Memorandum

Topline DEVOTE results demonstrate non-inferiority of Novo Nordisk’s Tresiba (insulin degludec) to Lantus (insulin glargine) for cardiovascular outcomes – November 29, 2016

Executive Highlights

  • In topline results from the DEVOTE CVOT, Novo Nordisk announced today that Tresiba (insulin degludec) demonstrated non-inferiority to Sanofi’s Lantus (insulin glargine U100) on a primary endpoint of three-point MACE (non-fatal MI, non-fatal stroke, and CV death) – the hazard ratio for CV events was 0.91 in favor of Tresiba, though the difference was not statistically significant.
  • Tresiba also showed 40% reduced risk for severe hypoglycemia and a 54% reduced risk for severe hypoglycemia overnight vs. Lantus. In the Tresiba treatment arm, 27% fewer participants experienced an episode of severe hypoglycemia compared to the Lantus arm. In our view, this reduced risk for hypoglycemia could be huge for patients in the real-world.

Earlier today, Novo Nordisk announced topline results from the DEVOTE cardiovascular outcomes trial (n=7,637) for its next-generation basal insulin Tresiba (insulin degludec). The trial met its primary endpoint by demonstrating non-inferiority of Tresiba to Sanofi’s Lantus (insulin glargine U100) for the composite outcome of three-point MACE (non-fatal MI, non-fatal stroke, and CV death), with a hazard ratio of 0.91 in favor of Tresiba, though the relative risk reduction was not statistically significant. The company announcement did not share the confidence interval, though the upper bound of the confidence interval must be <1.3 based on the FDA’s 2008 CVOT guidelines for non-inferiority. The difference in mean A1c between the two treatment arms was 0.01% at the end of the trial, which reinforces the glycemic equipoise design of this study, intended to isolate the cardiovascular effects of a drug itself (as opposed to the potential cardiovascular benefits or harms conferred by A1c reduction in general). These resoundingly neutral results are long-awaited – the DEVOTE trial was initiated in response to the Complete Response Letter issued by the FDA for Tresiba in 2013. The requirement for a CVOT delayed Tresiba’s launch to early 2016, following the product’s late 2015 approval on the basis of interim data from DEVOTE. The neutral results from DEVOTE are not unexpected given the product’s earlier approval, but are reassuring nonetheless.

Notably, several secondary endpoints in DEVOTE highlighted Tresiba’s advantage over Lantus in reducing hypoglycemia: (i) 27% fewer patients on Tresiba vs. Lantus experienced severe hypoglycemia;(ii) there was a 40% overall risk reduction for an adjudicated, severe hypoglycemic event with Tresiba vs. Lantus; and (iii) there was a 54% relative risk reduction for severe nocturnal hypoglycemia with Tresiba vs. Lantus. The company shared that all of these findings were statistically significant. These hypoglycemia findings further reinforce the results from the SWITCH 1 and SWITCH 2 trials for Novo Nordisk’s next-generation basal insulin. In fact, the company recently submitted data from the SWITCH trials to the FDA and EMA for inclusion on the Tresiba label – we expect a hypoglycemia benefit, now corroborated by DEVOTE as well, could go a long way in differentiating the product in an increasingly crowded basal insulin market as patients and providers look for diabetes therapies that can reduce hypoglycemia, improve glycemic variability, and address other outcomes beyond A1c. Indeed, the presentation of full SWITCH 2 results included intriguing positive patient-reported outcomes data and we’re curious if similar measures were evaluated in DEVOTE. In our view, this reduced risk for hypoglycemia could be huge for patients in the real-world. As we understand it, there were billions of dollars of claims on severe hypoglycemia last year, with more than half coming from type 2 diabetes patients. Hypoglycemia is a clearly a serious concern, both on the population-level and in the way it affects individual patients’ quality of life (see data presented at the FDA’s Outcomes Beyond A1c workshop for more on this) – a basal insulin that reliably reduces this risk is something to celebrate in the diabetes community.

Novo Nordisk will host a conference call on this news at 11 pm PST tonight. The company plans to submit DEVOTE findings to the FDA in 1H17 and hopes to present full results from DEVOTE at a scientific meeting in 1H17 – we’d wager ADA 2017 in San Diego in June. See our updated timeline of ongoing CVOTs for more.

Close Concerns Questions

Q: What was the p-value for risk reduction on three-point MACE with Tresiba vs. Lantus? Was the p-value “close” to statistical significance?

Q: What was the p-value for reduced risk of severe hypoglycemia, both overall and overnight?

Q: How many total MACE events were recorded throughout the course of the DEVOTE trial (which began in 2013 following an FDA Complete Response Letter for Tresiba)?

Q: When can we expect to see full results from DEVOTE?

Q: How will be results be reflected in the label for Tresiba? What bearing, if any, might the hypoglycemia data have on the ongoing submission for a hypoglycemia benefit?

Q: How will these results affect promotion, sales, and utilization of Tresiba going forward? How might they impact formulary positioning?

-- by Payal Marathe, Helen Gao, and Kelly Close