Zinc fingers get the thumbs down

Reaction to data from Sangamo's ongoing genome-editing trial shows that small numbers can equal big risks.

Trial Results

Orphan drug makers have made hay in recent years by releasing data from small numbers of patients in ongoing early-stage trials, a strategy that has generated huge share jumps for pre-commercial companies like Sarepta and Bluebird Bio. Yesterday Sangamo learned that this is not always a winning strategy.

The first results of a phase I/II trial of the group's mucopolysaccharidosis type II (MPS II) candidate SB-913 in four subjects disappointed investors, who drove shares down 24%. While some biomarker data looked promising, the Zinc finger-based genome editing project was not shown to increase levels of the enzyme on which its mechanism of action depends.

Given the small number of patients it is far too early to pass judgement on this trial, named Champion, especially since Sangamo 's data relates only to two patients taking a low SB-913 dose, believed to be less than an effective amount, and two taking a medium dose. Two more patients have received the highest of the three doses in the trial, but efficacy results from this cohort were not available for yesterday's presentation, at the Society for the Study of Inborn Errors of Metabolism meeting.

GAG reflex

It was the medium-dose of 1x1013vg/kg that Sangamo emphasised yesterday. In the two patients in this arm there was a 51% mean reduction after 16 weeks in glycosaminoglycans (GAGs), which in MPS II accumulate, causing damage to tissues and organs. This reduction came on top of a backbone of enzyme-replacement therapies.

However, tests to detect iduronate 2-sulfatase (IDS), the enzyme for which SB-913 codes, found no detectable levels in the blood plasma. IDS is absent in MPS II patients, and is necessary to break down the GAGs.

In a call with analysts, Sangamo executives offered two possibilities for the failure to detect IDS. One was that cells were starved of IDS and absorbed all of it from the bloodstream to help break down the GAGs that had accumulated; the other was that the assay the company has developed was not sensitive enough.

The group's chief executive, Sandy Macrae, argued that the reduction in GAGs should be a sufficient sign that SB-913 is doing what it is supposed to, stating: “The GAG levels are convincingly reduced. The only way that could have happened is if IDS is produced. The only way that could have happened is for the gene to have been edited.”

Sangamo's technology is based on Zinc finger nucleases, an approach that since the advent of Crispr has been seen by some as outdated. Still, Crispr has faced recent criticism about lack of safety, and a setback for one technology is no longer seen as a win for the other: Crispr stocks were down yesterday.

Biomarker confusion

Mr Macrae said the US FDA had used GAG reduction as an approval endpoint for MPS products in the past. But this does not appear to have been the case with the leading marketed product, Shire’s Elaprase. To gain approval Shire had to show patients' improvement on the six-minute walk test and in predicted forced vital capacity, measures of mobility and respiratory function, over a 53-week trial.

Given that in Champions the reduction in GAG came on a backbone of enzyme-replacement therapy any effect specifically due to SB-913 is even harder to deduce. Mr Macrae said the only way to be certain was to wean patients off of their weekly infusions of Elaprase and see if GAG levels increased, something Sangamo plans to test by carrying out a "controlled withdrawal" of enzyme-replacement therapy soon.

Until this happens, however, and until the potential of higher SB-913 doses is shown, Sangamo investors will have to keep guessing whether the hype lives up to executives’ promises. The company has found out that the recent trend of piecemeal data releases for DNA and RNA therapeutics can generate unwanted controversy.

Study Trial ID
Champion NCT03041324

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