Memorandum

Novo Nordisk announces positive topline phase 3a results for semaglutide vs. Merck’s Januvia (sitagliptin) – December 18, 2015

Executive Highlights

  • Novo Nordisk announced positive topline results yesterday from the SUSTAIN 2 phase 3a trial demonstrating superior A1c reductions (-1.3% with the 0.5 mg dose and -1.6% with the 1.0 mg dose vs. -0.5%; baseline=8.1%) and weight loss (4.3 kg and 6.1 kg vs. 1.9 kg; baseline = 89 kg) compared to Merck’s Januvia (sitagliptin).

Novo Nordisk announced positive topline results this morning from SUSTAIN 2, the fourth phase 3a trial for its once-weekly GLP-1 agonist semaglutide. The randomized, double-blind trial (n=1,231) demonstrated significantly greater A1c reductions with both the 0.5 mg and 1.0 mg doses of semaglutide compared to Merck’s Januvia (sitagliptin) after 56 weeks (-1.3% with the 0.5 mg dose and -1.6% with the 1.0 mg dose vs. -0.5% with sitagliptin; baseline A1c = 8.1%). In addition, a significantly greater percentage of participants in both semaglutide groups achieved an A1c target <7% (69% in the 0.5 mg group and 78% in the 1.0 mg group vs. 36% with sitagliptin). As expected, weight loss was also significantly greater in the semaglutide-treated groups (mean weight loss of 4.3 kg [~9.5 lbs] and 6.1 kg [~13.4 lbs] with the 0.5 mg and 1.0 mg doses, respectively vs. 1.9 kg [4.2 lbs] with sitagliptin; baseline body weight=89 kg [~196 lbs]). Consistent with previous SUSTAIN trial results, semaglutide appeared to be safe and well-tolerated in SUSTAIN 2. Predictably, the most common adverse event was a fairly high rate of nausea. Interestingly, however, both doses of semaglutide reported the same nausea rate (18%, compared to 7% in the sitagliptin group). The discontinuation rate was also higher (though still fairly low) in the semaglutide-treated groups (8% and 10% in the 0.5 mg and 1.0 mg dose groups, respectively, vs. 3% in the sitagliptin group).  

The positive SUSTAIN 2 results are consistent with expectations and with the positive results from earlier SUSTAIN trials demonstrating greater glycemic control and weight loss with semaglutide compared to many existing diabetes drugs. However, the greater efficacy appears to come at the cost of fairly high nausea rates, even in comparison to other GLP-1 agonists – the SUSTAIN 3 head-to-head trial found the rate of nausea was twice as high with semaglutide compared to AZ’s Bydureon (exenatide once-weekly). Novo Nordisk did note in its announcement of the SUSTAIN 2 results that the nausea diminished over time. The remaining two trials in the program are expected to report in the first half of 2016 (see below for more). Novo Nordisk plans to submit semaglutide to the FDA at the end of 2016, resulting in a US approval in late 2017 at the earliest and EMA approval in early 2018. We’d be interested in seeing how semaglutide’s efficacy and nausea rate compares to other once-weekly GLP-1 agonists already on the market such as Lilly’s very patient-friendly Trulicity (dulaglutide) and GSK’s Tanzeum (dulaglutide). We’d also like to see how semaglutide compares to other “next-generation” GLP-1 agonists, such as Sanofi/Hanmi’s ultra-long-acting efpeglenatide. We assume additional head-to-head studies are unlikely given how extensive the existing development program is, but they could be excellent questions to investigate in post-marketing registry studies. 

  • To date, semaglutide has demonstrated superior efficacy in comparison to a placebo (SUSTAIN 1), AZ’s GLP-1 agonist Bydureon (exenatide once weekly) (SUSTAIN 3), Sanofi’s Lantus (insulin glargine) (SUSTAIN 4), and now the DPP-4 inhibitor sitagliptin. We’d be interested in seeing how semaglutide might stack up against SGLT-2 inhibitors, which have been gaining in popularity and could become standard second-line therapy if future CVOTs reproduce the positive results from EMPA-REG OUTCOME. A trial at a later date evaluating semaglutide against or in combination with an SGLT-2 inhibitor would be much-welcomed.
  • The announcement of the SUSTAIN 2 results noted that the remaining two phase 3a trials for semaglutide – SUSTAIN 5 and 6 – are expected to report in the first half of 2016. SUSTAIN 5 investigated semaglutide as an add-on to basal insulin or metformin and completed in November 2015, according to ClinicalTrials.gov. SUSTAIN 6 is a cardiovascular outcomes trial (CVOT) that is expected to complete in January 2016. Novo Nordisk Chief Scientific Officer Dr. Mads Thomsen has previously gone on the record expressing cautious optimism that the LEADER CVOT for the company’s market-leading GLP-1 agonist Victoza (liraglutide) may be able to demonstrate cardioprotection. We wonder if this optimism extends to semaglutide’s potential for cardioprotection as well.
  • Novo Nordisk clearly views semaglutide as an extremely versatile peptide and is developing it for a variety of delivery methods and dosing schedules. In addition to its phase 3a program for semaglutide as a once-weekly injectable, Novo Nordisk recently advanced an oral formulation of semaglutide into phase 3 with its PIONEER clinical development program. The company has also initiated two phase 2 trials of semaglutide as a once-daily injectable, one in type 2 diabetes and one in obesity. In the company’s 3Q15 update, management shared that while the product is being developed primarily for once-weekly dosing, once-daily dosing could provide steadier concentrations and therefore offer better coverage and fewer peak-related side effects compared to once-weekly administration. We imagine Novo Nordisk is covering its bases in preparation for the next generation of GLP-1 agonists and will be pushing for switches from Victoza to various formulations of semaglutide as Victoza’s patent expiry date approaches.

Table 1: SUSTAIN phase 3 trial program for semaglutide

Trial

Estimated Enrollment

Actual Enrollment

Comparator/Design

Estimated Primary Completion Date

Status

SUSTAIN 1

390

388

Placebo

May 2015

Topline results reported July 2015

SUSTAIN 2

1,200

1,231

Merck’s Januvia (sitagliptin)

October 2015

Topline results reported December 2015

SUSTAIN 3

798

813

AZ’s Bydureon (exenatide)

July 2015

Topline results reported September 2015

SUSTAIN 4

1,047

1,089

Sanofi’s Lantus (insulin glargine)

September 2015

Topline results reported November 2015

SUSTAIN 5

397

 

Placebo; add-on to basal insulin and/or metformin

November 2015

Completed

SUSTAIN 6

3,297

 

Placebo; CVOT

January 2016

Ongoing

 

Close Concerns Questions

Q: How will Novo Nordisk prioritize Victoza vs. semaglutide?

Q: What will be the pricing strategy for the various formulations of semaglutide?

Q: Will semaglutide be able to sufficiently differentiate itself from existing once-weekly GLP-1 agonists and upcoming “next-generation” formulations of GLP-1 agonists?

Q: Will Novo Nordisk develop a GLP-1 agonist/basal insulin fixed-ratio combination involving semaglutide?

Q: Will the higher nausea rates be a problem in a real-world clinical setting?

Q: Will other companies with long-acting GLP-1 agonists in development follow Novo Nordisk’s example and develop different formulations for more flexibility in dosing schedules?

Q: Where will Novo Nordisk primarily aim to position semaglutide in the type 2 diabetes treatment algorithm?

 

-- by Helen Gao, Emily Regier, and Kelly Close