Novo Nordisk declines to pursue type 1 diabetes indication for Victoza (liraglutide) following modest results from ADJUNCT ONE trial – August 24, 2015

This morning, Novo Nordisk announced modest topline results from the phase 3 ADJUNCT ONE trial (n=1,398) investigating Victoza (liraglutide) as an adjunct to insulin in type 1 diabetes. The trial met its primary endpoint of demonstrating non-inferior A1c reductions with liraglutide vs. placebo after 52 weeks for the 1.2 mg and 1.8 mg doses (~0.5% reductions vs. 0.3% with placebo; baseline = ~8.2%). The 0.6 mg dose did not meet the primary endpoint. The two higher doses also demonstrated a statistically significant weight benefit (3-4 kg [~7-9 lb] weight loss vs. 1 kg [~2 lb] weight gain with placebo; baseline = ~86 kg [~190 lbs]). Rates of severe hypoglycemia were numerically but not significantly lower with all doses of liraglutide vs. placebo, and rates of confirmed symptomatic hypoglycemia were actually significantly increased with the two higher doses. Essentially, the striking “composite” results seen with liraglutide in type 2 diabetes (significantly lower A1c, substantial weight loss, and significantly less hypoglycemia) were not reproduced in this population. The topline results announcement did not mention whether glycemic variability/time in range was assessed, but it was not listed as a secondary endpoint on ClinicalTrials.gov. There were no notable safety signals; transient GI side effects were the most common adverse events.

Based on these results and those from the similarly designed ADJUNCT TWO study, Novo Nordisk does not currently plan to pursue an expanded indication for Victoza in type 1 diabetes. The press release left the door slightly open for “future clinical and regulatory initiatives” once the full results are analyzed, but our expectations are not very high. We are of course disappointed by this news, though it was not entirely unexpected following similarly modest results from both ADJUNCT TWO and the Steno Diabetes Center’s Lira-1 trial (presented at ADA). We do suspect that this may be a case of a mismatch between what is clinically meaningful for patients and the bar set by the FDA and especially payers. We imagine that this level of weight loss, hypoglycemia advantages that we suspect may be greater in a real-world setting, and possible reductions in glycemic variability likely add up to meaningful benefits for at least some patients (as evidenced by what we understand are fairly high rates of off-label use). However, Novo Nordisk’s assessment is likely correct that such incremental benefits are unlikely to pass muster in an increasingly cost-conscious payer environment. We imagine that the company may also be taking a more cautious regulatory approach given its experience with Tresiba (insulin degludec). We look forward to seeing full results from both trials to gain more insight on the trends over time and results for responder vs. non-responder subgroups. There are several ongoing studies of other GLP-1 agonists in type 1 diabetes (see below), but we unfortunately expect that these results will likely deter other companies from pursuing this indication. Nonetheless, we were glad to see Novo Nordisk emphasize its continuing broad commitment to type 1 diabetes in the announcement and look forward to the results of future research efforts.

• We spoke to Dr. Irl Hirsch (University of Washington, Seattle, WA) at length about his response to this news - Dr. Hirsch is a renowned thinker on GLP-1 and has an active clinic where both type 1s (off label) and type 2s have taken GLP-1. Dr. Hirsch emphasized that he was disappointed by the decision, but not surprised:  "Clinically I can't predict who has a great response, who has a modest response, and who has no response. Put it together in a trial, and the impact is not large enough for a new indication. What would be important is to try to figure out why we see such heterogeneous response rates for glucose and weight. I am hopeful there is enough data available for post-hoc analysis to see what is associated with an improved response.” In talking to Dr. Hirsch about the different patient groups that might respond to GLP-1, he shared "I remain interested in other populations, the most important being the impact of this drug and GLP-1 agonists in general on beta cell function in newly diagnosed type 1 diabetes. It also makes me wonder if there were differences in response rate in this study for those type 1s still making significant C-peptide. The other population [outside type 1] to think about is MDI patients with type 2 diabetes."
• Results from other recent trials of liraglutide in type 1 diabetes have been similarly modest. Results from the Lira-1 trial, run by the Steno Diabetes Center and presented at ADA, found no significant difference in A1c after 26 weeks with liraglutide in type 1 diabetes in patients taking insulin vs. the insulin-only comparator group, with a substantial 6 kg (~14 lb) weight benefit, lower insulin doses, and a non-significant trend toward less hypoglycemia. Results from Novo Nordisk’s ADJUNCT TWO study demonstrated similar results to ADJUNCT ONE: 0.2-0.3% A1c reductions with lower insulin doses and 2-5 kg weight loss with liraglutide vs. no change with placebo and no improvements in hypoglycemia. During Novo Nordisk’s 2Q15 update, Chief Scientific Officer Dr. Mads Thomsen indicated that ADJUNCT TWO (the largest and longest of the three) would function as a pivotal trial that would be gating for a regulatory submission for a type 1 diabetes indication.
• Several trials of other GLP-1 agonists in type 1 diabetes are ongoing. Yeshiva University is conducting a trial (n=20) evaluating the effect of AZ’s Byetta (exenatide twice daily) on postprandial hyperglycemia in new onset type 1 diabetes and Yale University is conducting a study (n=120) evaluating AZ’s Bydureon (exenatide once weekly) in patients with more established type 1 diabetes. Both are currently recruiting participants; the Byetta trial is expected to complete in December 2015 and the Bydureon trial in September 2016. GSK is also currently recruiting participants for a trial (n=68) of its GLP-1 agonist Tanzeum (albiglutide) in type 1 diabetes that is expected to complete in December 2016. We do expect that the disappointing results for Victoza will likely deter many companies from pursuing a type 1 diabetes indication for their GLP-1 agonists; Dr. Thomsen even suggested during Novo Nordisk’s 2Q15 update that other GLP-1 agonists are unlikely to match liraglutide’s performance. However, we would love to see studies with more unconventional designs (such as real-world studies or CGM studies) that might be able to demonstrate benefits that are less apparent in an RCT designed to support regulatory approval. Future studies could also take advantage of tools like Abbott’s FreeStyle Libre or Dexcom’s Gen 5 CGM that were not available for this study.  
• We wonder if results could be better with Intarcia’s ITCA 650 in type 1 diabetes due to the adherence advantage. As a reminder, the company recently reported impressive phase 3 results for ITCA 650 (implantable exenatide mini-pump) vs. Merck’s Januvia (sitagliptin) in type 2 diabetes. While Intarcia remains focused on type 2 diabetes at the moment, we imagine there could be potential in type 1 diabetes in the future.
• SGLT-2 inhibitors may prove to be the more promising type 2 diabetes drug class for type 1 diabetes, though the risk of ketoacidosis remains a concern. Preliminary studies have demonstrated a range of benefits in type 1 diabetes similar to those proposed for GLP-1 agonists (weight loss, lower insulin doses, reduced glycemic variability), and the class’ insulin-independent mechanism may enable more potent glycemic efficacy. However, the recent reports of ketoacidosis certainly provide cause for caution, and more robust ongoing trials will be key in determining the overall risk/benefit profile. We are eagerly awaiting results from J&J’s phase 2 trial of Invokana in type 1 diabetes at EASD and the company’s subsequent decision on whether to pursue a type 1 diabetes indication.

Close Concerns Questions

• What were the trends over time for glycemic control and weight loss? Did efficacy “wear off” over time?
• Were insulin doses reduced with liraglutide in ADJUNCT ONE?
• Were there clear responder and non-responder subgroups or were the results consistent across the board?
• Was glycemic variability or time in range assessed using CGM?
• How large was the numerical difference in severe hypoglycemia? What were the rates of hospitalization?
• What were the rates of GI side effects?
• Might the results have been better in patients with new-onset diabetes?
• Could a higher dose be required to produce benefit?
• To what extent was Novo Nordisk’s decision not to pursue a type 1 diabetes indication due to clinical vs. economic/regulatory factors?
• Will these results impact rates of off-label use of GLP-1 agonists in type 1 diabetes?

-- by Emily Regier and Kelly Close