Geron blow could put final nail in telomerase inhibitor coffin

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The discontinuation of a phase II trial of imetelstat looks bleak not only for its originator, Geron, but also for the concept of targeting the enzyme telomerase, which was once hailed as a possible breakthrough in cancer treatment.

Given how bullish analysts were on imetelstat, also known as GRN163L, it came as little surprise that that Geron’s stock took a beating on the news, closing down 56% at $1.28 yesterday and valuing the California-based biotech at $168m – barely $45m above its cash balance. The project is the only small-molecule telomerase inhibitor in clinical development, and while officially the plug has not yet been pulled the setback does threaten to consign the approach to biotech’s scrapheap.

Geron discontinued a phase II breast cancer trial early, after seeing a statistically significant shortening of progression-free survival and an increase in deaths in the imetelstat arm versus placebo, as well as saying that an NSCLC trial was unlikely to succeed. Imetelstat’s future now rests on two phase II studies, in multiple myeloma and essential thrombocythaemia, due to read out by the end of this year.

The blow came less than a year after the company changed its CEO and narrowed its focus to small molecules, scrapping earlier work on human embryonic stem cells (Geron exits embryonic stem cell stage, November 15, 2011). Consensus sales forecasts for imetelstat stood at $468m by 2018, and even accounting for a 31% risk adjustment EvaluatePharma computed a net present value of $482m.

Significantly worse

The trial in Her2-negative metastatic breast cancer tested the addition of imetelstat to paclitaxel and Avastin. It was terminated after a scheduled interim analysis found that progression-free survival was 8.0 months for placebo but only 6.2 months in the active arm – a statistically significant difference with p=0.028.

More patients also died in the active arm – 16 versus 10 placebo recipients – although this was not statistically significant. Geron blamed concerns over the haemotoxicity of combining imetelstat with paclitaxel, which had caused it to allow patients to reduce their paclitaxel dose if needed; it said there was an increase in such reductions in the active arm, and this was likely responsible for the fall in survival.

But the findings also prompted an unplanned analysis of an advanced NSCLC study, and this found no meaningful difference in progression-free survival; while this trial will continue, Geron says it is doubtful that phase III in this indication will now take place.

Telomerase days numbered?

Telomerase inhibition was once seen as an important breakthrough in treating proliferative as well as degenerative diseases. However, the discovery of the enzyme has failed to translate into clinical successes, and now the days of the few projects remaining in the R&D pipeline look numbered.

The only other non-vaccine approach was Telomelysin, a telomerase-specific replication-component adenovirus in clinical development by the two private Japanese companies Medigen Biotechnology and Oncolys BioPharma; nothing has been heard about this for some time.

Anti-telomerase vaccine approaches included one that Geron itself had had in studies together with Merck & Co, but this too seems to have been dropped. Beyond a couple of private company-sponsored projects little remains of this field.

Geron insists that the differing designs of the imetelstat studies means that the failure of one does not necessarily spell doom for any of the others, and presumably this too can in theory be applied across the pharmacological class.

But given its dismal success rate, the company might soon find itself undergoing another change of focus.

Study Trial ID Notes
166 patients, metastatic breast cancer NCT01256762 Terminated
116 patients, advanced NSCLC NCT01137968 Unlikely to succeed
48 patients, multiple myeloma NCT01242930 Readout Q4 2012
40 patients, essential thrombocythaemia NCT01243073 Readout Q4 2012

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com

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