Market sees hard path ahead for Gensight


Despite its best efforts, Gensight has failed to capitalise on the resurgence of gene therapy. The French company maintains that a phase III flop for its lead project, GS010, does not mean the end of the line, but investors were not convinced, sending its stock down 48% yesterday.

Gensight might be helped by the fact that its candidate is being studied in Leber’s hereditary optic neuropathy (LHON), a genetic disease that leads to blindness and for which there are few options – the mid to late-stage pipeline also looks sparse (see table below). All now hinges on a second phase III trial of GS010 due to report later this year.

Unfortunately a win in that study does not look likely based on topline data from the Reverse trial, which failed to show any difference between active and sham treatment groups on its primary endpoint, change in visual acuity at 48 weeks.

The trial was complicated by the fact that patients acted as their own controls, receiving GS010 in one eye and a sham injection in the other – or at least that is what Gensight believes. The GS010-treated eyes did show an improvement in visual acuity, of 11 letters over baseline on the standard ETDRS test, but a similar benefit was also seen in the sham-treated eyes.

The company suggested that the injection of GS010 into one eye could produce a benefit in both eyes, and plans to investigate this possibility. To back up this hypothesis, Gensight noted that spontaneous vision recovery is seen in only 8-22% of patients with LHON caused by the G11778 ND4 mutation – the population studied in Reverse.

However, secondary endpoints measuring structural changes within patients’ eyes – which showed significant improvements with GS010 versus sham – appear to contradict this view, suggesting that GS010 is not in fact having an effect on the untreated eye.

Hoping for Rescue

Gensight hopes that two-year results will demonstrate that these structural changes translate into improved visual acuity over the long term.

Until then there is likely to be scepticism about the company’s explanation for its miss, and the second phase III trial, Rescue, might not be able to clear this up this either. That study has a similar design, with patients receiving both GS010 and sham therapy; topline results are due in the third quarter.

Meanwhile, a third phase III study, Reflect, includes a cohort of patients receiving both GS010 and sham therapy, and a group that receives GS010 in both eyes.

On a conference call yesterday Gensight’s chief executive, Bernard Gilly, would not say whether the company would need to carry out a trial incorporating an untreated control group to gain approval – but if similar results are seen in Rescue and Reflect this could be a possibility.

With €55m ($67m) in the bank at the end of 2017, this would pose a problem for Gensight. The company has another candidate, GS030, which is due to start a phase I/II trial soon in retinitis pigmentosa, but GS010 was its big hope.

For now the group will be rueing a missed opportunity with GS010, particularly as there are so few options available for LHON. Santhera’s Raxone is the sole product approved, but only in Europe; its active ingredient, idebenone, is sold as a supplement for various disorders that are thought to benefit from its antioxidant properties.

There are just a handful of other candidates in clinical development, according to EvaluatePharma. All of these target mitochondria as LHON is caused by mutations in mitochondrial genes.

LHON pipeline
Project Company Description Status
Raxone Santhera Pharmaceuticals Coenzyme Q10 replacement therapy Marketed
GS010 Gensight Biologics NADH-ubiquinone oxidoreductase chain 4 gene therapy One phase III trial failed, two more to report
KH176 Khondrion Mitochondria targeted oral therapy Phase II completed
Visomitin Mitotech Mitochondria targeted eye drops Phase II completed
Elamipretide Stealth Biotherapeutics Mitochondria targeted eye drops Phase II (NCT02693119), primary completion May 2018
Source: EvaluatePharma.

Khondrion has said that it plans to move its oral agent, KH176, into phase III after last year completing the exploratory phase II Khenergy trial in various mitochondrial diseases including LHON, but it is not clear how important this indication is for the company.

Also in 2017, Mitotech touted phase II results with Visomitin, its antioxidant eyedrops – albeit from an open-label study in Russia. And another topical project, Stealth Biotherapeutics’ elamipretide, should yield results this year.

Gensight appears to be the only company trying to address the underlying cause of LHON, but it has missed its first chance to set its candidate apart from the chasing pack. The company will have a second bite at the cherry later this year, but the signs are not looking good.

GS010 phase III trials
Study Details Trial ID Data due
Reverse 7-12 months of onset of vision loss NCT02652780 Failed
Rescue <6 months of onset of vision loss NCT02652767 Topline data due Q3 2018
Reflect <1 year of onset of vision loss NCT03293524 Primary completion Jun 2020
Reality Natural history study NCT03295071 Primary completion Mar 2019

To contact the writer of this story email Madeleine Armstrong in London at or follow @ByMadeleineA on Twitter

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