Geron's blood disorder drug faces uphill battle amid bevy of FDA concerns

2024-03-12

临床3期临床结果寡核苷酸上市批准

Geron's hopes of getting its investigational antisense oligonucleotide imetelstat approved for myelodysplastic syndromes (MDS), and eventually positioning it as a competitor to Bristol Myers Squibb's Reblozyl (luspatercept), may have been thrown into serious doubt ahead of an FDA advisory committee meeting this Thursday.

Imetelstat is under review to treat transfusion-dependent anaemia in lower-risk MDS based on Phase III results from the IMerge trial where roughly 40% of patients given the telomerase inhibitor achieved the primary endpoint of independence from red-blood-cell transfusions (RBC-TI) at 8 weeks, compared to only 15% for placebo.

Magnitude and durability

Despite the Phase III win, FDA staff didn't seem convinced about how impactful that outcome was, noting that MDS experts generally consider only a 16-week or longer period of RBC-TI as clinically meaningful. That assessment was released in briefing documents Tuesday, dragging down Geron shares by 15%.

The company did evaluate the rates of RBC-TI lasting over longer periods, but response rates tended to shrink as the target durations got longer. FDA staff said imetelstat had a response rate of 28% for RBC-TI lasting 24 weeks, while only 13.6% achieved 1-year RBC-TI in the primary analysis. The corresponding rates for placebo were 3.3% and 1.7%, respectively.

Agency scientists also said the IMerge results are "not supportive of a disease-modifying treatment effect" in either extending overall survival (OS) or helping drive disease remission. Though not formally tested, the OS data showed a numerically higher percentage of deaths in the imetelstat arm compared to placebo at both the primary (16.1% vs. 13.3%) and updated analyses (29.7% vs. 25%).

"Unlike growth factors such as ESAs (erythropoiesis stimulating agents) which artificially raise blood cell counts, imetelstat is purported to have a direct effect on the underlying MDS through telomerase inhibition resulting in cell-cycle arrest, apoptosis, or senescence of malignant cells. However, these OS results are not supportive of a substantial disease-modifying treatment effect," FDA staff reviewers said.

Higher rates of cytopenias

Meanwhile, they also raised doubts about how applicable the IMerge results are for a US population. The vast majority of study participants (93%) in the trial were enrolled outside the country, and the primary efficacy result "varied greatly" between the US and non-US sites, according to FDA staff. Very few patients, for example, had had prior treatment with Reblozyl, an erythroid maturation agent approved since August as a frontline medicine for transfusion-dependent anaemia in lower-risk MDS patients.

The agency's safety assessment was no rosier. At 91%, imetelstat was associated with nearly double the rate of Grade 3 or 4 treatment-emergent adverse events (TEAEs) than placebo (47%). Much of the difference was due to higher rates of cytopenias in the imetelstat arm, but even when thrombocytopenia and neutropenia cases were excluded from the analysis, Geron's drug was still associated with a higher rate of Grade 3-4 events (54% vs. 39%). In addition, there were 14 discontinuations with imetelstat compared to none for placebo.

Geron previously said the adverse effects were not uncommon, adding "the side effects are short-lived and reversible."

Analysts 'still confident'

Nevertheless, Stifel analysts said in a recent note that while they expected "some volatility" in Geron shares due to possible skittish investor reaction to the AdCom briefing documents, they were "still confident" in imetelstat's regulatory and long-term commercial prospects.

"FDA's scathing clinical review of Phase III MEDALIST data and subsequent decision to broadly expand the [Reblozyl] label into 1L LR-MDS despite questionable COMMANDS data in a RS-negative patient population…represents our best surrogate for how this recently re-organised FDA division tasked with reviewing imetelstat perceives overall risk/benefit in this disease setting," they said.

The analysts predict efficacy will likely be the "least controversial" topic of discussion, while safety topics are likely to expand "beyond the obvious (myelosuppression, hepatotoxicity) to also include secondary primary malignancy and disease progression/AML transformation risk."

Last year, Geron CEO John Scarlett said the company anticipates a peak market potential of $1.2 billion for imetelstat in the US and some key EU countries by 2030.