- Earlier today, Novo Nordisk announced topline results from SUSTAIN 7, which found superior A1c-lowering and weight loss with once-weekly GLP-1 agonist candidate semaglutide vs. Lilly’s once-weekly dulaglutide (branded Trulicity). There was a very impressive ~0.4% A1c treatment difference in favor of semaglutide, which Dr. John Buse called “thrashing in the head-to-head trial business… half a drug’s worth.” The ~0.4% difference reflected a 1.8% A1c drop for semaglutide vs. a 1.4% drop for Trulicity in the higher-dose segments – outstanding reductions for both, from a baseline A1c of 8.2%.
- Reassuringly, there was no imbalance in diabetic retinopathy between semaglutide (four events) and dulaglutide (five events). This is important safety data following SUSTAIN 6, which reported a 76% increase in retinopathy risk with semaglutide vs. placebo. Dr. Tina Vilsbøll spoke to a key difference in study populations, in that the baseline A1c was 9.4% among SUSTAIN 6 participants experiencing retinopathy vs. 8.2% across all groups in SUSTAIN 7 – this higher baseline A1c may be an explanation for the retinopathy signal seen in SUSTAIN 6. The two trials also differed in duration, however, and a few thought leaders (Dr. Daniel Drucker and Professor Philip Home) suggested that SUSTAIN 7 wasn’t quite long enough to totally rule out retinopathy as an adverse event, though all the KOLs with whom we spoke seemed reassured.
- Bottom line, these SUSTAIN 7 results support the incredible potency of semaglutide, not only as a diabetes drug vs. placebo but now compared to another once-weekly GLP-1 agonist with known efficacy. We’re so excited for real-world patients to have this additional option for GLP-1 agonist therapy – an FDA decision on semaglutide is expected in 4Q17. All this said, we see plenty of room for multiple GLP-1 products to be commercially successful, and based on these results, we expect semaglutide to grow the class as a whole.
Novo Nordisk today announced topline results from SUSTAIN 7, a head-to-head comparison of GLP-1 agonists semaglutide and Lilly’s dulaglutide (branded Trulicity). For 40 weeks, study participants (n=1,201) with type 2 diabetes on a background of metformin therapy were randomized to one of four treatment arms: (i) 0.5 mg semaglutide injection once-weekly, (ii) 0.75 mg dulaglutide injection once-weekly, (iii) 1.0 mg semaglutide once-weekly, or (iv) 1.5 mg dulaglutide once-weekly. Both low- and high-dose semaglutide demonstrated superior A1c-lowering efficacy vs. corresponding doses of dulaglutide. Mean A1c reduction was 1.5% in the 0.5 mg semaglutide group vs. a smaller 1.1% in the 0.75 mg dulaglutide group (baseline A1c 8.2%). Moreover, A1c dropped by an average 1.8% among patients on 1.0 mg semaglutide vs. 1.4% among people on 1.5 mg dulaglutide. The A1c treatment difference for both comparisons was ~0.4%: This is downright incredible at 40 weeks when the comparator arm is another GLP-1 agonist with known efficacy – UNC’s Dr. John Buse even called it a “thrashing” benefit in the head-to-head business, “half a drug’s worth” (very positive commentary!) According to Novo Nordisk’s announcement, the A1c difference reached statistical significance in favor of both 0.5 mg semaglutide and 1.0 mg semaglutide, though no p-values were reported. We look forward to these details from the full dataset, which will undoubtedly be presented at an upcoming scientific meeting.
In terms of getting to goal with GLP-1 agonist therapy, 69% of people on 0.5 mg semaglutide achieved A1c ≤7% after 40 weeks vs. 52% of people on 0.75 mg dulaglutide. These values were 79% and 68% for 1.0 mg semaglutide and 1.5 mg dulaglutide, respectively. The topline data release also shared that 51% of people on lower-dose semaglutide achieved A1c ≤6.5% after 40 weeks vs. 36% of people on lower-dose dulaglutide. These values were 68% and 49% for higher-dose semaglutide and dulaglutide, respectively. Notably, these are high percentages across the board, showing added glycemic benefits to semaglutide and also underscoring very strong efficacy from Trulicity. As Dr. Tina Vilsbøll (University of Copenhagen, Denmark) put it, “head-to-head trials are important, but so is the prize…” (referencing cardioprotection) and it’s very exciting for the diabetes field that we have multiple once-weekly GLP-1 agonists with superb efficacy. We see much room for growth in the GLP-1 class as a whole (i.e. only 5% of type 2 diabetes patients in the US were on a GLP-1 agonist as of 2013, per a Diabetes Care article published last fall). Novo Nordisk has filed semaglutide with the FDA, with the EMA, and with regulatory authorities in Japan. Stateside, a decision is expected in 4Q17. It is not yet known whether the FDA will convene an Advisory Committee beforehand, but if this meeting does come to fruition, we expect SUSTAIN 7 data to influence the discussion very positively.
We’ve been waiting in anticipation for this SUSTAIN 7 read out, and we were happy to hear management confirm on Novo Nordisk’s 2Q17 earnings call that head-to-head data would be available in 3Q17… and the results do not disappoint! Management seemed optimistic on the recent call that SUSTAIN 7 would give semaglutide an edge over Trulicity on the market, and the safety/efficacy findings are certainly something to write home about. Toronto’s Dr. Daniel Drucker endorsed that SUSTAIN 7 data boosts semaglutide’s commercial prospects relative to Trulicity and other GLP-1 agonists, though he also underscored that list price and reimbursement will come into play (these are questions we’ll surely be asking upon FDA approval). Overall, we see potential for semaglutide to be a positive disruptor: This new drug could spur greater uptake of all GLP-1 agonist products and could accelerate class growth, which is already going strong, up 29% YOY to $1.6 billion in 2Q17. Pooled GLP-1 agonist sales totaled nearly $5 billion in 2016, marking 25% YOY growth from an already high base of $3.9 billion in 2015.
- Importantly, there was no imbalance in retinopathy as an adverse event between semaglutide and dulaglutide groups in SUSTAIN 7. In general, retinopathy rate was low: four events across two semaglutide arms and five events across two dulaglutide arms. Following the 76% increase in retinopathy risk associated with semaglutide vs. placebo in SUSTAIN 6 (Novo Nordisk’s pre-market CVOT for the candidate), we imagine all eyes in the diabetes community (including ours) are peeled for semaglutide safety data, and the findings from SUSTAIN 7 are reassuring. Dr. Vilsbøll reiterated her remarks from ADA 2017, explaining that the retinopathy signal in SUSTAIN 6 was driven by patients with very high baseline A1c (9.4%) which led to rapid, steep A1c decline. In contrast, baseline A1c in SUSTAIN 7 was lower, 8.2% on average. We’ll be curious to learn more specific details on the SUSTAIN 7 study population and how it compares to SUSTAIN 6, but we breathe a sigh of relief for now that retinopathy does not seem inherently linked to the semaglutide molecule. Of course, there may be more nuance to the issue than that… Dr. Drucker pointed out that length of trial was shorter for SUSTAIN 7 vs. SUSTAIN 6 – an important variable to keep in mind, though he still found the lack of retinopathy signal reassuring. Said professor Philip Home, “the study is seemingly too small and short to contribute usefully to our knowledge of the retinopathy adverse findings apparent in SUSTAIN 6 and perhaps LEADER,” reminding us that the uptick in retinopathy associated with liraglutide vs. placebo, though not statistically significant, doesn’t completely refute the eye results from semaglutide. We’re keenly interested in the implications of SUSTAIN 7 retinopathy data, which we’ll continue to unravel. For now, we’re so glad that the worst-case scenario of another imbalance in retinopathy after 40 weeks in SUSTAIN 7 did not happen.
- Continuing the good news, semaglutide showed impressive weight loss efficacy in SUSTAIN 7. From an average baseline body weight of 209 lbs, people on 0.5 mg semaglutide lost a mean 10 lbs over 40 weeks vs. 5 lbs for people on 0.75 mg dulaglutide. Participants randomized to 1.0 mg semaglutide lost a mean 14 lbs vs. 7 lbs for people on 1.5 mg dulaglutide. The approximate doubling of weight loss benefit for semaglutide vs. dulaglutide was statistically significant for both comparisons (low-dose and high-dose), though once again, we’ll have to wait for the full dataset to see p-values. Novo Nordisk management recently announced that a dedicated phase 3 study of semaglutide in obesity will be initiated in 1H18 using once-weekly dosing (even though once-daily semaglutide injections were administered in phase 2 obesity trials). The company’s Chief Science Officer Dr. Mads Thomsen alluded to a “new level of efficacy” with semaglutide for weight loss, which certainly seems to be the case based on the remarkable phase 2 data. We view weight loss as an absolutely critical outcome beyond A1c in the context of type 2 diabetes and GLP-1 agonist therapy, so we’re happy to see this focus within the diabetes program alongside dedicated investigations in obesity.
- CV benefit is another key outcome beyond A1c to consider – semaglutide demonstrated significant CV risk reduction in SUSTAIN 6, while the REWIND trial for Trulicity (n=~9,622) is expected to complete in July 2018. Dr. Vilsbøll pointed out that both semaglutide and dulaglutide are based on human GLP-1 (as opposed to exendin-4, as is the case for lixisenatide and exenatide). This perhaps contributes to their potency, and it’s also interesting that human-based GLP-1 agents have yielded positive CVOT results so far (Novo Nordisk’s liraglutide and semaglutide), while exendid-4-based GLP-1 agents have shown neutral CV effects (the ELIXA trial for Sanofi’s lixisenatide, the FREEDOM-CVO study for Intarcia’s implantable exenatide mini-pump, and topline data from the EXSCEL trial for AZ’s once-weekly exenatide). Notably, this is mere observation/speculation right now, and we’ll need to glean much more from future studies to unpack the differential CV effects of various agents within the GLP-1 class. Other thought leaders have argued that the human vs. exendin-4 reasoning is thin, since there were actually several elements of trial design that differed between these CVOTs: For example, FREEDOM-CVO was designed to show non-inferiority rather than superiority and had a shorter duration than LEADER (as well as a smaller sample size). Furthermore, EXSCEL used single-dose trays of Bydureon (exenatide once-weekly) and saw participants after very long intervals, opening the door for mixing errors, poor medication adherence, and other factors interfering with CV benefit and making the data harder to interpret in the context of other CVOTs. This is certainly lots of food for thought. Overall, we can’t emphasize enough that cardioprotection is becoming increasingly important in diabetes care as the bar for new diabetes drugs rises and as the treatment paradigm shifts away from treat-to-fail toward prevention of complications. Novo Nordisk management has previously stated intentions to conduct a larger, post-market CVOT for semaglutide after the drug is approved, to provide more compelling evidence on CV benefit.
- Trulicity sales continued to climb skyward in 2Q17, more than doubling YOY to $480 million. Lilly’s once-weekly GLP-1 agonist, which comes in a patient-friendly, IDEO-designed pen (one that has received overwhelming positive feedback from real-world users), continues to “steal” market share from Novo Nordisk’s once-daily Victoza (liraglutide). In 2Q17, Trulicity accounted for 30% of pooled sales while Victoza captured 56% – this compares to a 26% share for Trulicity and a 57% share for Victoza in 1Q17. That said, both products are benefiting from underlying GLP-1 market growth, which may accelerate with the approval of semaglutide. And, we emphasize again that there’s more than enough room for multiple products in this highly-effective class to be commercially successful. Novo Nordisk management has suggested that semaglutide will help the company sustain its GLP-1 agonist business going forward.
-- by Payal Marathe and Kelly Close