Geron faces an uncertain future following a full clinical hold on its only pipeline product.
By Christina Vasiliou, Senior Analyst
14 March 2014
I joined Datamonitor Healthcare in early 2014, having completed an MPhil in Bioscience Enterprise at the University of C...
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On 12 March 2014, Geron Corporation announced that it has received verbal notice from the US Food and Drug Administration (FDA) that its Investigational New Drug application for imetelstat has been placed on full clinical hold.
Imetelstat, a first-in-class telomerase inhibitor, is the company’s only pipeline product. Geron was investigating imetelstat in two ongoing Phase II clinical trials, the first for the treatment of essential thrombocythemia (ET) and polycythemia vera (PV), and the second for the treatment of multiple myeloma. Both of these clinical studies are now on hold, due to the occurrence of persistent low-grade liver function test (LFT) abnormalities observed in ET/PV patients and the potential risk of chronic liver injury following long-term exposure to imetelstat. An investigator-sponsored trial for imetelstat in myelofibrosis may also be placed on hold.
In June 2013, Geron reported initial results from imetelstat’s Phase II ET/PV trial, noting that at least one abnormal liver function test had been observed in every patient receiving the drug. The majority of these abnormalities were grade 1 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, with some grade 2/3 elevations also observed. However, these elevations were found to be reversible upon dose reduction or interruption. In patients receiving more prolonged treatment with imetelstat, grade 1 increases in alkaline phosphatase levels were observed, which were associated with grade 1/2 unconjugated hyperbilirubinemia. The company periodically reviewed the safety concerns around these elevated LFTs, engaging with a panel of hepatology experts and internal safety experts. The conclusion of this panel was that the benefit to risk ratio for imetelstat’s use in ET/PV was favorable. However, it appears the FDA has not come to the same conclusion.
Geron is now waiting on a formal letter from the FDA highlighting the exact concerns that need to be addressed along with the clinical data that need to be assessed. The company expects the FDA to ask for information on the reversibility of these persistent LFT abnormalities when patients discontinue imetelstat treatment. Geron is likely to face challenges in correlating these low level persistent elevated LFTs with actual clinical manifestations. The company could also struggle to follow up with patients who have now left the imetelstat clinical studies, and where re-consent may be required in order to look at individual patient data.
This clinical hold is another in a long line of unfortunate events to hit Geron, following its 2012 abandonment of the novel LRP-1-targeted peptide-drug conjugate GRN1005, and imetelstat’s previous unsuccessful trials in metastatic HER2-negative breast cancer and non-small cell lung cancer. Interestingly, a similar pattern of elevated LFTs was also observed in these trials, but at a lower frequency to those observed in the ET/PV trial.
Geron may have prematurely hoped that its fortunes had changed following the promising results of a small study investigating the use of imetelstat in myelofibrosis, but this was not to be. While the company and its investors await the official FDA letter, they can only hope that they have sufficient data to demonstrate that the persistent elevated LFTs do not represent an insurmountable safety concern. If not, Geron could face an uncertain future with no announced developmental product in its pipeline.