Note: Patrick Deane holds shares in Gensight Biologics (EPA: SIGHT).
A trial with damagingly positive results
Gensight Biologics, a company researching – among other things – the movement of mitochondrial genetic information to the nucleus to treat hereditary genetic diseases (a strategy that could also have an impact on aging according to the SENS Research Foundation), has recently released data for its latest trial of GS010, a therapy against the blindness-causing genetic disease LHON. As a phase 3 trial, this stage is the final stage of research necessary before regulators may allow the company to bring this therapy to market.
While Gensight has focused on the significance of patient recovery against the normal progression of the disease, the trial now shows statistical insignificance in all areas (which is likely to lead to a future trial failure), despite notable improvements against the normal progression of the disease .
The outlook for the drug is not necessarily negative
This is not the drug’s first brush with statistical insignificance; it has failed a clinical trial before, though not necessarily due to ineffectiveness. In this, along with other clinical trials, the group directly exposed to the drug made an impressive recovery, far beyond the normal – but so did the group that it was being compared against (the “control group”), causing trial failure. The same issue appears to have happened in the latest trial.
Some people have suspected that the control group recovered due to the fact that its participants each had one eye treated with the drug. The drug specifically affects the eyes, and in this trial and in previous trials, the company has always randomly selected one eye of each of its patients to inject with the therapy. This unusual recovery in two trials could easily be explained by the drug being too effective – spreading from one eye to the other after injection and thus treating both of them.
If this suspicion is correct, Gensight’s therapy is much more promising than could be assumed by just seeing its trial failures – if so, the layout of its trials would be making an effective drug seem useless. With this in mind, I emailed Gensight Biologics a few days before the release of this data, questioning why the company set up the trials in this way – and got a response from its Chief Financial Officer.
A word from Gensight’s Chief Financial Officer
In his email, the CFO stated that individuals who are respected in the research and patient communities around LHON, along with European regulators, strongly disagreed with the concept of a trial in which the control group had no exposure to the drug. Only the FDA considered allowing such a trial. This was because the drug – potentially the only cure for the disease – needed to be used early in the disease’s progression to save the eyesight of patients. Having a ‘true’ control group would effectively sentence these patients to blindness.
These barriers made it impossible to run a trial with a full control group, leading to the current design in which at least one eye is treated in each patient, including the control group patients.
In 2018, the first preliminary results of the first Phase 3 trial were released, showing an improvement in both eyes, treated and untreated, which was a surprise both for the company and leading figures in the area, and it led to trial failure.
This effect was confirmed in two trials, and the company expects the same effect in the remaining three trials, which are still ongoing. Because of this, Gensight will consider starting a trial with a full control group if the FDA suggests it in a meeting in the summer. It’s important to note that the EMA will not allow such a trial to be done in Europe, so it will not support a release in EU countries under its jurisdiction. In addition, the company is running a study to further document the normal progression of the disease, which is likely to provide further evidence in favor of the drug having a beneficial impact on both treated and untreated eyes.
One possible alternative
To verify the suspicion that the drug is unintentionally treating the control group, in an upcoming summer meeting, the FDA may request a trial that shows the therapy’s effectiveness compared to a control group of completely untreated patients, which would encourage regulators to allow the drug’s sale as a treatment against LHON.
How is this relevant to aging?
GS010 is a gene therapy that moves one of the 13 vital protein-coding genes in mitochondria into the cell nucleus. Some scientists suggest that the transfer of each of these genes to the nucleus could prevent some of the issues caused by mitochondrial dysfunction in aging. In theory, the gene therapy used in GS010 could possibly be used as part of a suite of therapeutics to slow the accumulation of damage that causes the disabilities and diseases of old age.
If the drug works in humans, it will be an effective treatment for LHON and the degraded vision that accompanies it. Therefore, although this trial does not focus on an age-related disease, it is still very relevant, and its success would be a major step towards a therapeutic against one of the processes of aging.
Gensight Biologics is particularly interesting in aging research because of its focus on gene transfer to the nucleus. While this one therapy may have no real impact on aging by itself, transferring all 13 genes could possibly treat mitochondrial dysfunction, which is one of the hallmarks of aging.
Gensight’s drug is a very promising candidate to cure a crippling genetic disease and a step towards a treatment for an aspect of aging, and we look forward to the trial that will be discussed with the FDA this summer.
 Silva, M. Lloria, X. Catarino, C. Klopstock, T. (2018) Natural history findings from a large cohort of patients with Leber’s hereditary optic neuropathy (LHON): New insights into the natural disease‐course. Acta Ophthalmologica, 96(261), 117