Abstract
On June 6, 2024, the U.S. Food and Drug Administration (FDA) approved imetelstat (RYTELO, Geron) for adults with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring ≥4 red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents. The approval was based on a randomized (2:1), double-blind, placebo-controlled multicenter trial, Study MDS3001. In the protocol-specified primary analysis, the ≥8-week RBC transfusion independence (RBC-TI) rate was 39.8% (95% CI: 30.9, 49.3) in the imetelstat group versus 15% (95% CI: 7.1, 26.6) in the placebo group (p-value <0.001). This was supported by the rate of ≥24-week RBC-TI of 28% (95% CI: 20.1, 37) in the imetelstat group versus 3.3% (95% CI: 0.4, 11.5) in the placebo group (p-value <0.001). However, there was no major difference between arms regarding the key secondary endpoint of erythroid response (HI-E) per International Working Group 2006 criteria or secondary endpoints reflective of a disease modifying effect such as complete remission rate and overall survival. The most common adverse reactions were thrombocytopenia, leukopenia, neutropenia, increased liver enzymes, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache. The rate of grade 3–4 neutropenia and thrombocytopenia were 72% and 65%, respectively, in the imetelstat arm compared to 7% and 8% in the placebo arm. Despite the high incidence of neutropenia and thrombocytopenia, the FDA determined that the benefits outweighed the risks in this patient population with high unmet need. Post-marketing requirements were issued to evaluate long-term safety and to conduct a randomized trial comparing at least 2 dosages of imetelstat to potentially minimize risks of imetelstat treatment and improve tolerability.
Introduction
Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders resulting from clonal expansion of a hematopoietic progenitor, causing bone marrow dysplasia, ineffective hematopoiesis, and risk of transformation to acute myeloid leukemia. For lower-risk MDS (LR-MDS), median survival ranges from 2 to >10 years.1,2 Many patients with LR-MDS are affected by anemia and transfusion dependence, which may negatively impact health-related quality of life and correlate with shorter survival.3,4 However, evidence that reduction in transfusion dependence improves quality of life or survival is mixed.5–10
Frontline therapy for transfusion-dependent anemia due to LR-MDS includes erythropoiesis stimulating agents (ESAs) and luspatercept. Lenalidomide is approved for the subset of patients with deletion 5q (del5q). Hypomethylating agents are therapeutic options, though often reserved for treatment of higher-risk MDS, LR-MDS with multiple cytopenias, or refractory LR-MDS.11
Imetelstat is a lipidated oligonucleotide that is a competitive inhibitor of telomerase. Shorter telomere length and high telomerase activity have been reported to be poor prognostic features in LR-MDS.12–14 Herein, we summarize FDA’s review of the marketing application that led to approval of imetelstat for adults with low- to intermediate-1 risk MDS with transfusion-dependent anemia requiring ≥4 units red blood cells (RBCs) over 8 weeks who have not responded to or have lost response to or are ineligible for ESAs.
Regulatory History
Study 63935937MDS3001 (MDS3001, IMerge), the Phase 2/3 trial of imetelstat for the treatment of LR-MDS with transfusion-dependent anemia, was initiated in 2015. In 2017, imetelstat was granted fast track designation for patients with LR-MDS without del5q and who are refractory or resistant to treatment with an ESA based on early clinical data from the Phase 2 portion of the study.15
At a pre-new drug application (pre-NDA) meeting in March 2023, FDA stated that the data from Study MDS3001 may be adequate to support submission of the NDA. However, FDA noted that transfusion independence (TI) data should ideally be supported by additional evidence of clinical benefit. The NDA was submitted on June 16, 2023. On March 14, 2024, an Oncologic Drug Advisory Committee (ODAC) meeting was held to discuss the application.
Mechanism of Action
Imetelstat is an oligonucleotide that binds to the template region of the RNA component of human telomerase, inhibits telomerase enzymatic activity and prevents telomere binding. Imetelstat concentration-dependently inhibited telomerase activity in a cancer cell line in vitro, and single or repeated administration in mice resulted in telomerase inhibition in tumor xenografts and liver tissue. Imetelstat administered intraperitoneally in animals at 15 or 30 mg/kg for 50 days resulted in tumor growth inhibition with an average reduction in tumor volume of 34% and 53%, respectively.16
Clinical Pharmacology
Imetelstat doses of 0.4 mg/kg to 11 mg/kg, alone or in combination with other agents, and dosing schedules from weekly to once every 4 weeks were explored in different diseases throughout the drug development program. However, the evaluation of imetelstat in MDS has been limited to two studies. The first study evaluated imetelstat as a single agent given to patients with MDS or MDS/MPN at a dose of 7.1 mg/kg weekly with the possibility to escalate to 8.9 mg/kg weekly. The second study, MDS3001, evaluated the effect of imetelstat at 7.1 mg/kg every 4 weeks in patients with LR-MDS. Although telomerase activity data was collected throughout the drug development program, its relationship to TI is not well studied and considered exploratory in MDS.
At the approved recommended dose of 7.1 mg/kg once every 4 weeks, imetelstat geometric mean (coefficient of variation [CV]%) maximum plasma concentration (Cmax) is 18.3 μM (27.3%) and the area under the concentration-time curve from time 0 to 28 days (AUC0–28) is 114.2 h*μM (43.2%) without accumulation between treatment cycles. Following a single intravenous dose of 7.1 mg/kg imetelstat administered over two hours, the geometric mean (CV%) volume of distribution is approximately 14.1 L (27.2%) with in vitro human plasma protein binding greater than 94%. The imetelstat geometric mean (CV%) apparent plasma half-life is approximately 4.9 hours (43.2%) and is expected to be metabolized by nucleases into nucleotides of various lengths.
No clinically significant differences in the pharmacokinetics of imetelstat were observed based on age, sex, race, mild to moderate renal impairment (CLcr 30 to <90 mL/min), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1–1.5x ULN and any AST), or moderate hepatic impairment (total bilirubin >1.5–3x ULN and any AST). The effect of severe renal impairment (CLcr 15 - <30 mL/min), end-stage renal disease, or severe hepatic impairment (total bilirubin >3x ULN and any AST) has not been established.
Assessment of Efficacy
Clinical trial overview
Study MDS3001 (NCT02596881) was a multicenter, multipart trial that included a randomized, double-blind, placebo-controlled Phase 3 portion comparing imetelstat with placebo in adults with International Prognostic Scoring System (IPSS) low- or intermediate-1 risk MDS who were RBC transfusion dependent and relapsed/refractory to ESA treatment or had an erythropoietin level >500 mU/mL predicting non-response to ESA.17,18 RBC transfusion dependence was defined as requiring ≥4 RBC units over an 8-week period during the 16 weeks prior to randomization; pre-transfusion hemoglobin was required to be ≤9.0 g/dL to count towards the 4 units. Patients with del5q and/or prior treatment with an HMA or lenalidomide were excluded.
Patients were randomized 2:1 to receive imetelstat 7.1 mg/kg or placebo IV every 4 weeks until disease progression, unacceptable toxicity, or lack of response. Randomization was stratified by prior RBC transfusion burden (≤6 or >6 units RBC over any 8-week period during the 16 weeks prior to randomization) and IPSS risk group (low versus intermediate-1 risk) (Supplemental Figure 1).
The primary efficacy endpoint was rate of ≥8-week RBC-TI. The study was designed to have 88% power to detect a 22.5% difference in 8-week RBC-TI (30% versus 7.5%) between imetelstat and placebo with a 2-sided alpha of 0.05. Key secondary endpoints were ≥24-week RBC-TI and erythroid response (HI-E) per International Working Group (IWG) 2006 criteria; these were tested sequentially with 2-sided alpha of 0.05. Other secondary endpoints included duration of RBC-TI; rates of complete remission (CR), partial remission (PR), or marrow CR (mCR) per IWG 2006 criteria; and overall survival (OS). Laboratory assessments for Hgb levels were collected weekly for the first 2 cycles, then every 4 weeks and as needed. RBC transfusion data was collected at every patient encounter including visits for study drug administration (every 4 weeks) and every unscheduled visit while on treatment and in study follow up every 12–16 weeks until the first RBC transfusion was received in follow up.
Patient reported outcomes (PRO) were included as non-multiplicity controlled exploratory endpoints. PROs were collected using the FACT-Anemia (which contains 13 items that can be used to calculate the FACIT-Fatigue scale) and QUALMS measures.19,20 The main PRO endpoint of interest was the proportion of patients who reported deterioration in fatigue measured by FACIT-Fatigue.21 The assessment frequency was day 1 of each cycle until end of treatment, and then every 12–16 weeks during follow-up.
Demographics and disposition
A total of 178 patients were randomized, 118 to imetelstat and 60 to placebo. Demographic and disease characteristics of the efficacy population are shown in Table 1. At the time of primary efficacy analysis, median follow-up was 19.5 months in the imetelstat arm and 17.5 months in the placebo arm. Treatment was ongoing in 22.9% of subjects in the imetelstat group and 23.7% of subjects in the placebo group. Reasons for treatment discontinuation are shown in Supplemental Table 1. The most common reason was lack of efficacy (24% imetelstat versus 42% placebo). In the imetelstat arm, 16% of subjects discontinued treatment due to an AE compared to none in the placebo arm.
Table 1. Study MDS3001-Phase 3: Key demographic and baseline disease characteristics.
| Parameter | Imetelstat (Phase 3) N=118 | Placebo (Phase 3) N=60 |
|---|---|---|
|
| ||
| Sex | ||
| Male | 71 (60.2%) | 40 (66.7%) |
| Female | 47 (39.8%) | 20 (33.3%) |
|
| ||
| Age | ||
| Median in years (min, max) | 71.5 (44, 87) | 73.0 (39, 85) |
|
| ||
| Region | ||
| North America | 13 (11.0%) | 12 (20.0%) |
| European Union | 80 (67.8%) | 38 (63.3%) |
| Rest of world | 25 (21.2%) | 10 (16.7%) |
|
| ||
| IPSS risk category | ||
| Low | 80 (67.8%) | 39 (65.0%) |
| Intermediate-1 | 38 (32.2%) | 21 (35.0%) |
|
| ||
| Prior therapies | ||
| ESA | 108 (91.5%) | 52 (86.7%) |
| Luspatercept | 7 (5.9%) | 4 (6.7%) |
| HMA | 0 | 1 (1.7%) |
| Lenalidomide | 1 (<1%) | 0 |
|
| ||
| RBC transfusion burden per 8 weeks | ||
| Median RBC units (min, max) | 6.0 (4, 33) | 6.0 (4, 13) |
|
| ||
| Median baseline blood counts | ||
| Neutrophils (cells/L) | 2.6 × 109 | 2.7 × 109 |
| Hemoglobin (g/dL) | 7.9 | 7.8 |
| Platelets (cells/L) | 230 × 109 | 230 × 109 |
|
| ||
| WHO classification (2008) | ||
| Ringed sideroblast positive | 73 (61.9%) | 37 (61.7%) |
| Ringed sideroblast negative | 44 (37.3%) | 23 (38.3%) |
|
| ||
| Serum erythropoietin (EPO) level | ||
| Median (mU/mL) | 174.9 | 277.0 |
Efficacy Results
Key efficacy results from Study MDS3001 at the time of primary analysis (data cutoff October 13, 2022) are presented in Table 2. The ≥8-week RBC transfusion independence (RBC-TI) rate was 39.8% (95% CI: 30.9, 49.3) for imetelstat versus 15% (95% CI: 7.1, 26.6) for placebo, a difference of 24.8% (95% CI: 9.9, 36.9; p-value <0.001). The rate of ≥24-week RBC-TI was 28.0% (95% CI: 20.1, 37) for imetelstat versus 3.3% (95% CI: 0.4, 11.5) for placebo, a difference of 24.6% (95% CI: 12.6, 34.2; p-value <0.001).22 The rate of ≥1-year RBC-TI was evaluated post-hoc and results were supportive, 13.6% (95% CI: 8.0, 21.1) for imetelstat versus 1.7% (95% CI: 0, 8.9) for placebo.
Table 2. Study MDS3001-Phase 3: Primary analysis of rate of RBC-TI by Study Arm.
| Outcome | Imetelstat (Phase 3) N=118 | Placebo (Phase 3) N=60 | % Difference (95% CI)4 | p-value5 |
|---|---|---|---|---|
| 8-week RBC-TI1, n (%) (95% CI) | 47 (39.8) (30.9, 49.3) | 9 (15.0) (7.1, 26.6) | 24.8 (9.9, 36.9) | < 0.001 |
| 24-week RBC-TI2, n (%) (95% CI) | 33 (28.0) (20.1, 37.0) | 2 (3.3) (12.6, 34.2) | 24.6 12.6, 34.2) | < 0.001 |
| 1-year RBC-TI3, n (%) (95% CI) | 16 (13.6) (8.0, 21.1) | 1 (1.7) (0, 8.9) | ||
Source: U.S. Food and Drug Administration. Prescribing Information: RYTELO (imetelstat) and NDA Multi-disciplinary Review and Evaluation (NDA 217779).16,22
Primary endpoint
Key secondary endpoint
Additional endpoint evaluated by the Applicant post-hoc
95% CI based on Wilson Score method.
p-value is based on Cochran-Mantel-Haenszel (CMH) controlling for prior RBC transfusion burden (≤6 versus > 6 units RBC) and IPSS risk group (low versus intermediate-1) applied to randomization.
Data cutoff 13 October 2022
The median duration of longest RBC-TI interval for all subjects in Phase 3 was 5.0 (95% CI: 4.0, 7.7) weeks for imetelstat versus 3.9 (95% CI: 3.6, 4.0) weeks for placebo. In the subset of patients who achieved a ≥8-week RBC-TI response, the median duration of the longest RBC-TI interval was 51.6 (95% CI 26.9, 83.9) weeks for imetelstat versus 13.3 (95% CI: 8.0, 24.9) for placebo.
A statistically significant difference was not observed on the key secondary endpoint of HI-E per IWG 2006 criteria (63.6% versus 51.7%) or other secondary endpoints reflective of a disease-modifying effect such as CR+PR rate or OS. CR+PR rate was 0% versus 0% at the time of primary analysis and 5.9% at best for imetelstat versus 0% for placebo at the time of updated analysis (Supplemental Table 2). OS hazard ratio (HR) was 1.07 [95% CI: 0.46, 2.48] at the time of primary analysis when 27 events occurred (Supplemental Figure 2) and 0.98 [95% CI: 0.53, 1.8] at the time of updated analysis when 50 events occurred (Figure 1). A similar proportion of patients reported deterioration in fatigue in both arms (43% imetelstat versus 46% placebo).
Figure 1. Study MDS3001-Phase 3: Kaplan-Meier Plot of Overall Survival (ITT Set) at Updated Analysis.
Source: NDA Multi-disciplinary Review and Evaluation (NDA 217779).16
Data cutoff 5 January 2024
Assessment of Safety
A total of 177 patients received treatment with imetelstat (n= 118) or placebo (n=59) in Study MDS3001-Phase 3. The median duration of exposure in the safety population was 8 cycles in both arms.
The safety for imetelstat is summarized in Table 3. Common treatment-emergent adverse reactions (TEAR) in the imetelstat arm, including laboratory abnormalities, were decreased platelets, white blood cells, and neutrophils, increased AST, alkaline phosphatase, and ALT, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache (Table 4, Supplemental Table 3). Adverse events were similar in the phase 2 portion of the study (Supplemental Table 4).
Table 3. Study MDS3001-Phase 3: Summary of adverse events observed.
| TEAE | Imetelstat N=118 n (%) | Placebo N=59 n (%) |
|---|---|---|
| Overall TEAE1 | 117 (99) | 59 (100) |
| Serious Adverse Events | 38 (32) | 13 (22) |
| Grade 3–4 TEAE | 108 (92) | 29 (49) |
| Grade 3–4 TEAE excluding neutropenia and thrombocytopenia | 67 (57) | 24 (41) |
| Fatal TEAE | 1 (0.8) | 2 (3.4) |
| Deaths (including not related to TEAE) | 28 (24) | 13 (22) |
| TEAE leading to any dose modification | 103 (87) | 15 (25) |
| TEAE leading to treatment discontinuation | 18 (15) | 2 (3.4) |
| Dose decrease due to AE | 58 (49) | 4 (7) |
| Dose interruption due to AE2 | 94 (80) | 15 (25) |
| Dose delay by >3 days (any reasons) | 87 (74) | 18 (31) |
| Dose delay by >7 days (any reasons) | 77 (65) | 13 (22) |
| Infusion interrupted, decreased rate, or aborted due to AE3 | 7 (6) | 0 |
Source: NDA Multi-disciplinary Review and Evaluation (NDA 217779).16
TEAE = treatment emergent adverse event(s)
Includes delay in start of next cycle, infusion interrupted, decreased rate, or aborted due to AE
Reason for infusion interruption, decreased rate, or aborted missing for 5 patients.
Data cutoff 10 May 2023
Table 4. Study MDS3001-Phase 3: Treatment-emergent adverse reactions and laboratory abnormalities in the safety population.
| Imetelstat N=118 | Placebo N=59 | |||
|---|---|---|---|---|
| Adverse reaction1 | Any | Grade 3–4 | Any | Grade 3–4 |
| Infections | 55 (47) | 13 (11) | 20 (34) | 8 (14) |
| COVID-19 | 22 (19) | 2 (1.7) | 8 (14) | 3 (5) |
| Urinary tract infection | 11 (9) | 3 (2.5) | 4 (7) | 0 |
| Sepsis | 5 (4.2) | 5 (4.2) | 0 | 0 |
| Febrile neutropenia | 1 (0.8) | 1 (0.8) | 0 | 0 |
| Fatigue | 34 (29) | 0 | 12 (20) | 2 (3.4) |
| Arthralgia/myalgia | 30 (25) | 3 (2.5) | 11 (19) | 3 (5) |
| Hemorrhage | 26 (22) | 3 (2.5) | 7 (12) | 1 (1.7) |
| Epistaxis | 8 (7) | 0 | 0 | 0 |
| Hematoma | 7 (6) | 0 | 0 | 0 |
| Gastrointestinal hemorrhage | 2 (1.7) | 1 (0.8) | 0 | 0 |
| Headache | 15 (13) | 1 (0.8) | 3 (5) | 0 |
| Infusion related reactions | 9 (8) | 2 (1.7) | 2 (3.4) | 0 |
| Syncope | 8 (7) | 2 (1.7) | 1 (1.7) | 0 |
| Pruritus | 7 (6) | 0 | 1 (1.7) | 0 |
| Atrial arrhythmia | 7 (6) | 2 (1.7) | 2 (3.4) | 1 (1.7) |
| Fractures | 6 (5) | 4 (3.4) | 1 (1.7) | 1 (1.7) |
| Hypertension | 4 (3.4) | 4 (3.4) | 0 | 0 |
| Laboratory abnormalities 2 | ||||
| Platelet count decreased | 114 (97) | 77 (65) | 20 (34) | 5 (8) |
| WBC count decreased | 111 (94) | 63 (53) | 35 (59) | 1 (1.7) |
| Neutrophil count decreased | 109 (92) | 85 (72) | 28 (47) | 4 (7) |
| AST increased | 62 (53) | 1 (0.8) | 13 (22) | 1 (1.7) |
| ALP Increased | 57 (48) | 0 | 7 (12) | 0 |
| ALT increased | 50 (43) | 4 (3.4) | 22 (37) | 3 (5) |
| PTT prolonged | 25 (26) | 1 (1) | 9 (18) | 2 (3.8) |
Source: NDA Multi-disciplinary Review and Evaluation (NDA 217779).16
Includes adverse event grouped terms. See Supplemental Table 3 for further information.
Denominator varied from 97–118 for imetelstat arm and 50–59 for placebo arm based on number of patients with a baseline value and at least one post-treatment value for a given laboratory term.
Data cut-off date 10 May 2023
Treatment emergent thrombocytopenia and Grade 3–4 thrombocytopenia based on laboratory data were observed in 97% and 65% of patients in the imetelstat arm versus 34% and 8% in the placebo arm, respectively (Supplemental Table 5). Median duration (range) of grade 3–4 thrombocytopenia until resolution to grade 2 was 1.9 (0–15.9) weeks. Platelet transfusion was required more frequently (18% versus 2%), and bleeding events were more common (22% versus 12%) in the imetelstat arm.
Treatment-emergent neutropenia was observed in 92% and grade 3–4 neutropenia in 72% of patients who received imetelstat versus 47% and 7%, respectively, who received placebo. In the imetelstat arm, grade 3–4 neutropenia was most common in cycles 1–3, but was observed throughout treatment (Supplemental Table 5). Median duration (range) grade 3–4 neutropenia was 1.3 (0.1–12.6) weeks. More patients on the imetelstat arm required treatment with myeloid growth factor (MGF) (36% versus 3%) or anti-infectives (42% versus 34%), and more experienced infections compared to those on placebo (47% versus 34%). Sepsis was reported as a serious adverse reaction in 4.2% of patients on imetelstat and none on placebo.
Fatal TEAEs occurred in five patients (9%) in phase 2, including complications of fracture, arterial thrombosis (2), neurodegenerative disorder, and COVID-19 pneumonia. In phase 3, at the time of data cut-off (Jan 2024), 35 (30%) of patients in the imetelstat arm and 15 (25%) in the placebo arm died. Two fatal TEAEs occurred in each arm. One death due to sepsis was considered related to imetelstat.
Infusion-related reactions (IRRs) were observed in 8% of patients treated with imetelstat. Grade 3–4 IRRs occurred in 1.7%, including hypertensive crisis (0.8%). The most common IRR symptom was headache (4.2%). Premedication and monitoring for signs/symptoms of IRR are recommended in the prescribing information.
There was a high rate of dose modifications with imetelstat compared to placebo (Table 3). Higher Cmax correlated with a higher probability of Grade 3–4 thrombocytopenia (Supplemental Figure 3), which supports the observation of higher rates of thrombocytopenia with imetelstat. Higher imetelstat average concentration was associated with higher probability of achieving 8-week TI, however, the exposure-response analysis for efficacy has substantial limitations because of the single dose level and frequent dose modification in the study.
Regulatory Insights
FDA’s regular approval of imetelstat - for the treatment of adults with low- to intermediate-1 risk MDS with transfusion-dependent anemia requiring ≥4 units RBC over 8 weeks who have not responded to or have lost response to or are ineligible for ESAs - was based on substantial evidence of effectiveness from Study MDS3001. The review included a comprehensive benefit/risk assessment with input from an ODAC (Table 5).
Table 5. FDA Benefit-Risk Analysis1.
| Dimension | Evidence and Uncertainties | Conclusions and Reasons |
|---|---|---|
| Analysis of Condition | • MDS is a chronic condition with no curative treatment options except hematopoietic stem cell transplant (HSCT) • Lower-risk MDS (LR-MDS) has a long life expectancy and treatment is typically aimed at reducing symptom burden • Transfusion burden due to anemia is a common complication of lower risk MDS and can lead to lower quality of life, iron overload, and other issues |
There is a need for new therapeutic options for patients with MDS, including both treatment for the underlying disease and for amelioration of symptoms. |
| Current Treatment Options | • Typical frontline therapy for transfusion-dependent anemia due to LR-MDS includes erythropoiesis stimulating agents (ESAs). • Luspatercept is another option for frontline therapy; it is also indicated for use after ESA failure in patients with anemia due to MDS with ringed sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasms with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T). • Lenalidomide is approved for the treatment of transfusion-dependent anemia in the subset of patients with LR-MDS with deletion 5q (del5q). • Hypomethylating agents such as azacitidine, decitabine, and decitabine-cedazuridine, are additional therapeutic options, though often reserved for the treatment of high-risk MDS or refractory LR-MDS in clinical practice. |
The current treatment options for treating anemia in the context of MDS after ESA failure are inadequate and further options are needed. |
| Benefit | • Study MDS3001-Part 2 (Phase 3) was an international, multi-center, double-blind, randomized (2:1), placebo-controlled trial comparing imetelstat (n=118) vs placebo (n=60) in patients with transfusion-dependent anemia (requiring at least 4 RBC units/8 weeks at baseline) due to IPSS low- or intermediate-1 risk MDS who have failed to respond, or have lost response to, or are ineligible for ESA. • In the ITT analysis of 8-week RBC-TI, the primary endpoint, the rate difference was 24.8% (95% CI 9.9, 36.9). • In the ITT analysis of 24-week RBC-TI, a key secondary endpoint, the rate difference was 24.6% (95% CI 12.6, 34.2). • The median duration of response was 51.6 weeks (95% CI 26.9, 83.9) for 8-week RBC-TI responders, suggesting a clinically meaningful duration of benefit for a subset of patients. However, the median duration of response was only 5.0 weeks (95% CI 4.0, 7.7) when considering all subjects treated with imetelstat. • Analyses of 8-week RBC-TI over subgroups showed a consistent treatment effect favoring imetelstat over placebo in most subgroups tested. The rate was higher with placebo in the subgroup of patients with prior luspatercept use but the number of patients in this subgroup was too few to draw conclusions. The treatment effect was marginal for subjects with lower transfusion burden at baseline (defined as 4–7 RBC units in 16 weeks in at least 2 transfusion episodes). • There was no major difference between arms with regard to the secondary endpoints of HI-E per IWG 2006 criteria, CR/PR, or OS. • Patient-reported outcomes were exploratory and not controlled for multiplicity. That said, there was no major difference between arms with regard to the PRO endpoint of interest, the proportion of patients who experienced deterioration of fatigue. |
Imetelstat demonstrated superiority over placebo in Study MDS3001-Part 2 (Phase 3) on the primary endpoint of 8-week RBC-TI and the key secondary endpoint of 24-week RBC-TI. A subset of patients had a clinically meaningful duration of RBC-TI benefit. However, the HI-E, CR/PR, and OS results are not supportive of a disease-modifying treatment effect. The patient-reported outcomes were exploratory but are also not supportive of a treatment effect. |
| Risk and Risk Management | • Imetelstat was associated with a higher risk of Grade 3+ AEs, SAEs, and AEs leading to treatment modification. However, the rate of fatal AEs is similar to placebo. • Imetelstat was associated with a high risk of cytopenias with resultant need for intervention and increased risk of all grade infection and hemorrhage. However, the rates of Grade 3–4 infection and hemorrhage were similar to placebo. • Infusion-related reactions occurred in 8% of patients with MDS treated with imetelstat; Grade 3–4 infusion-related reactions occurred in 1.7%. • Imetelstat was associated with a higher risk of fractures, arthralgias/myalgias, and bone pain. • Although patient-reported deterioration in fatigue for at least 2 consecutive fatigue assessments (as measured by FACIT-Fatigue) was similar between arms, investigator-reported all grade fatigue was slightly higher in the imetelstat arm. • A QT assessment has not been completed. • Lower dosages of imetelstat have not been evaluated in patients with LR-MDS. • Serious toxicities were mitigated in the clinical trials by use of premedications, frequent monitoring for known toxicities, and dose modifications. |
Imetelstat has increased toxicities compared to placebo, including cytopenias and tolerability issues. However, the rates of Grade 3–4 infection and hemorrhage with imetelstat are similar to placebo, suggesting that serious consequences of cytopenias are able to be mitigated. Per the Oncology Drug Advisory Committee discussion on 14 March 2024, the safety profile of imetelstat is acceptable for patients with transfusion-dependent anemia due to LR-MDS. Further characterizations of safety, optimal dosage, pharmacokinetics, and effects on QT are needed. A patient medication guide is required to inform and educate patients of the risks of thrombocytopenia and neutropenia and when to seek immediate medical attention. Labeling should include warnings for the serious risks of thrombocytopenia, neutropenia, infusion-related reactions, and embryofetal toxicity, and instructions for monitoring and dose modifications for toxicities. |
Results of Study MDS3001 met the statistical goals for the primary endpoint of ≥8-week RBC-TI and key secondary endpoint of ≥24-week RBC-TI but raised concerns as to whether the magnitude and durability of RBC-TI outweighed the risks of treatment with imetelstat. FDA noted that potential benefits of imetelstat include a 25% higher chance of achieving ≥8-week or ≥24-week RBC-TI; however, this is in the context of patients requiring monthly infusion visits, with no CR/PR or OS benefit, and no clear improvement in patient-reported fatigue or other anemia-related symptoms. Additionally, FDA noted minimal difference in the median duration of longest RBC-TI interval between arms when evaluating all subjects, rather than the subset of ≥8-week RBC-TI responders. This was considered relevant since the clinical meaningfulness of an 8-week cutoff to define RBC-TI responders versus non-responders is unclear.
FDA further noted that there was no significant difference between groups in the proportion of patients who achieved an HI-E response per IWG 2006 criteria. A high proportion of subjects in the placebo group achieved an HI-E response, suggesting fluctuations in hemoglobin and corresponding periods of transfusion reduction may be due to the natural history of the underlying disease and/or comorbidities contributing to anemia in this elderly population.
Most patients in Study MDS3001 had <5% bone marrow blasts at baseline and were therefore considered ineligible for CR response per Independent Review Committee (IRC) assessment at the time of primary analysis. However, there were few CR responses with imetelstat even in an updated analysis which considered all patients to be eligible for a CR response, regardless of baseline marrow blast percentage (Supplemental Table 2). This was considered relevant to the benefit/risk assessment since durable CR+PR has been historically viewed as a direct measure of clinical benefit in MDS, reflecting the restoration of trilineage hematopoiesis even in patients with <5% bone marrow blasts at baseline, and previously supported the regular approval of decitabine and azacitidine for MDS including lower-risk disease.23–25
OS is considered the gold standard time-to-event measure of clinical benefit in MDS clinical trials, as well as an important safety endpoint.23 Although Study MDS3001 was not adequately powered to detect an improvement in OS, the initial OS hazard ratio >1 raised concern, though the 95% CI included 1. The updated analysis of OS yielded similar results, though the stratified OS hazard ratio was <1.
These results were considered in the context of the potential risks of imetelstat, such as a high rate of neutropenia and thrombocytopenia, including more Grade ≥3 TEAR, serious TEAR, and TEAR leading to treatment modification. Although duration of grade 3–4 cytopenias were generally short, many patients experienced multiple events and patients continued to be at risk of cytopenias throughout treatment. Patients on imetelstat were also more likely to require MGF or platelet transfusion while on treatment and had consequences of cytopenias, such as infections and hemorrhage. Additionally, non-hematologic TEARs added to concerns about the safety profile of imetelstat.
Although the proportion of patients who reported deterioration in fatigue was similar between arms, more patients on imetelstat experienced fatigue per clinician-reported AEs. The median duration of the longest episode of fatigue per clinician-reported AEs was also longer with imetelstat (Supplemental Table 6). These findings called into question the benefit of the increased hemoglobin observed in the imetelstat arm, since one of the key symptoms of anemia is fatigue; thus, the adverse effects of the drug may negate some of the benefit.
FDA also noted that there is residual uncertainty regarding the optimal dose of imetelstat, given the limited dose exploration in the target population and high rate of dose modifications in Study MDS3001.
Given these identified risks and uncertainties, FDA convened an ODAC meeting on March 14, 2024 to discuss the benefit/risk profile of imetelstat.26 The ODAC voted 12:2 (yes:no) that the potential benefits of imetelstat outweigh its risks. The committee members who voted “yes” highlighted the limited options available to treat MDS. They stated that avoiding transfusion as long as possible reduces toxicity which is meaningful for patients with MDS even in the absence of a disease-modifying effect or survival benefit. Committee members acknowledged the severity of side effects (particularly cytopenias) observed from imetelstat but discussed that these events could be managed by hematologists.
A post-marketing randomized trial evaluating at least two dosages of imetelstat to potentially minimize serious risks and improve tolerability was required at the time of approval. Post-marketing assessments evaluating the long-term safety, risk of QT prolongation, and carcinogenicity of imetelstat were also required to inform future labeling.
Conclusion
The benefit-risk analysis of the results of Study MDS3001 supported regular approval of imetelstat for the treatment of adult patients with low- to intermediate-1 risk MDS with transfusion-dependent anemia requiring ≥4 RBC units over 8 weeks who have not responded to, have lost response to or are ineligible for ESAs. The primary endpoint was met, and approval was granted based on demonstration of a ≥8-week and ≥24-week RBC-TI benefit with imetelstat compared to placebo in a population with limited treatment options. Notably, a statistically significant treatment effect was not observed on the key secondary endpoint of HI-E per IWG 2006 criteria or other secondary endpoints reflective of a disease-modifying effect. Significant toxicities such as neutropenia and thrombocytopenia, including more events requiring intervention, were identified as important risks of imetelstat. A randomized trial comparing at least two dose levels of imetelstat was required to potentially minimize the serious risks of treatment.
Supplementary Material
Source: FDA’s rendering based on the Applicant’s Summary of Clinical Efficacy in MDS
Source: NDA Multi-disciplinary Review and Evaluation (NDA 217779).16
Data cutoff 13 October 2022
Source: NDA Multi-disciplinary Review and Evaluation (NDA 217779).16
Data cutoff 13 October 2022
Footnotes
Disclosure of Potential Conflicts of Interest: The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report.
Dr. Marc Theoret left the FDA in April 2025, but the work completed for this article was performed during employment at the FDA.
References
- 1.Greenberg P, Cox C, LeBeau MM, et al. : International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–88, 1997 [PubMed] [Google Scholar]
- 2.Greenberg PL, Tuechler H, Schanz J, et al. : Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120:2454–65, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Platzbecker U, Kubasch AS, Homer-Bouthiette C, et al. : Current challenges and unmet medical needs in myelodysplastic syndromes. Leukemia 35:2182–2198, 2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Malcovati L, Della Porta MG, Cazzola M: Predicting survival and leukemic evolution in patients with myelodysplastic syndrome. Haematologica 91:1588–90, 2006 [PubMed] [Google Scholar]
- 5.Garcia-Manero G: Myelodysplastic syndromes: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol 98:1307–1325, 2023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Mo A, Poynton M, Wood E, et al. : Do anemia treatments improve quality of life and physical function in patients with myelodysplastic syndromes (MDS)? A systematic review. Blood Rev 61:101114, 2023 [Google Scholar]
- 7.Wan BA, Alibhai SMH, Chodirker L, et al. : Improvement in quality of life in MDS patients who become transfusion independent after treatment. Leuk Lymphoma 66:279–288, 2025 [DOI] [PubMed] [Google Scholar]
- 8.Santini V, Giagounidis A, Pelligra CG, et al. : Impact of Lenalidomide Treatment on Overall Survival in Patients With Lower-Risk, Transfusion-Dependent Myelodysplastic Syndromes. Clin Lymphoma Myeloma Leuk 22:e874–e883, 2022 [DOI] [PubMed] [Google Scholar]
- 9.De Witte T, Malcovati L, Fenaux P, et al. : Novel dynamic outcome indicators and clinical endpoints in myelodysplastic syndrome; the European LeukemiaNet MDS Registry and MDS-RIGHT project perspective. Haematologica 105:2516–2523, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.de Swart L, Crouch S, Hoeks M, et al. : Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes. Haematologica 105:632–639, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.National Comprehensive Cancer Network. Myeloysplastic Syndromes (Version 1.2024), [Google Scholar]
- 12.Briatore F, Barrera G, Pizzimenti S, et al. : Increase of telomerase activity and hTERT expression in myelodysplastic syndromes. Cancer Biol Ther 8:883–9, 2009 [DOI] [PubMed] [Google Scholar]
- 13.Poloni A, Serrani F, Berardinelli E, et al. : Telomere length, c-myc and mad-1 expression could represent prognosis markers of myelodysplastic syndrome. Leuk Res 37:1538–44, 2013 [DOI] [PubMed] [Google Scholar]
- 14.Yan S, Han B, Li H, et al. : Telomerase gene screening and telomere overhang detection in Chinese patients with myelodysplastic syndrome. Leuk Res 37:1359–62, 2013 [DOI] [PubMed] [Google Scholar]
- 15.U.S. Food and Drug Administration. Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics. 2014. https://www.fda.gov/media/86377/download. [Google Scholar]
- 16.U.S. Food and Drug Administration. Drugs@FDA [database on the internet]. Imetelstat. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217779Orig1s000MultidisciplineR.pdf., [Google Scholar]
- 17.Geron Corp. A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) that is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment. [Internet]. 2022. [cited 2025 June 16]; Available from: https://cdn.clinicaltrials.gov/large-docs/61/NCT02598661/Prot_000.pdf. [Google Scholar]
- 18.Platzbecker U, Santini V, Fenaux P, et al. : Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 403:249–260, 2024 [DOI] [PubMed] [Google Scholar]
- 19.Functional Assessment of Cancer Therapy – Anemia (FACT-An) version 4 [Internet]. FACIT.org; c1987, 1997. [cited 2025 Jul 11]. Available from: https://www.facit.org/measures/fact-an. [Google Scholar]
- 20.Abel GA, Efficace F, Buckstein RJ, et al. : Prospective international validation of the Quality of Life in Myelodysplasia Scale (QUALMS). Haematologica 101:781–8, 2016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT‑Fatigue) version 4 [Internet]. FACIT.org; c1987, 1997. [cited 2025 Jul 11]. Available from: https://www.facit.org/measures/facit-fatigue. [Google Scholar]
- 22.U.S. Food and Drug Administration. Drugs@FDA [database on the internet]. Imetelstat USPI. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217779s000lbl.pdf., [Google Scholar]
- 23.Mina A, McGraw KL, Cunningham L, et al. : Advancing drug development in myelodysplastic syndromes. Blood Adv 9:1095–1104, 2025 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.U.S. Food and Drug Administration. Drugs@FDA [database on the internet]. Decitabine. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021790s000_Dacogen_MedR.pdf. [Google Scholar]
- 25.U.S. Food and Drug Administration. Drugs@FDA [database on the internet]. Azacitidine. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/50-794_Vidaza_Medr_P1.pdf. [Google Scholar]
- 26.U.S. Food and Drug Administration. March 14, 2024: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. https://www.fda.gov/advisory-committees/advisory-committee-calendar/march-14-2024-meeting-oncologic-drugs-advisory-committee-meeting-announcement-03142024, [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Source: FDA’s rendering based on the Applicant’s Summary of Clinical Efficacy in MDS
Source: NDA Multi-disciplinary Review and Evaluation (NDA 217779).16
Data cutoff 13 October 2022
Source: NDA Multi-disciplinary Review and Evaluation (NDA 217779).16
Data cutoff 13 October 2022