Memorandum

Novo Nordisk announces positive topline SUSTAIN 5 results for semaglutide as add-on to basal insulin – February 23, 2016

Executive Highlights

  • Novo Nordisk announced positive topline results this morning from the SUSTAIN 5 phase 3a trial demonstrating superior A1c reductions (1.4%-1.8% vs. 0.1%; baseline = 8.4%), weight loss (3.7 kg-6.4 kg vs. 1.4 kg; baseline = 92 kg), and insulin dose reductions (10%-15% vs. 3%) with semaglutide vs. placebo as an add-on to basal insulin in type 2 diabetes.

Novo Nordisk announced positive topline results this morning from the SUSTAIN 5 phase 3a trial, the fifth of six phase 3 trials for its once-weekly GLP-1 agonist semaglutide. The double-blind trial randomized 397 patients with type 2 diabetes to receive one of two doses of semaglutide (0.5 mg and 1.0 mg) or placebo as an add-on to basal insulin, with or without metformin. The results demonstrated significantly greater (and very impressive) A1c reductions with both doses of semaglutide vs. placebo (1.4% and 1.8% with the lower and higher doses, respectively, vs. 0.1% with placebo; baseline = 8.4%) after 30 weeks. In addition, a significantly greater percentage of participants in the semaglutide groups achieved an A1c <7% (61% in the 0.5 mg group and 79% in the 1.0 mg group vs. 11% with placebo).

Both doses of semaglutide also led to significantly greater weight loss (3.7 kg [8.2 lbs] and 6.4 kg [14.1 lbs], respectively, vs. 1.4 kg [3.1 lbs] with placebo; baseline = 92 kg [203 lbs]) and insulin dose reductions (10% and 15%, respectively, vs. 3% with placebo) compared to placebo. Nausea was the most common adverse event, reported by 11% and 17% of patients in the respective semaglutide groups vs. 5% in the placebo group. Rates of severe or confirmed symptomatic hypoglycemia were also slightly higher with semaglutide (8% and 11%, respectively, vs. 5% with placebo), as were discontinuation rates due to adverse events (5% and 6%, respectively, vs. 1%).

These results further support the perception of semaglutide as a versatile product that can offer impressive A1c and weight reductions for patients at many points in the progression of type 2 diabetes. Nausea appears to be the main potential downside, though the rates in this trial were lower than those in some previous SUSTAIN trials. The only remaining SUSTAIN trial, the SUSTAIN 6 CVOT, is expected to report within the first half of 2016. The GLP-1 agonist class is arguably more likely than most diabetes drug classes to demonstrate cardioprotection, but we assume neutrality is still the most likely outcome of this trial due to the usual caveats - short duration, high-risk population, glycemic equipoise design. We would love to see trials start to use at least passive follow up so we could see the long-term effects of GLP-1. Novo Nordisk plans to submit semaglutide to the FDA at the end of 2016 and has a number of additional trials planned or ongoing to support a variety of formulations and indications.

  • As stated in its 4Q15 update, Novo Nordisk believes the available phase 3 results support a potential best-in-class profile for semaglutide. The previous SUSTAIN trials demonstrated superiority with semaglutide vs. placebo (SUSTAIN 1), Merck’s DPP-4 inhibitor Januvia (sitagliptin; SUSTAIN 2), AZ’s GLP-1 agonist Bydureon (exenatide once weekly; SUSTAIN 3), and Sanofi’s Lantus (insulin glargine; SUSTAIN 4) on A1c and weight. The phase 3 program has been very comprehensive and should support the use of semaglutide at a variety of points in the type 2 diabetes treatment algorithm. We would love to see future trials evaluating the drug against or in combination with an SGLT-2 inhibitor, or against other “next-generation” GLP-1 agonists like Sanofi/Hanmi’s efpeglenatide or Intarcia’s ITCA 650.
  • Novo Nordisk has an extensive development program for semaglutide beyond the SUSTAIN trials. The company unveiled the planned phase 3 PIONEER program for oral semaglutide at its Capital Markets Day in November. The program will include 10 trials involving >9,300 patients and should provide a very comprehensive indication (even more so than the SUSTAIN trials) of the product’s potential throughout the type 2 diabetes treatment algorithm. Novo Nordisk is also conducting two phase 2 trials of semaglutide dosed once daily and recently announced plans for a phase 2 trial in NASH to begin in 2H16.
  • Dr. John Buse (University of North Carolina, Chapel Hill, NC) expressed great excitement about semaglutide in correspondence with us. In his words: “Injected, it seems to be best in class. The oral formulation in particular could be a game-changer in GLP-1 based therapy. I cannot wait to have it in the clinic.”

Questions and Answers

Q: How will Novo Nordisk prioritize semaglutide vs. Victoza in the coming years? Injectable vs. oral semaglutide?

A: Based on the profiles we know today with injectable semaglutide and Victoza and oral semaglutide, we believe our products offerings will cover [a wide range of patients] but also be complementary depending on patients’ requirements in terms of efficacy, weight loss, and convenience.

Q: Are there plans for any long-term follow-up of SUSTAIN 6?

A: No. SUSTAIN 6 will be stopped after patients are treated for two years. No follow-up is expected.

Q: Will Novo Nordisk conduct any post-marketing trials of semaglutide?

A: Yes, that is the plan. Based on the results from the upcoming LEADER CVOT for Victoza and SUSTAIN 6 we will likely evaluate the opportunity of a long-term post-marketing trial with semaglutide.

Q: What will the nausea rates for semaglutide look like in real-world practice?

A: If patients are titrated according to protocol, nausea will likely occur in the early phase of use but should be transient over time, as seen in the clinical trials.

Q: Is there any potential for semaglutide in type 1 diabetes?

A: Currently, semaglutide is not planned for type 1 diabetes.

Q: How will semaglutide be priced and reimbursed?

A: Pricing is likely to reflect best-in-class properties, but it is generally too early to discuss.

Q: Are there any plans for a semaglutide/basal insulin fixed-ratio combination?

A: Not currently, but a combination of semaglutide and Novo Nordisk’s early-stage insulin candidates cannot be ruled out.

 

-- by Emily Regier and Kelly Close