- Sanofi will initiate a phase 3 study of once-weekly GLP-1 agonist efpeglenatide this coming week (on December 4). This candidate was licensed from Hanmi in 2015, and was originally slated for a 4Q16 start. We’re excited to see what happens here. This is now posted on ClinicalTrials.gov.
- Expected enrollment in the trial is 400 adults with type 2 diabetes, baseline A1c between 7%-10%. The primary endpoint is change in A1c at 30 weeks, though the study will continue out through 56 weeks.
- Efpeglenatide’s delivery technology carries potential for once-monthly dosing down the line, which could further differentiate the agent from others in its class, and which would be a huge win for patients in terms of lower injection burden.
Earlier this week, a 56-week phase 3 trial of Sanofi’s GLP-1 agonist candidate efpeglenatide (licensed from Hanmi) was posted to ClinicalTrials.gov, and we were excited to get our first glimpse at the details of this study (originally slated for a 4Q16 start, this timeline was pushed back to 4Q17). According to ClinicalTrials.gov, estimated enrollment is 400 adults with type 2 diabetes and a baseline A1c between 7%-10%. The scheduled start date is December 4, 2017, with expected completion in January 2020.
The trial’s primary endpoint is change in A1c from baseline to week 30. Secondary endpoints include 30- and 56-week changes in A1c, fasting plasma glucose, body weight, and seven-point self-monitored plasma glucose profile (although this can relay valuable data, we’d love to have seen CGM used simultaneously to test what actually might be missed). Additionally, proportion of patients with A1c <7% at weeks 30 and 56, proportion of patients on rescue therapy at weeks 30 and 56, and time to rescue therapy will be measured (we’d also love to see proportion of patients with A1c < 8% and <9% since those are the patients being enrolled). For each endpoint, low, middle, and high doses of a once-weekly efpeglenatide injection will be compared to placebo.
In phase 2, efpeglenatide showed dose-dependent A1c-lowering after 13 weeks, with impressive mean A1c decline of 1.4% on 3 mg once-weekly injections and 1.6% with 4 mg once-weekly injections (from a baseline ~8%). For comparison, in the 40-week SUSTAIN 7 trial, once-weekly GLP-1 agonists semaglutide (Novo Nordisk’s upcoming Ozempic) and dulaglutide (Lilly’s Trulicity) gave 1.8% and 1.4% A1c reductions, respectively, at their highest available doses (1.0 mg and 1.5 mg).
- We note that competition is fierce in the GLP-1 agonist market, especially with Ozempic’s anticipated market entry in 1Q18, and there’s tremendous room for growth, considering that only ~7% of prescriptions for a second-line diabetes drug in the US were for a GLP-1 agonist in 2016. Sanofi’s short-acting GLP-1 agonist Adlyxin (lixisenatide) was never designed as a “real” commercial product in our view; while some say it never quite gained commercial traction (capturing <1% of pooled class sales in recent quarters), we also did not see the investment for this. From our view, getting it approved was a means to getting Soliqua approved, and we see that product as one to invest in as Sanofi pursues other GLP-1 combos to come years from now. Given this, we have always seen it as a smart strategic move for the company to invest in multiple GLP-1 approaches, including this long-acting GLP-1. What’s more is that efpeglenatide’s delivery technology carries potential for once-monthly dosing down the line. This would be a remarkable innovation for the class and for patients, reducing injection burden to at least one-quarter that of current GLP-1 agonists (Intarcia’s ITCA 650 lowers injection burden even further, with an implantable mini pump that provides continuous exenatide release for three-six months, but the company recently received a Complete Response Letter from the FDA).
Cardioprotection and Combination Therapy
- With efpeglenatide, Sanofi also has another chance at a cardioprotective GLP-1 therapy – although ELIXA results were neutral on lixisenatide, again, we would say it was never the goal to demonstrate CV benefit with that study (we’d still love to see another CVOT with all products – we’ll save our commentary on that for a different article). Demonstrating CV benefit is becoming increasingly important for new diabetes drugs, particularly for new GLP-1 agonists, as semaglutide and liraglutide (Novo Nordisk’s Victoza) have already shown significant CV risk reduction (Victoza has even had a CV indication on its label since August 2017 – AstraZeneca results showing a trend toward cardioprotection with very different study design make us think it’s more likely that this is a class effect though there is nothing to say on this at this stage).
- We’ll keep an eye out for details on an efpeglenatide CVOT, and we’re also curious about the potential for a basal insulin/GLP-1 combination with this longer-acting agent. Sanofi’s Soliqua combines insulin glargine/short-acting lixisenatide. Would a fixed-ratio injection with the company’s next-gen basal insulin Toujeo (insulin glargine U300) show even greater efficacy? It’s been disappointing that there hasn’t been more commercial investment in the basal/GLP-1 combos, but this is a matter of time from our perspective.
- Much of this commentary is speculation on our part, as phase 3 clinical studies of efpeglenatide have yet to officially begin, but the opportunities for further clinical development here are intriguing to say the least. The world has changed in terms of potential for massive reduction of cardiac and kidney disease and we think we’re just getting started as a community in leveraging this transformational change.
-- by Ann Carracher, Payal Marathe, and Kelly Close