Memorandum

Novo Nordisk releases topline data from PIONEER 3 (oral semaglutide vs. DPP-4 Januvia) – June 28, 2018

Executive Highlights

  • Novo Nordisk today announced topline results from PIONEER 3, a phase 3 head-to-head trial of oral semaglutide vs. DPP-4 inhibitor Januvia (sitagliptin). The study (n=1,864) evaluated 3 mg, 7 mg, and 14 mg once-daily doses of oral semaglutide, and the two higher doses offered significantly more A1c-lowering and weight loss compared to 100 mg sitagliptin. In the on-treatment analysis, 14 mg oral sema was associated with a mean 1.4% A1c decline after 26 weeks and -1.1% after 78 weeks vs. -0.8% and -0.4% with sitagliptin. Weight loss with 14 mg oral sema was 7.3 lbs and 7.7 lbs vs. 1.5 lbs and 2.4 lbs with sitagliptin. Neither baseline A1c nor body weight were reported as part of this topline announcement.

  • As for safety/tolerability, nausea was more common with oral semaglutide vs. Januvia. Between 7%-15% of participants randomized to the study drug experienced nausea over the course of 78 weeks vs. 7% of patients on Januvia. Most instances of nausea were mild or moderate, occurring near the onset of treatment. Nevertheless, 6%-12% of oral semaglutide patients prematurely discontinued treatment vs. only 5% of sitagliptin patients. While a dropout rate as high as 12% from an RCT is noteworthy, we’re optimistic that Novo Nordisk will create oral semaglutide into a convenient product for real-world patients; in fact, this is a great opportunity for the company to invest in digital support tools.

  • Novo Nordisk is aiming to file oral semaglutide with FDA in 2019, which means a commercial product could be launched in the US as early as 2020. We’re beyond excited about oral GLP-1 and what it could mean for real-world patient outcomes and quality of life. That said, several questions remain, particularly around pricing and how the overall value proposition of oral semaglutide will compare to that of SGLT-2s and DPP-4s.

  • The phase 3 PIONEER program for oral semaglutide consists of 10 trials in total, all scheduled to read out this year, and all summarized in a table below. Full results from PIONEER 1 (oral sema vs. placebo) were featured on a late-breaking poster at ADA 2018.

This morning, Novo Nordisk announced a fifth set of topline results from the phase 3 PIONEER program: In PIONEER 3, oral semaglutide showed significant benefit on A1c and body weight vs. DPP-4 inhibitor sitagliptin (Merck’s Januvia). This follows full results from PIONEER 1 presented on a late-breaking ADA poster, plus topline data from PIONEER 2, 4, and 7.

Novo Nordisk is targeting 2019 for an oral semaglutide NDA, which means this first-in-class oral GLP-1 agonist could be available to real-world patients as soon as 2020.

PIONEER 3 randomized 1,864 people with type 2 diabetes to one of four treatment arms: (i) 3 mg oral sema, (ii) 7 mg oral sema, (iii) 14 mg oral sema, or (iv) 100 mg sitagliptin, all taken once-daily in the morning. The table below summarizes findings from the on-treatment analysis, excluding participants who prematurely discontinued therapy (more common in the GLP-1 group) or who required rescue medication (likely more common in the placebo group).

The two higher doses of oral semaglutide gave significantly greater A1c reductions at week 26 and week 78 compared to Januvia. Of note, A1c-lowering was significantly worse with 3 mg oral semaglutide vs. sitagliptin at week 26, but increasingly, it seems like Novo Nordisk will commercialize 14 mg oral sema given dose-dependent efficacy. In addition, we learned from management that mathematical modeling studies were used to determine an optimal dose, and that all signs pointed to 14 mg.

Unsurprisingly, all oral semaglutide formulations led to significantly more weight loss vs. Januvia; DPP-4 inhibitors are generally considered weight neutral, while weight loss is touted as one of the key clinical advantages to GLP-1 agonist therapy.

PIONEER 3 Summary of Results (On-Treatment Analysis)

 

Oral semaglutide 3 mg

Oral semaglutide 7 mg

Oral semaglutide 14 mg

Sitagliptin 100 mg

A1c drop at 26 weeks

0.5%*

1.1%*

1.4%*

0.8%

A1c drop at 78 weeks

0.3%

0.7%*

1.1%*

0.4%

Weight loss at 26 weeks (lbs)

2.6*

4.8*

7.3*

1.5

Weight loss at 78 weeks (lbs)

4.2*

5.9*

7.7*

2.4

*Statistically significant difference vs. sitagliptin 100 mg. Baseline and p-values were not disclosed.

Novo Nordisk’s announcement also reports topline results using the primary statistical principle, which is the approach used by FDA to evaluate new candidates. Under this approach, all participant data is included regardless of early discontinuation or rescue medication. Oral semaglutide 7 mg and 14 mg met the primary endpoint of superior A1c-lowering vs. Januvia after 26 weeks. These same doses showed significantly greater weight loss vs. Januvia after 26 weeks. Again, baseline and p-values were not disclosed. We’re curious about the margin of A1c-lowering and weight loss in the primary statistical analysis, and we hope to see this when full PIONEER 3 results are shared.

There’s been some criticism in the field about Novo Nordisk’s use of primary and secondary statistical approaches to report PIONEER data, but we note that it’s not uncommon for a manufacturer to emphasize on-treatment results. In fact, the beneficial effects of oral semaglutide might appear muted in the primary analysis because of more participants in the placebo arm receiving rescue medication. On the other hand, excluding patients who prematurely discontinued oral sema could inflate the candidate’s apparent efficacy in the secondary analysis.

Over 78 weeks, 6%-12% of patients on oral semaglutide dropped out from PIONEER 3 due to an adverse event. This dropout rate was lower in the Januvia group, at only 5%. Between 7%-15% of oral semaglutide patients experienced nausea (usually mild or moderate, and diminishing over time) vs. 7% of Januvia patients. These numbers reflect an acceptable tolerability profile for a GLP-1 agonist, in our view; for comparison, 9.5% of participants on liraglutide dropped out of LEADER due to an adverse event vs. 7.3% of participants on placebo (that said, the fact that the discontinuation rate was higher in the placebo arm as well indicates the greater burden on participants in a largescale CVOT vs. a phase 3 trial).

A discontinuation rate as high as 12% in a phase 3 study is noteworthy. We suspect premature discontinuation was more common with the higher doses that Novo Nordisk plans to bring to market. Adherence is consistently worse in the real world vs. a controlled clinical trial setting, and as we know all too well, drugs don’t work if patients don’t take them.

Oral semaglutide is so incredibly exciting because it could offer all the efficacy of a GLP-1 agonist in a more convenient, injection-free form. But will this product be as convenient as other oral agents for type 2 diabetes, namely DPP-4s and SGLT-2s? As we understand it, PIONEER participants (n=8,845 across all 10 trials) are asked to take their oral semaglutide pill in the morning after at least six hours of fasting, and are then instructed not to eat for another 30 minutes thereafter. We imagine ~6.5 hours of required fasting may be an undue burden for some patients, though the majority will see the upsides of oral semaglutide as far outweighing the downsides. This is only our speculation for now, but we’re optimistic that Novo Nordisk will be able to create a product that promotes better adherence compared to injectable GLP-1s, and if anything, we see this as an opportunity for the company to invest in digital support tools for patients starting an oral semaglutide prescription.

Lastly, PIONEER 3 (along with PIONEER 2 vs. SGLT-2 inhibitor Jardiance and PIONEER 7 also vs. Januvia) has especially important implications for Novo Nordisk’s marketing strategy around oral semaglutide. At Capital Markets Day in November 2017, management outlined a plan to positon oral sema ahead of injectable GLP-1s in the type 2 diabetes treatment paradigm, so that it would compete with SGLT-2s and DPP-4s for second-line prescriptions (see the image below for a clear visual). In order for this to work, the company would have to price oral semaglutide on par with existing oral agents, or the oral GLP-1 would have to blow the others out of the water in terms of glycemic and weight loss efficacy. The high doses of oral semaglutide did seem to give substantially more A1c-and body weight-lowering vs. a DPP-4 inhibitor in PIONEER 3 and 7 (though we’ll assess this more closely when full results are available, and we note that sitagliptin will go generic in the next ~five years, becoming much cheaper). The treatment difference on weight loss was underwhelming in PIONEER 2 (~9-10 lbs with oral semaglutide vs. ~8 lbs with empagliflozin), although Novo Nordisk’s candidate gave meaningfully more A1c decline (1.3%-1.4% vs. 0.8%-0.9%). Note that these numbers come from the PIONEER 2 on-treatment analysis.

Phase 3 PIONEER Program

Trial

Estimated Enrollment

Comparator/Design

Timeline

PIONEER 1

704

Placebo

Completed December 2017; Topline results announced February 2018; Full results coming on ADA poster (2-LB)

PIONEER 2

816

Lilly/BI’s Jardiance (empagliflozin)

Completed March 2018; Topline results announced May 2018

PIONEER 3

1,864

Merck’s Januvia (sitagliptin)

Completed March 2018, Topline results announced June 2018

PIONEER 4

711

Novo Nordisk’s Victoza (liraglutide)

Completed March 2018; Topline results announced June 2018

PIONEER 5

324

Moderate renal impairment

Completed May 2018

PIONEER 6

3,176

CVOT

Expected to complete September 2018

PIONEER 7

504

Flexible dose escalation

Completed March 2019; Topline results announced June 2018

PIONEER 8

720

Insulin add-on

Expected to complete August 2018

PIONEER 9

230

Placebo and liraglutide in Japan

Expected to complete August 2018

PIONEER 10

336

Lilly’s Trulicity (dulaglutide) as an add-on to oral agents in Japan

Expected to complete July 2018

 

-- by Payal Marathe and Kelly Close