Memorandum

Lilly’s GLP-1 agonist dulaglutide shows non-inferiority to Novo Nordisk’s Victoza in AWARD-6; does not show superiority – February 25, 2014

Executive Highlights

  • Lilly’s once-weekly GLP-1 agonist dulaglutide shows glycemic non-inferiority compared to Novo Nordisk’s Victoza with regard to A1c lowering over 26 weeks using a 95% confidence non-inferiority margin of 0.4%.
  • Full results to be released later this year, presumably at ADA.

Lilly announced topline results of the AWARD-6 trial this morning, reporting that its once-weekly GLP-1 agonist dulaglutide achieved glycemic non-inferiority against Novo Nordisk’s Victoza, but did not achieve superiority. This makes dulaglutide the first GLP-1 agonist to achieve non-inferiority compared to Victoza. The trial used a 0.4% A1c margin, which, it is worth clarifying, does not mean that dulaglutide’s mean A1c reduction could have been as low as 0.4% worse than Victoza to meet the non-inferiority endpoint. The 0.4% margin means that the lower bound of the 95% confidence interval for A1c reduction had to be within 0.4% of Victoza’s A1c reduction. Lilly management maintain that once full data are revealed, the scientific community will feel very confident in saying that dulaglutide is non-inferior to Victoza. As a reminder, AZ’s Bydureon (once-weekly exenatide) and GSK’s Eperzan (once-weekly albiglutide) both failed to show non-inferiority to Victoza in head-to-head phase 3 trials, with each of them falling short of Victoza’s mean A1c-lowering efficacy by about 0.2%. The full results of AWARD-6 (along with AWARD-2 [dulaglutide vs. insulin glargine], and AWARD-4 [dulaglutide vs. insulin glargine plus insulin lispro]) will be presented later this year at scientific meetings (presumably at ADA).

An important question not discussed in Lilly’s press release is whether dulaglutide was also non-inferior to Victoza on weight loss. If Victoza maintains its superiority on weight loss, which it very well may (see details below), that would be an important clinical differentiator.

Overall, this result is in line with expectations and will keep Lilly competitive in the GLP-1 agonist field: its once-weekly administration gives it an edge over the once-daily Victoza, and its one-step injection device gives it an edge over once-weekly Bydureon, which requires the extra step of manual reconstitution (see below for more discussion on competitive considerations). Lilly management has remarked in the past that these data will be critical for establishing good reimbursement for dulaglutide – we do hope that payers recognize that agents in the GLP-1 agonist class are differentiated enough to warrant coverage of multiple agents within the class.

  • The non-inferior result for AWARD-6 was consistent with management’s and investors’ expectations, and it sets the stage for Lilly to seek out competitive reimbursement. Lilly believes that, with comparable glycemic efficacy relative to Victoza, dulaglutide could emerge as the preferred GLP-1 agonist: its once-weekly administration gives it an edge over the once-daily Victoza, and its one-step injection device (both a pre-filled syringe and single-use pen device are under review) gives it an edge over once-weekly Bydureon, which requires the extra step of manual reconstitution (at least until the launch of AZ’s dual-chambered Bydureon pen). As we understand it, dulaglutide would have had to have shown 0.5 percentage points better than Victoza for superiority; though technically possible, we aren’t surprised at all this didn’t occur.
  • We hope that payers are able to recognize that the GLP-1 agonist class has enough differentiation to warrant coverage of multiple agents within this class, but we do feel a movement or trend toward single-product formularies continues to take hold within various drug classes – that said, this is more comment in classes that have compounds that are less differentiated, such as DPP-4 inhibitors and rapid acting insulin analogs, and we think will be less likely in classes like GLP-1, where there are more differences among products in a single class. Lilly recently out-competed Novo Nordisk on price to gain placement on Express Scripts’ 2014 rapid-acting insulin formulary and Lilly could do the same on dulaglutide for Victoza. Ultimately, we believe it is be a much greater service to patients to have coverage for multiple agents in this drug class.
  • Several other differentiating factors beyond the glycemic efficacy, frequency of administration, and injection device (discussed above) also contribute to patient/prescriber preferences for GLP-1 agonists:
    • Weight loss: Novo Nordisk believes that Victoza could beat out dulaglutide on weight loss, which would leave Victoza with a meaningful clinical advantage. Victoza has been shown to cause weight loss independent of A1c lowering, an effect that dulaglutide might not have, so there is still room for Victoza to come out on top with regards to weight effects. It has been hypothesized that GLP-1 agonists that have a large molecular size (e.g., dulaglutide, albiglutide), relative to smaller compounds (e.g., Victoza, Bydureon/Byetta, Lyxumia, and semaglutide), may have more difficulty traversing the blood-brain barrier to influence weight regulation pathways in the central nervous system .
    • Pharmacokinetic action profile: GLP-1 agonists can be divided into “short-acting” and “long-acting” agonists based on whether they offer more periodic or continuous stimulation of the GLP-1 receptor. Short-acting GLP-1 RAs have a more pronounced effect on postprandial glucose (PPG), and long-acting GLP-1 RAs have a greater effect on fasting plasma glucose (FPG). Therefore, although dulaglutide was non-inferior to Victoza with regards to A1c, there could be clinically meaningful differences in the factors such as glycemic variability, opening up possibilities for providers to individualize treatment based on a patient’s glycemic profile.   
    • Side effect profile: Lilly did not disclose specific data on adverse events, noting only that they were balanced across groups and that the most frequently reported events were gastrointestinal (GI) in nature, as would be expected. Long-acting GLP-1 agonists tend to be associated with less nausea over time compared to short-acting GLP-1 agonists.
    • Flexibility of titration: in relation to GI side effects, GLP-1 agonists’ titration schemes have a significant bearing on their tolerability. From the patient perspective, we imagine that Victoza’s daily administration may allow patients to more finely tune their titration scheme. While the on-label scheme for Victoza dictates starting at 0.6 mg for one week, going up to 1.2 mg for the next, and then escalating to 1.8 mg if needed, the Victoza pen allows for dose adjustments in 0.1 mg increments – a feature we imagine that many patients take advantage of in more finely tuning the titration to their own tolerability needs. By contrast, a once-weekly agent would only allow for dose adjustments every week. Dulaglutide, as a once-weekly agent, will not require any titration as it takes two-to-four weeks to reach a steady state concentration anyway. As such, this initial period of reaching steady state acts as an effective titration period.
  • A caveat of any non-inferiority trial is that it only applies to the population tested, but they are often interpreted as proving equality across all populations. AWARD-6 studied 599 patients with type 2 diabetes and background metformin therapy. While we will not know the exact demographics of the AWARD-6 population until full results are released, the trial’s listing on ClinicalTrials.gov suggests it may lean towards the newly diagnosed side, in which it may have been easier for Lilly to demonstrate non-inferiority (if the starting A1c was relatively low then the absolute difference between the drugs’ effects is harder to separate).
  • We continue to wish that more drug trials would use CGM so that we could understand more about how the agents affect “time in zone” – this could be particularly worthwhile for compounds that claim to work more on post-prandial hyperglycemia. In the EU, in contrast to the US, companies are urged to use CGM in trials to give more information on how well drugs work. http://www.closeconcerns.com/knowledgebase/r/1103ec4a While we hear complaints in the US about what a “hassle” this is from some PIs, we hope that more continue to see the benefits – using most recently approved CGM systems are a very far cry from using the systems introduced only several years back.
  • See our Lilly 4Q13 Report and Novo Nordisk 4Q13 Report for previous commentary on the results and implications of AWARD-6.

 

Table: Late-stage GLP-1 agonist competitive landscape

Drug

Status

Action Profile

Frequency of Administration

Injection Device

Relative Glycemic Efficacy

Novo Nordisk’s Victoza (liraglutide)

Approved

Long-acting

Once-daily

One step pen

Superior to Bydureon and Eperzan; “similar” to dulaglutide

AZ’s Bydureon (exenatide)

Approved

Long-acting

Once-weekly

Syringe and vial needing multi-step manual reconstitution; dual-chambered approved but not yet launched in US, regulatory decision expected 4Q14 in EU

Inferior to Victoza

AZ’s Bydureon suspension formulations (exenatide)

Once-weekly suspension: 2015 submission. Once-monthly suspension: no timeline provided.

Long-acting

Once-weekly / once-monthly

One step pen

 

AZ’s Byetta (exenatide)

Approved

Short-acting

Twice-daily

One step pen

 

Sanofi’s Lyxumia (lixisenatide)

Approved in the EU; US resubmission expected 2015

Short-acting

Once-daily

One step pen

Ongoing head-to-head trial against Victoza sponsored by Novo Nordisk

Lilly’s dulaglutide

Filed in US and EU October 2013

Long-acting

Once-weekly

One step pen

Non-inferior to Victoza

GSK’s Eperzan (albiglutide)

Positive CHMP opinion; US PDUFA date April 15, 2014

Long-acting

Once-weekly

Uncertain – presumably a one-step device

Inferior to Victoza

Novo Nordisk’s semaglutide

Phase 3

Long-acting

Once-weekly

Uncertain – presumably a one-step device

Expected to be similar or better than Victoza

Intarcia’s ITCA-650 (exenatide osmotic mini-pump)

Phase 3

Long-acting

Once- or twice-yearly

Implantable osmotic minipump device

Expected to be better than Victoza

 

-- by Jessica Dong and Kelly Close