Although trial results suggest imetelstat is effective against essential thrombocythemia (ET), the telomerase inhibitor is only being developed to treat myelofibrosis (MF).
Imetelstat produced “rapid and durable” responses in a phase 2 trial of ET patients, but the drug also produced side effects that caused the US Food and Drug Administration (FDA) to place a full clinical hold on the drug.
The hold was lifted last November, but the company developing imetelstat decided not to pursue the drug as a treatment for ET or polycythemia vera.
Development continues for MF, however, and results of the pilot study of imetelstat in MF appear in NEJM.
Results from the trial of imetelstat in ET have been published in NEJM as well. Both studies were funded by Geron Corporation, the company developing imetelstat.
The ET trial included 18 patients with a median age of 59.5 (range, 21-83). All patients had received one or more prior treatments, including hydroxyurea (n=17, 94%), anagrelide (n=13, 72%), and interferon (n=4, 22%). Half of patients (n=9) were resistant to at least 1 prior therapy, and 78% (n=14) had experienced unacceptable side effects from a previous therapy.
The patients received imetelstat at an initial dose of 7.5 or 9.4 mg per kilogram of body weight intravenously once a week. Treatment continued until patients attained a platelet count of approximately 250,000 to 300,000 per cubic millimeter.
Responses
All 18 patients experienced hematologic responses, and 16 (89%) had a complete hematologic response. At a median follow-up of 17 months, 10 patients were still receiving treatment, and the median duration of response had not been reached (range, 5 to 30 months).
“[I]metelstat had a clinically significant effect on disease burden in ET patients,” said study investigator David Snyder, MD, of City of Hope in Duarte, California.
“This study was a first look at what happens when you treat ET patients with a drug that has a totally novel mechanism of action.”
Seven of the 8 patients (88%) who were positive for the JAK2 V617F mutation had a molecular response. All of the patients with CALR (n=5) or MPL (n=2) mutations saw a reduction in mutant allele burden, ranging from 15% to 66%.
“The molecular responses suggest that imetelstat may have broad activity across hematologic myeloid malignancies, which warrants further clinical study in other myeloproliferative neoplasms,” said investigator Gabriela M. Baerlocher, MD, of the University of Bern in Switzerland.
Toxicity, clinical hold, and discontinuation
The most common adverse events (≥50%) in this trial were fatigue (83%), diarrhea (78%), nausea (72%), dizziness (61%), increased alanine aminotransferase (ALT, 56%), increased aspartate aminotransferase (AST, 56%), constipation (50%), cough (50%), epistaxis (50%), and headache (50%).
Grade 3/4 adverse events included decreased neutrophil count (22%), neutropenia (22%), anemia (11%), syncope (11%), headache (11%), upper respiratory tract infection (6%), decreased white cell count (6%), myalgia (6%), hypokalemia (6%), fatigue (6%), cellulitis (6%), increased ALT (6%), increased AST (6%), and epistaxis (6%).
All 18 patients had at least one increase in grade, from baseline, in a liver-function value. Seventeen patients had an elevation in ALT, 17 in AST, 15 in alkaline phosphatase, and 8 in total bilirubin. Fourteen patients had persistent abnormalities (≥ 6 weeks), all of which were grade 1 or 2 in severity.
It was these liver-function abnormalities and the potential risk of chronic liver injury that prompted the FDA to place a clinical hold on imetelstat. The agency was concerned about whether the effects were reversible.
It turned out that, in many cases, abnormalities resolved after patients permanently discontinued treatment (as a result of the clinical hold). Sixteen of 17 patients with elevated ALT experienced a resolution, as did 12 of 17 patients with elevated AST, 9 of 15 with elevated alkaline phosphatase, and 7 of 8 with elevated bilirubin.
Of the 14 patients who had persistent abnormalities, 11 had their values reversed to normal or baseline values after stopping imetelstat. The median time to resolution after treatment discontinuation was 12 weeks.
Still, Geron Corporation decided not to develop imetelstat for patients with ET or polycythemia vera. And the FDA said the proposed clinical development plan for the drug, which is focused on MF and other high-risk myeloid disorders, was acceptable. So the clinical hold was lifted.
