No cardiac benefit for Lantus but Origin confirms cancer safety

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Publication of the Origin trial of Lantus has turned out largely as expected: No evidence of a cardiovascular benefit when used as an early intervention in diabetics and people with impaired glucose function, but additional confirmation that the basal insulin does not raise cancer risks.

However, evidence of improved glycaemic control over the course of the study strengthens arguments in favour of insulin use sooner in disease progression, a claim counterbalanced by weight gain, increased incidence of hypoglycaemia and patient resistance. After nine years of study, it appears that Origin will not meaningfully expand Lantus’ use, but at least the French group can rest easier knowing the safety worries related to its biggest seller have dissipated.

Early intervention

Presented at the ADA meeting yesterday, Origin tested Lantus in more than 12,000 patients over six years to determine whether insulin intervention in pre-diabetics and early diabetics could prevent cardiovascular death or non-fatal events such as heart attacks or stroke. No benefit was found on the primary endpoints. (Event - Origin trial to reveal if Lantus has heart, June 1, 2012). However, its use in the pre-diabetic population delayed progression to type 2 diabetes, with those pre-diabetics at randomization randomised to take Lantus 28% less likely to develop diabetes in the three to four week interval between the end of the treatment phase and a first glucose tolerance test.  

The negatives of weight-gain and hypoglycaemia are likely to outweigh the positive aspects of delaying disease progression for that population, however. Asked in an investor call whether Sanofi would consider pursuing a label expansion, Pierre Chancel, senior vice president of Sanofi Diabetes, said, “The answer is clearly no.”

The Origin data is “the first convincing demonstration that we have a way to delay beta cell deterioration,” added Matthew Riddle, professor of medicine at Oregon Health & Science University and a trial steering committee member. Dr Riddle said that effect will need to be confirmed in additional research, however.

Even so, the big risks resulting from early use were still fairly limited. Hypoglycaemia, while elevated in the Lantus patients when compared with standard-of-care use, was fairly uncommon, with an incidence of a first episode of severe hypoglycaemia of 1 per 100 patient years. Weight gain in patients taking Lantus was a median of 1.6kg over the course of the trial, compared with a 0.5kg weight loss in the control arm.

The best news for Sanofi came in the form of confirmation that Lantus does not raise cancer risks, a finding supported by additional retrospective data presented at ADA covering 1 million patients that found no link between any form of cancer and use of Lantus. The finding throws additional doubt on data published in 2008 suggesting a correlation (ADA – Experts rally round Lantus, June 28, 2010).

Defence

Thus the company has fairly ably defended its $6bn-a-year cash cow at a time when earnings are being dented by patent expiries elsewhere – a negative finding on cancer would have been damaging. In the call today, company executives were quick to emphasise how Sanofi plans to extend the franchise, particularly as patent expiry for Lantus approaches in 2015.

The main plans include combinations with up-and-coming GLP-1 agonist Lyxumia and a new Lantus formulation with a “flatter” pharmacokinetic-pharmacodynamic profile to reduce hypoglycaemia, one of its perceived weaknesses against Novo Nordisk’s new long acting insulin Tresiba. Generically known as degludec, the FDA recently delayed its decision on the product from July 29 to October 29.

If any company was hurt by the Origin findings, it was Pronova BioPharma, whose omega-3 fatty acid pill Lovaza was included as a comparative arm in the trial. Researchers found no reduced risk of cardiovascular events in diabetics taking the pill; shares in the Norwegian group were down 1% to NKr9.81 in afternoon trade today.

However, it was clear Origin met expectations – Sanofi’s shares were barely moved today, standing at €54.91 in afternoon trading. Relieving the cancer worries will enable the company to better combat the looming launch of Tresiba; Lantus’ performance post-launch will be closely watched.

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