John “Chip” Scarlett, MD
The FDA has placed a full clinical hold on the development of the investigational telomerase inhibitor imetelstat following concerns over consistent low-grade liver function test (LFT) abnormalities, according to a verbal notification received by Geron Corporation, the company developing the drug. As part of this hold, all clinical trials investigating imetelstat that are sponsored by Geron have been stopped.
Imetelstat initially garnered attention at the 2012 American Society of Hematology (ASH) annual meeting when phase II results were presented for patients with refractory essential thrombocythemia (ET). In the study, patients were treated with weekly intravenous imetelstat at 7.5 mg/kg or 9.4 mg/kg. Updated findings from 18 patients with ET were presented in June 2013 at the European Hematology Association (EHA) Congress. At this point, imetelstat elicited a complete response rate of 89% following a median 14-month duration of treatment.
“We were surprised by these actions,” John “Chip” Scarlett, MD, the president, chief executive officer, and director at Geron, said regarding the verbal notice of the full clinical hold during a webcast conducted following the announcement on March 12.
“An expert panel of liver experts along with our internal safety staff have periodically reviewed the data and all possible liver-related SAEs [serious adverse events],” Scarlett said. “Our and their conclusions were that the benefit-risk profile of imetelstat was favorable. These conclusions remained consistent as the ET trial progressed.”
At the time of the EHA Congress update, results indicated that every enrolled patient had a least one abnormal LFT, with the majority representing grade 1 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The safety results indicated that two grade 3 increases in ALT and AST occurred and were reversible with dose reduction. With longer dosing, grade 1 increases in alkaline phosphatase (ALP) were observed that were associated with grade 1/2 unconjugated hyperbilirubinemia.
Based on the initial promising results in ET, the Mayo Clinic initiated an investigator-sponsored pilot study looking at imetelstat in patients with myelofibrosis. Preliminary results from this study, presented at the 2013 ASH annual meeting, suggested that approximately 18% of patients with myelofibrosis experienced a complete remission. The overall response rate by IWG-MRT consensus criteria was approximately 41%.
In January 2014, the Mayo Clinic stopped recruiting new patients in the trial but continued to treat those who had already been enrolled. At this point, approximately 79 patients with myelofibrosis had been enrolled, with 20 patients having discontinued treatment. The study initially planned to enroll 40 patients when it began in October 2012.
In reference to the cessation of the myelofibrosis study, Scarlett said the “decision had nothing to do with liver test abnormalities. That was never discussed and we are unaware of any reason vis-Ã -vis liver abnormalities that played any role in stopping that study.”
In safety findings from 33 patients, treatment-related grade 2 increases in activated partial thromboplastin time occurred in 3% of patients (n = 1) and 6% of patients experienced grade 2 hyperbilirubinemia. All-cause grade 3/4 ALP abnormalities occurred in 6% of patients (n = 2). The investigators said that myelosuppression was the primary dose-limiting toxicity.
“Non-hematologic toxicity was very trivial. We have not seen any serious non-hematologic toxicity. We have not seen any grade 3/4 toxicity at all,” the myelofibrosis study lead investigator Ayalew Tefferi, MD, a hematologist at the Mayo Clinic, said in an interview with OncLive TV
at the 2013 ASH Annual Meeting.
“Fortunately, when you look at the drug doses that we’re going to use, which is every 3 weeks, the incidence of serious grade 4 thrombocytopenia or neutropenia is below 10%,” Tefferi said. “The problem is when we use it on an every week schedule; and there, out of 11 patients, 2 had severe myelosuppression with the platelet count severely suppressed. And so, as a result, we have abandoned that.”
The FDA has not yet issued a written statement to Geron regarding the full clinical hold. At this point, Geron is unaware of the incidence of LFT in the investigator-sponsored myelofibrosis trial. The FDA has asked for more data on the reversibility of liver-related side effects, Geron noted, both from the ET study and other investigations of imetelstat.
Geron Corporation’s shares fell 61.59% following the announcement on March 12.