FDA Decision Time Looms for Gelesis

November 29, 2018 FDA decision time looms for Gelesis

Elizabeth Cairns

Gelesis’s weight-loss capsule only hit one of the two co-primary endpoints in its approval trial. Will the FDA be persuaded?

When its obesity therapy, Gelesis100, fell short of a prespecified weight loss superiority margin over placebo in its pivotal US trial, Gelesis was able to point to a hit on the other endpoint. More patients given the product, a capsule containing a cellulose-based hydrogel which expands in the stomach, achieved the loss of 5% of their bodyweight than those in the placebo group.

“You do not have to have success on both endpoints for the FDA to approve a device,” says Harry Leider, chief medical officer at Gelesis. “Other drugs, in addition to devices, have been approved on the basis of success of one endpoint.” The marketing application is filed with the FDA, so the group will find out next year whether these data are in fact good enough.

Six-month data from the Glow trial showed that in the intent-to-treat population, 59% of Gelesis100-treated adults achieved weight loss of at least 5% vs. 42% in the placebo group – a success on the second co-primary endpoint. But the first, placebo-adjusted weight loss with a super-superiority margin of 3%, was not hit; the Gelesis100 treatment caused greater weight loss over placebo, but the margin was 2.1%.

Placebo

Mr Leider ascribes the miss on the placebo-adjusted weight loss metric to an unexpectedly high placebo response rate. “When you look at the drug studies, the percentage of patients that achieve 5% weight loss on placebo is about 20%. In our study it came out to be 42%.”

The reasons so many people lost weight on placebo are twofold, he adds. When patients take Gelesis, which they did twice daily in the Glow trial, they must drink a couple of glasses of water to enable the gel to expand. Naturally patients in the placebo group also drank water, and it appears that this helped them lose weight. The second explanation is psychological, he suggests, with people eating less as they believe taking a capsule, whether real or placebo, will make them feel full.

As for the endpoint that was hit, Mr Leider says that 59% of patients losing 5% of their weight compares well to the drugs that are approved for obesity. In three trials of Novo Nordisk’s Saxenda, for example, the proportions of patients who lost 5% of their weight at 56 weeks were 62%, 49% and 44%.

“It’s very much in the same ballpark with the exception of Qsymia,” Mr Leider says. According to its label, the high dose of Qsymia allows around 70% of patients to hit this 5% weight loss target at one year. But the Vivus drug, a combination of the anticonvulsant topiramate and phentermine, a stimulant, can be hard to tolerate. Mr Leider says the safety of Gelesis100 is “superlative”.

Though Gelesis is regulated as a device it will be viewed by patients and payers as more like a drug, Mr Leider says, and this is the niche the company hopes to occupy. “We don’t see ourselves competing with patients that are getting surgery or getting balloons, patients that are morbidly obese. We’re looking at patients who really would be happy losing 20lb or 30lb.”

This makes efficacy comparisons with drugs more apposite than with other devices or surgery. Cost comparisons, too. The company expects that Gelesis100 will generally be paid for out of pocket by patients, as obesity drugs generally are.

Lighting up

If the FDA is convinced by Gelesis100’s half-hit in the Glow trial, its clearance under the de novo 510(k) route will arrive next year. At that point the company might enter a new phase of its development.

“We should have some exciting options with the presumed FDA approval,” Mr Leider says, “and we’re evaluating our options whether we will be a standalone company.” Partnerships are a possibility, and the option of an IPO is also on the table.

Currently 20.5% of Gelesis is owned by Puretech Health, which also has stakes in Restorbio, which floated at the start of this year, and microbiome-focused Vedanta.

On the product side, the group hopes to file for CE mark of Gelesis100 by the end of the year, and it also has other projects in the pipeline. It is conducting a study, Light-Up, with a slightly different version of Gelesis for patients with diabetes or pre-diabetes. This new work is based on a finding in the Glow study: whereby pre- diabetic patients respond better to the product than patients with normal blood sugar levels.

Light-Up will test the effects of this second candidate, Gelesis200, on 420 patients’ weight and glycaemic control. Behind that, it intends to bring another project into the clinic early next year focusing on the diseases du jour, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

The group has seen signs in murine studies that lead it to believe that Gelesis could be effective here: it appears to improve insulin sensitivity and reduce gut permeability, which is part of the mechanism of fatty liver and Nash. The company is also, for the same reasons, looking into inflammatory bowel disease and mucositis.

The chances of these later pipeline hopes will improve if the Gelesis platform is validated by clearance in the US. Over to the FDA.