Sanofi’s ambitious Origin cardiovascular outcomes trial of Lantus in pre and early diabetics gets a detailed unveiling at the American Diabetes Association scientific sessions in two weeks, and expectations are low that the long-acting insulin will be shown to prevent heart attacks and strokes in these patients. Should it surprise, it raises the possibility that the French group will be able to make some new claims on the label of its best-selling product. Failure to show a benefit will have little commercial impact, but good safety data should provide further reassurance about cancer risk (ADA – Experts rally round Lantus, June 28, 2010).
The two-hour readout of the eight-year study will give specialists a better understanding about how to manage this population with multiple risks for cardiovascular events, not to mention other complications of elevated blood glucose levels. Early intervention with insulin is hypothesised to prevent the micro- and macrovascular damage that can lead to heart attacks and strokes, for example; the inclusion of a Lovaza arm in the study should provide additional insight into treatment strategies for this population.
|% of market cap||29%|
|Event type||Phase III Origin trial data|
|Date||June 11, 2012|
Long live the king
Lantus is the undisputed king of basal insulin having met the challenge of Levemir and prevailed; sales of $5.45bn last year were nearly four times the long acting Novo Nordisk product. Times they are a-changing, though – the Danish company is awaiting US and European Union decisions on its next long-acting product, degludec, now dubbed Tresiba, and Eli Lilly’s earlier-stage product, LY2605541 is expected to report phase III data next year (Lilly’s basal insulin surprises with weight loss data, May 28, 2012).
With patent expiry in 2015, Lantus is also vulnerable to biosimilar challengers – albeit on an older device with shorter patent protection. Lilly is preparing an insulin glargine in partnership with Boehringer Ingelheim, whilst Biocon and Wockhardt already market biosimilar Lantus elsewhere in the world, so it would not be a stretch to see them bringing a product into the big markets once Sanofi’s market exclusivity falls.
Meanwhile, the landscape of insulin therapy is also being influenced by the growth of the GLP-1 class, of which three are on the market and three more in late-stage development, including Sanofi’s own Lyxumia. Lantus sales are forecast to expand through 2015, when they will push $7bn, before falling to $6bn in 2018, according to EvaluatePharma data.
Thus should Lantus perform in Origin, a cardiovascular claim would no doubt be a small commercial advantage – given the scale of the trial, it would take years for Novo to catch up on cardiovascular benefit with Tresiba, for example.
Origin recruited more than 12,000 patients with early type 2 diabetes, impaired glucose tolerance or impaired fasting glucose and also with cardiovascular risk factors such as a prior heart attack or stroke. They were randomised into arms consisting of Lantus with Lovaza or with a Lovaza placebo, plus two non-insulin arms consisting of Lovaza alone or a Lovaza placebo. Chief measures are cardiovascular illness or death, along with death from any cause, progression from pre-diabetes to diabetes, or poor diabetes-related microvascular outcomes such as diabetic retinopathy.
Importantly, the population being tested is usually considered too early to be treated with insulin. Positive findings on any endpoint are likely to strengthen the case for earlier intervention, although that will benefit a wide variety of insulins.
With a trial of this size safety signals would be more easily spotted, and a cancer imbalance would surely have resulted in its cessation before it completed. Thus it likely holds some good news that will help Sanofi further shake off the Lantus cancer worries.
Likewise, however, a clear cardiovascular benefit would also have resulted in a premature end for the trial, and the fact that it ran to scheduled conclusion is what is leading many observers to conclude that it will have neutral findings.
The lag between conclusion and readout has caused some speculation about whether any conclusions can be drawn from the data at all. Given that the ADA has set aside a two-hour symposium, with independent presentations on multiple aspects of the trial, can also be taken as a sign that the investigators wanted to hold the data for a forum that would allow for the most detailed discussion possible.
Even if expectations of a benefit are low, there is no doubt that Origin will be closely watched. Whether or not Lantus or Lovaza prove to be effective in preventing death or poor health outcomes in this population, the data will be revealing.