FDA ODAC Votes Yes on Imetelstat for Patients with MDS

Primary myelofibrosis (PMF) cells in blood flow - closeup view 3D illustration: © LASZLO - stock.adobe.com

• The FDA’s Oncologic Drug Advisory Committee (ODAC) has voted that the benefits of imetelstat outweigh the risks for patients with lower-risk myelodysplastic syndromes (MDS) with anemia who are transfusion-dependent and ineligible for erythropoiesis stimulating agents (ESA).
• Findings from the IMerge/MDS3001 study (NCT02598661) were presented to the ODAC by Geron Corporation, the sponsor of imetelstat’s new drug application.
• While this vote does not represent a regulatory decision, it presents a positive step forward for this intent-to-treat population.

The FDA’s ODAC has voted 12 to 2 that imetelstat does serve as an improved treatment method for patients with MDS and anemia who are dependent on transfusions and are unresponsive to or ineligible for treatment with ESAs, and the benefits of the agent outweigh the risks.¹

“Transfusion independence is the quality metric here and why I think there’s efficacy and meaningfulness for patients here,” said Ashley Rosko, MD, professor in the Division of Hematology at The Ohio State University in Columbus, OH, and member of the ODAC.

About the Phase 2/3 IMerge Study

The new drug application for imetelstat, a liquidated oligonucleotide and a telomerase inhibitor, was supported by data from the IMerge/MDS3001 study. Findings were published in The Lancet in December 2023.² Patients were randomized 2:1 to receive imetelstat or placebo, and patients in the imetelstat arm received 7.5 mg/kg of intravenous imetelstat every 4 weeks until disease progression, toxicity, withdrawal of consent, or lack of response.

In the experimental imetelstat arm, 40% of patients (n = 40) achieved red blood cell (RBC) transfusion independence of at least 8 weeks vs 15% of patients (n = 9) in the placebo arm, meeting the study’s primary end point.

Regarding safety, 91% of patients in the imetelstat arm and 47% of patients in the placebo arm experienced grade 3 to 4 treatment-emergent adverse events, including neutropenia (68% vs 3%) and thrombocytopenia (62% vs 8%). No treatment-related deaths were reported. However, these safety issues were quickly resolved, according to Amer Zeidan, MBBS, associate professor at Yale School of Medicine.

“In this trial, the drug…was associated with treatment-related neutropenia and thrombocytopenia, which were grade 3 and higher in around two-thirds of patients. However, most of those were reversible within 2 weeks of holding the dose or delaying the cycle or reducing the dose and did not lead to an increase in the clinically significant adverse events such as bleeding and febrile neutropenia. I think overall, the efficacy and safety profiles are favorable,” Zeidan explained in an interview with Targeted Oncology^TM.

Applicant’s Stance

According to Geron, approximately 80% to 85% of patients with lower-risk MDS have anemia at diagnosis, with most being highly symptomatic, and 40% of these patients have anemia that is dependent on RBC transfusions.¹ Not only does the reliance on RBC transfusions strain medical resources, but chronic RBC transfusions are correlated with negative clinical outcomes, including risks of transfusion reactions, cardiovascular complications, infections, and iron overload and associate end-organ dysfunction. For these reasons, transfusion independence should be a therapeutic goal for patients and physicians, according to Michael Savona, MD, Beverly and George Rawlings Director of Hematology Research and professor of medicine and cancer biology at the Vanderbilt University School of Medicine, as well as an author of the IMerge study published in The Lancet.

The current landscape of care for this intent-to-treat population is limited, with only luspatercept (Reblozyl) and lenalidomide (Revlimid) approved for patients who are relapsed/refractory to ESAs. Further, these agents are only indicated in small subpopulations and do not show extended durability of transfusion independence, as presented by Savona.

The basis of many drug approvals in MDS, including lenalidomide and luspatercept, has been RBC transfusion independence, and only the approval for azacitidine in 2004 was supported by primary end point overall survival data.

“Geron’s position is that imetelstat meets the regulatory standards for approval. Given we are seeking an indication in transfusion-dependent anemia regulatory precedent exists where [transfusion independence] endpoints in the absence of disease-modifying effects have been used for the basis of approval for products treating transfusion dependent anemia in MDS,” said Faye Feller, MD, chief medical officer at Geron, during the meeting.

Geron also justified its dosing choice of 7.1 mg/kg every 4 weeks, noting that exposure-efficacy demonstrated a statistically significant improvement for both the 8-plus- and 24-plus-week transfusion independence rates, supporting that a lower dose may result in lower clinical efficacy. Moreover, the safety profile was manageable at its proposed dosage.

Rami Komrokji, MD, vice chair of the malignant hematology department and lead clinical investigation of the MDS program at Moffitt Cancer Center and Research Institute, provided the clinician’s perspective for the applicant’s presentation. Komorokji concluded that achieving transfusion independence was a meaningful clinical benefit for transfusion-dependent anemia in patients with lower-risk MDS, and that the duration of response was only clinically relevant in responders. Komorokji, who also served as an investigation on the IMerge study, noted that imetelstat provides long-term, continuous transfusion-free periods, and meaningful increases in hemoglobin and hematologic function were observed with imetelstat.

FDA’s Stance

In delivering the FDA’s opening remarks, Lori Ehrlich, MD, PhD, cross-disciplinary team leader in the Division of Hematology Malignancies I, stated, “For a new drug to be approved in the United States, the FDA must determine that the drug is safe and effective for use under the conditions prescribed, recommended, or suggested in the product labeling. The demonstration of effectiveness requires substantial evidence that the drug will have the effect it purports or is represented to have.”

“For a single randomized trial to support an application, results must be sufficiently robust and compelling. Because all drugs have adverse effects, the demonstration of safety requires showing that the benefits of the drug outweigh its risks,” Ehrlich continued.

The FDA’s issues with efficacy included that the secondary end points were not supportive of a disease-modifying treatment effect and that the patient-reported outcomes did not corroborate a treatment effect. Nina Kim, MD, clinical reviewer, presented on behalf of the FDA.

Kim noted that the clinical meaningfulness of an 8-week transfusion independence period in the context of lower-risk MDS is uncertain. Further, the association between a treatment-induced increased transfusion independence rate and an improvement in overall survival has not been demonstrated, and to support a marketing application, this connection should be present. However, no other trial has demonstrated a survival advantage in lower-risk MDS with transfusion-dependent anemia.

In lieu of these findings, the FDA held that patient-reported outcomes should demonstrate significant improvements. While the patient-reported outcome findings were only exploratory, the FDA did not find compelling evidence to support an improvement in anemia-related symptoms, primarily fatigue.

Kim also raised the point of medical resource utilization. As blood transfusions can put significant strains of medical resources, a benefit of imetelstat would be that it would reduce this utilization. However, the number of patients who had at least 1 medical encounter was higher in the imetelstat arm (56% vs 52%), indicating that treatment with imetelstat did not reduce medical resource utilization.

Most of the study sites of IMerge/MDS3001 were not conducted within the United States, and 93% of patients were enrolled at non-United States. sites. Kim noted that the primary efficacy results varied between United States and non-United States sites, indicating that imetelstat may not be an ideal applicant for approval in the United States population.

While incidence of grade 3 to 4 AEs was noted to be higher in the imetelstat arm, additionally, a higher percentage of patient deaths were observed in the imetelstat arm compared with the placebo arm.

Kim also identified issues with the dosing of imetelstat.

“Although other dose levels of imetelstat have been explored in myelofibrosis and solid tumors, only 1 dose has been explored in lower-risk MDS. The question remains whether this is actually the optimal dose in MDS given the dose modification rate with imetelstat observed in the MDS3001 study when compared with the placebo group, combined with the fact that there were high rates and a positive dose exposure response relationship for grade 3 to 4 thrombocytopenia,” Kim said.

“This data suggests that this may not, in fact, be the optimal dose,” Kim continued.

Blood cells: © Dr_Microbe - stock.adobe.com

ODAC’s Decision

Members of the committee who specialize in hematologic malignancies were encouraged by the results that imetelstat produced, especially for a patient population with limited options.

“I think transfusion independence is the standard of what to look for in these low risk MDS patients. I think looking at things like [complete response] and [partial response] really are not applicable in this population…The transfusion independence is the benchmark that is used in these patients. It’s been the benchmark that's used for other therapies in this setting,” said Anthony Hunter, MD, assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, GA.

“While [the cytopenias] are numerically important, it was really gratifying to see that they did not result in complications. When you take a look at the infections that were reported, it looked like nearly the majority were viral infections. It has been really hard for any of us to conduct and help our patients during the [COVID-19] pandemic, and for a lower-risk MDS, they're coming in frequently for transfusions. It was a laudable effort,” said Jacqueline Garcia, MD, medical oncologist in the Adult Leukemia Program at the Dana-Farber Cancer Institute in Boston, MA.

“One of the things particularly with the MDS population is fatigue. When I'm looking at this data in terms of being able to say what the applicant has presented here sufficiently robust. I think yes, I do,” said Rosko.

“This is a supportive drug….they did a trial and met their primary end point,” said Jorge Nieva, MD, associate professor of clinical medicine and section head of solid tumors, University of Southern California Norris Comprehensive Cancer Center in Los Angeles, CA. “The data here I think are sufficient.”

REFERENCES:

1. Oncologic Drugs Advisory Committee (ODAC) Meeting. FDA. March 14, 2024. Accessed March 14, 2024.

2. 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. 2024;403(10423)P249-260. doi:10.1016/S0140-6736(23)01724-5