After 33 years Geron could have an approved drug

The strange journey of Geron’s telomerase inhibitor imetelstat is reaching a conclusion, nine years after a controversial haematologist endorsed the project’s use in myelofibrosis. Today the group toplined imetelstat’s phase 3 Imerge study as positive, setting the stage for a filing later this year in low-risk myelodysplastic syndromes.

That said, imetelstat’s precise positioning is complicated by Bristol Myers Squibb’s Reblozyl, which recently succeeded in front-line disease, and Geron’s press release gives only limited commentary on safety. If approved, however, imetelstat would represent Geron’s first actual drug since the company was founded in 1990 to focus on diseases of ageing.

The outcome of Imerge is biotech’s first big catalyst of the new year as investors hope to put the nightmare of 2022 behind them. It represents the culmination of Geron’s solo effort to develop imetelstat, specifically in myelodysplastic syndromes (MDS) patients who are at low or intermediate risk.

Primary hit

Imetelstat has aced Imerge's primary endpoint, transfusion independence at eight weeks, with a rate of 40%, versus 15% for placebo (p<0.001); all patients in Imerge had to have failed on or been ineligible for erythropoiesis-stimulating agents (ESAs).

Median duration of transfusion independence – a vital metric for prescribers – was around one year. In a phase 2 trial imetelstat achieved eight-week transfusion independence of 42%, with a median duration of 88 weeks, so Imerge shows a slight and not unexpected dropoff in efficacy.

What will doctors hold the Imerge data up against? Because Incyte’s Jakafi is approved for high-risk myelofibrosis, the relevant comparator is Bristol Myers Squibb’s Reblozyl, approved for low to intermediate-risk MDS patients who have failed ESAs, and whose label cites eight-week transfusion independence of 38%.

So on a straight cross-trial basis imetelstat appears to have at least matched Reblozyl. But of course there are subtleties.

Firstly, Reblozyl is approved only for use in patients with ringed sideroblasts (some 25% of the post-ESA market), and Geron stresses imetelstat’s activity in patients with or without this abnormal cell type. However, a KOL cited by B Riley analysts says Reblozyl is routinely used off-label in ringed sideroblast-negative patients too.

As such, perhaps the most important differentiation for imetelstat is its activity in patients with high transfusion burden, where on Imerge’s primary endpoint imetelstat scored 34%; for Reblozyl the figure is just 10%, and some analysts say this niche represents the area of unmet need to which imetelstat might be limited.

But a further complication is Reblozyl’s Commands trial – in MDS patients naive to ESAs – which was toplined positive in October. If this gives Reblozyl an earlier-line label then doctors will want to know how imetelstat performs in patients who progress on the BMS drug, and here there is little to go on.

Geron told Evaluate Vantage that the small number of Imerge patients who had previously received Reblozyl did not allow conclusions to be drawn. “For patients with low-risk MDS, what is most important is that imetelstat is differentiated from any other drugs in this field [by its] mechanism of action,” a spokesperson said.

A long history

Before turning its attention to imetelstat in MDS Geron had flirted with work on embryonic stem cells. But a talk at the 2013 Ash meeting by the Mayo Clinic’s Dr Ayalew Tefferi, who said imetelstat “clearly showed antimyeloproliferative activity” in an academic trial, prompted Johnson & Johnson to license the project for $35m up front, and the die was cast.

However, Dr Tefferi had used an unorthodox definition of clinical response, and his trial saw some patients suffer myelosuppression, in one case resulting in death. Later the FDA put imetelstat in hold because of liver toxicity, and this was not lifted until eight months later, just before the J&J deal was struck.

Ultimately the Imbark study, in post-Jakafi patients, failed to match Dr Tefferi’s data, and J&J walked away from the deal in late 2018, leaving Geron to press on with Imerge alone.

The earlier clinical hold means that safety data remain closely watched. Imerge saw some grade 3 liver function test elevations, but these were said to be reversible to grade 2 or lower, with no cases consistent with Hy’s Law. As for myelosuppression, Geron said “limited grade 3 cytopenias ... resolved to grade 2 or lower within four weeks”.

In an investor presentation Geron said ALT elevations of any grade were seen in 39% and 37% of imetelstat and placebo subjects respectively. The respective discontinuation rates in Imerge were very high, 77% and 76%, presumably as patients sought to switch to Reblozyl outside the scope of the trial.

Barring any further nasty revelations imetelstat looks approvable. How broadly it might be used will depend on the FDA and on the view doctors take of its activity after Reblozyl.

This is an updated version of a story published earlier.