The discovery of hypersensitivity reactions in Roche’s 6,000-patient taspoglutide phase III programme is a significant blow to the company’s attempts to break into the diabetes space (see tables below).
Although the rate of events, seen in skin and gastrointestinal symptoms, is very low at less than 1% and patients staged a full recovery the GLP-1 analogue would face intense competition from similar but more established drugs should it reach the market. Therefore, it is probably no exaggeration to say that this unwanted differentiator, and the resulting delay in seeking marketing approval, could well be enough to scupper the whole programme.
Roche believes the hypersensitivity is linked to anti-drug antibodies (ADAs), meaning patients with heightened ADAs are more likely to react to taspoglutide (RG1583). As such, the company plans to identify patients at risk through routine monitoring, and those with pre-specified ADA levels will discontinue treatment.
This risk mitigation plan means the trial protocols for the taspo phase III programme have to be amended and a minimum delay of 12 to 18 months in regulatory filings has been mooted.
According to analysts at Citi, Roche is trying to resolve the hypersensitivity by improving tolerability, for example by implementing additional purification of the drug. If this can be achieved and demonstrated via bridging studies then the company might indeed get away with a one or two year delay.
If it cannot, this guidance begins to look very optimistic and starting from scratch with new phase III trials is surely out of the question, if only because this would set taspo so far behind the other GLP-1s already on or close to the market.
Unfortunately for Roche, and Ipsen from whom the drug was licensed, this issue follows reports earlier this week of a worrying GI side effect rate seen in a trial that pitted taspo against Byetta. Analysts have already been concerned about nausea-related discontinuation rates, which appear higher than with both Byetta and Bydureon, the twice-daily and once-weekly GLP-1s owned by Amylin Pharmaceuticals and Eli Lily.
These issues have to be viewed in the context that the commercial potential of Byetta has already been curtailed by its own tolerability problems. The drug, which was launched in 2005, has failed to live up to initial expectations due to the severe nausea and vomiting that many patients experience when they first start taking it.
Follow-on Bydureon is thought to have better tolerability although this has yet to win approval so patient acceptance is not yet known. Demand for Novo Nordisk’s Victoza, which has been on the market for approximately six months, is thought to be benefiting from doctors’ willingness to seek a new GLP-1 with better tolerability.
With two long-acting GLP-1s already on the market and others on their way, most notably in the shape of GlaxoSmithKline’s Syncria, new products have no choice but to demonstrate better tolerability than the incumbents if commercial success is to be attained.
As for anti-drug antibody monitoring, if this was a requirement following approval any competitive edge for taspo would surely disappear.
The GI concerns that emerged earlier this week originated from abstracts released ahead of the American Diabetes Association conference, being held next week in the US. Full data from five of the eight phase III taspo trials are due to be presented and were already going to be a major draw, so today's news will guarantee extra attention.
The companies developing the other long-acting GLP-1s will all be presenting data at this conference and no doubt hypersensitivity events will be scrutinised, although this has not really emerged as an issue for the others so far.
Taspo has certainly suffered a huge blow today, as illustrated by the share price reactions at the companies involved, shown in the table below.
Roche is big enough to weather the storm, although its reputation in bringing best-in-class molecules to the market will be somewhat damaged. Ipsen is more vulnerable, and if the worst happens and Roche throws in the towel it will lose vital future revenues. Shares in the French company plunged 16% to a 10-month low of €27 on the news.
However, the real winner here is Amylin, as the 16% surge in its share price in early trade reveals, touching $19.21. The main issue for the company is the future success of Bydureon, and a weakening competitive landscape is only good news; the table below illustrates just how big a threat analysts expected taspo to become, all numbers are now likely to shift signficantly.
Roche has invested too much in taspo to give up just yet, but the signs are not looking encouraging.