Memorandum

Novo Nordisk submits once-weekly GLP-1 agonist semaglutide to FDA and EMA – December 5, 2016

 

Executive Highlights

  • Novo Nordisk has filed semaglutide, a once-weekly GLP-1 agonist injection, with the FDA and EMA. Assuming a standard review process, regulatory decisions are expected in 4Q17.
  • The New Drug Application (NDA) and Marketing Authorisation Application (MAA) draw upon results from the SUSTAIN clinical development program for semaglutide. Notably, in the SUSTAIN 6 cardiovascular outcomes trial (CVOT) semaglutide demonstrated a 26% risk reduction in three-point MACE (non-fata MI, non-fatal stroke, CV death), and the company plans to launch a larger CVOT “as soon as possible after approval.”
  • If approved, semaglutide will join six major GLP-1 agonist products currently on the market, including Novo Nordisk’s own Victoza (liraglutide), which leads the class in US prescriptions and sales. Semaglutide would be the fourth once-weekly GLP-1 agonist formulation, after AZ’s Bydureon (exenatide), GSK’s Tanzeum (albiglutide), and Lilly’s Trulicity (dulaglutide). This news comes about two weeks after Intarcia filed an NDA for its GLP-1 agonist candidate ITCA 650 (implantable exenatide mini-pump) – FDA decisions on ITCA 650 and semaglutide could be released in very close proximity in 4Q17.

Novo Nordisk announced this morning that the company’s once-weekly GLP-1 agonist semaglutide has been submitted as a New Drug Application (NDA) to the FDA and as a Marketing Authorisation Application (MAA) to the EMA. This news follows timing outlined during the company’s 3Q16 update, when management shared plans to file semaglutide by end of year. Assuming a standard 10-12 month review process, regulatory decisions for the US and Europe are expected in 4Q17. This is tremendously exciting news given the incredible potency of the semaglutide compound, as demonstrated in the phase 3 SUSTAIN program. As we understand it, semaglutide packs a bigger punch than Novo Nordisk’s current market-leading GLP-1 agonist Victoza (liraglutide) in terms of A1c efficacy, weight reduction, and potentially renal and cardioprotection, all in a more convenient once-weekly dose formulation. We certainly see best-in-class potential for semaglutide from an efficacy perspective, though of course potentially disruptive GLP-1 agonists are on the horizon as well, including Novo Nordisk’s own oral formulation of semaglutide and Intarcia’s implantable ITCA 650 (exenatide mini-pump).

 If approved, semaglutide will be the seventh or eighth GLP-1 agonist product available for patients with type 2 diabetes (depending on the approval timeline for Intarcia’s ITCA 650, submitted last month) and the fourth once-weekly formulation. Commercial competitors include AZ’s Byetta (exenatide twice-daily) and Bydureon (exenatide once-weekly), Lilly’s Trulicity (dulaglutide once-weekly), Sanofi’s Lyxumia (lixisenatide once-daily), GSK’s Tanzeum (albiglutide once-weekly), and Novo Nordisk’s own Victoza (liraglutide once-daily). Novo Nordisk currently leads the GLP-1 agonist market, with Victoza capturing 61% of pooled revenues in 3Q16 along with 51% of total GLP-1 agonist prescriptions (TRx) in the US. We imagine that adding semaglutide to its portfolio will provide an additional boost to the company’s GLP-1 agonist business and allow Novo Nordisk to maintain its leadership in this arena, especially since once-weekly semaglutide offers a lower injection burden than Victoza – and clinical data thus far suggests that semaglutide offers enhanced potency compared to Victoza. That said, existing once-weekly GLP-1 agonist injections are already on the market: Trulicity currently holds 22% of the class’s market share, compared to Bydureon’s 19% and Tanzeum’s 8%. (That said, semaglutide has already demonstrated superiority to Bydureon in the head-to-head SUSTAIN 5 trial.) Moreover, ITCA 650 could reduce administration burden to as low as two-three times per year. As things currently stand, FDA decisions on ITCA 650 and semaglutide will be announced in close proximity toward the end of 2017.

  • Novo Nordisk’s submission for semaglutide are based on results from the phase 3 SUSTAIN clinical development program demonstrating the agent’s A1c reduction efficacy compared to Merck’s DPP-4 inhibitor Januvia (sitagliptin), Bydureon, Sanofi’s Lantus (insulin glargine), and placebo. In the phase 3 SUSTAIN 5 study, semaglutide demonstrated superiority vs. placebo as an add-on to basal insulin in terms of A1c-lowering, weight loss, and smaller insulin dose requirements.
    • Perhaps most notably, results from the SUSTAIN 6 cardiovascular outcomes trial (CVOT) for semaglutide were presented at EASD 2016 – the agent was associated with a statistically significant 26% risk reduction for three-point MACE (non-fatal MI, non-fatal stroke, and CV death), driven primarily by a 39% relative risk reduction for non-fatal stroke (p=0.04). Novo Nordisk management has confirmed plans to initiate a much larger CVOT soon after approval – SUSTAIN 6 was not powered to demonstrate superiority and collected only 254 MACE events, compared to 1,302 events in LEADER for Victoza and 772 events in Lilly/BI’s EMPA-REG OUTCOME trial for SGLT-2 inhibitor Jardiance (empagliflozin). A larger CVOT is almost certainly required to support a cardiovascular benefit indication for semaglutide, though not necessarily required for approval of the drug itself (since the 0.74 hazard ratio demonstrated in SUSTAIN 6 meets both the pre-approval and post-approval requirements of 1.8 and 1.3, respectively). In our view, demonstrating a CV benefit is becoming increasingly important for new diabetes drugs – CV data from a larger study of semaglutide would certainly be valuable, if not necessary for the drug’s long-term success, especially in an environment when diabetes therapies such as Lilly/BI’s Jardiance are successfully winning expanded cardiovascular benefit indications.
    • Hopefully, a post-approval CVOT will also address the 76% increase in retinopathy observed in semaglutide-treated patients in SUSTAIN 6. During Novo Nordisk’s 3Q16 earnings call, management attributed this retinopathy risk to precipitous, large reductions in A1c over a short period of time as per findings from a mediation analysis. We assume this risk can be mitigated with conservative titration procedures and perhaps with appropriate patient selection (avoiding the use of semaglutide in patients with existing degrees of retinopathy, for instance). Convincing outcomes data for retinopathy safety, however, would be reassuring and will likely be important for semaglutide’s long-term success as well.
  • The semaglutide filing comes at a time of tremendous growth for the GLP-1 agonist class, and we see terrific opportunity for semaglutide to grow the class even more. GLP-1 agonist sales are growing remarkably fast from an already-high base: Revenue hit $4 billion in 2015, up 20% year-over-year (YOY) vs. 2014, when it grew 12%; the class will likely total >$5 billion for the full-year 2016. With Novo Nordisk’s experience in the GLP-1 agonist arena and the strong evidence-base behind semaglutide in the SUSTAIN program, we imagine the new once-weekly formulation could spur further growth in prescriptions and sales, if approved. Of course a big question always looming after an NDA – and one that directly influences uptake – is how pricing and formulary positioning will shake out. We’re eager for more information on this front.
    • Novo Nordisk’s recently-approved Xultophy (insulin degludec/liraglutide) also marks an opportunity for growth in the GLP-1 agonist class. Xultophy and Sanofi’s Soliqua (insulin glargine/lixisenatide) were FDA-approved within hours of each other on November 21. This new class of basal insulin/GLP-1 agonist fixed-ratio combinations has been highly-anticipated and will likely have a substantial effect on each company’s GLP-1 agonist business as well as the overall GLP-1 agonist market – in fact, we think this category of products needs its own class name! We wonder how Novo Nordisk will now prioritize Victoza, Xultophy, and semaglutide within its diabetes portfolio. As we understand it, Novo Nordisk will shift much of its post-marketing efforts in the GLP-1 agonist field to semaglutide and is investigating several additional applications of the drug – as an oral formulation, as a once-daily injectable, for obesity, and for NASH. Could there be a semaglutide/insulin degludec fixed-ratio combination somewhere down the line? This of course would require either a combination with once-daily semaglutide (extremely potent but potentially expensive) or with a once-weekly formulation of insulin degludec (a big win but a difficult proposition given insulin’s narrow therapeutic range).
    • Semaglutide’s submission to the FDA comes about two weeks after Intarcia’s NDA for ITCA 650 (implantable exenatide mini-pump). These will be two products to watch closely, as FDA decisions on both are expected in 4Q17. Both Intarcia and Novo Nordisk have plans to initiate a second, larger CVOT for their respective product (the first for ITCA 650 was FREEDOM-CVO, which demonstrated CV safety). CVOTs are also ongoing for AZ’s Bydureon (EXSCEL, expected to complete in April 2018), Lilly’s Trulicity (REWIND, expected to complete in April 2018), and Tanzeum (HARMONY, expected to complete in May 2019). See our CVOT timeline for a complete overview.
    • Novo Nordisk also has an oral formulation of semaglutide in phase 3, which would be another innovative addition to the GLP-1 agonist landscape. As of the company’s 3Q16 update, five of 10 PIONEER trials for oral semaglutide had started recruitment.

Close Concerns Questions

Q: Will the FDA convene an Advisory Committee prior to a regulatory decision on semaglutide? We would expect not given that several GLP-1 agonists are already available on the market, but perhaps the FDA would like to further explore some of the results from SUSTAIN 6, particularly if it has concerns about the retinopathy data.

Q: How will pricing for semaglutide compare to Victoza, to ITCA 650, and to other GLP-1 agonists on the market?

Q: Of all results from the SUSTAIN program, what results will Novo Nordisk emphasize in the approval process? Looking ahead, what evidence-based benefits to semaglutide (beyond reduced injection burden) might be emphasized in the commercialization process?

Q: What will be the brand name for semaglutide in the US and in Europe?

Q: What timing can we expect for the start of a larger semaglutide CVOT?

Q: How will further data address the heightened risk for diabetic retinopathy shown in SUSTAIN 6?

Q: What other clinical development for semaglutide will continue in the years ahead?

Q: Could semaglutide eventually be combined with Tresiba, in parallel to Xultophy?

 

-- by Payal Marathe, Abigail Dove, Helen Gao, and Kelly Close