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An FDA panel overwhelmingly backed investigational imetelstat as a treatment option for transfusion-dependent anemia in adults with lower-risk myelodysplastic syndromes (MDS) who failed on erythropoiesis-stimulating agents (ESAs) or are ineligible for this standard treatment.

Despite concerns registered by FDA staff ahead of Thursday's meeting of the Oncologic Drugs Advisory Committee (ODAC), the committee members agreed by a 12-2 margin that the transfusion-independence benefit demonstrated in a phase III study of the first-in-class telomerase inhibitor was enough to overcome concerns about adverse effects associated with the drug.

"This trial met its primary endpoint," pointed out panelist Neil Vasan, MD, PhD, of Columbia University Medical Center in New York City, in explaining his vote in support of imetelstat's benefit.

"It offers a new therapy for some patients who may have no other options," he added. "The benefit in improvement in transfusion independence outweighed the risk of cytopenias in a patient population and a blood cancer oncology community that is well versed in these adverse events and their management."

Geron, imetelstat's developer, is seeking traditional approval for the drug, with its application supported by , a multinational phase III trial that included 178 heavily transfused patients who failed on ESAs.

The primary outcome showed that the group randomized to imetelstat had significantly higher rates of red blood cell (RBC) transfusion independence for at least 8 weeks compared with the group assigned to placebo (39.8% vs 15%, P=0.001). The trial also met the key secondary endpoint of 24-week transfusion independence (28% vs 3.3%, P=0.001).

As noted, incidence of high-grade thrombocytopenia and neutropenia were higher in the study arm versus the placebo arm, as was the use of myeloid growth factors:

• Grade 3/4 neutropenia: 71% vs 7%, respectively
• Grade 3/4 thrombocytopenia: 65% vs 8%
• Myeloid growth factors: 36% vs 3%

"Clinicians can continually evaluate the risks and benefits of the drug, and if it's not working they can stop it," said Jorge Nieva, MD, from the Keck School of Medicine of the University of Southern California in Los Angeles. "The data here is sufficient ... so that they can make their own decision."

"The long-term consequences of blood transfusions cannot be understated," said Jacqueline Garcia, MD, of the Dana-Farber Cancer Center in Boston. "Seeing the 25% of patients that could have potential long-term benefit beyond the 24 weeks and up to a year is really impressive."

She also noted that many of the grade 3/4 cytopenias in the imetelstat-treated group were transient, and said she was "impressed by the fact they did not result in serious infections."

ODAC Chair Ravi Madan, MD, of the National Cancer Institute in Bethesda, Maryland, one of the two votes against the drug, noted that while the data are encouraging for a subset of patients who benefited from imetelstat, the majority of patients did not derive a benefit.

"That combined with the increased toxicity seen with the agent ... makes the data less clear to me that the risks totally outweigh the benefits for all patients treated," he explained.

In presenting its case for imetelstat, Geron emphasized that the population addressed in MDS3001 represents a significant unmet need.

Once patients become ESA relapsed or refractory, only two FDA approved treatments -- luspatercept (Reblozyl) and lenalidomide (Revlimid) -- remain for transfusion-dependent anemia, noted Michael Savona, MD, of Vanderbilt University in Nashville, Tennessee, speaking for the drugmaker.

"And these options currently do not meet the unmet medical need for about 75% of lower-risk MDS patients," he said. "There is a clear unmet need for a new treatment option that achieves durable transfusion independence in patients with transfusion-dependent anemia."

During the hearing's open public hearing segment, many of the speakers spoke to that question of unmet need.

Gail Roboz, MD, of Weill Cornell Medicine in New York City, told the panel that the biggest clinical problem facing low-risk MDS patients is progression to bone marrow failure and transfusion dependence.

"If you talk to MDS patients, they know to dread this complication," she said, adding that what is needed is a treatment that results in higher levels of hemoglobin and fewer transfusions.

"While we do have approved treatments ... the reality is most of our patients cycle through most or all of these options, and they don't respond at all, or lose their response after just weeks or months on treatment," said Roboz. "It is no surprise that I, along with patients and doctors in the MDS community, are enthusiastic about the prospect of having imetelstat as a treatment option."

While the FDA is not required to follow the recommendations of its advisory committees, the agency typically does.

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