients enrolled in this study as of October 2013 reported an overall response rate of 41% (9/22). A subsequent safety analysis was conducted in the first 33 patients treated. This analysis found that myelosuppression was the primary dose-limiting toxicity.