On December 10, 2024 Geron Corporation (Nasdaq: GERN), a commercial-stage biopharmaceutical company aiming to change lives by changing the course of blood cancer, reported new analyses presented at the 66 th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting from the IMerge clinical trial in patients with lower-risk myelodysplastic syndromes (LR-MDS) with transfusion-dependent anemia suggesting clinical activity of first-in-class telomerase inhibitor RYTELO (imetelstat) regardless of type or number of prior therapies, as well as favorable patient-reported outcomes (PROs) (Press release, Geron, DEC 10, 2024, View Source [SID1234648979]).

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"These latest IMerge analyses presented at ASH (Free ASH Whitepaper) contribute to a growing body of clinical evidence that support RYTELO as a second-line option in red blood cell transfusion-dependent lower-risk MDS, regardless of prior treatments," said Faye Feller, M.D., Executive Vice President, Chief Medical Officer of Geron. "Additionally, the sustained improvement in fatigue observed in the IMerge Phase 3 patient-reported outcomes population is meaningful for this progressive disease that is characterized by fatigue."

"Patients with red blood cell transfusion-dependent lower-risk MDS often cycle through limited available therapies. The IMerge data presented at ASH (Free ASH Whitepaper) suggesting clinical activity of imetelstat regardless of prior therapies, offers physicians important clinical evidence while assessing sequencing of treatments," said Rami S. Komrokji, M.D., Vice Chair, Malignant Hematology Department, Moffitt Cancer Center, an investigator of the IMerge clinical trial, who presented IMerge results at ASH (Free ASH Whitepaper). "Further, anemia and fatigue remain two of the most burdensome symptoms of lower-risk MDS, and patient-reported outcomes such as improvement in fatigue and maintenance of quality of life and anemia symptoms may inform treatment choices as we aim to improve outcomes for our patients."

"Effect of Prior Treatments on the Clinical Activity of Imetelstat in Transfusion-Dependent Patients with Erythropoiesis-Stimulating Agent, Relapsed or Refractory/Ineligible Lower-Risk Myelodysplastic Syndromes"

This oral presentation reported findings from analyses investigating the effects of prior therapies on the clinical activity of imetelstat using pooled data from IMerge Phase 2, Phase 3, and the QTc substudy. Of the 226 total imetelstat-treated LR-MDS patients included in this analysis, 90% had prior treatment with an erythropoiesis-stimulating agent (ESA), 12% had prior treatment with lenalidomide, 16% had prior treatment with luspatercept and 10% had prior treatment with a hypomethylating agent (HMA). Across this pooled population, median imetelstat treatment duration was 33.6 weeks (range: 0.1-260.1 weeks).

Imetelstat clinical activity was observed in the pooled patient population consistent with that of the IMerge Phase 3 pivotal trial with regards to safety and critical efficacy measures that include ≥8-week red blood cell transfusion independence (RBC-TI), ≥24-week RBC-TI, RBC transfusion reduction ≥4 U/8 weeks and hemoglobin rise ≥1.5 g/dL/8 weeks.

The results suggest that patients who were ESA ineligible, patients who had prior treatment with luspatercept or lenalidomide, or patients who had prior treatment with ESAs followed by luspatercept or lenalidomide experienced clinical benefit from imetelstat treatment similar to that demonstrated in the IMerge Phase 3 pivotal trial. Patients who had prior treatment with HMAs, or with ESAs followed by HMAs, showed modest clinical activity with imetelstat. Overall, while these analyses were limited by the small number of patients in each group, imetelstat showed clinical activity regardless of prior ESA response status and regardless of the number of prior lines of therapy.

"Initial Results from the QTc Substudy of the IMerge Phase 3 Trial Demonstrate Clinically Meaningful Efficacy, Manageable Safety, and Absence of Proarrhythmic Risk in Patients with Lower-Risk Myelodysplastic Syndromes Who Received Prior Therapies Beyond Erythropoiesis Stimulating Agents"

This poster presentation reports initial results from the ventricular repolarization (QTc) substudy of IMerge conducted per FDA guidance. This substudy differed from the IMerge Phase 3 trial in its crossover design, the inclusion of patients with del(5q) MDS, and by allowing prior lenalidomide and HMA therapy besides ESAs. The QTc substudy population comprised 53 treated patients (n=35 imetelstat, n=18 placebo). As of the data cutoff on May 10, 2024, 16 of 18 placebo recipients crossed over to receive imetelstat. Median treatment duration on imetelstat, including crossover (n=51) was 29.3 weeks; median duration in the imetelstat group (n=35) was 37.0 weeks and median duration in the crossover group (n=16) was 27.9 weeks.

In the total imetelstat population (n=51), 41% of patients (n=21) achieved ≥8-week RBC-TI, 25% of patients (n=13) achieved ≥24-week RBC-TI, 41% of patients (n=21) achieved hematologic improvement-erythroid (HI-E) per IWG 2018 criteria, 35% of patients (n=18) had hemoglobin rises ≥1.5 g/dL lasting ≥8 weeks and 75% of patients (n=38) had RBC transfusion reductions ≥4 U/8 weeks.

In patients with prior luspatercept, lenalidomide or HMA (azacitidine or decitabine) treatment, 30% (7/23), 38% (5/13), and 21% (3/14) of patients achieved ≥8-week RBC-TI, and 22% (5/23) 15% (2/13), and 14% (2/14) achieved ≥24-week RBC-TI, respectively. Patients treated with imetelstat showed no treatment-related changes in absolute and change in QTcF nor clinically meaningful effects on cardiac repolarization compared with placebo.

The poster concludes that in this QTc substudy, imetelstat was associated with an absence of proarrhythmic risk, durable RBC-TI, transfusion reduction, clinically meaningful increases in hemoglobin, and a safety profile comparable to the overall population of the pivotal Phase 3 IMerge trial. RBC-TI was attained in imetelstat-treated patients who received prior therapies with HMA, luspatercept and lenalidomide, supporting the use of imetelstat in patients with relapsed or refractory LR-MDS regardless of prior therapies.

"Correlation of Patient-Reported Outcomes with Red Blood Cell Transfusion Reduction and Rise in Hemoglobin in Patients with Lower-Risk Myelodysplastic Syndromes in the IMerge Trial"

This poster reports on the exploratory PRO analysis from IMerge Phase 3, with a data cutoff of October 2022. PROs were assessed with validated using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Functional Assessment of Cancer Therapy-Anemia (FACT-An), and Quality of Life in Myelodysplasia Scale (QUALMS) questionnaires. Sustained meaningful improvement in fatigue was defined as a ≥3-point increase in FACIT-Fatigue score for ≥2 consecutive assessments. The PRO population (n=175) included all patients in the intent-to-treat population who had FACIT-Fatigue data at baseline and consisted of 118 imetelstat-treated patients and 57 patients who received placebo.

In the subgroup analysis, more patients treated with imetelstat than placebo reported sustained improvement in fatigue regardless of ring sideroblast (RS) status, prior transfusion burden and baseline serum EPO levels. Additionally, improvement in fatigue was seen in more patients who responded to imetelstat versus those who did not across measures of response including RBC-TI, hemoglobin rise and transfusion reduction. The QUALMS and FACT-An analyses suggested that imetelstat maintained QOL and anemia symptoms, while placebo recipients experienced worsening QOL and anemia symptoms.

The poster concludes that data from the pivotal IMerge phase 3 trial showed that improvement in fatigue with imetelstat was associated with reduced transfusion burden and a rise in hemoglobin and that imetelstat appears to offer the advantage of sustained RBC-TI benefit while maintaining QOL in patients with LR-MDS with TD anemia.

The ASH (Free ASH Whitepaper) presentations are available on Geron’s website in the investor section under publications.

About RYTELO (imetelstat)

RYTELO (imetelstat) is an FDA-approved oligonucleotide telomerase inhibitor for the treatment of adult patients with low-to-intermediate-1 risk myelodysplastic syndromes (LR-MDS) with transfusion-dependent anemia requiring four or more red blood cell units over eight weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs). It is indicated to be administered as an intravenous infusion over two hours every four weeks.

RYTELO is a first-in-class treatment that works by inhibiting telomerase enzymatic activity. Telomeres are protective caps at the end of chromosomes that naturally shorten each time a cell divides. In LR-MDS, abnormal bone marrow cells often express the enzyme telomerase, which rebuilds those telomeres, allowing for uncontrolled cell division. Developed and exclusively owned by Geron, RYTELO is the first and only telomerase inhibitor approved by the U.S. Food and Drug Administration.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Thrombocytopenia

RYTELO can cause thrombocytopenia based on laboratory values. In the clinical trial, new or worsening Grade 3 or 4 decreased platelets occurred in 65% of patients with MDS treated with RYTELO.

Monitor patients with thrombocytopenia for bleeding. Monitor complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated. Administer platelet transfusions as appropriate. Delay the next cycle and resume at the same or reduced dose, or discontinue as recommended.

Neutropenia

RYTELO can cause neutropenia based on laboratory values. In the clinical trial, new or worsening Grade 3 or 4 decreased neutrophils occurred in 72% of patients with MDS treated with RYTELO.

Monitor patients with Grade 3 or 4 neutropenia for infections, including sepsis. Monitor complete blood cell counts prior to initiation of RYTELO, weekly for the first two cycles, prior to each cycle thereafter, and as clinically indicated. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose, or discontinue as recommended.

Infusion-Related Reactions

RYTELO can cause infusion-related reactions. In the clinical trial, infusion-related reactions occurred in 8% of patients with MDS treated with RYTELO; Grade 3 or 4 infusion-related reactions occurred in 1.7%, including hypertensive crisis (0.8%). The most common infusion-related reaction was headache (4.2%). Infusion-related reactions usually occur during or shortly after the end of the infusion.

Premedicate patients at least 30 minutes prior to infusion with diphenhydramine and hydrocortisone as recommended and monitor patients for one hour following the infusion as recommended. Manage symptoms of infusion-related reactions with supportive care and infusion interruptions, decrease infusion rate, or permanently discontinue as recommended.

Embryo-Fetal Toxicity

RYTELO can cause embryo-fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RYTELO and for 1 week after the last dose.

ADVERSE REACTIONS

Serious adverse reactions occurred in 32% of patients who received RYTELO. Serious adverse reactions in >2% of patients included sepsis (4.2%) and fracture (3.4%), cardiac failure (2.5%), and hemorrhage (2.5%). Fatal adverse reactions occurred in 0.8% of patients who received RYTELO, including sepsis (0.8%).

Most common adverse reactions (≥10% with a difference between arms of >5% compared to placebo), including laboratory abnormalities, were decreased platelets, decreased white blood cells, decreased neutrophils, increased AST, increased alkaline phosphatase, increased ALT, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache.

Please see RYTELO (imetelstat) full Prescribing Information, including Medication Guide, available at View Source