Memorandum

PIONEER 6 topline results demonstrate non-inferiority, strong trends toward superiority with oral semaglutide; PIONEER 9 results – November 23, 2018

Executive Highlights
  • Novo Nordisk just announced topline results from the PIONEER 6 CVOT (n=3,183) for oral semaglutide, demonstrating non-inferiority but not superiority to placebo on CV safety. While the trial was not designed to demonstrate superiority, there was a strong trend toward benefit on three-point MACE (HR=0.79, NS). Significance was achieved on CV death (HR=0.49, p=0.03) and all-cause mortality (HR=0.51, p=0.008). Non-fatal MI (HR=1.18, NS) and non-fatal stroke (HR=0.74, NS) trended in opposite directions, though likely on only a few events. While no confidence intervals were given, we do find the magnitude of these reductions very promising. 

  • Median follow-up for PIONEER 6 was 16 months (137 MACE events total), and 85% of participants had CVD at baseline. This makes PIONEER 6 the shortest GLP-1 agonist CVOT to date, beating even HARMONY’s 1.6 years, as well as the smallest, beating SUSTAIN 6’s 3,297. From where we stand and with the limited data that has been made available, this makes the results of the trial more impressive, and we wouldn’t be surprised to see a very narrow statistical miss on superiority when full results are announced. Of course, PIONEER 6 is unique in that it is the first-ever CVOT for an oral GLP-1 agonist, adding another layer of distinction that keeps us from drawing very strong comparisons to other GLP-1 CVOTs.

  • Novo Nordisk still plans to file oral semaglutide for regulatory approval in the US and EU in 1H19, and the company is also currently evaluating the potential to use the combination of SUSTAIN 6 and PIONEER 6 data to obtain a CV indication for Ozempic. Plans for obtaining an oral semaglutide indication were not mentioned, and our understanding is that another CVOT for oral semaglutide will still be conducted. But, because SUSTAIN 6 did demonstrate superiority of Ozempic vs. placebo on three-point MACE (HR=0.74, 95% CI: 0.58-0.95), it seems as if Novo Nordisk is hopeful that FDA will view SUSTAIN 6 data, newly bolstered by a trend toward superiority in PIONEER 6, as sufficient evidence of Ozempic’s CV benefit. However, a CV indication for oral semaglutide will almost definitely require another CVOT – see our questions about this and more at the end of this story.

  • Also this week, Novo Nordisk announced results from PIONEER 9 (n=243), examining oral semaglutide vs. Victoza in Japanese patients. All three doses of oral semaglutide (3, 7, and 14 mg) achieved significance on the primary endpoint of change in A1c at week 26, with reductions of 1.1%, 1.5%, and 1.7%, respectively and from baseline 8.2%; this compares to 0.1% with placebo and 1.4% with Victoza 0.9 mg – to which 14 mg oral semaglutide was superior. Body weight loss at week 52 was 2.8 kg (6.2 lbs) with 14 mg oral semaglutide, 0.6 kg (1.3 lbs) with 14 mg, and 0.0 kg with 3 mg, compared to 1.0 kg (2.2 lbs) of weight loss with placebo and 0.4 kg (0.9 lbs) of weight gain with Victoza. At week 52, A1c <7.0% was achieved by 80% of participants on 14 mg, vs. 49% on Victoza and 12% on placebo. With no safety signals or unexpected tolerability issues, PIONEER 9 joins PIONEER 10 in supporting regulatory approval of oral semaglutide in Japan.

    Novo Nordisk just announced topline results from the PIONEER 6 CVOT (n=3,183) for oral semaglutide, demonstrating non-inferiority to placebo on CV safety. While the trial did not demonstrate superiority on three-point MACE, outcomes trended very strongly in favor of oral semaglutide. As a reminder, PIONEER 6 was designed to demonstrate pre-market CV safety for oral semaglutide but was not powered to demonstrate superiority; however, there was possibly hope – especially following surprise superiority for Ozempic in SUSTAIN 6 – that superiority could be achieved. Notably, it is safety that really matters for FDA – but superiority that is now important for ongoing commercial outsized success.

    A non-significant 21% relative risk reduction (HR=0.79) was achieved on three-point MACE (CV death, non-fatal MI, non-fatal stroke); however, no 95% CI or p-value was given. Novo Nordisk did provide individual MACE results, revealing that this trend was driven by a 51% risk reduction on CV death (HR=0.49, p=0.03). However, non-fatal MI trended toward placebo (HR=1.18, NS), while non-fatal stroke trended toward oral semaglutide (HR=0.74, NS). We don’t think this trend on MI will cause much concern, nor should it, given the low number of events and what we anticipate to be very wide confidence intervals. Indeed, trends toward placebo are not very unusual: SUSTAIN 6 trended toward placebo on all-cause mortality (HR=1.05, 95% CI: 0.74-1.50) and hospitalization for heart failure (HR=1.11, 95% CI: 0.77=1.61), as did EMPA-REG OUTCOME on stroke (HR=1.24, 95% CI: 0.92-1.67).

    Also of high note, oral semaglutide was associated with a very significant but technically exploratory 49% reduction on all-cause mortality (HR=0.51, p=0.008). We find the magnitude of effects on all-cause and CV death very compelling, though it’s difficult to draw any conclusions without confidence intervals.

    To be sure, it would have been extremely exciting to see a significant risk reduction on three-point MACE, but it is of paramount importance to remember that PIONEER 6 was not meant to do so. Indeed, as former CMO Dr. Alan Moses put it, “The results of PIONEER 6 are very exciting and probably beyond what was expected. For a small number of events, it would be very surprising to have individual components achieve statistical significance and to do so in the two most important (CV death and all-cause mortality) really supports the CV protection afforded by semaglutide and, it appears, long-acting GLP-1 analogs.” From where we stand, these are incredibly positive and promising results for a trial much shorter and smaller than other GLP-1 CVOTs – see below for more on both the commercial and class implications of these findings.

    Median follow-up was 16 months, and there was a total of 137 MACE events; all participants were either (i) ≥50 years old with established CVD or (ii) ≥60 years old with at least one CV risk factor, and 85% had CVD at baseline. All participants were randomized to placebo or 14 mg oral semaglutide, the highest dose under phase 3 investigation. The announcement notes that improvements on A1c, body weight, and blood pressure were similar to those seen throughout the PIONEER program, as was the safety and tolerability profile of oral semaglutide.

    In communication with our team, Novo Nordisk's Global Chief Medical Officer Dr. Stephen Gough remarked: "The excellent CV outcome data in our PIONEER 6 CV safety study further highlights the potential benefit of the semaglutide molecule for people with type 2 diabetes. Rarely do you get the opportunity to evaluate the same molecule twice and observe such consistent and compelling efficiency and safety data"

    We tentatively expect full results to be presented at ADA 2019 in San Francisco, though ACC 2019 in New Orleans is also a possibility. Finally, we applaud Novo Nordisk for making so much data available in a topline CVOT release, where it’s so rare to see actual numbers. We are eager, that said, to see A1c drop (and baseline) and weight reduction – and we’d love to start seeing Time in Range data.

    CVOT and Commercial Implications

    • Novo Nordisk still plans to file oral semaglutide for regulatory approval in the US and EU in 1H19, and PIONEER 6 will offer very convincing evidence of the drug’s cardiovascular safety and glycemic benefit. Perhaps the more important implication of this result, however, pertains to Novo Nordisk’s ongoing effort to support a CV indication for both Ozempic (injectable semaglutide) and oral semaglutide. According to the announcement, Novo Nordisk is currently evaluating the potential to use the combination of SUSTAIN 6 and PIONEER 6 data to obtain a CV indication for Ozempic, and discussions with FDA will continue. Plans for obtaining an oral semaglutide indication were not mentioned, and our understanding is that another CVOT for oral semaglutide will still be conducted. But, because SUSTAIN 6 did demonstrate superiority of Ozempic vs. placebo on three-point MACE (HR=0.74, 95% CI: 0.58-0.95), it seems as if Novo Nordisk is hopeful that FDA will view SUSTAIN 6 data, newly bolstered by a trend toward superiority in PIONEER 6, as sufficient evidence of Ozempic’s CV benefit. In our view, and in light of increasing consensus around cardioprotection as a GLP-1 agonist class effect, Ozempic almost certainly deserves a CV indication in some form. Most importantly, it would be beneficial to everyone involved – patients above all – to get a CV indication onto Ozempic’s label sooner rather than later. 

      • However, a CV indication for oral semaglutide will likely require another CVOT. As CSO Dr. Mads Thomsen outlined on the company’s 2Q18 earnings call, Novo Nordisk has developed a plan in cooperation with FDA to minimize the burden of obtaining a CV indication for both of its semaglutide products. In the best-case scenario, PIONEER 6 would have demonstrated superiority and FDA would have accepted the combination of SUSTAIN 6 and PIONEER 6 data as evidence of both formulations’ cardioprotection. Though this scenario is no longer fully viable, there’s still an upside in that FDA has also agreed to accept a single, superiority-powered CVOT for oral semaglutide as evidence of Ozempic’s and oral semaglutide’s cardioprotection. That is, two CVOTs for the price of one, as long as Novo Nordisk can demonstrate similar bioavailability between the two products. While it seems Novo Nordisk is hopeful that FDA will grant Ozempic a CV indication without this new oral semaglutide CVOT, it’s also possible that the agency will decide to wait for the third semaglutide CVOT to grant any new indications – at this point, we can only speculate. No new CVOT has been posted to ClinicalTrials.gov.

    GLP-1 Agonist CVOTs

    • Compared to other completed GLP-1 agonist CVOTs, PIONEER 6 has the shortest median follow-up (beating HARMONY’s 1.6 years) and the smallest enrollment (beating SUSTAIN 6’s 3,297). It would seem that the combination of these factors worked against PIONEER 6’s ability to demonstrate superiority, and we wouldn’t be surprised to see a very narrow statistical miss on superiority when full results are announced. Of course, PIONEER 6 is unique in that it is the first-ever CVOT for an oral GLP-1 agonist, adding another layer of distinction that keeps us from drawing very strong comparisons to other GLP-1 CVOTs. In the end, the study did what it was meant to do – demonstrate CV safety ­– and it did that extremely well. Similarly to the EXSCEL CVOT for AZ’s Bydureon, we think these results do far more to support cardioprotection as a GLP-1 class effect than they do to refute it, and we fully anticipate a superior result from a second oral semaglutide CVOT that we expect to follow soon.

    Trial and Status

    Enrollment, Percent w/ Baseline CV Disease

    Mean Age (years), BMI (kg/m2), A1c, and Diabetes Duration at Baseline

    Study Design:

    Median Follow Up, Concomitant Medications Allowed?

    Primary Endpoint Result (components)

    Mortality Results:

    CV Death, All-Cause Mortality

    Other Notable Findings

    PIONEER 6 for oral semaglutide (Novo Nordisk)

    Topline results announced

    3,183

    85%

    Age: 66

    BMI: --

    A1c: 8.2%

    Diabetes duration: 15 years

    1.3 years

    No other GLP-1 agonists or DPP-4 inhibitors

    NS (HR=0.79)

    3-point MACE (CV death, non-fatal MI, non-fatal stroke)

    CV: 51% RRR

    (HR=0.49, p=0.03)

    All-Cause: 49% RRR

    (HR=0.51, p=0.008)

     

    LEADER for liraglutide (Novo Nordisk’s Victoza) (outcomes paper)

    Completed – reported ADA 2016

    9,340

    81%

    Age: 64

    BMI: 33

    A1c: 8.7%

    Diabetes Duration: 13 years

    3.8 years

    No other GLP-1 agonists or DPP-4 inhibitors

    13% RRR

    (HR=0.87, 95% CI: 0.78-0.97, p=0.01 for superiority, p<0.001 for non-inferiority)

    3-point MACE (CV death, non-fatal MI, non-fatal stroke)

    CV: 22% RRR

    (HR=0.78, 95% CI: 0.66-0.93)

    All-Cause: 15% RRR

    (HR=0.85, 95% CI: 0.74-0.97)

    Indication for reducing MACE approved by FDA August 2017

    Heart Failure: NS

    (HR=0.87, 95% CI; 0.73-1.05)

    EXSCEL for exenatide once-weekly (AZ’s Bydureon) (outcomes paper)

    Completed – reported EASD 2017

    14,752

    73%

    Age: 63

    BMI: 32

    A1c: 8.0%

    Diabetes Duration: 12 years

    3.2 years

    No other GLP-1 agonists

    NS

    (HR=0.91, 95% CI: 0.83-1.00, p<0.001 for non-inferiority, p=0.06 for superiority)

    3-point MACE (CV death, non-fatal MI, non-fatal stroke)

    CV: NS

    (HR=0.88, 95% CI: 0.76-1.02)

    All-Cause: exploratory

    (HR=0.86, 95% CI: 0.77-0.97)

    Heart Failure: NS

    (HR=0.94, 95% CI: 0.78-1.13)

    SUSTAIN-6 for semaglutide (Novo Nordisk’s Ozempic) (outcomes paper)

    Completed – reported EASD 2016

    3,297

    83%

    Age: 65

    BMI: 33

    A1c: 8.7%

    Diabetes Duration: 14 years

    2.1 years

    No other GLP-1 agonists or DPP-4 inhibitors

    26% RRR

    (HR=0.74, 95% CI: 0.58-0.95, p=0.02 for superiority, p<0.001 for non-inferiority)

    3-point MACE (CV death, non-fatal MI, non-fatal stroke)

    CV: NS

    (HR=0.98, 95% CI: 0.65-1.48)

    All-Cause: NS

    (HR=1.05, 95% CI: 0.74-1.50)

     

    76% increased risk for retinopathy w/ semaglutide (HR=1.76, 95% CI: 1.11-2.78); Premarket CVOT not designed for superiority; does not support CV indication

    Heart Failure: NS

    (HR=1.11, 95% CI: 0.77-1.61)

    ELIXA for lixisenatide (Sanofi’s Adlyxin) (outcomes paper)

    Completed – reported ADA 2015

    6,068

    100%

    Age: 60

    BMI: 30

    A1c: 7.7%

    Diabetes Duration: 9 years

    2.1 years

    No other GLP-1 agonists or DPP-4 inhibitors

    NS

    (HR=1.02, 95% CI: 0.89-1.17, p=0.81)

    4-point MACE (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina)

    CV: NS

    (HR=0.98, 95% CI: 0.78-1.22)

    All-Cause: NS

    (HR=0.94, 95% CI: 0.78-1.13)

    Heart Failure: NS

    (HR=0.96, 95% CI: 0.75-1.23)

    HARMONY for albiglutide (GSK’s Tanzeum)

    (outcomes paper)

    Completed – reported EASD 2018

    9,463

    100%

    Age: 64

    BMI: 32

    A1c: 8.7%

    Diabetes Duration: 14 years

    1.6 years

    No other GLP-1 agonists

    22% RRR

    (HR=0.78, 95% CI: 0.68-0.90, p=0.0006 for superiority, p<0.0001 for non-inferiority)

    CV: NS

    (HR=0.93, 95% CI: 0.73-1.19)

    All-Cause: NS

    (HR=0.95, 95% CI: 0.79-1.16)

    GSK has withdrawn commercial support for Tanzeum; current commercial status unclear

    REWIND for dulaglutide (Lilly’s Trulicity)

    Topline results announced; full results at ADA 2019

    9,901

    31%

    Age: 66

    BMI: 32

    A1c: 7.3%

    Diabetes Duration: 10 years

    5.4 years

    No other GLP-1 agonists or DPP-4 inhibitors

    Met superiority on three-point MACE

    -

    -

    SOUL for Novo Nordisk's oral semaglutide 

    Expected to begin 2019 (will serve as superiority CVOT for both oral and injectable semaglutide)

    ~13,000

    -

    -

    -

    -

    -

    PIONEER 9 Results + The PIONEER Phase 3 Program

    • This is the final study of the ten-trial phase 3 PIONEER program to read out; Novo Nordisk also announced results from PIONEER 9 this week, examining oral semaglutide vs. Victoza in Japanese patients. PIONEER 9 randomized 243 people with type 2 diabetes equally to 3, 7, or 14 mg oral semaglutide, Victoza 0.9 mg, or placebo. On the primary endpoint of change in A1c at week 26, all three doses achieved significant reductions from a baseline of 8.2%: A1c fell by 1.1% with 3 mg, 1.5% with 7 mg, and 1.7% with 14 mg, vs. 0.1% with placebo. Impressively, the 14 mg dose was also superior to Victoza, which gave a 1.4% drop in A1c. These improvements were largely sustained at 52 weeks, when A1c reductions were 0.9%, 1.3%, and 1.5% from placebo, respectively, vs. a 0.5% increase with placebo and a 1.1% drop with Victoza.

      • Body weight loss at week 52 was 2.8 kg (6.2 lbs) with 14 mg oral semaglutide, 0.6 kg (1.3 lbs) with 14 mg, and 0.0 kg with 3 mg, compared to 1.0 kg (2.2 lbs) of weight loss with placebo and 0.4 kg (0.9 lbs) of weight gain with Victoza. Baseline weight was 71.1 kg (157 lbs). It is strange to see weight gain with a GLP-1 agonist, but we note that weight gain of ~2.4 lbs was also seen with Trulicity in PIONEER 10. Given that people of Asian descent, on average, develop diabetes at a lower BMI than other races, though, baseline weight does tend to be lower, theoretically making it harder to achieve weight loss.

      • At week 52, A1c <7.0% was achieved by 50% of participants on 3 mg oral semaglutide, 67% on 7 mg, and 80% on 14 mg. This compares very impressively to 49% on Victoza and 12% on placebo.

      • According to the release, oral semaglutide’s safety profile was consistent with other GLP-1 agonists in PIONEER 9. As expected, the most common adverse events were mild to moderate nausea and constipation. Treatment discontinuation due to adverse events was 2-4% with oral semaglutide; no comparison was given to placebo or Victoza, and this discontinuation rate is similar to that seen in PIONEER 10.

    • PIONEER 9 joins PIONEER 10 in supporting regulatory approval of oral semaglutide in Japan. PIONEER 10 was a head-to-head trial of oral semaglutide vs. Trulicity 0.75 mg, also in Japanese people. In the intention-to-treat analysis, oral semaglutide 14 mg was superior to Trulicity 0.75 mg on both A1c lowering and weight loss. The primary endpoint was safety in this study, and oral semaglutide demonstrated comparable safety and tolerability to Trulicity.

    Trial

    Estimated Enrollment

    Comparator/Design

    Timeline

    PIONEER 1

    704

    Placebo

    Completed December 2017; Topline results announced February 2018; Full results at ADA 2018

    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; Topline results announced August 2018

    PIONEER 6

    3,183

    CVOT

    Completed September 2018; Topline results announced November 2018

    PIONEER 7

    504

    Flexible dose escalation

    Completed March 2019; Topline results announced June 2018

    PIONEER 8

    731

    Insulin add-on

    Completed August 2018; Topline results announced October 2018

    PIONEER 9

    230

    Placebo and liraglutide in Japan

    Completed August 2018; Topline results announced November 2018

    PIONEER 10

    336

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

    Completed July 2018; Topline results announced September 2018

    Close Concerns Questions

    • What will the confidence intervals and significance of the MACE and other endpoints be? Given that a 21% RRR on three-point MACE did not meet significance, we imagine CI’s will be quite wide.

    • What effects would a pooled analysis of PIONEER 6 and SUSTAIN 6 data demonstrate?

    • How will FDA’s recent Advisory Committee meeting on its 2008 CVOT guidance impact all of these dynamics and the design of the new oral semaglutide CVOT?

    • Will Novo Nordisk consider enrolling a larger primary prevention cohort in a new oral semaglutide CVOT, given ongoing discussion about the generalizability (or lack thereof) of CVOT results?

    • How receptive will FDA be to granting Ozempic a CV indication based on PIONEER 6 and SUSTAIN 6 results?

     

    --by Ann Carracher and Kelly Close