Much odder than the failure and discontinuation yesterday of Roche’s aleglitazar was the fact that the diabetes project was in such a huge phase III programme to begin with.
Aleglitazar was one of the few surviving members of the so-called “glitazar” class, which had largely been written off years ago. Yet it featured as one of 12 antidiabetics being studied in large cardiovascular trials, and its failure turns the spotlight on Takeda’s DPP-IV inhibitor Nesina, the next candidate with a shot at becoming the first diabetes drug to show a cardiovascular benefit (see table).
The ability to boast a positive effect on cardiovascular outcomes would be a boon for any diabetes drug’s label, but demonstrating such a benefit has proved elusive. Long-term cardiovascular studies with DPP-IV inhibitors, GLP-1 agonists and SGLT2 inhibitors are ongoing – several to fulfil post-marketing commitments – in more than 80,000 patients.
There is anecdotal evidence suggesting that several drug classes improve cardiovascular outcomes, and retrospective analyses have also borne this out. But, although some 70% of people with diabetes die from heart disease and diabetes drugs clearly have glucose-lowering effects, no prospectively designed phase III trial has yet shown any antidiabetic to reduce cardiovascular risk.
Plenty are still hoping, even if the primary aim is to rule out risk. Most recently AstraZeneca and Bristol-Myers Squibb unveiled the results of a 16,500-patient study of their DPP-IV inhibitor Onglyza, showing neither an increase nor a reduction in cardiovascular risk (Move along, nothing to see here: Onglyza Savor trial result leaves diabetes world unrocked, June 19, 2013).
|Drug||Company||Study name||Patients||Completion||Trial ID||Status US||Status EU|
|Januvia||Merck & Co||Tecos||14,000||Dec 2014||NCT00790205||marketed||marketed|
|Victoza||Novo Nordisk||Leader||9,340||Jan 2016||NCT01179048||marketed||marketed|
|dulaglutide||Lilly||Rewind||9,622||Apr 2019||NCT01394952||phase III||phase III|
|empagliflozin||Boehringer Ingelheim||(none)||7,000||Mar 2018||NCT01131676||filed||filed|
|Invokana||Johnson & Johnson||Canvas||4,330||Jun 2018||NCT01032629||marketed||filed|
|Forxiga||AstraZeneca/Bristol||Declare||17,150||Apr 2019||NCT01730534||phase III||marketed|
But Onglyza and most of the other studied agents are already approved for treating diabetes, and a market enlargement strategy has clear logic. Not so for aleglitazar, and Roche’s move to begin a 19,000-patient cardiovascular trial before it had seen any significant phase III data can clearly be questioned.
After all, glitazars – molecules with dual agonist action at PPAR alpha and gamma – were seen as a busted flush since the 2006 discontinuations of Bristol-Myers Squibb’s muraglitazar and AstraZeneca’s tesaglitazar. Perhaps the Swiss company simply took the view that for a member of such a beleaguered drug class to make it it had to move fast or lose any chance of success.
In any case, all studies of aleglitazar are now being wound down; this includes the Alecardio trial, which formally was the one that failed a futility analysis yesterday, and the huge cardiovascular study that began recruitment in December (Aleglitazar failure will have little impact on booming diabetes market, July 10, 2013). It is not known how many of the 19,000 patients had been enrolled so far.
While some have suggested that the muraglitazar failure has a read-across to the related “glitazones” – agents that act preferentially at PPAR gamma – this is likely to be of little more than academic interest. Glitazones, like GlaxoSmithKline’s Avandia and Takeda’s Actos, are insignificant contributors to the current diabetes market.
It is, however, interesting that another PPAR agonist threw up a safety signal shortly after the FDA voted to ease restrictions on Avandia’s label, and could lead to criticism of the US regulator’s attempt to clear its name in the oversight of the Glaxo drug.
Of course, the issue with Avandia was cardiovascular; that drug’s Record study attempted to address this, and ultimately showed no differences between Avandia and active control for cardiovascular death, myocardial infarction or stroke.
While other pharma companies carrying out long-term studies are hoping to show a cardiovascular benefit, the ability to demonstrate a statistically robust lack of increase of risk is equally important. And the sheer size of the populations studied could also be handy in elucidating other factors – such as the pancreatitis risk that has clouded DPP-IV inhibitors and GLP-1 agonists.
For some, results will be a long time coming, and most of the studies do not read out until towards the end of the decade. For instance, none of the SGLT2 inhibitors – this class has been marred by genitourinary infections – will yield results before 2018.
Nesina’s trial, also measuring occurrence of a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, has been completed and could read out late this year. Much more important will be the Tecos study of Januvia, Merck & Co’s $4bn blockbuster, which could generate data next year.
The demonstration of a cardiovascular benefit could be a big advantage on a diabetes drug’s label, and perhaps sooner or later one of the companies will get lucky. Roche’s gamble with aleglitazar shows just how important big pharma still thinks this is.