FDA approves Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s Soliqua (insulin glargine/lixisenatide) within hours of each other – November 21, 2016

Novo Nordisk and Sanofi both announced FDA approvals this afternoon of their fixed-ratio basal insulin/GLP-1 agonist combinations, Xultophy (insulin degludec/liraglutide) and Soliqua (insulin glargine/lixisenatide), respectively. Both combinations have been highly anticipated in the US – the FDA held Advisory Committee meetings for the products back-to-back in May 2016 (see our coverage of the Xultophy meeting and of the Soliqua meeting) and then issued a three-month delay for both before the approvals today (see our coverage of the Xultophy delay and of the Soliqua delay). Now, it seems the products will be neck and neck hitting the commercial market as well – depending on how quickly the companies are prepared to launch the product – and will share “first-to-market” status as fixed-ratio basal insulin/GLP-1 agonist combinations in the US. Race aside, we’re happy to see both of these FDA approvals come through, especially following the three-month delays that could’ve been a bigger deal but turned out to just provide FDA with more time – it’s very understandable that the under-resourced FDA would benefit from this extra time to dot I’s and cross t’s. Phase 3 trials conclusively demonstrated the superior efficacy and milder side-effect profile of a basal insulin/GLP-1 agonist combination vs. either drug alone (these include the DUAL program for Xultophy; LixiLan-O and LixiLan-L for Soliqua). The patient convenience factor of a single injection cannot be understated. Moreover, we’ve noticed tremendous excitement surrounding this particular drug class – discussion of basal insulin/GLP-1 agonist combinations among diabetes thought leaders was a standout theme at EASD 2016 and EASD 2015 – and these are perhaps the most highly-anticipated new therapies in diabetes. We’re excited to see both Xultophy and Soliqua become available to US patients with type 2 diabetes as once-daily injections, and we expect to see real-world outcomes match or exceed the potential demonstrated in phase 3 clinical trials.

• Notably, Soliqua was only FDA-approved for delivery through a single, pre-filled SoloStar pen, despite both Sanofi and Zealand (which out-licensed lixisenatide) previously pointing to the availability of two pens with two ratios as an advantage over Novo Nordisk’s Xultophy. In the US, both Xultophy and Soliqua will be available in one pen, although the EMA may still approve both SoloStar pens for Suliqua (the EU trade name for the combination) – one delivering a 2:1 ratio of insulin:lixisenatide and the other delivering a 3:1 ratio. Possible confusion stemming from the availability of two pens with distinct ratios was a major concern cited at the FDA Advisory Committee meeting for Sanofi’s fixed-ratio combination (where the vote, in the end, was 12-2 in favor), and presumably this contributed to the agency’s delayed decision. We’d be curious to hear the company’s comments on how the single pen may affect marketing strategy going forward, given the earlier emphasis on Soliqua’s two-pen advantage over Xultophy. From our view, the benefit is largely about the combination and we don’t see it as a big deal that two ratios won’t be available. See below for a photo of the FDA-approved SoloStar pen.

• Xultophy is currently launched in seven countries (excluding the US), while Soliqua is not yet commercially-available in any ex-US market. However, the Committee for Medicinal Products for Human Use (CHMP) recently recommended Sanofi’s drug for EMA approval – a regulatory decision is expected in early 2017. Soliqua would be second-to-market in the EU, following Xultophy, which was approved by the EMA in 2014 and also received a positive CHMP opinion prior to EMA approval. Although Xultophy currently has a more established global franchise, US sales of both of these newly-approved drugs will likely drive their franchises, as the US is the largest regional market for diabetes pharmacotherapies. The relative success of Xultophy and Soliqua will depend on many factors – from commercialization strategy, to their clinical profile, to cost, to patient assistance programs, to formulary positioning, to familiarity among endocrinologists and other HCPs, to name a few – and we’ll be keeping a close watch on all of them as these stories continue to unfold and both products are launched.
• Xultophy may benefit from the cardioprotection demonstrated by liraglutide in LEADER, whereas Sanofi’s ELIXA trial for lixisenatide showed neutral CV effects. In our view, showing a positive CV benefit is becoming critical for GLP-1 agonists, with both LEADER and SUSTAIN 6 (for Novo Nordisk’s phase 3 semaglutide) published, and a basal insulin/GLP-1 agonist combination that improves glycemic control and quality of life while also reducing risk for CV events is all the better. That said, this class of combination therapy has generated so much buzz and we think there’s unspeakably big room for both these products to establish impressive sales in the US and to enhance type 2 diabetes care as we know it today. The other question is, of course, whether Sanofi/Zealand will benefit from what we assume will be a cheaper product given a less expensive basal insulin is being used. 
• Scores of world diabetes leaders have expressed deep enthusiasm about the approval of these two basal insulin/GLP-1 agonist combination therapies​
  • Former ADA President Dr. John Buse (University of North Carolina, Chapel Hill, NC): "My personal journey as an investigator with the combination of insulin and GLP-1 receptor agonists started in 1999. From the first patient we studied, I was blown away by the efficacy of the combined approach to control glucose and reduce A1C. That 15-year effort exceeded expectations with the IDegLira trials which were among the most gratifying that I have participated. In the DUAL trials with IDegLira, we have a clear demonstration of impressive A1C reduction at lower rates of hypoglycemia than insulin alone and significant differences in weight trajectories. As impressive to me is the substantial mitigation of GLP-1 receptor agonist associated nausea. I do think with the data available now and the convenience of the proposed titration scheme for IDegLira, that it is hard to rationalize the use of basal insulin without a GLP-1 receptor agonist, except on price. Without a doubt, for the majority of patients with type 2 diabetes, IDegLira is the most effective antihyperglycemic agent on the planet. And in the context of the results of the LEADER trial, the rationale for its use in patients with cardiovascular disease is extremely compelling."
  • Dr. Phillip Home (Newcastle Diabetes Center, UK) emphasized that both newly-approved products contain leading diabetes drugs that are even more effective in combination: “For both, the base medications in each pair have been widely used globally as single agents, and indeed one of the long-acting insulin analogues and one of the GLP-1 receptor agonists are world leaders.  The evidence base of advantage of these combinations goes beyond a single clinical trial, and can be summed up as much greater blood glucose reduction than any other single medication, with neutralization of the weight gain sometimes associated with insulin, and no increase in hypoglycemia compared to insulin alone despite the better glucose control. Downsides are a limited insulin dose range, and likely high cost of combinations of premium medications.”
  • Dr. Bernard Zinman (Mount Sinai Hospital, Toronto, Canada) also called attention to the superior efficacy and milder side-effect profile of these combinations: “As an injectable therapy for type 2 diabetes, the combination of a basal insulin with a GLP-1 receptor agonist provides unique complementary clinical/metabolic benefits. This combination results in robust reductions in A1c, lower rates of hypoglycemia, and less weight gain as compared to basal insulin therapy. In addition, the slower titration employed with this combination reduces the gastrointestinal side effects of GLP-1s as well as the total insulin dose.”
• Notably, Zealand hosted a conference call to discuss the Soliqua approval. CEO Ms. Britt Meelby Jensen cited Soliqua’s approval as a “historic moment” in the company’s history; Zealand outlicensed lixisenatide to Sanofi, and Soliqua marks the second product based on a Zealand invention (after Adlyxin) to receive US approval. Soliqua’s approval will trigger a $27 million milestone payment to Zealand from Sanofi, and Zealand management shared that up to $110 million in milestone payments are still available in the future. Zealand’s cash position stands at DKK 381.9 million (~$57 million) as of September 30, 2016 according to the company’s 3Q16 update, so these milestone payments offer a significant opportunity for the company to expand its clinical programs. Ms. Jensen shared that these funds will be directed toward projects such as the development of next-generation glucagon candidates such as dasiglucagon, a liquid-stable glucagon formulation being developed as both a single-dose rescue pen and as a multi-dose component of a dual hormone artificial pancreas system. Additional details can be found in Zealand’s press release. We salute the company’s leadership for making time for people to learn more about this therapy. 

Close Concerns Questions 

Q: How will the combinations be priced, given that one will include a cheaper basal insulin (Lantus) than the other (Tresiba)?

Q: How will healthcare providers view the different combinations given that one will include a GLP-1 (Victoza) that has cardiovascular risk lowering data associated with it (used individually rather than in combo) and the other currently does not?

Q: What will happen in the US with formulary status?

Q: Will there be patient advocacy growing to ensure patient access to these drugs? 

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