AstraZeneca and Bristol-Myers Squibb’s Savor trial, assessing the cardiovascular risks of DPP-IV Onglyza, was a shot at redemption for the beleaguered oral diabetes space. Instead it merely succeeded in maintaining the status quo.
Also gone is any chance Astra and Bristol-Myers might have had to drive up sales of Onglyza, the growth rate of which has in recent months started to stagnate along with the rest of the DPP-IV class. So the very little that Onglyza's owners can take from the expensive 16,500-patient, four-year trial is that the drug does not increase cardiovascular risk – but, by failing to show superiority, neither does it do anything to reduce it.
The Savor trial randomised patients with type II diabetes and a history of cardiovascular disease to Onglyza or placebo in the hope of proving that the drug would not increase cardiovascular risk, and would reduce cardiovascular death as well as non-fatal myocardial infarction or non-fatal ischaemic stroke.
Until earlier this year there had been aspirations that Onglyza would produce a positive cardiovascular effect, prompted by a 4,607-patient meta-analysis of previous clinical trials from 2010, which showed a 52% reduction in cardiovascular risk (Event – DPP-IVs could Savor the moment, courtesy of Onglyza, May 22, 2013).
But investors rightly tempered their expectations regarding the outcome of Savor by focusing on the much larger 14,611-patient meta-analysis of Januvia studies carried out earlier this year that showed the same cardiovascular risk for Januvia as placebo.
The fact that the Savor non-outcome had been widely predicted was supported by today’s negligible share price reaction for both Astra and Bristol-Myers. Also Merck & Co, perhaps the company that really stood the most to gain because of the read through DPP-IV best seller, Januvia, was also unmoved.
Same old same old
With no detailed information from Astra and Bristol-Myers over the pancreatic safety profile of Onglyza, one of the issues that the FDA is looking into in its wider look at both DPP-IV inhibitors and GLP-1 diabetes drugs, doctors are unlikely to change their prescribing habits.
So Onglyza revenues will most probably remain modest; last year sales were $545m, with another $164m for the metformin combination, compared with the $4.1bn reported for Januvia and its metformin combination Janumet.
The detailed safety data is expected to be released at the European Society of Cardiology meeting in September. Given the FDA’s current scrutiny of incretin mimetics, which both DPP-IV and GLP-1’s fall under, thanks to a possible link to pancreatitis and pancreatic cancer, the results will be closely watched (Diabetes drug safety controversy grows with new analysis, April 19, 2013).
So with Savor being little to savor for DPP-IV developers, the next two big trials that could alter the landscape are Takeda and Merck’s respective Examine and Tecos trials, both expected to read out in 2014 (see table).
While the chances of either one of them showing superiority has to be reduced following both the Januvia meta-analysis and now the Savor results, if by some chance either one does then they could be the winners in what is looks to be a very stagnant treatment space.
|Selected DPP-IV CV outcomes trials|
|Drug||Company||Details||Primary endpoint||Trial name||Trial ID||Primary completion date|
|Onglyza||Bristol-Myers Squibb/Astrazeneca||16,500 pts, versus placebo||CV death, non-fatal MI or non-fatal stroke||Savor-Timi 53||NCT01107886||Completed|
|Nesina||Takeda||5,389 pts, versus placebo||CV death, non-fatal MI or non-fatal stroke||Examine||NCT00968708||Completed, expected to report in 2014|
|Januvia||Merck||14,000 pts, versus placebo||CV-related death, nonfatal MI, nonfatal stroke, or unstable angina||Tecos||NCT00790205||Dec 2014|
|Tradjenta||Eli Lilly/Boehringer Ingelheim||6,000 pts, versus glimepiride||CV-related death, nonfatal MI, nonfatal stroke, or unstable angina||Carolina||NCT01243424||Sept 2018|