Novo Nordisk releases topline data from PIONEER 2 (oral semaglutide vs. SGLT-2 empagliflozin) – May 29, 2018

Novo Nordisk today released topline results from PIONEER 2, a head-to-head trial comparing oral GLP-1 agonist semaglutide to SGLT-2 inhibitor Jardiance (Lilly/BI’s empagliflozin). This announcement follows topline data from PIONEER 1 released in February, and full results from the placebo-controlled PIONEER 1 trial will be featured as a late breaking poster at ADA 2018.

PIONEER 2 (n=816) randomized adults with type 2 diabetes on background metformin to 14 mg oral semaglutide or to a 25 mg Jardiance tablet, both taken once-daily. After 26 weeks of treatment, oral semaglutide showed statistically significant superiority in A1c-lowering (no p-value reported), but was associated with comparable weight loss vs. empagliflozin (i.e. no statistically significant difference). Novo Nordisk hasn’t shared mean baseline A1c or body weight, and we’ll be looking for this in a future full results presentation, which will also offer more detail on the margin of A1c reduction and weight loss in each group. According to ClinicalTrials.gov, patients with A1c between 7.0%-10.5% inclusive were eligible for PIONEER 2, so a very broad group.

Investigators also conducted an on-treatment analysis, looking at participants who did not discontinue therapy and who didn’t require rescue medication. Below, we break down the available data from this secondary statistical approach, focusing first on efficacy findings and then on safety/tolerability. Lastly, we discuss the implications of PIONEER 2 – in short, oral GLP-1 could be a major stride forward for the diabetes field, offering all the potency of this class without any of the injection burden, but many questions remain when it comes to dosing, marketing (will the product compete with other oral agents or with injectable GLP-1 agonists – presumably this is a question that relates to pricing), etc.

Novo Nordisk is targeting 2019 for an oral semaglutide NDA, meaning a commercial product could be available to patients by 2020.

Glucose-Lowering and Weight Loss Efficacy

• In the on-treatment analysis, mean A1c decline was 1.4% in the oral semaglutide arm vs. 0.9% in the SGLT-2 arm after 26 weeks. After 52 weeks, A1c dropped by a mean 1.3% from baseline in the semaglutide arm vs. 0.8% in the empagliflozin arm. No p-values were reported, but Novo Nordisk’s announcement mentioned that both comparisons met statistical significance, implying superior glycemic efficacy of oral semaglutide vs. Jardiance. For comparison, in the on-treatment analysis of PIONEER 1, 14 mg oral semaglutide was associated with an A1c reduction of 1.5% after 26 weeks. After one year in PIONEER 2, 72% of people on oral semaglutide achieved A1c <7% vs. only 47% of people on Jardiance. In PIONEER 1, an astounding 80% of patients on 14 mg oral semaglutide reached this target A1c after 26 weeks vs. 34% of patients taking placebo.

• Mean weight loss in the on-treatment analysis of PIONEER 2 was ~9 lbs after 26 weeks of oral semaglutide therapy and ~10 lbs after 52 weeks vs. ~8 lbs at both time points with empagliflozin therapy. No p-values were reported, but Novo Nordisk highlighted a significant weight loss benefit to oral semaglutide at one year. In PIONEER 1, 14 mg oral semaglutide gave a mean ~9 lbs weight loss after 26 weeks (from a baseline ~194 lbs) for participants who remained on treatment without rescue therapy. In general, PIONEER 2 corroborates the candidate’s efficacy in glucose-lowering and weight loss – and we’ll have plenty more evidence coming up to confirm these effects, as all 10 PIONEER trials are supposed to read out this year (scroll down to see a summary table). Interestingly, in presenting phase 2 data on injectable semaglutide in obesity at ENDO 2018, Dr. Patrick O’Neil emphasized that patients continued to lose weight through at least 52 weeks (and maybe even longer). We’ll be curious to see if oral semaglutide carries a similar property. This would certainly be a meaningful advantage, since most therapies do show attenuated weight loss efficacy over time.

Adverse Events and Dosing

• According to the topline release, 11% of participants on oral semaglutide discontinued treatment during the course of the study due to adverse events; only 4% of Jardiance-treated participants discontinued. By our calculations, this translates to 45 patients stopping semaglutide therapy and 16 patients stopping empagliflozin therapy early (408 participants in each arm with 1:1 randomization). A looming question surrounding oral semaglutide is how tolerable and “easy to take” the pill will be. In PIONEER 2, 20% of patients in the oral semaglutide group experienced nausea – this was mostly mild-to-moderate and usually subsided over time, which follows the pattern we’re accustomed to seeing with injectable GLP-1 agonists. Per the US product labels, 18%-20% of people taking Victoza may experience nausea while 16%-20% of people taking Ozempic may experience nausea, on average. Ultimately, 11% or 45 people discontinuing treatment is not trivial, and we imagine that fewer had been hoped for. It’s so exciting to see that oral semaglutide brings profound glucose-lowering and weight loss benefits to people who can adhere to the regimen; while we can still see this scaling even with an 11% dropout, we very curious what the “real-world” dropout is since these patients may have been carefully chosen to avoid dropout (this is hard to say). If the medicine adds to the daily burden of diabetes for a subset of patients, we wonder if at least the subset is easy to identify. Overall, we think oral GLP-1 could do enormously well on the market if side-effects can be managed, but this safety/tolerability caveat is nonetheless important to note.

• Beyond GI side-effects, there are also fasting requirements surrounding oral semaglutide that could impede optimal adherence and persistence. CSO Dr. Mads Thomsen has emphasized that fasting requirements were relaxed and simplified between phase 2 and phase 3. Participants in phase 2 trials were instructed to fast for six hours prior to taking a dose, and to then refrain from eating for another 30 minutes thereafter. As we understand it, participants in phase 3 were instructed to take their dose in the morning in a fasting state at least 30 minutes before the first meal of the day, which doesn't seem drastically different from phase 2, although we expect there's more nuance to this. This is another detail we'll be looking for as full results from PIONEER studies are presented at scientific meetings. In our view, ~6.5 hours of fasting will be perceived as burdensome by some patients, although it’s certainly not an insurmountable inconvenience for a drug that’s offering increased glucose-lowering, meaningful weight loss, possible cardioprotection, and needle-free administration. As is the case for many therapies, we imagine there will be ideal and less ideal candidates for oral semaglutide. This agent may not be preferred by every person with type 2 diabetes (or type 1 – we’re expecting it to be tested in this population eventually), but we’re certainly enthusiastic about its addition to the diabetes treatment toolkit considering how few patients are reaching their glycemic goals right now.

• Notably, 14 mg was the highest dose of oral semaglutide used in PIONEER 1 (it was the only dose administered in PIONEER 2), and it may be associated with greater efficacy as well as more frequent/severe GI side-effects. Both A1c and body weight results in PIONEER 1 trended along a dose response curve, with higher doses of oral semaglutide offering larger reductions (e.g. 0.8% A1c-lowering with 3 mg oral sema vs. 1.5% with 14 mg oral sema). The company hasn’t specified whether nausea and treatment discontinuation also showed a dose response relationship, but the PIONEER 1 topline release mentioned 5%-16% of patients on study drug experiencing nausea and 2%-7% discontinuing treatment, and we suspect that higher doses led to more GI symptoms and a higher chance of dropout. As Novo Nordisk approaches regulatory submission, we’ll be very curious to see what dose of oral semaglutide management chooses to commercialize. Like PIONEER 1, PIONEER 3 (oral sema vs. Merck’s DPP-4 inhibitor sitagliptin, branded Januvia) was also dose-ranging, randomizing participants to 3 mg semaglutide, 7 mg semaglutide, 14 mg semaglutide, or 100 mg sitagliptin once-daily; that study is expected to report toward the end of 2Q18. PIONEER 9 (oral sema vs. Novo Nordisk’s GLP-1 liraglutide vs. placebo) is similarly dose-ranging and is expected to complete in August 2018. To our knowledge, the rest of the phase 3 trials for oral semaglutide use only one dose. Jardiance 25 mg is the higher available dose of empagliflozin, which also comes in 10 mg oral tablets.

Implications of PIONEER 2

• This head-to-head comparison vs. empagliflozin could be key to Novo Nordisk’s business plan for oral semaglutide, because management has previously mentioned a strategy of positioning the new drug earlier in the course of diabetes development so that it competes with oral agents (SGLT-2s, DPP-4s) more so than with injectable GLP-1 agonists. The image below is from the company’s Capital Markets Day presentation last year, when CEO Mr. Lars Jørgensen suggested that oral semaglutide could compete with SGLT-2s and DPP-4s for second-line prescriptions, while Novo Nordisk’s injectable semaglutide (Ozempic) could be initiated slightly later in disease progression but should still be considered before insulin. Of course, so much of the company’s ultimate marketing strategy will come down to price and Mr. Jørgensen specified on Novo Nordisk’s recent 1Q18 earnings call that management will no longer comment on oral semaglutide pricing, from now until FDA submission. Lilly management has remarked that “it’ll be difficult for oral semaglutide to match” Jardiance’s current value proposition. Indeed, if oral semaglutide bioavailability is low, it may be challenging for Novo Nordisk to price the drug on par with SGLT-2 inhibitors and still profit; Mr. Jørgensen has noted that activities are ongoing internally to optimize cost of goods sold. Perhaps the company could get away with a relatively higher price point had oral semaglutide blown Jardiance out of the water in this head-to-head trial – that doesn’t seem to be the case from the topline data alone (especially given the non-significant difference on weight loss after 26 weeks though the A1c difference is impressive – we’d love to also have seen “time in zone” comparisons), but we’ll have to wait for full results before making this determination. Above all, we want to underscore that GLP-1s and SGLT-2s both are reaching far too few people with diabetes in the real world, and there is more than enough room for injectable GLP-1s, oral GLP-1s, and SGLT-2s to be commercially successful while helping many, many patients in-need.

Phase 3 PIONEER Program

-- by Payal Marathe and Kelly Close