FDA Halts Patient Enrollment in Myelofibrosis Trial
Agency cites potential for hepatotoxicity with imetelstat
Patients currently enrolled in an investigator-sponsored clinical trial of imetelstat in myelofibrosis who are deriving clinical benefit may continue treatment under a partial clinical hold placed by the FDA.
The partial clinical hold means that no new patients may be enrolled into the study, and that patients currently enrolled must demonstrate that they are deriving clinical benefit in order to continue taking imetelstat.
The Mayo Clinic in Rochester, Minnesota, informed the drug’s developer (Geron Corp.) in January 2014 that the trial had ceased enrolling new patients, but did not cite any safety concerns as the basis for that decision. The study’s investigator — Dr. Ayalew Tefferi — has agreed to provide the FDA with specific criteria he will use to determine which patients will continue treatment with imetelstat.
In its written notification to Tefferi, the FDA said the reason for the partial clinical hold was that a safety signal of hepatotoxicity had been identified in clinical studies of imetelstat, and that it is not known whether this hepatotoxicity is reversible.
To resolve the partial clinical hold, Tefferi is required to provide the FDA with follow-up information regarding the reversibility of hepatotoxicity for all patients who have received imetelstat. For patients who did not experience abnormalities in liver function tests (LFTs), follow-up of these tests until 30 days from the last imetelstat dose must be performed. For patients who experienced an abnormality in LFTs, follow-up LFTs must be obtained until resolution to baseline or normal range for at least two consecutive determinations.
As previously reported, the investigational new drug (IND) application related to imetelstat is currently on full clinical hold following the FDA’s review of data related to safety in the then-ongoing clinical trials. A full clinical hold is an order that the FDA issues to a trial sponsor to suspend all ongoing clinical trials and to delay all proposed trials under that IND.
With the full clinical hold, Geron Corp. has stopped treatment with imetelstat in a total of ten patients in its phase II clinical trials of imetelstat in patients with essential thrombocythemia or polycythemia vera and in patients with multiple myeloma.
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 proprietary 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 significantly 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) is 0.5 to 10.0 nM in cell-free assays. The compound’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.
In January 2011, Geron Corp. initiated an open-label phase II trial of imetelstat in patients with essential thrombocytopenia (ET). A total of 18 patients were enrolled into the study.
Imetelstat induced platelet-count reductions in all 18 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 with imetelstat. Partial molecular responses were maintained in six of the seven patients (86%), with a median follow-up period of 9.5 months (range, 0 to 19 months), after they achieved a clinical response.
Fatigue, gastrointestinal symptoms (i.e., nausea, diarrhea, constipation, and vomiting) and cytopenias were the most common adverse events. At least one abnormal LFT was observed in laboratory findings, and some patients experienced persistent low-grade LFT abnormalities with longer dosing.
In March 2014, Geron Corp. received written notice from the FDA that the company’s IND for imetelstat had been placed on full clinical hold following the agency’s review of data related to hepatotoxicity in ongoing clinical studies.