Geron has discontinued a phase 3 trial of its Rytelo in JAK inhibitor-pretreated myelofibrosis after an independent data monitoring committee ruled that the study was unlikely to succeed, just as Novartis is gearing up for a delayed FDA approval bid for its pelabresib.
News of the phase 3 IMpactMF trial failure drove down Geron’s stock price by nearly 16% Wednesday to below $1 apiece at close for the first time since a pandemic-led market crash in March 2020.
The study was testing Rytelo (imetelstat), a first-in-class telomerase inhibitor, against best available therapy among 327 patients with intermediate-2 or high-risk myelofibrosis who had failed on a JAK inhibitor, such as Incyte and Novartis’ Jakafi.
At an interim analysis, the independent data monitoring committee deemed Rytelo unlikely to show a significant overall survival benefit on the trial’s primary endpoint, and Geron followed the panel’s recommendation to end the trial.
“Hematologic malignancies are complex diseases, with distinct biological characteristics and treatment challenges across patient populations,” Geron’s R&D chief, Joseph Eid, M.D., said in an Oct. 28 statement. “We remain committed to thoroughly evaluating the data, understanding what we can learn, and sharing insights that may help inform future research and address the significant unmet needs that remain.”
Rytelo got its initial FDA approval in 2024 for patients with low- to intermediate-risk myelodysplastic syndromes (MDS) and transfusion-dependent anemia who have failed on, or are ineligible for, erythropoiesis-stimulating agents. MDS is a group of blood cancers in which immature blood cells in the bone marrow fail to mature or become healthy blood cells.
For that indication, Rytelo is dosed at 7.1 mg/kg administered as an intravenous infusion every four weeks. Thrombocytopenia and neutropenia are among some serious side effects tied to the drug that require monitoring of patients’ blood cell counts.
In IMpactMF, Geron tested a higher, more frequent dose, at 9.4 mg/kg every three weeks.
According to Geron’s previous public disclosures, the FDA urged the company to consider adding another dosing arm to the trial to assess a lower dose and/or a more frequent dosing schedule to improve its chance of success. The rationale was that doing so might reduce toxicity with more effective spleen response, one of the trial’s secondary endpoints.
However, citing findings from its phase 2 IMbark trial, Geron argued that “testing a lower dose regimen would likely result in a lower median OS” for Rytelo, according to its most recent quarterly filing.
“Existing data also suggest that lowering the dose would not result in a clinically meaningful reduction in toxicity, and for these reasons we determined not to add a third dosing arm to the trial design,” the company said.
In its Oct. 28 announcement, Geron said the phase 3 trial saw no new safety signals that would “change the known safety profile of imetelstat or require additional safety monitoring.”
The company didn’t respond to Fierce’s question on whether it would consider another trial testing a lower dose or whether the trial setback would lead to any job cuts. In response to Fierce’s inquiry, a media aide pointed back to the company’s press release. The company will report third-quarter earnings on Nov. 4.
“As we fully analyze the data from the IMpactMF trial, we remain committed to growing Rytelo demand in the U.S. and broadening access to eligible LR-MDS patients outside the U.S.,” Geron’s CEO, Harout Semerjian, said in the release. “We have a growing commercial business, a strong financial foundation, and a clear strategy to pursue innovation to create long-term value and build a leading hematology company.”
Toxicity has recently tripped up Novartis’ BET inhibitor candidate, pelabresib, the centerpiece of its $2.9 billion MorphoSys buyout, in myelofibrosis. Citing an imbalance in the rate of malignant transformations into acute myeloid leukemia, Novartis in 2024 had to wait for longer follow-up of the phase 3 Manifest-2 trial in post-JAK inhibitor myelofibrosis to determine pelabresib’s U.S. path. The trial pits pelabresib’s combination with Jakafi against Jakafi alone.
The Swiss pharma recently completed filing pelabresib in the EU based on the Manifest-2 results, which the company said “showed deep and durable disease control, with a safety profile comparable to [Jakafi] alone, including numerically fewer deaths and disease progressions in the pelabresib arm,” according to its third-quarter earnings report.
Novartis now expects to speak with the FDA about a potential accelerated approval of pelabresib before the end of the year, CEO Vas Narasimhan told investors on a call Tuesday.
The company is running the phase 3 Manifest-3 trial testing pelabresib-Jakafi in primary myelofibrosis.