Unexpectedly Better Results Cause Phase III Trial Failure for Gensight

Clinical trials must produce exactly the expected result or they are declared a failure. A clinical trial can fail by producing unexpected benefit, and this has happened to Gensight Biologics' work on allotopic expression of the mitochondrial NH4 gene, aimed at the treatment of inherited retinal degeneration caused by mutation in NH4. Allotopic expression is a process in which a copy of the correctly formed gene is placed into the cell nucleus, suitably altered to enable transport of the protein produced back to the mitochondria where it is need.

In a sane world, this therapy would long ago have been available to anyone willing to accept the risk, based on positive earlier results and lack of serious side-effects. In that same sane world, the therapy would now be available to anyone willing undergo the risk of gaining a greater benefit than was hoped for. Unfortunately we don't live in that world, and Gensight will now have to run further very expensive trials before regulators will permit the treatment to reach the clinic.

We watch progress at Gensight because allotopic expression of NH4 is one-thirteenth of a rejuvenation therapy - Gensight is the result of research supported and encouraged by the Methuselah Foundation some ten years ago. If all thirteen important mitochondrial genes can be copied into the cell nucleus, then that would make an individual largely invulnerable to stochastic mitochondrial DNA damage and resultant dysfunction. It is thought that this is an important root cause of degenerative aging.

GenSight Biologics, a biopharma company focused on discovering and developing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced topline results from the REVERSE Phase III clinical trial evaluating the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 37 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) commenced between 6 and 12 months prior to study treatment.

Topline results further highlight the favorable safety and tolerability profile of GS010, and demonstrate a clinically meaningful improvement of +11 ETDRS letters in treated eyes at 48 weeks as compared to baseline in all 37 patients. Unexpectedly, untreated contralateral eyes (treated with a sham injection) show a similar improvement of +11 ETDRS letters. Due to this improvement in untreated eyes, the trial did not meet its primary endpoint, defined as a difference of improvement in visual acuity in GS010-treated eyes compared to sham-treated eyes at 48 weeks.

The improvement of visual acuity in sham-treated eyes was unexpected based on the natural history of LHON, for which partial spontaneous recovery is reported in only 8-22% of patients with the G11778 ND4 mutation. "This meaningful improvement of untreated eyes observed at week 48 was totally unexpected given what is known and has been published about the natural history of this devastating disease. We will continue to analyze the data to better understand our results, but they suggest that GS010 benefits both eyes in a way that is still to be understood. The fact that structural measures of the retina showed such a large statistical difference with treatment is compelling and objective evidence that this gene therapy protects the integrity of many retinal ganglion cells from the damage of LHON."

Based on preliminary analysis of the safety data, GS010 was well tolerated after 48 weeks. The ocular adverse events most frequently reported in the therapy group were mainly related to the injection procedure, except for the occurrence of intraocular inflammation (accompanied by elevation of intraocular pressure in some patients) that is likely related to GS010, and which was responsive to conventional treatment and without sequelae. There were no withdrawals from the trial. GS010 is currently being investigated in two additional ongoing Phase III trials, RESCUE and REFLECT, while patients in REVERSE continue to be followed for another 4 years.

Link: https://www.gensight-biologics.com/2018/04/03/gensight-biologics-announces-topline-results-from-reverse-phase-iii-clinical-trial-of-gs010-in-patients-with-leber-hereditary-optic-neuropathy-lhon/


Unfortunately it will take anther year or two delays to rethinking the study and change the protocol. Let's say if the study didn't involve one placebo eye but rather one placebo patient we could know if the vector was too powerful and infected both eyes and probably the brain. That would give us a proven vector for the whole brain genetic therapy, provided it is safe and without long term effects.

Posted by: Cuberat at May 14th, 2018 7:50 AM

I've never seen an outcome like this.

This is amazing!

And yet, because of protocol, millions will suffer while we 'retool' the expectation outcome instead of grabbing this with both hands and improving peoples lives.

Will we ever see meaningful change in the FDA approval process?

Posted by: Mark Borbely at May 14th, 2018 10:12 AM

It is time for GenSight go to medical tourism way! ;-)

Posted by: Ariel at May 14th, 2018 10:53 AM

Well, if you have an unexpected outcome it has to be explained away. Otherwise it might mean that the AAV vector is not safe and spreading trough the nerve tissues. Or there is a cross contamination, either by patient or during the administration.

I don't understand the chart that well: https://www.gensight-biologics.com/wp-content/uploads/2018/04/graph.png
But until week 10 the sham eyes have opposite dynamic than the GS010 ones. After about week 12 the dynamic is the same.

So the vector could have passed through the neurons or from the "outside" from the other eye or mucous. If it passed through the neurons, it is scary as it can affect the brain but opens the possibilities of whole brain treatments. If has come by non-neural paths that means that the instead of an injection drops could be enough...

Posted by: cuberat at May 14th, 2018 11:47 AM

good points

Posted by: CD at May 14th, 2018 12:07 PM

can someone explain me what exactly the number 11 means ? Is it like restoring 100% or just a marginal improvement?

Posted by: cuberat at May 14th, 2018 12:48 PM

The improvement was between 10 and 15 letters.
15 letters is basically twice as better as what you are at the moment.
So for instance if you're 20/40 15 letters means you'll be 20/20.

Posted by: Anonymoose at May 14th, 2018 1:10 PM

Given what we want GenSight's therapy to be used for in the long term, the possibility of the vector even spreading into the brain wouldn't be unwelcome...

Posted by: Patrick Deane at May 14th, 2018 6:20 PM

Please explain yourself Reason. This is a confusing post.

If the vector is taking an unknown route throughout the body that seems like a very dangerous effect. What if the also alters the heart muscle or something like that.

You certainly remember the deadly incident in England in the late 90's.

I do realize 30.000 people die of old age every day, but regulators don't have that mindset. So these scientists should be cautious.

Posted by: arren brandt at May 16th, 2018 12:58 AM

Actually, it's around 110,000. I agree that the strange result must be investigated and clarified before selling the treatment, since it could have unwanted consequences when more time passes or more people receive it (this was a quite small phase III trial, only 37 patients). Even more strange is the fact that physiological measures, like macular ganglion cell volume, improved in only one eye but vision improved in both.

Posted by: Antonio at May 16th, 2018 6:54 AM

@arren brandt: People should be permitted to adopt the risk they want to adopt. This therapy has been used in humans for a few years now with no meaningful downsides yet observed. In a better world, every therapy would be open to anyone at any stage.

Posted by: Reason at May 16th, 2018 8:07 AM

@Antonio: Maybe it could be that while one eye DID degenerate, it just didn't degenerate to a large enough extent to be clinically detectable.

Posted by: Patrick Deane at May 16th, 2018 4:25 PM
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